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data are needed on the potential risk of vaccination with live vaccines, which are therefore not recommended for rituximab-treated patients. European League Against Rheumatism (EULAR) recommendations on vaccination provide additional guidance for patients with rheumatological diseases treated with biological agents.65 Treatment dose and co-medication Treatment dosage In patients who have received previous TNF inhibitor treatment, rituximab use is licensed at a dose of 1000 mg per infusion on days 1 and 15.3 Rituximab showed significant efficacy on signs and symptoms as well as physical function in this population. The effect on structural damage was also evaluated in that trial (REFLEX), in which the 2×1000 mg dose was studied. Radiographic benefit compared with placebo was demonstrated at 1 year26 (but not at 24 weeks),3 26 with recent data confirming maintenance of retardation at 2 years.27 Subsequent studies in all other RA populations, namely patients with previous inadequate response to traditional DMARD including methotrexate and patients naive to methotrexate, have also evaluated a lower dose of 500 mg per infusion.2 23–25

A recent advance in rheumatoid arthritis (RA) has been the introduction of B-cell depletion as a therapeutic modality. Rituximab, a chimeric anti-CD20 monoclonal antibody is the currently available, licensed B-cell depleting agent, with several studies supporting the efficacy and acceptable safety profile of this approach.1–3 To address the benefits, limitations and safety concerns of its application, a consensus statement on the use of rituximab in patients with RA was formulated in 2006.4 Since then a large amount of new information has become available, with new insights into both the efficacy and the safety of B-cell depletion with rituximab. Therefore, an international group of experts and patient representatives mainly from Europe experienced in clinical research, the use of biological agents and the development of recommendations, convened in Amsterdam in May 2010 to revise the consensus statement. The members of the original expert group were re-invited to participate and, in addition, more recent contributors to the field primarily based on the original publication. The steering group, consisting of MHB, JSS and PE had full control over the invitations. This update will concern the following areas: ▶ Mode of action ▶ Indication, considerations and screening for initiating rituximab in RA ▶ Treatment dose algorithm and co-medication ▶ Evaluation and management of response as well as lack of response and considerations for retreatment ▶ Predictive factors of response ▶ Contraindications and adverse events (AE) ▶ Long-term exposure—efficacy and safety issues ▶ Research agenda

▶ Indication, considerations and screening for initiating rituximab in RA ▶ Treatment dose algorithm and co-medication ▶ Evaluation and management of response as well as lack of response and considerations for retreatment ▶ Predictive factors of response ▶ Contraindications and adverse events (AE) ▶ Long-term exposure—efficacy and safety issues ▶ Research agenda Importantly, we have on this occasion placed greater emphasis on the patient perspective. To achieve our objective, a systematic literature review of the published literature on the efficacy and safety of rituximab in treating patients with RA was first undertaken (MHB) to identify relevant data and information (details included in the supplementary material, available online only). The outcome of the discussion of the new data and results of this activity will be presented in this publication. Categories of evidence will be indicated next to each reference in line with published guidelines (Table 1);5 assignment of the Ia category was agreed to require the availability of two or more randomised controlled trials (RCT) with similar results. Table 1 Evidence hierarchy Category of evidence Type of study Ia Meta-analyses of RCT or RCT ≥1 result Ib RCT IIa Controlled study without randomisation IIb Quasi-experimental study III Non-experimental descriptive studies such as comparative, correlation and case–control studies IV Expert committee reports or opinion or clinical experience of respective authorities, or both Modified from Shekelle et al.5 RCT, randomised controlled trial.

Category of evidence Type of study Ia Meta-analyses of RCT or RCT ≥1 result Ib RCT IIa Controlled study without randomisation IIb Quasi-experimental study III Non-experimental descriptive studies such as comparative, correlation and case–control studies IV Expert committee reports or opinion or clinical experience of respective authorities, or both Modified from Shekelle et al.5 RCT, randomised controlled trial. Significant amounts of data have been generated and discussed, all of which could not be included within this document but have instead been added in the supplementary material available online only. Mechanism of action of rituximab in RA Rituximab targets the CD20 molecule, which is expressed on the surface of B cells from pre-B-cell through memory B-cell stages6 7 but not on stem cells and pro B cells nor on plasma cells/blasts. Rituximab leads to transient but almost complete depletion of B cells in the blood and only partial depletion in the bone marrow8–13 and synovial tissue.14–16 Response has been shown to correlate with the level of synovial membrane B-cell depletion9 and early peripheral blood depletion of B cells measured by sensitive assays,9 possibly useful as a surrogate. It also frequently induces a reduction of immunoglobulins, notably IgM17 18 (see supplementary material, available online only, for more detailed discussion).

h the level of synovial membrane B-cell depletion9 and early peripheral blood depletion of B cells measured by sensitive assays,9 possibly useful as a surrogate. It also frequently induces a reduction of immunoglobulins, notably IgM17 18 (see supplementary material, available online only, for more detailed discussion). B-cell repopulation studies following rituximab treatment suggest reconstitution with antigenically inexperienced, transitional B cells derived from an immature population.8 19 In some patients, B-cell repopulation leads to a relapse of the disease. However, further investigations to be able to clarify clear patterns predictive of relapse are still needed. Background Rituximab is licensed and well established for patients with non-Hodgkin's lymphoma. Rituximab has also been approved by the US Food and Drug Administration and by the European Medicines Agency in Europe for the treatment of patients with RA who have had an inadequate response or were intolerant to tumour necrosis factor (TNF) inhibitors. In these patients, according to the licence, rituximab is given intravenously as two 1 g infusions (with intravenous glucocorticoid premedication; table 2), separated by 2 weeks, with concomitant methotrexate.2 3 Worldwide, more than 100 000 patients have received rituximab to date for RA.20 21 Table 2 Doses of rituximab and glucocorticoids in six randomised controlled clinical trials

Background Rituximab is licensed and well established for patients with non-Hodgkin's lymphoma. Rituximab has also been approved by the US Food and Drug Administration and by the European Medicines Agency in Europe for the treatment of patients with RA who have had an inadequate response or were intolerant to tumour necrosis factor (TNF) inhibitors. In these patients, according to the licence, rituximab is given intravenously as two 1 g infusions (with intravenous glucocorticoid premedication; table 2), separated by 2 weeks, with concomitant methotrexate.2 3 Worldwide, more than 100 000 patients have received rituximab to date for RA.20 21 Table 2 Doses of rituximab and glucocorticoids in six randomised controlled clinical trials Study Rituximab dose Intravenous glucocorticoid Oral glucocorticoid Edwards et al1 (MTX-IR) 2×1000 mg 2×100 mg MP on days 1 and 15 60 mg P days 2, 4–7 + 30 mg P days 8–14 Emery et al2 (DANCER) (MTX±TNF-IR) 2×1000 mg or 2×500 mg (1) 0 (1) 0 (2) 2×100 mg MP (2) 0 (3) 2×100 mg MP (3) 60 mg P days 2–7 + 30 mg P days 8–14 Cohen et al3 (REFLEX) (TNF-IR) 2×1000 mg 2×100 mg MP 60 mg P days 2–7 + 30 mg P days 8–14 Tak et al25 (IMAGE) (MTX-naive) 2×1000 mg or 2×500 mg 2×100 mg MP Rubbert-Roth et al23 (MIRROR) (MTX-IR) 2×1000 mg or 2×500 mg or 1×1000 mg and 1×500 mg 2×100 mg MP Emery et al24 (SERENE) (MTX-IR) 2×1000 mg or 2×500 mg 2×100 mg MP No marked difference in efficacy between the two rituximab doses.2 31–33 IMAGE: 2×1000 mg associated with structural retardation first 24 weeks; maintenance with both rituximab doses week 24 to 2 years. Premedication associated with reduced infusion-related events infusion one; minimal difference for infusion two.

g MP No marked difference in efficacy between the two rituximab doses.2 31–33 IMAGE: 2×1000 mg associated with structural retardation first 24 weeks; maintenance with both rituximab doses week 24 to 2 years. Premedication associated with reduced infusion-related events infusion one; minimal difference for infusion two. IR, inadequate-responder; MP, methylprednisolone; MTX, methotrexate; P, prednisolone; TNF, tumour necrosis factor.

g MP No marked difference in efficacy between the two rituximab doses.2 31–33 IMAGE: 2×1000 mg associated with structural retardation first 24 weeks; maintenance with both rituximab doses week 24 to 2 years. Premedication associated with reduced infusion-related events infusion one; minimal difference for infusion two. IR, inadequate-responder; MP, methylprednisolone; MTX, methotrexate; P, prednisolone; TNF, tumour necrosis factor. In earlier studies, rituximab has shown efficacy when used alone (category Ib) and in combination with other agents, including methotrexate1 (category Ia). The efficacy and durability of monotherapy is less than that of combination treatment with methotrexate (category Ib). Subsequent studies on rituximab in combination with methotrexate have proved to be successful in markedly reducing inflammatory activity and increasing functional ability and quality of life3 (category Ia). In responding patients, the duration of the response to a single course of rituximab usually lasts more than 6 months22 (category Ib). Recent phase III studies have also expanded information on the efficacy of rituximab in methotrexate inadequate responders (‘MIRROR’ and ‘SERENE’ studies)23 24 and addressed methotrexate-naive patients (‘IMAGE’ study).25 Response rates in the former studies demonstrated the superiority of rituximab over placebo. In the IMAGE study involving methotrexate-naive patients, rituximab plus methotrexate was superior in clinical and functional outcomes to methotrexate alone; there was also a significant reduction in radiographic progression versus methotrexate monotherapy after 6, 12 and 24 months.25 Inhibition of structural damage progression had already been shown previously in patients with previous inadequate response to TNF inhibitors treated with methotrexate and rituximab, and this effect was sustained after 2 years (category Ib).26 27

progression versus methotrexate monotherapy after 6, 12 and 24 months.25 Inhibition of structural damage progression had already been shown previously in patients with previous inadequate response to TNF inhibitors treated with methotrexate and rituximab, and this effect was sustained after 2 years (category Ib).26 27 The wider use of rituximab has meant a better appreciation of the associated safety issues with, in particular, focus on infection risk. The oncology literature has highlighted concerns over hepatitis B reactivation.28 29 In addition, more specific consequences of B-cell depletion, namely low baseline IgG levels and the observation of subsequent greater infection risk has indicated the value of checking IgG levels before administering rituximab.30 In addition to data from clinical trials on the efficacy and safety of rituximab, drug registries may provide information that is complementary to information from the trials. Registries include patients with severe comorbidities that contraindicate the use of, for example, TNF inhibitors, as well as patients treated with rituximab without the previous use of other biological agents and/or receiving rituximab as monotherapy.31 32

ormation that is complementary to information from the trials. Registries include patients with severe comorbidities that contraindicate the use of, for example, TNF inhibitors, as well as patients treated with rituximab without the previous use of other biological agents and/or receiving rituximab as monotherapy.31 32 Recommendations Indication At present, in line with the current licensed indication, rituximab may be used in adult patients with RA who qualify for treatment with biological agents and have had an inadequate response or intolerance to one or more TNF inhibitors33; patients with a contraindication to TNF inhibitors have not yet been adequately studied. However, registry and non-interventional studies have reported 17–20.5% of patients receiving rituximab as their first biological disease-modifying antirheumatic drug (DMARD).30 34 Before concluding that a patient has not responded to a TNF inhibitor, attempts should be made to improve the ongoing regimen by optimising the DMARD or TNF inhibitor treatment,35 considering respective recommendations. The SERENE and MIRROR studies (described later) confirm efficacy in a methotrexate-inadequate responder/TNF inhibitor-naive population and the IMAGE study in methotrexate-naive patients.23–25

ade to improve the ongoing regimen by optimising the DMARD or TNF inhibitor treatment,35 considering respective recommendations. The SERENE and MIRROR studies (described later) confirm efficacy in a methotrexate-inadequate responder/TNF inhibitor-naive population and the IMAGE study in methotrexate-naive patients.23–25 Current evidence on the efficacy of rituximab relates primarily to rheumatoid factor (RF) positive patients1 2 (category Ia). While in the phase III (REFLEX) study on TNF inhibitor non-responders, a response was seen in RF-negative patients,3 other substudy analyses on RF-negative patients showed that the response in this population was not significantly different from placebo-treated patients.2 36 Indeed, in the first of these studies (REFLEX), protection from joint damage was only evident in seropositive patients.37

onse was seen in RF-negative patients,3 other substudy analyses on RF-negative patients showed that the response in this population was not significantly different from placebo-treated patients.2 36 Indeed, in the first of these studies (REFLEX), protection from joint damage was only evident in seropositive patients.37 Recently, pooled data from two phase III studies in methotrexate-inadequate responder populations as well as a substudy from the IMAGE study that evaluated methotrexate-naive patients have all reinforced the view that seropositive patients (anti-citrullinated peptide antibody (ACPA), RF or both) demonstrate a more robust response to rituximab25 38 (table 3; data discussed in the supplementary material available online only). In the IMAGE study,25 there was evidence of significantly greater joint protection in the seropositive subpopulation treated with rituximab and methotrexate; while in the seronegative group, inhibition of progression of damage in each treatment group was comparable and generally low even in the placebo/methotrexate group. Superior efficacy has also been demonstrated in drug registries for patients who were RF and/or ACPA positive39–42 when compared with the seronegative patient group. Another study (discussed further in the supplementary material available online only) identified the four best potential biomarkers from the REFLEX study (that included IgA RF and IgG anti-CCP3) and applied these, together with IgM and IgG isotypes of RF to the SERENE study; the presence of any RF isotype or IgG ACPA was associated with a higher American College of Rheumatology (ACR50) response.43 A multivariate analysis from a single-centre study suggested RF (and not ACPA), low disability and the previous number of TNF inhibitors as predictive of response to rituximab.44 Therefore, while one randomised trial suggested efficacy for rituximab in seronegative patients, data from the other trials described above, together with descriptions of a more unpredictable safety profile in these patients,45 suggest it would perhaps be more appropriate for alternative treatment approaches to be considered.

re, while one randomised trial suggested efficacy for rituximab in seronegative patients, data from the other trials described above, together with descriptions of a more unpredictable safety profile in these patients,45 suggest it would perhaps be more appropriate for alternative treatment approaches to be considered. Table 3 Pooled analysis38 of response rates for autoantibody positive and negative patients from the MIRROR23 and SERENE24 studies Week 24 Week 48 Seropositive Seronegative Seropositive Seronegative ACR responses (n) 514 106 506 101 ACR20 (%) 62.3* 50.9 71.1* 51.5 ACR50 (%) 32.7* 19.8 44.9** 22.8 ACR70 (%) 12.1 5.7 20.9* 6.9 EULAR outcomes (n) 507 105 496 101 EULAR response (%) 74.8* 62.9 84.3* 72.3 Mean change DAS28 −1.97** −1.50 −2.48*** −1.72 DAS28 categories (n) 510 105 499 101 Low disease (%) 16.9 10.5 26.5* 12.9 DAS28 remission (%) 10.6 4.8 13.2 5.9 * p<0.05, ** p<0.001, *** p<0.0001 vs seronegative. ACR, American College of Rheumatology; DAS28, disease activity score 28; EULAR, European League Against Rheumatism.

Week 24 Week 48 Seropositive Seronegative Seropositive Seronegative ACR responses (n) 514 106 506 101 ACR20 (%) 62.3* 50.9 71.1* 51.5 ACR50 (%) 32.7* 19.8 44.9** 22.8 ACR70 (%) 12.1 5.7 20.9* 6.9 EULAR outcomes (n) 507 105 496 101 EULAR response (%) 74.8* 62.9 84.3* 72.3 Mean change DAS28 −1.97** −1.50 −2.48*** −1.72 DAS28 categories (n) 510 105 499 101 Low disease (%) 16.9 10.5 26.5* 12.9 DAS28 remission (%) 10.6 4.8 13.2 5.9 * p<0.05, ** p<0.001, *** p<0.0001 vs seronegative. ACR, American College of Rheumatology; DAS28, disease activity score 28; EULAR, European League Against Rheumatism. Considerations for initiating treatment Before treatment, an individual therapeutic goal should be established as a shared decision between each patient and the treating physician. The doctor should be experienced in the diagnosis and treatment of RA, including the use of biological DMARD agents. The general principles should follow published recommendations.46 47 Patients considered for treatment generally should thus have active disease in line with inclusion in clinical trials, defined as at least moderate disease activity by composite scores, such as by the 28-joint disease activity score (DAS28, >3.2), the simplified disease activity index (SDAI, >11), the clinical disease activity index (CDAI, >10) or similar measures.48 49

hus have active disease in line with inclusion in clinical trials, defined as at least moderate disease activity by composite scores, such as by the 28-joint disease activity score (DAS28, >3.2), the simplified disease activity index (SDAI, >11), the clinical disease activity index (CDAI, >10) or similar measures.48 49 So far, in the phase II and phase III studies of TNF inhibitor failure patients, rituximab was started as soon as 4 weeks after the last dose of etanercept and 8 weeks after the last dose of infliximab or adalimumab. Exclusion criteria comprised evidence of major systemic involvement due to RA, other major illnesses or laboratory abnormalities, and a history of recurrent relevant infections.2 3 Patients treated in real life are more heterogeneous than in RCT with regard to comorbidities, disease activity as well as previous and concomitant use of other medications; information from drug registries, therefore, provides additional important insights.34 50 51 Screening before initiating rituximab Initiation of rituximab should be preceded by recording a detailed history (regarding chronic or recent comorbidity, such as cardiovascular and pulmonary diseases, recurrent infections and allergies) and a complete physical examination to consider possible contraindications in all patients, especially the older patient. Special attention should be paid to vaccinations. Patients should be well informed of the full therapeutic profile of rituximab, including all risks and benefits.

recurrent infections and allergies) and a complete physical examination to consider possible contraindications in all patients, especially the older patient. Special attention should be paid to vaccinations. Patients should be well informed of the full therapeutic profile of rituximab, including all risks and benefits. In clinical trials on rituximab, patients with RA have been prescreened for hepatitis B and C; patients testing negative for hepatitis B virus (HBV), hepatitis B surface antigen (HBsAg), but positive for antibodies against hepatitis B core (HBc) antigen were allowed rituximab therapy if negative for HBV DNA. While cases of HBV reactivation are widely described in the oncology literature, only one case report of HBV reactivation in a patient with RA treated with rituximab52 has been reported. Data from patients with RA as well as from the oncology and hepatology literature are discussed in the supplementary material, available online only. The risk of hepatitis C virus is in contrast, unclear with conflicting data and perspectives on the possible consequences of rituximab and chemotherapy generally.53 54

d. Data from patients with RA as well as from the oncology and hepatology literature are discussed in the supplementary material, available online only. The risk of hepatitis C virus is in contrast, unclear with conflicting data and perspectives on the possible consequences of rituximab and chemotherapy generally.53 54 As always, the individual risk–benefit ratio should be evaluated and discussed with the patient. Management of such patients should be in consultation with an expert gastroenterologist/hepatologist. Expert advice is that serological markers of HBV infection should be obtained before starting treatment. As discussed in the supplementary material (available online only), reactivation has been documented in HBsAg-negative as well as HBsAg-positive patients,28 29 stressing the importance of measuring not only HBsAg but also antibodies against HBc antigen to identify positive carrier status. HBsAg negativity (with also anti-HBs antibody negativity) identifies those requiring vaccination before immunosuppressive therapy. HBV DNA titres are not indicated for screening, rather assessment of viral load and response in established chronic HBV infection. Several recommendations have been published including those by the Centers for Disease Control and Prevention, although they partly differ.55 57 Nevertheless, patients who are HBsAg positive and/or anti-HBc positive should be treated prophylactically. The management of occult HBV infection with anti-HBc positivity alone remains unclear; in such patients HBV DNA could be determined and then prophylactic therapy considered; if not undertaken, close follow-up to detect a rise in HBV DNA is recommended. Routine testing for hepatitis C should also be considered. A recent review paper and editorial advise a similar approach with a call for revision of ACR guidelines with, in addition, a recent publication of a provisional clinical opinion from the American Society of Clinical Oncology.58–60

se in HBV DNA is recommended. Routine testing for hepatitis C should also be considered. A recent review paper and editorial advise a similar approach with a call for revision of ACR guidelines with, in addition, a recent publication of a provisional clinical opinion from the American Society of Clinical Oncology.58–60 Chest radiography was also carried out in the clinical trials. Patients who did not respond to TNF inhibitor treatment will also have been prescreened for the presence of active or latent tuberculosis. In the RA clinical trials on rituximab before TNF inhibitor, patients with active tuberculosis were excluded, but patients were not screened for latent tuberculosis by any testing. The fact that rituximab is administered in RA with two pulses of glucocorticoid may by itself contribute to the risk of reactivation of tuberculosis.61 However, there is no evidence of an increased frequency of tuberculosis in patients with lymphoma treated with rituximab62 and, therefore, at this time there is no evidence indicating the necessity to screen patients systematically for tuberculosis before using rituximab in those with RA.

eactivation of tuberculosis.61 However, there is no evidence of an increased frequency of tuberculosis in patients with lymphoma treated with rituximab62 and, therefore, at this time there is no evidence indicating the necessity to screen patients systematically for tuberculosis before using rituximab in those with RA. Apart from routine laboratory tests usually performed in patients with RA before initiating new treatments, baseline Ig levels should be determined, as a reduced baseline level of IgG is a risk factor for severe infections with rituximab;30 in addition, decreased levels of IgM and IgA have been observed with rituximab over time18 (category Ia). Monitoring the IgG level at baseline before each rituximab cycle and longitudinally is therefore advised, with patients particularly at risk, such as those showing reduced IgG levels at baseline or indeed other higher risk groups such as older people, requiring particularly close monitoring of levels and vigilance for infections. On all these grounds, rituximab treatment in RA patients with hypogammaglobulinaemia (below the lower limit of normal) should be considered with caution (see also section on ‘Immunoglobulins and infection risk’). In clinical trials, B-cell levels have been measured, but the utility of these measurements in routine practice is not confirmed.

Apart from routine laboratory tests usually performed in patients with RA before initiating new treatments, baseline Ig levels should be determined, as a reduced baseline level of IgG is a risk factor for severe infections with rituximab;30 in addition, decreased levels of IgM and IgA have been observed with rituximab over time18 (category Ia). Monitoring the IgG level at baseline before each rituximab cycle and longitudinally is therefore advised, with patients particularly at risk, such as those showing reduced IgG levels at baseline or indeed other higher risk groups such as older people, requiring particularly close monitoring of levels and vigilance for infections. On all these grounds, rituximab treatment in RA patients with hypogammaglobulinaemia (below the lower limit of normal) should be considered with caution (see also section on ‘Immunoglobulins and infection risk’). In clinical trials, B-cell levels have been measured, but the utility of these measurements in routine practice is not confirmed. Vaccination Some data from the oncology literature indicate that in patients receiving rituximab, response to vaccination may be ineffective.62 Patients with RA receiving rituximab have been investigated for their response to vaccination in two studies, one of which was a RCT63 64 (discussed in the supplementary material, available online only). Any patient considered for rituximab therapy should receive all indicated vaccines (hepatitis B for at-risk population, pneumococcus, tetanus toxoid every 10 years, influenza annually) before treatment. Ideally, vaccination should be undertaken at least 4 weeks before rituximab therapy. More data are needed on the potential risk of vaccination with live vaccines, which are therefore not recommended for rituximab-treated patients. European League Against Rheumatism (EULAR) recommendations on vaccination provide additional guidance for patients with rheumatological diseases treated with biological agents.65

Treatment dose and co-medication Treatment dosage In patients who have received previous TNF inhibitor treatment, rituximab use is licensed at a dose of 1000 mg per infusion on days 1 and 15.3 Rituximab showed significant efficacy on signs and symptoms as well as physical function in this population. The effect on structural damage was also evaluated in that trial (REFLEX), in which the 2×1000 mg dose was studied. Radiographic benefit compared with placebo was demonstrated at 1 year26 (but not at 24 weeks),3 26 with recent data confirming maintenance of retardation at 2 years.27 Subsequent studies in all other RA populations, namely patients with previous inadequate response to traditional DMARD including methotrexate and patients naive to methotrexate, have also evaluated a lower dose of 500 mg per infusion.2 23–25 The SERENE24 and MIRROR23 studies both addressed methotrexate-inadequate responder patients and included two courses of 2×500 and 2×1000 mg 6 months apart; SERENE also had a placebo arm for comparison, while MIRROR adopted an additional dose escalation regimen—one course of 2×500 mg followed by a course of 2×1000 mg. ACR20, ACR50 and ACR70 response rates in patients treated with these rituximab doses were similar (as detailed in table 4 and discussed further in the supplementary material, available online only) (category Ib). Effects on joint damage were not assessed in this study. Table 4 Summary of response rates in the six key randomised controlled studies evaluating rituximab and methotrexate

The SERENE24 and MIRROR23 studies both addressed methotrexate-inadequate responder patients and included two courses of 2×500 and 2×1000 mg 6 months apart; SERENE also had a placebo arm for comparison, while MIRROR adopted an additional dose escalation regimen—one course of 2×500 mg followed by a course of 2×1000 mg. ACR20, ACR50 and ACR70 response rates in patients treated with these rituximab doses were similar (as detailed in table 4 and discussed further in the supplementary material, available online only) (category Ib). Effects on joint damage were not assessed in this study. Table 4 Summary of response rates in the six key randomised controlled studies evaluating rituximab and methotrexate Study Response measure 6 Months 12 Months Plc + MTX RTX (2×500 mg) + MTX RTX (2×1000 mg) + MTX Plc + MTX RTX (2×500 mg) + MTX RTX (2×1000 mg) + MTX MTX-naive IMAGE25 (n=755) ACR 20 64.3 76.7 80.0 ACR 50 41.8 59.4 64.8 ACR 70 24.9 42.2 46.8 EULAR (mod+good) 71.1 82.3 86.0 DAS28 Rem 12.6 25.4 30.5 MTX-IR Phase IIa1 (n=80) ACR 20 38.0 73.0 20.0 65.0 ACR 50 13.0 43.0 5.0 35.0 ACR 70 5.0 23.0 0 15.0 EULAR (mod+good) DAS28 Rem SERENE24 (n=512) ACR 20 23.3 54.5 50.6 55.7 57.6 ACR 50 9.3 26.3 25.9 32.9 34.1 ACR 70 5.2 9.0 10.0 12.6 13.5 EULAR (mod+good) 50.0 82.0 87.0 89.0 81.0 DAS28 Rem 4.0 16.0 16.0 15.0 19.0 MIRROR72 (n=227; excludes dose escalation group) ACR 20 64.0 72.0 ACR 50 39.0 48.0 ACR 70 20.0 23.0 EULAR (mod+good) 73.0 89.0 DAS28 Rem 9.0 19.0 MTX±TNF-IR DANCER2 (n=465) ACR 20 28.0 55.0 54.0 ACR 50 13.0 33.0 34.0 ACR 70 5.0 13.0 20 EULAR (mod+good) 37.0 73.0 67.0 DAS28 Rem TNF-IR REFLEX3 ACR 20 18.0 51.0 ACR 50 5.0 27.0 ACR 70 1.0 12.0 EULAR (mod+good) 20.0 50.0 DAS28 Rem 0 9.0 ACR, American College of Rheumatology; DAS28, disease activity score 28; EULAR, European League Against Rheumatism; IR, inadequate-responder; mod, moderate; MTX, methotrexate; Plc, placebo; Rem, remission; RTX, rituximab; TNF, tumour necrosis factor.

0 5.0 27.0 ACR 70 1.0 12.0 EULAR (mod+good) 20.0 50.0 DAS28 Rem 0 9.0 ACR, American College of Rheumatology; DAS28, disease activity score 28; EULAR, European League Against Rheumatism; IR, inadequate-responder; mod, moderate; MTX, methotrexate; Plc, placebo; Rem, remission; RTX, rituximab; TNF, tumour necrosis factor. In the IMAGE study in methotrexate-naive patients, the 2×500 and 2×1000 mg dose groups were again compared.25 The clinical and functional outcomes were very similar. The higher dose (2×1000 mg) cohort demonstrated significantly superior joint protection compared with placebo, while the lower dose (2×500 mg) had numerical, although not statistical, radiographic benefit during the first 24 weeks. Beyond this time point, however, (study duration of 2 years) radiographic progression was minimal and indeed similar in both dose groups. These results are illustrated in the supplementary section available online only. These data are important in expanding upon those observed in the previoius TNF inhibitor-experienced population from the REFLEX study described above. The optimal dose of rituximab thus remains insufficiently defined, with considerable data suggesting an overall equivalence of 2×500 mg with the licensed dose of 2×1000 mg for clinical efficacy outcomes and medium-term maintenance of radiographic non-progression. More research is required in this area.

described above. The optimal dose of rituximab thus remains insufficiently defined, with considerable data suggesting an overall equivalence of 2×500 mg with the licensed dose of 2×1000 mg for clinical efficacy outcomes and medium-term maintenance of radiographic non-progression. More research is required in this area. In the phase II trial, the ACR responses of patients treated with rituximab in combination with methotrexate were numerically superior to those receiving rituximab monotherapy (table).2 Rituximab monotherapy was also shown to be more effective than placebo only in ACR20 response but not in ACR50 and ACR70 responses2 (category Ib). Rituximab is therefore only licensed in combination with methotrexate (www.accessdata.fda.gov/scripts/cder/drugsatfda, www.ema.eu.int/humans/Humans/EPAR/mabthera/mabthera). In clinical practice this will usually be a dose of 10–25 mg methotrexate per week, unless intolerance precludes such doses (category Ib).

ory Ib). Rituximab is therefore only licensed in combination with methotrexate (www.accessdata.fda.gov/scripts/cder/drugsatfda, www.ema.eu.int/humans/Humans/EPAR/mabthera/mabthera). In clinical practice this will usually be a dose of 10–25 mg methotrexate per week, unless intolerance precludes such doses (category Ib). Other combinations A number of abstracts (small observational studies and registry data) have described the use of rituximab with DMARD other than methotrexate31 66 (category III). They consistently demonstrate that leflunomide can be used safely and effectively as background DMARD therapy. The observational study, SUNDIAL, demonstrated the safety of rituximab on a variety of background non-biological DMARD and combinations66 (category III). An initial, relatively small randomised study (TAME) assessed rituximab on background etanercept or adalimumab and showed more infections with this combination67 (category IIa); this approach should therefore be avoided. Data are available from the phase II trials on cyclophosphamide as co-medication,1 although given the availability of safer and more effective alternatives, in patients with RA at least, this expert group felt that cyclophosphamide is unnecessary as a co-medication.

gory IIa); this approach should therefore be avoided. Data are available from the phase II trials on cyclophosphamide as co-medication,1 although given the availability of safer and more effective alternatives, in patients with RA at least, this expert group felt that cyclophosphamide is unnecessary as a co-medication. Rituximab administration and glucocorticoid premedication To reduce the frequency and severity of infusion reactions, patients should receive 100 mg methylprednisolone intravenously before rituximab infusions (category Ib). This is particularly indicated before the first infusion and can also be given before the second infusion of each cycle, although the indication may not be as strong for the latter.2 68 Paracetamol and antihistamines may be required, and although they have been used for premedication in all clinical trials on RA, there is no clear evidence from these that antihistamines should be used systematically.

re the second infusion of each cycle, although the indication may not be as strong for the latter.2 68 Paracetamol and antihistamines may be required, and although they have been used for premedication in all clinical trials on RA, there is no clear evidence from these that antihistamines should be used systematically. Evaluation and management of response/non-response Response assessment Routine rheumatological assessments should be performed at baseline and periodically according to standards of care for therapies with biological agents and methotrexate. Response to rituximab should be assessed by validated composite measures of disease activity (eg, the DAS28, SDAI or CDAI);48 functional assessment (health assessment questionnaire), and evaluation of radiographic progression further complement the use of these scores. At least a low disease activity range (DAS28 ≤3.2, SDAI <11 or CDAI <10) and a maximisation of functional ability and quality of life should be the target to aim for with regard to a desirable disease state.49

essment questionnaire), and evaluation of radiographic progression further complement the use of these scores. At least a low disease activity range (DAS28 ≤3.2, SDAI <11 or CDAI <10) and a maximisation of functional ability and quality of life should be the target to aim for with regard to a desirable disease state.49 Response profile Rituximab has a more distinctive response profile in that the onset of action of rituximab is slower than that of the other biological DMARD. Furthermore, it should be noted that intravenous glucocorticoid premedication will produce an early, albeit a usually transient, response before 8 weeks. It is important that this is communicated to the patient. A patient should be regarded as a responder if the response criteria are met after an observation period of at least 16 weeks from the initiation of treatment according to the recommended dosing schedule. Indeed, in most patients, a response (ie, some degree of improvement in disease activity) is usually seen by 16 weeks after the first infusion1–3 (category Ia). Rituximab usually leads to rapid B-cell depletion1–3 (category Ia).

ast 16 weeks from the initiation of treatment according to the recommended dosing schedule. Indeed, in most patients, a response (ie, some degree of improvement in disease activity) is usually seen by 16 weeks after the first infusion1–3 (category Ia). Rituximab usually leads to rapid B-cell depletion1–3 (category Ia). Considerations for repeated treatment Repeated treatment should be considered after at least 24 weeks (category IV). In line with the ‘treat-to-target’ and EULAR RA management recommendations,46 47 this should be considered in patients who do not reach remission (exhibiting a DAS28 ≥2.6, SDAI >3.3 or CDAI >2.8)49 or at least low disease activity (although with consideration of alternative targets if individual factors make it unlikely that either of these are achieveable).46 It is worth noting that the earliest retreatment was undertaken after 4 months.3

do not reach remission (exhibiting a DAS28 ≥2.6, SDAI >3.3 or CDAI >2.8)49 or at least low disease activity (although with consideration of alternative targets if individual factors make it unlikely that either of these are achieveable).46 It is worth noting that the earliest retreatment was undertaken after 4 months.3 Notwithstanding the above, the optimal treatment paradigm for rituximab has not been definitively determined. Options include treatment on flare as practised in earlier RCT, regular re-treatment, for example, every 6 months, treatment with any deterioration or treatment-to-target. This is discussed in more detail in the supplementary material, available online only, with data from pooled phase II and III studies69 as well as preliminary data from the German registry.70 Retrospective data support in principle a treatment-to-target strategy, whereas regular re-treatment may risk overtreatment in some patients. Of note, a lack of long-term safety data relating to different dosing regimens in the re-treatment of RA means it is important that caution is exercised if or when patients are being regularly re-treated.

in principle a treatment-to-target strategy, whereas regular re-treatment may risk overtreatment in some patients. Of note, a lack of long-term safety data relating to different dosing regimens in the re-treatment of RA means it is important that caution is exercised if or when patients are being regularly re-treated. Managing non-response Several studies have reported the outcome of re-treating rituximab non-responders with a further cycle. Several of these (with, in one study, 95% of non-responders showing poor early peripheral blood B-cell depletion using a high sensitivity assay)71 demonstrate that seropositive patients who fail to respond to a first course of rituximab may respond to a second course23 24 36 66 70 71 (accompanied by more complete B-cell depletion).71 A couple of other studies, however, suggest little improvement to be gained with re-treatment.36 72 In light of the availability of other therapeutic options, for individual (particularly seronegative) patients who are rituximab non-responders or insufficient responders, other treatment options should be considered depending on previous drug history.

er, suggest little improvement to be gained with re-treatment.36 72 In light of the availability of other therapeutic options, for individual (particularly seronegative) patients who are rituximab non-responders or insufficient responders, other treatment options should be considered depending on previous drug history. Post-TNF inhibitor failure and biological DMARD therapy after rituximab Post-TNF inhibitor failure A few observational, registry-based and single-centre studies have compared the use of rituximab in TNF inhibitor inadequate responders versus switching to another TNF inhibitor73–77 (discussed in the supplementary material, available online only). There has been no head-to-head comparison to date, with a recent meta-analysis confirming similar clinical benefits from these RCT;78 associated management recommendations did not establish a preference for a particular biological agent in this situation.47

scussed in the supplementary material, available online only). There has been no head-to-head comparison to date, with a recent meta-analysis confirming similar clinical benefits from these RCT;78 associated management recommendations did not establish a preference for a particular biological agent in this situation.47 Safety of other biological DMARD post-rituximab Switching from rituximab to a TNF inhibitor has been associated with a numerically, but not statistically, significant increase in serious infections in an early study;79 a subsequent report providing further follow-up of the same cohort did not suggest a major increase in infections under these circumstances.80 In this latter report TNF inhibitors were usually initiated at least 4 months after rituximab (when insufficient treatment response would be judged). No significant increase in serious infections was noted compared with the incidence before the new biological DMARD (TNF inhibitors in the majority of cases), with similar rates to a biological DMARD-naive group commenced on a TNF inhibitor; however, a wide interval from rituximab exposure to subsequent biological DMARD exposure was present (0.5–37 months) with a small sample size.80 Data from the French Autoimmunity and Rituximab and Orencia in Rheumatoid Arthritis registries indicate that previous use of rituximab followed by treatment with abatacept does not increase the short-term risk of severe infection.81 These are preliminary reports and clearly further data on the safety of using other biological DMARD before or after rituximab need to be established.

Rheumatoid Arthritis registries indicate that previous use of rituximab followed by treatment with abatacept does not increase the short-term risk of severe infection.81 These are preliminary reports and clearly further data on the safety of using other biological DMARD before or after rituximab need to be established. Cost-effectiveness Rituximab has been evaluated as a cost-effective treatment82 with three studies comparing rituximab with TNF inhibitor83–85 following TNF inhibitor failure; the methods differed slightly but all suggested equivalent/favourable results towards rituximab. Role of rituximab in other autoimmune diseases In addition to RA, accumulating evidence suggests rituximab could also be an effective treatment option in the management of patients with vasculitis, connective tissue diseases and other autoimmune conditions. Data that have emerged from recent RCT are summarised in the supplementary material available online only. Contraindications and AE Contraindications Contraindications to rituximab include hypersensitivity to rituximab or other murine proteins, active severe infections and severe heart failure (New York Heart Association class IV; www.accessdata.fda.gov/scripts/cder/drugsatfda, www.ema.eu.int/humans/Humans/EPAR/mabthera/mabthera).33 In non-Hodgkin's lymphoma, contraindications have been restricted to hypersensitivity to components of this product or murine proteins. Patients with active infections (acute or chronic) should not be treated with rituximab.

ssdata.fda.gov/scripts/cder/drugsatfda, www.ema.eu.int/humans/Humans/EPAR/mabthera/mabthera).33 In non-Hodgkin's lymphoma, contraindications have been restricted to hypersensitivity to components of this product or murine proteins. Patients with active infections (acute or chronic) should not be treated with rituximab. Use in children Safety and efficacy in children with rheumatic diseases has not been established although an increasing number of case reports and series of successful rituximab usage are available in the literature.86–92

ssdata.fda.gov/scripts/cder/drugsatfda, www.ema.eu.int/humans/Humans/EPAR/mabthera/mabthera).33 In non-Hodgkin's lymphoma, contraindications have been restricted to hypersensitivity to components of this product or murine proteins. Patients with active infections (acute or chronic) should not be treated with rituximab. Use in children Safety and efficacy in children with rheumatic diseases has not been established although an increasing number of case reports and series of successful rituximab usage are available in the literature.86–92 Pregnancy Rituximab treatment during pregnancy is contraindicated. A recent review93 of pregnancy outcomes from the rituximab global drug safety database identified 231 cases of pregnancy associated with maternal rituximab exposure. Of 153 pregnancies with known outcomes, 90 resulted in live births, 33 ended in spontaneous abortion, with one stillbirth at 20 weeks' gestation (umbilical knot) and 28 elective terminations. Twenty-two of the live births were premature, with one neonatal death at 6 weeks. Eleven infants had haematological abnormalities at birth; four neonatal infections and two congenital malformations were reported. A recent review of RA medications in pregnancy included B-cell levels during eight of these cases of rituximab exposure during pregnancy,94 two cases were during the first trimester and were not associated with any B-cell depletion in the fetus; six cases in the second or third trimesters included three with similar rituximab levels to the mother with markedly reduced/undetectable B-cell numbers—spontaneous recovery was, however, observed within 6 months. IgG levels were tested and were normal in four out of the six cases and vaccination responses remained intact. The appropriate time interval between the last rituximab treatment and subsequent conception remains unclear. Although additional data are now becoming available, further data are required before safety recommendations for pregnancy can be produced; until that time contraception is recommended for 12 months after the last rituximab application in the label, and rituximab should also be avoided in lactating women (www.accessdata.fda.gov/scripts/cder/drugsatfda, www.ema.eu.int/humans/Humans/EPAR/mabthera/mabthera).33

ty recommendations for pregnancy can be produced; until that time contraception is recommended for 12 months after the last rituximab application in the label, and rituximab should also be avoided in lactating women (www.accessdata.fda.gov/scripts/cder/drugsatfda, www.ema.eu.int/humans/Humans/EPAR/mabthera/mabthera).33 Adverse events Table 5 lists the more frequent (≥2%) AE recorded during the 6-month placebo-controlled period from nine studies (IIa, IIb (DANCER), DANCER extension, REFLEX (and REFLEX extension), SERENE, MIRROR, SUNRISE and SIERRA studies);18 data for the placebo and methotrexate group have been pooled from the phase IIa, IIb (DANCER), REFLEX and SERENE studies. Table 5 AE occurring during the 6-month placebo-controlled period of nine studies18

Adverse events Table 5 lists the more frequent (≥2%) AE recorded during the 6-month placebo-controlled period from nine studies (IIa, IIb (DANCER), DANCER extension, REFLEX (and REFLEX extension), SERENE, MIRROR, SUNRISE and SIERRA studies);18 data for the placebo and methotrexate group have been pooled from the phase IIa, IIb (DANCER), REFLEX and SERENE studies. Table 5 AE occurring during the 6-month placebo-controlled period of nine studies18 Placebo+MTX (n=570) Rituximab+MTX (n=877) Total patients (%) with ≥1 AE infection 223 (39.1) 353 (40.3) Infections occurring in ≥2% of patients Nasopharyngitis 43 (7.5) 63 (7.2) Upper respiratory tract infections* 37 (6.5) 64 (7.3) Urinary tract infection* 31 (5.4) 31 (3.5) Bronchitis* 19 (3.3) 27 (3.1) Sinusitis 20 (3.5) 25 (2.9) Gastroenteritis 14 (2.5) 12 (1.4) Pharyngitis 12 (2.1) 11 (1.3) Total patients (%) with a serious infection 9 (1.6) 15 (1.7) Pneumonia 2 (0.4) 2 (0.2) Gastroenteritis 2 (0.4) 1 (0.1) Pyelonephritis 0 3 (0.3) Respiratory tract infection 2 (0.4) 0 Abscess bacterial 1 (0.2) 0 Abscess intestinal 1 (0.2) 0 Bronchitis 0 1 (0.1) Bronchopneumonia 1 (0.2) 0 Cellulitis 0 1 (0.1) Cellulitis gangrenous 0 1 (0.1) Infusion-related reactions were the most common adverse event (AE) (25% infusion 1). Data for the placebo + methotrexate (MTX) group pooled from trials IIa, DANCER, REFLEX and SERENE. The overall rate (95% CI) of AE was 359.6 events per 100 patient-years (354.4 to 364.9) with highest rates during course 1; for serious AE, the rate (95% CI) was 17.85 events per 100 patient-years (16.72 to 19.06).

on 1). Data for the placebo + methotrexate (MTX) group pooled from trials IIa, DANCER, REFLEX and SERENE. The overall rate (95% CI) of AE was 359.6 events per 100 patient-years (354.4 to 364.9) with highest rates during course 1; for serious AE, the rate (95% CI) was 17.85 events per 100 patient-years (16.72 to 19.06). * Occurred in ≥10% patients. Infusion-related reactions The tolerability and safety of rituximab has been well described in clinical trials on patients with RA and review articles on non-Hodgkin's lymphoma62 (category III)1 2 18 (category Ia). The most frequent AE are infusion reactions (30–35% with the first infusion with concomitant glucocorticoids). Fewer reactions are observed with the second and subsequent infusions1–3 18 (category Ia). They are usually mild to moderate, but may require therapeutic intervention (additional paracetamol, antihistamines, bronchodilators, eventually glucocorticoids). Severe infusion reactions leading to drug discontinuation are uncommon (<1%) and are mainly restricted to the first infusion (Roche data on file). Their frequency is reduced by the use of concomitant intravenous steroids1–3 (category Ia; www.accessdata.fda.gov/scripts/cder/drugsatfda, www.ema.eu.int/humans/Humans/EPAR/mabthera/mabthera).33 There have been several reports from haematology experience on the safety of shortened (60–90 min) infusion times.95–99 In the context of glucocorticoid use with rituximab, AE due to glucocorticoids also need to be considered.

Infusion-related reactions The tolerability and safety of rituximab has been well described in clinical trials on patients with RA and review articles on non-Hodgkin's lymphoma62 (category III)1 2 18 (category Ia). The most frequent AE are infusion reactions (30–35% with the first infusion with concomitant glucocorticoids). Fewer reactions are observed with the second and subsequent infusions1–3 18 (category Ia). They are usually mild to moderate, but may require therapeutic intervention (additional paracetamol, antihistamines, bronchodilators, eventually glucocorticoids). Severe infusion reactions leading to drug discontinuation are uncommon (<1%) and are mainly restricted to the first infusion (Roche data on file). Their frequency is reduced by the use of concomitant intravenous steroids1–3 (category Ia; www.accessdata.fda.gov/scripts/cder/drugsatfda, www.ema.eu.int/humans/Humans/EPAR/mabthera/mabthera).33 There have been several reports from haematology experience on the safety of shortened (60–90 min) infusion times.95–99 In the context of glucocorticoid use with rituximab, AE due to glucocorticoids also need to be considered. Serious infections Rituximab does not seem to increase the risk of infections in patients with HIV with lymphoma62 100 (category IIb). In the oncology literature, rituximab does not markedly add to the risk of infections induced by chemotherapy; this includes opportunistic infections62 and also herpes zoster infections, although there was one case of disseminated and fatal herpes zoster infection.62 101 In the long-term safety analysis of RA trials18 herpes zoster occurred in 2% of patients (n=49; 0.98 events/100 patient-years) with only one case a serious AE; this rate appears to be similar to the rate seen with TNF inhibitors (1.11 events/100 patient-years).102

f disseminated and fatal herpes zoster infection.62 101 In the long-term safety analysis of RA trials18 herpes zoster occurred in 2% of patients (n=49; 0.98 events/100 patient-years) with only one case a serious AE; this rate appears to be similar to the rate seen with TNF inhibitors (1.11 events/100 patient-years).102 In two clinical trials carried out on patients with RA,2 3 a numerically higher rate of serious infections (but not opportunistic infections, including tuberculosis) was seen in patients receiving rituximab at 2×1000 mg compared with those receiving placebo: 4.7 versus 3.2/100 patient-years in the DANCER study and 5.2 versus 3.7/100 patient-years in the REFLEX study2 3 (category III). In the recent IMAGE study in methotrexate-naive patients, however, serious infections were lower in the two rituximab dosage groups (1000 and 500 mg) compared with placebo (3.74, 4.61 and 6.09 events/100 patient-years, respectively).25 A recent meta-analysis included three RCT and did not observe an increased risk of severe infections in RA patients treated with rituximab compared with placebo.103 Registry data have suggested that serious infections tend to occur in the initial months following rituximab, with predisposing factors comprising age, comorbidity, extra-articular involvement and low IgG.30

t observe an increased risk of severe infections in RA patients treated with rituximab compared with placebo.103 Registry data have suggested that serious infections tend to occur in the initial months following rituximab, with predisposing factors comprising age, comorbidity, extra-articular involvement and low IgG.30 Hepatitis B reactivation has been widely documented in the oncology literature60 62 highlighting the need to pre-screen patients (see the earlier section on ‘Screening before initiating rituximab’ with additional information provided in the supplementary material, available online only). Clinical trials in RA pre-screened patients for hepatitis B and C. Only one case of hepatitis B reactivation in a patient with RA has been reported.52 Although the risk of hepatitis C virus is not as clear54 we would also recommend pre-screening. Management in consultation with an expert gastroenterologist/hepatologist is advised.In the clinical trial safety database, two cases of pulmonary tuberculosis have been reported; these appear to have been de novo infections (information from Roche). Among patients with RA, three cases of tuberculosis and five cases with non-tuberculous mycobacterial infections haven been reported through a survey carried out in the USA and Canada.104 However, patients with records of tuberculosis have been treated with rituximab without any tuberculosis reactivation.30

rom Roche). Among patients with RA, three cases of tuberculosis and five cases with non-tuberculous mycobacterial infections haven been reported through a survey carried out in the USA and Canada.104 However, patients with records of tuberculosis have been treated with rituximab without any tuberculosis reactivation.30 In RA, six cases with progressive multifocal leukoencephalopathy (PML) have been reported (Roche data on file), including one case from the REFLEX trial3 giving an incidence of less than 1:20 000 treated RA patients, compared with PML risks for patients with psoriasis treated with efalizumab (1:400) and patients with Crohn's disease and multiple sclerosis treated with natalizumab (1:1000).105 106 Most PML cases with RA had long-standing disease with numerous previous immunosuppressive treatments; only one patient had early RA naive to methotrexate and other DMARD. Currently, there is no identified risk profile for developing PML. Although the risk seems small, at this stage we would still advise clinicians to maintain vigilance. Additional background information on PML is provided in the supplementary material, available online only.

rly RA naive to methotrexate and other DMARD. Currently, there is no identified risk profile for developing PML. Although the risk seems small, at this stage we would still advise clinicians to maintain vigilance. Additional background information on PML is provided in the supplementary material, available online only. Immunoglobulin levels and infection risk The literature on patients with RA treated with rituximab describes low baseline levels of IgG, including before rituximab administration, as being associated with an increased risk of serious infections—these data come from a registry (hypo-IgG being present at baseline before rituximab in 5% of patients) as well as from compiled data from clinical trials.18 30 In open extension studies, the occurrence of IgG levels below the lower limit of normal under rituximab treatment, especially sustained (≥4 month) IgG below the lower limit, was associated with an increased risk of serious infections18 (data provided by Roche). In general, in addition to more traditional risk factors for infection such as age and concomitant glucocorticoid, patients with low IgG levels particularly need careful observation. Better definition and clarity on the management of low level IgG is still needed; nevertheless, from the data summarised to date, as recommended earlier, IgG should be monitored in patients treated with rituximab, particularly in those who demonstrate low baseline levels, with close monitoring particularly in higher-risk patient groups such as the older patient. The more frequent decreases in IgM, in contrast, have not been associated with increased rates of infections. After 1 year of treatment, levels of IgM were lower in patients receiving 2×1000 mg versus those receiving 2×500 mg (unpublished Roche data).

articularly in higher-risk patient groups such as the older patient. The more frequent decreases in IgM, in contrast, have not been associated with increased rates of infections. After 1 year of treatment, levels of IgM were lower in patients receiving 2×1000 mg versus those receiving 2×500 mg (unpublished Roche data). Malignancy risk Although patients with previous malignancy are usually excluded in clinical trials; so far, no enhanced rates of solid malignancies or lymphoma under rituximab treatment have been observed18 62 (category Ia)107 (category III), with the exception of individuals with T-cell deficiency in HIV infection108 (category III). Therefore, to date, there have been no safety signals regarding malignancies; however, with respect to RA, larger databases on safety data are required before any firm conclusions can be drawn. Haematological side-effects In the oncology literature, late-onset neutrocytopaenia has been reported in up to 8% of patients treated with rituximab monotherapy and combination treatment and may occur up to 1 year after treatment62 (category Ia)100 109–112 (category III). For unknown reasons, this complication is very rare in patients treated for autoimmune diseases. In some patients treatment with granulocyte colony-stimulating factor has been required. A multifactorial aetiology is likely to underlie the blood dyscrasia.

year after treatment62 (category Ia)100 109–112 (category III). For unknown reasons, this complication is very rare in patients treated for autoimmune diseases. In some patients treatment with granulocyte colony-stimulating factor has been required. A multifactorial aetiology is likely to underlie the blood dyscrasia. Human antichimeric antibodies As rituximab is a chimeric antibody, human antichimeric antibodies (HACA) may occur. In the long-term, pooled safety analysis, 11% (273/2578 patients) were HACA positive on at least one visit.18 The rate of infusion reaction with re-treatment was similar in the HACA-positive compared with HACA-negative patients. AE related to HACA are rare, but a case of a severe allergic reaction was reported in which HACA apparently prevented B-cell depletion33 (category IV) (www.accessdata.fda.gov/scripts/cder/drugsatfda, www.ema.eu.int/humans/Humans/EPAR/mabthera/mabthera). The development of HACA does not appear to influence the clinical efficacy of rituximab treatment.113 Long-term safety of rituximab A recent pooled analysis of safety data from the rituximab in combination with methotrexate global clinical trial programme were based on 5013 patient-years of rituximab exposure (n=2578 having received at least one course of rituximab).18 The rate of AE and serious events including infections and serious infections remained stable across several courses.

ta from the rituximab in combination with methotrexate global clinical trial programme were based on 5013 patient-years of rituximab exposure (n=2578 having received at least one course of rituximab).18 The rate of AE and serious events including infections and serious infections remained stable across several courses. Additional aspects to be considered and research agenda It is evident from this document that several areas of future investigation and research are warranted. These are summarised in table 6 but are discussed in detail in the supplementary material, available online only. These relate particularly to mode of action, safety and efficacy issues; with respect to the latter, questions such as optimal dose regimen, direct comparison with other biological agents and indicators for retreatment require appropriate answers. Table 6 Summary of additional clinical and research aspects for future consideration

Additional aspects to be considered and research agenda It is evident from this document that several areas of future investigation and research are warranted. These are summarised in table 6 but are discussed in detail in the supplementary material, available online only. These relate particularly to mode of action, safety and efficacy issues; with respect to the latter, questions such as optimal dose regimen, direct comparison with other biological agents and indicators for retreatment require appropriate answers. Table 6 Summary of additional clinical and research aspects for future consideration Future clinical and research agenda Safety Rituximab in the context of concomitant Milder congestive heart failure (NYHA I–III) Demyelinating disorders (efficacy seen in phase I–II studies of MS/NMO) New-onset malignancy Registry data tuberculosis reactivation Rare serious AE (PML) Parameters associated with infection risk (Ig) Vaccination—minimal interval between vaccine and RTX administration Efficacy Disease groups Connective tissue disorders RA/vasculitis; overlap syndromes Dosage regimen Dose, dosage schedule Different induction and maintenance regimens? Impact of different dosage regimens on structural progression Concomitant medication Alternative DMARD to MTX Timing and initiation of DMARD Combination RTX with other biological agent Flare and retreatment Early signs of flare/reactivation Long-term impact of re-treatment/repeat multiple cycles Translational research Mechanism of action of RTX Biomarkers of response Indicators of re-treatment (B cell/subsets) Switching biological therapies Merit of RTX following initial TNF-i failure compared to alternative TNF-i or other biological agent Pharmacoeconomic analyses DMARD, disease-modifying antirheumatic drug; MS, multiple sclerosis; MTX, methotrexate; NMO, neuromyelitis optica; NYHA, New York Heart Association; PML, progressive multifocal leukoencephalopathy; RA, rheumatoid arthritis; RTX, rituximab; TB, tuberculosis; TNF-i, tumour necrosis factor inhibitor.

macoeconomic analyses DMARD, disease-modifying antirheumatic drug; MS, multiple sclerosis; MTX, methotrexate; NMO, neuromyelitis optica; NYHA, New York Heart Association; PML, progressive multifocal leukoencephalopathy; RA, rheumatoid arthritis; RTX, rituximab; TB, tuberculosis; TNF-i, tumour necrosis factor inhibitor. Conclusion Additional data on rituximab in the management of RA have accumulated since publication of the first consensus statement and have provided further insights into its use (box 1). Benefit in earlier disease has been demonstrated together with novel radiographic information. It is now also firmly established that rituximab is effective primarily in seropositive RA. Recent studies have further supported the efficacy of reduced dosage and different regimens, although more work is needed to establish the optimal strategy. Safety data from rheumatology as well as oncology literature highlight the need for hepatitis screening as well as checking pretreatment immunoglobulin levels to identify patients possibly at greater risk of infection. Data thus far do not indicate the need for routine tuberculosis screening. As with other biological agents, the need for vaccination should be assessed. Safety concerns for very rare events such as PML have emerged. Ongoing evaluations should clarify the remaining open issues and ultimately lead to a more refined application of rituximab therapy. Box 1 Points to consider for treatment with rituximab ▶ Indication ▶  RA with inadequate response to (or intolerance of) TNF inhibitors ▶   Active RA (at least moderate disease activity)

Conclusion Additional data on rituximab in the management of RA have accumulated since publication of the first consensus statement and have provided further insights into its use (box 1). Benefit in earlier disease has been demonstrated together with novel radiographic information. It is now also firmly established that rituximab is effective primarily in seropositive RA. Recent studies have further supported the efficacy of reduced dosage and different regimens, although more work is needed to establish the optimal strategy. Safety data from rheumatology as well as oncology literature highlight the need for hepatitis screening as well as checking pretreatment immunoglobulin levels to identify patients possibly at greater risk of infection. Data thus far do not indicate the need for routine tuberculosis screening. As with other biological agents, the need for vaccination should be assessed. Safety concerns for very rare events such as PML have emerged. Ongoing evaluations should clarify the remaining open issues and ultimately lead to a more refined application of rituximab therapy. Box 1 Points to consider for treatment with rituximab ▶ Indication ▶  RA with inadequate response to (or intolerance of) TNF inhibitors ▶   Active RA (at least moderate disease activity) ▶  Possibly: RA with contraindication to TNF inhibitors (especially lymphoma) and inadequate response to disease-modifying antirheumatic drugs such as methotrexate, particularly given new data on methotrexate-inadequate responder and naive patient groups ▶ Contraindications ▶  Allergy to rituximab

▶   Active RA (at least moderate disease activity) ▶  Possibly: RA with contraindication to TNF inhibitors (especially lymphoma) and inadequate response to disease-modifying antirheumatic drugs such as methotrexate, particularly given new data on methotrexate-inadequate responder and naive patient groups ▶ Contraindications ▶  Allergy to rituximab ▶  Clinically relevant comorbidities, including active infections and severe heart failure (New York Heart Association class IV) ▶  Pregnancy ▶ Pretreatment screening ▶  History and physical examination ▶   Consider possible contraindications ▶   Consider radiograph of the chest ▶  Routine laboratory testing ▶  Immunoglobulin levels ▶  Testing for hepatitis B; consider testing for hepatitis C ▶  Assess necessity of vaccination ▶ Treatment dose and co-medication ▶  Two 1000 mg intravenous infusions separated by 2 weeks (licensed regimen in TNF inhibitor failures) ▶  Two 500 mg intravenous infusions separated by 2 weeks have similar clinical, functional and long-term radiographic efficacy (studied in all populations except TNF inhibitor failures) ▶   100 mg intravenous methylprednisolone or equivalent before infusions ▶  Weekly methotrexate to increase efficacy (if tolerated) ▶   Other DMARD (especially leflunomide) may be used as an alternative ▶ Evaluation and definition of response ▶  Validated composite indices to assess response ▶  Minimum improvement of DAS28 of 1.2 or greater or equivalent measure ▶   Aim for remission (DAS28 <2.6, SDAI ≤3.3 or CDAI ≤2.8) or low disease activity state (DAS28 ≤3.2, simplified disease activity index (SDAI) ≤11, clinical disease activity index (CDAI) ≤10)

▶ Evaluation and definition of response ▶  Validated composite indices to assess response ▶  Minimum improvement of DAS28 of 1.2 or greater or equivalent measure ▶   Aim for remission (DAS28 <2.6, SDAI ≤3.3 or CDAI ≤2.8) or low disease activity state (DAS28 ≤3.2, simplified disease activity index (SDAI) ≤11, clinical disease activity index (CDAI) ≤10) ▶   Aim for improvement in function and quality of life; minimum response is usually achieved in 16 weeks ▶ Repeated treatment ▶  Should be considered in responders after week 16 ▶   Residual active disease (at least low disease activity state, ie, DAS28 ≥>2.6, SDAI >>3.3, CDAI >>2.8) ▶   Reactivation of disease from low disease activity state (increase in DAS28 of >0.6 or equivalent) ▶ Adverse events ▶  Infusion reactions (30–35% after the first infusion; less with the second infusion) ▶   Severe infusion reactions may occur but are rare ▶  Slight increase in infections compared with placebo population, especially in patients with low IgG ▶   Cases of PML have been reported (∼1:20 000) Rituximab Consensus Expert Committee Jordi Carbonell Abello (Spain), Marwan Bukhari (UK), Harald Burkhardt (Germany), Bernard Combe (France), Juan-Jesus Gomez-Reino Carnota (Spain), Leonor Barile Fabris (Mexico), Lars Klareskog (Sweden), Jose Luis Marenco de la Fuente (Spain), Carlo-Maurizio Montecucco (Italy), Mikkel Ostergaard (Denmark), Eliseo Pascual Gomez (Spain), Raimon Sanmarti Sala (Spain), Hans-Peter Tony (Germany), Guido Valesini (Italy), Jaap van Laar (UK), Piet van Riel (The Netherlands).

nor Barile Fabris (Mexico), Lars Klareskog (Sweden), Jose Luis Marenco de la Fuente (Spain), Carlo-Maurizio Montecucco (Italy), Mikkel Ostergaard (Denmark), Eliseo Pascual Gomez (Spain), Raimon Sanmarti Sala (Spain), Hans-Peter Tony (Germany), Guido Valesini (Italy), Jaap van Laar (UK), Piet van Riel (The Netherlands). Funding Hoffmann-La Roche provided an unrestricted educational grant to facilitate the development of this document. The views expressed in this guidance document including the final recommendations were not influenced by the sponsor and no representative of the sponsor was present in any of the discussion sessions. Competing interests All participants except the patient representative have been active on advisory boards or participated in clinical trials by the sponsor. Provenance and peer review Not commissioned; externally peer reviewed.

Introduction The long-term prognosis of rheumatoid arthritis (RA) has improved dramatically following the introduction of highly effective medications, such as methotrexate leflunomide and biological agents,1 2 and as the result of close monitoring and regular adjustment of treatment to the targets of low disease activity or remission.3 However, comorbidities may shorten the life span of patients with RA.4–6 This higher death rate appears to be the consequence of an increased prevalence of cardiovascular disease, a greater incidence of infections, and the development of certain malignancies in patients with RA.7–11 Also, osteoporotic fractures are more commonly observed in patients with RA and significantly affect the prognosis for functional decline.12 13 In addition, RA patients with more comorbidities experience greater functional impairment.14 Some of these comorbidities are observed more often among RA patients because of the medications with which they are treated, especially glucocorticoids,10 and because of traditional risk factors, such as tobacco smoking.15 However, chronically active inflammation also predisposes to the development of these comorbidities.16

f these comorbidities are observed more often among RA patients because of the medications with which they are treated, especially glucocorticoids,10 and because of traditional risk factors, such as tobacco smoking.15 However, chronically active inflammation also predisposes to the development of these comorbidities.16 Unfortunately, comorbidities are not well managed in RA patients.17–20 To address this disparity, the European League Against Rheumatism (EULAR) proposed specific recommendations for detecting and managing specific comorbidities and preventing their development when possible. These include recommendations that all patients with RA should be vaccinated against influenza every year and against pneumococci every 5 years21 and should be evaluated for cardiovascular risk annually. Because chronically active inflammation contributes to the development of cardiovascular disease, these recommendations suggest that the cardiovascular risk score be multiplied by a factor of 1.5 when two of the following three criteria are met: (1) disease duration longer than 10 years; (2) presence of circulating rheumatoid factor or anti-citrullinated protein antibodies; (3) presence of extra-articular manifestations.22

commendations suggest that the cardiovascular risk score be multiplied by a factor of 1.5 when two of the following three criteria are met: (1) disease duration longer than 10 years; (2) presence of circulating rheumatoid factor or anti-citrullinated protein antibodies; (3) presence of extra-articular manifestations.22 The COMORA (COMOrbidities in Rheumatoid Arthritis) Study had two major objectives. The first was to evaluate variability in the prevalence of comorbidities and their risk factors between participating countries. The second was to assess whether there is a disparity between existing national recommendations and the actions implemented in daily clinical practice to detect and prevent the development of these comorbidities. Patients and methods Study design This was a cross-sectional, observational, multicentre, international study. Patient recruitment The scientific committee chose national principal investigators for this study. Their task was to select rheumatologists who would be representative of their country and to conduct the study in accordance with good clinical practice. The protocol was reviewed and approved by all local institutional review boards or ethics committees. Consecutive patients visiting the participating rheumatologists were invited to enrol in the study if they were at least 18 years of age, fulfilled the 1987 American College of Rheumatology classification criteria for RA,23 and were able to understand and complete the questionnaires that were administered. Written informed consent was obtained from all subjects before enrolment.

ts were invited to enrol in the study if they were at least 18 years of age, fulfilled the 1987 American College of Rheumatology classification criteria for RA,23 and were able to understand and complete the questionnaires that were administered. Written informed consent was obtained from all subjects before enrolment. Sample size The sample size calculation was based on the precision (width) of the 95% CI of the proportions of expected events (eg, prevalence of each comorbidity). For example, it was calculated that a sample of 4000 patients would allow the 35% prevalence of a given comorbidity, X, to be estimated with a precision of 1.5% (95% CI 33.5% to 36.5%), or the 1% prevalence of another comorbidity, Y, to be estimated with a precision of 0.3% (95% CI 0.7% to 1.3%). Investigators in each participating country were expected to enrol at least 200 patients.

Sample size The sample size calculation was based on the precision (width) of the 95% CI of the proportions of expected events (eg, prevalence of each comorbidity). For example, it was calculated that a sample of 4000 patients would allow the 35% prevalence of a given comorbidity, X, to be estimated with a precision of 1.5% (95% CI 33.5% to 36.5%), or the 1% prevalence of another comorbidity, Y, to be estimated with a precision of 0.3% (95% CI 0.7% to 1.3%). Investigators in each participating country were expected to enrol at least 200 patients. Data collected A case report form specifically created for this study was used to collect four categories of data. Characteristics of demographics and the disease. Patients’ demographic characteristics included: age, gender, body mass index, smoking status, alcohol intake, marital status, socioeconomic status and highest level of education completed. Disease activity was assessed using the DAS28 (Disease Activity Score using 28 joints)–erythrocyte sedimentation rate (ESR)24 and the C-reactive protein level. Disease severity was evaluated from the history of joint surgery to address structural damage caused by RA (eg, total joint arthroplasty, arthrodesis, metacarpophalangeal or metatarsophalangeal joint resections). Past and current medications used to treat RA were also recorded, including non-steroidal anti-inflammatory drugs, corticosteroids and conventional and biological disease-modifying anti-rheumatic drugs (DMARDs).

RA (eg, total joint arthroplasty, arthrodesis, metacarpophalangeal or metatarsophalangeal joint resections). Past and current medications used to treat RA were also recorded, including non-steroidal anti-inflammatory drugs, corticosteroids and conventional and biological disease-modifying anti-rheumatic drugs (DMARDs). History or current evidence of comorbidities. Ischaemic cardiovascular disease (myocardial infarction, stroke), cancers (colon, skin, lung, breast and uterus for women, prostate for men) and lymphoma, gastrointestinal diseases (diverticulitis, ulcers), infections (hepatitis), lung disease (chronic obstructive pulmonary disease (COPD), asthma) and psychiatric disorders (depression). Coexisting risk factors. Risk factors for cardiovascular diseases (hypertension, diabetes, dyslipidaemia, family history of myocardial infarction or sudden death), risk factors for infectious diseases and vaccination status, risk factors for cancers (family history of prostate, breast or colon cancer; adenomatosus polyposis and/or personal history of inflammatory bowel disease (for colon cancer) and history of numerous (>40) nevi for skin cancer). Compliance with current national recommendations regarding management (prevention, detection and treatment) of these comorbidities. For example, annual estimation of cardiovascular risk. For each patient, information was gathered by a study investigator during a face-to-face interview at a dedicated study visit and through review of the medical record.

Compliance with current national recommendations regarding management (prevention, detection and treatment) of these comorbidities. For example, annual estimation of cardiovascular risk. For each patient, information was gathered by a study investigator during a face-to-face interview at a dedicated study visit and through review of the medical record. Data analysis The first step of the analysis was to describe the baseline characteristics of the enrolled patients, by country, including the prevalence of each comorbidity and associated disease risk factors (% and 95% CI). To estimate any disparity that might exist between published recommendations and daily clinical practice in the prevention, detection and management of these comorbidities, the percentage of patients monitored and managed according to national guidelines was calculated. The definition of ‘optimal’ management for the evaluated comorbidities was primarily based on recommendations made by international scientific societies17 18 and/or national healthcare systems25 and/or the recommendations of the French Society of Rheumatology to prevent, detect and control comorbidities in patients with inflammatory rheumatic diseases.26

nt for the evaluated comorbidities was primarily based on recommendations made by international scientific societies17 18 and/or national healthcare systems25 and/or the recommendations of the French Society of Rheumatology to prevent, detect and control comorbidities in patients with inflammatory rheumatic diseases.26 For cardiovascular diseases, a patient was considered to be optimally monitored when risk factors for cardiovascular events (eg, blood pressure, blood glucose level, low-density lipoprotein (LDL) cholesterol level) were evaluated annually. Patients older than 50 years were considered to be managed optimally if they were receiving an antithrombotic drug, in the setting of a past thrombotic cardiovascular event, or if their Framingham Risk Score27 was calculated to be 20% or more above the upper limit of normal after being adjusted for RA (multiplied by a factor of 1.5), in the presence of specific RA characteristics.22 Finally, we evaluated the proportion of patients in whom the systematic evaluation of risk factors for cardiovascular diseases during the conduct of the study detected hypertension (eg, systolic pressure >140 mm Hg or diastolic pressure >80 mm Hg or >130 mm Hg and 70 mm Hg, respectively, in the setting of concomitant diabetes mellitus26), elevated LDL cholesterol (above the targeted value defined with regard to the number of concomitant additional cardiovascular risk factors28) and hyperglycaemia (random blood glucose level >1.26 g/L28).

olic pressure >80 mm Hg or >130 mm Hg and 70 mm Hg, respectively, in the setting of concomitant diabetes mellitus26), elevated LDL cholesterol (above the targeted value defined with regard to the number of concomitant additional cardiovascular risk factors28) and hyperglycaemia (random blood glucose level >1.26 g/L28). A patient was considered to be monitored optimally for infectious diseases if he or she had had (1) a dental examination within the previous year, (2) an influenza vaccination within the previous year, and (3) a pneumococcal vaccination within the previous 5 years.

olic pressure >80 mm Hg or >130 mm Hg and 70 mm Hg, respectively, in the setting of concomitant diabetes mellitus26), elevated LDL cholesterol (above the targeted value defined with regard to the number of concomitant additional cardiovascular risk factors28) and hyperglycaemia (random blood glucose level >1.26 g/L28). A patient was considered to be monitored optimally for infectious diseases if he or she had had (1) a dental examination within the previous year, (2) an influenza vaccination within the previous year, and (3) a pneumococcal vaccination within the previous 5 years. A patient was considered to be monitored optimally for cancer if age- and sex-appropriate cancer screening recommendations for the general population were followed. A male patient without known prostate cancer was considered to have been screened optimally for prostate cancer if a digital rectal examination and prostate-specific antigen (PSA) level had been performed between the ages of 50 and 75 years (or between the ages of 45 and 75 years for patients of African ancestry) or with at least two first-degree relatives who had prostate cancer. Subsequently, this evaluation had to have been repeated every 3 years for those with PSA <1 ng/mL and annually for those with PSA between 1 and 4 ng/mL. For men with PSA >4 ng/mL, evaluation by an urologist was required for the patient to be considered to have been monitored optimally.28 For breast cancer detection, a woman between the ages of 50 and 74 years without known breast cancer was considered to have been screened optimally if a mammogram had been performed within 2 years of the study visit.28 For uterine cancer detection, a woman between the ages of 25 and 65 years without known uterine cancer was considered to have been monitored optimally if a Papanicolaou smear of the cervix had been performed within 3 years of the study visit.28 For colon cancer screening, a patient over 50 years old without known colon cancer was considered to have been optimally monitored if stool had been tested for occult blood and at least one colonoscopy had been performed.

ally if a Papanicolaou smear of the cervix had been performed within 3 years of the study visit.28 For colon cancer screening, a patient over 50 years old without known colon cancer was considered to have been optimally monitored if stool had been tested for occult blood and at least one colonoscopy had been performed. For those patients at high risk of developing colon cancer (eg, those with inflammatory bowel disease or with at least two first-degree relatives who had colon or rectal cancer or at least one first-degree relative with adenomatous polyposis or with Lynch syndrome), a colonoscopy had to have been performed in the 2 years before the study visit for a patient to be considered to have been optimally monitored.28 For skin cancer detection, a patient was considered to be optimally monitored if he or she had been examined at least once by a dermatologist; if more than 40 nevi were present, annual evaluation by a dermatologist was required for optimal monitoring.28 For lung cancer screening, a patient was considered to have been monitored optimally if a chest radiograph had been performed after the onset of RA.26 A patient was considered to have been screened optimally for osteoporosis if at least one bone densitometry study had been performed after the onset of RA and if he or she was taking vitamin D supplementation at the time of the study visit.26

For those patients at high risk of developing colon cancer (eg, those with inflammatory bowel disease or with at least two first-degree relatives who had colon or rectal cancer or at least one first-degree relative with adenomatous polyposis or with Lynch syndrome), a colonoscopy had to have been performed in the 2 years before the study visit for a patient to be considered to have been optimally monitored.28 For skin cancer detection, a patient was considered to be optimally monitored if he or she had been examined at least once by a dermatologist; if more than 40 nevi were present, annual evaluation by a dermatologist was required for optimal monitoring.28 For lung cancer screening, a patient was considered to have been monitored optimally if a chest radiograph had been performed after the onset of RA.26 A patient was considered to have been screened optimally for osteoporosis if at least one bone densitometry study had been performed after the onset of RA and if he or she was taking vitamin D supplementation at the time of the study visit.26 Results Patients and study course A total of 4586 patients were recruited by investigators in the 17 participating countries between 2011 and 2012. Because a disproportionately high number of subjects were enrolled in South Korea (n=1052) compared with each of the other 16 countries, 400 patients from South Korea were randomly selected for inclusion in the analysis. Fourteen patients from a single centre were excluded from the current analysis because of too many missing data, leaving a total of 3920 patients for further evaluation.

South Korea (n=1052) compared with each of the other 16 countries, 400 patients from South Korea were randomly selected for inclusion in the analysis. Fourteen patients from a single centre were excluded from the current analysis because of too many missing data, leaving a total of 3920 patients for further evaluation. The baseline characteristics are summarised in table 1. There was enormous intercountry variability for some characteristics: patients in North Africa tended to have more active and more severe disease, and fewer patients in some South American countries had been treated with biological agents. Detailed comparisons of the baseline characteristics for each individual country are provided in online supplementary tables S1 and S2. Table 1 Baseline patient and disease characteristics of the 3920 analysed patients enrolled in the COMORA Study

The baseline characteristics are summarised in table 1. There was enormous intercountry variability for some characteristics: patients in North Africa tended to have more active and more severe disease, and fewer patients in some South American countries had been treated with biological agents. Detailed comparisons of the baseline characteristics for each individual country are provided in online supplementary tables S1 and S2. Table 1 Baseline patient and disease characteristics of the 3920 analysed patients enrolled in the COMORA Study Variable Results Global results Extremes (countries) Number 3920 From 30 (Uruguay) to 411 (France) Female gender (%) 81.7 From 66 (Netherlands) to 91 (Venezuela) Age (years), mean±SD 56±13 From 48 (Morocco/Egypt) to 63 (Japan) Smoking status (% current smokers) 13.2 From 0.9 (Morocco) to 48 (Austria) Educational level (% university or graduate school) 24.5 From 5.3 (Italy) to 75 (Netherlands) Marital status (% married) 69.7 From 50 (Venezuela) to 86 (Netherlands) BMI (% overweight or obese) 50.7 From 0 (Netherlands) to 69 (USA) Work status (% currently employed) 31.4 From 16 (Morocco) to 46 (USA) Disease duration (years), mean±SD 9.6±8.7 From 7 (Morocco) to 14 (France) DAS28–ESR, mean±SD 3.7±1.6 From 2.6 (Netherlands) to 5.3 ( Egypt) HAQ, mean±SD 1.0±0.7 From 0.7 (Taiwan) to 1.5 (Morocco) Prednisone (% currently taking) 54.3 From 9 (UK) to 82 (Morocco) NSAID use (% having taken dose during previous 3 months) 55.2 From 25 (Morocco) to 94 (Taiwan) MTX (% ever treated) 88.6 From 79 (Italy) to 98 (UK) Any biological therapy (% ever treated) 38.9 From 3 (Uruguay) to 77 (UK) BMI, body mass index; DAS28–ESR, Disease Activity Score using 28 joints–erythrocyte sedimentation rate; HAQ, Health Assessment Questionnaire; MTX, methotrexate; NSAID, non-steroidal anti-inflammatory drug.

treated) 88.6 From 79 (Italy) to 98 (UK) Any biological therapy (% ever treated) 38.9 From 3 (Uruguay) to 77 (UK) BMI, body mass index; DAS28–ESR, Disease Activity Score using 28 joints–erythrocyte sedimentation rate; HAQ, Health Assessment Questionnaire; MTX, methotrexate; NSAID, non-steroidal anti-inflammatory drug. Prevalence of comorbidities The prevalence of those comorbidities that were evaluated is depicted in figure 1. Depression (past or current symptoms) was the most commonly observed comorbidity (mean 15.0%, 95% CI 13.8% to 16.1%); however, the prevalence of depression varied widely among countries (from 2% in Morocco to 33% in the USA). Figure 1 Prevalence of evaluated comorbidities in the 3920 patients with rheumatoid arthritis. COPD, chronic obstructive pulmonary disease.

Prevalence of comorbidities The prevalence of those comorbidities that were evaluated is depicted in figure 1. Depression (past or current symptoms) was the most commonly observed comorbidity (mean 15.0%, 95% CI 13.8% to 16.1%); however, the prevalence of depression varied widely among countries (from 2% in Morocco to 33% in the USA). Figure 1 Prevalence of evaluated comorbidities in the 3920 patients with rheumatoid arthritis. COPD, chronic obstructive pulmonary disease. There was a history of ischaemic cardiovascular disease (myocardial infarction or stroke) in 6.0% (95% CI 5.3% to 6.8%) of the patients. This prevalence ranged from a low of 1% in Morocco to a high of 17% in Hungary. A history of any solid tumour, excluding basal cell skin cancers, was found in 4.5% (95% CI 3.9% to 5.2%) of the patients and ranged from a low of 0.3% in Egypt to a high of 12.5% in the USA). Hepatitis B infection was observed more frequently in Italy (9%) and Taiwan (7%) than in other countries (2.8% (95% CI 2.3% to 3.3%)). The prevalence of hepatitis C infection was highest in Italy (6.6%), Egypt (6.8%) and Taiwan (4.8%). The overall prevalence of past or present gastrointestinal ulcer was 10.8% (95% CI 9.8% to 11.8%). This ranged from a low of 1% in Morocco to a high of 22% in Egypt. Episodes of diverticulitis that had required surgical intervention were rarely observed (0.4% (95% CI 0.2% to 0.6%)). Pulmonary diseases, especially COPD, were observed less commonly in Asian countries (Japan, 1.4%; Korea, 1.3%; Taiwan, 0.3%) than in European countries or the USA (Hungary, 8.0%; USA, 7.5%). Detailed listings by country of the prevalence of the various comorbidities, grouped by category, are presented in online supplementary tables S3–S7.

especially COPD, were observed less commonly in Asian countries (Japan, 1.4%; Korea, 1.3%; Taiwan, 0.3%) than in European countries or the USA (Hungary, 8.0%; USA, 7.5%). Detailed listings by country of the prevalence of the various comorbidities, grouped by category, are presented in online supplementary tables S3–S7. Prevalence of risk factors for comorbidities The prevalence of various risk factors for cardiovascular disease and several malignancies is depicted in figure 2. As might be expected, given the increased prevalence of cardiovascular disease associated with RA, the most prevalent risk factors were those that predispose to cardiovascular disease, such as increased Framingham Risk Score (42.8% (95% CI 41.2% to 44.3%)), hypertension (40.4% (95% CI 38.9% to 41.9%)) and hypercholesterolaemia (31.7% (95% CI 30.3% to 33.2%)). As with the prevalence of comorbidities, there was considerable intercountry variability in the prevalence of risk factors. For example, the prevalence of smoking ranged from 3% in Morocco to 48% in Austria. Detailed listings by country of the prevalence of the various risk factors, grouped by comorbidity, are presented in online supplementary tables S8 and S9. Figure 2 Prevalence of risk factors for cardiovascular and cancer diseases in the 3920 patients with rheumatoid arthritis. IBD, inflammatory bowel disease.

Prevalence of risk factors for comorbidities The prevalence of various risk factors for cardiovascular disease and several malignancies is depicted in figure 2. As might be expected, given the increased prevalence of cardiovascular disease associated with RA, the most prevalent risk factors were those that predispose to cardiovascular disease, such as increased Framingham Risk Score (42.8% (95% CI 41.2% to 44.3%)), hypertension (40.4% (95% CI 38.9% to 41.9%)) and hypercholesterolaemia (31.7% (95% CI 30.3% to 33.2%)). As with the prevalence of comorbidities, there was considerable intercountry variability in the prevalence of risk factors. For example, the prevalence of smoking ranged from 3% in Morocco to 48% in Austria. Detailed listings by country of the prevalence of the various risk factors, grouped by comorbidity, are presented in online supplementary tables S8 and S9. Figure 2 Prevalence of risk factors for cardiovascular and cancer diseases in the 3920 patients with rheumatoid arthritis. IBD, inflammatory bowel disease. Management of comorbidities Cardiovascular diseases Annual evaluation of cardiovascular risk, including measurement of blood pressure, total serum cholesterol (high-density lipoprotein (HDL) and LDL), blood glucose and serum creatinine, was performed in 59.4% (95% CI 57.9% to 60.9%) of the patients. Of the 236 patients who had a prior myocardial infarction or stroke, 162 (68.6%) were currently receiving an antithrombotic drug, but 74 (31.4%) were not. Among the other 3684 patients who had no history of myocardial infarction or stroke, 366 would appropriately have been given prophylactic antithrombotic drug treatment because they were older than 50 years and had a calculated Framingham Risk Score above 20%; however, of these, 299 were not receiving any antithrombotic agent. Thus, 373 (9.5%) of the total number of patients enrolled in this study should have been treated with antithrombotic drug prophylaxis, but were not being managed optimally to prevent cardiovascular events (figure 3).

ed Framingham Risk Score above 20%; however, of these, 299 were not receiving any antithrombotic agent. Thus, 373 (9.5%) of the total number of patients enrolled in this study should have been treated with antithrombotic drug prophylaxis, but were not being managed optimally to prevent cardiovascular events (figure 3). Figure 3 Percentage of patients optimally monitored with respect to some comorbidities. Vit.D suppl., vitamin D supplementation. The systematic assessment of certain cardiovascular risk factors in this study allowed their detection in previously undiagnosed patients. Among the 2489 patients without known hypertension, elevated blood pressure was detected in 454 (18%). An elevated blood glucose level was detected in 131 (3.7%) of the 3522 patients without previously diagnosed diabetes mellitus. An LDL cholesterol level above the optimal target was detected in 325 (11.0%) of the 2966 patients not previously diagnosed to have a dyslipidaemia or not receiving lipid-lowering therapy.

%). An elevated blood glucose level was detected in 131 (3.7%) of the 3522 patients without previously diagnosed diabetes mellitus. An LDL cholesterol level above the optimal target was detected in 325 (11.0%) of the 2966 patients not previously diagnosed to have a dyslipidaemia or not receiving lipid-lowering therapy. Infectious diseases During the year before the study visit, 42.3% (95% CI 40.8% to 43.9%) of all 3920 enrolled patients had undergone a dental examination. However, fewer patients were vaccinated in accordance with current recommendations: an influenza vaccination had been performed during the year before the study visit in only 938 (25.3% (95% CI 23.9% to 26.7%)) of the patients and a pneumococcal vaccination had been performed within 5 years of the study visit in only 636 (17.2% (95% CI 16.0% to 18.4%)) of the patients. Both an influenza and a pneumococcal vaccination were performed according to current recommendations in only 316 (10.3% (95% CI 9.3% to 11.4%)) of the patients. Cancers Optimal screening for malignancies, according to recommended guidelines, was performed in only 909 (23.9%) of the patients for skin cancers, 608 (26.7%) of the patients for colon cancer, 202 (38.2%) of the patients for prostate cancer, 938 (51.5%) of the patients for breast cancer, and 1383 (59.3%) of the patients for uterine cancer.

ng for malignancies, according to recommended guidelines, was performed in only 909 (23.9%) of the patients for skin cancers, 608 (26.7%) of the patients for colon cancer, 202 (38.2%) of the patients for prostate cancer, 938 (51.5%) of the patients for breast cancer, and 1383 (59.3%) of the patients for uterine cancer. Osteoporosis Bone densitometry had been performed at least once in 2281 (58.2% (95% CI 56.6% to 59.7%)) of the 3920 patients. Of all enrolled patients, 1733 (44.4% (95% CI 42.9% to 46.0%)) were receiving vitamin D supplementation at the time of the study visit. Detailed listings by country of the percentage of patients optimally monitored for cardiovascular, infectious and cancer diseases are presented in online supplementary tables S10–S12. Discussion This is the first population-based, cross-sectional observational study to assess multiple comorbidities and their management among a relatively large sample of patients with RA who were enrolled by rheumatologists in 17 participating countries on five different continents. This study confirms not only the relatively high prevalence of comorbidities among patients with RA, but also considerable intercountry variability in the prevalence of these comorbidities.29 It demonstrates that, at present, the management of comorbidities in patients with RA is far from optimal. As in this study, the systematic evaluation of RA patients for evidence of comorbidities may uncover previously undiagnosed conditions in some patients.

ntry variability in the prevalence of these comorbidities.29 It demonstrates that, at present, the management of comorbidities in patients with RA is far from optimal. As in this study, the systematic evaluation of RA patients for evidence of comorbidities may uncover previously undiagnosed conditions in some patients. An important aim of this study was to evaluate the gap between current recommendations for detecting, managing and preventing comorbidities and their implementation in observed daily practice. To accomplish this objective, the scientific committee for the study created an a priori definition of optimal monitoring based largely on current recommendations provided by various international medical organisations. The optimal LDL cholesterol level on which the analysis of this study was based is that currently recommended by the French Ministry of Health,28 and this standard was applied to all study subjects in all participating countries regardless of local recommendations. However, for comorbidities such as cardiovascular disease, definitions were country-specific, and recommendations for monitoring or prevention varied slightly between participating countries. For example, the indication for initiation of antithrombotic drug prophylaxis was a history of a prior cardiovascular event in some countries and a >20% risk of experiencing a cardiovascular event based on the Framingham Risk Score in others.27 Had this study used other standards for the detection, management and prevention of comorbidities,30 31 it might have found slightly different proportions. Regardless, this study demonstrates that compliance with recommended strategies is far from perfect and that this varies significantly among countries.

in others.27 Had this study used other standards for the detection, management and prevention of comorbidities,30 31 it might have found slightly different proportions. Regardless, this study demonstrates that compliance with recommended strategies is far from perfect and that this varies significantly among countries. Although this study has numerous strengths, it also has several weaknesses. The comorbidities evaluated were selected for the study by the scientific committee and were not all-inclusive; some important comorbidities, such as tuberculosis, were not among those assessed. Despite the principal investigators in each country having been instructed to recruit rheumatologists working in different practice settings to enrol RA patients, it cannot be guaranteed that the prevalent cohort of 3920 patients studied here were fully representative of all RA patients in the participating countries. The study did not enrol RA patients from general practices who were not under the care of a rheumatologist. Moreover, some of the intercountry variability in the degree of RA disease activity observed in this study might reflect differences in the reason for which the patient was visiting the rheumatologist at the time of study participation: in some countries, patients are evaluated routinely even when their RA is under good control, whereas, in other countries, patients go to see their rheumatologist only when they experience a flare of disease activity. Also, cultural differences among patients recruited from different countries might lead to diverse interpretations of questions included in the questionnaire. Varied interpretation of the term ‘depression’ by subjects in different countries could account, in part, for the wide differences observed across countries in the prevalence of depression.

mong patients recruited from different countries might lead to diverse interpretations of questions included in the questionnaire. Varied interpretation of the term ‘depression’ by subjects in different countries could account, in part, for the wide differences observed across countries in the prevalence of depression. Several different types of bias are inherent in a prevalent cohort study of a chronic disease. The prevalence of some comorbidities might be overestimated because of diagnostic bias, in that patients with RA may more likely be offered screening for recognised comorbidities, or because of reporting bias, in that RA patients may more likely be diagnosed with comorbidities known to be associated with this inflammatory disease. The prevalence of other comorbidities might be underestimated because of truncation bias, in that RA patients with potentially life-threatening comorbidities may have been lost from the population before the cohort was enrolled. These biases may produce diverse effects in different countries. The lack of a comparator group without RA did not allow comparison in this study between the observed prevalence of comorbidities and their optimal management among RA patients with that in the general population or among patients with another disease state.

se biases may produce diverse effects in different countries. The lack of a comparator group without RA did not allow comparison in this study between the observed prevalence of comorbidities and their optimal management among RA patients with that in the general population or among patients with another disease state. This study achieved its main objective, which was to evaluate and demonstrate intercountry variation in the detection, management and prevention of comorbidities among RA patients. It shows clear differences in the prevalence of certain risk factors, which might influence national policies regarding prevention strategies. For example, the high prevalence of tobacco smoking found among RA patients in the Netherlands (41.2%) and Austria (47.5%) might prompt targeted programmes to reduce this behaviour, which clearly predisposes not only to the development of RA,32 but also to cardiovascular disease33 and lung cancer,34 both of which are also significant comorbidities of RA. Other studies that have compared the prevalence of comorbidities among RA patients with those in the general population have shown a higher prevalence of cardiovascular events,8 infections,10 11 osteoporotic fractures12 and lung cancer14 among RA patients. Nevertheless, the relatively large sample of RA patients who were enrolled from 17 countries on various continents allowed the present study to confirm the high prevalence of hepatitis in Asian35 36 and southern European countries37 and in Egypt.38 39

,10 11 osteoporotic fractures12 and lung cancer14 among RA patients. Nevertheless, the relatively large sample of RA patients who were enrolled from 17 countries on various continents allowed the present study to confirm the high prevalence of hepatitis in Asian35 36 and southern European countries37 and in Egypt.38 39 This study confirms the observation that monitoring of RA patients for cardiovascular risk is suboptimal19 40–42 and extends this assumption to other comorbidities. Moreover, it demonstrates that systematic assessment of RA patients for comorbidities facilitates the detection of abnormalities such as elevated blood pressure, hyperglycaemia and hypercholesterolaemia. These findings are in agreement with those of previous studies that suggested that cardiovascular risk factors are not optimally monitored and managed in 30–50% of RA patients.40 41

ts for comorbidities facilitates the detection of abnormalities such as elevated blood pressure, hyperglycaemia and hypercholesterolaemia. These findings are in agreement with those of previous studies that suggested that cardiovascular risk factors are not optimally monitored and managed in 30–50% of RA patients.40 41 Given the findings of the present study, the question arises as to how best to improve this situation. The treating rheumatologist should consider the periodic assessment of comorbidities as one of the tasks involved in treating a patient with RA. This should be carried out in collaboration with primary care providers and other specialists who are involved in the care of these patients. However, the increasing complexity of managing treatment of RA with effective combinations of traditional and biological DMARDs in the setting of progressively decreasing amounts of time available for direct interaction with the patient makes this additional responsibility challenging. The development and implementation of standardised programmes to detect, manage and prevent comorbidities in daily clinical practice, working in partnership with other healthcare providers such as nurses,42 43 might greatly facilitate the identification of and intervention to reduce the prevalence of comorbidities among patients with RA. Supplementary Material Web tables Correction notice: This article has been corrected since it was published Online First. The affiliations have been corrected. The authors would like to thank all patients and investigators who participated in this study.

Given the findings of the present study, the question arises as to how best to improve this situation. The treating rheumatologist should consider the periodic assessment of comorbidities as one of the tasks involved in treating a patient with RA. This should be carried out in collaboration with primary care providers and other specialists who are involved in the care of these patients. However, the increasing complexity of managing treatment of RA with effective combinations of traditional and biological DMARDs in the setting of progressively decreasing amounts of time available for direct interaction with the patient makes this additional responsibility challenging. The development and implementation of standardised programmes to detect, manage and prevent comorbidities in daily clinical practice, working in partnership with other healthcare providers such as nurses,42 43 might greatly facilitate the identification of and intervention to reduce the prevalence of comorbidities among patients with RA. Supplementary Material Web tables Correction notice: This article has been corrected since it was published Online First. The affiliations have been corrected. The authors would like to thank all patients and investigators who participated in this study. Contributors: MD was the principal investigator for the study. Authors and study investigators gathered the data and interpreted the data. All authors reviewed and approved the report before submission. MD had full access to all of the data and had final responsibility for the decision to submit the manuscript for publication.

tors: MD was the principal investigator for the study. Authors and study investigators gathered the data and interpreted the data. All authors reviewed and approved the report before submission. MD had full access to all of the data and had final responsibility for the decision to submit the manuscript for publication. Funding: This study was conducted with the support of an unrestricted grant from Roche Ltd. Competing interests: None. Patient consent: Obtained. Ethics approval: Each appropriate body in the 17 participating countries. Provenance and peer review: Not commissioned; externally peer reviewed.

Introduction Recommendations from the Ankylosing Spondylitis Assessment Study (ASAS)/European League Against Rheumatism (EULAR) for the management of ankylosing spondylitis (AS)1 and from EULAR for the management of psoriatic arthritis (PsA)2 are to monitor the disease,1 2 adjust treatment appropriately,2 and adapt the frequency of monitoring depending on the course and severity of the disease.1 However, no evidence that a guided treatment strategy is as effective for AS and PsA as it is for rheumatoid arthritis (RA)3 has yet been established. This is partly due to the heterogeneity of the presentations of these and related diseases, which some would group under the broader term, spondyloarthritis (SpA). In fact, it has been suggested that the terms axial SpA and peripheral SpA could be considered rather than the traditional names.4 To address this issue, an international panel of expert rheumatologists and patients convened to discuss recommendations on a ‘treat-to-target’ (T2T) concept for SpA. In line with respective recommendations by EULAR,5 a systematic literature review of the current state of evidence was deemed necessary. In the following, we present this systematic literature review, which served as the background for generating the recommendations document.6

a ‘treat-to-target’ (T2T) concept for SpA. In line with respective recommendations by EULAR,5 a systematic literature review of the current state of evidence was deemed necessary. In the following, we present this systematic literature review, which served as the background for generating the recommendations document.6 Methods We performed a systematic literature search of the Medline, Embase and Cochrane databases. This search was based on a PICO (population, intervention, control and outcome) strategy and search terms developed in the course of discussions of the task force's steering committee. Box 1 shows the PICO strategy, and online supplementary table S1 lists the search terms. Box 1 PICO strategy Population: adult patients with axial or peripheral SpA or psoriasis Intervention: targeted use of NSAIDs, synthetic DMARDs or biologicals Control: routine treatment Outcome: the applied definition of a therapeutic target; parameters of disease activity that serve as surrogates for clinical, functional or radiographic success Design: ‘strategy trial’: interventional, prescheduled therapeutic adaptation; RCT, open-label controlled, or single-arm study Duration: any given follow-up Excluded: DX: degenerative and dialysis-associated SpA, psoriasis, spondylodiscitis TX: intervention other than drugs (surgery, physiotherapy, balneotherapy, hydrotherapy, exercise, radon, cryotherapy, mud bath), excluded drugs (bisphosphonates, antidepressants, complementary and alternative medicine (CAM)) and excluded applications (intra-articular injections, intravascular steroids)

Excluded: DX: degenerative and dialysis-associated SpA, psoriasis, spondylodiscitis TX: intervention other than drugs (surgery, physiotherapy, balneotherapy, hydrotherapy, exercise, radon, cryotherapy, mud bath), excluded drugs (bisphosphonates, antidepressants, complementary and alternative medicine (CAM)) and excluded applications (intra-articular injections, intravascular steroids) Study setting: non-interventional (ie, observational/retrospective) Publication form: letters, editorials, narrative reviews CAM, ; DMARD, disease-modifying antirheumatic drug; DX, diagnosis; NSAID, non-steroidal anti-inflammatory drug; RCT, randomised controlled trial; PICO, population, intervention, control, outcome; SpA, spondyloarthritis; TX, treatment.

Study setting: non-interventional (ie, observational/retrospective) Publication form: letters, editorials, narrative reviews CAM, ; DMARD, disease-modifying antirheumatic drug; DX, diagnosis; NSAID, non-steroidal anti-inflammatory drug; RCT, randomised controlled trial; PICO, population, intervention, control, outcome; SpA, spondyloarthritis; TX, treatment. We retrieved publications from each database's inception to September 2011. We also screened 2010 and 2011 EULAR and American College of Rheumatology (ACR) conference abstracts7 8 and accessed the US National Institutes of Health (NIH) database on clinical trials.9 We selected eligible studies according to our inclusion criteria (see box 1 and online supplementary table S1) and compiled the applied measures of disease activity and the thresholds and timelines that guided the decision to change therapy in the respective study protocols. The primary aim of the search was retrieval of strategic studies that compared a therapy steered towards a prespecified treatment target versus a conventional, non-steered approach, as is available for RA.10 Secondly, we reviewed ancillary literature providing circumstantial evidence that a steered therapy might be beneficial during long-term follow-up.

etrieval of strategic studies that compared a therapy steered towards a prespecified treatment target versus a conventional, non-steered approach, as is available for RA.10 Secondly, we reviewed ancillary literature providing circumstantial evidence that a steered therapy might be beneficial during long-term follow-up. Results We initially retrieved 1976 publications in Medline and Embase, and 1002 in Cochrane. By title and abstract screening, we selected 159 of these for full-text review, and finally included 21 papers plus one additional publication found by hand-search. Of these, 12 trials enrolled patients with AS, five included patients with PsA, and two studies included both AS and PsA patients (table 1). No studies on peripheral SpA were obtained; three studies addressed patients with psoriasis. No conference abstracts and no trials from the NIH database provided data on treatment targets. Figure 1 illustrates the search and selection process. Table 1 Treatment targets and timeline definition in trials of ankylosing spondylitis and psoriatic arthritis

Results We initially retrieved 1976 publications in Medline and Embase, and 1002 in Cochrane. By title and abstract screening, we selected 159 of these for full-text review, and finally included 21 papers plus one additional publication found by hand-search. Of these, 12 trials enrolled patients with AS, five included patients with PsA, and two studies included both AS and PsA patients (table 1). No studies on peripheral SpA were obtained; three studies addressed patients with psoriasis. No conference abstracts and no trials from the NIH database provided data on treatment targets. Figure 1 illustrates the search and selection process. Table 1 Treatment targets and timeline definition in trials of ankylosing spondylitis and psoriatic arthritis Measure of disease activity Target definition Assessment after Study (drug) Ankylosing spondylitis ASAS ≥20% response Week 12 (OLE) ATLAS (ADA)*11 BASDAI <3 at both current and prior assessment Week 36 ASSERT (IFX)†12 ASAS ≥40% response Week 12 Haibel (ADA)*14 BASDAI ≥50% reduction, or ≤3 Week 22 and 38 CANDLE (IFX)†15 BASDAI ≥20% reduction Month 3 Jois (IFX)17 ≥50% reduction Month 6 BASDAI ≥40% reduction Week 14 Cherouvim (IFX)*18 ESR ≥1 mm reduction per week: escalate ≤20 (women)/≤10 (men) mm/h for step down Remission: ESR ≤10 (men ≤5) and BASDAI, BASFI, BASG, BASMI scores mean <1: taper Weekly for escalation Month 6 for step down Darmawan (IS)†21 Combined/alternative targets Total back pain (VAS), MST (min) ≥20% reduction in both back pain and MST Week 16 GO-RAISE (GOL)†13 BASDAI, IFX serum level <40 and 5.0 μg/ml After 4th IFX (∼22 weeks) Meric (IFX)*16 BASDAI, ESR/CRP <4 (BASDAI) or <30 mm/h ESR and <5 mg/l CRP Week 38 Collantes (IFX)†19 MST (VAS), pain (VAS), ESR ≥20% reduction in 2/3 Week 4 Van Denderen (mesalazine)*20 BASDAI, ESR/CRP ≥2 patients. BASDAI reduction and ≥20% ESR/CRP reduction Week 2, then 6-weekly Cheung (IFX)22 Q1: disease has remained under control? Q2: disease has been worsening?

0 mm/h ESR and <5 mg/l CRP Week 38 Collantes (IFX)†19 MST (VAS), pain (VAS), ESR ≥20% reduction in 2/3 Week 4 Van Denderen (mesalazine)*20 BASDAI, ESR/CRP ≥2 patients. BASDAI reduction and ≥20% ESR/CRP reduction Week 2, then 6-weekly Cheung (IFX)22 Q1: disease has remained under control? Q2: disease has been worsening? VAS pain, BASDAI No relapse; definition: Q1 ‘Yes’ and Q2 ‘No’ and either <2/10 pain increase and <1/10 BASDAI increase ≥4 weeks after stopping for on-demand week 40 for dose escalation Breban (IFX)†23 BASMI, PhysGA No relapse; definition: ≤4 BASMI and ≤4 PhysGA 26 weeks after stop Braun (IFX)†24 Psoriatic arthritis TJC and SJC ≥20% reduction 12 weeks ADEPT (ADA)25 TJC and SJC ≥10% reduction 16 weeks GO-REVEAL (GOL)26 TJC and SJC combined N ≥20% reduction 38 and 46 weeks IMPACT 2 (IFX)27 Joint count ‘actively inflamed’ ≥30% reduction 14 weeks Feletar (IFX)28 Joint count ≥40% reduction 3 months Rahman (SSZ)29 PGA ≥40% reduction 14 weeks Cherouvim (IFX)18 BASDAI, ESR/CRP <4 (BASDAI) or <30 mm/h ESR and <5 mg/l CRP Week 38 (cave diff AB 30/text38) Collantes (IFX)†19 Psoriasis MPSS MPSSpresent visit >MPSSprevious visit−0.2* (MPSSprevious visit−MPSSbaseline) Max 18 weeks De Jong (MTX)37 PASI Improvement >25% 6 weeks Beissert (CsA, MMF)38 PASI Improvement ≥75% 12 weeks Nevin (CsA)39 *Target measure is identical with primary end point measure. †Target measure is not identical with primary end point measure.

VAS pain, BASDAI No relapse; definition: Q1 ‘Yes’ and Q2 ‘No’ and either <2/10 pain increase and <1/10 BASDAI increase ≥4 weeks after stopping for on-demand week 40 for dose escalation Breban (IFX)†23 BASMI, PhysGA No relapse; definition: ≤4 BASMI and ≤4 PhysGA 26 weeks after stop Braun (IFX)†24 Psoriatic arthritis TJC and SJC ≥20% reduction 12 weeks ADEPT (ADA)25 TJC and SJC ≥10% reduction 16 weeks GO-REVEAL (GOL)26 TJC and SJC combined N ≥20% reduction 38 and 46 weeks IMPACT 2 (IFX)27 Joint count ‘actively inflamed’ ≥30% reduction 14 weeks Feletar (IFX)28 Joint count ≥40% reduction 3 months Rahman (SSZ)29 PGA ≥40% reduction 14 weeks Cherouvim (IFX)18 BASDAI, ESR/CRP <4 (BASDAI) or <30 mm/h ESR and <5 mg/l CRP Week 38 (cave diff AB 30/text38) Collantes (IFX)†19 Psoriasis MPSS MPSSpresent visit >MPSSprevious visit−0.2* (MPSSprevious visit−MPSSbaseline) Max 18 weeks De Jong (MTX)37 PASI Improvement >25% 6 weeks Beissert (CsA, MMF)38 PASI Improvement ≥75% 12 weeks Nevin (CsA)39 *Target measure is identical with primary end point measure. †Target measure is not identical with primary end point measure. ADA, adalimumab; ADEPT, Adalimumab Effectiveness in Psoriatic Arthritis Trial; ASAS, Ankylosing Spondylitis Assessment Study; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BASFI, Bath Ankylosing Spondylitis Functional Index; BASG, Bath Ankylosing Spondylitis Global Score; BASMI, Bath Ankylosing Spondylitis Metrology Index; CRP, C-reactive protein; CsA, ciclosporin; DMARD, disease-modifying antirheumatic drug; ESR, erythrocyte sedimentation rate; GOL, golimumab; IFX, infliximab; IS, immunosuppressant therapy (consisting of combined DMARDs); mesa, mesalazine; MMF, mycophenolate mofetil; MPSS, Modified Psoriasis Severity Score; MST, morning stiffness; MTX, methotrexate; OLE, open label extension; PASI, Psoriasis Area Severity Index; PGA, Patient global assessment of disease activity; PhysGA, physician global assessment; Q1, Q2, question 1 and 2; SJC, swollen joint count; SSZ, sulfasalazine; TJC, tender joint count; VAS, visual analogue scale.

MST, morning stiffness; MTX, methotrexate; OLE, open label extension; PASI, Psoriasis Area Severity Index; PGA, Patient global assessment of disease activity; PhysGA, physician global assessment; Q1, Q2, question 1 and 2; SJC, swollen joint count; SSZ, sulfasalazine; TJC, tender joint count; VAS, visual analogue scale. Figure 1 Search and selection process. AS, ankylosing spondylitis; clin, clinical; DX, diagnosis; PsA, psoriatic arthritis; publ., publication; T2T, treatment to target; TX, treatment. The most important result of the search was the failure to find any randomised comparison evaluating a T2T approach versus routine treatment. However, several publications report on targets and timelines that were used as thresholds before escalating therapy. Axial SpA (including AS and non-radiographic axial SpA) Overall, we found 14 studies11–24 with predetermined treatment targets in AS that were suitable for inclusion. Table 1 specifies the measures of disease activity or function and timelines as well as cut-off points used as indication of (in)sufficient response. The baseline characteristics of the study populations were comparable with regard to inclusion criteria, disease activity, function, age and disease duration (online supplementary table S2 lists details of the included studies and baseline characteristics of the patients).

used as indication of (in)sufficient response. The baseline characteristics of the study populations were comparable with regard to inclusion criteria, disease activity, function, age and disease duration (online supplementary table S2 lists details of the included studies and baseline characteristics of the patients). Definitions of treatment targets and timelines The majority of studies used the Bath AS Disease Activity Index (BASDAI) at follow-up for treatment ‘escalation’ until a prespecified outcome was achieved.12 15 17 18 This outcome was defined as BASDAI<3 at two consecutive assessments starting from weeks 30 and 36 in one trial,12 while in most studies, a percentage reduction from baseline was required, being either ≥20% after 12 weeks,17 ≥40% after 14 weeks18 or ≥50% after 6 months.15 17 Two protocols required a decline of ≥20%11 or ≥40%14 in the response criteria of the ASAS after 12 weeks. One study21 based treatment decisions on the erythrocyte sedimentation rate (ESR) at follow-up and required a ≥1 mm reduction per week. One trial that included AS and PsA patients18 required a ≥40% reduction in patient global assessment of disease activity (PGA) after 14 weeks, otherwise infliximab (IFX) frequency was increased from an 8-weekly to a 4-weekly schedule (table 1).

imentation rate (ESR) at follow-up and required a ≥1 mm reduction per week. One trial that included AS and PsA patients18 required a ≥40% reduction in patient global assessment of disease activity (PGA) after 14 weeks, otherwise infliximab (IFX) frequency was increased from an 8-weekly to a 4-weekly schedule (table 1). Several authors used combined targets, mostly combinations of the BASDAI19 22 or the Bath AS Metrology Index (BASMI)24 with either acute phase reactants19 22 or the physician global assessment (PhysGA).24 Meric et al16 measured serum IFX levels after four infusions to customise infusion schedules previously determined according to the BASDAI. Reductions in morning stiffness and pain were used to adjust golimumab therapy13 and—expanded by the ESR—also to guide dose escalations of mesalazine.20 Cheung et al22 reported therapeutic outcomes using Australian Pharmaceutical Benefit Schedule standards, which only reinforce ‘continuation’ of IFX after decline of BASDAI by ≥2 points and ≥20% improvement in ESR and/or C-reactive protein (CRP) (table 1). Several studies tested the efficacy of ‘on-demand’ treatment in the case of relapse after cessation of IFX.23 24 The definition of relapse was based on a short questionnaire in combination with BASDAI and an increase in acute phase reactants (table 1),23 or an absolute BASMI or PhysGA of ≥4.24 Therapy was tapered according to ESR,21 BASDAI and serum IFX levels16 (table 1).

tment in the case of relapse after cessation of IFX.23 24 The definition of relapse was based on a short questionnaire in combination with BASDAI and an increase in acute phase reactants (table 1),23 or an absolute BASMI or PhysGA of ≥4.24 Therapy was tapered according to ESR,21 BASDAI and serum IFX levels16 (table 1). In AS, prospective analyses to identify the predictive value of the above measures for long-term functional and radiographic outcomes have not been carried out. Psoriatic arthritis Seven studies fulfilled our inclusion criteria for PsA.18 19 25–29 Table 1 details their treatment targets. Online supplementary table S2 shows study details and patients’ baseline characteristics. In the majority, the treatment target was a reduction in swollen and tender joint counts.26–29 The prespecified decrease for a treatment to be considered sufficiently effective was a reduction in joint counts of ≥10% after 16 weeks,26 ≥20% after 38 and 46 weeks,27 29 ≥30% after 14 weeks28 or ≥40% after 3 months.29 Two trials18 19 included mixed SpA populations and used ≥40% reduction in PGA after 14 weeks18 or ESR and CRP19 (table 1). Some prospective studies investigated the correlation between clinical symptoms and progression of radiographic damage and reported a predictive capacity of synovitis,30–32 dactylitis33 and CRP,34 while other authors did not observe these associations.35 Serological markers that can predict long-term outcome in PsA are under investigation.36

s investigated the correlation between clinical symptoms and progression of radiographic damage and reported a predictive capacity of synovitis,30–32 dactylitis33 and CRP,34 while other authors did not observe these associations.35 Serological markers that can predict long-term outcome in PsA are under investigation.36 There were no trials available that specifically investigated targeted treatment in other peripheral SpAs or contributed evidence on correlation with long-term outcomes. Psoriasis In psoriasis also, there are no randomised controlled trials available to compare T2T with routine treatment. The Modified Psoriasis Severity Score (MPSS) was used to titrate weekly dosage of methotrexate,37 and the Psoriasis Area and Severity Index (PASI) was used to titrate ciclosporin38 39 or mycophenolate mofetil38 (table 1 and online supplementary table S2). Other than that, there has been no defined target to guide treatment escalation, although some studies used thresholds to decide whether to pause therapy—for example, to pause etanercept as soon as a target of PGA of ≤2 (clear, almost clear or mild) was reached.40 Discussion and conclusion We present a systematic review of targeted treatment for SpA and psoriasis that informed the consensus-finding process of the expert committee for T2T-SpA recommendations.

Psoriasis In psoriasis also, there are no randomised controlled trials available to compare T2T with routine treatment. The Modified Psoriasis Severity Score (MPSS) was used to titrate weekly dosage of methotrexate,37 and the Psoriasis Area and Severity Index (PASI) was used to titrate ciclosporin38 39 or mycophenolate mofetil38 (table 1 and online supplementary table S2). Other than that, there has been no defined target to guide treatment escalation, although some studies used thresholds to decide whether to pause therapy—for example, to pause etanercept as soon as a target of PGA of ≤2 (clear, almost clear or mild) was reached.40 Discussion and conclusion We present a systematic review of targeted treatment for SpA and psoriasis that informed the consensus-finding process of the expert committee for T2T-SpA recommendations. Randomised trials designed to compare targeted treatment with another type of care are not available, but evidence can be derived from studies that apply target-oriented treatment adaption. The majority of designs suggest use of the BASDAI to evaluate therapeutic response in AS (but other composite measures such as ASDAS41 42 seem to be increasingly used), swollen and tender joint counts for PsA, and MPSS and PASI for psoriasis. In many studies, response was evaluated after 12–14 weeks, while others stretched out to 36 weeks. Importantly, no information on long-term outcomes is available. Composite measures of disease activity have not yet been formally evaluated for PsA. Likewise, no such studies are available for other peripheral spondyloarthritides including reactive arthritis. Some trials for reactive arthritis used antibiotic therapy (reviewed by Hannu43). These studies are not included here because they did not use criteria for insufficient response.

en formally evaluated for PsA. Likewise, no such studies are available for other peripheral spondyloarthritides including reactive arthritis. Some trials for reactive arthritis used antibiotic therapy (reviewed by Hannu43). These studies are not included here because they did not use criteria for insufficient response. The definition of pertinent treatment targets for SpA is challenging because of the heterogeneity of the disease, including axial, peripheral and extra-articular/extraspinal manifestations. Moreover, no data on a positive effect on physical function and radiographic damage resulting from a T2T strategy have been published for SpA. The data presented informed the task force on the current state of evidence and clearly reveal that further research is needed. In particular, clinical trials comparing the value of treatment steered by levels of disease activity versus conventional therapy in SpA, both axial and peripheral, are needed. Supplementary Material Web tables Correction notice: This article has been corrected since it was published Online First. The fourth author affiliation has been amended. Contributors: MS performed the search, and all authors contributed to the manuscript and finally approved it. Funding: Supported by an unrestricted grant from Abbott/Abbvie. Competing interests: None. Provenance and peer review: Not commissioned; externally peer reviewed.

The management of rheumatoid arthritis (RA) rests primarily on the use of disease-modifying antirheumatic drugs (DMARDs). These agents are commonly characterised by their capacity to reduce or reverse signs and symptoms, disability, impairment of quality of life, inability to work, and progression of joint damage and thus to interfere with the entire disease process.1 DMARDs form two major classes: synthetic chemical compounds (sDMARDs) and biological agents (bDMARDs). In this respect, a new nomenclature for DMARDs was recently proposed which we will adhere to in this report.2 Consequently, the term conventional sDMARDs (csDMARDs) will be used to include chemical agents such as methotrexate (MTX), sulfasalazine and leflunomide, whereas tofacitinib, a new sDMARD specifically designed to target janus kinases (JAKs), will be designated as a targeted sDMARD (tsDMARD). The five available tumour necrosis factor (TNF) inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab and infliximab), the T cell costimulation inhibitor, abatacept, the anti-B cell agent, rituximab, and the interleukin (IL)-6 receptor (IL-6R)-blocking monoclonal antibody, tocilizumab, as well as the IL-1 inhibitor, anakinra, will be subsumed as biological originator (bo) DMARDs, while biosimilars (bs), such as bs-infliximab, recently approved by the European Medicines Agency (EMA), will be named bsDMARDs.2

uximab, and the interleukin (IL)-6 receptor (IL-6R)-blocking monoclonal antibody, tocilizumab, as well as the IL-1 inhibitor, anakinra, will be subsumed as biological originator (bo) DMARDs, while biosimilars (bs), such as bs-infliximab, recently approved by the European Medicines Agency (EMA), will be named bsDMARDs.2 With abundant therapeutic options available and insufficient information on differential efficacy and safety, making treatment decisions in clinical practice remains challenging. To this end, the European League Against Rheumatism (EULAR) has recently developed recommendations for the management of RA with these drugs.3 These recommendations were based on five systematic literature reviews (SLRs)4–8 and focused on indications for the use of, and suggestions for, differential and strategic employment of csDMARDs and bDMARDs based on treatment targets, disease risk assessment, safety aspects and contraindications. While some of the individual recommendations have elicited extensive discussions, all of them were based on the evidence available at that point in time4–8 and on the results of the discussions and votes by the expert committee. Moreover, the EULAR recommendations have been used and adopted widely, as suggested by their application as a template for many national and regional recommendations after their publication.9–12 However, as with most recommendations and especially in a rapidly evolving field such as RA, it was anticipated that the 2010 recommendations would need updating within a few years.3 Indeed, more experience and additional evidence on agents approved at that time, as well as data on new compounds, have become available over the last 3–4 years, motivating us to update the recommendations as described here.

s RA, it was anticipated that the 2010 recommendations would need updating within a few years.3 Indeed, more experience and additional evidence on agents approved at that time, as well as data on new compounds, have become available over the last 3–4 years, motivating us to update the recommendations as described here. Methods With the approval of the EULAR Executive Committee, the convenor (JSS) and epidemiologist (RL) who led the 2010 activity formed a Steering Group and a Task Force with the aim of updating the 2010 EULAR recommendations for the management of RA. Task force Comprised of 33 members from 11 European countries and the USA, this EULAR Task Force included four patient representatives, 24 rheumatologists, an infectious disease specialist, a health economist and three fellows; care was taken to have a good representation of clinicians and experts experienced in RA clinical trials and their analysis from all European regions.

ies and the USA, this EULAR Task Force included four patient representatives, 24 rheumatologists, an infectious disease specialist, a health economist and three fellows; care was taken to have a good representation of clinicians and experts experienced in RA clinical trials and their analysis from all European regions. Initially, a Steering Group prioritised research questions and search terms for the three SLRs. These searches expanded and updated the available published information on efficacy of csDMARDs (as monotherapy or combination therapy, with and without glucocorticoids), efficacy of bDMARDs (as monotherapy or combined with csDMARDs) and safety aspects of csDMARDs and bDMARDs; treatment strategies were contained in the present SLRs rather than being separate as in 2010.7 Although the SLRs informing the 2010 EULAR recommendations also included a search on economic evaluations,8 the Steering Group felt that re-evaluation was not necessary because the approval status and price of new agents such as bsDMARDs was unknown. Subsequently, with the help of their mentors, the three fellows performed the respective SLRs using established databases, including registry data for safety outcomes, and abstracts, especially from recent meetings (American College of Rheumatology 2012, EULAR 2012 and 2013). Details on and results of the SLRs are reported separately.13–15 Levels of evidence and grades of recommendation were determined according to the standards of the Oxford Centre for Evidence-Based Medicine.16

es, and abstracts, especially from recent meetings (American College of Rheumatology 2012, EULAR 2012 and 2013). Details on and results of the SLRs are reported separately.13–15 Levels of evidence and grades of recommendation were determined according to the standards of the Oxford Centre for Evidence-Based Medicine.16 Consensus finding At a subsequent meeting, these data were presented first to the Steering Group consisting of nine rheumatologists, an infectious disease specialist and a patient representative, who drafted a preliminary set of new recommendations based on their discussions. The search results as well as the drafted proposal for the recommendations were subsequently presented to the whole Task Force and discussed in detail in four break-out groups focusing on (i) csDMARDs and tsDMARDs, (ii) glucocorticoids, (iii) bDMARDs and (iv) safety aspects. After these deliberations, each subgroup reported their respective results and made new proposals for the recommendations to the entire group. After discussion, the Task Force then amended them as deemed appropriate to achieve final consensus, ultimately voting on each individual recommendation. When an initial majority of 70% in favour of—or against—a recommendation or formulation was not achieved, the contents or wordings were amended until a majority of the Task Force members approved the individual item. The results of the final ballot are presented for each of the recommendations as a percentage of voting members. An ultimate round of wording refinements was carried out via electronic communication but with no changes of the meaning permitted. This was accompanied by anonymous voting on the strength of recommendation (level of agreement) for each item on a 0–10 scale (0, no agreement at all; 10, full agreement).

voting members. An ultimate round of wording refinements was carried out via electronic communication but with no changes of the meaning permitted. This was accompanied by anonymous voting on the strength of recommendation (level of agreement) for each item on a 0–10 scale (0, no agreement at all; 10, full agreement). A few principal considerations had already been developed by the Steering Group before the SLRs and were subsequently approved by the whole Task Force: (i) all of the 2010 recommendations should be reconsidered on the basis of new available supportive or contradicting evidence and voted upon; (ii) any of the previous recommendations could be kept as had been formulated, could undergo textual amendments, could be totally abandoned or could be shifted from a prominent place in the table listing the individual recommendations to the text accompanying them; (iii) although not yet approved and used in clinical practice outside the USA at the start of the current activity, it was deemed important to at least discuss and possibly formulate a recommendation on the application of tofacitinib based on the evidence from the literature; (iv) while not yet approved or used in practice in Europe or North America, it was also deemed important to at least discuss and potentially express a view on the place of biosimilars in the therapeutic arena based on available evidence.

ation on the application of tofacitinib based on the evidence from the literature; (iv) while not yet approved or used in practice in Europe or North America, it was also deemed important to at least discuss and potentially express a view on the place of biosimilars in the therapeutic arena based on available evidence. In line with these a priori considerations and the potential need to provide some totally new recommendations, each of the three overarching principles and 15 recommendations of the consensus published in 2010 underwent thorough re-evaluation for their validity based on information that had become available from trials and registries during the years since the last SLR and consensus finding; where no new evidence had been found, the evidence from the 2010 searches was applied. Results General aspects As with the 2010 recommendations, this 2013 update reflects the balance of efficacy and safety, but does not deal with the toxicity of DMARDs in detail; this can be derived from the results of the safety SLR; all three SLRs provide an important adjunct to these recommendations, since they establish the evidence base. Thus, in line with the 2010 recommendation, the 2013 update primarily considers agents with toxicity that appears to be manageable, assuming that prescribers are either aware of the respective risks or will adhere to the information provided in the package inserts. However, where toxicity appears to be a major issue, a general warning is included in the respective recommendation.

imarily considers agents with toxicity that appears to be manageable, assuming that prescribers are either aware of the respective risks or will adhere to the information provided in the package inserts. However, where toxicity appears to be a major issue, a general warning is included in the respective recommendation. Overarching principles In line with the 2010 recommendations, the Task Force felt again that some of the principles of treating RA are of such a generic nature that they should be separated from individual recommendations on individual therapeutic approaches or compounds. However, the sequence of these principles was changed and the wording refined (table 1). Treatment of RA patients should aim at the best care and must be based on a shared decision between the patient and the rheumatologist. This principle was originally ranked as B,3 but the Task Force decided that decision-sharing by patient and rheumatologist is of such overwhelming importance that it should spearhead the recommendations. Shared decision-making includes the need to inform the patient of the risks of RA and the benefits of reaching the targeted disease activity states as well as the pros and cons of respective therapies. It also means two-way communication and joint or shared decision-making on the therapeutic target and management plan as well as support for the patient to develop personal preferences. The term ‘best care’ inherently refers to the recommendations provided here.

tes as well as the pros and cons of respective therapies. It also means two-way communication and joint or shared decision-making on the therapeutic target and management plan as well as support for the patient to develop personal preferences. The term ‘best care’ inherently refers to the recommendations provided here. Rheumatologists are the specialists who should primarily care for RA patients. Shifting this item from rank A to B was not at all meant to diminish the role of the rheumatologist in the care of patients with RA. Indeed, the wording of this principle remained unchanged and the rheumatologist is already mentioned in item A and should constitute the main counselling anchor for patients with RA. Further, the evidence for provision of better care by rheumatologists in comparison with other physicians (see item A: ‘best care’) has been briefly reviewed in the 2010 recommendations and further corroborated since then.17 18 The term ‘primarily’ constitutes a short cut with several thoughts behind it that go even beyond the considerations expressed in 2010: first, it reflects the necessity to involve other physicians experienced in the care of RA patients, including experience in novel therapies and their potential complications, where there is a lack of trained rheumatologists; second, it is consistent with multiprofessional care and thus with current trends in some countries for an increasing role of non-physician health professionals who are well trained in the care of patients with RA, such as rheumatology nurses,19 as long as the responsibility in general is in the hands of the rheumatologist; and third, the term ‘primarily’ should also remind the rheumatologist that multidisciplinary care may sometimes be needed, especially when dealing with comorbidities, such as cardiovascular disease,20 or complications of applied therapies, such as serious infections.

ty in general is in the hands of the rheumatologist; and third, the term ‘primarily’ should also remind the rheumatologist that multidisciplinary care may sometimes be needed, especially when dealing with comorbidities, such as cardiovascular disease,20 or complications of applied therapies, such as serious infections. RA incurs high individual, societal and medical costs, all of which should be considered in its management by the treating rheumatologist. Slightly reworded, the meaning of this principle has not changed from last time. It consists of two parts. The first part relates to the costs incurred by RA for the individual patient/family and society and mentions the costs of modern therapies. It has been well established that RA incurs a substantial socioeconomic burden,21 and this has recently been supported by the Global Burden of Disease studies.22 23 In this context, the cost-effectiveness of treating RA has been repeatedly addressed, and the impact of modern therapies on late, costly consequences of RA, such as joint replacement surgery, is noteworthy.24 25 While rheumatologists cannot generally be held responsible for costs of treatment when attempting to provide best care in line with overarching principle A, this item does reiterate the responsibility of the rheumatologist to consider economic implications when selecting between treatment strategies or modalities with similar efficacy and safety in the short or intermediate term. Comparative meta-analyses and head-to-head studies help us to judge similarities or differences between therapies,26–30 although—as will be discussed below—the qualities of the studies may differ, which should be thoroughly weighed in therapeutic decision-making. Cost considerations by rheumatologists will become more important once biosimilar biological agents become available.31 In parallel, payers (governments or social security agencies) ought to take the overall individual and societal implications of RA into account when making decisions on medical costs.

decision-making. Cost considerations by rheumatologists will become more important once biosimilar biological agents become available.31 In parallel, payers (governments or social security agencies) ought to take the overall individual and societal implications of RA into account when making decisions on medical costs. Table 1 2013 Update of the EULAR recommendations (the table of 2010 recommendations can be seen in the online supplement or the original publication)

decision-making. Cost considerations by rheumatologists will become more important once biosimilar biological agents become available.31 In parallel, payers (governments or social security agencies) ought to take the overall individual and societal implications of RA into account when making decisions on medical costs. Table 1 2013 Update of the EULAR recommendations (the table of 2010 recommendations can be seen in the online supplement or the original publication) Overarching principles A. Treatment of RA patients should aim at the best care and must be based on a shared decision between the patient and the rheumatologist B. Rheumatologists are the specialists who should primarily care for RA patients C. RA incurs high individual, societal and medical costs, all of which should be considered in its management by the treating rheumatologist Recommendations 1. Therapy with DMARDs should be started as soon as the diagnosis of RA is made 2. Treatment should be aimed at reaching a target of remission or low disease activity in every patient 3. Monitoring should be frequent in active disease (every 1–3 months); if there is no improvement by at most 3 months after the start of treatment or the target has not been reached by 6 months, therapy should be adjusted 4. MTX should be part of the first treatment strategy in patients with active RA 5. In cases of MTX contraindications (or early intolerance), sulfasalazine or leflunomide should be considered as part of the (first) treatment strategy 6. In DMARD-naïve patients, irrespective of the addition of glucocorticoids, csDMARD monotherapy or combination therapy of csDMARDs should be used 7. Low-dose glucocorticoids should be considered as part of the initial treatment strategy (in combination with one or more csDMARDs) for up to 6 months, but should be tapered as rapidly as clinically feasible 8. If the treatment target is not achieved with the first DMARD strategy, in the absence of poor prognostic factors, change to another csDMARD strategy should be considered; when poor prognostic factors are present, addition of a bDMARD should be considered 9. In patients responding insufficiently to MTX and/or other csDMARD strategies, with or without glucocorticoids, bDMARDs (TNF inhibitors*, abatacept or tocilizumab, and, under certain circumstances, rituximab†) should be commenced with MTX 10. If a first bDMARD has failed, patients should be treated with another bDMARD; if a first TNF inhibitor therapy has failed, patients may receive another TNF inhibitor* or a biological agent with another mode of action 11. Tofacitinib may be considered after biological treatment has failed 12.

d be commenced with MTX 10. If a first bDMARD has failed, patients should be treated with another bDMARD; if a first TNF inhibitor therapy has failed, patients may receive another TNF inhibitor* or a biological agent with another mode of action 11. Tofacitinib may be considered after biological treatment has failed 12. If a patient is in persistent remission after having tapered glucocorticoids, one can consider tapering‡ bDMARDs§, especially if this treatment is combined with a csDMARD 13. In cases of sustained long-term remission, cautious reduction of the csDMARD dose could be considered, as a shared decision between patient and physician 14. When therapy needs to be adjusted, factors apart from disease activity, such as progression of structural damage, comorbidities and safety issues, should be taken into account *TNF inhibitors: adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, biosimilars (as approved according to a thorough approval process, such as by EMA and/or FDA). †The ‘certain circumstances’, which include history of lymphoma or a demyelinating disease, are detailed in the accompanying text. ‡Tapering is seen as either dose reduction or prolongation of intervals between applications. §Most data are available for TNF inhibitors, but it is assumed that dose reduction or interval expansion is also pertinent to biological agents with another mode of action.

†The ‘certain circumstances’, which include history of lymphoma or a demyelinating disease, are detailed in the accompanying text. ‡Tapering is seen as either dose reduction or prolongation of intervals between applications. §Most data are available for TNF inhibitors, but it is assumed that dose reduction or interval expansion is also pertinent to biological agents with another mode of action. DMARD, disease-modifying antirheumatic drug; EMA, European Medical Agency; EULAR, European League against Rheumatism; FDA, Food and Drug Administration; MTX, methotrexate; RA, rheumatoid arthritis; TNF, tumour necrosis factor.

§Most data are available for TNF inhibitors, but it is assumed that dose reduction or interval expansion is also pertinent to biological agents with another mode of action. DMARD, disease-modifying antirheumatic drug; EMA, European Medical Agency; EULAR, European League against Rheumatism; FDA, Food and Drug Administration; MTX, methotrexate; RA, rheumatoid arthritis; TNF, tumour necrosis factor. Recommendations The discussion process of the Task Force led to 14 (rather than the previous 15) recommendations. This reduction is due to the elimination of three of the 2010 items (Nos 10, 11 and 14) and the addition of two new recommendations. The decision to delete old item 10 (mentioning the potential use of ‘azathioprine, cyclosporine A [or…cyclophosphamide]’) was taken unanimously; the decision to remove old item 11 (‘Intensive medication strategies should be considered in every patient, although patients with poor prognostic factors have more to gain’) was likewise taken unanimously because those treatment strategies are now well established, and several of the revised recommendations inherently incorporate a strategic approach to treating RA intensively. Finally, a 94% majority vote supported deleting previous recommendation 14 (‘DMARD-naïve patients with poor prognostic markers might be considered for combination therapy of MTX plus a biological’); for more details see explanations on new No 9. However, it was simultaneously decided to mention these therapeutic considerations in the text accompanying pertinent recommendations.

ommendation 14 (‘DMARD-naïve patients with poor prognostic markers might be considered for combination therapy of MTX plus a biological’); for more details see explanations on new No 9. However, it was simultaneously decided to mention these therapeutic considerations in the text accompanying pertinent recommendations. The 14 recommendations arising from the current activity are presented in table 1 and discussed in detail below. With the exception of the first two items, which are the mainstay of the therapeutic approach to RA, they are not primarily weighted by an order of importance, but rather follow a logical sequence and procedural hierarchy. They are summarised in abbreviated form in the algorithm presented in figure 1. Table 2 displays the levels of evidence and grades of recommendation based on the Oxford Levels of Evidence assessment, as well as the primary voting results at the Task Force meeting and level of agreement/strength of recommendation voting by the Task Force. Therapy with DMARDs should be started as soon as the diagnosis of RA is made. This recommendation is almost the same as in 2010; the term ‘synthetic’ before DMARDs was omitted to emphasise the generic nature of this recommendation, focusing particularly on the importance of diagnosing RA early and treating it appropriately as soon as such a diagnosis is presumed. To this end, the 2010 American College of Rheumatology (ACR)–EULAR classification criteria (which had only been in development when the 2010 EULAR RA management recommendations were discussed and are now well established)32 should be used to support diagnosis and facilitate early introduction of effective therapy in RA. Although diagnosis relies on the individual rheumatologist's judgement about the disease in a particular patient at a particular point in time, whereas classification relates to the group level and is important primarily for clinical studies, the new classification establishes general criteria for early diagnosis. In the course of its discussions, the Task Force reiterated both the importance of the presence of clinical synovitis in at least one joint (in line with the 2010 classification criteria) and the essential importance of starting DMARD therapy as soon as possible.

cation establishes general criteria for early diagnosis. In the course of its discussions, the Task Force reiterated both the importance of the presence of clinical synovitis in at least one joint (in line with the 2010 classification criteria) and the essential importance of starting DMARD therapy as soon as possible. Treatment should be aimed at reaching a target of remission or low disease activity in every patient. The definition of the treatment target was deemed of such fundamental importance that the Task Force decided that aspects of patient follow-up should not dilute it. Therefore the former recommendation 2 is now split into two recommendations, items 2 and 3. When the 2010 EULAR recommendations were set forth to target remission,3 33 the ACR–EULAR remission definition was still in development; in the meantime, more stringent criteria have been published34 by ACR and EULAR and should be applied in the context of these recommendations for the actual definition of remission as the optimal treatment target. Remission as defined by the Disease Activity Score based on 28 joint counts (DAS28<2.6) is not regarded as sufficiently stringent to define remission.34 The proportion of patients reaching remission by the ACR–EULAR criteria in clinical trials and practice is sufficiently large to warrant their preferential and widespread use in daily care of RA patients.35–38 A large array of data has confirmed the value of reaching stringent remission not only with regard to signs and symptoms of RA, but also with regard to achieving maximal functional improvement and halting progression of structural damage39–44; thus good outcomes in terms of physical function and structural changes are implicitly included in targeting good clinical outcome. Moreover, the Task Force agreed with the 2010 recommendations and similar recommendations by another expert committee,27 namely that low disease activity defined by composite measures45 is a good alternative goal for many patients who cannot attain remission even today, especially those with long-standing disease who actually constitute the majority of patients in clinical care.

and similar recommendations by another expert committee,27 namely that low disease activity defined by composite measures45 is a good alternative goal for many patients who cannot attain remission even today, especially those with long-standing disease who actually constitute the majority of patients in clinical care. Indeed, although somewhat worse than remission, low disease activity conveys much better functional and structural outcomes than moderate or high disease activity.38 40 46 Because a significant proportion of patients in clinical practice still do not attain a state of remission,37 47 48 implementation of this combined therapeutic target appears to be particularly relevant and significant. Also, once any patient has reached a low disease activity that is close to remission, the individual disease activity variables have to be considered in detail before major therapeutic changes are made.

sion,37 47 48 implementation of this combined therapeutic target appears to be particularly relevant and significant. Also, once any patient has reached a low disease activity that is close to remission, the individual disease activity variables have to be considered in detail before major therapeutic changes are made. Monitoring should be frequent in active disease (every 1–3 months); if there is no improvement by at most 3 months after treatment start or the target has not been reached by 6 months, therapy should be adjusted. In contrast with the second half of prior recommendation 2, which also dealt with follow-up and treatment adjustments that could be interpreted or used differently than intended, statement 3 of the updated recommendations is very specific and clarifies any potential incongruity. First, monitoring should be performed as frequently as disease activity necessitates, namely more frequently (such as every 1–3 months) with active disease and less frequently (such as every 6–12 months) once the treatment target has been stabilised. EULAR also advocates the use of composite measures of disease activity, which include formal joint counts and the application of the ACR–EULAR criteria for remission.34 45 Further, this item clearly specifies that the treatment target (remission or at least low disease activity, see item 2) should be attained within 6 months and not necessarily within 3 months; the 3-month time point relates solely to assessing improvement, meaning reduction of disease activity from a high to at least a moderate state by composite measures.45 If there is no improvement in disease activity (such as persistence of high disease activity as assessed by composite scores) after 3 months and provided that therapy has already been adjusted to maximise treatment effect, the ongoing therapeutic regimen is usually unlikely to lead to the treatment goal in many additional patients even by 1 year and should be modified.49 Maximisation of treatment effects includes reaching an optimal MTX dose within a few weeks and maintaining the maximal dose (25–30 mg weekly) for at least 8 weeks.50 If improvement is achieved at 3 months,51 52 it must be borne in mind that maximal efficacy will not be seen before 6 months in many patients with most treatment strategies. This is true for all types of therapies, including most biological agents. A similar approach should be made if the treatment target (remission or low disease activity) is not attained at 6 months.

t be borne in mind that maximal efficacy will not be seen before 6 months in many patients with most treatment strategies. This is true for all types of therapies, including most biological agents. A similar approach should be made if the treatment target (remission or low disease activity) is not attained at 6 months. Of note, individual patients may be well on their way to reaching the targets of low disease activity or remission at 6 months and might just take slightly more time to attain this desired state. Therefore the change in disease activity from treatment start to the 6-month time point will have to be taken into account when making final treatment decisions in the individual patient.

ng the targets of low disease activity or remission at 6 months and might just take slightly more time to attain this desired state. Therefore the change in disease activity from treatment start to the 6-month time point will have to be taken into account when making final treatment decisions in the individual patient. MTX should be part of the first treatment strategy in patients with active RA. This statement (previously No 3) remains unchanged. The Task Force felt reassured by the respective SLR13 that MTX is a highly effective agent both as monotherapy and in combination with glucocorticoids, other csDMARDs and bDMARDs, and thus continues to serve as an anchor drug in RA.53 As monotherapy with or without glucocorticoids, it is effective in DMARD-naïve patients and leads to low disease activity states or 70% improvement rates according to the criteria of the ACR (which correspond to nearly a state of low disease activity)54 in about 25–50% of patients with early RA within 6–12 months.35 55–60 Generally, this statement combines three aspects: first, by using the term ‘part of the first treatment strategy’, it implies that MTX, although effective as monotherapy, may be combined with other agents, such as glucocorticoids but also other csDMARDs (see above and below); second, by stating ‘active disease’ (suggested definitions: Clinical Disease Activity Index (CDAI)>10, DAS28>3.2 or Simplified Disease Activity Index (SDAI)>11),45 it implies that some patients with low disease activity (defined as CDAI≤10, DAS28<3.2, SDAI≤11) may not need MTX and can do well on alternative csDMARD therapies; the third aspect relates to patients previously treated with other csDMARDs who should receive MTX at a sufficient dose and for sufficient time before progressing to potentially more intensive therapies. Important aspects include dose optimisation,50 optimal use of folic acid,61 and recognition that the maximum effect of MTX is attained only after 4–6 months55–59; in this respect, the optimal dose (25–30 mg a week with folate substitution, or somewhat less in the case of dose-limiting side effects62), should be maintained for at least 8 weeks as an important aspect on the way to ultimate treatment success.50 For patients with contraindications to MTX, other drugs should be used (see next recommendation).

al dose (25–30 mg a week with folate substitution, or somewhat less in the case of dose-limiting side effects62), should be maintained for at least 8 weeks as an important aspect on the way to ultimate treatment success.50 For patients with contraindications to MTX, other drugs should be used (see next recommendation). In cases of MTX contraindications (or early intolerance), leflunomide or sulfasalazine should be considered as part of the (first) treatment strategy. While MTX is usually quite well tolerated, especially with folate supplementation,61 63 safety issues do exist62 64 and contraindications to MTX include hepatic or renal disease; a further safety aspect of concern may be MTX-induced lung disease. Sulfasalazine and leflunomide were also included as alternatives for MTX in 2010 in statement 4, so this item has only been shifted. Both sulfasalazine and leflunomide have shown clinical, functional and structural efficacy,65–69 and, although MTX doses in respective comparative trials may not have been optimal, both have shown efficacies similar to MTX. No new studies have disproved this conclusion, and both drugs have been used effectively in combination with biological agents.70 71 Optimal therapeutic dosing of sulfasalazine is 3–4 g/day as enteric coated tablets72–76; the usual leflunomide dose is 20 mg/day. As with all other agents mentioned, safety risks and contraindications should be considered, and—aside from its higher cost—some issues stated in relation to MTX above may also pertain to leflunomide. Of note, sulfasalazine is considered to be safe during pregnancy.77 Prior recommendation No 4 also mentioned injectable gold salts as an alternative to MTX. While the Task Force does not at all withdraw its evidence-based opinion on the efficacy of parenteral gold salts (which is similar to that of MTX in clinical, functional and structural terms) set forth in 2010, gold salts are used rarely and, indeed, are unavailable in many countries. Although some members of the Task Force expressed safety concerns, these were not found to be substantiated in the previous SLR4; however, no study has evaluated intramuscular gold since the last SLR was performed.

ural terms) set forth in 2010, gold salts are used rarely and, indeed, are unavailable in many countries. Although some members of the Task Force expressed safety concerns, these were not found to be substantiated in the previous SLR4; however, no study has evaluated intramuscular gold since the last SLR was performed. Therefore it was decided to remove gold salts from its relatively prominent place in the table, while acknowledging that its efficacy remains established by high-quality evidence.78 Further, antimalarials, such as hydroxychloroquine and chloroquine, are used in RA, especially in combination therapy, but also as monotherapy in patients with very mild disease.79 Interestingly, beyond their mild DMARD activity, antimalarials exhibit a variety of positive metabolic effects and are also considered to be safe during pregnancy.80 81 Because they may not retard progression of joint damage to the same extent as other agents,65 82 they have not been mentioned more prominently in this statement, although patients with low disease activity have a low propensity for joint destruction. Finally, compared with the previous statement on these drugs, the term ‘early’ has now been added to ‘intolerance’ to indicate the Task Force's view that early intolerance to MTX (within 6 weeks) should be viewed as a contraindication and not as a failure of the first treatment strategy. Of note, the Task Force decided unanimously to delete recommendation 10, which also dealt with potential alternative therapies for desperate cases (‘In the case of refractory severe RA or contraindications to biological agents or the previously mentioned sDMARDs, the following sDMARDs might be also considered, as monotherapy or in combination with some of the above: azathioprine, cyclosporine A [or exceptionally cyclophosphamide]’) from the table of recommendations. Given the many currently available effective csDMARDs and bDMARDs and the view that the benefit/risk ratio of the mentioned drugs was not convincingly favourable, especially in relation to other therapies, their use in a first treatment strategy should be restricted to rare, exceptional situations (for details see 2010 recommendations).3

ently available effective csDMARDs and bDMARDs and the view that the benefit/risk ratio of the mentioned drugs was not convincingly favourable, especially in relation to other therapies, their use in a first treatment strategy should be restricted to rare, exceptional situations (for details see 2010 recommendations).3 In DMARD-naïve patients, irrespective of the addition of glucocorticoids, csDMARD monotherapy or combination therapy of csDMARDs should be used. In the previous set of recommendations, item 5 read: ‘In DMARD-naïve patients, irrespective of the addition of glucocorticoids, sDMARD monotherapy rather than combination therapy of sDMARDs may be applied.’ This wording expressed a preference for monotherapy based on the respective SLRs,64 83 which had revealed no superiority of combination therapy using csDMARDs when excluding the concomitant use of glucocorticoids. However, by saying ‘may’, that statement did not generally oppose the use of csDMARD combination therapy; this was also reflected in the respective figure depicting the proposed algorithm. Since then, several additional studies suggest that csDMARD combination may be superior to MTX monotherapy, and some even found efficacy to be similar to that of bDMARDs.84–88 Nevertheless, although these trials yielded similar results strengthening their interpretation, controversy persists because of methodological limitations of these studies,13 which were also clearly stated in some of the reports themselves. Moreover, additional recent data suggest that sequential monotherapy is as effective as combination therapy in clinical, functional and structural outcomes89 90 and that stepping up from MTX monotherapy to a biological agent has significant superiority over a combination of csDMARDs.89 Nonetheless, the Task Force agreed unanimously that the use of csDMARD combination therapy should be mentioned as an appropriate alternative strategy alongside the use of csDMARD monotherapy, with or without glucocorticoids. The Committee thus felt that both monotherapy and combination therapy of csDMARDs are effective and that patient preferences and expectations of adverse events should be considered when discussing treatment options with them. In general, combination therapy with csDMARDs should include MTX, since other combinations have not been sufficiently studied.

h monotherapy and combination therapy of csDMARDs are effective and that patient preferences and expectations of adverse events should be considered when discussing treatment options with them. In general, combination therapy with csDMARDs should include MTX, since other combinations have not been sufficiently studied. Finally, the Task Force recognised the limitations of meta-analyses in the light of new studies84 86 contradicting a meta-analysis that had suggested similar structural efficacy for csDMARD combinations and bDMARD treatment.91

h monotherapy and combination therapy of csDMARDs are effective and that patient preferences and expectations of adverse events should be considered when discussing treatment options with them. In general, combination therapy with csDMARDs should include MTX, since other combinations have not been sufficiently studied. Finally, the Task Force recognised the limitations of meta-analyses in the light of new studies84 86 contradicting a meta-analysis that had suggested similar structural efficacy for csDMARD combinations and bDMARD treatment.91 Low-dose glucocorticoids should be considered as part of the initial treatment strategy (in combination with one or more csDMARDs) for up to 6 months, but should be tapered as rapidly as clinically feasible. As before, the Task Force heavily debated the role of glucocorticoids (previously recommendation 6). Indeed, this item was reworded (previously: ‘Glucocorticoids added at low to moderately high doses to sDMARD monotherapy [or combinations of sDMARDs] provide benefit as initial short term treatment, but should be tapered as rapidly as clinically feasible.’). Rather than just making the general statement that glucocorticoids may ‘provide benefit’, the Task Force now recommends that they should be considered as part of the initial therapeutic approach. This change is based on the respective SLR13 which includes additional information accrued over the last few years.85 92 Low dose refers primarily to a dose of 7.5 mg prednisone or equivalent per day or less.93 Mentioning glucocorticoids in a separate recommendation results from their proven capacity to increase clinical, functional and structural efficacy when combined with csDMARDs,92 94–96 and this combination has similar efficacy when compared with TNF inhibitors plus MTX60 97; thus glucocorticoids, both in initially high and rapidly tapered regimens (eg, COBRA) and at lower doses extended over a year or two, may increase DMARD activity and are even effective in this regard as monotherapy.98 99 However, glucocorticoid monotherapy is not specifically recommended by the Task Force and should only be used in exceptional cases when all other DMARDs have contraindications. A separate EULAR committee has concluded that the literature on safety of long-term glucocorticoid therapy at low doses still has important gaps, but in general does not support the notion of unacceptable safety issues100; subsequently, that committee formulated management guidelines that also address preventive measures against glucocorticoid-induced adverse events.101 The current SLRs13 15 are not in disagreement with any of the above findings.

important gaps, but in general does not support the notion of unacceptable safety issues100; subsequently, that committee formulated management guidelines that also address preventive measures against glucocorticoid-induced adverse events.101 The current SLRs13 15 are not in disagreement with any of the above findings. Nevertheless, the adverse event profile and comorbidity implications of glucocorticoids (and thus their benefit/risk profile) elicited a fierce debate within the Task Force. A compromise (based on expert opinion) to be more specific with respect to the time frame of their application by stating ‘up to 6 months’ rather than just ‘short term’ ultimately led to a majority vote; however, only 73% of the members approved this item (the lowest majority level of all recommendations), reflecting divergent opinions, with both proponents of a stronger and a weaker recommendation voting against. However, the level of agreement (strength of recommendation) was quite high (mean of 8.9) upon final anonymous grading. Thus, the Task Force suggests using them only as bridging therapy and limiting their use to a maximum of 6 months, ideally tapering them at earlier time points. However, neither chronic use of glucocorticoids in established RA nor intra-articular glucocorticoid applications were discussed. Of note, it was also decided to change the algorithm in figure 1 from the 2010 version by downsizing the ‘−’ compared with the ‘+’ in the ‘±’ symbol to reflect the increasing agreement of the Task Force that glucocorticoids should be combined with MTX or other csDMARD regimens.

ucocorticoid applications were discussed. Of note, it was also decided to change the algorithm in figure 1 from the 2010 version by downsizing the ‘−’ compared with the ‘+’ in the ‘±’ symbol to reflect the increasing agreement of the Task Force that glucocorticoids should be combined with MTX or other csDMARD regimens. If the treatment target is not achieved with the first DMARD strategy, in the absence of poor prognostic factors, change to another csDMARD strategy should be considered; when poor prognostic factors are present, addition of a bDMARD should be considered. Slightly reworded compared with 2010, this statement reiterates the unanimous view of the Task Force that risk stratification is an important aspect in the therapeutic approach to RA. These risks have been well defined over the years and include a high disease activity state, autoantibody positivity (rheumatoid factor and/or antibodies to citrullinated proteins) and the early presence of joint damage.102 103 In patients with a low risk of poor RA outcome, another csDMARD strategy (plus glucocorticoids) would be preferred, while in patients with a high risk, the addition of a bDMARD would be preferred. It should be noted that the Task Force changed the sequence compared with the 2010 recommendation, since it assumed that many patients may not be at high risk after a first DMARD strategy, especially in terms of a reduced disease activity and maybe even lower autoantibody levels, and that a rapid change of the csDMARD regimen within 6 months, in line with recommendation 3, may convey further efficacy for a significant proportion of patients. ‘Change’ rather than the previously used ‘switch’ is semantically more in line with potentially adding drugs, especially in patients initially treated with MTX monotherapy, and inherently also comprises switching. ‘Another conventional DMARD strategy’ has to be seen in relation to the first DMARD strategy; if the first DMARD was MTX monotherapy, then a switch to, or the addition of, other csDMARDs would be the appropriate choice; if the first DMARD strategy was combination therapy of MTX, sulfasalazine and hydroxychloroquine, then the next csDMARD strategy to choose in patients at low risk of poor outcome may be leflunomide, all of this under the proviso that optimal doses of the csDMARDs have already been used before (see above).

riate choice; if the first DMARD strategy was combination therapy of MTX, sulfasalazine and hydroxychloroquine, then the next csDMARD strategy to choose in patients at low risk of poor outcome may be leflunomide, all of this under the proviso that optimal doses of the csDMARDs have already been used before (see above). The term ‘considered’ was used in both instances to reflect the Committee's preferences, but inherently acknowledges and implies that treatment decisions have to be made individually and that using a bDMARD after a first csDMARD also in a patient with lower risk of a poor outcome may be appropriate, just as using another csDMARD strategy in a patient at high risk of a poor outcome may be appropriate, as long as the target-oriented strategy to attain remission or low disease activity within 6 months remains paramount; the latter approach, indeed, may be a common or enforced approach in many healthcare systems. Studies suggesting that step-up csDMARD combination therapy was as effective as a step-up combination of a biological agent with MTX87 88 104 were seen to be in conflict with results from other studies showing better efficacy of addition of a bDMARD.89 Obviously, and for reasons of clarity, when speaking of csDMARDs, the Task Force had only the hitherto employed csDMARDs in mind and not any potential new targeted synthetic (ts) DMARD, such as a kinase inhibitor.

seen to be in conflict with results from other studies showing better efficacy of addition of a bDMARD.89 Obviously, and for reasons of clarity, when speaking of csDMARDs, the Task Force had only the hitherto employed csDMARDs in mind and not any potential new targeted synthetic (ts) DMARD, such as a kinase inhibitor. In patients responding insufficiently to MTX and/or other csDMARD strategies, with or without glucocorticoids, bDMARDs (TNF inhibitors, abatacept or tocilizumab, and, under certain circumstances, rituximab) should be commenced with MTX. This point was approved as worded by 90% of the participants. First, the Task Force reiterated here that bDMARDs should primarily be started when patients did not achieve the therapeutic target after treatment with csDMARDs for 6 months (or had no improvement at 3 months). Second, it explicitly defined the agents it meant when mentioning ‘biological DMARDs’. In the 2010 recommendations, the Committee had added ‘current practice would be to start a TNF inhibitor’, and explained this expert opinion with the long-term use of TNF blockers and the availability of registry data when compared with abatacept and tocilizumab; this was simply an expression of a preference based on their larger and longer evidence base and was not intended to preclude use of other biological agents after csDMARD failures. Also, at that time, their application in patients with an inadequate response to csDMARDs was not yet approved for tocilizumab in the USA and for abatacept in Europe. Meanwhile, the approval status has changed for both drugs, the clinical experience with these agents has now grown for several years, and initial registry data do not seem to reveal differences in their safety profiles from the clinical trial data or when compared with TNF inhibitors.105–109 Moreover, a direct comparison of abatacept and adalimumab in patients with active disease despite MTX revealed very similar efficacy and overall safety.110 Therefore the Task Force decided by a 90% majority vote that no preference of one over another biological agent should be expressed in the 2013 update of the recommendations. However, the Task Force recognised that there was still more experience with TNF inhibitors than with other bDMARDs, and that more safety data from registries would be desirable for the newer bDMARDs.

that no preference of one over another biological agent should be expressed in the 2013 update of the recommendations. However, the Task Force recognised that there was still more experience with TNF inhibitors than with other bDMARDs, and that more safety data from registries would be desirable for the newer bDMARDs. Notably, IL-1 inhibitors have not shown strong efficacy when compared with other bDMARDs in meta-analyses, so anakinra is not specifically mentioned in the abbreviated recommendation; nevertheless, some patients may respond to this bDMARD. Thirdly, the Task Force intentionally added ‘under certain circumstances rituximab’; while rituximab is approved for use after patients have responded insufficiently to TNF blockers, the Committee acknowledged that trial data in patients who were naïve for csDMARDs and those who had an inadequate response to csDMARDs have been published111 112 (level 1 evidence) and that, in the presence of certain contraindications for other agents—such as a recent history of lymphoma, latent tuberculosis (TB) with contraindications to the use of chemoprophylaxis, living in a TB-endemic region, or a previous history of demyelinating disease—rituximab may be considered as a first-line biological agent. Some rheumatologists also prioritise this drug in patients with a recent history of any malignancy, because there are no indications that rituximab use is associated with the occurrence of cancers113 114; furthermore, rituximab is the least expensive biological agent at present. Fourth, when speaking of TNF inhibitors, the Task Force listed the presently approved agents, adalimumab, certolizumab pegol, etanercept, golimumab and infliximab, but also decided to mention biosimilars under the proviso that they become approved in the USA and/or Europe; current data suggest that at least one biosimilar, CT-P13, has a similar efficacy and safety profile to the original antibody, infliximab, in RA and axial spondyloarthritis.115 116 Fifth, the Task Force felt that all bDMARDs should be used preferentially in combination with MTX or other csDMARDs. For neither TNF inhibitors nor rituximab or abatacept has monotherapy been consistently found to be superior to MTX alone, whereas combination therapy has; a dose of 10 mg MTX or more a week appears to be effective and appropriate for use with adalimumab and infliximab63 117 and, until proven otherwise, also with all other TNF inhibitors.

bitors nor rituximab or abatacept has monotherapy been consistently found to be superior to MTX alone, whereas combination therapy has; a dose of 10 mg MTX or more a week appears to be effective and appropriate for use with adalimumab and infliximab63 117 and, until proven otherwise, also with all other TNF inhibitors. Only tocilizumab has been repeatedly demonstrated to be superior as a monotherapy over MTX or other csDMARDs, although the Japanese study had an oplen label design and the MTX dose was low.118 119 In 2010, the Committee explicitly mentioned that a three-arm trial in early RA is needed to gain full insight, and, most recently, these data became available, albeit only in abstract form,120 revealing that only in combination with MTX tocilizumab (8 mg/kg) showed consistent significant superiority over MTX with regard to clinical, functional and structural outcomes. The other arms, tocilizumab monotherapy (8 mg/kg) and tocilizumab (4 mg/kg) in combination with MTX, showed superiority mainly in reaching the primary clinical end point (DAS28–erythrocyte sedimentation rate <2.6, a measure confounded by placing a high weight on acute phase reactant levels121), with only numeric differences in most of the clinical and functional secondary end points, most of which did not reach statistical significance. On the other hand, a head-to-head trial in patients with established RA who stopped MTX therapy revealed tocilizumab monotherapy to be superior to adalimumab monotherapy in most (though not all) endpoints.36 Thus, if biological monotherapy must be initiated, tocilizumab has some supportive evidence, but taken together, the data strongly support the use of all biological agents in combination with MTX. While clinical response is usually maintained even on withdrawal of MTX in patients receiving established therapy with MTX plus tocilizumab or a TNF inhibitor (and therefore presumably also other bDMARDs),122–124 there is rarely a reason to withdraw MTX, since, with established therapy, it is usually well tolerated. Also monotherapy is not a major recommendation by the Task Force, which clearly preferred maintenance of combination therapy. Finally, it is important to note that the Task Force agreed to abandon former recommendation No 14: ‘DMARD-naïve patients with poor prognostic markers might be considered for combination therapy of MTX plus a biological’.

ajor recommendation by the Task Force, which clearly preferred maintenance of combination therapy. Finally, it is important to note that the Task Force agreed to abandon former recommendation No 14: ‘DMARD-naïve patients with poor prognostic markers might be considered for combination therapy of MTX plus a biological’. In 2010 it was already stated that early use of a biological agent should only be considered in exceptional patients; however, as it stood, this statement could have been misinterpreted as advocating use of biological agents even before an initial csDMARD strategy had failed. With the current decision, the use of bDMARDs before trying a csDMARD approach is even more strongly discouraged than signified by the 2010 recommendation. The majority of the current Committee members felt that using a treat-to-target strategy that gave patients the initial opportunity to respond to treatment in line with items 4, 5 and 7 still provides the option of adding a biological agent within 6 months—and thus quite early in the disease course or therapeutic chronology—if the treatment target was not reached. This approach was supported by several recent clinical trials.29 88 125 126 Although bDMARDs in comparison with csDMARDs in early disease confer a significant structural benefit, this benefit was deemed to be neither sufficiently large nor sufficiently frequent, provided that a treat-to-target strategy with treatment adaptations within 6 months was adhered to.125–127 This decision was probably the most heavily debated one: an initial ballot revealed a 94% majority for deleting the old recommendation No 14; subsequently, after thorough discussions, a re-voting process was solicited, but only 33% of the members voted for re-inclusion of old recommendation No 14.

as adhered to.125–127 This decision was probably the most heavily debated one: an initial ballot revealed a 94% majority for deleting the old recommendation No 14; subsequently, after thorough discussions, a re-voting process was solicited, but only 33% of the members voted for re-inclusion of old recommendation No 14. In this context it should be clarified that the Task Force was fully aware of the data in patients with early RA who have significantly higher response rates with bDMARDs combined with MTX than MTX alone; however, embedded within this responder population are good responders to MTX monotherapy who experience about 25% (or more) ACR70 improvement (corresponding to a low disease activity state including remission) across studies without any additional treatment adaptations being allowed over a 1-year trial period; in clinical practice, many of these patients would have been overtreated if they had received biological agents instead, placing them at a potentially increased risk of serious adverse events and incurring high costs. Also, it must be borne in mind that the BeSt study showed that csDMARDs plus glucocorticoids led to very similar initial clinical, functional and structural results as with bDMARDs,97 and the IMPROVED trial showed a very high rate of good outcomes using MTX plus low-dose glucocorticoids within a few months.60 Nevertheless, there may still be an exceptional patient in whom the use of a bDMARD in combination with MTX as the first DMARD strategy is considered appropriate. One can imagine patients whose professional or family life entirely depends on a rapid complete resolution of the joint symptoms and where glucocorticoids as adjunctive therapy with csDMARDs have failed or cannot be used because of contraindications. In such cases, the exceptional use of a biological agent is not precluded now that we have dismissed this recommendation from its former place in the table, but the prominence that could be misinterpreted has now been removed.

adjunctive therapy with csDMARDs have failed or cannot be used because of contraindications. In such cases, the exceptional use of a biological agent is not precluded now that we have dismissed this recommendation from its former place in the table, but the prominence that could be misinterpreted has now been removed. Importantly, however, there are studies suggesting that early induction therapy with anti-TNF plus MTX may result in good outcomes even after withdrawal of the biological agent.128 129 Nevertheless, another study, although partly confirming these results, resulted in a relatively high relapse rate on withdrawal of the TNF inhibitor.130 Thus, more data are needed to support induction therapy, but further evidence confirming the maintenance of remission after withdrawal of the biological agent may lead to a paradigm change in our approach to treating RA (see item 12).

ts, resulted in a relatively high relapse rate on withdrawal of the TNF inhibitor.130 Thus, more data are needed to support induction therapy, but further evidence confirming the maintenance of remission after withdrawal of the biological agent may lead to a paradigm change in our approach to treating RA (see item 12). If a first bDMARD has failed, patients should be treated with another bDMARD; if a first TNF inhibitor therapy has failed, patients may receive another TNF inhibitor or a biological agent with another mode of action. A consequence of item 9, recommendation 10 simply states that once the treatment target has not been reached with an initial biological therapy, other bDMARDs should be used; no preference is stated. The second part of this recommendation focusing on patients who have initially received a TNF inhibitor may seem somewhat redundant. However, it has two purposes: (i) to express the conclusion of the Task Force that current evidence does not suggest any one agent to be better than another TNF inhibitor when active disease prevails despite initial treatment with a TNF blocker; (ii) over the next few years, new biological agents targeting the IL-6 receptor (sarilumab) or IL-6 (clazakizumab, sirukumab) may become available131–133; without specific note on the options after failure of an initial TNF inhibitor therapy, one could infer that potentially approved new IL-6 inhibitors might be used after failure of tocilizumab, but in contrast with TNF inhibition, the efficacy of such an approach is currently unknown for IL-6 inhibition (or costimulation blockers or rituximab). Of note, with biosimilars approaching, it is self-evident that an infliximab biosimilar cannot be regarded as ‘another TNF inhibitor’ in patients with an insufficient response to infliximab. This recommendation was voted for by 97% of the members.

ly unknown for IL-6 inhibition (or costimulation blockers or rituximab). Of note, with biosimilars approaching, it is self-evident that an infliximab biosimilar cannot be regarded as ‘another TNF inhibitor’ in patients with an insufficient response to infliximab. This recommendation was voted for by 97% of the members. Tofacitinib may be considered after biological treatment has failed. Tofacitinib, a JAK inhibitor, was approved for the treatment of RA in the USA, Japan and Russia at the time of the Task Force's meeting on 9 April 2013. For reasons stated above, an a priori decision had been made to address tofacitinib in the recommendations based on evidence of efficacy and safety available from the literature and accrued in the course of the respective SLR.13 Tofacitinib is not a bDMARD, but a synthetic chemical compound. It is a targeted molecule interfering with specific signal-transduction pathways and thus could not be subsumed within the term ‘conventional synthetic DMARDs’. Therefore the Task Force decided to address its use in a separate recommendation as a tsDMARD, rather than as part of csDMARDs or bDMARDs.2 The evidence from published papers and abstracts has convinced the Committee that tofacitinib is sufficiently efficacious in improving clinical, functional and structural outcomes to be considered a DMARD.134–136 The fact that the 5 mg dose approved in the USA and Japan just misses statistical significance for inhibition of joint damage progression compared with placebo at 12 months (p=0.06)137 did not preclude the Task Force from recognising its structural efficacy, given significant radiological differences at this dose in another trial.138 However, little is currently known about its long-term safety. Data from clinical trials reveal a numerical increase in serious infection rates compared with controls; herpes zoster infections in particular appear to be more common than seen with TNF inhibitors;134 139 several cases of TB and non-TB opportunistic infections have been reported; lymphocytopenia and anaemia also occur, and haemoglobin levels appear to increase less upon clinical improvement than seen with csDMARDs and bDMARDs. In light of the many available csDMARDs and bDMARDs that have long-standing clinical experience data, the Task Force felt that tofacitinib should primarily be used when bDMARDs have been insufficiently effective, even though it is already approved in the USA, Japan, Russia and meanwhile Switzerland for use after failure of csDMARDs.

e many available csDMARDs and bDMARDs that have long-standing clinical experience data, the Task Force felt that tofacitinib should primarily be used when bDMARDs have been insufficiently effective, even though it is already approved in the USA, Japan, Russia and meanwhile Switzerland for use after failure of csDMARDs. Indeed, the discussion initially focused on whether tofacitinib should only be recommended for use only after failure with two bDMARDs with different modes of action, but ultimately it was decided to just reflect this discussion item in the accompanying text and not in the recommendation. More clinical experience and safety data from registries, with a particular focus on serious infections, herpes zoster and malignancies, will be needed before the actual place of tofacitinib in the treatment sequence can be clarified, and at present the Committee did not feel that tofacitinib was safer or more efficacious than rituximab, which, according to currently existing labelling, should be used after TNF inhibitor failure. While the Task Force mainly focused on efficacy and safety, it also considered economic aspects, as supported by GRADE140 and as occurred in the 2010 recommendations when all recommendations were supported by cost-effectiveness data, with the exception of starting biological agents before sDMARDs.8 Given constrained healthcare budgets, the inefficient use of healthcare resources (ie, funding those interventions that are not cost-effective) often results in either a lost opportunity to improve the health of other individuals with cost-effective interventions or increased costs through taxes or insurance premiums. Hence the Committee noticed that the annual cost of tofacitinib in the USA and Switzerland is currently about US$25 000 and CHF25 000, respectively, placing it at a similar level to biological agents.141 142 Notably, the first biosimilar has been approved in Europe in the meantime143 144 and is expected to be priced at lower levels than the currently available bDMARDs.31 Therefore, although the Task Force appreciates that tofacitinib is an oral first-in-class drug with a different mechanism of action and is aware of the approval situation in the USA, Japan and other countries, it did not believe it was yet possible to conclude that tofacitinib has a similar safety profile to tocilizumab or other biological agents for which far more person-years of exposure have been accumulated and reported to date.

anism of action and is aware of the approval situation in the USA, Japan and other countries, it did not believe it was yet possible to conclude that tofacitinib has a similar safety profile to tocilizumab or other biological agents for which far more person-years of exposure have been accumulated and reported to date. Thus, additional long-term safety data and clinical experience will be needed to determine an overall benefit/harm ratio. Also, a proper cost-effectiveness analysis would be desirable. Accordingly, the Committee preferred not to recommend tofacitinib after MTX failure as it did for other biological agents. Among the Task Force members, 90% voted in favour of this recommendation as phrased here. Of particular importance, at the time of the Task Force's meeting on 9 April 2013, it was unknown when the EMA would release its decision on the approval of tofacitinib. Thus, the discussions, formulation of recommendation, explanatory stipulations and on-site voting of the Committee occurred before EMA published its first and second negative decision on tofacitinib (with resubmission being planned by the company).145–147 Anonymous voting on the level of agreement (strength of recommendation), however, occurred electronically after the first EMA decision became known and was the lowest of all items (7.6 on a scale of 0–10), which may have been influenced by this information.

tinib (with resubmission being planned by the company).145–147 Anonymous voting on the level of agreement (strength of recommendation), however, occurred electronically after the first EMA decision became known and was the lowest of all items (7.6 on a scale of 0–10), which may have been influenced by this information. If a patient is in persistent remission after having tapered glucocorticoids, one can consider tapering bDMARDs, especially if this treatment is combined with a csDMARD. In contrast with 2010—when a similar recommendation was stated—more evidence is now available and there was unanimous approval within the Task Force. In established RA, the available data suggest that most patients flare upon withdrawal of a TNF inhibitor,148–151 and more profound and persistent responses increase the likelihood of maintenance of a good outcome with csDMARDs even after withdrawal of the bDMARD.150 In the PRESERVE trial, the time frame was at least 4 months.152 However, for early RA, the data are somewhat contradictory. While the primary target in early RA clearly should be stringent remission,33 34 most data on withdrawal of bDMARDs come from patients who are in sustained low disease activity. The OPTIMA trial showed that a 6-month induction regimen with adalimumab plus MTX soon after diagnosis may be sufficient to allow most patients to maintain low disease activity or remission after open label and even after double-blind withdrawal of the TNF inhibitor128 153 154; however, while similar findings on withdrawal of a TNF blocker were obtained in an open label fashion in the HIT HARD study,129 somewhat contradicting data were seen in the PRIZE trial, where dose reduction but not withdrawal of the biological agent was accompanied by maintenance of good outcome.130 Thus, only if further and more broadly confirmed can short-term inclusion of a biological agent in a first DMARD strategy become a true option (see discussion to recommendation No 9). On the other hand, reduction of the TNF inhibitor dose after attainment of DAS28<2.6 in early RA allows excellent outcomes to be maintained,130 as also seen in established RA.152 155 While most studies on dose reduction or withdrawal have been performed with TNF blockers, some data on other bDMARDs are emerging with similar overall results,156–158 but clearly more information is needed in this regard. Importantly, before bDMARDs are tapered, glucocorticoids should have been withdrawn in line with point 7.

ost studies on dose reduction or withdrawal have been performed with TNF blockers, some data on other bDMARDs are emerging with similar overall results,156–158 but clearly more information is needed in this regard. Importantly, before bDMARDs are tapered, glucocorticoids should have been withdrawn in line with point 7. Also of note, reinstitution of bDMARDs appears to allow the good outcome to be recaptured.150 156 159

ost studies on dose reduction or withdrawal have been performed with TNF blockers, some data on other bDMARDs are emerging with similar overall results,156–158 but clearly more information is needed in this regard. Importantly, before bDMARDs are tapered, glucocorticoids should have been withdrawn in line with point 7. Also of note, reinstitution of bDMARDs appears to allow the good outcome to be recaptured.150 156 159 In cases of sustained long-term remission, cautious reduction of the csDMARD dose could be considered, as a shared decision between patient and physician. Except for minimal rewording (the term ‘titration’ is replaced by ‘reduction’), this item is identical with point 13 of the 2010 recommendations; it refers solely to those patients in whom glucocorticoids, if used, have already been stopped and/or who have attained and maintained the targeted therapeutic state on csDMARDs or those in whom bDMARDs have been successfully withdrawn (see above). This recommendation received 100% of the votes. As stated then, it must be borne in mind that stopping csDMARDs in patients with established RA in remission is followed by flares in about 70% of patients, twice as frequently as maintaining therapy irrespective of regimen.160 161 Therefore the focus of this item is on csDMARD reduction rather than cessation. On the other hand, drug-free remission may be an option in patients in whom therapy was initiated very early and who therefore also had achieved remission early in their disease course.162 Of note, in light of the availability of the ACR–EULAR remission definitions, the term ‘persistent remission’ in this recommendation primarily pertains to these definitions; however, formal DMARD withdrawal studies using them have not yet been performed.

ore also had achieved remission early in their disease course.162 Of note, in light of the availability of the ACR–EULAR remission definitions, the term ‘persistent remission’ in this recommendation primarily pertains to these definitions; however, formal DMARD withdrawal studies using them have not yet been performed. When therapy needs to be adjuusted, factors apart from disease activity, such as progression of structural damage, comorbidities and safety issues, should be taken into account. Again, this point is essentially identical with the last recommendation of 2010 and was unanimously approved at the Task Force meeting. It is intended to raise awareness that reaching the outcome of low disease activity or remission is not an absolute prerequisite and that it is equally important to account for comorbidities and other contraindications when targeting a good outcome. Conversely, high disease activity is typically associated with comorbidities,163 164 so effective therapeutic intervention may also prevent comorbidity.165–167 Finally, some patients with low disease activity may still develop seriously progressive radiographic joint damage, so after potential lag periods have been accounted for to recognise progression,168 such patients may then need intensification of therapy. Table 2 Levels of evidence (LoE), grades of recommendations (GoR), strength of recommendation (SoR; = level of agreement), and % of votes for the respective items as worded LoE GoR SoR % A. na na 9.8±0.9 100 B. na na 9.8±0.5 100 C. na na 9.6±0.6 100

When therapy needs to be adjuusted, factors apart from disease activity, such as progression of structural damage, comorbidities and safety issues, should be taken into account. Again, this point is essentially identical with the last recommendation of 2010 and was unanimously approved at the Task Force meeting. It is intended to raise awareness that reaching the outcome of low disease activity or remission is not an absolute prerequisite and that it is equally important to account for comorbidities and other contraindications when targeting a good outcome. Conversely, high disease activity is typically associated with comorbidities,163 164 so effective therapeutic intervention may also prevent comorbidity.165–167 Finally, some patients with low disease activity may still develop seriously progressive radiographic joint damage, so after potential lag periods have been accounted for to recognise progression,168 such patients may then need intensification of therapy. Table 2 Levels of evidence (LoE), grades of recommendations (GoR), strength of recommendation (SoR; = level of agreement), and % of votes for the respective items as worded LoE GoR SoR % A. na na 9.8±0.9 100 B. na na 9.8±0.5 100 C. na na 9.6±0.6 100 1. 1a A 9.8±0.5 97 2. 1a A 9.6±0.7 100 3. 2b B 9.5±1.0 100 4. 1a A 9.6±0.9 100 5. 1a A 9.0±1.7 87 6. 1a A 9.5±0.8 100 7. 1a− A 8.9±1.2 73 8. 5 D 8.9±1.3 100 9. 1b A 9.2±1.2 90 10. 1a A 9.4±0.8 97 11. 1b* 5† A* D† 7.6±1.8 90 12. 2b B 8.7±1.8 100 13. 4 C 8.9±1.0 100 14 3b C 9.7±0.7 100 LoE and GoR are based on the recommendations of the Oxford Centre for Evidence-Based Medicine.

4. 1a A 9.6±0.9 100 5. 1a A 9.0±1.7 87 6. 1a A 9.5±0.8 100 7. 1a− A 8.9±1.2 73 8. 5 D 8.9±1.3 100 9. 1b A 9.2±1.2 90 10. 1a A 9.4±0.8 97 11. 1b* 5† A* D† 7.6±1.8 90 12. 2b B 8.7±1.8 100 13. 4 C 8.9±1.0 100 14 3b C 9.7±0.7 100 LoE and GoR are based on the recommendations of the Oxford Centre for Evidence-Based Medicine. *The general statement is evidence based. †The place in the treatment algorithm is based on expert consensus opinion. na, not applicable. Figure 1 Algorithm based on the 2013 European League Against Rheumatism recommendations on rheumatoid arthritis management. ACPA, anti-citrullinated protein antibody; DMARD, disease-modifying antirheumatic drug; RF, rheumatoid factor; TNF, tumour necrosis factor. Discussion The 2013 update of the EULAR RA management recommendations comprises three overarching principles and 14 recommendations. The overarching principles bring the patient into even closer focus than in 2010 by moving shared decision-making to become principle A. In recommendation 2 the Task Force reconfirmed that the therapeutic target was low disease activity (especially in patients with established RA) or remission (especially in patients with early, newly diagnosed RA), although the target may have to be modified in accordance with comorbidities and safety considerations (item 14); importantly, since publication of the 2010 recommendations, ACR and EULAR have provided a new index- and Boolean-based definition of remission, for both clinical trials and practice, and these criteria should be used accordingly.34

ave to be modified in accordance with comorbidities and safety considerations (item 14); importantly, since publication of the 2010 recommendations, ACR and EULAR have provided a new index- and Boolean-based definition of remission, for both clinical trials and practice, and these criteria should be used accordingly.34 Compared with the 2010 recommendations, the current update continues to advocate the efficacy of csDMARDs as monotherapy or combination therapy as the initial DMARD treatment strategy, ideally combined with glucocorticoids, which—as now proposed—should primarily be of low dose (≤10 mg per day) and applied for only a limited time (6 months; item 7). Intra-articular application of glucocorticoids was not part of the search activities, but is evidently an important aspect in the treatment of RA, especially when there is residual joint activity in patients who do well on DMARD therapy otherwise.169 170 The Task Force now also regards all currently approved bDMARDs as being similarly effective (with the exception of anakinra) and generally safe for use as an initial biological therapy after csDMARD failure. While the 2010 Task Force had recognised a shortage of longer-term and, especially, registry data on non-TNF inhibitor biological agents, these have now become available to a sufficient extent to warrant this change. However, there is still a need for more observational/registry data for abatacept, rituximab and tocilizumab; there are still many fewer ‘real world’ safety data available for these three compounds than for the TNF inhibitors.

ogical agents, these have now become available to a sufficient extent to warrant this change. However, there is still a need for more observational/registry data for abatacept, rituximab and tocilizumab; there are still many fewer ‘real world’ safety data available for these three compounds than for the TNF inhibitors. Further, in the 2013 update, the preference to use a bDMARD in combination with csDMARDs, particularly MTX, rather than as monotherapy is reiterated. Moreover, although the 2010 Task Force made clear statements disfavouring biological therapy as part of the initial DMARD strategy, the 2013 Task Force wished to enforce this point and avoid any misunderstanding by abandoning any statement in this respect within the abbreviated recommendation statements. The Task Force had sufficient evidence and was in full agreement that disease-modifying therapy should start with csDMARDs, ideally combined with glucocorticoids, and that, in a treat-to-target approach, patients who do not attain the therapeutic target by 6 months and have poor prognostic markers would benefit to a similar extent from the addition of biological agents as if they had received them from the beginning. This approach prevents overtreatment of a significant proportion of patients who can achieve low disease activity or remission with an initial csDMARD plus glucocorticoid strategy. There was also agreement that the current lack of support for initiating the therapeutic cascade with bDMARDs might fade if the promise of persistent good outcomes following withdrawal of biological agents after a respective induction therapy in early RA is maintained.129 154

itial csDMARD plus glucocorticoid strategy. There was also agreement that the current lack of support for initiating the therapeutic cascade with bDMARDs might fade if the promise of persistent good outcomes following withdrawal of biological agents after a respective induction therapy in early RA is maintained.129 154 The Task Force now also briefly addressed the use of bsDMARDs. Currently, data are available for one biosimilar infliximab poduct115 which shows similar efficacy and safety profiles to the original biological agent and was placed alongside the other TNF inhibitors in the therapeutic cascade; it is assumed that the price of this biosimilar will be significantly lower. Finally, the Task Force also dealt with the available data for tofacitinib.13 The abundance of efficacy data available has convinced the Task Force that tofacitinib at the twice daily 5 mg dose has clinical, functional and structural efficacy resembling that seen with bDMARDs; this may not be surprising given its pharmacological profile, namely inhibition of the JAK pathway, which is involved, among others, in IL-6 signalling. However, as detailed in the Results section, some safety aspects of tofacitinib are of concern and precluded recommendation of its use before the failure of at least one and preferably two biological agents, since many bDMARDs are currently available on the market and familiar to rheumatologists. In the absence of a cost-effectiveness analysis, the Task Force was also concerned about the remarkably high price in the USA (and meanwhile also in Switzerland).141 142 While the Task Force's major focus was and should be efficacy and safety of available therapies, it did not ignore its own overarching principle C, which includes cost considerations of medications in general and in its own therapeutic recommendations, as evidenced by inclusion of a health economist in the Task Force. Thus, the current recommendation for the first tsDMARD considers its entire net profile (risk/benefit/costs); this aspect was also addressed for other therapies, especially boDMARDs, in 2010.3 8 However, it is evident that economic approaches will differ between countries depending on their healthcare systems. This recommendation was voted on while the Task Force had knowledge about the US label and literature on tofacitinib, but before the negative opinion of EMA became known.

especially boDMARDs, in 2010.3 8 However, it is evident that economic approaches will differ between countries depending on their healthcare systems. This recommendation was voted on while the Task Force had knowledge about the US label and literature on tofacitinib, but before the negative opinion of EMA became known. Finally, tapering bDMARDs was addressed, as new data had become available (item 12) that suggest that, once low disease activity and, especially, remission is sustained, a dose reduction of bDMARDs will allow maintenance of the good outcome. The Task Force did not address issues of immunogenicity reported for some but not other bDMARDs, since the SLRs performed did not reveal any significant differences in efficacy among the different bDMARDs and also since agents that induce drug antibodies were not shown to convey worse outcome than agents that do not.171 In addition, although there are data available that suggest that baseline TNF levels may predict response to TNF inhibitor therapy,150 the Task Force did not focus on predictors of response and regarded this aspect as part of the research agenda.

bodies were not shown to convey worse outcome than agents that do not.171 In addition, although there are data available that suggest that baseline TNF levels may predict response to TNF inhibitor therapy,150 the Task Force did not focus on predictors of response and regarded this aspect as part of the research agenda. Thus, looking at the major changes in comparison with the 2010 recommendations,3 this update placed combination therapy of csDMARDs at the same level as MTX monotherapy as a first-line DMARD strategy (in addition to its potential use as a second csDMARD strategy after insufficient efficacy of MTX in patients without adverse prognostic markers), all preferably in combination with glucocorticoids. For the use of biological agents as a second-line DMARD strategy in patients with adverse prognostic signs, a preference for TNF inhibitors is no longer maintained, and the use of bDMARDs in combination with csDMARDs is generally advocated. Further, biosimilars and tofacitinib are addressed. Compared with the 2012 update of the ACR management recommendations,172 the EULAR update is of a more general nature and avoids discussing individual case scenarios, focuses less on safety aspects (which are covered in the respective SLR and are widely available in the respective package inserts), addresses glucocorticoids, disregards minocycline, does not advocate the use of biological agents as monotherapy or part of the initial treatment strategy, places tocilizumab at the same level as other biological agents, and also discusses tofacitinib and biosimilars.

idely available in the respective package inserts), addresses glucocorticoids, disregards minocycline, does not advocate the use of biological agents as monotherapy or part of the initial treatment strategy, places tocilizumab at the same level as other biological agents, and also discusses tofacitinib and biosimilars. One of the most important aspects in the context of developing recommendations or guidelines is their implementation173 and actual application. Implementation is a multistep procedure, which benefits from the adoption of international recommendations by local societies, as was the case for the 2010 EULAR recommendations.9–12 Nevertheless, adoption of therapeutic targets and means to reach these targets in clinical practice have been shown to be far from ideal,174 and, in a very recent analysis of the implementation of guidelines and recommendations across Europe, there was some room for further improvement.175 Thus, it will clearly be a challenge for EULAR to ensure and find ways to monitor whether these updated recommendations are at least considered widely in clinical care.

4 and, in a very recent analysis of the implementation of guidelines and recommendations across Europe, there was some room for further improvement.175 Thus, it will clearly be a challenge for EULAR to ensure and find ways to monitor whether these updated recommendations are at least considered widely in clinical care. The 2013 update of the EULAR recommendations was developed by a Task Force consisting of 33 members from 11 European countries and the USA; among them were four patients, an infectious disease specialist and a health economist. While it may be seen to be a limitation that the rheumatologists of the Task Force came only from Europe and none was from the USA, Japan or other countries, it is important to state that most of these recommendations are based on a large body of evidence and only a few reflect elements of expert opinion (see also table 2). Even if these recommendations are regarded to reflect primarily a European view, they can be used as a template for slightly amended versions by other national or international rheumatological societies outside Europe, as has, indeed, been the case with the 2010 recommendations.9 10 The recommendations are intended to assist and inform rheumatologists, patients, hospital managers, representatives of social security agencies, regulatory authorities and government officials. Although some of the medications discussed are not yet licensed at all or in all countries, they are expected to receive this status in due course, and sufficient literature was available to address them accordingly. Importantly, most of the recommendations have a very high level of evidence, received a large majority vote, and have a high strength of recommendation. Nevertheless, some items were developed just by expert opinion or comprise a mixture of high evidence level and expert opinion, and this drove the research agenda presented in box 1. It is rewarding to see that some of the items of the research agenda presented in 2010 (eg, items 2, 4, 6)3 have already been partly or fully addressed and this, indeed, informed the current update. Box 1 Research agenda After insufficient response to MTX, is step-up therapy using a combination of csDMARDs as efficacious as step-up therapy using a bDMARD? Such trials should be thoroughly performed by defining an appropriate end point, adhering to the a priori primary end point, and recruiting/evaluating sufficient numbers of patients in accordance with the original power calculation.

erapy using a combination of csDMARDs as efficacious as step-up therapy using a bDMARD? Such trials should be thoroughly performed by defining an appropriate end point, adhering to the a priori primary end point, and recruiting/evaluating sufficient numbers of patients in accordance with the original power calculation. Can triple therapy with MTX, sulfasalazine and hydroxychloroquine be regarded as a treatment with ‘three different DMARDs’ or is it just a ‘single DMARD strategy’? What is the most successful tapering strategy of glucocorticoids after bridging or longer-term therapy? What is the balance of benefit/harm of long-term (>6 months) treatment with glucocorticoids at doses up to 10 mg/day in established RA? How long can low-dose glucocorticoids be applied with benefit and without causing harm? How do biological agents plus MTX compare with MTX plus low-dose glucocorticoids in patients with early RA? Is induction therapy with bDMARDs plus MTX as a first treatment strategy followed by withdrawal of the biological agent after 6–12 months as promising an option for abatacept and tocilizumab as it appears to be for TNF inhibitors, and can therefore an induction regimen with bDMARDs plus MTX become a new therapeutic paradigm? With respect to the efficacy and safety of tofacitinib, can biological agents be safely used after tofacitinib (with or without a washout period) and can tofacitinib be safely and effectively used after abatacept, rituximab and tocilizumab? How comparable are the different biological agents to each other and to tofacitinib?

With respect to the efficacy and safety of tofacitinib, can biological agents be safely used after tofacitinib (with or without a washout period) and can tofacitinib be safely and effectively used after abatacept, rituximab and tocilizumab? How comparable are the different biological agents to each other and to tofacitinib? Are there, aside from rituximab, differences in responsiveness to bDMARDs between seropositive and seronegative patients? Is there a difference between reducing dose and increasing interval when tapering biological agents after the targeted state has been reached? Is it correct that, when patients have not reached the target on MTX, those with risk factors for bad outcome benefit more from the addition of a biological agent than from switching to or addition of csDMARDs? Is it correct that, when patients have not reached the target on MTX, those with no risk of bad outcome benefit equally from switching to or addition of csDMARDs as they would from addition of a biological agent? Can we find common or specific predictors of response to the different biological agents, csDMARDs and tsDMARDs? What are the risk factors that define patients who benefit from a more intensive initial treatment modality? Which factors predict who will be able to successfully withdraw bDMARDs and who not? How big is the difference in clinical, functional and structural efficacy when treatment strategies aiming to achieve remission are compared with those aiming to achieve low disease activity?

What are the risk factors that define patients who benefit from a more intensive initial treatment modality? Which factors predict who will be able to successfully withdraw bDMARDs and who not? How big is the difference in clinical, functional and structural efficacy when treatment strategies aiming to achieve remission are compared with those aiming to achieve low disease activity? How can immunogenicity of bDMARDs explain the similarity of clinical trial data observed with both immunogenic and non-immunogenic compounds? How good is patient adherence to biological agents and can lack of adherence be related to loss of efficacy? Is measurement of serum drug and/or drug antibody levels useful in clinical practice? Which degree of improvement is needed at 3 months to ensure reaching the treatment target at 6 months and beyond? How long should we aim to use concomitant GC therapy in RA? To understand more in detail how the molecular mechanisms of genomic and non-genomic GC actions (and their dose dependency!) mediate the clinically wanted benefits but also the known adverse effects. To improve treatment with conventional GCs (eg, in respect of timing and circadian rhythms) and develop innovative GC or novel GC receptor ligands. To evaluate further possibilities to reduce the (subjective) adverse events of MTX, the anchor drug in treating RA. Long-term safety data in real life (registries) are needed for non-TNF inhibitor biological agents and tofacitinib. Is tocilizumab monotherapy as efficacious and safe as other bDMARDs plus MTX?

To improve treatment with conventional GCs (eg, in respect of timing and circadian rhythms) and develop innovative GC or novel GC receptor ligands. To evaluate further possibilities to reduce the (subjective) adverse events of MTX, the anchor drug in treating RA. Long-term safety data in real life (registries) are needed for non-TNF inhibitor biological agents and tofacitinib. Is tocilizumab monotherapy as efficacious and safe as other bDMARDs plus MTX? Can bDMARDs and/or sDMARDs be safely withdrawn in patients with established disease who have long-standing (>6 months) remission according to the ACR–EULAR definition? ACR, American College of Rheumatology; bDMARD, biological DMARD; csDMARD, conventional synthetic DMARD; DMARD, disease-modifying antirheumatic drug; EULAR, European League against Rheumatism; GC, ; MTX, methotrexate; RA, rheumatoid arthritis; TNF, tumour necrosis factor; tsDMARD, targeted synthetic DMARD.

Can bDMARDs and/or sDMARDs be safely withdrawn in patients with established disease who have long-standing (>6 months) remission according to the ACR–EULAR definition? ACR, American College of Rheumatology; bDMARD, biological DMARD; csDMARD, conventional synthetic DMARD; DMARD, disease-modifying antirheumatic drug; EULAR, European League against Rheumatism; GC, ; MTX, methotrexate; RA, rheumatoid arthritis; TNF, tumour necrosis factor; tsDMARD, targeted synthetic DMARD. The 2013 update of the EULAR recommendations provides the current state of thinking in the field of RA management from a mainly European perspective. The updated recommendations comprise the synthesis of available information based primarily on efficacy and safety of the agents addressed, with inclusion of some health economic considerations. They should enable optimal outcomes in our patients. However, a significant proportion of patients may still not reach the desired therapeutic target. Therefore new therapies are still needed and, indeed, are on the horizon. Also, some items will need to be further developed in the context of future research activities. Consequently, we will carefully follow the developments in the field and anticipate that yet another update may be needed in 2–3 years. Until then, we hope that the current recommendations will find their way into clinical practice either directly or through national societies that may wish to use them as a framework for development of local guidance documents.

developments in the field and anticipate that yet another update may be needed in 2–3 years. Until then, we hope that the current recommendations will find their way into clinical practice either directly or through national societies that may wish to use them as a framework for development of local guidance documents. Supplementary Material Web table We would like to thank the European League Against Rheumatism (EULAR) for providing the funds to perform this task. Contributors: JSS and RL wrote the first draft with help from DvdH. SR, JN and CGV performed the literature review. All authors participated in the activities of the Task Force and have provided important contributions to the manuscript. Funding: European League Against Rheumatism.

Supplementary Material Web table We would like to thank the European League Against Rheumatism (EULAR) for providing the funds to perform this task. Contributors: JSS and RL wrote the first draft with help from DvdH. SR, JN and CGV performed the literature review. All authors participated in the activities of the Task Force and have provided important contributions to the manuscript. Funding: European League Against Rheumatism. Competing interests: All the participants in this initiative have disclosed any conflicts of interest. After review by the EULAR Steering Committee, these potential conflicts have been considered as either absent or acceptable with this initiative. The individual declarations of conflicts are available on demand at the EULAR secretariat and are summarised below as remuneration for consultation and/or speaking engagements (‘R’), research funding (‘F’) or ‘none’. JSS—R: Abbott/Abbvie, Amgen, Astra-Zeneca, BMS, Celgene, Glaxo, Infinity, Janssen, Lilly, Medimmune, MSD, Novo-Nordisk, Pfizer, Roche, Samsung, Sandoz, Sanofi, UCB, Vertex; F: Abbott, BMS, MSD, Pfizer, Roche, UCB. RL—R: Abbott/AbbVie, Ablynx, Amgen, Astra-Zeneca, Bristol Myers Squibb, Centocor, Glaxo-Smith-Kline, Novartis, Merck, Pfizer, Roche, Schering-Plough, UCB, Wyeth; F: Abbott, Amgen, Centocor, Novartis, Pfizer, Rhoche, Schering-Plough, UCB, Wyeth. FCB—R: Abbvie, Merck. MB—R: Abbott, Bristol Myers-Squibb, Chugai, Pfizer, Roche; F: Pfizer. GB—Abbott/Abbvie, BMS, MSD, Pfizer, Roche, UCB; F: Abbott, BMS, Pfizer, Roche, UCB. MD—R: Abbott/Abbvie, Pfizer, Roche, UCB, BMS, Hospira, Lilly, Novartis, Sanofi; F: Abbott, Roche. PE—R: MSD, Pfizer, Abbott, Novartis, UCB, Roche, BMS, Lilly, Takeda, Janssen; F: MSD, Roche. CGV—R: Abbvie, BMS, MSD, Pfizer, Roche-Chugai, UCB; F: Expanscience, Nordic Pharma, Pfizer. LG—R: Abbott, BMS, Chugai, Pfizer, Roche, UCB. JN—R: UCB. SR—R: Fundação para a Ciência e Tecnologia. KW—R: Pfizer, Genentech, UCB, Abbott. MdW—R: Abbvie. DA—R: Pfizer, Abbott, MSD, Janssen, Grünenthal, Medac; F: MSD. NB—R: Pfizer, BMS, Roche. JWJB—R: Abbott, BMS, MSD, Mundipharma, Novartis, Pfizer, Roche, UCB; F: Abbott, BMS, MSD, Novartis, Pfizer, Roche, UCB. MB—R: Novartis, Celgene, BMS, UCB, AstraZeneca, Roche, Mundipharma. FB—R: Abbott, Amgen, Horizon, Medac, Mundipharma, Pfizer, Roche, Servier, UCB, Zalicos; F: Horizon, Medac, Pfizer. BC—BMS, Celgene, Lilly, MERCK, Novartis, Pfizer, Roche-Chugai, UCB; F: Pfizer. MC—R: Abbott, Pfizer, Sanofi Aventis, Theva, Celgene, Mundipharm, BMS, Actelion; F: BMS, Actelion. ND—R: Pfizer, MSD, Abbott, Roche. JMWH—none. MK—none.

on, Medac, Mundipharma, Pfizer, Roche, Servier, UCB, Zalicos; F: Horizon, Medac, Pfizer. BC—BMS, Celgene, Lilly, MERCK, Novartis, Pfizer, Roche-Chugai, UCB; F: Pfizer. MC—R: Abbott, Pfizer, Sanofi Aventis, Theva, Celgene, Mundipharm, BMS, Actelion; F: BMS, Actelion. ND—R: Pfizer, MSD, Abbott, Roche. JMWH—none. MK—none. TKK—R: Abbott, Astra-Zeneca, BMS, MSD, Pfizer, Roche, UCB; F: BMS, MSD, Pfizer, Roche, UCB. XM—BMS, GSK, Neovacs, Pfizer, Roche, UCB. KP—R: AbbVie, Gedeon Richter, Roche, Pfizer, MSD, Amgen, Servier, BMS. PLCMvR—R: Abbvie, BMS, Roche, Pfizer, UCB, MSD; F: Abbvie, BMS, Roche, Pfizer, UCB. ARR—R: Abbott, BMS, UCB, MSD, Roche, Chugai, Pfizer. MSV—none. DLS—R: MSD, UCB, BMS; F: Pfizer. TSI—R: Abbott, Medac, Pfizer, UCB, BMS, GSK, MSD; F: Abbott, Pfizer. JBW—None. DvdH—R: Abbott, Amgen, AstraZeneca, BMS, Centocor, Daiichi, Eli-Lilly, GSK, Janssen Biologics, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB; Director of Imaging Rheumatology bv; F: UCB, Pfizer. Provenance and peer review: Not commissioned; externally peer reviewed.

Introduction Since rheumatoid arthritis (RA) imposes a considerable burden for patients, their families and society, therapeutic approaches call for early intervention with, and timely adaptation of, disease-modifying antirheumatic drugs (DMARDs), either as monotherapy or as combination therapy, in order to avoid irreversible damage, long-term disability and premature death. In 2010 a European League Against Rheumatism (EULAR) task force aggregated the available information on RA treatment into practical recommendations,1 based on several systematic literature reviews (SLRs) providing the state of evidence at that time.2–4 DMARDs form two major classes: synthetic chemical compounds (synthetic DMARDs, sDMARDs) and biological agents (bDMARDs). We have now updated these 2009 searches to obtain the available published information on efficacy of synthetic DMARDs as monotherapy or combination therapy, with and without addition of glucocorticoids (GCs). Where appropriate, we will adhere to the recently proposed nomenclature for sDMARDs which, among other aspects, differentiates between conventional synthetic (cs) and targeted synthetic (ts) DMARDs.5

efficacy of synthetic DMARDs as monotherapy or combination therapy, with and without addition of glucocorticoids (GCs). Where appropriate, we will adhere to the recently proposed nomenclature for sDMARDs which, among other aspects, differentiates between conventional synthetic (cs) and targeted synthetic (ts) DMARDs.5 Methods The four main research questions pertained to the efficacy on signs and symptoms, disability and joint damage. Topics considered were (1) the addition of GCs to csDMARDs in early RA; (2) methotrexate (MTX) as monotherapy versus its combination with other csDMARDs (disregarding the addition of biological agents discussed elsewhere)6; (3) individual csDMARDs and (4) tofacitinib, a new tsDMARD specifically targeted at inhibition of Janus kinases. Safety concerns were examined in a separate SLR.7 Tapering strategies for GCs were not dealt with in this SLR. Guidelines for SLRs were followed and are detailed in the online supplementary material. Study selection A SLR was performed in PubMed Medline, Embase, Cochrane library and major congress abstracts after January 2009 until January 2013 for GCs and csDMARDs and until March 2013 for tofacitinib. In addition, abstracts of the American College of Rheumatology (ACR) meetings 2011–2012 and EULAR Congresses 2011–2013 were screened and full publications related to such abstracts taken into account until mid-2013. Only randomised controlled trials (RCTs) were included in this analysis. The risk of bias of the included studies was assessed using the Cochrane Collaboration's tool for risk of bias.8

1–2012 and EULAR Congresses 2011–2013 were screened and full publications related to such abstracts taken into account until mid-2013. Only randomised controlled trials (RCTs) were included in this analysis. The risk of bias of the included studies was assessed using the Cochrane Collaboration's tool for risk of bias.8 Data collection Efficacy was assessed by the change in signs and symptoms and disability status between baseline and week 24, week 52 and week 104, when available, and by the change in radiographic joint damage between baseline and week 52 and week 104. Statistical analysis In each trial the effect size or the standardised response mean for continuous measures and ORs for dichotomous measures were determined to assess the magnitude of the treatment effect. Where possible, pooled effect size, pooled standardised response mean and pooled OR were calculated by meta-analysis, using the inverse of variance method. RevMan V.5.2 (Review Manager, Copenhagen, The Nordic Cochrane Centre, The Cochrane Collaboration, 2012) statistical software was used. Statistical heterogeneity was tested by Q test and I2 test. All meta-analyses were carried out using random-effects models in cases of statistical heterogeneity.

rse of variance method. RevMan V.5.2 (Review Manager, Copenhagen, The Nordic Cochrane Centre, The Cochrane Collaboration, 2012) statistical software was used. Statistical heterogeneity was tested by Q test and I2 test. All meta-analyses were carried out using random-effects models in cases of statistical heterogeneity. Results Glucocorticoids in early RA Of 222 potentially relevant articles, five new studies relating to four RCTs were included (table 1). The selection of articles is shown in online supplementary figure A. Of the five studies, two trials were open-label trials with a high ‘risk of bias’ score10–12; one study was reported only as an abstract at the 2011 EULAR congress10 and two studies were RCTs with a low ‘risk of bias’.9 13 The SAVE (Stop Arthritis Very Early) trial has a particular design since its objective was to prevent development of RA in patients with very early arthritis who did not yet meet RA classification criteria; it did not show efficacy of a single GC injection in this respect, irrespective of added csDMARDs.9 In the other studies all patients had early RA, with a mean disease duration of <1 year and a mean Disease Activity Score in 28 joints (DAS28) of between 5.0 and 5.9. Overall, initial treatment of RA with low-dose prednisone plus MTX showed higher rates of remission at 12 and 52 weeks, lower DAS at 24 weeks and lower Health Assessment Questionnaire (HAQ) scores at 24, 52 and 104 weeks (table 1).10–13 A highly informative study (CAMERA II (Computer Assisted Management in Early Rheumatoid Arthritis trial-II)) reported the efficacy of GCs in a 2-year, prospective, randomised, placebo-controlled, double-blind, multicentre trial in 236 patients with early RA (duration <1 year). The MTX plus prednisone (10 mg/day) strategy was more effective than MTX plus placebo in reducing the progression of erosive joint damage at 104 weeks (primary outcome) (table 1). Patients receiving MTX plus prednisone attained sustained remission at an earlier time point during the trial than patients receiving MTX alone. In addition, the need for additional treatment (subcutaneous MTX, ciclosporin or adalimumab) was significantly lower in the MTX plus prednisone group than in the MTX monotherapy group.13

ceiving MTX plus prednisone attained sustained remission at an earlier time point during the trial than patients receiving MTX alone. In addition, the need for additional treatment (subcutaneous MTX, ciclosporin or adalimumab) was significantly lower in the MTX plus prednisone group than in the MTX monotherapy group.13 Table 1 Randomised controlled trials of glucocorticoids added to DMARDs in early arthritis Study N Glucocorticoid regimen Trial duration (years) Outcome Results in glucocorticoids group (%) Results in control group (%) p Value Machold, 20109 383 Single IM 120 mg methylprednisolone 1 Drug-free persistent clinical remission (both at 12 and 52 weeks) 16.2 17.8 0.685 Fedorenko, 201110 141 Prednisolone 10 mg/day or Prednisolone 10 mg/day+methylprednisolone 1 g IV first day 1 ‘Clinical EULAR remission’ at 12 weeks* 21.3 (oral GC) 3.1 0.027 28.6 (oral GC+IV GC) 0.006 ‘Clinical EULAR remission’ at 52 weeks* 37.5 (oral GC) 11.4 0.012 29.4 (oral GC+IV GC) 0.133 Montecucco, 201211 Todoerti, 201012 220 Prednisone 12.5 mg/day for 2 weeks tapered to 6.25 mg/day for the follow-up period† 1 DAS28≤3.2 at 52 weeks 80.2 75.5 0.44 DAS28<2.6 at 52 weeks 44.8 27.8 0.02 Bakker, 201213 236 Prednisone 10 mg/day† 2 ACR70 at 104 weeks 38 19, 0.002 SHS erosion score at 104 weeks 0 (0–0) 0 (0–2) 0.022 SHS total score at 104 weeks 0 (0–3) 0 (0–4) 0.32 Studies were of glucocorticoids added to MTX except for the study of Machold et al concerning glucocorticoids added to no other therapy, NSAIDs or DMARDs at the investigators’ discretion.

R70 at 104 weeks 38 19, 0.002 SHS erosion score at 104 weeks 0 (0–0) 0 (0–2) 0.022 SHS total score at 104 weeks 0 (0–3) 0 (0–4) 0.32 Studies were of glucocorticoids added to MTX except for the study of Machold et al concerning glucocorticoids added to no other therapy, NSAIDs or DMARDs at the investigators’ discretion. *Study only reported as an abstract at the 2011 EULAR congress: definition of ‘Clinical EULAR remission’ unclear. †Tight control, treatment to target. DAS28, Disease Activity Score in 28 joints; DMARDs, disease-modifying antirheumatic drugs; GC, glucocorticoids; IM, intramuscular; IV, intravenous; MTX, methotrexate; NSAIDs, non-steroidal anti-inflammatory drugs; SHS, median Sharp–van der Heijde score (interquartile range). Overall, there were no new safety concerns over 2 years beyond those previously reported.13–15 csDMARDs Initially, 498 potentially relevant articles were screened by their abstracts. Efficacy of MTX in monotherapy versus in combination Two new studies were RCTs comparing MTX monotherapy with MTX in combination with another csDMARD, without differences in GC usage between the arms, in adult RA (selection process shown in online supplementary figure B).

csDMARDs Initially, 498 potentially relevant articles were screened by their abstracts. Efficacy of MTX in monotherapy versus in combination Two new studies were RCTs comparing MTX monotherapy with MTX in combination with another csDMARD, without differences in GC usage between the arms, in adult RA (selection process shown in online supplementary figure B). The tREACH study was a randomised, single-blinded clinical trial in patients with recent-onset arthritis who had a ‘high probability of progressing to persistent arthritis’, with three arms: (A) combination therapy with csDMARDs (MTX+sulfasalazine (SSZ)+hydroxychloroquine (HQ)) with intramuscular GCs (91 patients); (B) combination therapy with oral GCs starting at 15 mg/day and tapering over 10 weeks (93 patients) and (C) MTX with oral GCs (same tapering scheme, 93 patients). Medication was intensified to MTX+etanercept (50 mg/week) if the DAS44 was≥2.4 at 3 months,16 which is rather early in light of the time to maximal effects of csDMARDs and current recommendations.2 At 3 months (interim analysis) the change in DAS was similar in both arms with the triple combination and higher than in the arm with monotherapy (mean (SD) change: −1.4 (1.0), −1.5 (1.0) and −1.2 (1.0), respectively), but baseline scores for HAQ disability index, tender joint count and C-reactive protein were 10% higher in the monotherapy arm than in both combination arms.16 Other outcomes, such as change in HAQ score, swollen joint count and erythrocyte sedimentation rate (ESR), did not differ across the groups,16 and the significant advantage of change in DAS score at 3 months was lost at 1 year.17

C-reactive protein were 10% higher in the monotherapy arm than in both combination arms.16 Other outcomes, such as change in HAQ score, swollen joint count and erythrocyte sedimentation rate (ESR), did not differ across the groups,16 and the significant advantage of change in DAS score at 3 months was lost at 1 year.17 The Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) study is a 2-year, randomised, double-blind trial with a two-by-two factorial design, of which two arms are pertinent for the current SLR: immediate oral triple therapy (MTX+SSZ+HQ) (132 patients), or step-up from MTX monotherapy to MTX+SSZ+HQ (124 patients) at week 24 if the DAS28-ESR was >3.2.18 The objective was to assess which approach is better—that is, to immediately treat all patients with early RA and a more severe phenotype (anti-cyclic citrullinated peptide antibody and/or rheumatoid factor positivity, or erosive disease) with combinations of DMARDs, or to reserve combination DMARD therapy for patients who do not have an appropriate response to monotherapy. The number of participants who did not complete this study was higher (32%) than the authors had originally expected (10%), resulting in loss of statistical power and interpretational problems. Furthermore, the main analysis presented was a completers-only analysis. An earlier improvement occurred with immediate combination arms, but after initial MTX monotherapy in those patients who lacked sufficient response a rapid improvement to similar levels as with immediate triple therapy was seen upon intensification of treatment. There were no radiographic advantages in favour of combination therapy. So, using principles of tight control and treat-to-target, clinical and radiographic benefits were no higher with immediate triple therapy than with ‘step-up’ therapy’.18

as with immediate triple therapy was seen upon intensification of treatment. There were no radiographic advantages in favour of combination therapy. So, using principles of tight control and treat-to-target, clinical and radiographic benefits were no higher with immediate triple therapy than with ‘step-up’ therapy’.18 Efficacy of csDMARDs Twenty-five studies were analysed. No new data conflicting with the previous conclusions were found. Several RCTs confirmed the efficacy of MTX as both first and second DMARD.19–24 Only one RCT included leflunomide: it compared MTX and leflunomide in 368 patients with early RA. Of the 240 subjects who were randomised and treated, 129 received leflunomide and 111 received MTX. This study showed that MTX was better than leflunomide for the four primary clinical efficacy endpoints (tender joint count, swollen joint count, physician and patient global assessment score). The difference was not statistically significant for the three secondary clinical efficacy endpoints (morning stiffness, pain intensity, HAQ).25 Very few studies confirmed the efficacy of sulfasalazine.26 27 The studies analysed did not provide new information on other csDMARDs. Tofacitinib Literature search results and trials characteristics Initially, 27 potentially relevant articles were screened. Finally, 10 RCTs were included—four phase II studies and six phase III trials (selection process is shown in online supplementary figure C). Studies’ and patients’ characteristics are detailed in table 2. Table 2 Randomised controlled trials of tofacitinib in rheumatoid arthritis

Tofacitinib Literature search results and trials characteristics Initially, 27 potentially relevant articles were screened. Finally, 10 RCTs were included—four phase II studies and six phase III trials (selection process is shown in online supplementary figure C). Studies’ and patients’ characteristics are detailed in table 2. Table 2 Randomised controlled trials of tofacitinib in rheumatoid arthritis Study N Population Disease duration (years) Background treatment Comparator Trial duration Kremer, 200928 264 DMARD-IR 9.5 DMARDs Placebo 6 Weeks Tanaka, 201129 140 MTX-IR 8.3 MTX Placebo 12 Weeks Kremer, 201230 507 MTX-IR 9.5 MTX Placebo 24 Weeks Fleischmann, 201231 384 DMARD-IR 9.0 None Placebo 24 Weeks ORAL Scan Van der Heijde, 201332 797 MTX-IR 9.0 MTX Placebo 24 Months ORAL Sync Kremer, 2011*33 792 DMARDs-IR 9.1 Non biological DMARDs Placebo 12 Months ORAL Standard Van Vollenhoven, 201234 717 MTX-IR 7.5 MTX Placebo 12 Months ORAL Step” Burmester, 201335 399 TNFi-IR 12.0 MTX Placebo 6 Months ORAL Solo” Fleischmann, 201236 611 DMARDs-IR 8.2 None Placebo 6 Months ORAL Start* Lee, 201237 952 MTX naïve NA None MTX 24 Months All trials were randomised controlled trials with a low ‘risk of bias’ score. *This study was reported in abstract form only. DMARDs, disease-modifying antirheumatic drugs; IR, inadequate responder; MTX, methotrexate; NA, not available; TNFi, tumour necrosis factor inhibitor.

Study N Population Disease duration (years) Background treatment Comparator Trial duration Kremer, 200928 264 DMARD-IR 9.5 DMARDs Placebo 6 Weeks Tanaka, 201129 140 MTX-IR 8.3 MTX Placebo 12 Weeks Kremer, 201230 507 MTX-IR 9.5 MTX Placebo 24 Weeks Fleischmann, 201231 384 DMARD-IR 9.0 None Placebo 24 Weeks ORAL Scan Van der Heijde, 201332 797 MTX-IR 9.0 MTX Placebo 24 Months ORAL Sync Kremer, 2011*33 792 DMARDs-IR 9.1 Non biological DMARDs Placebo 12 Months ORAL Standard Van Vollenhoven, 201234 717 MTX-IR 7.5 MTX Placebo 12 Months ORAL Step” Burmester, 201335 399 TNFi-IR 12.0 MTX Placebo 6 Months ORAL Solo” Fleischmann, 201236 611 DMARDs-IR 8.2 None Placebo 6 Months ORAL Start* Lee, 201237 952 MTX naïve NA None MTX 24 Months All trials were randomised controlled trials with a low ‘risk of bias’ score. *This study was reported in abstract form only. DMARDs, disease-modifying antirheumatic drugs; IR, inadequate responder; MTX, methotrexate; NA, not available; TNFi, tumour necrosis factor inhibitor. Efficacy of tofacitinib at 5 mg twice daily The meta-analysis showed that tofacitinib was better than the respective control groups in its effect on signs and symptoms and physical function at 12, 24 and 52 weeks. As an example, the pooled OR (95% CI) for ACR20 response at 24 weeks versus placebo was 2.44 (1.97 to 3.02) (figure 1 and online supplementary material). Figure 1 Efficacy of tofacitinib on ACR20 response criteria at 24 weeks.

Efficacy of tofacitinib at 5 mg twice daily The meta-analysis showed that tofacitinib was better than the respective control groups in its effect on signs and symptoms and physical function at 12, 24 and 52 weeks. As an example, the pooled OR (95% CI) for ACR20 response at 24 weeks versus placebo was 2.44 (1.97 to 3.02) (figure 1 and online supplementary material). Figure 1 Efficacy of tofacitinib on ACR20 response criteria at 24 weeks. Radiographic progression was assessed in two studies. In the ORAL Start study (early RA, MTX-naïve) mean change in total Sharp–van der Heijde score (SHS) score at 6 months was 0.18 for tofacitinib 5 mg twice daily versus 0.84 for MTX monotherapy (p<0.05) and the proportion of ‘non-progressors’ (≤0.5 unit increase from baseline in total SHS) was 83.5% versus 70.5%, respectively.37 In the ORAL Scan study (established RA, MTX-inadequate responder), mean change in total SHS score was 0.12 versus 0.47 (p=0.079) at 24 weeks and 0.3 versus 1.0 (p=0.0558) at 52 weeks and the proportion of ‘non-progressors’ was 86% versus 74.1% (p≤0.05) at 52 weeks.32 More details are shown in the online supplementary material. Discussion This SLR was performed to inform the EULAR task force involved in updating the 2010 recommendations for the management of RA on the efficacy of csDMARDs as monotherapy or combination therapy, with and without GCs in adult patients with RA. Overall, this SLR confirmed the SLRs performed in 20092–4 and expanded the overall insights.

performed to inform the EULAR task force involved in updating the 2010 recommendations for the management of RA on the efficacy of csDMARDs as monotherapy or combination therapy, with and without GCs in adult patients with RA. Overall, this SLR confirmed the SLRs performed in 20092–4 and expanded the overall insights. Although the place of GC therapy in early RA is still a matter of debate, previous studies have clearly shown the benefit of adding GCs to csDMARD monotherapy or combination therapy, whether at low (≤10 mg/day) or higher doses, especially in patients with early RA.38–41 In 2010, we suggested that GCs might be used as ‘bridge therapy’ before slow-acting DMARDs have taken full effect. Several new studies have confirmed these data. Interestingly, the tREACH trial showed that intramuscular and oral GCs are equally effective as bridging treatments16 and thus answered one of the research questions posed in 2010.1 Moreover, accumulating evidence suggests that low-dose treatment is well tolerated and similarly effective, while reducing the risk of side effects associated with higher doses.13 42 However, bone loss should be prevented using appropriate strategies.43 Further research is needed, especially into chronotherapy44 and intra-articular GC therapy.

idence suggests that low-dose treatment is well tolerated and similarly effective, while reducing the risk of side effects associated with higher doses.13 42 However, bone loss should be prevented using appropriate strategies.43 Further research is needed, especially into chronotherapy44 and intra-articular GC therapy. For combination therapy of csDMARDs, some studies suggest that triple therapy with MTX+SSZ+HQ may be better than MTX monotherapy in improving signs and symptoms.45 46 The tREACH study in its interim analysis at 3 months showed a somewhat faster improvement on DAS28 (but not on HAQ score, swollen joint count or ESR) with triple therapy+GCs than with MTX+GCs, but this difference was not maintained at 1 year.16 17 Moreover the TEAR trial has shown that, using tight control and principles of treat-to-target, clinical, functional and structural outcomes were no better with immediate triple therapy than with ‘step-up’ therapy.18

For combination therapy of csDMARDs, some studies suggest that triple therapy with MTX+SSZ+HQ may be better than MTX monotherapy in improving signs and symptoms.45 46 The tREACH study in its interim analysis at 3 months showed a somewhat faster improvement on DAS28 (but not on HAQ score, swollen joint count or ESR) with triple therapy+GCs than with MTX+GCs, but this difference was not maintained at 1 year.16 17 Moreover the TEAR trial has shown that, using tight control and principles of treat-to-target, clinical, functional and structural outcomes were no better with immediate triple therapy than with ‘step-up’ therapy.18 It has been difficult to interpret the results of several investigator-initiated pragmatic or effectiveness trials such as TEAR and tREACH and use them to choose the most appropriate treatment strategy. These trials are justified by clear practical clinical questions that go beyond whether a particular treatment is effective or not; however, the trial methodology is often so complicated that the trial performance and reporting may be jeopardised. Examples of these aspects are trials that do not reach their target number of patients (with lack of statistical power as a consequence), trials with high drop-out rates, or with relatively small numbers of patients (‘completers’) in which the primary endpoint has been assessed (with a risk of ‘bias by completion’), trials with an unplanned interim analysis or a change of primary endpoint (with the risk of convenience reporting, or reporting at odds with the definite results) and trials with an a priori superiority design that are reported with spurious non-inferiority conclusions.47 However, these studies explored valuable concepts that are of significant practical importance to rheumatologists and patients.

the risk of convenience reporting, or reporting at odds with the definite results) and trials with an a priori superiority design that are reported with spurious non-inferiority conclusions.47 However, these studies explored valuable concepts that are of significant practical importance to rheumatologists and patients. There are some limitations to our analyses; some outcomes from some studies could not be included in this meta-analysis because we needed at least one measure of variability such as SD. Nevertheless, the current SLR informs the Task Force on the evidence that (i) addition of low-dose GC to csDMARD monotherapy or combination therapy increases overall efficacy; (ii) combination of csDMARDs as triple therapy, is efficacious, but MTX monotherapy appears to be similarly efficacious, especially when combined with GCs and employing a treat-to-target approach; (iii) tofacitinib is a clinically, structurally and functionally efficacious agent. Importantly, safety aspects were not covered here, since they were part of a separate SLR.7 Supplementary Material Web supplement The authors thank Michel Viala for his help with the literature search. Contributors: All authors contributed and finally approved the current manuscript.

There are some limitations to our analyses; some outcomes from some studies could not be included in this meta-analysis because we needed at least one measure of variability such as SD. Nevertheless, the current SLR informs the Task Force on the evidence that (i) addition of low-dose GC to csDMARD monotherapy or combination therapy increases overall efficacy; (ii) combination of csDMARDs as triple therapy, is efficacious, but MTX monotherapy appears to be similarly efficacious, especially when combined with GCs and employing a treat-to-target approach; (iii) tofacitinib is a clinically, structurally and functionally efficacious agent. Importantly, safety aspects were not covered here, since they were part of a separate SLR.7 Supplementary Material Web supplement The authors thank Michel Viala for his help with the literature search. Contributors: All authors contributed and finally approved the current manuscript. Competing interests: CG-V—consultation and/or speaking engagements: Abbvie, BMS, MSD, Pfizer, Roche-Chugai, UCB; research funding: Expanscience, Nordic Pharma, Pfizer. JN—consultation and/or speaking engagements: UCB. SR—consultation and/or speaking engagements: Fundação para a Ciência e Tecnologia. RL—consultation and/or speaking engagements: Abbott/AbbVie, Ablynx, Amgen, Astra-Zeneca, Bristol Myers-Squibb, Centocor, Glaxo-Smith-Kline, Merck, Novartis, Pfizer, Roche, Schering-Plough, UCB, Wyeth; research funding: Abbott, Amgen, Centocor, Novartis, Pfizer, Roche, Schering-Plough, UCB, Wyeth. MHB—consultation and/or speaking engagements: Abbott, Bristol Myers-Squibb, Chugai, Pfizer, Roche; research funding: Pfizer. JSS—consultation and/or speaking engagements: Abbott/Abbvie, Amgen, Astra-Zeneka, BMS, Celgene, Glaxo, Infinity, Janssen, Lilly, Medimmune, Menarini, MSD, Novo-Nordsik, Pfizer, Roche, Samsung, Sandoz, Sanofi-Aventis, UCB, Vertex; research funding: Abbott, BMS, MSD, Pfizer, Roche, UCB. LG—consultation and/or speaking engagements: Abbott, BMS, Chugai, Pfizer, Roche, UCB.

t/Abbvie, Amgen, Astra-Zeneka, BMS, Celgene, Glaxo, Infinity, Janssen, Lilly, Medimmune, Menarini, MSD, Novo-Nordsik, Pfizer, Roche, Samsung, Sandoz, Sanofi-Aventis, UCB, Vertex; research funding: Abbott, BMS, MSD, Pfizer, Roche, UCB. LG—consultation and/or speaking engagements: Abbott, BMS, Chugai, Pfizer, Roche, UCB. Provenance and peer review: Not commissioned; externally peer reviewed.

omplete case analysis; the latter was based on evaluation of all trial participants as allocated. For the ITT approach, missing data were imputed via multiple imputation using chained equations; 20 imputed datasets were computed on guidance that the number needed should approximate the percentage of incomplete cases.38 The focus of the evaluation of clinical outcomes was on difference in change scores. A value of 0.6 defined the inferiority/non-inferiority margin for the primary outcome (DAS28 follow-up change score from baseline),30 with the test hypothesis pre-stated as: Null hypothesis (inferiority): mean ΔDAS28RLC—mean ΔDAS28NLC ≥0.6 where Δ=change from baseline value. Allowing for a 10% participant dropout rate, a total sample size of 180 participants (90 per treatment arm) was needed on the basis of a repeated-measures analysis of between-group differences averaged over four equidistant follow-up time points given 90% power and one-sided statistical testing with 2.5% significance level (with anticipated SD of 1.5, intraclass correlation coefficient of 0.5).30

Introduction Rheumatoid arthritis (RA) is a chronic inflammatory disease characterised by joint swelling, joint tenderness and destruction of synovial joints, leading to severe disability and premature mortality.1 Approximately two million people live with RA in Europe where the average prevalence is 0.49%.2 RA has a negative impact on individuals’ physical, social and psychological functioning, and the resulting disability contributes significantly to the burden of disease in RA.3–6 The primary goal of treatment is to suppress disease activity, thus preventing structural damage and optimising function and social participation.7 The management of RA has seen significant changes over the past decade due to increased understanding of the disease processes, diagnostic techniques and the development of more efficacious therapies and assessments. The goal of treatment now includes remission, which was once unobtainable at the onset of RA.7 8 This change in the emphasis of treatment has resulted in better health-related outcomes for people with RA, but it has also meant an increased need for monitoring, more coordinated multidisciplinary teams and the development of nurse-led care (NLC).9 10

udes remission, which was once unobtainable at the onset of RA.7 8 This change in the emphasis of treatment has resulted in better health-related outcomes for people with RA, but it has also meant an increased need for monitoring, more coordinated multidisciplinary teams and the development of nurse-led care (NLC).9 10 NLC involves adopting a holistic approach taking account of patients’ physical, psychological, social and spiritual needs. Nurses involved in providing this service are advanced practitioners in their speciality and function either independently and/or interdependently with other members of the multidisciplinary team.11 The role titles clinical nurse specialist (CNS) or rheumatology nurse practitioner are used interchangeably in rheumatology nursing, therefore in this report they are all referred to as CNS. Although the model of NLC was already established in Canada, the USA and Australia in chronic diseases, it was pioneered in the UK in rheumatology services,12 and has been shown to be effective, safe and associated with more patient satisfaction.13–16 Under this model of care, a patient is referred to NLC following diagnosis and a treatment plan is initiated by the rheumatologist. The role components of NLC include an assessment of disease activity, monitoring effects of therapy, prescribing or recommending medication or dosage changes including intramuscular/intra-articular steroid injections, provision of patient education, psychological support, providing patients with a contactable knowledgeable and accessible professional through telephone advice lines, coordinating complex care and referring to other health professionals.17

on or dosage changes including intramuscular/intra-articular steroid injections, provision of patient education, psychological support, providing patients with a contactable knowledgeable and accessible professional through telephone advice lines, coordinating complex care and referring to other health professionals.17 In Europe, there are wide variations in the role of the CNS. In The Netherlands and the Scandinavian countries NLC is well established,14–16 18 19 while in other countries it is in its infancy.20–22 The European League Against Rheumatism (EULAR) has recently published recommendations for the role of the nurse in the management of inflammatory arthritis, in order to enable a homogenisation of rheumatology nursing care across Europe.23 These recommendations support the implementation of NLC and have also identified the need for cost-effectiveness studies of NLC. Although previous UK studies have shown positive results for NLC, they were all single-centre randomised controlled trials (RCT) and focused on clinical effectiveness only.24–27 Despite being the pioneer of rheumatology NLC in Europe, the UK has never undertaken an economic evaluation of this model of care until now. The aim of this study was to determine the clinical effectiveness and cost-effectiveness of NLC.

andomised controlled trials (RCT) and focused on clinical effectiveness only.24–27 Despite being the pioneer of rheumatology NLC in Europe, the UK has never undertaken an economic evaluation of this model of care until now. The aim of this study was to determine the clinical effectiveness and cost-effectiveness of NLC. Methods Study design This was a multicentre pragmatic RCT. The assessment of clinical effects followed a non-inferiority design, while patient satisfaction and cost-effectiveness assessments followed a superiority design. The study was conducted in outpatient clinics of 10 rheumatology centres across the UK. The study protocol is published elsewhere.28

lticentre pragmatic RCT. The assessment of clinical effects followed a non-inferiority design, while patient satisfaction and cost-effectiveness assessments followed a superiority design. The study was conducted in outpatient clinics of 10 rheumatology centres across the UK. The study protocol is published elsewhere.28 Participants and randomisation The inclusion criteria were: a positive diagnosis of RA (1987 American College of Rheumatology (ACR) criteria),29 age 18 years or older and the ability to complete questionnaires unaided. Exclusions were: unstabilised concomitant disease, awaiting surgery and already receiving care from the practitioners involved in the study. After gaining patient consent, demographics and disease activity score in 28 joints (DAS28), patients were randomly assigned using a remote secure telephone randomisation service provided by Leeds University Clinical Trials Research Unit. Randomisation was on a 1 : 1 basis to either NLC (experimental group) or rheumatologist-led care (RLC) (control group), by random permuted blocks, using the stratification factors, centre and DAS28 (low disease activity DAS28≤3.2, or moderate to high disease activity DAS28>3.2).30 The independent assessors, performing the joint counts for DAS28, were masked.

ther NLC (experimental group) or rheumatologist-led care (RLC) (control group), by random permuted blocks, using the stratification factors, centre and DAS28 (low disease activity DAS28≤3.2, or moderate to high disease activity DAS28>3.2).30 The independent assessors, performing the joint counts for DAS28, were masked. Interventions This study required three practitioners at each centre; a CNS, a rheumatologist and a blind independent assessor. Nine CNS and 10 rheumatologists delivered the interventions. The CNS had a median experience of 10 years in their current post while the rheumatologists had a median of 9 years at consultant level. The CNS have experience in running nurse-led clinics and usually have a postgraduate qualification in rheumatology nursing and/or prescribing. Independent assessors were health professionals trained to perform joint counts and calculating the DAS28.

while the rheumatologists had a median of 9 years at consultant level. The CNS have experience in running nurse-led clinics and usually have a postgraduate qualification in rheumatology nursing and/or prescribing. Independent assessors were health professionals trained to perform joint counts and calculating the DAS28. When patients arrived at the clinic, the independent assessor performed ‘joint counts’ for DAS28 and then oversaw the completion of self-reported pain visual analogue scale (pain-VAS), fatigue-VAS and duration of morning stiffness. The patients were then given questionnaires in ‘freepost’ return envelopes before consultation with their allocated practitioner. The training of independent assessors was conducted during the study set-up meetings. The rheumatologists and CNS delivering the interventions did not have any special training as they were expected to undertake their ‘normal’ practice, having agreed to follow the study protocol. Patients were seen by their respective practitioners at baseline and at weeks 13, 26, 39 and 52.

g the study set-up meetings. The rheumatologists and CNS delivering the interventions did not have any special training as they were expected to undertake their ‘normal’ practice, having agreed to follow the study protocol. Patients were seen by their respective practitioners at baseline and at weeks 13, 26, 39 and 52. The NLC interventions usually include allocated 30-min time slots in which the CNS takes history, performs physical examination, pain control, prescribing or recommending medication and dosage changes, intra-articular or intramuscular steroid injections, provision of patient education, psychosocial support and ordering blood tests or X-rays. Referrals for ward admission, to the rheumatologist or other health professionals, were carried out as appropriate. The usual RLC is similar to the above except that it usually involves an allocated 15-min time slot. All interventions, referrals and the duration of the consultation were recorded in a standard ‘consultation checklist’ designed for this study. Both practitioners saw patients according to the protocol and any extra visits or admissions were recorded.

above except that it usually involves an allocated 15-min time slot. All interventions, referrals and the duration of the consultation were recorded in a standard ‘consultation checklist’ designed for this study. Both practitioners saw patients according to the protocol and any extra visits or admissions were recorded. Outcome measures The primary outcome was DAS28 and secondary outcomes were pain severity (pain-VAS), fatigue (fatigue-VAS) and duration of morning stiffness measured at each study visit. Other secondary outcome measures were at baseline, weeks 26 and 52: RA quality of life;31 health assessment questionnaire disability index;32 hospital anxiety and depression scale;33 arthritis self-efficacy scale;34 and Leeds satisfaction questionnaire (LSQ).35 The health economic questionnaire including EuroQoL (EQ5D)36 and healthcare resource data were collected at weeks 0, 13, 26, 39 and 52. Details of the costs applied to units of resource use are provided in supplementary table S1 (available online only). Statistical analysis Analysis followed per-protocol (PP) and intention-to-treat (ITT) approaches.37 The former was based on evaluation of all participants who completed the five treatment sessions and focussed on a complete case analysis; the latter was based on evaluation of all trial participants as allocated. For the ITT approach, missing data were imputed via multiple imputation using chained equations; 20 imputed datasets were computed on guidance that the number needed should approximate the percentage of incomplete cases.38

pants (90 per treatment arm) was needed on the basis of a repeated-measures analysis of between-group differences averaged over four equidistant follow-up time points given 90% power and one-sided statistical testing with 2.5% significance level (with anticipated SD of 1.5, intraclass correlation coefficient of 0.5).30 Analysis of the primary endpoint (average ΔDAS28) and other endpoint comparisons was carried out using linear regression modelling adjusting for age, gender, centre and baseline DAS28 score. Estimates for secondary health outcome measures included additional adjustment for corresponding baseline value. For the ΔDAS28, p values were generated that tested against the null hypothesis of a between-group difference of 0.6 in favour of RLC. In order to test the secondary outcomes in the same way an equivalent standardised effect size of 0.4 was utilised for the inferiority margin; this level of effect size has been reported to translate to a ‘minimal clinically important difference’ across typical health-related outcomes.39

erence of 0.6 in favour of RLC. In order to test the secondary outcomes in the same way an equivalent standardised effect size of 0.4 was utilised for the inferiority margin; this level of effect size has been reported to translate to a ‘minimal clinically important difference’ across typical health-related outcomes.39 The null hypothesis of zero difference was used in testing patient satisfaction and cost. The health economic evaluation addressed both cost-effectiveness analysis (in relation to the ΔDAS28) and cost utility (in relation to quality-adjusted life-years (QALY) derived from area under the curve calculation of the EQ5D from baseline to last follow-up). Evaluation focused on the incremental cost-effectiveness ratio—ratio of the mean difference in cost to the mean difference in effect (denoting the extra average cost per unit gain in effect); or otherwise dominance of one treatment over the other with respect to lower mean cost and greater mean effect. These estimates were derived through linear regression modelling additionally adjusting for baseline EQ5D. Analysis of uncertainty in the joint estimation of the incremental cost-effectiveness ratio is illustrated via cost-effectiveness planes (via bootstrapping with 5000 replications). Cost-acceptability curves were derived to show the probability of the NLC (experimental treatment) being cost-effective at different willingness-to-pay (WTP) thresholds.

joint estimation of the incremental cost-effectiveness ratio is illustrated via cost-effectiveness planes (via bootstrapping with 5000 replications). Cost-acceptability curves were derived to show the probability of the NLC (experimental treatment) being cost-effective at different willingness-to-pay (WTP) thresholds. Although the primary evaluation was carried out on a priori adjustment for baseline age, gender, centre, DAS28 and EQ5D, a sensitivity analysis was deemed necessary additionally adjusting for baseline biological agent use given the extent of the observed imbalance in that variable at baseline assessment. Results Of the 622 patients who were assessed for eligibility, 181 were eventually randomly assigned and 133 (73.5%) had complete DAS28 data for all the five visits (PP analysis). The demographics and baseline characteristics of patients under NLC (n=91) were comparable to those under RLC (n=90) except in the proportion of patients receiving biological disease-modifying antirheumatic drugs (DMARD). Figure 1 shows the trial profile and table 1 summarises the baseline characteristics of participants. Table 1 Baseline characteristics of study population stratified by study group

Results Of the 622 patients who were assessed for eligibility, 181 were eventually randomly assigned and 133 (73.5%) had complete DAS28 data for all the five visits (PP analysis). The demographics and baseline characteristics of patients under NLC (n=91) were comparable to those under RLC (n=90) except in the proportion of patients receiving biological disease-modifying antirheumatic drugs (DMARD). Figure 1 shows the trial profile and table 1 summarises the baseline characteristics of participants. Table 1 Baseline characteristics of study population stratified by study group RLC (n=90) NLC (n=91) Women, n (%) 67 (74.44) 67 (73.63) Age, years, mean (SD) 57.27 (12.20) 60.20 (11.26) Disease duration, years, mean (SD) (89; 90)* 10.21 (11.47) 9.57 (9.84) Comorbidities, n (%) Osteoarthritis 4 (4.44) 5 (5.49) Osteoporosis 16 (17.78) 9 (9.89) Hypertension 19 (21.11) 20 (21.98) Asthma 7 (7.78) 6 (6.59) Depression 3 (3.33) 1 (1.10) Hypothyroidism 6 (6.67) 1 (1.10) Baseline RA regimen, n (%) Methotrexate 57 (63.33) 62 (68.13) Sulfasalazine 16 (17.78) 9 (9.89) Hydroxychloroquine 4 (4.44) 3 (3.30) Leflunomide 6 (6.67) 4 (4.40) Prednisolone 11 (12.22) 6 (6.59) Biological DMARD 6 (6.67) 15 (16.48) Outcomes, mean (SD) DAS28 (86; 88)* 3.89 (1.54) 3.65 (1.24) Pain (0–100 VAS, 0=no pain) (86; 87)* 39.33 (21.26) 43.29 (23.77) Fatigue (0–100 VAS, 0=no fatigue) (86; 87)* 49.58 (25.09) 49.92 (24.50) Stiffness (0 –240 Min, 0=no stiffness) (84; 87)* 50.50 (63.42) 43.78 (55.50) RAQoL (0–30, 0=better quality of life) (76; 78)* 13.54 (7.05) 13.33 (8.09) HAQ (0–3, 0=no disability) (86; 83)* 1.25 (0.76) 1.19 (0.77) Anxiety (0–21, 0=no anxiety) (87; 84)* 7.56 (4.24) 7.13 (3.83) Depression (0–21, 0=no depression) (87; 84)* 6.20 (3.74) 5.94 (3.84) ASES (11–110, 11=poor self-efficacy) (85; 84)* 55.53 (17.49) 59.14 (18.98) Satisfaction, median (IQR) LSQ–General (1–5), 1=dissatisfied) (86; 83)* 2.7 (2.3, 3.4) 2.7 (2.3, 3.7) LSQ–Information (1–5), 1=dissatisfied) (86; 83)* 3.2 (3.0, 3.5) 3.0 (2.9, 3.7) LSQ–Empathy (1–5), 1=dissatisfied) (86; 83)* 3.1 (3.0, 3.6) 3.0 (2.9, 3.6) LSQ–Technical (1–5), 1=dissatisfied) (86; 83)* 3.2 (3.0, 4.0) 3.1 (2.9, 4.0) LSQ–Attitude (1–5), 1=Dissatisfied) (86; 83)* 3.2 (3.0, 3.7) 3.2 (2.8, 3.8) LSQ–Access (1–5), 1=dissatisfied) (86; 83)* 3.1 (3.0, 3.6) 3.1 (3.0, 3.5) ASES, arthritis self-efficacy scale; DAS28, disease activity score in 28 joints; DMARD, disease-modifying antirheumatic drug; HAQ: health assessment questionnaire disability index; LSQ, Leeds satisfaction questionnaire; NLC, nurse-led clinic; RA, rheumatoid arthritis; RAQoL, rheumatoid arthritis quality of life; RLC, theumatologist-led clinic; VAS, visual analogue scale.

ctivity score in 28 joints; DMARD, disease-modifying antirheumatic drug; HAQ: health assessment questionnaire disability index; LSQ, Leeds satisfaction questionnaire; NLC, nurse-led clinic; RA, rheumatoid arthritis; RAQoL, rheumatoid arthritis quality of life; RLC, theumatologist-led clinic; VAS, visual analogue scale. *Number of available data were as per randomised allocation that is, 90 for RLC and 91 for NLC unless otherwise stated in parentheses. Figure 1 Trial profile. Ninety-two per cent (83/90) of patient under NLC attended all five clinic sessions, with a mean total consultation time of 111 min compared to 85% (77/91) of the RLC group who had a mean total consultation time of 71 min. NLC had longer consultations (median 20 min, IQR=15–30 vs RLC, 15, 10–15), made fewer medication and dosage changes; ordered fewer intra-articular and intramuscular steroid injections and requested fewer radiological investigations than RLC. There was little difference in the ordering of non-protocol bloods or referrals to other health professionals. NLC provided patient education and psychosocial support more frequently than RLC, and CNS conferred more with the rheumatologist than vice versa. NLC had fewer rates of unplanned admissions or visits to the accident and emergency department than RLC. (see supplementary table S2, available online only).

h professionals. NLC provided patient education and psychosocial support more frequently than RLC, and CNS conferred more with the rheumatologist than vice versa. NLC had fewer rates of unplanned admissions or visits to the accident and emergency department than RLC. (see supplementary table S2, available online only). The improvement in disease activity (change in DAS28) over follow-up was better in the NLC group than the RLC group, and significance for non-inferiority was reached in the PP and ITT analyses at all individual follow-up time points and for the primary endpoint (ie, average DAS change). Figure 2 graphically displays the difference between groups in the DAS28 change over the 12-month follow-up period. Table 2 shows the descriptive and inferential results for the DAS28. Table 2 Summary estimates for change in DAS28 (primary outcome measure) over 12 months

The improvement in disease activity (change in DAS28) over follow-up was better in the NLC group than the RLC group, and significance for non-inferiority was reached in the PP and ITT analyses at all individual follow-up time points and for the primary endpoint (ie, average DAS change). Figure 2 graphically displays the difference between groups in the DAS28 change over the 12-month follow-up period. Table 2 shows the descriptive and inferential results for the DAS28. Table 2 Summary estimates for change in DAS28 (primary outcome measure) over 12 months RLC NLC Difference† Mean (SD) Mean (SD) Mean (95% CI) p Value* Week 13 PP (73;76)*‡ −0.11 (1.48) −0.04 (1.30) −0.19 (−0.60 to 0.22) 0.0002 ITT −0.10 (1.51) −0.05 (1.36) −0.15 (−0.54 to 0.23) <0.0001 Week 26 PP (72; 80)‡ 0.03 (1.49) 0.05 (1.22) −0.15 (−0.53 to 0.24) 0.0001 ITT 0.04 (1.52) 0.04 (1.33) −0.12 (−0.49 to 0.26) 0.0001 Week 39 PP (69; 76)‡ 0.18 (1.61) 0.36 (1.19) −0.34 (−0.71 to 0.03) <0.0001 ITT 0.20 (1.68) 0.33 (1.33) −0.27 (−0.64 to 0.10) <0.0001 Week 52 PP (70; 80)‡ 0.18 (1.41) 0.07 (1.22) −0.02 (−0.40 to 0.35) 0.0011 ITT 0.12 (1.50) 0.08 (1.32) −0.07 (−0.44 to 0.30) 0.0005 Average§ PP (64; 69)‡ 0.02 (1.32) 0.11 (1.05) −0.31 (−0.63to 0.02) <0.0001 ITT 0.06 (1.32) 0.10 (1.10) −0.15 (−0.45 to 0.14) <0.0001 *p Values based on non-inferiority testing (ie, null hypothesis: standardised mean difference (mean difference/pooled baseline SD)=0.4; based on a clinically significant threshold of 0.6 with anticipated SD of 1.5).

1.32) 0.11 (1.05) −0.31 (−0.63to 0.02) <0.0001 ITT 0.06 (1.32) 0.10 (1.10) −0.15 (−0.45 to 0.14) <0.0001 *p Values based on non-inferiority testing (ie, null hypothesis: standardised mean difference (mean difference/pooled baseline SD)=0.4; based on a clinically significant threshold of 0.6 with anticipated SD of 1.5). †Difference in mean DAS28 change scores for the RLC group minus NLC group (adjusted for age, gender, centre and baseline DAS28 score). ‡Analysis of complete-cases (number of DAS responders—RLC group; NLC group). §Primary endpoint evaluation. DAS28, disease activity score in 28 joints; ITT, intention-to-treat; NLC,  nurse-led clinic; PP, per protocol; RLC, rheumatologist-led clinic. Figure 2 Summary estimates for change in disease activity score in 28 joints (DAS28) (primary outcome measure) over 12 months.

‡Analysis of complete-cases (number of DAS responders—RLC group; NLC group). §Primary endpoint evaluation. DAS28, disease activity score in 28 joints; ITT, intention-to-treat; NLC,  nurse-led clinic; PP, per protocol; RLC, rheumatologist-led clinic. Figure 2 Summary estimates for change in disease activity score in 28 joints (DAS28) (primary outcome measure) over 12 months. Results for the secondary outcomes are shown in supplementary table S3 (available online only). Significance for non-inferiority was also reached in all secondary outcomes (at corresponding standardised effect size margins of 0.4). Improvements were consistently better for NLC in pain and physical function outcomes but in fatigue, stiffness and hospital anxiety and depression scale anxiety there was a slight worsening in the NLC compared to slight improvements in the RCL group. In other outcomes, there were some differences between PP and ITT results but all results supported non-inferiority. NLC had higher ‘general satisfaction’ scores (one subscale of LSQ) than RLC in week 26, but not in week 52 or other satisfaction subscales, which showed no significant difference between the two groups (see supplementary table S4, available online only). NLC has lower consultation costs. While there were no significant differences in the overall mean costs, NLC tended to have lower healthcare costs especially after adjustment for baseline biological agent use (table 3). A summary of disaggregated costs is provided in supplementary table S5 (available online only).

Results for the secondary outcomes are shown in supplementary table S3 (available online only). Significance for non-inferiority was also reached in all secondary outcomes (at corresponding standardised effect size margins of 0.4). Improvements were consistently better for NLC in pain and physical function outcomes but in fatigue, stiffness and hospital anxiety and depression scale anxiety there was a slight worsening in the NLC compared to slight improvements in the RCL group. In other outcomes, there were some differences between PP and ITT results but all results supported non-inferiority. NLC had higher ‘general satisfaction’ scores (one subscale of LSQ) than RLC in week 26, but not in week 52 or other satisfaction subscales, which showed no significant difference between the two groups (see supplementary table S4, available online only). NLC has lower consultation costs. While there were no significant differences in the overall mean costs, NLC tended to have lower healthcare costs especially after adjustment for baseline biological agent use (table 3). A summary of disaggregated costs is provided in supplementary table S5 (available online only). Table 3 Summary of economic estimates including aggregated cost (£) and effects (QALY and average DAS28 change) estimates

NLC has lower consultation costs. While there were no significant differences in the overall mean costs, NLC tended to have lower healthcare costs especially after adjustment for baseline biological agent use (table 3). A summary of disaggregated costs is provided in supplementary table S5 (available online only). Table 3 Summary of economic estimates including aggregated cost (£) and effects (QALY and average DAS28 change) estimates RLC NLC Difference† Mean (SD) Mean (SD) Mean (95% CI) p Value* Costs Clinic consultations (only) PP (69; 79)‡ 198 (57.9) 158 (76.7) 34.2 (14.9 to 53.5) 0.0008 ITT 184 (79.5) 148 (81.2) 35.9 (15.6 to  56.1) 0.0006 NHS (Clinic plus additional NHS resources) PP (42; 50)‡ 2171 (2822) 1239 (2063) 663 (−403 to 1730) 0.2194 ITT 2191 (3814) 2282 (4277) −150 (−1240 to 939) 0.7858 Healthcare (NHS resources plus out-of-pocket expenditure) PP (42; 50)‡ 2286 (2793) 1276 (2091) 710 (−352 to 1773) 0.1872 ITT 2304 (3773) 2386 (4565) −128 (−1263 to 1006) 0.8245 Societal (Healthcare plus productivity loss through time off work) PP (42; 50)‡ 2485 (2844) 1357 (2107) 863 (−219 to 1944) 0.1161 ITT 2415 (3785) 2550 (4727) −195 (−1354 to 963) 0.7406 Effects QALY PP (39; 48)‡ 0.561 (0.228) 0.552 (0.244) 0.016 (−0.049 to 0.082) 0.0002 ITT 0.575 (0.234) 0.554 (0.259) 0.020 (−0.030 to 0.071) <0.0001 Average DAS28 change§ PP (64; 69) ‡ 0.02 (1.32) 0.11 (1.05) −0.31 (−0.63 to 0.02) <0.0001 ITT 0.06 (1.32) 0.10 (1.10) −0.15 (−0.45 to 0.14) <0.0001 Results of sensitivity test—after additional adjustment for baseline biological agents Costs NHS PP (42; 50)‡ 2171 (2822) 1239 (2063) 806.05 (–111.62 to 1723.72) ITT 2191 (3814) 2282 (4277) 447.67 (−526.16 to 1421.50) Healthcare PP (42; 50)‡ 2286 (2793) 1276 (2091) 852.15 (−63.37 to 1767.67) ITT 2304 (3773) 2386 (4565) 494.53 (−516.34 to 15015.41) Effects QALY PP (39; 48)‡ 0.561 (0.228) 0.552 (0.244) 0.017 (−0.049 to 0.083) ITT 0.575 (0.234) 0.554 (0.259) 0.018 (−0.034 to 0.070) Average DAS28 change§ PP (64; 69)‡ 0.02 (1.32) 0.11 (1.05) −0.308 (−0.640  to 0.025) ITT 0.06 (1.32) 0.10 (1.10) −0.220 (−0.5458 to 0.105) *p  Values based on superiority testing (ie, null hypothesis: standardised mean difference = 0.0) in relation to comparison of costs, and non-inferiority testing (ie, null hypothesis: standardised mean difference = 0.4) in relation to comparison of effects.

o 0.025) ITT 0.06 (1.32) 0.10 (1.10) −0.220 (−0.5458 to 0.105) *p  Values based on superiority testing (ie, null hypothesis: standardised mean difference = 0.0) in relation to comparison of costs, and non-inferiority testing (ie, null hypothesis: standardised mean difference = 0.4) in relation to comparison of effects. †Difference in mean DAS28 change scores for the RLC group minus NLC group (adjusted for age, gender, centre, baseline DAS28 score and baseline EQ5D) with CI. ‡Analysis of complete cases (number of responders to resource/time-off work questions—RLC group; NLC group). §As presented in table 2. DAS28, disease activity score in 28 joints; ITT, intention-to-treat; NLC, nurse-led clinic; PP, per protocol; QALY; quality-adjusted life-year; RLC, rheumatologist-led clinic. Figure 3 shows cost-utility planes and cost-acceptability curves in respect of healthcare costs (similar graphs with respect to NHS costs are provided in supplementary figure S1, available online only). NLC was more cost-effective in respect of costs relative to ΔDAS28 for both ITT and PP analyses; therefore, the probability that NLC was cost-effective in relation to the primary outcome was in excess of 80% across all WTP thresholds. However, in relation to QALY gain, in both healthcare and NHS perspectives, the probability of NLC being cost-effective was dependent of the type of analysis used; favourable in PP but not in ITT analyses (figure 3E and supplementary figure S1E, available online only). Figure 3 Summary of economic evaluation (healthcare perspective).

Figure 3 shows cost-utility planes and cost-acceptability curves in respect of healthcare costs (similar graphs with respect to NHS costs are provided in supplementary figure S1, available online only). NLC was more cost-effective in respect of costs relative to ΔDAS28 for both ITT and PP analyses; therefore, the probability that NLC was cost-effective in relation to the primary outcome was in excess of 80% across all WTP thresholds. However, in relation to QALY gain, in both healthcare and NHS perspectives, the probability of NLC being cost-effective was dependent of the type of analysis used; favourable in PP but not in ITT analyses (figure 3E and supplementary figure S1E, available online only). Figure 3 Summary of economic evaluation (healthcare perspective). Discussion This was the first study to provide information on cost-effectiveness of NLC in RA patients with different disease levels. The primary endpoint shows that NLC was not inferior to RLC at any follow-up time point. This suggests that NLC could manage most RA patients without loss of efficacy in terms of disease activity. Disease activity is the best predictor of joint damage and physical disability, both of which can lead to reduction in quality of life and premature mortality.7 These results support this model of care in the UK and are consistent with previous studies in the UK and elsewhere.13–16 Whereas other studies have focused on subgroups of patients; for example the Swedish and the Danish studies focused on patients with low disease activity,14–16 and the Dutch study on patients with difficulty in performing activities of daily living;18 this present study has demonstrated the effectiveness of NLC in managing patients with different disease activity levels.

tients; for example the Swedish and the Danish studies focused on patients with low disease activity,14–16 and the Dutch study on patients with difficulty in performing activities of daily living;18 this present study has demonstrated the effectiveness of NLC in managing patients with different disease activity levels. The baseline difference in the proportion of patients receiving biological DMARD was a result of chance (not systematic).40 In the follow-up period, the proportion of patients receiving biological agents in NLC remained more or less constant while that in RLC doubled. Assuming that change onto biological agents would significantly improve DAS28, this was likely to favour RLC. Predictably, additional adjustment for baseline biological agents increased the effects on NLC.

roportion of patients receiving biological agents in NLC remained more or less constant while that in RLC doubled. Assuming that change onto biological agents would significantly improve DAS28, this was likely to favour RLC. Predictably, additional adjustment for baseline biological agents increased the effects on NLC. The conclusion about the cost-effectiveness of NLC was dependent on the type of outcome; disease specific (DAS28) or generic (QALY) outcome, and on the type of statistical approach used (PP or ITT) in the analysis. The cost-effectiveness of NLC was clearly evident in respect of the primary outcome (ΔDAS28)—for example, the estimated probability that NLC is cost-effective exceeded 80% for a cost as little as £5000 per minimal clinically important difference (ie, per 0.6 change) in DAS28. By contrast, at a guideline WTP threshold of £20 000–30 000 per QALY (set by the National Institute for Health and Clinical Excellence),41 the probability of NLC being cost-effective was in the range of 62–74% by PP analysis but 25–27% by ITT analysis. Given that health policy in the UK is based on generic measures (QALY),42 we cannot make strong health policy conclusions about the cost-effectiveness of NLC as the results of QALY (ITT) analysis are inconsistent with the disease-specific measures.

e was in the range of 62–74% by PP analysis but 25–27% by ITT analysis. Given that health policy in the UK is based on generic measures (QALY),42 we cannot make strong health policy conclusions about the cost-effectiveness of NLC as the results of QALY (ITT) analysis are inconsistent with the disease-specific measures. Significance for non-inferiority was reached in all measures although the direction of effects in secondary outcomes did not always favour NLC. For example, NLC giving patient education and psychological support more frequently than RLC did not translate into better improvements in psychological wellbeing outcomes. Understanding the significance of the contribution of each individual outcome in this context is limited because of the interaction effect between outcomes. For example, disease activity is directly related to pain and functional disability;43–45 both of which have been shown to determine other outcomes such as quality of life and psychological wellbeing.45 Further research on the effect of this interaction is required. Previous RCT have demonstrated more satisfaction with NLC across most LSQ subscales,15 25 27 but this study has shown this to be the case in ‘general satisfaction’ only. This study being multicentred might have contributed to this difference. Also, in chronic diseases when some outcomes take a longer time to develop, a person may be ‘generally’ satisfied with care but still have dissatisfaction with some aspects of it. Patient satisfaction with care is important and may affect adherence to treatment,46 therefore there is always room for improvement in a busy clinic.

chronic diseases when some outcomes take a longer time to develop, a person may be ‘generally’ satisfied with care but still have dissatisfaction with some aspects of it. Patient satisfaction with care is important and may affect adherence to treatment,46 therefore there is always room for improvement in a busy clinic. In this multicentre study, practitioners undertook their ‘normal’ practice except the frequency of clinic visits, which had to be standardised to ensure comparability between the two groups. Inclusion of patients with different disease levels reflects practice and demonstrates the effectiveness of NLC in managing different groups of patients with RA. In the UK, NLC consultations take place within the rheumatology unit, therefore patients have access to the rheumatologist as required. Based on the number of unplanned admissions, visits to the general practitioner and to the emergency department, there is no reason to question the safety of this model of care.

th RA. In the UK, NLC consultations take place within the rheumatology unit, therefore patients have access to the rheumatologist as required. Based on the number of unplanned admissions, visits to the general practitioner and to the emergency department, there is no reason to question the safety of this model of care. This study has three main limitations: First, only 73.5% of the randomly assigned patients had complete data for the primary endpoint in all five visits. The strict criteria for PP analysis was set in order to prevent erroneous claiming of non-inferiority.37 In the ITT analyses, missing data were inputted using multiple imputation methods, which results in unbiased estimates providing more validity than other approaches to missing data.38 47 Second, information on interventions was quantitative (eg, frequencies of conferrals, giving patient education and psychological support) rather than qualitative detail of what was involved. Third, the generalisability of these findings across Europe is limited as NLC effectiveness is likely to be related to the level of its development as a service model. Conclusion This study provides robust evidence to support the non-inferiority of NLC in managing RA. Indeed, our findings have shown that there may be some clinical benefit of NLC, particularly in respect of disease-specific outcome and general satisfaction with care. In terms of health policy, we are not able to draw firm conclusions on cost-effectiveness given the variation in results between disease-specific and generic outcomes.

dings have shown that there may be some clinical benefit of NLC, particularly in respect of disease-specific outcome and general satisfaction with care. In terms of health policy, we are not able to draw firm conclusions on cost-effectiveness given the variation in results between disease-specific and generic outcomes. Supplementary Material Web figure Web table 1 Web table 2 Web table 3 Web table 4 Web table 5 First, the authors would like to express their sincere gratitude to all patients who took part in this trial. Second, they would like to thank Arthritis Research UK who funded the study (grant reference 17632). This study was adopted by UK Clinical Research Network (UKCRN ID 4386) and was provided with infrastructure support in all participating NHS trust hospitals. The authors thank the multicentre study team, the trial support team and the trial steering committee. The multicentre study team comprises Dr Jacqueline Andrews, Mr Zakari Akaribire, Dr Atheer Al-Ansari, Dr Victoria Bejarano, Dr Sarah Bingham, Sr Deborah Bond, Mr Hilary Brownett, Sr Gail Burbage, Sr Deborah Chagadama, Mrs Patricia Cornell, Mrs Elizabeth Gilmore, Dr Sandra Green, Sr Theresa Gripton, Dr Ali Jawad, Miss Lucy Kadiki, Dr Lesley Kay, Sr Clare Kellett, Dr Ken Lim, Mr Hugh Lloyd-Jones, Dr Anne McEntegart, Sr Elizabeth McIvor, Mrs Steph Mole, Dr Adrian Pace, Dr Fouz Rahmeh, Sr Susan Sisson, Sr Julia Taylor, A Tehseen, Sr Victoria Toner, Sr Jo White, Dr J Williams, Sr Gill Wilson and Mr Tom Wooldridge. The trial support team comprises Ms Helen Greenwood, Mr Glen Saunders and Mrs Jullie Whittle. The trial steering committee (independent members) comprises Mr David Blithe, Mrs Gill Bowskill, Mrs Sarah Fahy and Professor Andy Hassell.

, Sr Victoria Toner, Sr Jo White, Dr J Williams, Sr Gill Wilson and Mr Tom Wooldridge. The trial support team comprises Ms Helen Greenwood, Mr Glen Saunders and Mrs Jullie Whittle. The trial steering committee (independent members) comprises Mr David Blithe, Mrs Gill Bowskill, Mrs Sarah Fahy and Professor Andy Hassell. Contributors: JH was the chief investigator and the main grant holder responsible for the original idea and oversaw the project conduct. ML was the study statistician and health economist and was responsible for the protocol development, data analysis, and interpretation of the results and reporting. MN contributed to the protocol development and was responsible for the study set-up, recruiting sites, ethics and research governance applications, study coordinating, interpretation of the results and writing up the manuscripts. HQ, a grant holder, contributed her expertise in planning evaluation of health economics. CH contributed to grant application, supervising the study and reviewing the manuscripts. SR, also a grant holder, contributed to the protocol development, interpretation of the results and reviewing the manuscripts. PE contributed to the grant application, interpretation of the clinical results and reviewing the manuscripts. HB contributed to the grant application, protocol development, advised on ethics and data monitoring, interpretation of the clinical results and the review of the manuscripts. MN and ML had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

contributed to the grant application, protocol development, advised on ethics and data monitoring, interpretation of the clinical results and the review of the manuscripts. MN and ML had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Funding: Arthritis Research UK funded the study (Grant 17632). The funder was not involved in the preparation of the study protocol, running of the study or preparation of the report. The University of Leeds sponsored the trial, approved the study design and oversaw the overall management of the study. Competing interests: None. Ethics approval: Multicentre ethics approval was obtained from the Leeds West Research Ethics Committee (MREC ref 06/Q1205/198). Provenance and peer review: Not commissioned; externally peer reviewed.

sive disease control; DAS, Disease Activity Score; FACIT, Functional Assessment of Chronic Illness Therapy; HAQ-DI, Health Assessment Questionnaire disability index; RA, rheumatoid arthritis; SF-36, Short Form 36; VAS, Visual Analogue Scale; mTSS, modified total Sharp score; ΔmTSS, change in modified total Sharp score. Pooled RA population After adjusting for the baseline value of the outcome, CDC at week 26 was associated with the following improvements in PROs at week 26: a 20.0 (95% CI 16.9 to 23.2) point improvement in change from baseline in VAS-Pain; a 5.8 (4.4 to 7.1) point improvement in FACIT-F; a 10.8 (9.1 to 12.4) point improvement in SF-36 PCS and a 3.1 (1.4 to 4.8) point improvement in SF-36 MCS. Further, after adjusting for the baseline value of the outcome, CDC at week 26 was associated with the following improvements in PROs at week 52: a 16.9 (13.5–20.2) point improvement in VAS-Pain; a 4.9 (3.5–6.4) point improvement in FACIT-F; a 9.3 (7.6–11.1) point improvement in SF-36 PCS and a 2.2 (0.4–3.9) point improvement in SF-36 MCS (table 2). All improvements were statistically significant. In addition, the differences in SF-36 PCS, VAS-Pain and FACIT-F exceeded their respective MCIDs at both week 26 and 52. The difference in SF-36 MCS only exceeded the MCID at week 26. Table 2 Comparison of patient-reported and work-related outcomes by week 26 CDC achievement*†

Pooled RA population After adjusting for the baseline value of the outcome, CDC at week 26 was associated with the following improvements in PROs at week 26: a 20.0 (95% CI 16.9 to 23.2) point improvement in change from baseline in VAS-Pain; a 5.8 (4.4 to 7.1) point improvement in FACIT-F; a 10.8 (9.1 to 12.4) point improvement in SF-36 PCS and a 3.1 (1.4 to 4.8) point improvement in SF-36 MCS. Further, after adjusting for the baseline value of the outcome, CDC at week 26 was associated with the following improvements in PROs at week 52: a 16.9 (13.5–20.2) point improvement in VAS-Pain; a 4.9 (3.5–6.4) point improvement in FACIT-F; a 9.3 (7.6–11.1) point improvement in SF-36 PCS and a 2.2 (0.4–3.9) point improvement in SF-36 MCS (table 2). All improvements were statistically significant. In addition, the differences in SF-36 PCS, VAS-Pain and FACIT-F exceeded their respective MCIDs at both week 26 and 52. The difference in SF-36 MCS only exceeded the MCID at week 26. Table 2 Comparison of patient-reported and work-related outcomes by week 26 CDC achievement*† Patient-reported outcomes in the pooled population CDC achievers (A) Non-achievers (B) Difference (C)=(A)–(B) N=200 N=1267 Mean (95% CI) Mean (95% CI) Mean (95% CI) p Value Week 26 VAS-Pain change, N=1463 −46.91 (−49.83 to −43.98) −26.88 (−28.04 to −25.72) −20.03 (−23.18 to −16.88)‡ <0.0001 n=200 n=1263 FACIT-Fatigue change, N=1452 13.29 (12.03 to 14.54) 7.51 (7.02 to 8.00) 5.78 (4.42 to 7.13)‡ <0.0001 n=196 n=1256 SF-36 mental change, N=1086§ 8.06 (6.45 to 9.66) 4.98 (4.39 to 5.57) 3.07 (1.36 to 4.78)‡ 0.0004 n=131 n=955 SF-36 physical change, N=1086§ 19.66 (18.13 to 21.19) 8.91 (8.35 to 9.47) 10.76 (9.12 to 12.39)‡ <0.0001 n=131 n=955 Week 52 VAS-Pain change, N=1306 −45.68 (−48.76 to −42.61) −28.83 (−30.08 to −27.57) −16.86 (−20.18 to −13.53)‡ <0.0001 n=189 n=1117 FACIT-Fatigue change, N=1326 12.98 (11.66 to 14.30) 8.05 (7.52 to 8.57) 4.93 (3.51 to 6.36)‡ <0.0001 n=186 n=1140 SF-36 mental change, N=1001§ 7.26 (5.61 to 8.92) 5.12 (4.49 to 5.74) 2.15 (0.38 to 3.91) 0.0174 n=126 n=875 SF-36 physical change, N=1001§ 19.37 (17.73 to 21.01) 10.03 (9.42 to 10.65) 9.34 (7.57 to 11.10)‡ <0.0001 n=126 n=875 Work-related outcomes in PREMIER/DE032¶ CDC achievers (A) Non-achievers (B) Difference (C)=(A)−(B) N=98 N=563 Mean (95% CI) Mean (95% CI) Mean (95% CI) p Value Week 26 P-HEQ absenteeism among employed patients, N=284 9.69 (3.36 to 16.02) 11.87 (8.82 to 14.93) −2.19 (−9.22 to 4.85) 0.5414 n=54 n=230 P-HEQ presenteeism among employed patients, N=278 −44.23 (−50.30 to −38.17) −29.94 (−32.84 to −27.04) −14.30 (−21.03 to −7.56) <0.0001 n=52 n=226 P-HEQ absenteeism among homemakers, N=182 2.30 (−5.88 to 10.48) 8.51 (5.32 to 11.69) −6.21 (−14.99 to 2.58) 0.1650 n=24 n=158 P-HEQ presenteeism among homemakers, N=179 −52.00 (−61.89 to −42.11) −31.52 (−35.16 to −27.87) −20.49 (−31.07 to −9.90) 0.0002 n=22 n=157 Week 52 P-HEQ absenteeism among employed patients, N=239 6.80 (−2.71 to 16.32) 14.03 (9.09 to 18.98) −7.23 (−17.96 to 3.51) 0.1860 n=51 n=188 P-HEQ presenteeism among employed patients, N=237 −46.29 (−51.49 to −41.10) −33.65 (−36.33 to −30.97) −12.64 (−18.50 to −6.78) <0.0001 n=50 n=187 P-HEQ absenteeism among homemakers, N=154 2.94 (−12.62 to 18.49) 12.97 (6.46 to 19.47

239 6.80 (−2.71 to 16.32) 14.03 (9.09 to 18.98) −7.23 (−17.96 to 3.51) 0.1860 n=51 n=188 P-HEQ presenteeism among employed patients, N=237 −46.29 (−51.49 to −41.10) −33.65 (−36.33 to −30.97) −12.64 (−18.50 to −6.78) <0.0001 n=50 n=187 P-HEQ absenteeism among homemakers, N=154 2.94 (−12.62 to 18.49) 12.97 (6.46 to 19.47 ) −10.03 (−26.90 to 6.84) 0.2420 n=23 n=131 P-HEQ presenteeism among homemakers, N=152 −51.12 (−60.83 to −41.41) −34.16 (−38.09 to −30.24) −16.96 (−27.49 to −6.42) 0.0018 n=22 n=130 Work-related outcomes in OPTIMA** CDC achievers (A) Non-achievers (B) Difference (C)=(A)−(B) N=58 N=255 Mean (95% CI) Mean (95% CI) Mean (95% CI) p Value Week 26 WPAI activity impairment, N=308 −28.89 (−34.12 to −23.67) −10.94 (−13.37 to −8.51) −17.96 (−23.81 to −12.10) <0.0001 n=58 n=250 WPAI work impairment, N=131 −25.47 (−32.88 to −18.06) −7.77 (−12.30 to −3.24) −17.70 (−26.59 to −8.80) 0.0001 n=37 n=94 WPAI absenteeism, N=131 −8.20 (−14.42 to −1.99) −1.53 (−5.42 to 2.35) −6.67 (−14.02 to 0.68) 0.0750 n=37 n=94 WPAI presenteeism, N=144 −23.19 (−29.04 to −17.34) −9.41 (−12.99 to −5.82) −13.78 (−20.82 to −6.74) 0.0002 n=41 n=103 RA-WIS, N=153 −5.72 (−7.45 to −3.99) −2.09 (−3.00 to −1.18) −3.63 (−5.61 to −1.65) 0.0004 n=34 n=119 Week 52 WPAI activity impairment, N=284 −29.85 (−35.69 to −24.01) −10.60 (−13.37 to −7.84) −19.24 (−25.81 to −12.68) <0.0001 n=55 n=229 WPAI work impairment, N=125 −26.09 (−32.86 to −19.33) −11.63 (−16.00 to −7.27) −14.46 (−22.72 to −6.20) 0.0007 n=38 n=87 WPAI absenteeism, N=125 −8.93 (−14.10 to −3.76) −4.56 (−7.96 to −1.15) −4.37 (−10.59 to 1.84) 0.1659 n=38 n=87 WPAI presenteeism, N=134 −24.31 (−30.07 to −18.56) −9.81 (−13.39 to −6.23) −14.50 (−21.48 to −7.53) 0.0001 n=39 n=95 RA-WIS, N=146 −6.38 (−8.40 to −4.36) −1.74 (−2.81 to −0.67) −4.64 (−6.96 to −2.32) 0.0001 n=33 n=113 Boldface indicates statistical significance at the 0.05 level.

Introduction Rheumatoid arthritis (RA) is characterised by progressive inflammation of the joints and leads to irreversible joint damage that reduces function and increases disability.1 2 Current treatment options have shown to reduce inflammation, slow or prevent joint damage and improve patient-related outcomes. As per the treat-to-target recommendations, the primary goal in the treatment of RA should be achieving the control of symptoms, prevention of structural damage, normalisation of function and social participation.3 In the European League Against Rheumatism (EULAR) 2013 guidelines, achievement of clinical, functional and structural efficacy is also the basis for treatment comparison. However, the impact of such achievement on patient outcomes has not been adequately and explicitly assessed.

n of function and social participation.3 In the European League Against Rheumatism (EULAR) 2013 guidelines, achievement of clinical, functional and structural efficacy is also the basis for treatment comparison. However, the impact of such achievement on patient outcomes has not been adequately and explicitly assessed. While the achievement of all clinical, functional and structural efficacy is the ultimate goal for disease management, in real world practice, remission has been recommended as a key treatment target for adjusting therapy to optimise outcomes accordingly.3 Over the years, remission has been defined in several ways, but even with the recently more stringent American College of Rheumatology (ACR)-EULAR criteria, nearly 23% of the patients who achieved ACR-EULAR remission did not achieve the desired radiographic inhibition.4 It is, therefore, not guaranteed that remission target achievement alone would ensure functional and structural goal achievement. While remission could be the target for adjusting therapy, the goal of every treatment should be inhibition of structural damage and normalise function, in addition to symptom control.

ion.4 It is, therefore, not guaranteed that remission target achievement alone would ensure functional and structural goal achievement. While remission could be the target for adjusting therapy, the goal of every treatment should be inhibition of structural damage and normalise function, in addition to symptom control. In defining the three elements of the treatment goal, there has been a greater evolution in the definition of clinical remission relative to what is defined for normalised function based on Health Assessment Questionnaire disability index (HAQ-DI) and for structural non-progression based on modified Sharp score. Remission criteria derived from Disease Activity Score (DAS) and 28-joint Disease Activity Score (DAS28) have been the dominant treatment target in clinical practice in this evolution. Recently developed ACR-EULAR remission is so stringent that it is difficult to be achieved by most patients especially those with long-standing disease who actually constitute the majority of patients in clinical care. Hence, the EULAR 2013 guidelines recommended less stringent measures as a good alternative target for many patients who cannot attain stringent forms of remission.5 Given this, in the current study, we define clinical remission based on DAS28. A cut-off point of DAS28 using C reactive protein (DAS28(CRP)) <2.6 is an acceptable, as well as stringent enough, quantitative treatment target for the signs and symptoms of RA inflammation.6

who cannot attain stringent forms of remission.5 Given this, in the current study, we define clinical remission based on DAS28. A cut-off point of DAS28 using C reactive protein (DAS28(CRP)) <2.6 is an acceptable, as well as stringent enough, quantitative treatment target for the signs and symptoms of RA inflammation.6 Patient-reported outcomes (PROs) provide important assessments of functioning and well-being from the patient's perspective and may provide additional tangible impact for a patient, and thus be more sensitive to the effects of treatment than physician-assessed measures.7–10 In some cases, work limitations are important considerations in the treatment of RA given that the disease affects patients in their productive years.11 12 RA has also been noted to critically impact the health-related quality of life (HRQoL) of patients through the clinical manifestations of the disease and by socioeconomic, personal and environmental factors.7 13 Pain and fatigue are other important features of RA which are especially relevant from the patient perspective.8 14–16 In this study, we sought to quantify the impact of simultaneous achievement of clinical, functional and structural efficacy on work-related outcomes, HRQoL, pain and fatigue by pooling data from three randomised clinical trials of adalimumab for the treatment of RA among patients with both early-stage and late-stage disease.

s study, we sought to quantify the impact of simultaneous achievement of clinical, functional and structural efficacy on work-related outcomes, HRQoL, pain and fatigue by pooling data from three randomised clinical trials of adalimumab for the treatment of RA among patients with both early-stage and late-stage disease. Patients and methods Patients Data were drawn from three separate randomised controlled trials in RA: DE019 (NCT00195702), which enrolled patients with experienced RA (disease duration of at least 3 years with moderately to severely active RA despite a minimum of 3 months of treatment with methotrexate (MTX)); PREMIER (NCT00195663), which enrolled MTX-naive patients with early RA (disease duration <3 years) and OPTIMA (NCT00420927), which enrolled patients with early RA and included patients who failed to achieve stable low disease activity (LDA) (DAS28(CRP) <3.2 at weeks 22 and 26) with MTX. The design and primary results of the DE019, PREMIER and OPTIMA trials have been described elsewhere.17–20

sease duration <3 years) and OPTIMA (NCT00420927), which enrolled patients with early RA and included patients who failed to achieve stable low disease activity (LDA) (DAS28(CRP) <3.2 at weeks 22 and 26) with MTX. The design and primary results of the DE019, PREMIER and OPTIMA trials have been described elsewhere.17–20 A pooled intent-to-treat population included all patients from these trials who were randomised and received at least one dose of study drug. The present analysis includes all patients from DE019 and PREMIER. Due to the rerandomisation in the OPTIMA trial, only patients who failed to achieve LDA (DAS28(CRP) <3.2) with MTX during Period 1 of OPTIMA were included in the analysis. For these patients, the beginning of Period 2 was considered the baseline period. Patients with missing DAS28(CRP), HAQ-DI or change in modified total Sharp score (ΔmTSS) at baseline or week 26 were excluded from the present study.

LDA (DAS28(CRP) <3.2) with MTX during Period 1 of OPTIMA were included in the analysis. For these patients, the beginning of Period 2 was considered the baseline period. Patients with missing DAS28(CRP), HAQ-DI or change in modified total Sharp score (ΔmTSS) at baseline or week 26 were excluded from the present study. The simultaneous achievement of stringent control of the signs and symptoms of inflammation, normal physical function and the absence of radiographic progression, herein referred as comprehensive disease control (CDC), was evaluated at week 26. Stringent control of the signs and symptoms of inflammation was assessed by DAS28(CRP) and defined as DAS28(CRP) <2.6.2 6 21 Normal physical function was assessed using the Disability Index of the HAQ-DI22 and defined as HAQ-DI <0.5.4 23 Radiographic progression was assessed using radiographs of the hands/wrists and feet scored using the mTSS method.24–26 Absence of radiographic progression was defined as a ≤0.5 unit change from baseline in mTSS.27 Patients who achieved all three components were considered to have achieved CDC (‘CDC achievers’), while patients who achieved either none or any one or two (partial achievers) of the three components were considered to have not achieved CDC (‘CDC non-achievers’).

defined as a ≤0.5 unit change from baseline in mTSS.27 Patients who achieved all three components were considered to have achieved CDC (‘CDC achievers’), while patients who achieved either none or any one or two (partial achievers) of the three components were considered to have not achieved CDC (‘CDC non-achievers’). Outcomes Work-related outcomes were measured in DE032, the economic companion to PREMIER, and in OPTIMA. Work outcomes were analysed in each trial separately because of different definitions across the trials. Work outcomes in PREMIER/DE032 were measured using the Patient Health Economic Questionnaire (P-HEQ) and included the number of work days missed and the level at which work performance has been affected for employed patients with RA and homemakers separately. The level at which work performance has been affected was measured using a Visual Analogue Scale (VAS) scale ranging from 0 to 100.28 Work outcomes in OPTIMA were measured using the Work Productivity and Activity Impairment (WPAI) questionnaire29 and the RA-Work Instability Scale (RA-WIS).30 WPAI consists of six questions regarding the ability to work and perform regular activities during the past 7 days. WPAI evaluates absenteeism, presenteeism and work impairment among employed patients and activity impairment among all patients. RA-WIS is a 23-item questionnaire which quantifies ‘the state in which the consequences of a mismatch between an individual's functional abilities and the demands of his or her job can threaten continuing employment if they are not resolved’.30

airment among employed patients and activity impairment among all patients. RA-WIS is a 23-item questionnaire which quantifies ‘the state in which the consequences of a mismatch between an individual's functional abilities and the demands of his or her job can threaten continuing employment if they are not resolved’.30 HRQoL was measured using the Short Form 36 (SF-36) health survey. The SF-36 is a 36-item generic HRQoL measure to assess the patient’s view of his or her health consisting of two summary scales: physical (PCS) and mental component scores (MCS). For each component, a normalised summary score was calculated such that the average in the general population is 50 (with an SD of 10) using eight subdomains: Physical Functioning, Role-Physical, Bodily Pain and General Health for PCS, and Vitality, Social Functioning, Role-Emotional and Mental Health for MCS. Scores range from 0 to 100, with greater scores reflecting better health status.31–34 The minimal clinically important difference (MCID) for the SF-36 PCS and MCS is a 2.5-point increase from baseline.35 SF-36 information was not collected in the OPTIMA trial.

cial Functioning, Role-Emotional and Mental Health for MCS. Scores range from 0 to 100, with greater scores reflecting better health status.31–34 The minimal clinically important difference (MCID) for the SF-36 PCS and MCS is a 2.5-point increase from baseline.35 SF-36 information was not collected in the OPTIMA trial. Pain was measured using a VAS ranging from no pain to worst pain imaginable, with a higher score indicating worse pain. The MCID for VAS-Pain was a 10-mm decrease from baseline.36 Fatigue was measured using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), a symptom-specific scale validated for patients with RA. The 13-item subscale is self-administered using a 5-point Likert rating scale and ranges between 0 and 52 with higher values indicating less fatigue.37 The MCID for FACIT-Fatigue is a 4-point increase from baseline.32

of Chronic Illness Therapy-Fatigue (FACIT-F), a symptom-specific scale validated for patients with RA. The 13-item subscale is self-administered using a 5-point Likert rating scale and ranges between 0 and 52 with higher values indicating less fatigue.37 The MCID for FACIT-Fatigue is a 4-point increase from baseline.32 Statistical analysis Baseline characteristics were described for patients who achieved and did not achieve CDC at week 26. The change from baseline to week 26 for each outcome variable was compared between CDC achievers and non-achievers using linear regression adjusting for the baseline value of each outcome. Work outcomes measured using the P-HEQ were analysed in PREMIER only, while work outcomes measured using WPAI and RA-WIS were analysed in OPTIMA only. Similar analyses were performed to compare change from baseline to week 52. VAS-Pain and FACIT-F were analysed by pooling data from all three randomised clinical trials and in each trial separately. SF-36 PCS and SF-36 PCS were analysed by pooling DE019 and PREMIER because these HRQoL measures were not collected in OPTIMA. Separate analyses were conducted within the early RA (PREMIER), the MTX-failure (OPTIMA) and the experienced RA (DE019) populations. To gauge the incremental benefit of the simultaneous achievement of the three CDC components, the differences in SF-36 PCS, MCS, FACIT-F and VAS-Pain were compared between patients achieving all three components compared with achieving each component individually using a full interaction model adjusting for the baseline value of each outcome. To assess differences between CDC achievement and ACR-EULAR remission achievement, the differences in SF-36 PCS, MCS, FACIT-F and VAS-Pain were compared between patients achieving CDC compared with those achieving ACR-EULAR remission (Boolean-based definition4) but not CDC adjusting for the baseline value of each outcome.

assess differences between CDC achievement and ACR-EULAR remission achievement, the differences in SF-36 PCS, MCS, FACIT-F and VAS-Pain were compared between patients achieving CDC compared with those achieving ACR-EULAR remission (Boolean-based definition4) but not CDC adjusting for the baseline value of each outcome. Results A total of 1467 patients were included in the pooled trial sample (493 (33.6%) from DE019, 661 (45.1%) from PREMIER and 313 (21.3%) from OPTIMA) of whom 200 (13.6%) achieved CDC. Overall, patients who achieved CDC at week 26 were younger, had lower mean DAS28(CRP), HAQ-DI, mTSS and VAS-Pain, and higher mean FACIT-F, SF-36 PCS and SF-36 MCS scores (table 1). Table 1 Patient characteristics of week 26 CDC achievers and non-achievers

Results A total of 1467 patients were included in the pooled trial sample (493 (33.6%) from DE019, 661 (45.1%) from PREMIER and 313 (21.3%) from OPTIMA) of whom 200 (13.6%) achieved CDC. Overall, patients who achieved CDC at week 26 were younger, had lower mean DAS28(CRP), HAQ-DI, mTSS and VAS-Pain, and higher mean FACIT-F, SF-36 PCS and SF-36 MCS scores (table 1). Table 1 Patient characteristics of week 26 CDC achievers and non-achievers CDC achievers Non-achievers N=200 N=1267 Demographics Age, mean±SD 48.5±13.3 53.9±13.0 Female, n (%) 123 (61.5) 973 (76.8) Trial, n (%) OPTIMA 58 (29.0) 255 (20.1) PREMIER 98 (49.0) 563 (44.4) DE019 44 (22.0) 449 (35.4) Study outcomes, mean±SD Continuous CDC components DAS28 5.2±1.3 5.8±1.1 HAQ-DI 0.9±0.6 1.5±0.6 mTSS 20.9±31.6 37.1±44.7 Patient-reported outcomes SF-36 physical component score*,† 34.2±8.9 29.7±8.0 SF-36 mental component score*,† 48.2±12.4 45.9±12.0 VAS-Pain* 47.8±25.9 56.3±23.5 FACIT-Fatigue‡ 35.3±10.8 29.0±11.2 Lab values Haemoglobin (g/dL) 13.1±1.5 12.8±1.5 Creatine (mg/dL) 0.8±0.2 0.7±0.2 Work-related outcomes in OPTIMA§ Absenteeism* 9.6±23.1 17.3±30.9 Presenteeism* 25.9±25.2 45.6±27.2 Activity impairment* 26.9±24.2 47.8±23.9 Work impairment* 29.4±26.5 49.9±30.9 Work instability scale 6.7±6.6 11.7±7.2 Work-related outcomes in PREMIER/DE032¶ Number of work days missed among employed patients in the last 4 weeks 3.2±6.1 5.2±8.6 Level work performance has been affected among employed patients in the last week* 45.6±32.6 53.5±32.0 Number of work days missed among homemakers in the last 4 weeks 4.7±8.3 7.2±10.1 Level work performance has been affected among homemakers in the last week* 43.6±26.8 62.4±26.4 Additional measures Clinical characteristics, mean±SD RA duration (years) 2.7±5.1 4.4±7.3 Swollen joint count (66) 16.1±8.0 19.8±9.8 Tender joint count (68) 21.1±10.2 29.0±13.7 C reactive protein (mg/L) 20.1±23.7 27.7±33.6 Physician’s global assessment of disease activity* 58.7±18.5 64.5±17.2 Patient’s global assessment of disease activity* 55.0±25.6 60.6±23.3 Radiographic findings, mean±SD Erosion score 12.6±18.5 20.9±25.0 Joint space narrowing 8.3±14.3 16.3±21.4 Components of CDC achievement at week 26, n (%) Full achievement 200 (100.0) 0 (0.0) Achieved HAQ <0.5 and DAS <2.6 0 (0.0) 58 (4.6) Achieved HAQ <0.5 and ΔmTSS ≤0.5 0 (0.0) 216 (17.0) Achieved DAS <2.6 and ΔmTSS ≤0.5 0 (0.0) 89 (7.0) Achieved HAQ <0.5 only 0 (0.0) 95 (7.5) Achieved DAS <2.6 only 0 (0.0) 33 (2.6) Achieved ΔmTSS ≤0.5 only 0 (0.0) 495 (39.1) Achieved none 0 (0.0) 281 (22.2) ACR-EULAR remission achievement at week 26, n (%) Yes 65 (33.0) 29 (2.3) *Measured from 0 to 100.

0.0) 216 (17.0) Achieved DAS <2.6 and ΔmTSS ≤0.5 0 (0.0) 89 (7.0) Achieved HAQ <0.5 only 0 (0.0) 95 (7.5) Achieved DAS <2.6 only 0 (0.0) 33 (2.6) Achieved ΔmTSS ≤0.5 only 0 (0.0) 495 (39.1) Achieved none 0 (0.0) 281 (22.2) ACR-EULAR remission achievement at week 26, n (%) Yes 65 (33.0) 29 (2.3) *Measured from 0 to 100. †Not measured in OPTIMA patients. ‡Measured from 0 to 52. Greater values indicate less fatigue. §Among OPTIMA patients only. ¶Among PREMIER/DE032 patients only. ACR-EULAR, American College of Rheumatology-European League Against Rheumatism; CDC, comprehensive disease control; DAS, Disease Activity Score; FACIT, Functional Assessment of Chronic Illness Therapy; HAQ-DI, Health Assessment Questionnaire disability index; RA, rheumatoid arthritis; SF-36, Short Form 36; VAS, Visual Analogue Scale; mTSS, modified total Sharp score; ΔmTSS, change in modified total Sharp score.

−4.37 (−10.59 to 1.84) 0.1659 n=38 n=87 WPAI presenteeism, N=134 −24.31 (−30.07 to −18.56) −9.81 (−13.39 to −6.23) −14.50 (−21.48 to −7.53) 0.0001 n=39 n=95 RA-WIS, N=146 −6.38 (−8.40 to −4.36) −1.74 (−2.81 to −0.67) −4.64 (−6.96 to −2.32) 0.0001 n=33 n=113 Boldface indicates statistical significance at the 0.05 level. *The adjusted analysis compared the mean change from baseline for each outcome by CDC achievement using an analysis of covariance model in which the impact of CDC on change in the outcome was estimated adjusting for the baseline value of the outcome. †For VAS-Pain, negative change from baseline indicates an improvement in the outcome. For FACIT-Fatigue, SF-36 Mental Health and SF-36 Physical Health, positive change from baseline indicates an improvement in the outcome. ‡Indicates difference exceeds the respective MCID for the outcome. §SF-36 Physical and Mental Health Component Scores were not measured in OPTIMA. ¶For P-HEQ absenteeism, the mean cumulative number of work days missed from baseline to week 26 and from baseline to week 52 was compared by CDC achievement. For P-HEQ presenteeism, the mean change from baseline to week 26 and from baseline to week 52 was compared by CDC achievement adjusting for the baseline P-HEQ presenteeism. **For WPAI measures and RA-WIS, the mean change from baseline to week 26 and from baseline to week 52 was compared by CDC achievement adjusting for the baseline value.

¶For P-HEQ absenteeism, the mean cumulative number of work days missed from baseline to week 26 and from baseline to week 52 was compared by CDC achievement. For P-HEQ presenteeism, the mean change from baseline to week 26 and from baseline to week 52 was compared by CDC achievement adjusting for the baseline P-HEQ presenteeism. **For WPAI measures and RA-WIS, the mean change from baseline to week 26 and from baseline to week 52 was compared by CDC achievement adjusting for the baseline value. CDC, comprehensive disease control; FACIT, Functional Assessment of Chronic Illness Therapy; MCID, minimal clinically important difference; P-HEQ, Patient Health Economic Questionnaire; RA-WIS, Rheumatoid Arthritis-Work Instability Scale; SF-36, Short Form 36; VAS, Visual Analogue Scale; WPAI, Work Productivity and Activity Impairment. Early RA population Among patients with early RA enrolled in PREMIER, CDC achievement was associated with statistically significant improvements in P-HEQ presenteeism at weeks 26 and 52 (table 2). Achievement of CDC at week 26 was also associated with statistically significant and clinically meaningful differences in SF-36 PCS, VAS-Pain and FACIT-F at both week 26 and 52 and statistically significant and clinically meaningful differences in SF-36 MCS at week 26 (figures 1 and 2).

sm at weeks 26 and 52 (table 2). Achievement of CDC at week 26 was also associated with statistically significant and clinically meaningful differences in SF-36 PCS, VAS-Pain and FACIT-F at both week 26 and 52 and statistically significant and clinically meaningful differences in SF-36 MCS at week 26 (figures 1 and 2). Figure 1 Comparison of patient-reported outcomes by CDC achievement and trial population at week 26.1 FACIT, Functional Assessment of Chronic Illness Therapy; SF-36, Short Form 36; VAS, Visual Analogue Scale; RA, rheumatoid arthritis; MCS, mental component score; PCS, physical component score; CDC, comprehensive disease control; MTX, methotrexate. Figure 2 Comparison of patient-reported outcomes by CDC achievement and trial population at week 52.1 FACIT, Functional Assessment of Chronic Illness Therapy; SF-36, Short Form 36; VAS, Visual Analogue Scale; RA, rheumatoid arthritis; MCS, mental component score; PCS, physical component score; CDC, comprehensive disease control; MTX, methotrexate.

t-reported outcomes by CDC achievement and trial population at week 52.1 FACIT, Functional Assessment of Chronic Illness Therapy; SF-36, Short Form 36; VAS, Visual Analogue Scale; RA, rheumatoid arthritis; MCS, mental component score; PCS, physical component score; CDC, comprehensive disease control; MTX, methotrexate. Early RA MTX-failure population Among all patients with early RA enrolled in OPTIMA who failed to achieve LDA with MTX, achievement of CDC at week 26 was associated with statistically significant improvements in change in WPAI activity impairment, WPAI work impairment, WPAI presenteeism and RA-WIS at weeks 26 and 52 after adjusting for baseline values (table 2). Among all MTX-failure patients, achievement of CDC at week 26 was associated with statistically significant differences in VAS-Pain and FACIT-F at weeks 26 and 52 after adjusting for baseline values. The differences in VAS-Pain exceeded the MCID at both week 26 and 52 (figures 1 and 2). Established RA population Among patients with established RA enrolled in DE019, achievement of CDC at week 26 was associated with statistically significant improvements in change in SF-36 PCS, FACIT-F and VAS-Pain at weeks 26 and 52 after adjusting for the baseline scores (figures 1 and 2).

Early RA MTX-failure population Among all patients with early RA enrolled in OPTIMA who failed to achieve LDA with MTX, achievement of CDC at week 26 was associated with statistically significant improvements in change in WPAI activity impairment, WPAI work impairment, WPAI presenteeism and RA-WIS at weeks 26 and 52 after adjusting for baseline values (table 2). Among all MTX-failure patients, achievement of CDC at week 26 was associated with statistically significant differences in VAS-Pain and FACIT-F at weeks 26 and 52 after adjusting for baseline values. The differences in VAS-Pain exceeded the MCID at both week 26 and 52 (figures 1 and 2). Established RA population Among patients with established RA enrolled in DE019, achievement of CDC at week 26 was associated with statistically significant improvements in change in SF-36 PCS, FACIT-F and VAS-Pain at weeks 26 and 52 after adjusting for the baseline scores (figures 1 and 2). Incremental value of CDC Compared with patients achieving DAS remission alone, CDC achievement was associated with statistically significant and clinically meaningful differences of 7.0 (4.0–10.0) and 6.9 (3.5–10.4) in SF-36 PCS at weeks 26 and 52, respectively. CDC achievement was also associated with a 9.0 (1.6–16.3) point decrease in VAS-Pain compared with DAS remission alone. When compared with patients achieving normal physical function alone, CDC achievement was associated with statistically significant differences of 4.0 (2.0–6.0) and 2.9 (0.6–5.2) in SF-36 PCS and 7.6 (3.1–12.1) and 5.5 (0.5–10.6) reductions in VAS-Pain at weeks 26 and 52, respectively. CDC achievement was associated with statistically significant and clinically meaningful improvements in SF-36 PCS, MCS, FACIT-F and VAS-Pain at both week 26 and 52 compared with patients with the absence of radiographic progression alone (table 3).

5.5 (0.5–10.6) reductions in VAS-Pain at weeks 26 and 52, respectively. CDC achievement was associated with statistically significant and clinically meaningful improvements in SF-36 PCS, MCS, FACIT-F and VAS-Pain at both week 26 and 52 compared with patients with the absence of radiographic progression alone (table 3). Table 3 Change in patient-reported outcomes from baseline to week 26 and week 52 by week 26 CDC components achieved (DE019, PREMIER and OPTIMA)

5.5 (0.5–10.6) reductions in VAS-Pain at weeks 26 and 52, respectively. CDC achievement was associated with statistically significant and clinically meaningful improvements in SF-36 PCS, MCS, FACIT-F and VAS-Pain at both week 26 and 52 compared with patients with the absence of radiographic progression alone (table 3). Table 3 Change in patient-reported outcomes from baseline to week 26 and week 52 by week 26 CDC components achieved (DE019, PREMIER and OPTIMA) Continuous outcomes*† CDC achievers (A) Achieved DAS remission (B) Achieved normal physician function (C) Achieved non-radiographic progression (D) Difference (E)=(A)−(B) Difference (F)=(A)−(C) Difference (G)=(A)−(D) N=200 N=380 N=569 N=1000 Mean (95% CI) Mean (95% CI) Mean (95% CI) Mean (95% CI) Mean (95% CI) Mean (95% CI) Mean (95% CI) Week 26 VAS-Pain change, N=1463 −47.49 (−50.07 to −44.91) −42.21 (−48.53 to −35.90) −39.89 (−43.62 to −36.16) −18.32 (−19.95 to −16.68) −5.27 (−12.09 to 1.55) −7.60 (−12.11 to −3.08) −29.17 (−32.24 to −26.11) 200 378 568 997 FACIT-Fatigue change, N=1452 13.65 (12.49 to 14.81) 10.81 (8.02 to 13.60) 13.92 (12.27 to 15.56) 4.42 (3.70 to 5.15) 2.84 (−0.18 to 5.86) −0.27 (−2.27 to 1.74) 9.23 (7.84 to 10.61) 196 373 563 988 SF-36 mental change, N=1086 8.08 (6.50 to 9.67) 8.96 (5.55 to 12.38) 7.97 (5.94 to 9.99) 3.54 (2.56 to 4.52) −0.88 (−4.64 to 2.89) 0.12 (−2.45 to 2.68) 4.54 (2.68 to 6.41) 131 246 420 680 SF-36 physical change, N=1086 20.36 (19.09 to 21.62) 13.39 (10.70 to 16.08) 16.33 (14.73 to 17.93) 4.81 (4.04 to 5.59) 6.97 (3.99 to 9.95) 4.03 (2.01 to 6.05) 15.55 (14.05 to 17.04) 131 246 420 680 Week 52 VAS-Pain change, N=1306 −46.11 (−48.95 to −43.27) −37.16 (−43.92 to −30.40) −40.61 (−44.80 to −36.42) −21.02 (−22.87 to −19.17) −8.95 (−16.28 to −1.62) −5.50 (−10.55 to −0.45) −25.09 (−28.49 to −21.68) 189 350 516 900 FACIT-Fatigue change, N=1326 13.27 (12.01 to 14.52) 10.35 (7.43 to 13.27) 13.61 (11.82 to 15.40) 5.42 (4.63 to 6.22) 2.92 (−0.26 to 6.09) −0.35 (−2.52 to 1.83) 7.84 (6.34 to 9.34) 186 348 521 912 SF-36 mental change, N=1001 7.28 (5.64 to 8.92) 8.52 (4.91 to 12.13) 6.93 (4.80 to 9.06) 3.95 (2.92 to 4.99) −1.24 (−5.21 to 2.73) 0.35 (−2.34 to 3.04) 3.33 (1.38 to 5.27) 126 236 393 630 SF-36 physical change, N=1001 20.01 (18.57 to 21.45) 13.07 (9.96 to 16.18) 17.12 (15.29 to 18.96) 6.42 (5.52 to 7.31) 6.94 (3.51 to 10.37) 2.89 (0.57 to 5.20) 13.59 (11.88 to 15.30) 126 236 393 630 Boldface indicates statistical significance at the 0.05 level.

3) 0.35 (−2.34 to 3.04) 3.33 (1.38 to 5.27) 126 236 393 630 SF-36 physical change, N=1001 20.01 (18.57 to 21.45) 13.07 (9.96 to 16.18) 17.12 (15.29 to 18.96) 6.42 (5.52 to 7.31) 6.94 (3.51 to 10.37) 2.89 (0.57 to 5.20) 13.59 (11.88 to 15.30) 126 236 393 630 Boldface indicates statistical significance at the 0.05 level. *The adjusted analysis compared the mean change from baseline for each outcome by CDC component achievement using an analysis of covariance model in which the impact of component achievement on change in the outcome was estimated adjusting for the baseline value of the outcome. †For VAS-Pain, negative change from baseline indicates an improvement in the outcome. For FACIT-Fatigue, SF-36 Mental Health and SF-36 Physical Health, positive change from baseline indicates an improvement in the outcome. CDC, comprehensive disease control; DAS, Disease Activity Score; FACIT, Functional Assessment of Chronic Illness Therapy; SF-36, Short Form 36; VAS, Visual Analogue Scale. Comparison with ACR-EULAR remission There were no statistically significant differences in VAS-Pain, FACIT-Fatigue, SF-36 PCS and SF-36 MCS between patients achieving CDC and patients achieving ACR-EULAR remission but not CDC at weeks 26 and 52 (table 4). Table 4 Change in patient-reported outcomes from baseline to week 26 and week 52 by week 26 CDC/ACR-EULAR remission achievement (DE019, PREMIER and OPTIMA)

Comparison with ACR-EULAR remission There were no statistically significant differences in VAS-Pain, FACIT-Fatigue, SF-36 PCS and SF-36 MCS between patients achieving CDC and patients achieving ACR-EULAR remission but not CDC at weeks 26 and 52 (table 4). Table 4 Change in patient-reported outcomes from baseline to week 26 and week 52 by week 26 CDC/ACR-EULAR remission achievement (DE019, PREMIER and OPTIMA) CDC achievers (A) ACR-EULAR remission but not CDC (B) Neither ACR-EULAR remission nor CDC (C) Difference (D)=(A)−(B) N=200 N=29 N=1226 Continuous outcomes*† Mean (95% CI) Mean (95% CI) Mean (95% CI) Mean (95% CI) p Value Week 26 VAS-Pain change, N=1451 −47.07 (−49.96 to −44.19) −51.59 (−59.12 to −44.05) −26.45 (−27.61 to −25.29) 4.51 (−3.55 to 12.57) 0.2722 200 29 1222 FACIT-Fatigue change, N=1440 13.31 (12.06 to 14.56) 12.82 (9.62 to 16.01) 7.42 (6.92 to 7.91) 0.50 (−2.93 to 3.92) 0.7764 196 29 1215 SF-36 mental change, N=1085 8.06 (6.46 to 9.67) 6.05 (2.52 to 9.57) 4.95 (4.35 to 5.55) 2.02 (−1.85 to 5.89) 0.3065 131 27 927 SF-36 physical change, N=1085 19.69 (18.19 to 21.20) 19.17 (15.91 to 22.44) 8.59 (8.03 to 9.15) 0.52 (−3.07 to 4.11) 0.7754 131 27 927 Week 52 VAS-Pain change, N=1294 −45.84 (−48.87 to −42.80) −51.22 (−59.36 to −43.09) −28.52 (−29.79 to −27.26) 5.39 (−3.29 to 14.07) 0.2234 189 26 1079 FACIT-Fatigue change, N=1314 13.00 (11.69 to 14.31) 14.16 (10.64 to 17.68) 7.97 (7.44 to 8.50) −1.16 (−4.90 to 2.59) 0.5441 186 25 1103 SF-36 mental change, N=1000 7.27 (5.62 to 8.93) 8.19 (4.48 to 11.89) 5.03 (4.39 to 5.66) −0.91 (−4.97 to 3.14) 0.6580 126 25 849 SF-36 physical change, N=1000 19.38 (17.77 to 21.00) 20.54 (16.97 to 24.11) 9.72 (9.11 to 10.34) −1.16 (−5.08 to 2.76) 0.5626 126 25 849 *The adjusted analysis compared the mean change from baseline for each outcome by CDC/ACR-EULAR achievement using an analysis of covariance model in which the impact of achievement on change in the outcome was estimated adjusting for the baseline value of the outcome.

1 to 10.34) −1.16 (−5.08 to 2.76) 0.5626 126 25 849 *The adjusted analysis compared the mean change from baseline for each outcome by CDC/ACR-EULAR achievement using an analysis of covariance model in which the impact of achievement on change in the outcome was estimated adjusting for the baseline value of the outcome. †For VAS-Pain, negative change from baseline indicates an improvement in the outcome. For FACIT-Fatigue, SF-36 Mental Health and SF-36 Physical Health, positive change from baseline indicates an improvement in the outcome. ACR-EULAR, American College of Rheumatology-European League Against Rheumatism; CDC, comprehensive disease control; FACIT, Functional Assessment of Chronic Illness Therapy; SF-36, Short Form 36; VAS, Visual Analogue Scale. Discussion Clinical, functional and structural efficacy outcomes are the three aspects against which therapies are evaluated in the disease management for RA. In additional, simultaneous achievement of all three is proposed as the long-term treatment goal with implied benefits on patients. While correlated, these three aspects have respective variations and each of them adds value while being achieved simultaneously. The purpose of this study is to assess the impact of such achievement, referred to as CDC, on short-term as well as long-term patient outcomes including fatigue, pain, work outcomes and general physical and mental health. CDC includes DAS remission of <2.6, normal physical function (as measured by HAQ-DI) and absence of radiographic progression (as measured by mTSS).

of such achievement, referred to as CDC, on short-term as well as long-term patient outcomes including fatigue, pain, work outcomes and general physical and mental health. CDC includes DAS remission of <2.6, normal physical function (as measured by HAQ-DI) and absence of radiographic progression (as measured by mTSS). In the present study, CDC was associated with significant improvements in patient's work-related outcomes, HRQoL, pain and fatigue. These improvements were observed both at the time of CDC achievement and 26 weeks later. The improvements in HRQoL are especially pronounced, as patients who achieve CDC are 2.5 times more likely to have SF-36 MCS score greater than the general population norm and 9.8 times more likely to have SF-36 PCS greater than the general population norm at week 26. Similarly, CDC achievers are 2.3 times more likely to have SF-36 MCS score greater than the general population norm and 6.7 times more likely to have SF-36 PCS greater than the general population norm at week 52. These improvements are associated with reduced healthcare use and costs and reduced mortality,38 39 further demonstrating that CDC achievement is associated with broad and significant improvements in patient outcomes. Also, the differences between the CDC achievers and non-achievers for all the measured outcomes were greater than the clinically meaningful thresholds for each of the outcome. The simultaneous achievement of all three CDC domains was also demonstrated to be associated with significant improvements in physical function and pain compared with achieving the individual domains in isolation. This result suggests there may be an incremental benefit related to achieving all three components. An adjusted correlation analysis of the individual components showed that nearly 50%–55% of the variations in the outcomes at week 26 (SF-36 and VAS-Pain) were explained by improvements in DAS28 remission, 35%–47% by improvements in HAQ-DI score and 2%–9% by mTSS scores.

nefit related to achieving all three components. An adjusted correlation analysis of the individual components showed that nearly 50%–55% of the variations in the outcomes at week 26 (SF-36 and VAS-Pain) were explained by improvements in DAS28 remission, 35%–47% by improvements in HAQ-DI score and 2%–9% by mTSS scores. Current recommendations state that treatment of RA should focus on achieving clinical remission to inhibit progression of joint damage and improve physical function and quality of life.3 The ACR and EULAR also recognise the importance of remission for predicting improvement in physical function and halting radiographic progression. It is noted in the EULAR 2013 recommendation update that ACR-EULAR remission should serve as the optimal treatment target to be used in routine clinical practice, while LDA is a good alternative for the many patients who cannot attain remission. Within the pooled population in this study, a total of 94 patients experienced ACR-EULAR remission, of whom 65 (69.1%) also achieved CDC. The presence of radiographic progression was the most common reason for discordance (17 patients). There were no significant differences in SF-36 PCS, MCS, FACIT-F or VAS-Pain between patients achieving CDC and those achieving ACR-EULAR remission (but not CDC), although this analysis was limited by small sample size (table 4). Regardless of which treatment target is selected, the long-term goal remains to maximise long-term HRQoL through control of symptoms, prevention of structural damage, normalisation of function and social participation. Discussions around the simultaneous achievement of clinical, physical and structural efficacy can also engage patients and encourage patients to involve their observation around physical function.

erm HRQoL through control of symptoms, prevention of structural damage, normalisation of function and social participation. Discussions around the simultaneous achievement of clinical, physical and structural efficacy can also engage patients and encourage patients to involve their observation around physical function. This analysis has several strengths. First, we pooled data from three large RCTs of early RA, established RA and MTX non-responders and found that within trial, analyses were consistent with the results from the pooled data. So while patients with experienced disease may achieve CDC at a lower rate, there is no differential impact of CDC achievement on quality of life by RA duration. Further, improvements in PROs observed at 52 weeks were similar to those observed at 26 weeks, demonstrating that achievement of CDC may have a long-standing effect on quality of life. This analysis has limitations. First, patient characteristics were not balanced between CDC achievers and non-achievers. However, adjustment for these factors may not account for all baseline differences between CDC achievers and non-achievers. An observed case analysis was performed, which led to 17% of patients being dropped from the analysis. However, imputation procedures require assumptions about the underlying missing data mechanism and may not be appropriate for this analysis. Last, not all outcomes, such as SF-36, were measured in all trials making it difficult to assess the full impact of CDC achievement on SF-36 in patients who were non-responders to MTX.

er, imputation procedures require assumptions about the underlying missing data mechanism and may not be appropriate for this analysis. Last, not all outcomes, such as SF-36, were measured in all trials making it difficult to assess the full impact of CDC achievement on SF-36 in patients who were non-responders to MTX. This post hoc analysis of three individual clinical trials demonstrated the benefits of CDC at the time of achievement and 6 months postachievement. This finding can be strengthened if supported by the results of a future prospective randomised controlled trial using CDC as a ranked secondary endpoint. Future research into whether the benefits of CDC are maintained over a longer-term is also warranted. CDC achievement was associated with clinically meaningful improvements in work-related outcomes, HRQoL, pain and fatigue compared with those who did not achieve CDC. These results demonstrate that simultaneous improvement in all three RA domains can provide meaningful benefits to patients.

This post hoc analysis of three individual clinical trials demonstrated the benefits of CDC at the time of achievement and 6 months postachievement. This finding can be strengthened if supported by the results of a future prospective randomised controlled trial using CDC as a ranked secondary endpoint. Future research into whether the benefits of CDC are maintained over a longer-term is also warranted. CDC achievement was associated with clinically meaningful improvements in work-related outcomes, HRQoL, pain and fatigue compared with those who did not achieve CDC. These results demonstrate that simultaneous improvement in all three RA domains can provide meaningful benefits to patients. Contributors: PE, AK and PM conceptualised the research and contributed to the interpretation of the data. YB and AG wrote the statistical analysis plan and analysed the data. AG, PE, AK, PM and YB contributed to the drafting of the paper and approved the final version. Significant contribution towards medical writing and analytical support was provided by Keith Betts, PhD, of Analysis Group; this support was funded by AbbVie. AbbVie sponsored the studies, participated in study design, data collection, analysis and interpretation, and in the writing, reviewing and approval of the final version. Funding: AbbVie funded the studies DE019 (NCT00195702), PREMIER (NCT00195663) and OPTIMA (NCT00420927), contributed to their design and was involved in the collection, analysis and interpretation of the data, and in the writing, review and approval of the manuscript.

Contributors: PE, AK and PM conceptualised the research and contributed to the interpretation of the data. YB and AG wrote the statistical analysis plan and analysed the data. AG, PE, AK, PM and YB contributed to the drafting of the paper and approved the final version. Significant contribution towards medical writing and analytical support was provided by Keith Betts, PhD, of Analysis Group; this support was funded by AbbVie. AbbVie sponsored the studies, participated in study design, data collection, analysis and interpretation, and in the writing, reviewing and approval of the final version. Funding: AbbVie funded the studies DE019 (NCT00195702), PREMIER (NCT00195663) and OPTIMA (NCT00420927), contributed to their design and was involved in the collection, analysis and interpretation of the data, and in the writing, review and approval of the manuscript. Competing interests: PE—Grant/research support: AbbVie, Pfizer, Novartis, BMS and Roche; Consultant for: AbbVie, Pfizer, MSD, UCB, Roche, Novartis and BMS. AK—Grant/research support: AbbVie, Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche and UCB; Consultant for: AbbVie, Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche and UCB. AG—Shareholder of: AbbVie; Employee of: AbbVie. YB—Shareholder of: AbbVie; Employee of: AbbVie. PM—Shareholder of: AbbVie; Employee of: AbbVie. Provenance and peer review: Not commissioned; externally peer reviewed.

Introduction Rheumatoid arthritis (RA) is a progressive disease characterised by chronic joint inflammation and subsequent structural damage.1 There may be a ‘window of opportunity’ in early RA to alter the course of the disease if tightly controlled, which diminishes once the inflammatory processes are more established.2 If so, this could aid decisions on the use of a combination of biological disease-modifying antirheumatic drugs (DMARD) and conventional synthetic (cs)DMARDs versus step-up therapy in early RA.3 Once RA is well controlled, the ability to sustain remission following the withdrawal of immunomodulatory medications would be an indication of disease modification.

se of a combination of biological disease-modifying antirheumatic drugs (DMARD) and conventional synthetic (cs)DMARDs versus step-up therapy in early RA.3 Once RA is well controlled, the ability to sustain remission following the withdrawal of immunomodulatory medications would be an indication of disease modification. Abatacept, a fusion protein of cytotoxic T lymphocyte-associated antigen-4 and immunoglobulin G1, selectively modulates the CD80/CD86:CD28 costimulatory signal required for full T-cell activation.4 Due to a greater impact on naive T cells, there is a rationale for the use of abatacept in early RA; the unique upstream mechanism of abatacept impacts downstream inflammatory mediators and autoantibodies, and may allow removal of drug therapy. In the Abatacept study to Gauge Remission and joint damage progression in methotrexate naïve patients with Early Erosive rheumatoid arthritis (AGREE), after all patients had completed 2 years of abatacept treatment, 50 patients had a dose reduction from 10 mg/kg to 5 mg/kg without change in efficacy.5 In patients with undifferentiated and early RA in the Abatacept study to Determine the effectiveness in preventing the development of rheumatoid arthritis in patients with Undifferentiated inflammatory arthritis and to evaluate Safety and Tolerability (ADJUST), abatacept was withdrawn following 6 months of monotherapy, and maintained inhibition of joint damage progression for 6 months after withdrawal.6 Similarly, in a study of patients with type 1 diabetes, the treatment effect observed with abatacept was maintained for a year following drug withdrawal.7

lerability (ADJUST), abatacept was withdrawn following 6 months of monotherapy, and maintained inhibition of joint damage progression for 6 months after withdrawal.6 Similarly, in a study of patients with type 1 diabetes, the treatment effect observed with abatacept was maintained for a year following drug withdrawal.7 In this phase 3b trial, we evaluated the efficacy and safety of subcutaneous (SC) abatacept plus methotrexate (MTX), and abatacept monotherapy versus MTX in inducing clinical remission after 12 months in patients with early RA, and their ability to sustain drug-free remission at 18 months. Whereas a few studies have examined the strategy of achieving disease control followed by various de-escalation approaches reducing either steroids, MTX or biologicals,8–17 this is the first study to investigate the possibility of achieving absolute drug-free remission after removing all RA therapies. Methods Study design Assessing Very Early Rheumatoid arthritis Treatment (AVERT) was a phase 3b, randomised, active-controlled trial of 24 months, with a 12-month, double-blind treatment period (see online figure S1 in the supplementary appendix).

In this phase 3b trial, we evaluated the efficacy and safety of subcutaneous (SC) abatacept plus methotrexate (MTX), and abatacept monotherapy versus MTX in inducing clinical remission after 12 months in patients with early RA, and their ability to sustain drug-free remission at 18 months. Whereas a few studies have examined the strategy of achieving disease control followed by various de-escalation approaches reducing either steroids, MTX or biologicals,8–17 this is the first study to investigate the possibility of achieving absolute drug-free remission after removing all RA therapies. Methods Study design Assessing Very Early Rheumatoid arthritis Treatment (AVERT) was a phase 3b, randomised, active-controlled trial of 24 months, with a 12-month, double-blind treatment period (see online figure S1 in the supplementary appendix). The study population included adults (≥18 years old) with active clinical synovitis of ≥2 joints for ≥8 weeks, persistent symptoms for ≤2 years, Disease Activity Score (DAS)28 (C reactive protein (CRP)) ≥3.2 and anticitrullinated peptide (CCP)-2 antibody positivity (see online table S1 in the supplementary appendix). Patients were MTX naive or received MTX (≤10 mg/week) for ≤4 weeks with no MTX for 1 month prior to enrolment. Patients receiving oral corticosteroids were required to be on a stable dose (≤10 mg/day for ≥4 weeks) at initiation and to maintain that dose until month 12.

ee online table S1 in the supplementary appendix). Patients were MTX naive or received MTX (≤10 mg/week) for ≤4 weeks with no MTX for 1 month prior to enrolment. Patients receiving oral corticosteroids were required to be on a stable dose (≤10 mg/day for ≥4 weeks) at initiation and to maintain that dose until month 12. In the 12-month treatment period, patients were randomised (1:1:1) to abatacept plus MTX, abatacept monotherapy or MTX, stratified by corticosteroid use at baseline (yes/no) using a Centralised Randomisation System. SC abatacept was administered at 125 mg/week. MTX was initiated at 7.5 mg/week and titrated to 15–20 mg/week within 6–8 weeks (≤10 mg/week permitted in patients with intolerance). All patients received concomitant folic acid therapy. Patients with DAS28 (CRP) <3.2 at month 12 could enter the 12-month withdrawal period, during which all treatment was stopped; abatacept immediately and MTX and steroids tapered over 1 month. Patients with DAS28 (CRP) ≥3.2 discontinued the study. After month 15, patients in the withdrawal period who experienced a flare of RA defined as two of the following: doubling of tender and swollen joint counts relative to month 12, increase in DAS28 (CRP) ≥1.2 from month 12, or investigator's judgement of RA flare, were eligible to enter a re-exposure period with open-label SC abatacept 125 mg plus MTX. All patients underwent contrast MRI of the wrist and hand of the major affected upper limb at baseline and at 6, 12, 18 and 24 months.

After month 15, patients in the withdrawal period who experienced a flare of RA defined as two of the following: doubling of tender and swollen joint counts relative to month 12, increase in DAS28 (CRP) ≥1.2 from month 12, or investigator's judgement of RA flare, were eligible to enter a re-exposure period with open-label SC abatacept 125 mg plus MTX. All patients underwent contrast MRI of the wrist and hand of the major affected upper limb at baseline and at 6, 12, 18 and 24 months. The study (NCT01142726) was conducted in accordance with Good Clinical Practice.18–20 Bristol-Myers Squibb (the sponsor) provided the study drug, designed the study, conducted the study in collaboration with the principal investigators, collected the data, monitored the conduct of the study and performed statistical analyses. Outcome measures For the purpose of this study, DAS-defined remission was DAS28 (CRP) <2.6. Co-primary endpoints were: the proportion of randomised and treated patients in DAS-defined remission at (A) month 12 and (B) months 12 and 18 for abatacept plus MTX versus MTX. Secondary endpoints included: DAS-defined remission at (A) month 12 and (B) months 12 and 18 for abatacept monotherapy versus MTX; Health Assessment Questionnaire-Disability Index (HAQ-DI) response (≥0.3 points reduction from baseline); osteitis, synovitis and erosion score by MRI; safety and tolerability. Additional assessments are given in the online supplementary information.

nth 12 and (B) months 12 and 18 for abatacept monotherapy versus MTX; Health Assessment Questionnaire-Disability Index (HAQ-DI) response (≥0.3 points reduction from baseline); osteitis, synovitis and erosion score by MRI; safety and tolerability. Additional assessments are given in the online supplementary information. Statistical analyses A sample size of 116 patients per arm yielded 90% power to detect an expected difference of 22% for the first co-primary endpoint. This power estimate assumed that 60% of patients in the abatacept plus MTX arm and 38% of patients in the MTX arm would achieve DAS-defined remission (DAS28 (CRP) <2.6) at month 12. Conditional on achieving the first co-primary endpoint, a sample size of 116 patients per arm yielded 98% power to detect an expected difference of 22% for the second co-primary endpoint. This power estimate assumed that 30% of patients in the abatacept plus MTX arm and 8% of patients in the MTX arm would achieve DAS-defined remission (DAS28 (CRP) <2.6) at both months 12 and 18.

ple size of 116 patients per arm yielded 98% power to detect an expected difference of 22% for the second co-primary endpoint. This power estimate assumed that 30% of patients in the abatacept plus MTX arm and 8% of patients in the MTX arm would achieve DAS-defined remission (DAS28 (CRP) <2.6) at both months 12 and 18. Co-primary endpoints were tested in hierarchical fashion. ORs (with 95% CIs) were calculated for abatacept plus MTX versus MTX using logistic regression adjusted for treatment group, corticosteroid use at baseline (yes/no) and baseline DAS28 (CRP); patients with missing baseline DAS28 (CRP) were not included. All patients who discontinued prior to completing the treatment or withdrawal period were imputed as non-responders for the month 12 or 18 analyses. Patients who entered the re-exposure period during the withdrawal period, prior to month 18, were imputed as non-responders at month 18. Adjusted mean MRI change from baseline and SE was calculated for all arms using a longitudinal repeated measures model. Safety assessments were based on the intent-to-treat population (patients who received ≥1 dose of study medication). Analysis of other secondary endpoints is described in the online supplementary information. Details on posthoc analyses of baseline characteristics of patients who achieved DAS-defined remission, the proportions of patients who achieved DAS-defined remission based on these characteristics, and overall treatment effect on mean change from baseline in DAS28 (CRP) are provided in the online supplementary materials.

Details on posthoc analyses of baseline characteristics of patients who achieved DAS-defined remission, the proportions of patients who achieved DAS-defined remission based on these characteristics, and overall treatment effect on mean change from baseline in DAS28 (CRP) are provided in the online supplementary materials. Results Results up to the 18-month co-primary endpoint are presented. Demographics and baseline characteristics A total of 511 patients were enrolled, and 351 patients at 72 worldwide sites were randomly assigned to treatment (abatacept plus MTX, n=119; abatacept monotherapy, n=116; MTX, n=116) (see online figure S2 in the supplementary appendix). Patients had early RA (mean symptom duration 0.56 years) with highly inflammatory disease (mean tender joint count 13.6, swollen joint count 11.1 and CRP 17.5 mg/L), severe disease activity (mean DAS28 (CRP) 5.4 and HAQ-DI 1.4) and poor prognostic factors (95.2% rheumatoid factor and anti-CCP-2 double positive) (table 1). The numbers of patients entering the withdrawal period were 84/119 (70.6%), 66/116 (56.9%) and 73/116 (62.9%) in the abatacept plus MTX, abatacept monotherapy and MTX arms, respectively (see online figure S2 in the supplementary appendix). Table 1 Demographics and baseline characteristics

Demographics and baseline characteristics A total of 511 patients were enrolled, and 351 patients at 72 worldwide sites were randomly assigned to treatment (abatacept plus MTX, n=119; abatacept monotherapy, n=116; MTX, n=116) (see online figure S2 in the supplementary appendix). Patients had early RA (mean symptom duration 0.56 years) with highly inflammatory disease (mean tender joint count 13.6, swollen joint count 11.1 and CRP 17.5 mg/L), severe disease activity (mean DAS28 (CRP) 5.4 and HAQ-DI 1.4) and poor prognostic factors (95.2% rheumatoid factor and anti-CCP-2 double positive) (table 1). The numbers of patients entering the withdrawal period were 84/119 (70.6%), 66/116 (56.9%) and 73/116 (62.9%) in the abatacept plus MTX, abatacept monotherapy and MTX arms, respectively (see online figure S2 in the supplementary appendix). Table 1 Demographics and baseline characteristics Characteristic Abatacept plus MTX (n=119) Abatacept monotherapy (n=116) MTX (n=116) Total (N=351) Age—year (median) 46.4±13.2 (45.0) 45.4±11.9 (45.0) 49.1±12.4 (49.0) 47.0±12.6 (47.0) Weight—kg (median) 73.0±17.7 (68.7) 72.1±16.8 (69.5) 74.1±17.1 (71.5) 73.1±17.2 (69.9) Female sex—number (%) 95 (79.8) 89 (76.7) 89 (76.7) 273 (77.8) White race—number (%) 100 (84.0) 95 (81.9) 102 (87.9) 297 (84.6) Geographic region—number (%) North America 17 (14.3) 21 (18.1) 15 (12.9) 53 (15.1) South America 26 (21.8) 24 (20.7) 25 (21.6) 75 (21.4) Europe 47 (39.5) 42 (36.2) 48 (41.4) 137 (39.0) ROW 29 (24.4) 29 (25.0) 28 (24.1) 86 (24.5) RA symptom duration—year 0.58±0.50 0.59±0.52 0.50±0.49 0.56±0.50 RA symptom duration <3 months—number (%) 36 (30.3) 36 (31.0) 48 (41.4) 120 (34.2) RF positive—number (%) 113 (95.0) 111 (95.7) 110 (94.8) 334 (95.2) Tender joint count (28 joints) 14.0±7.7 14.0±7.6 12.8±7.8 13.6±7.7 Swollen joint count (28 joints) 11.2±6.9 11.4±7.66 10.7±7.0 11.1±7.1 CRP—mg/L 18.1±28.4 16.9±23.9 17.3±22.4 17.5±25.0 Patient global assessment (0–100 mm VAS) 62.7±21.0 57.3±22.4 58.2±19.7 59.4±21.1 Physician global assessment (0–100 mm VAS) 58.4±19.1 58.7±20.6 58.6±20.3 58.6±20.0 DAS28 (CRP) 5.5±1.3 5.5±1.1 5.3±1.3 5.4±1.2 HAQ-DI 1.5±0.68 1.4±0.66 1.4±0.65 1.4±0.66 Pain (0–100 mm VAS) 62.4±20.8 61.3±21.6 59.5±18.3 61.1±20.3 Physical function (0–100, Short Form-36 subscale) 38.5±25.9 41.6±25.6 39.1±24.5 39.7±25.3 Plus-minus values are means±SD.

100 mm VAS) 58.4±19.1 58.7±20.6 58.6±20.3 58.6±20.0 DAS28 (CRP) 5.5±1.3 5.5±1.1 5.3±1.3 5.4±1.2 HAQ-DI 1.5±0.68 1.4±0.66 1.4±0.65 1.4±0.66 Pain (0–100 mm VAS) 62.4±20.8 61.3±21.6 59.5±18.3 61.1±20.3 Physical function (0–100, Short Form-36 subscale) 38.5±25.9 41.6±25.6 39.1±24.5 39.7±25.3 Plus-minus values are means±SD. CRP, C reactive protein; DAS, Disease Activity Score; HAQ-DI, Health Assessment Questionnaire-Disability Index; MTX, methotrexate; RA, rheumatoid arthritis; RF, rheumatoid factor; ROW, rest of the world; VAS, visual analogue scale. Signs and symptoms Abatacept plus MTX versus MTX during treatment period Abatacept plus MTX achieved statistically significantly higher rates of DAS-defined remission versus MTX at month 12 (70/115 (60.9%) patients vs 52/115 (45.2%) patients; OR (95% CI) 2.01 (1.18 to 3.43); p=0.010). Numerically higher DAS-defined remission rates were observed in the abatacept plus MTX group versus MTX from day 57, which were maintained over time for the rest of the treatment period (figure 1A). A posthoc analysis of the overall treatment effect over the 12 months of the treatment period in change from baseline in DAS28 (CRP) demonstrated an estimated treatment difference (95% CI) of –0.52 (–0.74 to –0.30) for abatacept plus MTX versus MTX.

maintained over time for the rest of the treatment period (figure 1A). A posthoc analysis of the overall treatment effect over the 12 months of the treatment period in change from baseline in DAS28 (CRP) demonstrated an estimated treatment difference (95% CI) of –0.52 (–0.74 to –0.30) for abatacept plus MTX versus MTX. Figure 1 Efficacy outcomes over time. (A) proportion of patients with DAS-defined remission (DAS28 (CRP) <2.6); (B) proportion of patients with SDAI remission (≤3.3); (C) proportion of patients with Boolean remission (tender joint count ≤1, swollen joint count ≤1, patient global assessment of disease activity ≤1 (0–10 scale), high-sensitivity CRP ≤1 mg/dL); (D) major clinical response (ACR 70 response for a minimum of six consecutive months at any time period prior to the time point). Error bars represent 95% CIs. Missing remission data not due to premature discontinuation and not at day 1 of the treatment period or at day 169 of the withdrawal period were imputed as a remission if the missing value occurred between two observed remissions. Missing ACR response data not due to premature discontinuation and not at day 1 of the treatment period or at day 169 of the withdrawal period were imputed as an ACR response if the missing value occurred between two observed ACR responses. ACR, American College of Rheumatology; CRP, C reactive protein; DAS, Disease Activity Score; MTX, methotrexate; SDAI, Simplified Disease Activity Index.

day 1 of the treatment period or at day 169 of the withdrawal period were imputed as an ACR response if the missing value occurred between two observed ACR responses. ACR, American College of Rheumatology; CRP, C reactive protein; DAS, Disease Activity Score; MTX, methotrexate; SDAI, Simplified Disease Activity Index. The proportion of patients achieving other remission endpoints (including Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI) and Boolean remission), American College of Rheumatology (ACR) responses and major clinical response (MCR) were numerically greater for abatacept plus MTX versus MTX over time (figure 1 and see online figure S3 in the supplementary appendix); HAQ-DI response rates at month 12 were 65.5% versus 44.0%, respectively (see online table S2 in the supplementary appendix).

umatology (ACR) responses and major clinical response (MCR) were numerically greater for abatacept plus MTX versus MTX over time (figure 1 and see online figure S3 in the supplementary appendix); HAQ-DI response rates at month 12 were 65.5% versus 44.0%, respectively (see online table S2 in the supplementary appendix). Abatacept monotherapy versus MTX during treatment period Abatacept monotherapy resulted in a similar proportion of patients achieving DAS-defined remission at month 12 compared with MTX (48/113 (42.5%) vs 52/115 (45.2%)). However, over time, DAS-defined remission rates were numerically higher for abatacept monotherapy (figure 1A) at most other time points. In fact, as determined by posthoc analysis, the overall estimated treatment difference (95% CI) between abatacept monotherapy versus MTX in change from baseline in DAS28 (CRP) was –0.26 (–0.11 to –0.48). Additionally, abatacept monotherapy demonstrated numerically higher rates of CDAI, SDAI, Boolean remission and ACR 20/50/70 and MCR rates versus MTX over time (figure 1 and see online figure S3 in the supplementary appendix) and HAQ-DI (see online table S2 in the supplementary appendix).

RP) was –0.26 (–0.11 to –0.48). Additionally, abatacept monotherapy demonstrated numerically higher rates of CDAI, SDAI, Boolean remission and ACR 20/50/70 and MCR rates versus MTX over time (figure 1 and see online figure S3 in the supplementary appendix) and HAQ-DI (see online table S2 in the supplementary appendix). Abatacept plus MTX and abatacept monotherapy versus MTX during withdrawal period Abatacept plus MTX achieved statistically significantly higher rates of DAS-defined remission versus MTX at both months 12 and 18 (17/115 (14.8%) patients vs 9/115 (7.8%) patients; OR (95% CI) 2.51 (1.02 to 6.18); p=0.045). The proportion of patients achieving DAS-defined remission at both months 12 and 18 was 14/113 (12.4%) versus 9/115 (7.8%) for abatacept monotherapy and MTX groups, respectively (analysis included only patients with DAS28 (CRP) available at baseline). Of the patients who entered the withdrawal period, 73, 50 and 53 patients in each treatment group were in DAS-defined remission at month 12. Of these, 18/73 (24.7%), 14/50 (28%) and 9/53 (17.0%) remained in DAS-defined remission at month 18 (figure 2). Figure 2 Proportion of patients in Disease Activity Score (DAS)-defined remission (DAS28 (C reactive protein, CRP) <2.6) during the withdrawal period. The numbers within the bars are percentages. Missing remission data not due to premature discontinuation and not at day 1 of the treatment period or at day 169 of the withdrawal period were imputed as a remission if the missing value occurred between two observed remissions. MTX, methotrexate.

ng the withdrawal period. The numbers within the bars are percentages. Missing remission data not due to premature discontinuation and not at day 1 of the treatment period or at day 169 of the withdrawal period were imputed as a remission if the missing value occurred between two observed remissions. MTX, methotrexate. A posthoc analysis indicated that in both abatacept treatment arms the proportions of patients with sustained DAS-defined remission following treatment withdrawal were numerically higher in patients who had lower baseline DAS28 (CRP), lower HAQ-DI and shorter symptom duration; this was not the case in the MTX arm (table 2). The same baseline factors were associated with DAS-defined remission at months 12 and 18 versus DAS-defined remission at month 12 only, also in the abatacept arm (see online table S3 in the supplementary appendix). Patients receiving abatacept also had more time with DAS28 (CRP) <2.6 than patients receiving MTX during the treatment period (10.2 vs 8.1 months for abatacept plus MTX; 8.9 vs 6.6 months for abatacept monotherapy; 5.8 vs 5.7 months for MTX). Table 2 Proportion of patients with DAS-defined remission (DAS28 (CRP) <2.6) at both months 12 and 18 by baseline characteristic subgroup (posthoc analyses)

A posthoc analysis indicated that in both abatacept treatment arms the proportions of patients with sustained DAS-defined remission following treatment withdrawal were numerically higher in patients who had lower baseline DAS28 (CRP), lower HAQ-DI and shorter symptom duration; this was not the case in the MTX arm (table 2). The same baseline factors were associated with DAS-defined remission at months 12 and 18 versus DAS-defined remission at month 12 only, also in the abatacept arm (see online table S3 in the supplementary appendix). Patients receiving abatacept also had more time with DAS28 (CRP) <2.6 than patients receiving MTX during the treatment period (10.2 vs 8.1 months for abatacept plus MTX; 8.9 vs 6.6 months for abatacept monotherapy; 5.8 vs 5.7 months for MTX). Table 2 Proportion of patients with DAS-defined remission (DAS28 (CRP) <2.6) at both months 12 and 18 by baseline characteristic subgroup (posthoc analyses) Baseline characteristic Abatacept plus MTX (n=119) Abatacept monotherapy (n=116) MTX (n=116) DAS28 (CRP) Missing—number/N (%) 1/4 (25.0) 0/3 (0) 0/1 (0) ≤Median (5.4)—number/N (%) 14/56 (25.0) 12/56 (21.4) 6/60 (10.0) >Median (5.4)—number/N (%) 3/59 (5.1) 2/57 (3.5) 3/55 (5.5) HAQ-DI, number (%) Missing—number/N (%) 3/6 (50.0) 1/3 (33.3) 0/11 (0) ≤Median (1.375)—number/N (%) 12/58 (20.7) 10/59 (16.9) 4/56 (7.1) >Median (1.375)—number/N (%) 3/55 (5.5) 3/54 (5.6) 5/49 (10.2) Symptom duration ≤Median (0.37 years)—number/N (%) 12/58 (20.7) 7/50 (14.0) 5/69 (7.2) >Median (0.37 years)—number/N (%) 6/61 (9.8) 7/66 (10.6) 4/47 (8.5) ≤6 months—number/N (%) 14/70 (20.0) 11/71 (15.5) 7/77 (9.1) >6 months—number/N (%) 4/49 (8.2) 3/45 (6.7) 2/39 (5.1) Pain (100 mm VAS) Missing—number/N (%) 3/6 (50.0) 1/3 (33.3) 0/11 (0.0) ≤Median (62)—number/N (%) 11/48 (22.9) 8/58 (13.8) 7/60 (11.7) >Median (62)—number/N (%) 4/65 (6.2) 5/55 (9.1) 2/45 (4.4) Erosion Missing—number/N (%) 1/15 (6.7) 0/14 (0) 2/13 (15.4) ≤Median (4.5)—number/N (%) 7/50 (14.0) 10/58 (17.2) 4/53 (7.5) >Median (4.5)—number/N (%) 10/54 (18.5) 4/44 (9.1) 3/50 (6.0) ≤Q1 (1.5)—number/N (%) 4/23 (17.4) 5/28 (17.9) 2/30 (6.7) >Q1 (1.5)–Q2 (4.5)—number/N (%) 3/27 (11.1) 5/30 (16.7) 2/23 (8.7) >Q2 (4.5)–Q3 (8.5)—number/N (%) 8/25 (32.0) 3/23 (13.0) 2/23 (8.7) >Q3 (8.5)—number/N (%) 2/29 (6.9) 1/21 (4.8) 1/27 (3.7) Osteitis Missing—number/N (%) 1/15 (6.7) 0/14 (0) 2/13 (15.4) ≤Median (0.5)—number/N (%) 8/54 (14.8) 10/47 (21.3) 4/54 (7.4) >Median (0.5)—number/N (%) 9/50 (18.0) 4/55 (7.3) 3/49 (6.1) ≤Q1 (0)—number/N (%) 6/41 (14.6) 9/43 (20.9) 4/49 (8.2) >Q1 (0)–Q2 (0.5)—number/N (%) 2/13 (15.4) 1/4 (25.0) 0/5 (0) >Q2 (0.5)–Q3 (5)—number/N (%) 7/25 (28.0) 2/27 (7.4) 2/26 (7.7) >Q3 (5)—number/N (%) 2/25 (8.0) 2/28 (7.1) 1/23 (4.3) Synovitis Missing—number/N (%) 1/15 (6.7) 0/14 (0) 2/13 (15.4) ≤Median (4.5)—number/N (%) 12/57 (21.1) 9/52 (17.3) 4/47 (8.5) >Median (4.5)—number/N (%) 5/47 (10.6) 5/50 (10.0) 3/56 (5.4) ≤Q1 (2)—number/N (%) 5/30 (16.7) 4/24 (16.7) 3/24 (12.5) >Q1 (2)–Q2 (4.5)—number/N (%) 7/27 (25.9) 5/28 (17.9) 1/23 (4.3) >Q2 (4.5)–Q3 (8.5)—number/N (%) 3/23 (13.0) 4/33 (12.1) 1/30 (3.3) >Q3 (8.5)—number/N (%) 2/

r/N (%) 12/57 (21.1) 9/52 (17.3) 4/47 (8.5) >Median (4.5)—number/N (%) 5/47 (10.6) 5/50 (10.0) 3/56 (5.4) ≤Q1 (2)—number/N (%) 5/30 (16.7) 4/24 (16.7) 3/24 (12.5) >Q1 (2)–Q2 (4.5)—number/N (%) 7/27 (25.9) 5/28 (17.9) 1/23 (4.3) >Q2 (4.5)–Q3 (8.5)—number/N (%) 3/23 (13.0) 4/33 (12.1) 1/30 (3.3) >Q3 (8.5)—number/N (%) 2/ 24 (8.3) 1/17 (5.9) 2/26 (7.7) CRP, C reactive protein; DAS, Disease Activity Score; HAQ-DI, Health Assessment Questionnaire-Disability Index; MTX, methotrexate; Q, quartile; VAS, visual analogue scale. Effect on structural damage Radiographic changes measured by MRI in each of the treatment groups were consistent with clinical efficacy outcomes. Abatacept plus MTX and abatacept monotherapy resulted in numerically greater decreases from baseline in synovitis and osteitis scores, and abatacept plus MTX resulted in less progression of erosion score than MTX at 12 months (see online figure S4 in the supplementary appendix). Safety During the treatment period, adverse events (AE) occurred in 101/119 (84.9%), 93/116 (80.2%) and 96/116 (82.8%) patients treated with abatacept plus MTX, abatacept monotherapy and MTX, respectively (table 3). Serious AEs occurred in 8/119 (6.7%), 14/116 (12.1%) and 9/116 (7.8%) patients; there were 2/119 (1.7%), 5/116 (4.3%) and 3/116 (2.6%) discontinuations due to serious AEs; and serious infections occurred in 1/119 (0.8%), 4/116 (3.4%) and 0 patients, respectively. There were no deaths during the treatment period. During the withdrawal period, two patients died in the MTX arm (uterine neoplasm, renal failure).

2/119 (1.7%), 5/116 (4.3%) and 3/116 (2.6%) discontinuations due to serious AEs; and serious infections occurred in 1/119 (0.8%), 4/116 (3.4%) and 0 patients, respectively. There were no deaths during the treatment period. During the withdrawal period, two patients died in the MTX arm (uterine neoplasm, renal failure). Table 3 Summary of safety in the treatment period* Abatacept plus MTX (n=119) Abatacept monotherapy (n=116) MTX (n=116) Deaths 0 0 0† Adverse events 101 (84.9) 93 (80.2) 96 (82.8) Serious adverse events 8 (6.7) 14 (12.1) 9 (7.8) Discontinuations due to serious adverse events 2 (1.7) 5 (4.3) 3 (2.6) Serious infections 1 (0.8) 4 (3.4) 0 Pneumonia 1 (0.8) 1 (0.9) 0 Limb abscess 0 1 (0.9) 0 Herpes zoster 0 1 (0.9) 0 Viral infection 0 1 (0.9) 0 Malignancies 1 (0.8) 2 (1.7) 1 (0.9) Basal cell carcinoma 1 (0.8) 0 0 Bowen's disease 0 1 (0.9) 0 Pulmonary carcinoid tumour 0 1 (0.9) 0 Invasive ductal breast carcinoma 0 0 1 (0.9) Includes data up to 56 days after the last dose of study medication. *All values are number (%). †Two patients in the MTX arm died during the withdrawal period (uterine neoplasm, renal failure). MTX, methotrexate.

Abatacept plus MTX (n=119) Abatacept monotherapy (n=116) MTX (n=116) Deaths 0 0 0† Adverse events 101 (84.9) 93 (80.2) 96 (82.8) Serious adverse events 8 (6.7) 14 (12.1) 9 (7.8) Discontinuations due to serious adverse events 2 (1.7) 5 (4.3) 3 (2.6) Serious infections 1 (0.8) 4 (3.4) 0 Pneumonia 1 (0.8) 1 (0.9) 0 Limb abscess 0 1 (0.9) 0 Herpes zoster 0 1 (0.9) 0 Viral infection 0 1 (0.9) 0 Malignancies 1 (0.8) 2 (1.7) 1 (0.9) Basal cell carcinoma 1 (0.8) 0 0 Bowen's disease 0 1 (0.9) 0 Pulmonary carcinoid tumour 0 1 (0.9) 0 Invasive ductal breast carcinoma 0 0 1 (0.9) Includes data up to 56 days after the last dose of study medication. *All values are number (%). †Two patients in the MTX arm died during the withdrawal period (uterine neoplasm, renal failure). MTX, methotrexate. Discussion AVERT is the first study to demonstrate that remission can be maintained after rapid withdrawal of all therapy (including csDMARDs, biological DMARDS and corticosteroids) in patients with early RA receiving abatacept plus MTX. Patients treated with abatacept plus MTX achieved significantly higher rates of DAS-defined remission than MTX on-treatment, and a small but significantly higher number of patients achieved sustained, absolute, drug-free, DAS-defined remission following withdrawal of all RA treatment. These results support the hypothesis that early treatment with a T-cell immunomodulator that can impact naive T-cell activation can induce drug-free remission in some patients.21

nificantly higher number of patients achieved sustained, absolute, drug-free, DAS-defined remission following withdrawal of all RA treatment. These results support the hypothesis that early treatment with a T-cell immunomodulator that can impact naive T-cell activation can induce drug-free remission in some patients.21 The results from this study are consistent with those of previous studies of abatacept in early RA, including ADJUST and AGREE.6 22 In AVERT, patients had highly active disease and poor prognostic markers; 95% of patients were anti-CCP-2-positive and rheumatoid factor-positive, a combination associated with enhanced probability of joint damage and disease progression.23 24 Abatacept plus MTX achieved robust efficacy versus MTX, as demonstrated by multiple measures of remission and HAQ-DI, and consistent structural benefits. While joint counts can be subjective and month-by-month variability was evident, the MRI results provide an objective measure of comparative efficacy in support of the clinical endpoints. Additionally, the safety profile observed in this study is consistent with the known safety profile of abatacept,25 with low rates of serious AEs and serious infections, which is relevant for early treatment with biologicals.

lts provide an objective measure of comparative efficacy in support of the clinical endpoints. Additionally, the safety profile observed in this study is consistent with the known safety profile of abatacept,25 with low rates of serious AEs and serious infections, which is relevant for early treatment with biologicals. AVERT provides a large dataset assessing abatacept monotherapy, which is of interest because many patients cannot tolerate MTX; approximately 30% of patients receive biologicals as monotherapy.26 AVERT showed that a similar number of patients receiving abatacept monotherapy achieved DAS-defined remission versus MTX at month 12. However, the numerically greater benefit on osteitis and synovitis measured by MRI, and the posthoc analysis estimating average efficacy over the 12-month treatment period, are suggestive that abatacept monotherapy may have a greater efficacy benefit compared with MTX. This remains to be confirmed in a prospective, randomised, controlled study.

reater benefit on osteitis and synovitis measured by MRI, and the posthoc analysis estimating average efficacy over the 12-month treatment period, are suggestive that abatacept monotherapy may have a greater efficacy benefit compared with MTX. This remains to be confirmed in a prospective, randomised, controlled study. Following withdrawal of all therapy, a small but significant number of patients sustained drug-free remission following prior treatment with abatacept plus MTX compared with MTX alone. The data indicate that, with abatacept plus MTX treatment, one in four patients was able to maintain drug-free remission through 6 months. This effect is not a consequence of the half-life of abatacept (14.3 days), as assessments were performed up to 6 months after the withdrawal of all treatment (>5 half-lives).27 Moreover, the posthoc analyses of the patients who sustained drug-free remission suggest that patients with shorter symptom duration and lower disease activity at baseline, or longer, sustained, DAS-defined remission prior to treatment withdrawal, were more likely to maintain drug-free remission. These associations were observed specifically in both abatacept arms, suggesting that a biological effect was responsible. Low baseline HAQ-DI, low baseline disease activity, and shorter disease duration are predictors of remission with antitumour necrosis factor agents.28–32 These data, therefore, generate a hypothesis that patients with early RA, with a very short symptom duration and milder disease activity who are possibly presenting within the ‘window of opportunity’, may be able to achieve sustained and complete drug-free remission following treatment with abatacept.

ctor agents.28–32 These data, therefore, generate a hypothesis that patients with early RA, with a very short symptom duration and milder disease activity who are possibly presenting within the ‘window of opportunity’, may be able to achieve sustained and complete drug-free remission following treatment with abatacept. Remission following withdrawal or tapering of RA therapy is an important goal in early RA. The unique study design of AVERT included the rapid withdrawal of all RA treatment, including abatacept, MTX and corticosteroids. Previous studies have examined a variety of treatment withdrawal paradigms with a number of biological agents, but have not assessed the rapid withdrawal of all RA treatment.8–17 Most antitumour necrosis factor withdrawal studies maintained MTX or maintained the biological at half dose. While in many withdrawal studies DAS28 remission was assessed at 6 months after biological withdrawal,8 9 11 12 14 15 in AVERT, assessment of drug-free remission was made by comparing the proportion of patients in DAS-defined remission at both 12 and 18 months. The approach of withdrawing or tapering biological therapy after achievement of remission may reflect a treatment benefit for patients and physicians that could be justifiable given the economic burden of treating patients with early RA. This is especially true if patients who are likely to maintain remission on MTX alone, following biological withdrawal, can be identified prospectively.

vement of remission may reflect a treatment benefit for patients and physicians that could be justifiable given the economic burden of treating patients with early RA. This is especially true if patients who are likely to maintain remission on MTX alone, following biological withdrawal, can be identified prospectively. The DAS-defined remission cut-off of <2.6, although corresponding to the American Rheumatology Association definition of clinical remission in RA,33 has now been replaced with other measures of remission,34 such as SDAI and Boolean remission, which are also reported here. The cut-off is based on erythrocyte sedimentation rate (ESR), and a CRP cut-off has yet to be defined.33 In AVERT, CRP was interchanged with ESR to reduce the variability of the acute phase reactant and aid standardisation across study centres. Data were obtained from patients with early RA with active disease and poor prognostic factors, which limit their generalisability to the overall RA population. The withdrawal analyses were limited by the small number of patients who remained in the withdrawal period. The gradual tapering of RA medication may result in higher remission rates than the rapid withdrawal of all RA therapy applied in AVERT and will be assessed in other trials.

sability to the overall RA population. The withdrawal analyses were limited by the small number of patients who remained in the withdrawal period. The gradual tapering of RA medication may result in higher remission rates than the rapid withdrawal of all RA therapy applied in AVERT and will be assessed in other trials. In conclusion, AVERT establishes the benefit of abatacept treatment in combination with MTX in an early RA population, and suggests that, in early RA, drug-free remission may be possible following treatment with abatacept. The novel achievement of sustained remission following withdrawal of all RA therapy in a small but significant number of patients is suggestive of an underlying effect of abatacept's mechanism on autoimmune processes. A withdrawal treatment strategy is a highly desirable goal for patients and physicians in the long-term treatment of RA, and further investigations with abatacept are warranted. Treat-to-remission is now a well-accepted goal of RA therapy. Supplementary Material Web supplement The first draft of the manuscript was prepared by academic and industry authors, with professional medical writing and editorial assistance provided by Stephen Moore, PhD, at Caudex Medical, and funded by Bristol-Myers Squibb. The academic authors vouch for the completeness and accuracy of the data and data analyses, and for the fidelity of the study to the protocol.

academic and industry authors, with professional medical writing and editorial assistance provided by Stephen Moore, PhD, at Caudex Medical, and funded by Bristol-Myers Squibb. The academic authors vouch for the completeness and accuracy of the data and data analyses, and for the fidelity of the study to the protocol. Contributors: PE, GRB, VPB, BGC, DEF and TWJH were involved in the conception and design of the study, acquisition of data, analysis and interpretation of data; drafting of manuscript and revising it critically for important intellectual content; final approval of the version to be published. EB and DAW were involved in the conception and design of the study, analysis and interpretation of data; drafting of manuscript and revising it critically for important intellectual content; final approval of the version to be published. CSK was involved in the acquisition, analysis and interpretation of data; drafting of manuscript and revising it critically for important intellectual content; final approval of the version to be published. Funding: This study was sponsored by Bristol-Myers Squibb.

Contributors: PE, GRB, VPB, BGC, DEF and TWJH were involved in the conception and design of the study, acquisition of data, analysis and interpretation of data; drafting of manuscript and revising it critically for important intellectual content; final approval of the version to be published. EB and DAW were involved in the conception and design of the study, analysis and interpretation of data; drafting of manuscript and revising it critically for important intellectual content; final approval of the version to be published. CSK was involved in the acquisition, analysis and interpretation of data; drafting of manuscript and revising it critically for important intellectual content; final approval of the version to be published. Funding: This study was sponsored by Bristol-Myers Squibb. Competing interests: PE reports receiving consulting fees from AbbVie, Bristol-Myers Squibb, Merck, Pfizer, Roche Takeda and UCB; and grant support from AbbVie, Bristol-Myers Squibb, Merck, Pfizer, Roche and UCB. GRB reports receiving grant support from Bristol-Myers Squibb, AbbVie, Pfizer, Roche and UCB; consulting fees from Bristol-Myers Squibb, AbbVie, Pfizer, MSD, Medimmune, Roche and UCB; and served on Speakers’ Bureau for Bristol-Myers Squibb, AbbVie, Pfizer, MSD, Roche and UCB. VPB reports receiving grant support from Amgen, Pfizer, Bristol-Myers Squibb, Janssen, UCB and Roche/Genentech. BGC reports receiving grant support from Pfizer and Roche-Chugai; and served on Speakers’ Bureau for Bristol-Myers Squibb, Merck, Pfizer, Roche-Chugai and UCB. DEF reports receiving grant support from AbbVie, Actelion, Amgen, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, National Institutes of Health, Novartis, Pfizer, Roche/Genentech and UCB; consulting fees from AbbVie, Actelion, Amgen, Bristol-Myers Squibb, Janssen, Gilead, GlaxoSmithKline, National Institutes of Health, Novartis, Pfizer, Roche/Genentech and UCB; and served on Speakers’ Bureau for AbbVie, Actelion and UCB. EB, CSK and DAW are employees of Bristol-Myers Squibb. TWJH reports receiving consulting fees from Abbott, Biotest, Bristol-Myers Squibb, Crescendo Bioscience, Novartis, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB and Eli Lilly; holding a position of influence on the Meteor Board; grant support from EU & Dutch Arthritis Foundation; served on Speakers’ Bureau for Abbott Laboratories, Biotest, Bristol-Myers Squibb, Novartis, Pfizer, Roche, Sanofi-Aventis and Schering-Plough; and travel support from Abbott and Roche.

ng-Plough, UCB and Eli Lilly; holding a position of influence on the Meteor Board; grant support from EU & Dutch Arthritis Foundation; served on Speakers’ Bureau for Abbott Laboratories, Biotest, Bristol-Myers Squibb, Novartis, Pfizer, Roche, Sanofi-Aventis and Schering-Plough; and travel support from Abbott and Roche. Ethics approval: The study protocol was approved by the Institutional Review Board or Independent Ethics Committee at each site. Provenance and peer review: Not commissioned; externally peer reviewed.

Introduction A randomised controlled trial (RCT) is the most objective means of evaluating an intervention and underpins regulatory decision-making and, if appropriate, the introduction of therapies into clinical practice. Many benefits of RCTs have been seen in the specialty of rheumatology, and particularly in the management of rheumatoid arthritis (RA).1–10 While the aim of RCTs is to demonstrate the efficacy and safety of an experimental agent, their observation period typically spans a relatively short time frame. However, the use of therapies in chronic diseases necessitates more long-term evaluation. The introduction of new disease modifying anti-rheumatic drug (DMARD) therapies for the treatment of RA has been associated with a significant number of post-RCT extension studies,11–17 henceforth termed ‘trial extension studies’ (TES), to report the longer-term outcomes of an experimental agent. Role of TES TES can evaluate in particular, the effects of cumulative exposure to a drug, capturing events through systematic reporting, monitoring of source data, and consistent coding, thus enabling further assessment of the long-term safety profile observed during the RCT.18

Introduction A randomised controlled trial (RCT) is the most objective means of evaluating an intervention and underpins regulatory decision-making and, if appropriate, the introduction of therapies into clinical practice. Many benefits of RCTs have been seen in the specialty of rheumatology, and particularly in the management of rheumatoid arthritis (RA).1–10 While the aim of RCTs is to demonstrate the efficacy and safety of an experimental agent, their observation period typically spans a relatively short time frame. However, the use of therapies in chronic diseases necessitates more long-term evaluation. The introduction of new disease modifying anti-rheumatic drug (DMARD) therapies for the treatment of RA has been associated with a significant number of post-RCT extension studies,11–17 henceforth termed ‘trial extension studies’ (TES), to report the longer-term outcomes of an experimental agent. Role of TES TES can evaluate in particular, the effects of cumulative exposure to a drug, capturing events through systematic reporting, monitoring of source data, and consistent coding, thus enabling further assessment of the long-term safety profile observed during the RCT.18 An additional benefit of TES that is cited is continued access to an effective but otherwise unlicensed treatment by RCT participants. However, since a favourable effect of the treatment may not have been clearly determined at the time of TES participation (with results from the preceding RCT and/or indeterminate prior studies not available), this raises legitimate ethical issues about the appropriateness of exposing patients to potentially ineffective or only partially effective treatments for additional periods of time.

early determined at the time of TES participation (with results from the preceding RCT and/or indeterminate prior studies not available), this raises legitimate ethical issues about the appropriateness of exposing patients to potentially ineffective or only partially effective treatments for additional periods of time. Challenges of TES While TES play a valid role, there are clear limitations that should be considered and potential weaknesses in the design and method of analysis that should be addressed.19 TES benefit from the systematic reporting on cumulative drug exposure but have clear limitations in the detection of rare and unexpected events. In addition, selection bias associated with TES populations and lack of generalisability are key factors. These issues are discussed in more detail in the online supplementary material. This makes interpretation challenging and sometimes unreliable. While guidance for reporting of RCTs20 21 and safety data from biological DMARD registers22 are available, no recommendations for TES in rheumatology have been published to date.23 With this in mind, a task force was created with the principal aim of developing practical recommendations on key aspects of TES on the basis of the European League Against Rheumatism (EULAR) standard operating procedures,24 and thereby a recommended standardised format for future TES data reporting to achieve greater transparency. This manuscript reports the final recommendations as agreed by the task force.

ecommendations on key aspects of TES on the basis of the European League Against Rheumatism (EULAR) standard operating procedures,24 and thereby a recommended standardised format for future TES data reporting to achieve greater transparency. This manuscript reports the final recommendations as agreed by the task force. Methods The task force agreed that a systematic literature review was not indicated for this initiative, as it would merely serve to further establish the lack of consistency in TES and emphasise the need for the development of a standard for future application.25 The target population for these recommendations was chosen to be rheumatologists, trialists and researchers working in the field of rheumatology, patient organisations and policymakers. The general approach to this project followed the EULAR standardised operating procedures for the elaboration and implementation of evidence-based recommendations.24 The two task force conveners (MHB and MB) set up a multidisciplinary task force with participants selected based on their field of expertise, knowledge and experience as well as appropriate geographical distribution, primarily across Europe but also North America.

The target population for these recommendations was chosen to be rheumatologists, trialists and researchers working in the field of rheumatology, patient organisations and policymakers. The general approach to this project followed the EULAR standardised operating procedures for the elaboration and implementation of evidence-based recommendations.24 The two task force conveners (MHB and MB) set up a multidisciplinary task force with participants selected based on their field of expertise, knowledge and experience as well as appropriate geographical distribution, primarily across Europe but also North America. A first meeting of all task force members was convened in January 2011 to primarily define the domains for evaluation. This comprised two breakout sessions, with the task force split into two groups. Each group had a rapporteur who reported the outcome to the whole task force. After a final round of discussion, the task force agreed on the individual items for inclusion in a Delphi exercise. The Delphi method offers a consensus method that is widely used in health service research.26 The two-step Delphi exercise for this initiative was web based, which permitted opinions to be provided and votes on the level of agreement to be cast independently and anonymously. Geographical limitations were also avoided by this approach. It was designed by LS-F and reviewed and modified as indicated by MHB, LC and MB. Details on how the Delphi exercise was formulated, responses were scored and the approach for informing final recommendations was devised can be found in the online supplementary material.

l limitations were also avoided by this approach. It was designed by LS-F and reviewed and modified as indicated by MHB, LC and MB. Details on how the Delphi exercise was formulated, responses were scored and the approach for informing final recommendations was devised can be found in the online supplementary material. Results Task force composition The multidisciplinary task force comprised 22 participants consisting of 17 rheumatologists, of whom six were clinical epidemiologists and 11 clinical trialists/expert clinicians, two biostatisticians, one fellow and two patient representatives. Participants represented 10 European countries, the USA and Canada. Response rate Of the 22 invited experts, three could not attend the first meeting (January 2011) but were subsequently apprised of the discussion and participated in the Delphi exercise. One of the patient representatives could not continue participation after the first meeting. Twenty of the 21 participants responded to the first and all 21 responded to the second Delphi exercise.

the first meeting (January 2011) but were subsequently apprised of the discussion and participated in the Delphi exercise. One of the patient representatives could not continue participation after the first meeting. Twenty of the 21 participants responded to the first and all 21 responded to the second Delphi exercise. The two-step Delphi exercise was completed by January 2012, with subsequent analysis and dissemination of draft recommendations in March 2012. Final voting took place in May 2012. However, subsequent steps of involving additional stakeholders (see ‘Results’ section) and a meeting to discuss the recommendations (June 2013) led to a delay in establishing the recommendations for the purposes of submission. The task force approved this final document that included some modifications following the last step. More details on the timelines, responses and involvement of other stakeholders are detailed in the online supplementary material. Domains for evaluation At the initial meeting, the task force agreed on seven main domains to form the basis of the exercise. These are listed in box 1 with components within each domain that we wished to cover. Box 1 The key domains underpinning the Delphi exercise 1. Definition of a trial extension study (TES) Study design definition Definition of start of TES Duration of TES Patient population of TES 2. Development of a checklist of minimal data items/outcome necessary for a TES Minimal information a TES should collect Elements not amenable to accurate assessment by a TES Safety elements that may be elicited Efficacy

Box 1 The key domains underpinning the Delphi exercise 1. Definition of a trial extension study (TES) Study design definition Definition of start of TES Duration of TES Patient population of TES 2. Development of a checklist of minimal data items/outcome necessary for a TES Minimal information a TES should collect Elements not amenable to accurate assessment by a TES Safety elements that may be elicited Efficacy 3. Additional data/outcomes Additional legitimate outputs from a TES 4. Method of analysis 5. Method of reporting results Inclusion of a flowchart Detail minimal standards by way of a checklist Frequency and nature of TES 6. Ethics and obtaining consent 7. Over-arching principles Consultation and stakeholder involvement General comments on TES and its reporting Sources of bias and generalisability Final results Percentage agreement for each recommendation (following the second Delphi exercise) is given. Where appropriate, mean (SD) scores have also been provided. Median (range) scores were also calculated and are included in the online supplementary material. Definition of a TES Study design definition (100% agreement): A TES is a study that follows all patients beyond a pre-specified trial period whether the trial was (a) a placebo-controlled RCT with the possibility to cross over to an open-label experimental drug or (b) a placebo-controlled RCT with the possibility to cross over to usual care or (c) an active comparator RCT.

ment): A TES is a study that follows all patients beyond a pre-specified trial period whether the trial was (a) a placebo-controlled RCT with the possibility to cross over to an open-label experimental drug or (b) a placebo-controlled RCT with the possibility to cross over to usual care or (c) an active comparator RCT. Start of a TES (100% agreement): Should be stated in the pre-specified protocol with clear justification, and should be at the point of exposure to the experimental drug of interest. For the experimental randomised arm, this will be the start of the original RCT, while for those randomised to placebo/active comparator arm, this point will be on switching to experimental treatment. Minimum duration of a TES (100% agreement): It was agreed by consensus not to define this; nevertheless, the rationale for the length chosen should be stated in the pre-defined protocol with adequate justification. Population for inclusion in a TES (96% agreement): Should include all patients included in the RCT, with the ability to separately report on patients who are of specific interest, for example, those in remission or with low disease activity. Checklist of minimal data items/outcome necessary for a TES Minimal information The minimal information that should be collected and reported by a TES is listed in box 2. Minimum and maximum mean (SD) scores following the first Delphi exercise were 7.2 (2.72) and 9.9 (0.36) (refer to the online supplementary material for individual mean and median scores) with agreement by 100% of the task force in the second Delphi exercise.

should be collected and reported by a TES is listed in box 2. Minimum and maximum mean (SD) scores following the first Delphi exercise were 7.2 (2.72) and 9.9 (0.36) (refer to the online supplementary material for individual mean and median scores) with agreement by 100% of the task force in the second Delphi exercise. Box 2 Minimal information to be included in a TES report Progress of subjects at each stage from RCT start to TES completion with: A flow diagram detailing absolute numbers of subjects at each relevant time-point Duration of active treatment Time of last observation All drop-outs detailed The drop-out rates from each arm during the original RCT and the cross-over groups Reason for exclusion from the TES if the patient discontinues the drug Reason for cessation of follow-up Specification of reasons for cessation of follow-up other than adverse event or inefficacy as above, for example, geographical or doctor-related reasons Functional status at the time of inclusion in the TES if applicable Functional status at last observation if applicable Disease activity at the time of inclusion in the TES if applicable Disease activity at last observation if applicable For those patients entering the TES having achieved low disease activity or remission during the RCT, the sustainability of each disease state should be evaluated and reported

Functional status at last observation if applicable Disease activity at the time of inclusion in the TES if applicable Disease activity at last observation if applicable For those patients entering the TES having achieved low disease activity or remission during the RCT, the sustainability of each disease state should be evaluated and reported For those subjects who enter a TES not having achieved remission/an acceptable disease activity state following the RCT, the number who achieve this during the TES should be reported to determine whether longer drug exposure has the potential to improve the disease state of such subjects further Disease-related co-medication (DMARD, corticosteroid) at each stage from RCT start to TES completion Any serious adverse events and outcome related to safety at each stage from RCT start to TES completion DMARD, disease modifying anti-rheumatic drug; RCT, randomised controlled trial; TES, trial extension studies. The entire group also accepted the following statements relating to the nature of the initial RCT design following the first Delphi exercise: The minimum data requirements for TES following placebo- and active comparator RCTs should be the same (93% agreement). A TES that follows an active comparator RCT should follow all randomised patients for the same period of time (not only patients on the experimental treatment) and including patients who may switch to an active comparator treatment (analysed separately) (mean (SD) 7.9 (2.23), median (range) 8.5).2–10

The entire group also accepted the following statements relating to the nature of the initial RCT design following the first Delphi exercise: The minimum data requirements for TES following placebo- and active comparator RCTs should be the same (93% agreement). A TES that follows an active comparator RCT should follow all randomised patients for the same period of time (not only patients on the experimental treatment) and including patients who may switch to an active comparator treatment (analysed separately) (mean (SD) 7.9 (2.23), median (range) 8.5).2–10 Safety and efficacy outcomes Evaluation of safety aspects includes several elements, some of which it may not be feasible to capture within certain study designs. The following statements were agreed during the first Delphi exercise (minimum and maximum mean score of 7.0 and 8.4; refer to online supplementary material for individual scores) with 90% accepting all statements in the second round. Box 3 Guidance on data management and statistical approach statement The null hypothesis should be stated at the start where appropriate. Multiple comparisons should be taken into account when determining the level of statistical significance. The null hypothesis should take account of the results of the original RCT. Depending on the research question, the results of an RCT should be accommodated in the TES.

Box 3 Guidance on data management and statistical approach statement The null hypothesis should be stated at the start where appropriate. Multiple comparisons should be taken into account when determining the level of statistical significance. The null hypothesis should take account of the results of the original RCT. Depending on the research question, the results of an RCT should be accommodated in the TES. The report should comment on cumulative outcome analysis (beneficial and adverse events) maintaining the original trial groups, that is, from RCT start not TES start, to avoid reporting of only the sub-selected patient group that proceeds to the TES. The selection bias associated with a TES population means meaningful non-inferiority/superiority analysis would not be reliable. The report should focus on how data for sustained effect from the start to the end of the TES period, within a single group or the difference between groups was analysed and whether there was any suggestion of increased effect (although this could not be subject to formal statistical testing). The plan for subjects that drop out of a TES should be specified to demonstrate sustained effect from the start to the end of the TES period. With reducing number of participants (the denominator), the proportion responding will artificially increase if/when the number of patients (numerator) responding stays the same. The analysis should include survival/retention rates on therapy explicitly reporting the number of patients at each milestone with reasons for change detailed.

The plan for subjects that drop out of a TES should be specified to demonstrate sustained effect from the start to the end of the TES period. With reducing number of participants (the denominator), the proportion responding will artificially increase if/when the number of patients (numerator) responding stays the same. The analysis should include survival/retention rates on therapy explicitly reporting the number of patients at each milestone with reasons for change detailed. A plan on how to analyse this should be included with both intent-to-treat (ITT) (denominator as the original number entering the RCT) and completer (those entering TES only) population analyses reported. A completer analysis should always be reported together with an ITT analysis. The repeated measures analysis of the data from a TES in rheumatology should include the area under the curve of absolute disease activity (ie, not dichotomous response/change) preferentially expressed as a score (eg, DAS, SDAI, etc). A TES should preferably include hard endpoints (eg, death, work disability, joint replacement surgery, hospital admission) from the TES with or without linkages with other data sources. RCT, randomised controlled trial; TES, trial extension studies. The agreement scores were recorded after Delphi round 1. Safety TES may identify new adverse effects that the original RCT was not able to detect due to greater cumulative drug exposure. TES may identify whether the incidence of known adverse effects changes with longer-term drug exposure.

S-F analysed the DELPHI data. MHB, LS-F, LC and MB reviewed the DELPHI data analysis before dissemination to the task force. MHB wrote the paper and the supplementary materials. All authors discussed the summaries presented in the Delphi exercises, results and implications and commented on the manuscript at all stages. Funding: MHB was supported by a National Institute of Health and Research (NIHR) Clinician Scientist Award. RC is based at the Musculoskeletal Statistics Unit, The Parker Institute, which is supported by grants from the Oak Foundation. Competing interests: None. Provenance and peer review: Not commissioned; externally peer reviewed.

RCT, randomised controlled trial; TES, trial extension studies. The agreement scores were recorded after Delphi round 1. Safety TES may identify new adverse effects that the original RCT was not able to detect due to greater cumulative drug exposure. TES may identify whether the incidence of known adverse effects changes with longer-term drug exposure. TES may confirm whether the nature of known adverse effects identified from the RCT changes with longer-term exposure. TES are sub-optimal to detect rare safety events because they are not powered for this. TES are sub-optimal to detect rare safety events because they include a selected population (responders with likely no previous serious adverse events). Efficacy Greater cumulative exposure to the active drug per patient in a TES might identify additional information on the drug's efficacy. While definitions of relapse are currently not available and require further work, if/when validated, a TES might allow evaluation of relapse including time to relapse and therefore the sustainability of original disease control. Additional data/outcomes Economic evaluation of long-term treatment with the active drug may be possible if appropriate measures are recorded in the TES. A TES could not accurately evaluate health-related quality of life. Method of analysis Following the second Delphi exercise, this section required further iterations to refine the initial Delphi statements. These are detailed in box 3. Minimum and maximum scores of agreement were 7.3 and 9.4 (refer to the online supplementary material for individual scores).

A TES could not accurately evaluate health-related quality of life. Method of analysis Following the second Delphi exercise, this section required further iterations to refine the initial Delphi statements. These are detailed in box 3. Minimum and maximum scores of agreement were 7.3 and 9.4 (refer to the online supplementary material for individual scores). Method of reporting results Inclusion of a flowchart All TES reports should include a flowchart. This was agreed as a minimal piece of information to accurately illustrate the treatment arms, and changes in treatment and in patient numbers during the course of the study (mean (SD) 9.9 (0.36)). In particular, the absolute measure/count should be reported (with/without the percentage). In a TES, the denominator of a cohort typically decreases over time, which results in the reporting of (artificial) increasing percentages of response rates over time.27 The use of absolute numbers ensures accurate synthesis of the data. Figure 1 includes a schematic of suggested flowcharts for either placebo-controlled or active comparator RCTs that was accepted by the group (mean (SD) 9.0 (2.06)).

In a TES, the denominator of a cohort typically decreases over time, which results in the reporting of (artificial) increasing percentages of response rates over time.27 The use of absolute numbers ensures accurate synthesis of the data. Figure 1 includes a schematic of suggested flowcharts for either placebo-controlled or active comparator RCTs that was accepted by the group (mean (SD) 9.0 (2.06)). Figure 1 Schematic of flowcharts for inclusion in any trial extension study (TES) report following (A) a placebo-controlled randomised controlled trial (RCT) or (B) an active comparator trial. FU, follow-up; W, withdrawal. *And loss to follow-up number. The TES flowchart should detail the numbers from the start of the original RCT to the end of the TES. ‘W’ and the vertical dotted line shown between the RCT and TES phases denote those subjects who complete the RCT but opt not to proceed to the TES. During the RCT and TES, numbers of early withdrawals and patients subsequently lost to follow-up should also be included. (A) In the placebo-controlled RCT stage, subjects in the experimental arm who withdraw and proceed to standard of care, and in the placebo arm, subjects who withdraw and proceed to experimental or standard of care should be included. (B) Similarly, in the active comparator trial, subjects in the experimental arm who withdraw and proceed to standard of care, and in the active arm, subjects who withdraw and proceed to experimental or standard of care, should be included.

who withdraw and proceed to experimental or standard of care should be included. (B) Similarly, in the active comparator trial, subjects in the experimental arm who withdraw and proceed to standard of care, and in the active arm, subjects who withdraw and proceed to experimental or standard of care, should be included. Frequency and nature of reporting outputs from a TES The following recommendations were made (mean scores between 8.2 and 8.8; refer to the online supplementary material for individual scores): Reporting frequency should not be specified for all TES since this depends on the research question. However, the protocol of each TES should pre-specify the minimum frequency of reports to be written and the basis for them (purpose, outcomes, length of RCT). The efficacy and safety results of a TES should generally be reported together; abstract selection committees and journal editors should carefully consider reporting of efficacy alone before acceptance. Consent The recommendations related to obtaining consent are detailed below; this item in particular required specific input from the patient representative (refer to the online supplementary material for individual scores on additional questions that had means scores of between 6.2–9.4). All of the subjects undergoing an RCT should be informed of the importance of long-term surveillance and be given the opportunity of entering in the long-term follow-up (mean (SD) 9.4 (0.85)). Subjects should sign a new consent form both for continuation of the drug and for data collection at that time point (mean (SD) 7.6 (2.87)).

Consent The recommendations related to obtaining consent are detailed below; this item in particular required specific input from the patient representative (refer to the online supplementary material for individual scores on additional questions that had means scores of between 6.2–9.4). All of the subjects undergoing an RCT should be informed of the importance of long-term surveillance and be given the opportunity of entering in the long-term follow-up (mean (SD) 9.4 (0.85)). Subjects should sign a new consent form both for continuation of the drug and for data collection at that time point (mean (SD) 7.6 (2.87)). Annual updates for consent are not recommended (mean (SD) 3.7 (4.4)). Over-arching principles The report of a TES should be consistent with and consolidate existing established guidelines including CONSORT20 28 and STROBE29 (mean (SD) score 9.4 (0.85)). The report of a TES should be consistent with the ACR/EULAR recommendations on the reporting of clinical trials in RA21 (mean (SD) score 8.9 (1.88)). General comments on TES and its reporting All the following statements were accepted by 95% of the group in the second Delphi exercise, agreement with the individual statements having been established as part of the initial Delphi exercise (agreement score out of 10): While data linkage is important for long-term observation, access may be difficult as pharmaceutical companies conduct most TES; this may in turn limit the overall benefit of such studies (mean (SD) 7.1 (2.06)).

idual statements having been established as part of the initial Delphi exercise (agreement score out of 10): While data linkage is important for long-term observation, access may be difficult as pharmaceutical companies conduct most TES; this may in turn limit the overall benefit of such studies (mean (SD) 7.1 (2.06)). TES, by definition, comprise a sub-selected population, not reflective of routine care; hence, even if all patients in an RCT were entered into a TES, such a study is generalisable only to patients with similar disease characteristics (mean (SD) 7.9 (1.76)). The absence of a clear null hypothesis may make the definition of comparator groups in a TES difficult (mean (SD) 7.4 (1.74)) and should therefore be stated where appropriate (see table 3 for details on method of data analysis). Potential sources of bias or lack of generalisability Several factors were identified as possibly influencing the inclusion of patients in a TES following completion of an RCT, which could introduce sources of bias and lack of generalisability (80% agreement to include all the following statements): The requirement of a certain level of response (mean (SD) 7.9 (2.67)) The stage of the disease of the patient (mean (SD) 7 (2.18)). The fact that the investigator is remunerated for each patient recruited or that the patients may also receive financial compensation and that the drug is free of charge could be of importance in some health systems (mean (SD) 7.4 (1.7)).

Potential sources of bias or lack of generalisability Several factors were identified as possibly influencing the inclusion of patients in a TES following completion of an RCT, which could introduce sources of bias and lack of generalisability (80% agreement to include all the following statements): The requirement of a certain level of response (mean (SD) 7.9 (2.67)) The stage of the disease of the patient (mean (SD) 7 (2.18)). The fact that the investigator is remunerated for each patient recruited or that the patients may also receive financial compensation and that the drug is free of charge could be of importance in some health systems (mean (SD) 7.4 (1.7)). Geographical differences in practice/approach (leading to differences in the number and nature of patients included) (mean (SD) 7.5 (2.45)). Unwanted heterogeneity from countries where treatment options may be more limited (eg, patients with higher levels of disease activity recruited where otherwise only patients in remission/with low disease activity would be included) (mean (SD) 7.6 (1.45)). Consultation on recommendations and stakeholder involvement The Delphi process established whether input from relevant stakeholder organisations, namely, industry, regulatory authorities (Food and Drug Administration (FDA), European Medicines Agency (EMA)) and contract research organisations (CRO) should be sought. In the initial Delphi exercise, 75% voted in favour of some level of industry input, 94% for regulatory authorities and 81% for CRO.

r organisations, namely, industry, regulatory authorities (Food and Drug Administration (FDA), European Medicines Agency (EMA)) and contract research organisations (CRO) should be sought. In the initial Delphi exercise, 75% voted in favour of some level of industry input, 94% for regulatory authorities and 81% for CRO. The second Delphi exercise asked for agreement that each of these organisations be included in the initiative: Industry and regulatory authority input into the final recommendations was recommended, with mean (SD) scores out of 10 of 7.2 (2.48), 8.3 (1.77) and 4.9 (2.85) recorded for the FDA, EMA and CRO, respectively. Key industry companies that have been associated with new drugs in the RA arena were therefore approached (refer to online supplementary material for details of the companies represented).

The second Delphi exercise asked for agreement that each of these organisations be included in the initiative: Industry and regulatory authority input into the final recommendations was recommended, with mean (SD) scores out of 10 of 7.2 (2.48), 8.3 (1.77) and 4.9 (2.85) recorded for the FDA, EMA and CRO, respectively. Key industry companies that have been associated with new drugs in the RA arena were therefore approached (refer to online supplementary material for details of the companies represented). Discussion We present a series of pragmatic recommendations on the design and reporting of TES in rheumatological conditions (mainly inflammatory arthritis, although the basic principles are generally applicable), based on a high degree of expert consensus. Our EULAR task force comprised a group of experts encompassing a range of expertise including clinical trialists, clinicians experienced in RA treatment, and clinical epidemiologists as well as patient representatives. A wide range of countries and health systems were represented, albeit with some omissions (eg, absence of individuals from Asia), although the opportunity to evaluate these recommendations in the wider community in the future should highlight any differing perspectives. With a generally accepted methodology for prospective observational studies, we felt an additional systematic review was not necessary and decided to use our expert opinion to formulate guidance for TES. These recommendations complement those established for clinical trials21 and registries.22

y differing perspectives. With a generally accepted methodology for prospective observational studies, we felt an additional systematic review was not necessary and decided to use our expert opinion to formulate guidance for TES. These recommendations complement those established for clinical trials21 and registries.22 Central to the recommendations was the principle that a TES report should focus on cumulative outcome analysis, maintaining the original trial groups to avoid reporting of only the sub-selected patient group that proceeds to the TES, and thereby achieve better generalisability of results. Furthermore, the task force was clear that absolute numbers and not just percentage response rates should be reported. To facilitate this, we recommend a flow diagram detailing absolute numbers of subjects at each relevant time point, with clear illustration of drop-outs and the reason for cessation and/or exclusion at each relevant stage. While it was agreed that a TES might elaborate on the incidence and nature of adverse events over time, they are not designed to capture rare safety signals. TES reports may also have the potential to inform on the durability of response and the dynamics of achieving pre-determined targets of treatment (low disease activity and remission). It was agreed that any analysis should be pre-specified in the protocol but should always include an intention -to-treat in addition to a completer approach. We acknowledge there are elements that may in particular be the subject of further discussion in the wider community, for example, the issue of split reporting. While the task force discouraged this, each case should be considered individually as there may be instances when there is utility in this approach to ensure relevant data that is of interest is disseminated within the public domain.

further discussion in the wider community, for example, the issue of split reporting. While the task force discouraged this, each case should be considered individually as there may be instances when there is utility in this approach to ensure relevant data that is of interest is disseminated within the public domain. The recommendations were actively commented on by several industry companies (see the ‘Consultation of recommendations and stakeholder involvement’ section) and include their specific feedback (which has been indicated directly in the results where appropriate in the online supplementary material) and as such, gained the approval of the participating stakeholders. While EMA representation did not suggest changes to the recommendations, it acknowledged the importance of standardisation. The interaction also highlighted how regulatory expectations may drive the industry approach on whether and how TES should be undertaken.

ch, gained the approval of the participating stakeholders. While EMA representation did not suggest changes to the recommendations, it acknowledged the importance of standardisation. The interaction also highlighted how regulatory expectations may drive the industry approach on whether and how TES should be undertaken. While we acknowledge that the working group was perhaps relatively small for a consensus exercise, following dissemination of these recommendations, we would anticipate a subsequent exercise to capture how they have been received in the wider rheumatology, trial and industry communities. In future, it will be important for journal reviewers and editors to measure future TES reports against the standard set by these recommendations. The future research agenda will include a systematic review of forthcoming TES to evaluate how well this document is utilised, with further refinement based on the nature of outcomes observed. In addition, regulatory agencies may wish to consider the recommendations and associated issues and how these may influence their expectations from industry. This initiative and the interactive session at EULAR, Madrid 2013 with relevant stakeholders will hopefully be a springboard for further action (the outcome of the EULAR meeting is summarised in the online supplementary material).

tions and associated issues and how these may influence their expectations from industry. This initiative and the interactive session at EULAR, Madrid 2013 with relevant stakeholders will hopefully be a springboard for further action (the outcome of the EULAR meeting is summarised in the online supplementary material). In summary, there is a clear unmet need for a reliable approach to the reporting of TES to maximise our understanding of drug effects in chronic conditions. This initiative, its principles and resulting recommendations apply to TES for any drug in RA as well as for drugs used to treat other chronic rheumatological conditions. This document provides much needed first recommendations to ensure a transparent and standardised approach to the reporting of future TES. Supplementary Material Web supplement Web appendix A Web appendix B We would like to thank the European League Against Rheumatism (EULAR) for supporting and providing the funds for this task force initiative. Contributors: MHB, LS-F, LC and MB contributed substantially to the design, implementation and data collection of the Delphi exercises. LS-F analysed the DELPHI data. MHB, LS-F, LC and MB reviewed the DELPHI data analysis before dissemination to the task force. MHB wrote the paper and the supplementary materials. All authors discussed the summaries presented in the Delphi exercises, results and implications and commented on the manuscript at all stages.

Introduction Tumour necrosis factor-α (TNF-α) inhibitors are effective treatments for patients with rheumatoid arthritis (RA), improving signs and symptoms and slowing or preventing structural damage.1 However, up to 40% of patients either fail to respond adequately to these agents (primary inefficacy) or lose responsiveness over time (secondary inefficacy).2 Options available to patients with an inadequate response to TNF inhibitors (TNF-IRs) include treatment with an alternative TNF inhibitor and switching to a biological therapy with a different mode of action. Several studies have suggested that benefits may be gained by switching to an alternative TNF inhibitor.3–7 Among biological therapies with an alternative mode of action, rituximab (an anti-CD20 B-cell-depleting therapy), abatacept (a T-cell costimulation blocking agent) and, more recently, tocilizumab (anti-interleukin (IL)6 receptor monoclonal antibody) have been demonstrated to be significantly better than placebo in TNF-IR patients.8–10 Data on the comparative effectiveness of different switching strategies are, however, limited. No head-to-head trials have been conducted, and evaluation of this question has been largely restricted to indirect meta-analyses of the randomised controlled trials noted above.11–14 Recent registry data provide evidence that switching to rituximab may be more effective than cycling to an alternative TNF inhibitor.15–17

head-to-head trials have been conducted, and evaluation of this question has been largely restricted to indirect meta-analyses of the randomised controlled trials noted above.11–14 Recent registry data provide evidence that switching to rituximab may be more effective than cycling to an alternative TNF inhibitor.15–17 SWITCH-RA is a prospective, global, observational study, conducted in real-life practice conditions, with the primary objective of comparing the effectiveness of rituximab with an alternative TNF inhibitor in patients with an inadequate response to one previous TNF inhibitor. This paper reports the 6-month primary effectiveness and safety data from SWITCH-RA.

vational study, conducted in real-life practice conditions, with the primary objective of comparing the effectiveness of rituximab with an alternative TNF inhibitor in patients with an inadequate response to one previous TNF inhibitor. This paper reports the 6-month primary effectiveness and safety data from SWITCH-RA. Methods Study design and patient population This was a prospective, global, multicentre, open-label, observational study conducted in real-life practice in adult patients with RA who were non-responsive or intolerant to a single previous TNF inhibitor. Patients were screened and enrolled up to 4 weeks after starting their second biological therapy. In patients enrolled up to 4 weeks after the switch to a second biological therapy, the data collected at that visit were those available at the time of the start of the second biological therapy. Missing baseline Disease Activity Score in 28 joints (DAS28) values did not preclude enrolment. Patients receiving a second biological therapy as part of a clinical trial were excluded. No additional visits or laboratory tests were required outside of routine clinical practice. Patients discontinuing the second biological therapy continued to be observed for the planned 12-month study period. Concomitant non-biological disease-modifying antirheumatic drugs (DMARDs) or other medications could be added at the investigator's discretion.

y tests were required outside of routine clinical practice. Patients discontinuing the second biological therapy continued to be observed for the planned 12-month study period. Concomitant non-biological disease-modifying antirheumatic drugs (DMARDs) or other medications could be added at the investigator's discretion. The Study Committee, a scientific board of leading international rheumatologists, designed the SWITCH-RA study and assured its proper conduct. Data collection and statistical analyses were conducted by an independent contract research organisation (Quintiles, Rockville, Maryland, USA). The study was conducted in accordance with the principles of the Declaration of Helsinki. Approval from the institutional review boards at each study centre was received. All patients consented to data collection and review. ClinicalTrials.gov identifier NCT01557348. Assessments Patients were followed for 12 months from the start of the second biological therapy. Assessments included demographic and clinical variables at the time of switching to the new biological therapy and reasons for discontinuation of the first TNF inhibitor. Reasons for discontinuation were classified as intolerance, inefficacy or other. Inefficacy was further categorised as primary inefficacy (lack of initial clinical response to TNF inhibitor treatment) or secondary inefficacy (development of an inadequate response over time after an initial clinical response). Reasons classified as ‘other’ included patient choice.

s intolerance, inefficacy or other. Inefficacy was further categorised as primary inefficacy (lack of initial clinical response to TNF inhibitor treatment) or secondary inefficacy (development of an inadequate response over time after an initial clinical response). Reasons classified as ‘other’ included patient choice. Effectiveness was assessed using DAS28 excluding patient's global health component calculated with erythrocyte sedimentation rate (DAS28-3–ESR), a validated disease activity measure.18–20 DAS28-3 was used rather than DAS28-4 because patient's global health assessment data were disproportionately under-reported (particularly at baseline, in patients whose data were captured retrospectively). Other variables assessed included ESR, C-reactive protein (CRP), DAS28-3–CRP, swollen and tender joint counts (SJC-28, TJC-28), patient global assessment of disease, patient visual analogue scale pain score, Health Assessment Questionnaire Disability Index (HAQ-DI) and duration of morning stiffness. Adverse events (AEs) reported in the study were mapped to preferred terms in the Medical Dictionary for Drug Regulatory Activities (MedDRA). The relationship of AEs to study treatment was assessed by the investigator.

in score, Health Assessment Questionnaire Disability Index (HAQ-DI) and duration of morning stiffness. Adverse events (AEs) reported in the study were mapped to preferred terms in the Medical Dictionary for Drug Regulatory Activities (MedDRA). The relationship of AEs to study treatment was assessed by the investigator. Owing to the non-interventional nature of the study, strict adherence to visit windows was not feasible. DAS28-3–ESR values at the nearest time point within a given window (±2 months for the 6-month assessment) were used. Patients were enrolled up to 4 weeks after starting their second biological therapy, resulting in a high rate of missing baseline DAS28-3–ESR values. DAS28-ESR values directly reported by the investigator were used to substitute for missing DAS28-3–ESR values. If no values were available at the start of the second biological therapy, the value at the end of the first biological therapy was used as baseline. An ‘as observed’ analysis was performed to validate the robustness of the results. Statistical analysis The study did not enrol up to the planned sample size (631 patients with available data in each group). The retrospective power based on the actual number of patients with a mean change value in DAS28-ESR at 6 months (n=405 for rituximab and 323 for alternative TNF inhibitor) was 70% to detect a difference of 0.3 DAS units, assuming a common SD of 1.6, using a two-group t test with a 0.05 two-sided significance level.

). The retrospective power based on the actual number of patients with a mean change value in DAS28-ESR at 6 months (n=405 for rituximab and 323 for alternative TNF inhibitor) was 70% to detect a difference of 0.3 DAS units, assuming a common SD of 1.6, using a two-group t test with a 0.05 two-sided significance level. The primary end point was the mean change in DAS28-3–ESR, 6 months after the change in biological therapy (considered to be baseline). Six-month changes in clinical variables after the initiation of the new therapy in the two treatment groups were compared using analysis of covariance (ANCOVA), with adjustment for unbalanced baseline characteristics and baseline value of the outcome. Least squares (LS) means and p values were generated. As a sensitivity analysis, the end point was also analysed using an ANCOVA model with adjustment for a propensity score, calculated to determine the likelihood of selecting rituximab over an alternative TNF inhibitor as the second biological therapy driven by the patient's baseline disease characteristics and potential confounding factors (see online supplementary text and figure S1). A subanalysis was conducted to compare switching to rituximab with an alternative TNF inhibitor in seropositive (rheumatoid factor (RF) and/or anti-citrullinated protein antibody (ACPA) positive) and seronegative patients. Safety results were summarised descriptively by treatment group.

The primary end point was the mean change in DAS28-3–ESR, 6 months after the change in biological therapy (considered to be baseline). Six-month changes in clinical variables after the initiation of the new therapy in the two treatment groups were compared using analysis of covariance (ANCOVA), with adjustment for unbalanced baseline characteristics and baseline value of the outcome. Least squares (LS) means and p values were generated. As a sensitivity analysis, the end point was also analysed using an ANCOVA model with adjustment for a propensity score, calculated to determine the likelihood of selecting rituximab over an alternative TNF inhibitor as the second biological therapy driven by the patient's baseline disease characteristics and potential confounding factors (see online supplementary text and figure S1). A subanalysis was conducted to compare switching to rituximab with an alternative TNF inhibitor in seropositive (rheumatoid factor (RF) and/or anti-citrullinated protein antibody (ACPA) positive) and seronegative patients. Safety results were summarised descriptively by treatment group. Results Patient disposition A total of 1312 patients from 11 countries (Canada, Colombia, France, Germany, Great Britain, Greece, Italy, Mexico, Norway, Portugal and Spain) were screened, of whom 1239 were enrolled in the study. Nine enrolled patients were excluded from the analysis (missing information on second biological therapy (n=3) and missing reasons for selection (n=6)). An additional 119 patients were excluded as they had received more than one previous TNF inhibitor, leaving 1111 patients valid for analysis (full analysis population). Of these, 604 (54.4%) received rituximab and 507 (45.6%) an alternative TNF inhibitor as the second biological therapy. Patients could be enrolled up to 4 weeks after starting the second biological therapy. As a result, baseline DAS28-3–ESR scores were missing for about a quarter of the patients (see online supplementary figure S2). Data for 728 patients (rituximab, n=405; alternative TNF inhibitor, n=323) who had baseline DAS28-3–ESR and had completed 6 months after initiation of treatment with a second biological agent were available for the primary end point analysis (primary effectiveness population).

ents (see online supplementary figure S2). Data for 728 patients (rituximab, n=405; alternative TNF inhibitor, n=323) who had baseline DAS28-3–ESR and had completed 6 months after initiation of treatment with a second biological agent were available for the primary end point analysis (primary effectiveness population). Patient demographics and disease characteristics In the full analysis population, the majority of patients were female (79.1%); mean age was ∼55.5 years and mean disease duration was ∼8.3 years. Patients in the two groups had received a similar number of prior non-biological DMARDs and had been on their first TNF inhibitor for a similar length of time, ∼25 months (see online supplementary table S1). Baseline disease characteristics were generally similar between the two treatment groups, although patients who received rituximab appeared to have higher disease activity in terms of SJC, TJC, ESR and DAS28-3–ESR. Patients receiving rituximab were more likely to be seropositive (RF+). Reasons for discontinuing initial TNF inhibitor are given in table 1. Compared with patients discontinuing because of inefficacy, patients discontinuing because of intolerance had longer disease duration (mean (SD) 10.7 (8.7) vs 7.7 (6.6) years), and had been receiving their first TNF inhibitor for a shorter period of time (20.4 (24.0) vs 28.4 (26.3) months). In addition, intolerant patients had significantly lower SJC, TJC, DAS28-3–ESR and HAQ-DI scores at the end of their first TNF inhibitor treatment (data not shown). Table 1 Reasons for discontinuation of previous TNF inhibitor

Patient demographics and disease characteristics In the full analysis population, the majority of patients were female (79.1%); mean age was ∼55.5 years and mean disease duration was ∼8.3 years. Patients in the two groups had received a similar number of prior non-biological DMARDs and had been on their first TNF inhibitor for a similar length of time, ∼25 months (see online supplementary table S1). Baseline disease characteristics were generally similar between the two treatment groups, although patients who received rituximab appeared to have higher disease activity in terms of SJC, TJC, ESR and DAS28-3–ESR. Patients receiving rituximab were more likely to be seropositive (RF+). Reasons for discontinuing initial TNF inhibitor are given in table 1. Compared with patients discontinuing because of inefficacy, patients discontinuing because of intolerance had longer disease duration (mean (SD) 10.7 (8.7) vs 7.7 (6.6) years), and had been receiving their first TNF inhibitor for a shorter period of time (20.4 (24.0) vs 28.4 (26.3) months). In addition, intolerant patients had significantly lower SJC, TJC, DAS28-3–ESR and HAQ-DI scores at the end of their first TNF inhibitor treatment (data not shown). Table 1 Reasons for discontinuation of previous TNF inhibitor Reason Rituximab Alternative TNF inhibitor All patients Full analysis population (n=604) (n=507) (n=1111) Inefficacy 465 (77.0) 362 (71.4) 827 (74.4) Primary* 214 (46.0) 115 (31.8) 329 (39.8) Secondary* 244 (52.5) 233 (64.4) 477 (57.7) Missing data 7 (1.5) 14 (3.9) 21 (2.5) Intolerance 128 (21.2) 136 (26.6) 263 (23.7) Other 11 (1.8) 10 (2.0) 21 (1.9) Primary effectiveness population (n=405) (n=323) (n=728) Inefficacy 311 (76.8) 236 (73.1) 547 (75.1) Primary* 130 (41.8) 74 (31.4) 204 (37.3) Secondary* 176 (56.6) 156 (66.1) 332 (60.7) Missing data 5 (1.6) 6 (2.5) 11 (20.1) Intolerance 89 (22.0) 79 (24.5) 168 (23.1) Other 6 (1.2) 8 (2.5) 13 (1.8) Values are number (%).

rimary effectiveness population (n=405) (n=323) (n=728) Inefficacy 311 (76.8) 236 (73.1) 547 (75.1) Primary* 130 (41.8) 74 (31.4) 204 (37.3) Secondary* 176 (56.6) 156 (66.1) 332 (60.7) Missing data 5 (1.6) 6 (2.5) 11 (20.1) Intolerance 89 (22.0) 79 (24.5) 168 (23.1) Other 6 (1.2) 8 (2.5) 13 (1.8) Values are number (%). *Primary inefficacy, lack of initial clinical response to TNF inhibitor treatment; secondary inefficacy, development of an inadequate response over time after an initial clinical response. TNF, tumour necrosis factor. In this fully adjusted analysis, mean (SD) baseline DAS28-3–ESR in the primary effectiveness population was significantly higher in patients who switched to rituximab than in those who switched to an alternative TNF inhibitor: 5.2 (1.2) vs 4.8 (1.3), p<0.0001 (table 2). This difference was also observed in patients who discontinued their initial TNF inhibitor because of inefficacy (n=547) (5.3 (1.2) vs 4.9 (1.2), p<0.0001) and in those who discontinued because of intolerance (n=168) (5.0 (1.3) vs 4.5 (1.4), p=0.029). Table 2 Patient baseline demographics and clinical characteristics (primary effectiveness population)

In this fully adjusted analysis, mean (SD) baseline DAS28-3–ESR in the primary effectiveness population was significantly higher in patients who switched to rituximab than in those who switched to an alternative TNF inhibitor: 5.2 (1.2) vs 4.8 (1.3), p<0.0001 (table 2). This difference was also observed in patients who discontinued their initial TNF inhibitor because of inefficacy (n=547) (5.3 (1.2) vs 4.9 (1.2), p<0.0001) and in those who discontinued because of intolerance (n=168) (5.0 (1.3) vs 4.5 (1.4), p=0.029). Table 2 Patient baseline demographics and clinical characteristics (primary effectiveness population) Characteristic Rituximab (n=405) Alternative TNF inhibitor (n=323) p Value* Age (years), mean (SD) 56.5 (12.6) 54.7 (13.3) 0.0611 Female, n (%) 310 (76.5) 259 (80.2) 0.2376 RA duration (years), mean (SD) 9.1 (7.7) 7.8 (6.8) 0.1044 No of previous DMARDs, mean (SD) 2.2 (1.1) 2.3 (1.3) 0.3853 Receiving methotrexate, n (%) 199 (49.1) 180 (55.7) 0.0769 Methotrexate dose (mg/week), mean (SD) 13.3 (4.9) 14.4 (9.4) 0.1774 Receiving corticosteroid, n (%) 293 (72.3) 229 (70.9) 0.6666 Duration of previous TNF inhibitor therapy (months), mean (SD) 27.4 (25.9) 26.3 (26.6) 0.6478 RF positive, n (%) 318 (84.1) 204 (65.6) <0.0001 ACPA positive, n (%) 172 (69.1) 133 (59.4) 0.0277 Seropositive (RF+ or ACPA+), n (%) 331 (81.7) 228 (70.6) 0.0004 DAS28-3–ESR, mean (SD) 5.2 (1.2) 4.8 (1.3) <0.0001 ESR (mm/h), mean (SD) 38.9 (26.7) 32.5 (24.7) 0.0023 CRP (mg/L), mean (SD) 26.1 (41.4) 23.8 (39.7) 0.4856 SJC (28 joints), mean (SD) 7.5 (5.5) 6.1 (5.6) 0.0024 TJC (28 joints), mean (SD) 10.2 (7.1) 8.2 (6.8) 0.0008 HAQ-DI, mean (SD) 1.5 (0.8) 1.3 (0.8) 0.0945 *Analysis of covariance or χ2 test.

(1.2) 4.8 (1.3) <0.0001 ESR (mm/h), mean (SD) 38.9 (26.7) 32.5 (24.7) 0.0023 CRP (mg/L), mean (SD) 26.1 (41.4) 23.8 (39.7) 0.4856 SJC (28 joints), mean (SD) 7.5 (5.5) 6.1 (5.6) 0.0024 TJC (28 joints), mean (SD) 10.2 (7.1) 8.2 (6.8) 0.0008 HAQ-DI, mean (SD) 1.5 (0.8) 1.3 (0.8) 0.0945 *Analysis of covariance or χ2 test. ACPA, anti-citrullinated protein antibody; CRP, C-reactive protein; DAS28-3, Disease Activity Score in 28 joints excluding patient's global health component; DMARD, disease-modifying antirheumatic drug; ESR, erythrocyte sedimentation rate; HAQ-DI, Health Assessment Questionnaire Disability Index; RA, rheumatoid arthritis; RF, rheumatoid factor; SJC, swollen joint count; TJC, tender joint count; TNF, tumour necrosis factor.

joints excluding patient's global health component; DMARD, disease-modifying antirheumatic drug; ESR, erythrocyte sedimentation rate; HAQ-DI, Health Assessment Questionnaire Disability Index; RA, rheumatoid arthritis; RF, rheumatoid factor; SJC, swollen joint count; TJC, tender joint count; TNF, tumour necrosis factor. Effectiveness Changes in clinical characteristics over 6 months are summarised in table 3. The mean change in DAS28-3–ESR from baseline to 6 months was significantly greater in the rituximab group than in the alternative anti-TNF group (p=0.007) (table 3 and figure 1). This difference remained statistically significant among the cohort of patients who discontinued initial TNF inhibitor because of inefficacy. However, among patients who discontinued because of intolerance, there was no significant difference between rituximab and an alternative TNF inhibitor (figure 1). A greater decrease in ESR was also observed in the rituximab versus the alternative TNF inhibitor group, both overall and in the inefficacy cohort (−13.2 vs −7.0; p=0.009 and −10.0 vs −4.3; p=0.038). SJC and TJC showed numerically greater improvements with rituximab, although the differences were not statistically significant. Table 3 Mean changes in clinical characteristics from baseline to 6 months* (primary effectiveness population)

Effectiveness Changes in clinical characteristics over 6 months are summarised in table 3. The mean change in DAS28-3–ESR from baseline to 6 months was significantly greater in the rituximab group than in the alternative anti-TNF group (p=0.007) (table 3 and figure 1). This difference remained statistically significant among the cohort of patients who discontinued initial TNF inhibitor because of inefficacy. However, among patients who discontinued because of intolerance, there was no significant difference between rituximab and an alternative TNF inhibitor (figure 1). A greater decrease in ESR was also observed in the rituximab versus the alternative TNF inhibitor group, both overall and in the inefficacy cohort (−13.2 vs −7.0; p=0.009 and −10.0 vs −4.3; p=0.038). SJC and TJC showed numerically greater improvements with rituximab, although the differences were not statistically significant. Table 3 Mean changes in clinical characteristics from baseline to 6 months* (primary effectiveness population) Change over 6 months Rituximab (n=405) Alternative TNF inhibitor (n=323) p Value* DAS28-3–ESR† −1.5 (0.2) −1.1 (0.2) 0.007 Improved by at least 0.6, n (%) 280 (69.1) 191 (59.1) 0.005 Improved by at least 1.6, n (%) 156 (38.5) 95 (29.4) 0.010 DAS28-3–CRP −1.4 (0.3) −1.3 (0.3) 0.538 ESR (mm/h) −13.2 (3.9) −7.0 (4.2) 0.009 CRP (mg/L) −29.1 (8.0) −29.9 (8.4) 0.876 SJC (28 joints) −3.3 (0.9) −2.8 (1.0) 0.417 TJC (28 joints) −5.7 (1.2) −4.5 (1.2) 0.113 Physician global assessment of disease (mm) −21.0 (6.1) −14.8 (6.7) 0.076 Patient global assessment of disease (mm) −17.0 (5.5) −10.2 (5.8) 0.044 Patient VAS pain score (mm) −15.7 (6.5) −10.8 (7.0) 0.203 HAQ-DI −0.6 (0.2) −0.5 (0.2) 0.337 Duration of morning stiffness (min) −19.0 (25.4) −4.3 (27.4) 0.325 Values are LS mean (SE).

global assessment of disease (mm) −21.0 (6.1) −14.8 (6.7) 0.076 Patient global assessment of disease (mm) −17.0 (5.5) −10.2 (5.8) 0.044 Patient VAS pain score (mm) −15.7 (6.5) −10.8 (7.0) 0.203 HAQ-DI −0.6 (0.2) −0.5 (0.2) 0.337 Duration of morning stiffness (min) −19.0 (25.4) −4.3 (27.4) 0.325 Values are LS mean (SE). *LS means and p values were based on analysis of covariance (ANCOVA) models with change in outcome as the dependent variable and treatment group as the independent variable, with controls for baseline value on the outcome variable, and unbalanced baseline characteristics. p Values for counts were based on the Pearson's χ2 test. †Sensitivity analysis results using ANCOVA with adjustment for the propensity to receive treatment were rituximab −1.3 (0.1) and TNF inhibitor −1.0 (0.1) (p=0.006). CRP, C-reactive protein; DAS28-3, Disease Activity Score in 28 joints excluding patient's global health component; ESR, erythrocyte sedimentation rate; HAQ-DI, Health Assessment Questionnaire Disability Index; LS, least squares; SJC, swollen joint count; TJC, tender joint count; TNF, tumour necrosis factor; VAS, visual analogue scale. Figure 1 Mean change in Disease Activity Score in 28 joints excluding patient's global health component–erythrocyte sedimentation rate (DAS28-3–ESR) from baseline to 6 months. Analyses were adjusted for baseline value and other covariates found to be statistically significantly different between the two groups at baseline. Values are DAS28-3–ESR least squares means. TFNi, tumour necrosis factor inhibitor.

ealth component–erythrocyte sedimentation rate (DAS28-3–ESR) from baseline to 6 months. Analyses were adjusted for baseline value and other covariates found to be statistically significantly different between the two groups at baseline. Values are DAS28-3–ESR least squares means. TFNi, tumour necrosis factor inhibitor. In a robustness analysis, in which no imputations of missing DAS28 values were made, the mean change in DAS28-3–ESR from baseline to 6 months remained significantly greater in the rituximab group versus the alternative TNF inhibitor group (LS means −1.2 vs −0.9; p=0.033).

ealth component–erythrocyte sedimentation rate (DAS28-3–ESR) from baseline to 6 months. Analyses were adjusted for baseline value and other covariates found to be statistically significantly different between the two groups at baseline. Values are DAS28-3–ESR least squares means. TFNi, tumour necrosis factor inhibitor. In a robustness analysis, in which no imputations of missing DAS28 values were made, the mean change in DAS28-3–ESR from baseline to 6 months remained significantly greater in the rituximab group versus the alternative TNF inhibitor group (LS means −1.2 vs −0.9; p=0.033). Subanalysis by serotype Overall, 559 (77%) patients in the primary effectiveness population were seropositive. Baseline DAS28-3–ESR scores were higher in the rituximab group than the alternative TNF inhibitor group in both seropositive (mean (SD) 5.2 (1.2) vs 4.8 (1.3); p<0.0001) and seronegative (5.3 (1.1) vs 4.7 (1.3); p=0.0019) patients. After adjustment for baseline differences, seropositive patients showed a significantly greater improvement in DAS28-3–ESR over 6 months with rituximab than with an alternative TNF inhibitor (table 4). The relative benefit of rituximab in seropositive patients was observed in patients who discontinued their initial TNF inhibitor because of inefficacy but not in those who discontinued because of intolerance. Although seronegative patients also showed improvements in DAS28-3–ESR at 6 months, there was no significant difference between the rituximab and alternative TNF inhibitor groups. The seronegative group was, however, much smaller than the seropositive group, and was therefore underpowered to detect small differences. A similar pattern was seen with ESR as the outcome measure. Seropositive patients receiving rituximab showed greater changes in ESR (LS mean (SE)) over 6 months than those receiving an alternative TNF inhibitor (−14.4 (4.5) vs −7.3 (4.8); p=0.006); corresponding results in seronegative patients were −13.4 (8.3) vs −10.4 (9.0) (p=0.582).

was seen with ESR as the outcome measure. Seropositive patients receiving rituximab showed greater changes in ESR (LS mean (SE)) over 6 months than those receiving an alternative TNF inhibitor (−14.4 (4.5) vs −7.3 (4.8); p=0.006); corresponding results in seronegative patients were −13.4 (8.3) vs −10.4 (9.0) (p=0.582). Table 4 Changes in DAS28-3–ESR at 6 months according to serotype (primary effectiveness population) Seropositive patients (n=559) Seronegative patients (n=169) Rituximab Alternative TNF inhibitor p Value Rituximab Alternative TNF inhibitor p Value All patients −1.6 (0.3) −1.2 (0.3) 0.011 −1.3 (0.4) −1.1 (0.4) 0.449 Inefficacy −1.9 (0.3) −1.5 (0.4) 0.021 −0.5 (0.6) −0.2 (0.7) 0.472 Intolerance −0.5 (0.5) −0.5 (0.5) 0.997 −2.1 (1.2) −1.9 (1.3) 0.815 Values are LS mean (SE). Patient numbers (all/inefficacy/intolerance): seropositive, rituximab 331/253/74 and TNF inhibitor 228/171/51; seronegative, rituximab 74/58/15 and TNF inhibitor 95/65/28. LS means and p values were based on analysis of covariance models with change in outcome as the dependent variable and treatment group as the independent variable, with controls for baseline value on the outcome variable, and unbalanced baseline characteristics. DAS28-3, Disease Activity Score in 28 joints excluding patient's global health component; ESR, erythrocyte sedimentation rate; LS, least squares; TNF, tumour necrosis factor.

Patient numbers (all/inefficacy/intolerance): seropositive, rituximab 331/253/74 and TNF inhibitor 228/171/51; seronegative, rituximab 74/58/15 and TNF inhibitor 95/65/28. LS means and p values were based on analysis of covariance models with change in outcome as the dependent variable and treatment group as the independent variable, with controls for baseline value on the outcome variable, and unbalanced baseline characteristics. DAS28-3, Disease Activity Score in 28 joints excluding patient's global health component; ESR, erythrocyte sedimentation rate; LS, least squares; TNF, tumour necrosis factor. Safety A summary of safety is presented in table 5. The overall incidence of AEs was similar in the rituximab and alternative TNF inhibitor groups. The most commonly reported AEs (occurring in ≥2% of patients) in the rituximab group were urinary tract infections (4.8%), lower respiratory tract infections (2.8%), headache (2.5%) and nausea (2.0%). In the alternative TNF inhibitor group, the most frequent AEs were urinary tract infections (3.2%), headache (3.2%), rash (3.0%), cough (2.8%), nausea (2.6%), diarrhoea (2.4%), lower respiratory tract infections (2.0%) and nasopharyngitis (2.0%). Infections were reported at a similar rate in the two groups. Serious AEs were reported by 82 (13.6%) and 56 (11.0%) patients in the rituximab and alternative TNF inhibitor groups, respectively, and most commonly occurred within the musculoskeletal and connective tissue disorders system organ class (rituximab, 21 patients (3.5%); alternative TNF inhibitor, 22 patients (4.3%)). Serious infections were reported more frequently with rituximab (25 events in 23 patients, 3.8%) than with alternative TNF inhibitor treatment (nine events in nine patients, 1.8%) with corresponding rates (95% CI) per 100 patient-years of 4.42 (2.86 to 6.52) vs 1.94 (0.89 to 3.68). Overall, the most common serious infections (rituximab vs alternative TNF inhibitor group) were pneumonia (0.5% (0.7% vs 0.2%)), urinary tract infection (0.4% (0.7% vs 0.0%)) and lower respiratory tract infection (0.3% (0.5% vs 0.0%)). There was one positive mycobacterium tuberculosis complex test (T-SPOT; Oxford Immunotec, UK) in the alternative TNF inhibitor group. The patient received antituberculosis agents (rifampicin and pyridoxine), and the event resolved without sequelae. Malignancies (neoplasms—benign, malignant and unspecified) were reported by nine rituximab patients (1.5%) and 11 alternative TNF inhibitor patients (2.2%); two of these events in each group were considered to be possibly related to study treatment (stage 0 prostate cancer and Waldenstrom's macroglobulinaemia in the rituximab group and two patients with squamous cell carcinoma of the skin in the alternative TNF inhibitor group).

1 alternative TNF inhibitor patients (2.2%); two of these events in each group were considered to be possibly related to study treatment (stage 0 prostate cancer and Waldenstrom's macroglobulinaemia in the rituximab group and two patients with squamous cell carcinoma of the skin in the alternative TNF inhibitor group). Overall, seven (1.2%) and four (0.8%) patients receiving rituximab and alternative TNF inhibitor, respectively, died as a result of an AE during the study. None was considered to be related to the study treatment. Table 5 Safety summary (full analysis population) Adverse event Rituximab (n=604) Alternative TNF inhibitor (n=507) All adverse events 291 (48.2) 241 (47.5) Serious adverse events 82 (13.6) 56 (11.0) Infusion reactions 66 (10.9) 20 (3.9) Infections 112 (18.5) 99 (19.5) Serious infections 23 (3.8) 9 (1.8) Number of events (rate*) 25 (4.42) 9 (1.94) 95% CI of rate 2.86 to 6.52 0.89 to 2.68 Values are number (%). *Per 100 patient-years. TNF, tumour necrosis factor.

Adverse event Rituximab (n=604) Alternative TNF inhibitor (n=507) All adverse events 291 (48.2) 241 (47.5) Serious adverse events 82 (13.6) 56 (11.0) Infusion reactions 66 (10.9) 20 (3.9) Infections 112 (18.5) 99 (19.5) Serious infections 23 (3.8) 9 (1.8) Number of events (rate*) 25 (4.42) 9 (1.94) 95% CI of rate 2.86 to 6.52 0.89 to 2.68 Values are number (%). *Per 100 patient-years. TNF, tumour necrosis factor. Discussion Currently, there are no clear guidelines for managing patients with RA with an inadequate response to initial TNF inhibitor therapy. Consequently, decisions regarding further treatment generally depend on factors such as patient choice and how comfortable physicians are with the available alternatives.21 A common strategy for managing TNF-IR patients involves switching to a second TNF inhibitor. Although this strategy is beneficial in some patients,22 a number of studies have reported reduced efficacy with the second TNF inhibitor compared with the first and high rates of early discontinuation among patients who switch.2

common strategy for managing TNF-IR patients involves switching to a second TNF inhibitor. Although this strategy is beneficial in some patients,22 a number of studies have reported reduced efficacy with the second TNF inhibitor compared with the first and high rates of early discontinuation among patients who switch.2 The primary effectiveness results from this global study provide evidence from real-world practice that TNF-IR patients achieve significantly better clinical responses over 6 months if they receive rituximab rather than an alternative TNF inhibitor as their second biological therapy. Similar to most non-interventional studies, this open-label, observational study had the limitation of substantial missing data, especially due to enrolment of patients up to 4 weeks of starting the second biological therapy, which resulted in many with a missing baseline. Because the number and timing of visits were left to investigators’ discretion, limited data were available to implement most of the imputation methods appropriate to handle the withdrawal. However, the completer results are broadly in agreement with recent reports from national European registry studies. In a study of patients with a single TNF inhibitor failure from the British Society for Rheumatology Biologics Register, patients who received rituximab as their second biological therapy were significantly more likely to achieve a European League Against Rheumatism response and improvements in HAQ at 6 months than those who received a second TNF inhibitor.23 Data from a Swiss registry also indicated that rituximab treatment led to better clinical outcomes in TNF-IR patients than an alternative TNF inhibitor.16 17 The latter registry also recently reported that rituximab and alternative TNF inhibitors were as effective in preventing radiographical joint damage.24

hibitor.23 Data from a Swiss registry also indicated that rituximab treatment led to better clinical outcomes in TNF-IR patients than an alternative TNF inhibitor.16 17 The latter registry also recently reported that rituximab and alternative TNF inhibitors were as effective in preventing radiographical joint damage.24 The difference in clinical response at 6 months between rituximab and alternative TNF inhibitor therapy in the present study was observed in the primary effectiveness population, with differences greatest among patients who discontinued their first TNF inhibitor because of inefficacy. Patients who discontinued because of intolerance showed no statistically significant difference between rituximab and TNF inhibitor treatment. These results are also consistent with previous studies, in which TNF-IR patients who stopped because of primary inefficacy experienced lesser clinical responses with subsequent TNF therapy than those who stopped because of secondary inefficacy or intolerance.25 26 Enhancement of clinical response to rituximab in patients who discontinued their first TNF inhibitor because of inefficacy was observed in the Swiss registry.16 Patients exhibiting primary non-responsiveness to TNF inhibitors are likely to have non-TNF-α-mediated disease and consequently would be predicted to respond better to subsequent therapy with an alternative mode of action. In contrast, patients with secondary inefficacy to TNF inhibitors may have lost response because of the development of drug antibodies; these patients would therefore be expected to exhibit a response to an antigenically distinct treatment, whether within or distinct from the previous class. The presence of drug antibodies was not measured in this study. Finally, as most toxicity is independent of a class effect, this explains the similarities between outcomes with rituximab and TNF inhibitors in patients discontinuing their initial TNF inhibitor because of intolerance.

or distinct from the previous class. The presence of drug antibodies was not measured in this study. Finally, as most toxicity is independent of a class effect, this explains the similarities between outcomes with rituximab and TNF inhibitors in patients discontinuing their initial TNF inhibitor because of intolerance. A subanalysis according to serological status revealed that the difference between rituximab and an alternative inhibitor was further enhanced among the ∼80% of patients who were seropositive at baseline. In addition, as observed with the entire primary effectiveness population, the improvement with rituximab versus TNF inhibitor treatment was significantly greater in seropositive patients with a previous TNF inhibitor failure due to inefficacy. Assessing the relative effectiveness of rituximab and TNF inhibitor therapy in seronegative patients was limited by the lower patient numbers in this subgroup. Interestingly, of patients discontinuing a TNF inhibitor because of intolerance, seronegative patients in both the rituximab and TNF inhibitor groups exhibited numerically greater responses than those observed in seropositive patients. In general, responses to rituximab in seronegative patients were numerically, but not statistically significantly, superior to those achieved with TNF inhibitors. Overall, the results of the subanalysis by serological status concur with recent studies reporting enhancement of clinical responsiveness to rituximab in seropositive over seronegative patients.27–30 In addition, serological status did not appear to influence responsiveness to TNF inhibitors in our study. Previous studies examining the influence of serological status on responsiveness to TNF inhibitors yielded inconsistent results.31–34

al responsiveness to rituximab in seropositive over seronegative patients.27–30 In addition, serological status did not appear to influence responsiveness to TNF inhibitors in our study. Previous studies examining the influence of serological status on responsiveness to TNF inhibitors yielded inconsistent results.31–34 The incidence and type of AEs observed with the two treatments evaluated in this study were broadly similar and as expected on the basis of the known safety profiles of these therapies. Rituximab was associated with a slightly higher incidence of serious AEs and serious infections, while there was one positive mycobacterium tuberculosis test in the TNF inhibitor group. In conclusion, these results from the SWITCH-RA study, conducted in real-life conditions reflective of current clinical practice, indicate that, after discontinuation of a first TNF inhibitor, patients switching to rituximab achieved greater clinical effectiveness on average over 6 months compared with patients switching to an alternative TNF inhibitor. This difference was particularly evident among seropositive patients who discontinued their initial TNF inhibitor because of inefficacy. Supplementary Material Web supplement Contributors: The study was designed by PE, AF, VMMT, LB-F, JEG, AR-R, RJM, CM, and conducted by PE, AO, EG, JEG, RJM, CM, CC and LHG. Data analysis and interpretation were carried out by PE, AF, VMMT, LB-F, AO, EG, JEG, AR-R, RJM, CM, CC and LHG. The manuscript was developed and approved by all authors.

Web supplement Contributors: The study was designed by PE, AF, VMMT, LB-F, JEG, AR-R, RJM, CM, and conducted by PE, AO, EG, JEG, RJM, CM, CC and LHG. Data analysis and interpretation were carried out by PE, AF, VMMT, LB-F, AO, EG, JEG, AR-R, RJM, CM, CC and LHG. The manuscript was developed and approved by all authors. Funding: Support for third-party writing assistance for this manuscript was provided by F Hoffmann-La Roche, Ltd. Adelphi Communications and Vivian Chen, PharmD of Health Interactions drafted the manuscript based on consultation with senior authors and revised the manuscript based on the involvement and input of all authors. All authors read and approved the final content of the manuscript.

as provided by F Hoffmann-La Roche, Ltd. Adelphi Communications and Vivian Chen, PharmD of Health Interactions drafted the manuscript based on consultation with senior authors and revised the manuscript based on the involvement and input of all authors. All authors read and approved the final content of the manuscript. Competing interests: PE has undertaken clinical trials and provided expert advice for Pfizer, MSD, Abbvie, Novartis, Roche and Bristol Myers Squibb. AF has received consulting and speaker fees from Roche, Abbott, Pfizer, Bristol Myers Squibb and MSD. AR-R has received consulting and speaker fees from Roche, Chugai, Abbott, Pfizer, Bristol Myers Squibb, UCB and MSD. PS-P has received consulting and speaker fees from Roche Products, Bristol Myers Squibb, Johnson & Johnson, Pfizer and Merck. DC has received consulting and speaker fees from Abbvie, Amgen, Astra-Zeneca, Jenssen, Bristol Myers Squibb, GlaxoSmithKline, Pfizer, UCB and F Hoffmann La Roche. VMMT has received research funding from Schering-Plough, Wyeth-Pharma and Roche, has participated on advisory boards for UCB-Pharma, Bristol-Myers Squibb, Roche, Cellerix, Pfizer, Sobi and Boehringer Ingelheim, and has been involved in clinical trials for Novartis, Schering-Plough, Centocor, Wyeth-Pharma, Abbott, Bristol Myers Squibb, Roche, Serono, Amgen, GlaxoSmithKline and Pfizer. LB-F has received consulting and speaker fees from Roche, UCB, GlaxoSmithKline, Jansen, MSD and Bristol Myers Squibb. AO has received support from (including attendance at conferences), undertakes clinical trials for, and acts as a consultant to Roche, Chugai, MSD, Abbott, Pfizer and Bristol Myers Squibb. AA has received speaker fees from Roche and MSD. EG is an employee of Quintiles. CM and LHG are employees of F Hoffmann-La Roche Ltd. CC is an employee of Genentech Inc.

g attendance at conferences), undertakes clinical trials for, and acts as a consultant to Roche, Chugai, MSD, Abbott, Pfizer and Bristol Myers Squibb. AA has received speaker fees from Roche and MSD. EG is an employee of Quintiles. CM and LHG are employees of F Hoffmann-La Roche Ltd. CC is an employee of Genentech Inc. Patient consent: Obtained. Ethics approval: Institutional review boards at each study centre. Provenance and peer review: Not commissioned; externally peer reviewed. Data sharing statement: All authors had full access to all the data in the study and contributed to data interpretation.

Introduction Inhibition of structural joint damage is a primary goal of rheumatoid arthritis (RA) therapy, and a number of disease-modifying antirheumatic drugs (DMARDs), including rituximab, have demonstrated this ability.1–5 While assessment of structural damage has traditionally been performed using radiography, the importance of earlier and more sensitive joint imaging has been recognised by recent guidelines.1 6 7 Although more expensive than radiography, MRI can simultaneously assess all relevant structures in the inflamed joint and is more sensitive at detecting bone erosions, allowing for smaller and shorter clinical trials.6 7 Furthermore, MRI visualises articular cartilage loss directly, whereas radiography evaluates cartilage loss indirectly through joint-space narrowing. MRI can also detect joint inflammation, which is particularly useful when assessing early or undifferentiated joint disease.8 9 Rituximab is approved in the European Union and the USA for the treatment of RA after inadequate response (IR) to ≥1 tumour necrosis factor (TNF) inhibitor. The approved dose of rituximab for the treatment of RA is two 1000-mg intravenous infusions separated by 2 weeks every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. Rituximab inhibits joint damage progression in the indicated patient population, those with an IR to anti-TNF therapies (TNF-IR), and non-indicated populations.2 3 10

tment of RA is two 1000-mg intravenous infusions separated by 2 weeks every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. Rituximab inhibits joint damage progression in the indicated patient population, those with an IR to anti-TNF therapies (TNF-IR), and non-indicated populations.2 3 10 This study evaluated changes in structural damage and joint inflammation assessed by MRI following rituximab treatment in patients with active RA despite methotrexate (MTX) who were naive to biological therapy.

tment of RA is two 1000-mg intravenous infusions separated by 2 weeks every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. Rituximab inhibits joint damage progression in the indicated patient population, those with an IR to anti-TNF therapies (TNF-IR), and non-indicated populations.2 3 10 This study evaluated changes in structural damage and joint inflammation assessed by MRI following rituximab treatment in patients with active RA despite methotrexate (MTX) who were naive to biological therapy. Methods Study design and patients RA-SCORE was a phase 3b, randomised, placebo-controlled, double-blind, multicentre, international study. Patients met the American College of Rheumatology (ACR) criteria for RA with a disease duration ≥3 months and ≤10 years, had active RA (Disease Activity Score in 28 joints (DAS28) C reactive protein score ≥3.2), and had experienced an IR to MTX (MTX-IR) at a dose of 12.5–25 mg/week for ≥12 weeks, with the last 4 weeks before baseline maintained at a stable dose. Minimal MTX doses of 7.5 mg/week or 10 mg/week were permitted only in cases of documented intolerance to higher doses. Patients were biological naive and were either positive for anticyclic citrullinated protein (≥20 U) or for rheumatoid factor (≥20 IU/mL). Patients were also required to have erosion and/or clinical signs and symptoms of synovitis in a single (MRI) joint (metacarpophalangeal and/or wrist). In patients with a disease duration of >1 year, clinical evidence of synovitis and ≥1 definitive radiographic erosion at screening based on central review were required. In those with disease duration of ≤1 year, clinical synovitis needed to be confirmed by MRI at baseline. Key exclusion criteria included a history of rheumatic autoimmune disease other than RA or significant systemic involvement secondary to RA. Secondary Sjögren's syndrome and secondary limited cutaneous vasculitis with RA were permitted.

duration of ≤1 year, clinical synovitis needed to be confirmed by MRI at baseline. Key exclusion criteria included a history of rheumatic autoimmune disease other than RA or significant systemic involvement secondary to RA. Secondary Sjögren's syndrome and secondary limited cutaneous vasculitis with RA were permitted. Patients were randomised in a 1:1:1: ratio to receive two infusions of placebo, rituximab 500 mg, or rituximab 1000 mg intravenously on days 1 and 15. Premedication with analgesics, antihistamines and intravenous methylprednisolone 100 mg were required before each rituximab infusion. Patients continued to receive stable doses of MTX and folic acid/folate (≥5 mg/week). Concomitant oral glucocorticoids (at a stable dose ≤10 mg/day) were allowed; intra-articular glucocorticoid injections could be used in a limited fashion to treat severe RA flares. Rescue therapy, or increased dose of MTX or use of non-biological DMARDs, was permitted at week 16 for patients with <20% improvement in tender and swollen joint counts compared with baseline. Rituximab retreatment was permitted after week 24 if patients had a DAS28 C reactive protein score ≥2.6 and no contraindications to treatment (such as active infections).

use of non-biological DMARDs, was permitted at week 16 for patients with <20% improvement in tender and swollen joint counts compared with baseline. Rituximab retreatment was permitted after week 24 if patients had a DAS28 C reactive protein score ≥2.6 and no contraindications to treatment (such as active infections). This study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Harmonised Tripartite Guideline for Good Clinical Practice (NCT00578305). The protocol and any accompanying material provided to the patient were approved by an Independent Ethics Committee or Institutional Review Board before starting the study. Patients provided written informed consent before enrolment. Efficacy assessments Patients returned for efficacy and safety assessments at weeks 4, 6, 12, 16, 24, 36, 44 and 52. MRI scans and radiographs were acquired at baseline (within 14 days before the first study medication infusion) and at weeks 12 (MRI only), 24 and 52. The most clinically inflamed hand and wrist (or the dominant hand, in case of equal inflammation) were imaged with a 1.5-Tesla whole-body MRI scanner using a commercial surface coil and an acrylic frame11 designed to ensure proper and reproducible positioning of the hand and wrist. The hand and wrist were scanned separately using coronal short-tau inversion recovery and coronal fat-suppressed three-dimensional gradient echo with and without intravenous gadolinium-based contrast agent. The same hand and wrist were used for all assessments.

proper and reproducible positioning of the hand and wrist. The hand and wrist were scanned separately using coronal short-tau inversion recovery and coronal fat-suppressed three-dimensional gradient echo with and without intravenous gadolinium-based contrast agent. The same hand and wrist were used for all assessments. All images were scored centrally by two independent radiologists who were blind to treatment allocations, clinical information and the order in which serial images were acquired. MRI images were scored using the Outcome Measures in Rheumatology Clinical Trials RA MRI Scoring (RAMRIS) method.6 12–14 Cartilage loss determined by MRI was assessed using a previously validated 9-point cartilage loss scale (CARLOS).11 15 Radiographs of hands and both feet were scored using the Genant-modified Sharp method.16 No progression was defined as a change from baseline in the RAMRIS erosion score of ≤0. Total damage scores were calculated using the following formula: RAMRIS erosion score+(2.5×CARLOS).15 Total inflammation scores were calculated using the following formula: RAMRIS osteitis score+(3×RAMRIS synovitis score). Clinical efficacy parameters included ACR 20/50/70 and European League Against Rheumatism (EULAR) response rates and change from baseline in the DAS28-erythrocyte sedimentation rate (DAS28-ESR) and in the Health Assessment Questionnaire Disability Index (HAQ-DI). Safety parameters included treatment-emergent adverse events (AEs), clinical laboratory parameters, and human antichimeric antibody (HACA) to rituximab at week 24.

rates and change from baseline in the DAS28-erythrocyte sedimentation rate (DAS28-ESR) and in the Health Assessment Questionnaire Disability Index (HAQ-DI). Safety parameters included treatment-emergent adverse events (AEs), clinical laboratory parameters, and human antichimeric antibody (HACA) to rituximab at week 24. Statistical analyses The intent-to-treat population was defined as all patients who were randomised and received any part of an infusion, with analysis groups defined according to randomisation. The safety population included all patients who received any part of an infusion, analysed according to the treatment received. Additional details are provided in online supplementary text 1. In the primary analysis, the change in RAMRIS erosion score from baseline at week 24 (primary end point) was compared between patients receiving rituximab 1000 mg and those receiving placebo. Secondary end points included changes from baseline in the RAMRIS erosion score at weeks 12 and 52; RAMRIS synovitis and osteitis at weeks 12, 24 and 52; and proportions of patients with no progression in RAMRIS erosion score at weeks 24 and 52. Post hoc analyses evaluated for total inflammation scores at weeks 12, 24 and 52 and change in CARLOS and total damage scores at weeks 24 and 52.

on score at weeks 12 and 52; RAMRIS synovitis and osteitis at weeks 12, 24 and 52; and proportions of patients with no progression in RAMRIS erosion score at weeks 24 and 52. Post hoc analyses evaluated for total inflammation scores at weeks 12, 24 and 52 and change in CARLOS and total damage scores at weeks 24 and 52. The van Elteren test stratified for the factors used at randomisation (duration of MTX use < or ≥6 months and presence of bone erosions) was used for the primary analysis and to assess changes from baseline in RAMRIS erosion scores, Genant-modified Sharp radiographic erosion scores and CARLOS (imputation by linear extrapolation), and to assess changes from baseline in RAMRIS synovitis and osteitis scores (last observation carried forward). The Cochran-Mantel-Haenszel test was used to assess the proportions of patients with no newly eroded joints (no imputation used), of patients with no progression of erosions, of patients with improvements in synovitis and osteitis, and of patients achieving a EULAR and ACR 20/50/70 response (non-responder imputation). Analysis of covariance was used to assess changes from baseline in DAS28-ESR and HAQ-DI (last observation carried forward). All tests were two-sided and were conducted at the 5% significance level without correction for multiplicity.

nd of patients achieving a EULAR and ACR 20/50/70 response (non-responder imputation). Analysis of covariance was used to assess changes from baseline in DAS28-ESR and HAQ-DI (last observation carried forward). All tests were two-sided and were conducted at the 5% significance level without correction for multiplicity. Results Patient disposition and baseline characteristics A total of 283 patients from 37 centres in 17 countries were screened. Of these, 185 patients were randomised and received study drug and were therefore included in the intent-to-treat and safety populations (19 November 2007 to 12 April 2010 from first patient randomised to last patient visit). Of the patients receiving placebo, 22% failed to complete the study, compared with 5% and 7% of patients receiving rituximab 500 mg and rituximab 1000 mg, respectively. The predominant reasons for withdrawal in all treatment groups were non-safety related (see online supplementary table S1). Patient disposition is shown in online supplementary figure S1. The proportion of patients who remained in the study until week 52 was higher in the rituximab groups than in the placebo group.

ly. The predominant reasons for withdrawal in all treatment groups were non-safety related (see online supplementary table S1). Patient disposition is shown in online supplementary figure S1. The proportion of patients who remained in the study until week 52 was higher in the rituximab groups than in the placebo group. Baseline demographics and disease characteristics were generally well balanced among the treatment groups (table 1). The mean age of the patients was 50 years, and the mean disease duration was slightly less than 5 years. At baseline, the mean DAS28-ESR was 6.2. Patients were receiving a mean MTX dose of >15 mg/week, and slightly more than half were receiving concomitant corticosteroids. Approximately 77% (48/62) and 72% (43/60) of patients in the rituximab 500-mg and rituximab 1000-mg groups, respectively, were retreated with a second cycle of rituximab after 24 weeks. Table 1 Patient demographics and characteristics (safety population) at baseline

Baseline demographics and disease characteristics were generally well balanced among the treatment groups (table 1). The mean age of the patients was 50 years, and the mean disease duration was slightly less than 5 years. At baseline, the mean DAS28-ESR was 6.2. Patients were receiving a mean MTX dose of >15 mg/week, and slightly more than half were receiving concomitant corticosteroids. Approximately 77% (48/62) and 72% (43/60) of patients in the rituximab 500-mg and rituximab 1000-mg groups, respectively, were retreated with a second cycle of rituximab after 24 weeks. Table 1 Patient demographics and characteristics (safety population) at baseline Placebo+MTX (n=63) Rituximab 500 mg+MTX (n=62) Rituximab 1000 mg+MTX (n=60) Female, n (%) 48 (76.2) 45 (72.6) 50 (83.3) Age, mean (SD), years 50.3 (11.9) 48.7 (11.1) 50.7 (11.7) RA duration, mean (SD), years 4.4 (3.1) 4.5 (2.9) 4.9 (2.9) MTX dose, mean (SD), mg/wk 16.8 (3.3) 15.8 (4.0) 15.2 (3.5) Concomitant CS, n (%) 35 (55.6) 33 (53.2) 35 (58.3) SJC, mean (SD) 11.4 (6.1) 12.5 (7.1) 10.9 (5.9) TJC, mean (SD) 14.9 (6.7) 15.2 (7.5) 14.0 (6.9) DAS28-CRP, mean (SD) 5.6 (1.1) 5.6 (1.1) 5.3 (1.0) DAS28-ESR, mean (SD) 6.3 (1.1) 6.3 (1.2) 6.0 (1.1) HAQ-DI, mean (SD) 1.5 (0.8) 1.4 (0.7) 1.3 (0.7) RAMRIS erosion score, mean (SD) 14.1 (13.4) 13.2 (12.0) 12.7 (12.0) CARLOS, mean (SD) 5.9 (9.4) 8.1 (10.4) 7.8 (10.9) RAMRIS synovitis score, mean (SD) 7.4 (4.8) 7.9 (4.0) 8.1 (4.9) RAMRIS osteitis score, mean (SD) 6.1 (6.7) 8.8 (9.0) 6.8 (8.3) Total Genant-modified Sharp radiographic score, mean (SD) 20.2 (18.9) 17.9 (16.6) 19.8 (18.8) Annualised radiographic progression rate, mean (SD) 6.3 (6.7) 6.8 (8.9) 5.7 (7.4) CARLOS, cartilage loss score; CRP, C reactive protein; CS, corticosteroids; DAS28, Disease Activity Score in 28 joints; ESR, erythrocyte sedimentation rate; HAQ-DI, Health Assessment Questionnaire Disability Index; MTX, methotrexate; RA, rheumatoid arthritis; RAMRIS, RA MRI Scoring; SJC, swollen joint count; TJC, tender joint count.

age loss score; CRP, C reactive protein; CS, corticosteroids; DAS28, Disease Activity Score in 28 joints; ESR, erythrocyte sedimentation rate; HAQ-DI, Health Assessment Questionnaire Disability Index; MTX, methotrexate; RA, rheumatoid arthritis; RAMRIS, RA MRI Scoring; SJC, swollen joint count; TJC, tender joint count. MRI analysis The analysis of the primary end point showed significantly less progression in the mean RAMRIS erosion score at week 24 in patients treated with rituximab 1000 mg compared with those treated with placebo (figure 1A). Similar results were observed at week 52. Significant differences were also observed between the rituximab 500-mg group and the placebo group at weeks 24 and 52. The mean change in RAMRIS erosion score at week 12 was not significantly different between either of the rituximab groups and the placebo group. The cumulative distribution plots revealed increased RAMRIS erosion score at week 24 in a greater proportion of patients in the placebo group than in either rituximab group (figure 1B).

hange in RAMRIS erosion score at week 12 was not significantly different between either of the rituximab groups and the placebo group. The cumulative distribution plots revealed increased RAMRIS erosion score at week 24 in a greater proportion of patients in the placebo group than in either rituximab group (figure 1B). Figure 1 Primary end point. (A) Mean change in rheumatoid arthritis MRI Scoring (RAMRIS) erosion score (intent-to-treat (ITT) population). Missing values were imputed using linear extrapolation. Error bars represent the SE of the mean. (B) Cumulative distribution of change in RAMRIS erosion score at week 24. Missing values were imputed using linear extrapolation, ITT population. Broken horizontal lines represent ±SDC (smallest detectable change, determined according to the method of Bruynesteyn, et al.24 SDCs were 1.88 for RAMRIS erosion score, 1.54 for CARLOS, 2.11 for RAMRIS osteitis score and 1.56 for RAMRIS synovitis score).

g values were imputed using linear extrapolation, ITT population. Broken horizontal lines represent ±SDC (smallest detectable change, determined according to the method of Bruynesteyn, et al.24 SDCs were 1.88 for RAMRIS erosion score, 1.54 for CARLOS, 2.11 for RAMRIS osteitis score and 1.56 for RAMRIS synovitis score). Patients treated with rituximab 1000 mg demonstrated a progressively greater decrease in mean RAMRIS synovitis score at weeks 12, 24 and 52, which was significantly greater than placebo at each time point (figure 2A). Patients receiving rituximab 500 mg also showed a progressive decrease in the mean RAMRIS synovitis score at each time point; the decreases were numerically less than those in the rituximab 1000 mg-treated patients and were significantly different from those in the placebo-treated patients at weeks 24 and 52. The rituximab 1000-mg group demonstrated significantly greater reductions in RAMRIS osteitis scores compared with those in the placebo group at weeks 12, 24 and 52; similar results were observed in the rituximab 500-mg group at each time point (figure 2B). Mean cartilage loss scores based on CARLOS increased progressively at weeks 24 and 52 in patients treated with placebo, whereas patients treated with rituximab 1000 mg showed significantly greater improvement compared with those who received placebo (figure 2C) at week 52; a statistically significant difference was not observed at week 24. Patients receiving rituximab 500 mg demonstrated significantly less cartilage loss compared with those in the placebo group at weeks 24 and 52.

mg showed significantly greater improvement compared with those who received placebo (figure 2C) at week 52; a statistically significant difference was not observed at week 24. Patients receiving rituximab 500 mg demonstrated significantly less cartilage loss compared with those in the placebo group at weeks 24 and 52. Figure 2 Mean changes in rheumatoid arthritis MRI Scoring (RAMRIS) synovitis, RAMRIS osteitis and MRI cartilage loss score (CARLOS) (intent-to-treat population). (A) Synovitis. Missing values were imputed using last observation carried forward. Error bars represent the SE of the mean. (B) Osteitis. Missing values were imputed using last observation carried forward. Error bars represent the SE of the mean. (C) Cartilage loss. Error bars represent the SE of the mean. Patients who received rituximab 1000 mg demonstrated significantly better total damage scores compared with those in the placebo group at weeks 24 and 52 (figure 3A). Similar results were observed in the rituximab 500-mg group at weeks 24 and 52. Mean decreases in total inflammation score were significantly greater in the rituximab 1000-mg group compared with those in the placebo group as early as week 12 and were maintained through weeks 24 and 52 (figure 3B). Similar results were demonstrated in the rituximab 500-mg group.

mab 500-mg group at weeks 24 and 52. Mean decreases in total inflammation score were significantly greater in the rituximab 1000-mg group compared with those in the placebo group as early as week 12 and were maintained through weeks 24 and 52 (figure 3B). Similar results were demonstrated in the rituximab 500-mg group. Figure 3 Mean change in total damage and total inflammation scores. (A) Total damage score. Total damage score=erosion score+(2.5×cartilage loss score). Missing values were imputed using linear extrapolation using baseline and week 12 images. Error bars represent the SE of the mean. (B) Total inflammation score. Total inflammation score=osteitis score+(3×synovitis score). Missing values were imputed using linear extrapolation using baseline and week 12 images. Error bars represent the SE of the mean. The proportion of patients with no worsening of RAMRIS erosion score was significantly greater in the rituximab 1000-mg group than in the placebo group at week 24 (table 2) and week 52. Similar effects were observed for the rituximab 500-mg group, although the difference was only statistically significant at the 52-week time point. Table 2 Summary of efficacy outcomes

The proportion of patients with no worsening of RAMRIS erosion score was significantly greater in the rituximab 1000-mg group than in the placebo group at week 24 (table 2) and week 52. Similar effects were observed for the rituximab 500-mg group, although the difference was only statistically significant at the 52-week time point. Table 2 Summary of efficacy outcomes Placebo+MTX (n=63) Rituximab 500 mg+MTX (n=62) p Value* Rituximab 1000 mg+MTX (n=60) p Value† Patients with no newly eroded joints, % Week 24 55.6 77.4 0.011 73.3 0.045 Week 52 60.3 77.4 0.042 66.7 0.455 Patients with no progression of erosions, %‡ Week 24 33.3 50.0 0.055 51.7 0.039 Week 52 27.0 48.4 0.011 55.0 <0.001 Mean change from baseline in Genant-modified Sharp radiographic erosion score Week 24 0.62 0.21 0.049 0.14 0.097 Week 52 0.99 0.34 0.027 0.14 0.003 Mean change from baseline in Genant-modified Sharp radiographic JSN score Week 24 0.14 0.09 0.286 0.16 0.796 Week 52 0.38 0.06 0.003 0.15 0.102 Mean change from baseline in total Genant-modified Sharp radiographic score Week 24 0.76 0.31 0.034 0.30 0.310 Week 52 1.37 0.40 0.010 0.29 0.002 Mean change from baseline in DAS28-ESR Week 24 −0.85 −1.69 0.007 −1.64 0.277 Week 52 −0.81 −2.08 <0.001 −1.90 0.075 Patients with good EULAR response, % Week 24 19.0 29.0 0.017 35.0 <0.001 Week 52 7.9 33.9 <0.001 37.3 <0.001 Patients with moderate EULAR response, % Week 24 22.2 37.1 0.017¶ 42.4 <0.001¶ Week 52 31.7 45.2 <0.001¶ 49.2 <0.001¶ Change from baseline in HAQ-DI score Week 24 −0.19 −0.425 0.026 −0.44 0.778 Week 52 −0.18 −0.520 0.001 −0.42 0.165 Patients achieving ACR20, % Week 24 28.6 51.6 0.003 51.7 0.006 Week 52 28.6 67.7 <0.001 68.3 <0.001 Patients achieving ACR50, % Week 24 11.1 24.2 0.050 26.7 0.013 Week 52 14.3 37.1 0.003 35.0 0.005 Patients achieving ACR70, % Week 24 1.6 11.3 0.036 8.3 0.085 Week 52 6.3 17.7 0.056 16.7 0.049 *p Value for comparison of rituximab 500 mg versus placebo.

24 28.6 51.6 0.003 51.7 0.006 Week 52 28.6 67.7 <0.001 68.3 <0.001 Patients achieving ACR50, % Week 24 11.1 24.2 0.050 26.7 0.013 Week 52 14.3 37.1 0.003 35.0 0.005 Patients achieving ACR70, % Week 24 1.6 11.3 0.036 8.3 0.085 Week 52 6.3 17.7 0.056 16.7 0.049 *p Value for comparison of rituximab 500 mg versus placebo. †p Value for comparison of rituximab 1000 mg versus placebo. ‡No progression defined as a change from baseline in the RAMRIS erosion score of ≤0. ¶ p Values consider the three response levels: good, moderate and no response. ACR 20/50/70, 20%, 50% and 70% improvements in response per the American College of Rheumatology; DAS28, Disease Activity Score in 28 joints; ESR, erythrocyte sedimentation rate; EULAR, European League Against Rheumatism; HAQ-DI, Health Assessment Questionnaire Disability Index; JSN, joint-space narrowing; MTX, methotrexate; RAMRIS, RA MRI Scoring. Radiographic analysis At week 52, the analysis of the total radiographic Genant-modified Sharp score revealed significantly greater inhibition of radiographic damage in patients in the rituximab 1000-mg and 500-mg groups compared with the placebo group, although the study was not powered for the comparison of radiographic end points. The changes in mean erosion score from baseline were significantly lower in the two active treatment groups compared with that in the control group, whereas the changes in mean joint-space-narrowing score were numerically lower in both rituximab groups, but statistically significantly so in the rituximab 500-mg group

. The changes in mean erosion score from baseline were significantly lower in the two active treatment groups compared with that in the control group, whereas the changes in mean joint-space-narrowing score were numerically lower in both rituximab groups, but statistically significantly so in the rituximab 500-mg group Clinical assessment Clinical efficacy outcomes are presented in table 2. At weeks 24 and 52, patients who received rituximab 500 mg demonstrated significantly greater improvements in DAS28-ESR compared with those who received placebo; those who received 1000 mg demonstrated numerically greater improvements in DAS28-ESR scores compared with those who received placebo, but the difference was not statistically significant at either time point. Significantly more patients in both rituximab groups achieved ACR20 and ACR50 compared with patients in the placebo group at weeks 24 and 52. However, ACR70 rates at weeks 24 and 52 in either rituximab group were not consistently improved compared with the rate in the placebo group. At weeks 24 and 52, significantly more patients in the rituximab 1000-mg and 500-mg groups than in the placebo group had moderate or good EULAR responses. Significant improvements in HAQ-DI were seen in the rituximab 500-mg group at weeks 24 and 52. Numerical improvements were seen in the 1000-mg group compared with the placebo group at these time points, although these changes were not statistically significant.

in the placebo group had moderate or good EULAR responses. Significant improvements in HAQ-DI were seen in the rituximab 500-mg group at weeks 24 and 52. Numerical improvements were seen in the 1000-mg group compared with the placebo group at these time points, although these changes were not statistically significant. Safety The overall safety profiles were similar in both rituximab groups and are summarised in table 3. The incidence of AEs reported in the rituximab 1000-mg and 500-mg groups was numerically lower than that reported in the placebo group, as was the incidence of serious AEs per 100 patient-years. The incidence of infections was numerically higher in both rituximab groups compared with that in the placebo group, as was the incidence of serious infections per 100 patient-years. One patient in the rituximab 500-mg group reported a serious soft tissue infection (of suspected bacterial origin), which was treated and resolved after 11 days. Two serious infections were reported in the rituximab 1000-mg group: bronchitis and omphalitis due to Escherichia coli. The two infections resolved following treatment. One endometrial carcinoma was reported in the rituximab 1000-mg group. No deaths and no life-threatening AEs were reported. Additional safety data are provided in online supplementary tables S2 and S3. Table 3 Summary of safety events

Safety The overall safety profiles were similar in both rituximab groups and are summarised in table 3. The incidence of AEs reported in the rituximab 1000-mg and 500-mg groups was numerically lower than that reported in the placebo group, as was the incidence of serious AEs per 100 patient-years. The incidence of infections was numerically higher in both rituximab groups compared with that in the placebo group, as was the incidence of serious infections per 100 patient-years. One patient in the rituximab 500-mg group reported a serious soft tissue infection (of suspected bacterial origin), which was treated and resolved after 11 days. Two serious infections were reported in the rituximab 1000-mg group: bronchitis and omphalitis due to Escherichia coli. The two infections resolved following treatment. One endometrial carcinoma was reported in the rituximab 1000-mg group. No deaths and no life-threatening AEs were reported. Additional safety data are provided in online supplementary tables S2 and S3. Table 3 Summary of safety events Patients with event, n (%) Placebo+MTX (n=63) Rituximab 500 mg+MTX (n=62) Rituximab 1000 mg+MTX (n=60) Any TEAE 41 (65.1) 35 (56.5) 36 (60.0) Mild 20 (31.7) 17 (27.4) 13 (21.7) Moderate 17 (27.0) 18 (29.0) 19 (31.7) Severe 4 (6.3) − 4 (6.7) Treatment-related 14 (22.2) 13 (21.0) 9 (15.0) Any serious TEAE 5 (7.9) 3 (4.8) 4 (6.7) Events/100 PY 12.0 4.9 6.9 Any infection 16 (25.4) 25 (40.3) 27 (45.0) Any serious infection − 1 (1.6) 3 (5.0) Events/100 PY 0.0 1.6 3.4 Death on study − − − MTX, methotrexate; PY, patient-year; TEAE, treatment-emergent adverse event.

eatment-related 14 (22.2) 13 (21.0) 9 (15.0) Any serious TEAE 5 (7.9) 3 (4.8) 4 (6.7) Events/100 PY 12.0 4.9 6.9 Any infection 16 (25.4) 25 (40.3) 27 (45.0) Any serious infection − 1 (1.6) 3 (5.0) Events/100 PY 0.0 1.6 3.4 Death on study − − − MTX, methotrexate; PY, patient-year; TEAE, treatment-emergent adverse event. The incidence of infusion-related reactions decreased from 0%, 4.8% and 15.0% in the placebo, rituximab 500-mg and rituximab 1000-mg groups during the first course of rituximab to 0%, 0% and 5.0% during the second course, respectively. The maximum Common Toxicity Criteria for Adverse Events grade of the 13 total events was moderate. Overall, no safety concerns were raised by the laboratory data. At week 24, five patients in the rituximab 500-mg group (10.6%) and one in the rituximab 1000-mg group (3.8%) were positive for human HACA. At week 52, only one patient (2.8%) remained positive for HACA in the rituximab 500-mg group, whereas two patients (6.5%) remained positive for HACA in the rituximab 1000-mg group.

At week 24, five patients in the rituximab 500-mg group (10.6%) and one in the rituximab 1000-mg group (3.8%) were positive for human HACA. At week 52, only one patient (2.8%) remained positive for HACA in the rituximab 500-mg group, whereas two patients (6.5%) remained positive for HACA in the rituximab 1000-mg group. Discussion In this placebo-controlled, double-blind, study, we used MRI to evaluate changes in structural damage and joint inflammation in MTX-IR patients with active RA who were biologicals-naive and received MTX plus either rituximab or placebo. The mean RAMRIS erosion score progressed in the placebo arm over 52 weeks at a rate of approximately 0.3 RAMRIS units per month, consistent with the rates observed in the placebo arms of other randomised controlled trials of RA using MRI.17 Cartilage loss also progressed at 24 and 52 weeks in patients treated with placebo. Compared with placebo, rituximab 1000 mg significantly reduced MRI erosion at 24 weeks (primary end point) and erosion and cartilage loss at 52 weeks. The rituximab 500-mg dose demonstrated improvements relative to placebo that were generally in the same range as observed with the higher rituximab dose, but the study was not powered to detect differences between the two doses in the observed range. The secondary end points of synovitis, osteitis, cartilage loss, total inflammation and total joint damage scores each improved significantly with rituximab compared with placebo as early as 12 weeks, and improved further at weeks 24 and 52. The proportions of patients with no joint damage progression, with improvements in synovitis and osteitis, and with moderate or good EULAR response were all significantly higher with rituximab than with placebo. For some disease activity indices, such as DAS28 and HAQ-DI, the rituximab 1000-mg dose demonstrated numerically positive trends, which were not always statistically significant.

rovements in synovitis and osteitis, and with moderate or good EULAR response were all significantly higher with rituximab than with placebo. For some disease activity indices, such as DAS28 and HAQ-DI, the rituximab 1000-mg dose demonstrated numerically positive trends, which were not always statistically significant. Safety data were consistent with those previously reported for rituximab in biological-naive patients,3 18 19 and no new safety signals were detected. AEs were predominantly mild, and few severe or serious AEs and no deaths were observed with treatment. No major differences between the safety profiles of the 1000-mg and 500-mg doses were observed. These results are consistent with the findings of previous studies that used radiography to demonstrate inhibition of joint damage progression by rituximab,3 5 20 and may be explained by the inhibitory effect of rituximab treatment on osteoclastogenesis.21 Recent EULAR and ACR recommendations recognise the superiority of MRI to clinical examination at detecting joint inflammation and recommend the use of MRI to predict response to treatment.1 7

ge progression by rituximab,3 5 20 and may be explained by the inhibitory effect of rituximab treatment on osteoclastogenesis.21 Recent EULAR and ACR recommendations recognise the superiority of MRI to clinical examination at detecting joint inflammation and recommend the use of MRI to predict response to treatment.1 7 This study had several strengths. It is the first published report of MRI's ability to discriminate suppression of cartilage loss in a multicentre randomised controlled trial in RA. This is important because exclusion of the assessment of cartilage loss in prior clinical trials has been an obstacle to accepting MRI as a substitute for radiography in clinical trials. Previous studies have demonstrated that articular cartilage loss is at least as important as bone erosion in determining long-term disability in patients with RA,22 and suppression of bone erosion does not always indicate that cartilage loss has also been suppressed.23 Inclusion of the assessment of cartilage loss in this study further allowed determination of total joint damage by MRI, analogous to the Total Sharp Score that is used in RA clinical trials to assess radiographic joint damage. A limitation of this study was that suppression of cartilage loss and radiographic outcomes were not measured at week 12, limiting the ability to compare cartilage loss against bone erosion or discriminate progression between the two imaging techniques. Additionally, although treatment effects in the rituximab 500-mg and 1000-mg groups largely overlapped, in a few of the end points (particularly cartilage loss and joint-space narrowing), one or the other dosing arm did not reach statistical significance compared with placebo. Because this study was not powered to compare the two active treatment arms, additional analyses were not performed to explore this apparent discrepancy. Of note, in the IMAGE study, only the approved 2×1000-mg rituximab dosing group exhibited significant inhibition of radiographic progression compared with the placebo group, whereas those in the rituximab 500-mg group did not—a treatment effect that was robust to several analyses.3 Lastly, it is important to highlight that patients in this study were biological naive and DMARD-IR; therefore, the results cannot be extrapolated to patients with more progressive or refractory disease, such as TNF-IR patients.

the rituximab 500-mg group did not—a treatment effect that was robust to several analyses.3 Lastly, it is important to highlight that patients in this study were biological naive and DMARD-IR; therefore, the results cannot be extrapolated to patients with more progressive or refractory disease, such as TNF-IR patients. In conclusion, this study demonstrated that rituximab significantly reduced erosion and cartilage loss at weeks 24 and 52 in MTX-IR patients with active RA. These changes were preceded by reductions in synovitis and osteitis, and explain radiographic evidence that rituximab+MTX prevents joint damage in patients with active RA. Our results suggest that MRI is a valuable tool for assessing inflammatory and structural damage in patients with established RA receiving rituximab. Supplementary Material Web supplement The authors thank all the investigators and patients involved in RA-SCORE. Contributors: CP conceived and designed the research, was involved in generating data at his clinical research site, assured data collection from the NHIH and analysed and interpreted the data. PE, PPT, MØ, KO, FNS and KP were involved in generating the data at their clinical research sites. JD contributed analysis tools and performed statistical analysis. CB analysed and interpreted the data and performed statistical analysis. LHG and AG analysed and interpreted the data. All authors were involved in writing the manuscript and approved it.

involved in generating the data at their clinical research sites. JD contributed analysis tools and performed statistical analysis. CB analysed and interpreted the data and performed statistical analysis. LHG and AG analysed and interpreted the data. All authors were involved in writing the manuscript and approved it. Funding: This study was funded by Roche. Support for third-party writing assistance for this manuscript, furnished by Vivian Chen, PharmD, of Health Interactions based on the involvement and input of all authors, was provided by F Hoffmann-La Roche. All authors read and approved the final content of this manuscript.

involved in generating the data at their clinical research sites. JD contributed analysis tools and performed statistical analysis. CB analysed and interpreted the data and performed statistical analysis. LHG and AG analysed and interpreted the data. All authors were involved in writing the manuscript and approved it. Funding: This study was funded by Roche. Support for third-party writing assistance for this manuscript, furnished by Vivian Chen, PharmD, of Health Interactions based on the involvement and input of all authors, was provided by F Hoffmann-La Roche. All authors read and approved the final content of this manuscript. Competing interests: CP is a shareholder of Spire Sciences, Past Shareholder of Synarc (currently BioClinica), has undertaken clinical trials and/or provided expert advice for AbbVie, Acerta, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Five Prime, Genentech, Janssen, Medimmune, Merck, Novartis, Pfizer, Rigel, Roche, Salix-Santarus, Sanofi, Samsung, UCB and Vertex, Employee of Spire Sciences, Past Employee of Synarc (currently BioClinica). PE has undertaken clinical trials and provided expert advice for Pfizer, MSD, Abbvie, Novartis, Roche and Bristol-Myers Squibb. PPT has served as a consultant for Roche/Genentech and became an employee of GlaxoSmithKline after completion of this work. JD is a consultant for Abbott, Amgen, AstraZeneca, Biogen-Idec, Bristol-Myers Squibb, BioClinica, Celgene, Centocor, Core Lab Partners, Crescendo, Eli Lilly and Company, Genentech, Genzyme, Merck, Icon Medical Imaging, Novartis, Perceptive Informatics, Pfizer, Rigel, Roche, UCB, VirtualScopics, Wyeth, Employee of Spire Sciences, and Past Employee of Synarc. FNS has received consulting fees from: Roche, Pfizer, UCB, Abbott and Meiji Seika, Speakers bureau fees from: BMS Roche, Pfizer, UCB, Abbott and Meiji Seika. KP has received consulting fees and lecturer/speaker fees from Roche, AbbVie, BMS, Pfizer, Amgen and MSD. M-AB, LHG, CB and AG are employees of F Hoffmann-La Roche.

S has received consulting fees from: Roche, Pfizer, UCB, Abbott and Meiji Seika, Speakers bureau fees from: BMS Roche, Pfizer, UCB, Abbott and Meiji Seika. KP has received consulting fees and lecturer/speaker fees from Roche, AbbVie, BMS, Pfizer, Amgen and MSD. M-AB, LHG, CB and AG are employees of F Hoffmann-La Roche. Patient consent: Obtained. Ethics approval: Independent Ethics Committee or Institutional Review Board. Provenance and peer review: Not commissioned; externally peer reviewed.

years for their timeliness, appropriateness and accuracy, especially in the light of new developments in the field. Such reshaping of the recommendations may also help improving adherence of health professionals to the recommendations32 and adherence of patients to therapies they have agreed upon with their physicians. For all these reasons, a Task Force was convened to re-evaluate the treat-to-target recommendations with the objective of addressing all overarching principles and recommendations individually for their content and contextual positioning as well as evaluating the newest evidence accrued since the development of the 2010 treat-to-target recommendations based on a systematic literature review (SLR).33

The treatment of rheumatoid arthritis (RA) has undergone dramatic changes over the past 20 years, which may be subsumed under five captions: (i) availability of reliable assessment tools for clinical trials and practice;1–5 (ii) appreciation of the importance of early diagnosis and concomitant start of conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy, including their combination with low-dose glucocorticoids;6–10 (iii) recognition of the potential to halt or at least minimise damage progression upon attainment of good clinical states;11 12 (iv) appreciation that methotrexate, if applied in accordance with relevant insights on dose and folate use, is a powerful agent and the anchor drug in RA;13–15 and (v) development and approval of new biologic DMARDs (bDMARDs). In recent years, this knowledge has been further consolidated, not least by virtue of defining a treatment target and applying tight control and respective therapeutic adaptations to reach this target.16–18 This paradigm has been incorporated into the ‘treat-to-target’ recommendations.19 Indeed, this principle is also advocated by recommendations for the management of RA.20–24

ed, not least by virtue of defining a treatment target and applying tight control and respective therapeutic adaptations to reach this target.16–18 This paradigm has been incorporated into the ‘treat-to-target’ recommendations.19 Indeed, this principle is also advocated by recommendations for the management of RA.20–24 In line with all these developments, the main pillars of the 2010 treat-to-target recommendations were the definition of a treatment target, namely remission or at least low-disease activity (LDA); the assessment of disease activity using composite measures that include joint counts; the regular adaptation of therapy if the target is not achieved within a particular timeframe; the accounting for individual patient aspects including risks when pursuing the therapeutic goals; and the shared decision-making with the patient. The treat-to-target (T2T) recommendations are generic as they do not advocate any particular type of intervention, but just the principle that should be adhered to, irrespective of the availability of particular drugs. They were based on the rationale of first defining the aim and then considering how one may generally approach reaching that goal, before defining means to arrive there. Attaining (or not attaining) this target can serve as a benchmark for an individual practice, centre or country. The target was defined as clinical remission or at least low-disease activity since these states convey the best and second best outcomes in RA.25–27 At the time of the formulation of the recommendations, a task force of the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) was still engaged in elaborating new remission criteria that has meanwhile been accomplished;28 therefore, in the treat-to-target and related recommendations, remission originally had been defined in general terms, but reference was made to this activity as an ultimate definition of clinical remission.19 21

ism (EULAR) was still engaged in elaborating new remission criteria that has meanwhile been accomplished;28 therefore, in the treat-to-target and related recommendations, remission originally had been defined in general terms, but reference was made to this activity as an ultimate definition of clinical remission.19 21 There are several reasons to reconsider the treat-to-target recommendations. When they were developed, several of the items were based on expert opinion or indirect support rather than stringent, direct evidence and, therefore, it was deemed advisable to look out for new pieces of evidence for or against one or more of the items, as also stated as research agenda at that time. Beyond this aspect, some criticism had arisen.29 30 While most points of this critique had actually been already quite clearly accounted for in the recommendations or the accompanying text, it indicated that the verbalisation and/or the positioning of some of the recommendations might have not been sufficiently clear. Also, the adherence to the treat-to-target recommendations in clinical practice may be low,31 despite all the evidence regarding the importance of this approach. Therefore, revisiting the formulation of individual recommendations in line with available evidence and/or reassessment of expert opinion seemed desirable. Finally, all recommendations should be revisited every few years for their timeliness, appropriateness and accuracy, especially in the light of new developments in the field. Such reshaping of the recommendations may also help improving adherence of health professionals to the recommendations32 and adherence of patients to therapies they have agreed upon with their physicians.

t recommendations with the objective of addressing all overarching principles and recommendations individually for their content and contextual positioning as well as evaluating the newest evidence accrued since the development of the 2010 treat-to-target recommendations based on a systematic literature review (SLR).33 Methods This endeavour consisted of several stages. Initially, a Steering Committee comprised of rheumatologists from several areas of the world and a patient was brought together in 2012 to discuss the potential need for updating the recommendations. During these deliberations, questions related to the practicability of some of the items; aspects of risks on the way to attain the treatment target; the issue of comorbidities both from the viewpoint of their association with active RA and as potential contraindications for intensifying therapy; the role of work productivity; and reduction or withdrawal of therapy upon achievement of the target were distilled in an iterative discussion process as important themes that had not, or not sufficiently, been addressed in 2010. Also, in the SLR performed for the 2010 recommendations,34 only very few publications had focused on differences between treatment strategies as primary endpoint, namely comparing a treatment strategy towards a particular target with other therapeutic approaches, and these almost exclusively dealt with early but not established RA. As a consequence of these discussions, details for an SLR of studies published between 2008 and 2012 were elaborated and an initial search performed by MSch. When the Steering Committee reconvened at the end of 2012 and discussed these SLR results, it was disappointing to see that evidence for many of the questions addressed was still scarce. Therefore, it was decided to wait for additional information and the re-evaluation of the recommendations was postponed. A new SLR that accounted for the literature accumulated between 2012 and April 2014 was performed in the middle of 2014 by MSt and TS. These results were presented to the Steering Committee.33 Indeed, novel evidence related to the questions posed was found, expanding the data obtained by the initial SLR34 and the SLR performed in 2012.33 At a new meeting, the Steering Committee was informed on the results of the SLRs and subsequently revisited the individual recommendations and performed a preliminary reformulation, where necessary.

lated to the questions posed was found, expanding the data obtained by the initial SLR34 and the SLR performed in 2012.33 At a new meeting, the Steering Committee was informed on the results of the SLRs and subsequently revisited the individual recommendations and performed a preliminary reformulation, where necessary. The committee also evaluated the sequence of the recommendations for logical coherence or risk of being overlooked. Aspects to be discussed in the text accompanying the individual points were documented.

lated to the questions posed was found, expanding the data obtained by the initial SLR34 and the SLR performed in 2012.33 At a new meeting, the Steering Committee was informed on the results of the SLRs and subsequently revisited the individual recommendations and performed a preliminary reformulation, where necessary. The committee also evaluated the sequence of the recommendations for logical coherence or risk of being overlooked. Aspects to be discussed in the text accompanying the individual points were documented. In a next step, the proposal of the Steering Committee was presented to a large Task Force of 33 expert individuals, which comprised rheumatologists from many regions of the world (Australia, Europe, Japan, Latin America and North America), 5 patient representatives who had either been already involved in the development of the original recommendations or were identified as having particular interest in this area of research, and a rheumatology nurse. After presentation of the steering group's proposal and the background for it, three breakout groups were formed to address (a) the overarching principles, (b) recommendations 1–5 and (c) recommendations 6–10. Chaired by a patient representative (group dealing with the overarching principles) and rheumatologists (the other two groups), further discussions took place during these breakout sessions and the proposed wordings reformulated as deemed appropriate, with majority votes where controversy existed. It was agreed that individual items of the 2010 recommendations should only be changed based on new evidence, expansion of knowledge or if the wording appeared not being sufficiently clear. The results obtained by the breakout groups were reported to the whole Task Force, which then discussed these proposals, amended them and arrived at final wordings that were subjected to an anonymous voting process using voting cards. Items that achieved at least a two-third majority (≥67%) were taken as final recommendation in the exact way as they had been worded. Items that did not attain such majority approval straight away were re-discussed, re-formulated and re-voted on, until the majority was achieved.

ymous voting process using voting cards. Items that achieved at least a two-third majority (≥67%) were taken as final recommendation in the exact way as they had been worded. Items that did not attain such majority approval straight away were re-discussed, re-formulated and re-voted on, until the majority was achieved. In a final exercise, the bullet points were sent to each participant and additional members who could not be present at the face-to-face meeting by email to determine the level of agreement using an 11-point numerical rating scale (0=I do not agree at all, 10=I completely agree). At this stage, no changes to the wording could be made unless a mistake had been detected. Also, the final text of the manuscript was sent to all participants for their comments and ultimate approval.

rmine the level of agreement using an 11-point numerical rating scale (0=I do not agree at all, 10=I completely agree). At this stage, no changes to the wording could be made unless a mistake had been detected. Also, the final text of the manuscript was sent to all participants for their comments and ultimate approval. Results The new evidence base The two SLRs revealed a total of 176 T2T-related publications, of which 6 were found to provide new evidence that was useful for the update of the recommendations.33 A few randomised controlled approaches or cohort studies offered direct support, while others supplied indirect evidence found useful to expand the recommendations. Two studies of patients with early RA targeted ‘remission’ by the disease activity score (DAS) or DAS28 compared with usual care;35 36 another study in early RA focused at low-disease activity;37 a further investigation compared two cohorts of patients with early RA, one with a targeted and the other one with a conventional approach;38 and one comparative cohort study addressed treatment to target of DAS28 <2.6 versus conventional therapy in late RA;39 all these studies confirmed that a targeted therapy is superior to conventional therapeutic approaches, now even including a study on late RA.40 Two studies compared treatment approaches targeting good clinical outcomes versus sonographic remission, showing similar outcomes.41 42 One study compared the presence of comorbidities in relation to different definitions of remission and found that with ACR–EULAR remission criteria comorbidities such as osteoporosis were significantly less frequent than with less stringent criteria, and there was even a similar trend for cardiovascular disease,43 in line with data showing that cardiovascular risk is significantly lower with stringent remission than active disease and similar to that of the healthy population.44 Two studies compared different definitions of remission for residual sonographic activity and showed significantly lower power Doppler scores with ACR–EULAR than less stringent definitions.45 46

lar risk is significantly lower with stringent remission than active disease and similar to that of the healthy population.44 Two studies compared different definitions of remission for residual sonographic activity and showed significantly lower power Doppler scores with ACR–EULAR than less stringent definitions.45 46 With this database at hand, the steering committee discussed the limitations of the treat-to-target recommendations and potential means to adapt them. Many themes were addressed: clinical versus ‘imaging’ or ‘laboratory’ remission (the latter meaning remission by non-clinical means); minimisation of comorbidities, especially cardiovascular, but also the risk that LDA or remission may not be targeted by rheumatologists because comorbidities preclude intensifying therapy; individualised therapy; work productivity and work-force maintenance aspects; and factors confounding the treatment target. After the discussions on the SLR, its consequences for the recommendations and the rewording and repositioning proposals in relation to the 2010 recommendations as suggested by the steering committee and in the breakout groups all items underwent voting and the resulting recommendations are shown in table 1; for comparative purposes, the old version is presented in small font. Table 2 reveals the results of the ballots, the levels of evidence and grades of recommendation and the levels of agreement. Table 1 The updated recommendations (2014), including a comparison with the 2010 version

After the discussions on the SLR, its consequences for the recommendations and the rewording and repositioning proposals in relation to the 2010 recommendations as suggested by the steering committee and in the breakout groups all items underwent voting and the resulting recommendations are shown in table 1; for comparative purposes, the old version is presented in small font. Table 2 reveals the results of the ballots, the levels of evidence and grades of recommendation and the levels of agreement. Table 1 The updated recommendations (2014), including a comparison with the 2010 version Overarching principles* 2014 2010† A. The treatment of rheumatoid arthritis must be based on a shared decision between patient and rheumatologist A. The treatment of rheumatoid arthritis must be based on a shared decision between patient and rheumatologist B. The primary goal of treating patients with rheumatoid arthritis is to maximise long-term health-related quality of life through control of symptoms, prevention of structural damage, normalisation of function and participation in social and work-related activities B. The primary goal of treating the patient with rheumatoid arthritis is to maximise long-term health-related quality of life through control of symptoms, prevention of structural damage, normalisation of function and social participation C. Abrogation of inflammation is the most important way to achieve these goals C. Abrogation of inflammation is the most important way to achieve these goals D. Treatment to target by measuring disease activity and adjusting therapy accordingly optimises outcomes in rheumatoid arthritis D. Treatment to target by measuring disease activity and adjusting therapy accordingly optimises outcomes in rheumatoid arthritis Final set of 10 recommendations on treating rheumatoid arthritis to target based on both evidence and expert opinion* 2014 2010 1. The primary target for treatment of rheumatoid arthritis should be a state of clinical remission 1. The primary target for treatment of rheumatoid arthritis should be a state of clinical remission 2. Clinical remission is defined as the absence of signs and symptoms of significant inflammatory disease activity 2. Clinical remission is defined as the absence of signs and symptoms of significant inflammatory disease activity 3. While remission should be a clear target, low-disease activity may be an acceptable alternative therapeutic goal, particularly in long-standing disease 3.

ms of significant inflammatory disease activity 2. Clinical remission is defined as the absence of signs and symptoms of significant inflammatory disease activity 3. While remission should be a clear target, low-disease activity may be an acceptable alternative therapeutic goal, particularly in long-standing disease 3. While remission should be a clear target, based on available evidence low-disease activity may be an acceptable alternative therapeutic goal, particularly in established long-standing disease 4 The use of validated composite measures of disease activity, which include joint assessments, is needed in routine clinical practice to guide treatment decisions 6. The use of validated composite measures of disease activity, which include joint assessments, is needed in routine clinical practice to guide treatment decisions 5 The choice of the (composite) measure of disease activity and the target value should be influenced by comorbidities, patient factors and drug-related risks 9. The choice of the (composite) measure of disease activity and the level of the target value may be influenced by consideration of comorbidities, patient factors and drug-related risks 6. Measures of disease activity must be obtained and documented regularly, as frequently as monthly for patients with high/moderate disease activity or less frequently (such as every six months) for patients in sustained low-disease activity or remission 5. Measures of disease activity must be obtained and documented regularly, as frequently as monthly for patients with high/moderate disease activity or less frequently (such as every 3–6 months) for patients in sustained low-disease activity or remission 7. Structural changes, functional impairment and comorbidity should be considered when making clinical decisions, in addition to assessing composite measures of disease activity 7. Structural changes and functional impairment should be considered when making clinical decisions, in addition to assessing composite measures of disease activity 8. Until the desired treatment target is reached, drug therapy should be adjusted at least every three months* 4. Until the desired treatment target is reached, drug therapy should be adjusted at least every three months 9. The desired treatment target should be maintained throughout the remaining course of the disease 8. The desired treatment target should be maintained throughout the remaining course of the disease 10.

onths* 4. Until the desired treatment target is reached, drug therapy should be adjusted at least every three months 9. The desired treatment target should be maintained throughout the remaining course of the disease 8. The desired treatment target should be maintained throughout the remaining course of the disease 10. The rheumatologist should involve the patient in setting the treatment target and the strategy to reach this target 10. The patient has to be appropriately informed about the treatment target and the strategy planned to reach this target under the supervision of the rheumatologist The actual changes are highlighted in the online supplementary table. *As worded, these recommendations constitute solely a brief summary of the discussions on individual aspects of the Task Force's activity. The Task Force specifies that these recommendations must not be interpreted without taking the respective text accompanying each item into account. †The numbers at the left of the 2010 recommendations refer to the original numbering at that time. Table 2 Evidence, grade of recommendation, agreement and votes for each of the recommendations (as pertinent) Item Category of evidence Grade of recommendation Level of agreement Percentage of votes at last ballot* 1 1b A 9.53±0.80 100 2 2c B 9.50±0.69 100 3 1b, 4† A, D 9.68±0.57  97 4 1b, 4V‡ A, D 9.26±1.13  97 5 4 D 9.18±1.09  67 6 1b, 4§ A, D 9.21±1.09  94 7 4 D 9.47±1.06  67 8 1b, 4¶ A, D 9.08±1.08  67 9 2c B 9.61±0.75  67 10 4 D 9.73±0.77  67 *Most items required just one ballot and none underwent more than two votings.

lot* 1 1b A 9.53±0.80 100 2 2c B 9.50±0.69 100 3 1b, 4† A, D 9.68±0.57  97 4 1b, 4V‡ A, D 9.26±1.13  97 5 4 D 9.18±1.09  67 6 1b, 4§ A, D 9.21±1.09  94 7 4 D 9.47±1.06  67 8 1b, 4¶ A, D 9.08±1.08  67 9 2c B 9.61±0.75  67 10 4 D 9.73±0.77  67 *Most items required just one ballot and none underwent more than two votings. †1b for the evidence that low-disease activity is a good treatment target, but 4 because it is expert opinion that it is an alternative goal for remission. ‡1b for the evidence that the use of composite measures is important compared with routine care, but no large study has compared measures that included joint counts with some that did not; therefore 4 for the joint count part. §1b for the necessity to use composite measures, 4 for some of the time components mentioned. ¶1b for regular adjustment that was mostly done every three months, but 4 for the timelines mentioned, since no comparisons between adjustments at different time points were done. Overarching principles The treatment of RA must be based on a shared decision between patient and rheumatologist. While this principle remained unchanged, it was discussed that the follow-up of patients with RA and therapeutic dialogues are increasingly also involving other healthcare professionals (HCPs) than physicians, particularly specialist nurses. In healthcare systems where this is already established, the shared decision-making also has to include these HCPs, thus involving the whole team in the care of RA. All 33 participants voted in favour of the statement.

also involving other healthcare professionals (HCPs) than physicians, particularly specialist nurses. In healthcare systems where this is already established, the shared decision-making also has to include these HCPs, thus involving the whole team in the care of RA. All 33 participants voted in favour of the statement. The primary goal of treating patients with RA is to maximise long-term health-related quality of life through control of symptoms, prevention of structural damage, normalisation of function and participation in social and work-related activities. Two changes were made to the previous item B: a minor one, where ‘the patient’ was replaced by ‘patients’; but more importantly, the previous item B ended with ‘… social participation’ which was changed to ‘participation in social and work related activities’. It was deemed particularly important to include aspects of work productivity and employment, especially since work participation has been associated with a better quality of life,47 which is also implied by using the term ‘through’. Moreover, participation in work is an important part among the categories of the WHO's International Classification of Functioning, Disability and Health.48 Other aspects mentioned while discussing this item were comorbidities, including osteoporosis and cardiovascular risk, and systemic features of RA, but also the role of comorbidities as contraindication to amend therapy. However, it was decided by majority vote to only mention this in the text accompanying this item as an important consideration when treating RA but not to include it in the current wording of the point, especially also because comorbidity is mentioned specifically in one of the current recommendations (recommendation no. 7).

r, it was decided by majority vote to only mention this in the text accompanying this item as an important consideration when treating RA but not to include it in the current wording of the point, especially also because comorbidity is mentioned specifically in one of the current recommendations (recommendation no. 7). Abrogation of inflammation is the most important way to achieve these goals. This item remained unchanged compared with the 2010 version. As during the deliberations 4 years ago, the term ‘abrogation’ was discussed and also the question raised if the most important aspect was really inflammation, but at the end of these discussions everyone was convinced that this point should remain as it was since there were no data available allowing to make any other conclusion than that interfering with the inflammatory response was of utmost importance for optimal outcomes. Treatment to target by measuring disease activity and adjusting therapy accordingly optimises outcomes in RA. Also, this item remained unchanged compared with 2010; there was no further discussion and full agreement within the Task Force (33 positive votes).

Abrogation of inflammation is the most important way to achieve these goals. This item remained unchanged compared with the 2010 version. As during the deliberations 4 years ago, the term ‘abrogation’ was discussed and also the question raised if the most important aspect was really inflammation, but at the end of these discussions everyone was convinced that this point should remain as it was since there were no data available allowing to make any other conclusion than that interfering with the inflammatory response was of utmost importance for optimal outcomes. Treatment to target by measuring disease activity and adjusting therapy accordingly optimises outcomes in RA. Also, this item remained unchanged compared with 2010; there was no further discussion and full agreement within the Task Force (33 positive votes). Final set of 10 recommendations on treating RA to target based on both evidence and expert opinion* Before addressing the recommendations individually, it was decided to add a footnote (asterisk) to the heading of the table to ensure the recognition that the text accompanying each item is an integral part of the recommendations and that any interpretation that does not account for the information provided in the text should be seen as wrong. The primary target for treatment of RA should be a state of clinical remission. This first item was not changed at all versus 2010 and seen as the cardinal point of the recommendations. Clinical remission has consistently been shown to convey better outcomes than other disease activity states, even low-disease activity.11 25 26 49 Meanwhile, also two studies targeting DAS28<2.6 compared with conventional not DAS28-steered therapy, one in early RA and one in established RA, showed a significant advantage in favour of targeting this activity state.36 39 While the Task Force discussed in depth whether the term ‘clinical remission’ should be changed or expanded to include ‘imaging remission’ or ‘laboratory remission’, there was final agreement on the term clinical remission, especially as defined by the ACR–EULAR remission criteria for clinical trials and practice,28 since the vast majority of the literature, if not the entire inflammatory rheumatology literature addressing ‘hard outcomes’ of RA, like radiographic changes, disability and quality of life, has been based on clinical observations, not on observations using imaging techniques.

iteria for clinical trials and practice,28 since the vast majority of the literature, if not the entire inflammatory rheumatology literature addressing ‘hard outcomes’ of RA, like radiographic changes, disability and quality of life, has been based on clinical observations, not on observations using imaging techniques. Upon fulfilment of clinical remission according to the ACR–EULAR definition, functional and structural outcomes are maximised and only minimal abnormalities can be detected by imaging such as sonography.45 46 50 Also, a first study targeting a clinical low-disease activity state compared with targeting sonographic remission revealed no major differences in clinical or functional outcomes despite the use of low-disease activity rather than ACR–EULAR defined remission as the clinical target.42 On the other hand, some data indicate that there may still be residual active synovitis by sonographic examinations in patients in clinical remission51 and, therefore, further studies on sonography and MRI, especially in relation to important long-term outcomes, need to be awaited. Given all these data,52 imaging remission was not included into the current update of the recommendations, leaving clinical remission as the therapeutic target.

ents in clinical remission51 and, therefore, further studies on sonography and MRI, especially in relation to important long-term outcomes, need to be awaited. Given all these data,52 imaging remission was not included into the current update of the recommendations, leaving clinical remission as the therapeutic target. Clinical remission is defined as the absence of signs and symptoms of significant inflammatory disease activity. Also, this point was not changed. There was a major discussion ongoing as to which remission criteria should be used. Whereas with few exceptions everyone agreed that composite measures, in particular Clinical Disease Activity Index (CDAI), DAS, DAS28 or Simplified Disease Activity Index (SDAI),53 should be generally used to assess disease activity (see also item 4), several participants felt that, despite the existence of the new preliminary ACR–EULAR remission definition,28 one should not dismiss DAS and DAS28 remission, while others were of the opinion that the new definition of remission (Boolean or SDAI-based) should be used, to which the 2010 Task Force had already referred to, in particular given even considerations of its sonographic correlates (see above). It was then argued that the ACR–EULAR remission criteria had been developed for clinical trials, but this view was contended by the fact that also remission definitions for clinical practice (Boolean criteria without C-reactive protein (CRP) and CDAI remission criteria) had been presented in the ACR–EULAR publication.28 Moreover, evidence that the residual disease activity in the presence of DAS28 scores <2.6 is associated with progression of joint damage and some functional impairment has accumulated since the time of formulating the 2010 recommendations. Indeed, patients in DAS28 remission not fulfilling ACR–EULAR remission criteria compared with those achieving ACR–EULAR remission (Boolean- or index-based) may have a large number of residually swollen joints,54–56 show more damage progression, worse physical function, worse quality of life and increased rates of comorbidities.

atients in DAS28 remission not fulfilling ACR–EULAR remission criteria compared with those achieving ACR–EULAR remission (Boolean- or index-based) may have a large number of residually swollen joints,54–56 show more damage progression, worse physical function, worse quality of life and increased rates of comorbidities. DAS28 remission is thus not easily compatible with the term remission.27 46 57–59 Some fears were raised that using stringent remission criteria would allow for achievement by only few patients and might lead to overtreatment, but this view was opposed by pointing to the relatively large frequency of attaining these criteria in clinical practice and trials of patients with early RA.60 61 The significant residual disease activity that can be observed with DAS28<2.6 has been debated for long28 45 46 54 55 62 63 and is associated with progression of joint damage.57 64 Also, a recent publication evaluating several clinical trials addressed the underestimation of disease activity by the DAS28 remission criteria.65 Important in this context is further that the US Food and Drug Administration classifies DAS28<2.6 as reflection of low-disease activity,66 which is in line with all of the above notions. It was further mentioned that clinical remission was mainly a treatment goal for early disease and that there is an alternative target of low-disease activity, especially for established disease (see item 3), while in early disease one would aim for stringent remission with a minimum of residual disease activity. Moreover, since some of the discussions focused on imaging (sonographic) remission that is even more difficult to achieve, stringent clinical remission as defined by ACR–EULAR may currently be the definition best reflecting the wording of item 2, leaving other definitions reflecting low-disease activity as alternative targets (see item 3).

of the discussions focused on imaging (sonographic) remission that is even more difficult to achieve, stringent clinical remission as defined by ACR–EULAR may currently be the definition best reflecting the wording of item 2, leaving other definitions reflecting low-disease activity as alternative targets (see item 3). Another aspect of debate around this recommendation was the term ‘significant’. Some participants suggested to delete the term ‘significant’ and thus just define clinical remission as the ‘absence of signs and symptoms of disease activity’; however, that would have made even the ACR–EULAR remission criteria look insufficiently stringent, as they allow for a single residual swollen and tender joint (Boolean-based and index-based criteria) or possibly two of either plus none of the other joint count (index-based criteria). Thus, it was decided in the course of the deliberations to first vote on the sentence maintaining the term ‘significant’ that indeed received a unanimous result (33 ‘yes’). Notwithstanding all these discussions, maintaining the definition of remission as the ‘absence of signs and symptoms of significant inflammatory disease activity’ has been further supported by the evidence mentioned above since residual joint swelling beyond one or two, as an obvious sign of significant inflammatory activity, is associated with damage progression.57

ng the definition of remission as the ‘absence of signs and symptoms of significant inflammatory disease activity’ has been further supported by the evidence mentioned above since residual joint swelling beyond one or two, as an obvious sign of significant inflammatory activity, is associated with damage progression.57 While remission should be a clear target, low-disease activity may be an acceptable alternative therapeutic goal, particularly in long-standing disease. The meaning of this recommendation remained unchanged, but it was shortened by deleting the insert ‘based on available evidence’ because that evidence had further increased over the last four years, making obsolete to specifically point it out. It was further discussed that comorbidities may be present that might preclude the intensification of therapy to target remission, especially in long-standing disease. However, this aspect was not included here since it was felt that ‘long-standing’ disease in itself inferred not only RA with significant damage but also the potential presence of comorbidities and that this would be dealt with in a subsequent recommendation anyway (no. 5). Moreover, the word ‘particularly’ implied that low-disease activity could also be a target in early disease, although—as the item is worded—low-disease activity is not a preferred state for early disease but may be so more in established RA. Importantly, defining the alternative to remission as being low-disease activity in the context of treatment targets precludes any other state, such as moderate disease activity, as a therapeutic goal, although even this viewpoint is to some extent counterbalanced for exceptional situations by recommendation 7. It was also regarded important to recommend documentation of the chosen treatment target in the files and to share this decision with the patient, in line with overarching principle A (shared decision). Importantly and to reiterate, the Task Force does not insinuate to replace the target of remission by the alternative target of low-disease activity but rather implies that if remission cannot be achieved for any reason (such as in patients with long-standing disease), low-disease activity is an alternative and valid target, but any other state than low-disease activity would usually not be acceptable. However, patient factors, such as comorbidities, have to be taken into account in the course of a shared decision with the patient when defining the treatment target and the way to arrive there.

e activity is an alternative and valid target, but any other state than low-disease activity would usually not be acceptable. However, patient factors, such as comorbidities, have to be taken into account in the course of a shared decision with the patient when defining the treatment target and the way to arrive there. The use of validated composite measures of disease activity, which include joint assessments, is needed in routine clinical practice to guide treatment decisions. The wording of this recommendation has not been changed, but it was shifted upward from its previous position as no. 6. This change in order had two reasons: first, it appeared to be more rational to refer to the means to measure disease activity immediately after having defined the therapeutic targets, namely clinical remission or low-disease activity; second, making this item more visible in the order of recommendations reflects the Task Force's conviction on the importance of regular disease activity assessment by appropriate methods. As before, the vast majority of the Task Force members felt that the measures used should comprise joint counts, and mentioning 'joint assessments' (plural) refers to the evaluation of both swollen and tender joint counts. It has been known for long that swollen joint counts correlate with progression of joint damage,67–70 while tender joint counts relate to physical function.68 The respective instruments have been discussed in a EULAR–ACR publication,71 and the choice of the instrument should be recorded in the files. There was a discussion whether one should also recommend using an instrument purely based on patient-reported outcomes, such as the RAPID3,72 plus a swollen joint count, but this would require the rheumatologist to consider two scores rather than just one and thus would not be in line with the term ‘composite measures…which include joint assessments’. On the other hand, a recent study that compared a score comprising joint counts with one that did not, revealed higher frequencies of low-disease activity with the former, indicating that by using the measure not containing joint counts, patients are at risk of being overtreated when aiming for low-disease activity,73 because a larger number of patients would appear to have moderate or high disease activity than is truly the case according to the composite measure that includes joint counts.

cating that by using the measure not containing joint counts, patients are at risk of being overtreated when aiming for low-disease activity,73 because a larger number of patients would appear to have moderate or high disease activity than is truly the case according to the composite measure that includes joint counts. At this point, it is noteworthy that it is mostly expert view to use composite measures that include joint counts, since no head-to-head study comparing such measures has been performed. However, this expert view is based on the consistently shown relationship between swollen joint counts and damage progression.74

cating that by using the measure not containing joint counts, patients are at risk of being overtreated when aiming for low-disease activity,73 because a larger number of patients would appear to have moderate or high disease activity than is truly the case according to the composite measure that includes joint counts. At this point, it is noteworthy that it is mostly expert view to use composite measures that include joint counts, since no head-to-head study comparing such measures has been performed. However, this expert view is based on the consistently shown relationship between swollen joint counts and damage progression.74 The choice of the (composite) measure of disease activity and the target value should be influenced by comorbidities, patient factors and drug-related risks. This recommendation, previously comprised in no. 9, underwent a change in wording in two respects: first, the prior word ‘may’ was replaced by ‘should’, making a stronger point on the choice of other treatment targets than remission (or even low-disease activity) under certain circumstances (see below); second, old no. 9 stated “…influenced by consideration of co-morbidities,…” while the ‘consideration’ has now been removed and the recommendation calls for adaptation of treatment targets according to the presence of comorbidities, patient factors and drug-related risks. Moreover, this recommendation was shifted from its previous position as no. 9 of 10 to no. 5. Again, logic and the desire to give more prominence and thus attention to this recommendation were driving this decision. Logic, since this item now follows immediately after the recommendation on the importance to apply composite measures of disease activity and brings some respective caveats forward. Since in particular the presence of some comorbidities, such as severe cardiovascular disease, uncontrolled diabetes, or impaired renal or hepatic function, may preclude attempts to change treatment geared at reaching the main treatment target, the therapeutic goal may have to be different in such patients. Similar thoughts pertain to contraindications or safety aspects; if a patient suffers from recurrent infections, one will likely refrain from intensification of therapy to avoid risky overtreatment. Regarding the choice of the composite measure and the potential need to employ other instruments, such as comorbidities that increase or decrease acute phase reactants (which will confound scores that comprise erythrocyte sedimentation rate or CRP), some of our traditional composite measures may not be useful tools and other means may have to be the focus of disease activity assessment in such patients.

nstruments, such as comorbidities that increase or decrease acute phase reactants (which will confound scores that comprise erythrocyte sedimentation rate or CRP), some of our traditional composite measures may not be useful tools and other means may have to be the focus of disease activity assessment in such patients. On the other hand, with some particular aspects accompanying RA, such as pain hypersensitivity, patient-reported outcomes may not reflect the inflammatory events correctly but will likely be overshadowed by the comorbidity; this relates to the patient global assessment, but also to function and quality-of-life questionnaires as well as tender joint counts. Importantly, and in line with what was stated above, the instrument used to assess disease activity and the treatment target should be documented. The discussion partly focused around combining this point with the previous one, but it was felt that they address different issues and that this cautionary recommendation might be ‘diluted’ if it became an appendix of the previous one. Moreover, some criticism had arisen around this particular aspect29 despite its prior existence and, therefore, its presentation as a distinct recommendation was deemed important. It is now less likely to be overlooked. In the course of the discussion, another important point emerged: while comorbidities may preclude intensification of therapy due to perceived risks, some comorbid conditions (such as amyloidosis or cardiovascular disease) are a consequence of active inflammation and, therefore, they may even require to aim for a target of remission without tolerance of low-disease activity; indeed, there has been a significant survival advantage in recent years with modern treatment approaches.75–79 Also, in elderly patients with RA intensive therapy is frequently avoided out of the perception that they may not require it,80 although there is evidence against such contention.81 82 Another ‘patient factor’ to be considered is work capacity and its impairment. Moreover, it needs to be borne in mind that comorbidities and other patient factors may change in the course of the disease and its treatment, which may impact the maintenance of the treatment target as requested in recommendation 9. Thus, overall, this recommendation relates to a personalised approach of the treatment strategy, considering all factors related to the individual patient.

atient factors may change in the course of the disease and its treatment, which may impact the maintenance of the treatment target as requested in recommendation 9. Thus, overall, this recommendation relates to a personalised approach of the treatment strategy, considering all factors related to the individual patient. Measures of disease activity must be obtained and documented regularly, as frequently as monthly for patients with high/moderate disease activity or less frequently (such as every six months) for patients in sustained low-disease activity or remission. There was only a small change regarding this item, which was previously no. 5. It had stated ‘such as every 3–6 months’ for control examinations in patients who sustain the therapeutic target of low-disease activity or remission, maintenance of remission being an important goal. However, 3-month intervals were felt undue for this population of patients, and some rheumatologists may even consider less frequent control examinations than every six months to be appropriate. Nevertheless, assessments at different time points have not been compared and therefore most of these time-related aspects have a low level of evidence, but strong expert opinion with good agreement, as indicated by the 94% positive vote. This recommendation also explicitly calls for documentation of the measure of disease activity chosen in the patient's chart. On the other hand, since with very active disease frequent adaptation of therapy may be needed, the Task Force reiterated the potential need for monthly controls in such situations. Moreover, as will be also stated in a subsequent recommendation (no. 9), the necessity for maintenance of remission (or low-disease activity) is already mentioned at this point in time. However, even patients in sustained remission must be assessed at certain intervals to ensure maintenance of the good outcome and lack of adverse events. In the course of sharing decisions with the patient, it is also important to advise the patient to reach out for the rheumatologist earlier than at the predetermined time point if the condition changes unexpectedly. In many countries, follow-up assessments are undertaken by health professionals other than physicians in the setting of a multidisciplinary care. Irrespective of the assessing person, numerous practice trials have revealed the importance of regular disease activity assessments.

nt if the condition changes unexpectedly. In many countries, follow-up assessments are undertaken by health professionals other than physicians in the setting of a multidisciplinary care. Irrespective of the assessing person, numerous practice trials have revealed the importance of regular disease activity assessments. Without such regular evaluations using respective instruments, patients will be undertreated and therefore may encounter worse structural and functional outcomes, but also more comorbidities. It was also discussed if longer intervals should not be suggested for patients who have reached remission. However, the majority of participants felt that a first achievement of remission may still be a vulnerable situation and longer intervals should only be considered for patients in sustained remission; also the duration to which the term ‘sustained’ would pertain was not clear—3 months or 6 months might be considered as the absolute minimum requirement in this respect.

first achievement of remission may still be a vulnerable situation and longer intervals should only be considered for patients in sustained remission; also the duration to which the term ‘sustained’ would pertain was not clear—3 months or 6 months might be considered as the absolute minimum requirement in this respect. Structural changes and functional impairment and comorbidity should be considered when making clinical decisions, in addition to assessing composite measures of disease activity. ‘…and comorbidity’ was now added to this recommendation to reiterate the importance of considering comorbidities in the context of making clinical decisions. Otherwise, this item points again to the importance of using composite activity measures. However, it also addresses the issue of structural changes since the presence of early joint damage is a risk factor for further damage.22 67 69 In this context, estimation (not scoring) of damage progression may be done upon regular (such as annual) performance of radiographs. On the other hand, no specific imaging method is mentioned in this bullet point and some rheumatologist may wish to assess progression of damage using MRI or sonography, although joint space narrowing that has a particular impact on physical function83 may be more easily discernible on radiographs. Further, impairment of physical function and work performance may sometimes be associated with a residual activity of a functionally important joint (eg, wrist or ankle) despite improvement in (most) other joints; thus, while the overall status may appear good, this impairment may have to direct particular treatment decisions. Importantly, it has also to be borne in mind that functional impairment in patients with RA may not only be due to the joint disease but also a consequence of comorbidities; indeed, even patients in stringent remission may experience high disability scores as a consequence of such concomitant diseases.84–86

decisions. Importantly, it has also to be borne in mind that functional impairment in patients with RA may not only be due to the joint disease but also a consequence of comorbidities; indeed, even patients in stringent remission may experience high disability scores as a consequence of such concomitant diseases.84–86 Until the desired treatment target is reached, drug therapy should be adjusted at least every three months. The wording of this recommendation (originally no. 4) was not changed. Of particular importance, almost all practice trials have shown that patients under routine care that is not informed by a composite measure of disease activity have much worse outcomes than patients in whom treatment decisions are based on the disease activity assessment by such instruments.16 This is an important concept since the observations that routine care that does not apply clinical scoring and a targeted therapeutic approach suggest that patients with RA have been significantly undertreated. The shift to its new positioning, therefore, does not imply that the Task Force did not appreciate this point as sufficiently important to be among the initial items; on the contrary, the Task Force felt, just as before, that this is a key recommendation. However, appropriate adjustments of therapy have already been implied in items 4 and 6, where we advocate guidance of treatment decisions by the use of composite measures and a high frequency of taking these measures in the presence of active disease. ‘Adjust’ is then an expansion of the term ‘guide’, but it does not primarily, let alone exclusively, imply a change of a drug regimen, but also comprises aspects such as dose increases of ongoing therapy (where pertinent) or intra-articular glucocorticoid injections, for example, in the presence of residual joint swelling.

ust’ is then an expansion of the term ‘guide’, but it does not primarily, let alone exclusively, imply a change of a drug regimen, but also comprises aspects such as dose increases of ongoing therapy (where pertinent) or intra-articular glucocorticoid injections, for example, in the presence of residual joint swelling. The recommendation regarding the frequency of treatment adjustments (the verbalisation ‘at least every three months’ includes a higher frequency) is based on the results of strategic clinical trials that showed that adapting therapy every month leads to good outcomes compared with conventional care.16 17 36 39 Recommending adjustments in active disease ‘at least’ every three months, implying that this should not be later, is also based on evidence, since the treatment response at 3 months allows to predict if patients are highly likely or highly unlikely to achieve the treatment target at subsequent points in time.38 87–89 Therefore, adjustments, potentially also a change of the drug regimen, may have to be performed. Importantly, by recommending to see these patients every three months, this item indirectly will also serve the purpose of treatment monitoring and prevention of overtreatment, yet another important aspect in the context of treatment to target. The term adjustment also comprises reduction or even withdrawal of some therapies, when stability of the overall response allows such decision to be made (see also item 9). In any case, if medication is reduced or intervals prolonged, the patients should be carefully watched by composite measures of disease activity to be sure that they do not experience a deterioration of their clinical status.

ies, when stability of the overall response allows such decision to be made (see also item 9). In any case, if medication is reduced or intervals prolonged, the patients should be carefully watched by composite measures of disease activity to be sure that they do not experience a deterioration of their clinical status. The desired treatment target should be maintained throughout the remaining course of the disease. Unchanged compared with 2010 (then no. 8), this item refers to observations that complete halt of joint damage and further improvement of physical function depend on the maintenance of the clinical remission state.11 58 90 Moreover, loss of the targeted good outcome can reignite the process leading to joint damage.91 92 Maintenance of the treatment target does not in itself imply maintenance of treatment; indeed, a number of studies on tapering of therapy, especially dose reduction, interval increases and even withdrawal of biologicals, have been performed since 2010.92–101 These studies indicate that in established RA stopping biologicals leads to very frequent loss of low-disease activity or remission, while dose reduction or spacing of intervals of applications carries less risk of return of active disease. In early disease, the question of successful withdrawal is not yet resolved. Stopping conventional synthetic DMARDs102 is followed by flares more frequently compared with their continuation.103 In this context, the aspect of adherence to therapy has also to be considered since non-adherent patients flare up to four times more frequently than adherent patients,104 pointing to the significant importance of information and shared decision-making with the patients (items A and 10). Safety aspects and drug costs may also have to be taken into consideration in this respect.

to be considered since non-adherent patients flare up to four times more frequently than adherent patients,104 pointing to the significant importance of information and shared decision-making with the patients (items A and 10). Safety aspects and drug costs may also have to be taken into consideration in this respect. The rheumatologist should involve the patient in setting the treatment target and the strategy to reach this target. The involvement of the patient in making decisions and the type of information provided should be recorded, along with the treatment target and the measures to be used during follow-up. The agreed and documented target should be visible in the patient records to every HCP involved in the monitoring of the disease evolution of the individual patient. Compared with previous no. 10, this recommendation has not only been simplified, but a proactive role is now assigned to the rheumatologist (previously: ‘under the supervision of the rheumatologist’). Rheumatologists, but also all other health professionals caring for patients with RA, are reminded that the reasons to propose a particular treatment target and the means to achieve this ought to be not only properly communicated to the patient, but also agreed upon with the patient, in line with respective information on the disease and the benefits and risks of various therapies. Indeed, patients have a wide range of beliefs related to DMARD therapy105 and appropriate communication allows patients to make informed decisions.106 Moreover, adherence to treatment has been clearly shown to depend on the level of information and on a good interaction with the rheumatologist.107 In this context, it also must be reiterated that patients with RA require a multidisciplinary care and that in many countries nurse practitioners/specialists or other health professionals take a very important role in informing, following and managing patients (see also overarching principle A). Offering such care where available, or attempting to establish it, is also part of the overall role of the rheumatologist. This item inherently comprises all aspects of the present recommendations, such as the setting of the treatment target, the means of disease evaluation, the chosen drug and non-medical therapy including their risks, the focus on comorbidities and other patient factors, the follow-up process—all this has to be taken into consideration when the rheumatologist ‘involves’ the patient.

mendations, such as the setting of the treatment target, the means of disease evaluation, the chosen drug and non-medical therapy including their risks, the focus on comorbidities and other patient factors, the follow-up process—all this has to be taken into consideration when the rheumatologist ‘involves’ the patient. Indeed, it may be challenging to explain to a patient whose disease activity has significantly improved that therapy should be intensified—and these recommendations and especially their patient version108 may be helpful to this end. Educational programmes supporting this process need to be expanded. Discussion Like the 2010 ‘treat-to-target’ recommendations, the updated version is aimed at practising rheumatologists and other health professionals caring for patients with RA; official bodies such as governments or payers who may have an interest to assess clinical practice in their environment; but also clinical trialists and regulators, given that strategic trials have meanwhile become a focus of industry-initiated studies after having had a sole investigator initiated nature for long. Patients are another important audience for whom a separate version is planned in line with the 2010 recommendations.108

nt; but also clinical trialists and regulators, given that strategic trials have meanwhile become a focus of industry-initiated studies after having had a sole investigator initiated nature for long. Patients are another important audience for whom a separate version is planned in line with the 2010 recommendations.108 The procedures were initiated by a Steering Committee that adhered to the EULAR operating procedures.109 The Steering Committee solicited the SLRs.33 Based on this new evidence, a large Task Force was convened comprising 43 individuals, of whom 5 were patient representatives and 37 rheumatologists from around the world. Contrasting the previous Task Force, the current one also obtained input from a nurse specialist. As before, the recommendations focused on a treatment target that would allow for an optimal outcome of RA for the individual patient. In contrast to guidance documents on the management of RA with drugs,20 22 the present recommendations are of generic nature and do not address particular agents or classes of drugs. The Task Force was aware that with different accessibilities to certain medications overall outcomes may differ between countries and regions,110 111 but a good outcome can also be attained in a large proportion of patients with easily accessible and affordable therapies, as long as a strategic treatment approach is adhered to.16 112

was aware that with different accessibilities to certain medications overall outcomes may differ between countries and regions,110 111 but a good outcome can also be attained in a large proportion of patients with easily accessible and affordable therapies, as long as a strategic treatment approach is adhered to.16 112 The Task Force revisited the overarching principles and the 10 itemised recommendations and reiterated that a pivotal aspect in the care of RA is the shared decision-making with the patient. The whole set presented is framed by this aspect, with overarching principle A introducing it and item 10 calling again for the involvement of the patient in setting the goals and the strategy. Overarching principle B has been amended to now include work participation since this is not only an important aspect related to overall quality of life,47 but an important outcome that can be increasingly achieved with modern therapeutic strategies.

the involvement of the patient in setting the goals and the strategy. Overarching principle B has been amended to now include work participation since this is not only an important aspect related to overall quality of life,47 but an important outcome that can be increasingly achieved with modern therapeutic strategies. All Task Force members agreed unanimously that abrogation of inflammation (overarching principle C) and thus reaching a state of clinical remission (recommendation 1) is the most important goal in the treatment of RA, at least in its early stages, meaning 'the absence of signs and symptoms of significant inflammatory disease activity' (recommendation 2). The new ACR–EULAR remission definitions provide the assessment tools that account for this principle. Less stringent criteria comprise patients who have significant residual inflammation, less functional improvement and more damage progression, while potentially more stringent targets, such as remission by sonography, while having been discussed, have to await conclusive evidence of better outcomes compared with the stringent ACR–EULAR clinical criteria. Indeed, recommendations 1 and 2 remained unchanged from the 2010 version, but are now supported by more direct and indirect evidence.28 33 39 46 49 57 64 65

remission by sonography, while having been discussed, have to await conclusive evidence of better outcomes compared with the stringent ACR–EULAR clinical criteria. Indeed, recommendations 1 and 2 remained unchanged from the 2010 version, but are now supported by more direct and indirect evidence.28 33 39 46 49 57 64 65 Also, recommendation 3, namely that low-disease activity constitutes the alternative for remission, has not been changed and was regarded equally important as item 1 by the Task Force. This is particularly true for patients with long-standing disease who will mostly not be able to achieve clinical remission. Indeed, low-disease activity is the second best state, leading to much better functional and structural as well as work-related outcomes than moderate let alone high-disease activity.11 25 26 Indeed, most evidence for the benefit of targeting a good therapeutic outcome compared with conventional care exists for the low-disease activity state target. Having defined low-disease activity as the alternative target to remission implies that any higher disease activity state would not be an acceptable outcome. However, this conclusion is pertinent to the care of uncomplicated RA and may have to be adjusted in line with recommendation 5, when comorbidity, drug-related risks or other patient factors mandate to refrain from intensifying therapy to reach the most desired target. Likewise, while usually composite measures of disease activity that include joint counts, such as DAS, DAS28, CDAI or SDAI, should be employed to assess disease activity during follow-up (recommendation 4); other instruments may be a better choice to evaluate disease activity if one or more components of the composite measures are confounded by non-RA-related factors, especially comorbidities such as exaggerated pain sensitivity (fibromyalgia); this aspect is encompassed in item 5. On the other hand, in the course of caring for our patients we need to bear in mind that drugs are not the only therapeutic approach, and sometimes interventions, such as physiotherapy, surgical procedures to prevent tendon rupture or a particular focus on footcare,113 may be helpful and important.

compassed in item 5. On the other hand, in the course of caring for our patients we need to bear in mind that drugs are not the only therapeutic approach, and sometimes interventions, such as physiotherapy, surgical procedures to prevent tendon rupture or a particular focus on footcare,113 may be helpful and important. Recommendation 6 addresses the need for regular assessment of disease activity and its documentation. The major change here is the deletion of a 3-month assessment if the treatment target is maintained; the Task Force felt that once the desired state is achieved for prolonged periods of time, less frequent assessments, such as every six -months (or less), is sufficient. The term ‘sustained’ is important in this respect since if the targeted status is achieved for the first time additional control examinations to ensure maintenance of the therapeutic success are usually needed. Recommendation 7 now refers to comorbidity in addition to structural damage progression and functional impairment. Usually, joint damage will not progress in sustained clinical remission but may increase slightly in low-disease activity. Thus, addressing destruction may be particularly pertinent to a state of low-disease activity that, should damage be rapidly progressing or functional impairment increase, may require intensification of therapy. However, comorbidity may also require adaptation of treatment, such as withdrawal or dose reduction of certain agents. On the other hand, it should be borne in mind that some comorbidities may be a consequence of inflammation and their prevention may require more intensive therapy.

y require intensification of therapy. However, comorbidity may also require adaptation of treatment, such as withdrawal or dose reduction of certain agents. On the other hand, it should be borne in mind that some comorbidities may be a consequence of inflammation and their prevention may require more intensive therapy. As recommended in item 8, the adjustment of therapy in accordance with disease activity under the provisos discussed above is a pivotal item in the treatment strategy. It was shifted from position 4 to 8 for two reasons: first, it is only logical that before making treatment decisions disease activity has to be assessed and all factors pertaining to the treatment decision, starting with the target and ending with thoughtfulness regarding disease activity assessment, that is, recommendations 1–7, have to be accounted for; second, the need to control disease by therapeutic adaptations is implicitly included in several of the prior recommendations, namely items 4–6 (disease activity assessment), but also in items 1–3 (treatment target): how else than by treatment adaptation would one usually reach the treatment target? All the evidence currently available relates to such therapeutic adjustments at 1-to-3-month intervals—this is the foundation of treatment success, based on regular disease activity assessment and definition of a treatment target.33 The subsequent recommendation relates to the maintenance of the treatment target and implicitly includes the possibility to taper therapy by reducing dose or expanding intervals between applications, whether csDMARDs or bDMARDs.

ccess, based on regular disease activity assessment and definition of a treatment target.33 The subsequent recommendation relates to the maintenance of the treatment target and implicitly includes the possibility to taper therapy by reducing dose or expanding intervals between applications, whether csDMARDs or bDMARDs. During the 5 years since the first formulation of the recommendations, we have witnessed an increasing proportion of patients in low-disease activity or remission, both in clinical trials and observational studies, especially when the treat-to-target strategy is employed.92 99 100 114–117 The amended set of recommendations may allow for even further improvement as we have addressed aspects of work productivity and comorbidities more clearly and have strengthened the advice to not only evaluate disease activity but also record it in conjunction with recording the treatment target and strategy as well as the information given to the patient. This documentation is of particular importance in settings where patients are seen by different rheumatologists in the course of their disease, but are also a good prompt in all situations of interactions between patients with RA and health professionals.

et and strategy as well as the information given to the patient. This documentation is of particular importance in settings where patients are seen by different rheumatologists in the course of their disease, but are also a good prompt in all situations of interactions between patients with RA and health professionals. The updated recommendations constitute a major advancement when compared with the 2010 version because several of the items are now based on much better evidence. In particular, the SLR has now revealed evidence for the validity and effectiveness of the T2T approach also in patients with established RA (before evidence existed only for early RA); for remission as a treatment target (rather than only low-disease activity as before); and for the effect of a T2T approach on working ability. In addition, several items were strengthened by the new evidence. Overall, this also led to a dramatic change in the level of evidence: while originally only two recommendations had an evidence level of 1 or 2, now 7 of them are based on such high levels. Moreover, four recommendations in 2010 had levels of agreement of <9.0, while now all recommendations achieved agreement levels of ≥9.0, indicating that the members of the Task Force felt much more confident with the 2014 recommendations than was the case a few years ago. Moreover, the updated recommendations focus more strongly than the original version on the individual patient level since they more clearly address aspects of daily life that patients are rooted in, such as return to work, as well as comorbidity. They continue to emphasise the importance of shared decision-making with the patient. All this is also reflected in the algorithm depicting the recommendations in a graphic way (figure 1).

since they more clearly address aspects of daily life that patients are rooted in, such as return to work, as well as comorbidity. They continue to emphasise the importance of shared decision-making with the patient. All this is also reflected in the algorithm depicting the recommendations in a graphic way (figure 1). Figure 1 Algorithm of treating rheumatoid arthritis (RA) to target based on the updated recommendations provided in the table 1 and discussed in detail in the 'Results' section. Indicated as separate threads are the main target (remission and sustained remission) and the alternative target (low-disease activity in patients with long-term disease and sustained low-disease activity), but the approaches to attain the targets and sustain them are essentially identical. Adaptation of therapy should be usually done by performing control examinations with appropriate frequency and using composite disease activity measures that comprise joint counts, but should take comorbidities and other patient factors into account. Setting the target as well start and adaptation of therapy should be done as a shared decision with the patient.

e by performing control examinations with appropriate frequency and using composite disease activity measures that comprise joint counts, but should take comorbidities and other patient factors into account. Setting the target as well start and adaptation of therapy should be done as a shared decision with the patient. The research agenda for a potential next revision of these recommendations is inherent in the open question discussed before. To name a few: (i) Is attaining imaging remission superior to stringent clinical remission (ACR–EULAR) regarding structural and functional outcomes? (ii) If imaging remission provides statistically superior radiographic and functional outcomes compared with stringent clinical remission, is it of clinical significance that makes it worth the effort and risk of controlling patients regularly by sonography and intensifying therapy? (iii) Which measures of disease activity could be reliably used to evaluate patients with RA with particular pain sensitivity? (iv) Is monthly adaptation of therapy16 superior to adaptations done every three months?118 (v) How much improvement in outcomes do well informed patients experience compared with less informed patients? Finally, another important research item relates to (vi) adherence of T2T strategies in clinical practice.

sitivity? (iv) Is monthly adaptation of therapy16 superior to adaptations done every three months?118 (v) How much improvement in outcomes do well informed patients experience compared with less informed patients? Finally, another important research item relates to (vi) adherence of T2T strategies in clinical practice. While recommendations like the ones presented here may be able to summarise the current state of evidence and provide the respective target audience with some guidance, their implementation is difficult to follow. Evaluating the implementation of the T2T strategy is clearly an additional important research aspect of the future. To this end, it must be borne in mind that the success of T2T implementation, even if it constitutes a generic concept, may be different in different areas of the world. However, despite such differences the T2T concept is helpful for all societies, as so nicely summarised in a recent reflection on the situation in Russia.119 In summary, the updated version of the treat-to-target recommendations have brought this guidance document to a new level regarding evidence and agreement and will hopefully be adopted by the community of rheumatologists, patients and the other stakeholders. Supplementary Material Web table Contributors: All authors have participated in the development of the recommendations and/or the generation of the manuscript. No company representative was present at the Task Force meetings or had any influence on the contents of the literature search, the recommendations or this manuscript.

entary Material Web table Contributors: All authors have participated in the development of the recommendations and/or the generation of the manuscript. No company representative was present at the Task Force meetings or had any influence on the contents of the literature search, the recommendations or this manuscript. Funding: This activity was supported by an unrestricted educational grant from Abbvie to the Medical University of Vienna.

entary Material Web table Contributors: All authors have participated in the development of the recommendations and/or the generation of the manuscript. No company representative was present at the Task Force meetings or had any influence on the contents of the literature search, the recommendations or this manuscript. Funding: This activity was supported by an unrestricted educational grant from Abbvie to the Medical University of Vienna. Competing interests: JSS received grant support from and/or provided expert advice to Abbvie, Amgen, Astra-Zeneca, Astro, BMS, Celgene, Chugai, Glaxo, Janssen, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung and UCB; GRB has provided expert advice to AbbVie, Astra-Zeneca, BMS, MSD/Merck, Novartis/Sandoz, Pfizer, Roche and UCB; VB has been Consultant or received Research Grants from Amgen, Abbvie, BMS, UCB, Roche, Genentech, Crescendo, Antares, Medexus, Janssen, Pfizer; MD has participated at symposiums and/or advisory boards organised by Pfizer, Abbvie, UCB, Novartis, BMS, Merck, Lilly, Sanofi and his department has received research grants from Pfizer, Abbvie, UCB, Novartis, BMS, Merck, Lilly, Sanofi; PE has undertaken clinical trials and provided expert advice to Abbvie, BMS, Pfizer, UCB, MSD, Roche, Novartis, Samsung, Takeda and Lilly; TKK has provided expert advice to AbbVie, BMS, Celgene, Celltrion, Eli Lilly, Hospira, Merck Serono, MSD, Novartis, Orion Pharma, Pfizer, Roche, UCB; VN-C has received speaking fees or funding for research projects and attending congresses from Abbvie, BMS, MSD, Novartis, Pfizer, Roche; SO received honorariam for work undertaken in relation to education/training and expert advice from AbbVie, Pfizer, MSD, Regeneron; TT has received grants from Astellas, BMS, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, Pfizer, Santen, Takeda, Teijin, AbbVie, Asahikasei, Taisho Toyama, and SymBio, speaking fees from AbbVie, BMS, Chugai, Eisai, Janssen, Mitsubishi Tanabe, Pfizer, Takeda, Astellas, Diaichi Sankyo ,Celtrion, and Nipponkayaku, and consultant fees from Astra Zeneca, Eli Lilly, Novartis, Mitsubishi Tanabe, Asahi Kasei, Abbivie, Daiichi Sankyo BMS, and Nipponkayaku; DA received grant support from and/or provided expert advice to Abbvie, BMS, Glaxo, Janssen, Medac, MSD, Pfizer, and UCB; JLA has received speaker fees from AbbVie, GSK, MSD, Roche, Pfizer and UCB; and honoraria as expert advisor from Abbvie, GSK, Lilly, Sanofi and UCB; MA gave expert advice on advisory boards and/or had speaking engagements for Abbvie, BMS, Chugai, MSD, Pfizer, Roche and UCB; MB has consulted for Abbvie, Amgen, Astra-Zeneca, BMS, Janssen, Pfizer, Roche/G

AbbVie, GSK, MSD, Roche, Pfizer and UCB; and honoraria as expert advisor from Abbvie, GSK, Lilly, Sanofi and UCB; MA gave expert advice on advisory boards and/or had speaking engagements for Abbvie, BMS, Chugai, MSD, Pfizer, Roche and UCB; MB has consulted for Abbvie, Amgen, Astra-Zeneca, BMS, Janssen, Pfizer, Roche/G enentech, served as speaker for Abbvie and BMS and owns stock from Pfizer and BMS; NB has received fees totalling not more than 10 000 euros from each of the following companies: Abbvie, BMS, Celltrion Healthcare, Grunenthal, Janssen and Pfizer; JB has received advisory/lecture fees from AbbVie, BMS, Eli-Lily, Janssen, Mundipharma, MSD, Pfizer, SUN, UCB and Department grants from AbbVie, BMS, Crescendo, Hemics, Janssen, MSD, Pfizer, UCB; MC Mario H Cardiel has participated as a principal investigator, speaker or advisor for: Abbvie, Amgen, Astellas, Bristol Myers Squibb, Infinity, Pfizer, Roche and Sanofi; BC has received consultancy honoraria or research funding from: AbbVie, BMS, Janssen, Lilly, Merck, Novartis, Pfizer, Roche-Chugai and UCB; JEF received Grants or acted as a speaker or served in advisory boards for Abbvie, Pfizer, UCB, MSD, Jansen, Celgene, Novartis; AG is a Stockholder of AbbVie, Amgen, GSK, J&J, Pfizer, and Regeneron, was Consultant for AbbVie, Amgen, Celgene, Genentech, Horizon, Iroko, Medac, Pfizer, Takeda, and UCB and has served as Speaker for AbbVie, Amgen, Celgene, Genentech, Horizon, Iroko, and Pfizer; JJG-R is on Advisory Boards of Abbvie, BMS, Hospira, Jansen&Jansen, MSD, Pfizer, Roche, and UCB; has received lecture fees from Abbvie, BMS, Pfizer, Roche, and MSD and research grants from Pfizer, MSD, Roche, and UCB; WG served as advisor for or received speaker's honoraria from MSD, Pfizer, Roche, GSK, Lilly, Abbott, UCB; PH served on advisory boards for MSD, Pfizer and Roche and has received honoraria as a speaker from Abbvie, Astra-Zeneca, BMS, MSD, Pfizer and Roche; BH has taken part in advisory boards, received research grants, or speaking engagements for Abbvie, Amgen, BMS, Celgene, Janssen, Pfizer, Roche, UCB; RL has consulted for AbbVie, Ablynx, Amgen, Astra-Zeneca, Bristol Myers Squibb, Janssen (formerly Centocor), Glaxo-Smith-Kline, Novartis, Novo-Nordisk, Merck, Pfizer, Rhoche, Schering-Plough, TiGenics, and UCB, has received research grants from Abbvie, Amgen, Centocor, Novartis, Pfizer, Rhoche, Schering-Plough, and UCB, speakers fees from AbbVie, Amgen, Bristol Myers Squibb, Janssen (formerly Centocor), Merck, Pfizer, Rhoche

Glaxo-Smith-Kline, Novartis, Novo-Nordisk, Merck, Pfizer, Rhoche, Schering-Plough, TiGenics, and UCB, has received research grants from Abbvie, Amgen, Centocor, Novartis, Pfizer, Rhoche, Schering-Plough, and UCB, speakers fees from AbbVie, Amgen, Bristol Myers Squibb, Janssen (formerly Centocor), Merck, Pfizer, Rhoche , Schering-Plough, and UCB and is Director of Rheumatology Consultancy BV, which is a registered company under Dutch law; EMM has participated in advisory board of and/or had speaking fees from MSD, Janssen, BMS, Hospira, Biogen, Abbvie, and Pfizer; PN received funding for clinical research and honoraria for advice and lectures on behalf of Abbvie, Amgen, BMS, Janssen, Novartis, Pfizer, Roche, Sanofi and UCB; MO received consultancy/speaker fees and/or research support form Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Centocor, GSK, Janssen, Merck, Mundipharma, Novartis, Novo, Pfizer, Schering-Plough, Roche, Takeda, and UCB; AÖ has received consulting and expert testimony fees for expert opinion, honoraria for lectures; fees for the development of educational presentations and aids; and travel expenses to attend conferences from all or some of the following: Roche, Chugai, MSD, Abbvie, Pfizer, BMS & Lilly; TS-I has received Honoraria, consultation fees, support for travel, research grants from Abbott, Abbvie, BMS, DiaGraphIT, Eli Lilly, GSK, Hospira, Medac, MSD, Muikkusäätiö, Novo Nordisk, Orion Pharma, Pfizer, Roche, and UCB; AT's Department has received research grants from Abbvie, Pfizer, UCB, Novartis, GSK and MSD; RvV has received Research Support and Grants from AbbVie, BMS, GSK, Pfizer, Roche, and UCB and consultancy or other honoraria from AbbVie, Biotest, BMS, Crescendo, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB, and Vertex; MdW has received Consulting and/or speaker fees from AbbVie, BMS, Eli-Lilly, and Roche; DvdH has received honoraria or grant support from AbbVie, Amgen, AstraZeneca, Augurex, BMS, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GSK, Janssen Biologics, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB, and Vertex and is Director of Imaging Rheumatology bv, The Netherlands.

grant support from AbbVie, Amgen, AstraZeneca, Augurex, BMS, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GSK, Janssen Biologics, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB, and Vertex and is Director of Imaging Rheumatology bv, The Netherlands. Provenance and peer review: Not commissioned; externally peer reviewed.

Introduction In patients with rheumatoid arthritis (RA), early treatment helps prevent structural joint damage, resulting in better long-term outcomes.1–3 Recent studies suggest that a therapeutic ‘window of opportunity’ may exist in the early stages of RA when biologics may be more effective, due to the predominance of inflammation over joint damage.4–6 Certolizumab pegol (CZP) is a PEGylated, Fc-free anti-TNF. The efficacy of CZP in combination with methotrexate (MTX) has been proven in patients with established RA and insufficient response to MTX alone in the pivotal RAPID1 and RAPID2 studies (the mean disease duration was ∼6 years in both trials).7 8 More recently, CZP+MTX was shown to be efficacious in MTX-naïve patients with early RA and poor prognostic factors (C-OPERA study, conducted in Japan; the mean disease duration was ∼4 months),9 justifying the need for a more thorough examination of the efficacy and safety of CZP+MTX in patients with recently diagnosed RA. C-EARLY (NCT01519791) is the first randomised double-blind study to assess the efficacy and safety of CZP+MTX versus placebo (PBO)+MTX treatment over 52 weeks in inducing and sustaining clinical response, and inhibiting radiographic damage, in DMARD-naïve patients with moderate-to-severe, active RA with poor prognostic factors.

NCT01519791) is the first randomised double-blind study to assess the efficacy and safety of CZP+MTX versus placebo (PBO)+MTX treatment over 52 weeks in inducing and sustaining clinical response, and inhibiting radiographic damage, in DMARD-naïve patients with moderate-to-severe, active RA with poor prognostic factors. Methods Patients Eligible patients were DMARD-naïve, diagnosed with RA ≤1 year prior to randomisation, fulfilled the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria10 and had poor prognostic factors for severe disease progression (positive for rheumatoid factor (RF) or anticitrullinated peptide antibody (ACPA) at screening). Patients must have had active RA, defined at screening and baseline (BL) as ≥4 swollen and ≥4 tender joints (out of 28); DAS28(ESR) >3.2 and ESR ≥28 mm/h and/or C reactive protein (CRP) ≥10 mg/L (CRP at screening only). Patients were excluded if they had received treatment for RA with any biologic or non-biologic DMARD therapy, including MTX, prior to BL. Non-steroidal anti-inflammatory drugs and oral corticosteroids (≤10 mg/day prednisone equivalent) were permitted if the BL dose was not exceeded at any point during the study.

Methods Patients Eligible patients were DMARD-naïve, diagnosed with RA ≤1 year prior to randomisation, fulfilled the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria10 and had poor prognostic factors for severe disease progression (positive for rheumatoid factor (RF) or anticitrullinated peptide antibody (ACPA) at screening). Patients must have had active RA, defined at screening and baseline (BL) as ≥4 swollen and ≥4 tender joints (out of 28); DAS28(ESR) >3.2 and ESR ≥28 mm/h and/or C reactive protein (CRP) ≥10 mg/L (CRP at screening only). Patients were excluded if they had received treatment for RA with any biologic or non-biologic DMARD therapy, including MTX, prior to BL. Non-steroidal anti-inflammatory drugs and oral corticosteroids (≤10 mg/day prednisone equivalent) were permitted if the BL dose was not exceeded at any point during the study. Patients with a history of chronic or recurrent infections, serious infections, history of or active tuberculosis (TB), latent TB, malignancy or demyelinating disorders were excluded. Following a protocol amendment, TB testing methods were changed to Interferon Gamma Release Assay (IGRA) testing (QuantiFERON-TB Gold test (ELISpot test if not available)) or a purified protein derivative (PPD) skin test depending on local regulations. Patients were defined as having latent TB if they had a positive IGRA or PPD test (≥5 mm of induration) with chest imaging negative for TB infection, or a severe positive PPD reaction and a positive/indeterminate ELISpot or QuantiFERON test ≤3 months prior to screening.

e (PPD) skin test depending on local regulations. Patients were defined as having latent TB if they had a positive IGRA or PPD test (≥5 mm of induration) with chest imaging negative for TB infection, or a severe positive PPD reaction and a positive/indeterminate ELISpot or QuantiFERON test ≤3 months prior to screening. Study design C-EARLY was a multicentre, double-blind, PBO-controlled, randomised study conducted in Europe, Australia, North America and Latin America at 181 sites (see online supplementary figure S1). Patients were randomised 3:1 to receive CZP (400 mg subcutaneously at Weeks 0, 2, 4, then 200 mg every 2 weeks to Week 52)+MTX or PBO+MTX. Randomisation at Week 0 was performed centrally using an interactive voice and web response system and was stratified by disease duration of >4 months or ≤4 months.5 Following completion of this 52-week study, patients in sustained low disease activity (sLDA; DAS28(ESR) ≤3.2 at both Weeks 40 and 52) were eligible to enter a randomised, double-blind, dose-withdrawal study (C-EARLY Period 2 (NCT01521923); to be completed in 2016). The 3:1 randomisation was used to increase the pool of CZP patients eligible for Period 2 of the study. 10.1136/annrheumdis-2015-209057.supp1Supplementary data Oral MTX was initiated at 10 mg/week and was escalated by 5 mg every 2 weeks, if tolerated, to a maximum of 25 mg/week (minimum 15 mg/week) by Week 8. The maximum-tolerated dose (optimised MTX) was continued through Week 52.

Study design C-EARLY was a multicentre, double-blind, PBO-controlled, randomised study conducted in Europe, Australia, North America and Latin America at 181 sites (see online supplementary figure S1). Patients were randomised 3:1 to receive CZP (400 mg subcutaneously at Weeks 0, 2, 4, then 200 mg every 2 weeks to Week 52)+MTX or PBO+MTX. Randomisation at Week 0 was performed centrally using an interactive voice and web response system and was stratified by disease duration of >4 months or ≤4 months.5 Following completion of this 52-week study, patients in sustained low disease activity (sLDA; DAS28(ESR) ≤3.2 at both Weeks 40 and 52) were eligible to enter a randomised, double-blind, dose-withdrawal study (C-EARLY Period 2 (NCT01521923); to be completed in 2016). The 3:1 randomisation was used to increase the pool of CZP patients eligible for Period 2 of the study. 10.1136/annrheumdis-2015-209057.supp1Supplementary data Oral MTX was initiated at 10 mg/week and was escalated by 5 mg every 2 weeks, if tolerated, to a maximum of 25 mg/week (minimum 15 mg/week) by Week 8. The maximum-tolerated dose (optimised MTX) was continued through Week 52. Patients not achieving sufficient improvement (defined as DAS28(ESR) ≤3.2 and/or ≥1.2-point improvement in DAS28 (ESR) from BL) at Weeks 20 and 24 were withdrawn to allow them to switch to a complementary medication. All study personnel were blinded to treatment, except for a separate unblinded group who supervised/administered the study medication and determined ESR, but had no other involvement.

Patients not achieving sufficient improvement (defined as DAS28(ESR) ≤3.2 and/or ≥1.2-point improvement in DAS28 (ESR) from BL) at Weeks 20 and 24 were withdrawn to allow them to switch to a complementary medication. All study personnel were blinded to treatment, except for a separate unblinded group who supervised/administered the study medication and determined ESR, but had no other involvement. Statistical analysis Full details of all statistical analyses are described in the online supplementary materials. In brief, the sample size was calculated assuming an expected percentage of patients in sustained remission (sREM) at Week 52 of 50% in the CZP+MTX group and 30% in the PBO+MTX group. A minimum of 600 CZP patients and 200 PBO patients were required (for 3:1 randomisation). Hypothesis testing was performed on Week 52 data in a hierarchical manner starting with sREM, followed by the secondary endpoints in the following order: sLDA, ACR50, change from baseline (CFB) in the Health Assessment Questionnaire-Disability Index (HAQ-DI) and CFB in the van der Heijde modified total Sharp score (mTSS). All other statistical analyses are descriptive only. The full analysis set (FAS) was used for all efficacy data, except radiographic data which used the radiographic set (RAD). A logistic regression model was used for the primary and secondary Week 52 analyses and other dichotomous outcomes. CFB in HAQ-DI was analysed using analysis of covariance (ANCOVA) and CFB in mTSS was analysed using ANCOVA on the ranks.

all efficacy data, except radiographic data which used the radiographic set (RAD). A logistic regression model was used for the primary and secondary Week 52 analyses and other dichotomous outcomes. CFB in HAQ-DI was analysed using analysis of covariance (ANCOVA) and CFB in mTSS was analysed using ANCOVA on the ranks. Missing data were imputed using non-responder imputation for analyses on dichotomous outcomes and last observation carried forward for continuous outcomes. Study procedures and evaluations The primary efficacy endpoint was the proportion (%) of patients in sREM (DAS28(ESR) <2.6 at both Weeks 40 and 52). The key secondary endpoint was the proportion (%) of patients in sLDA (DAS28(ESR) ≤3.2 at both Weeks 40 and 52). Other secondary endpoints in the hierarchical testing procedure were ACR50 response, CFB in HAQ-DI and CFB in mTSS, all at Week 52. Secondary outcomes evaluated outside the hierarchical testing procedure included: radiographic non-progression (CFB in mTSS ≤0.5) and the proportion of patients with HAQ-DI normative function (HAQ-DI ≤0.5) at Week 52, CFB in HAQ-DI, DAS28(ESR) and ACR20/50/70 responses, the proportion of patients in remission by ACR/EULAR 2011 criteria,11 DAS28(ESR) <2.6, Clinical Disease Activity Index (CDAI) ≤2.8 and Simplified Disease Activity Index (SDAI) ≤3.3 at Weeks 12, 24 and 52 (additional visits exploratory). For the subgroup analyses, geographical regions were predefined according to their sociodemographic similarity, similar treatment guidelines (ie, EULAR/ACR treatment guidelines) and their similar patient numbers.

Secondary outcomes evaluated outside the hierarchical testing procedure included: radiographic non-progression (CFB in mTSS ≤0.5) and the proportion of patients with HAQ-DI normative function (HAQ-DI ≤0.5) at Week 52, CFB in HAQ-DI, DAS28(ESR) and ACR20/50/70 responses, the proportion of patients in remission by ACR/EULAR 2011 criteria,11 DAS28(ESR) <2.6, Clinical Disease Activity Index (CDAI) ≤2.8 and Simplified Disease Activity Index (SDAI) ≤3.3 at Weeks 12, 24 and 52 (additional visits exploratory). For the subgroup analyses, geographical regions were predefined according to their sociodemographic similarity, similar treatment guidelines (ie, EULAR/ACR treatment guidelines) and their similar patient numbers. Safety analysis included all adverse events (AEs), serious AEs (SAEs) and clinical laboratory measurements. Incidence rates (IRs) were calculated per 100 patient-years (PY), with 95% CIs.

For the subgroup analyses, geographical regions were predefined according to their sociodemographic similarity, similar treatment guidelines (ie, EULAR/ACR treatment guidelines) and their similar patient numbers. Safety analysis included all adverse events (AEs), serious AEs (SAEs) and clinical laboratory measurements. Incidence rates (IRs) were calculated per 100 patient-years (PY), with 95% CIs. Results Patient disposition and BL characteristics Six hundred and sixty patients received CZP+MTX and 219 patients received PBO+MTX (figure 1). Of these, 655 patients in the CZP+MTX group and 213 in the PBO+MTX group were included in the FAS; 528 CZP+MTX and 163 PBO+MTX patients were included in the RAD (a summary of RAD BL radiographic characteristics is listed in online supplementary table S1). The safety set (SS) included 659 CZP+MTX and 217 PBO+MTX patients. In the randomised set (RS), the proportion of patients discontinuing treatment by Week 52 was lower in the CZP+MTX group (24.2%) than in the PBO+MTX group (34.7%). The most common reasons for discontinuation were AEs (7.7% CZP+MTX vs 7.8% PBO+MTX), consent withdrawal (5.3% vs 6.8%) and ‘other’ (including some mandatory withdrawals at Weeks 24 and 36). BL characteristics were balanced between treatment arms, with most patients presenting with high disease activity (DAS28(ESR) >5.1), erosions and positivity for RF and ACPA early in the disease course (within 4 months after diagnosis; table 1). Table 1 Summary of baseline demographics and characteristics

Results Patient disposition and BL characteristics Six hundred and sixty patients received CZP+MTX and 219 patients received PBO+MTX (figure 1). Of these, 655 patients in the CZP+MTX group and 213 in the PBO+MTX group were included in the FAS; 528 CZP+MTX and 163 PBO+MTX patients were included in the RAD (a summary of RAD BL radiographic characteristics is listed in online supplementary table S1). The safety set (SS) included 659 CZP+MTX and 217 PBO+MTX patients. In the randomised set (RS), the proportion of patients discontinuing treatment by Week 52 was lower in the CZP+MTX group (24.2%) than in the PBO+MTX group (34.7%). The most common reasons for discontinuation were AEs (7.7% CZP+MTX vs 7.8% PBO+MTX), consent withdrawal (5.3% vs 6.8%) and ‘other’ (including some mandatory withdrawals at Weeks 24 and 36). BL characteristics were balanced between treatment arms, with most patients presenting with high disease activity (DAS28(ESR) >5.1), erosions and positivity for RF and ACPA early in the disease course (within 4 months after diagnosis; table 1). Table 1 Summary of baseline demographics and characteristics Characteristic PBO+MTX n=213 CZP+MTX n=655 All patients n=868 Mean age, years (SD) 51.2 (13.0) 50.4 (13.6) 50.6 (13.5) Female, n (%) 170 (79.8) 497 (75.9) 667 (76.8) BMI (kg/m2) n 213 652 865 Mean (SD) 28.8 (6.4) 28.0 (6.0) 28.2 (6.1) Region, n (%) Europe and Australia 107 (50.2) 354 (54.0) 461 (53.1) Latin and North America 106 (49.8) 301 (46.0) 407 (46.9) Systemic corticosteroids, n (%)a 64 (29.5) 222 (33.7) 286 (32.6) DAS28(ESR), mean (SD) 6.8 (0.9) 6.7 (0.9) 6.7 (0.9) Moderate disease activity: >3.2 to ≤5.1, n (%) 10 (4.7) 20 (3.1) 30 (3.5) High disease activity: >5.1, n (%) 203 (95.3) 635 (96.9) 838 (96.5) SDAI, mean (SD) 44.8 (13.9) 43.5 (13.6) 43.8 (13.7) CDAI, mean (SD) 42.6 (12.9) 41.3 (12.5) 41.6 (12.6) HAQ-DI, mean (SD) 1.7 (0.6) 1.6 (0.6) 1.6 (0.6) TJC (28 joints), mean (SD) 16.2 (6.5) 15.6 (6.5) 15.8 (6.5) SJC (28 joints), mean (SD) 13.0 (5.6) 12.4 (5.5) 12.5 (5.5) ESR (mm/h), median (min, max) 44.0 (10.0, 135.0) 42.0 (2.0, 150.0) 43.0 (2.0, 150.0) CRP (mg/L), median (min, max) 10.5 (0.3, 243.2) 11.1 (0.2, 231.1) 11.1 (0.2, 243.2) Months since RA was first diagnosed, mean (SD) 2.9 (2.9) 2.9 (4.6) 2.9 (4.3) >4 months, mean (SD) 7.1 (2.5)b 7.6 (7.8)c 7.4 (6.8) ≤4 months, mean (SD) 1.4 (1.0)d 1.4 (1.0)e 1.4 (1.0) Months since first RA symptom, mean (SD)f 9.6 (11.8)g 12.4 (32.3)h 11.7 (28.6) RF positive (≥14 IU/mL), n (%) 206 (96.7) 634 (96.8) 840 (96.8) ACPA positive (≥7 IU/mL), n (%) 182 (85.4) 546 (83.4) 728 (83.9) mTSS, median (min, max) 2.8 (0, 161) 3.0 (0, 130) 3.0 (0, 161) Mean (SD) 8.5 (17.5) 7.2 (13.8) 7.5 (14.8) >4 months, median (min, max) 5.0 (0, 106)i 3.0 (0, 38)j − ≤4 months, median (min, max) 2.3 (0, 161)k 2.5 (0, 130)l − Erosion score, median (min, max) 1.5 (0, 68) 1.5 (0, 69) 1.5 (0, 69) JSN, median (min, max) 0 (0, 94) 0 (0, 76) 0 (0, 94) Presence of erosions, n (%) 169 (79.3) 506 (77.3) 675 (77.8) aSafety set, all other data are reported for full analysis set; bn=56; cn=153; dn=157; en=502; fdata were collected retrospectively; gn=208; hn=631; in=43; jn=118; kn=120 and ln=410.

1.5 (0, 69) 1.5 (0, 69) JSN, median (min, max) 0 (0, 94) 0 (0, 76) 0 (0, 94) Presence of erosions, n (%) 169 (79.3) 506 (77.3) 675 (77.8) aSafety set, all other data are reported for full analysis set; bn=56; cn=153; dn=157; en=502; fdata were collected retrospectively; gn=208; hn=631; in=43; jn=118; kn=120 and ln=410. ACPA, anticitrullinated peptide antibody; CDAI, Clinical Disease Activity Index; CRP, C reactive protein; CZP, certolizumab pegol; HAQ-DI, Health Assessment Questionnaire-Disability Index; JSN, joint space narrowing; mTSS, van der Heijde modified total Sharp score; MTX, methotrexate; PBO, placebo; RA, rheumatoid arthritis; RF, rheumatoid factor; SDAI, Simplified Disease Activity Index. Figure 1 Patient disposition in the C-EARLY study. a‘Other’ included some mandatory withdrawals at Weeks 24 and 36. In addition, two patients in the certolizumab pegol (CZP)+methotrexate (MTX) group were randomised in error, were not dosed and were withdrawn shortly afterwards as screen failures (these two subjects were included in the RS). Patients completed Week 52 if they had a Week 52 visit. FAS, full analysis set; PBO, placebo; RAD, radiographic set; RS, randomised set; SS, safety set. The mean maximum-tolerated dose of MTX (optimised MTX) achieved by Week 8 was 21 mg/week for the CZP group and 22 mg/week for the PBO group.

Figure 1 Patient disposition in the C-EARLY study. a‘Other’ included some mandatory withdrawals at Weeks 24 and 36. In addition, two patients in the certolizumab pegol (CZP)+methotrexate (MTX) group were randomised in error, were not dosed and were withdrawn shortly afterwards as screen failures (these two subjects were included in the RS). Patients completed Week 52 if they had a Week 52 visit. FAS, full analysis set; PBO, placebo; RAD, radiographic set; RS, randomised set; SS, safety set. The mean maximum-tolerated dose of MTX (optimised MTX) achieved by Week 8 was 21 mg/week for the CZP group and 22 mg/week for the PBO group. Efficacy The C-EARLY study met its primary endpoint: treatment of DMARD-naïve patients with RA with CZP+MTX significantly reduced disease activity and sustained clinical response compared with PBO+MTX. At Week 52, sREM was achieved by 28.9% CZP+MTX patients versus 15.0% PBO+MTX patients (p<0.001), while sLDA was achieved by 43.8% CZP+MTX patients versus 28.6% in the PBO+MTX group (p<0.001; figure 2A). The similar results obtained for the sensitivity analysis on the 52-week completer group (sREM: 37.8% CZP+MTX vs 22.4% PBO+MTX, p<0.001; sLDA: 57.4% CZP+MTX vs 42.7% PBO+MTX, p=0.002) suggest that withdrawals did not significantly bias the results.

ZP+MTX patients versus 28.6% in the PBO+MTX group (p<0.001; figure 2A). The similar results obtained for the sensitivity analysis on the 52-week completer group (sREM: 37.8% CZP+MTX vs 22.4% PBO+MTX, p<0.001; sLDA: 57.4% CZP+MTX vs 42.7% PBO+MTX, p=0.002) suggest that withdrawals did not significantly bias the results. Figure 2 (A) Sustained remission (sREM), sustained low disease activity (sLDA) and American College of Rheumatology (ACR)50 response at Week 52. The results are shown for FAS; sREM was defined as DAS28(ESR) <2.6 at Week 40 and Week 52; sLDA was defined as DAS28(ESR) ≤3.2 at Week 40 and Week 52; non-responder imputation was used for missing data and ORs were estimated by logistic regression adjusted for treatment, geographic region and rheumatoid arthritis (RA) disease duration at baseline (BL). (B) The mean change from BL in van der Heijde modified total Sharp score (mTSS), erosion score and joint space narrowing at Week 52. The results are shown for RAD. Missing data (for patients who withdrew early) were imputed by linear extrapolation; data were analysed by analysis of covariance on the ranks with treatment, geographic region and RA disease duration at BL as factors and BL rank value as covariate; p values for erosion score and joint space narrowing are nominal only. CZP, certolizumab pegol; FAS, full analysis set; MTX, methotrexate; OR, odds ratio; PBO, placebo; RAD, radiographic set.

variance on the ranks with treatment, geographic region and RA disease duration at BL as factors and BL rank value as covariate; p values for erosion score and joint space narrowing are nominal only. CZP, certolizumab pegol; FAS, full analysis set; MTX, methotrexate; OR, odds ratio; PBO, placebo; RAD, radiographic set. All secondary endpoints showed statistically significant differences for CZP+MTX versus PBO+MTX at Week 52, respectively: more patients achieved ACR50 response (61.8% vs 52.6%, p=0.023; figure 2A), greater improvements in physical function (CFB in HAQ-DI: −1.00 vs −0.82, p<0.001; HAQ-DI normative function: 48.1% vs 35.7%, p=0.002) and significant inhibition of radiographic progression (CFB in mTSS: 0.2 vs 1.8, p<0.001, figure 2B). Mean changes from BL in joint erosion score and joint space narrowing score were smaller for CZP+MTX versus PBO+MTX (figure 2B). The proportion of patients with radiographic non-progression was significantly higher for CZP+MTX than for PBO+MTX (figure 3). When alternative definitions of remission were used, the proportion of patients in clinical remission at Week 52 by DAS28(ESR) <2.6, ACR/EULAR criteria, CDAI ≤2.8 and SDAI ≤3.3 was significantly greater for CZP+MTX compared with PBO+MTX (figure 4A). Figure 3 Cumulative probability plot of mean change from baseline in van der Heijde modified total Sharp score (mTSS) at Week 52. RAD; linear extrapolation; p values are nominal only. CZP, certolizumab pegol; MTX, methotrexate; PBO, placebo; RAD, radiographic set.

All secondary endpoints showed statistically significant differences for CZP+MTX versus PBO+MTX at Week 52, respectively: more patients achieved ACR50 response (61.8% vs 52.6%, p=0.023; figure 2A), greater improvements in physical function (CFB in HAQ-DI: −1.00 vs −0.82, p<0.001; HAQ-DI normative function: 48.1% vs 35.7%, p=0.002) and significant inhibition of radiographic progression (CFB in mTSS: 0.2 vs 1.8, p<0.001, figure 2B). Mean changes from BL in joint erosion score and joint space narrowing score were smaller for CZP+MTX versus PBO+MTX (figure 2B). The proportion of patients with radiographic non-progression was significantly higher for CZP+MTX than for PBO+MTX (figure 3). When alternative definitions of remission were used, the proportion of patients in clinical remission at Week 52 by DAS28(ESR) <2.6, ACR/EULAR criteria, CDAI ≤2.8 and SDAI ≤3.3 was significantly greater for CZP+MTX compared with PBO+MTX (figure 4A). Figure 3 Cumulative probability plot of mean change from baseline in van der Heijde modified total Sharp score (mTSS) at Week 52. RAD; linear extrapolation; p values are nominal only. CZP, certolizumab pegol; MTX, methotrexate; PBO, placebo; RAD, radiographic set. Figure 4 (A) Proportion of patients in remission (various definitions) at Week 52. The results are shown for FAS, non-responder imputation was used for missing data and ORs are estimated by logistic regression; p values shown are nominal only. (B) The mean change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) by visit. FAS, last observation carried forward; nominal p values are estimated by logistic regression: *p≤0.05, †p<0.001. (C) Proportion of patients in DAS28(ESR) low disease activity by visit. FAS, NRI; nominal p values are estimated by logistic regression: *p≤0.05, †p<0.001. ACR, American College of Rheumatology; CDAI, Clinical Disease Activity Index; CZP, certolizumab pegol; EULAR, European League Against Rheumatism; FAS, full analysis set; LS, least squares; MTX, methotrexate; OR, odds ratio; PBO, placebo; SDAI, Simplified Disease Activity Index.

y logistic regression: *p≤0.05, †p<0.001. ACR, American College of Rheumatology; CDAI, Clinical Disease Activity Index; CZP, certolizumab pegol; EULAR, European League Against Rheumatism; FAS, full analysis set; LS, least squares; MTX, methotrexate; OR, odds ratio; PBO, placebo; SDAI, Simplified Disease Activity Index. Physical function (as measured by HAQ-DI) improved over time in the CZP+MTX group through Week 52; a similar trend was observed in the PBO+MTX group, but with a consistently smaller improvement from BL at each time point (figure 4B and see online supplementary figure S2). A higher proportion of patients achieved LDA (DAS28(ESR) ≤3.2) at individual time points from Week 2 (8.4% vs 1.4%, p=0.002) in the CZP+MTX group compared with the PBO+MTX group, with the absolute percentage and mean difference between groups slowly increasing to Week 52 (54.7% CZP+MTX vs 39.4% PBO+MTX, p<0.001; figure 4C and see online supplementary figure S3). ACR20/50/70 response rates showed a separation of CZP+MTX treatment from PBO+MTX as early as Week 2 and was sustained to Week 52 for ACR50/70 (figure 5). From Week 6 onwards, there was no statistical difference between CZP+MTX and PBO+MTX in ACR20 response.

A higher proportion of patients achieved LDA (DAS28(ESR) ≤3.2) at individual time points from Week 2 (8.4% vs 1.4%, p=0.002) in the CZP+MTX group compared with the PBO+MTX group, with the absolute percentage and mean difference between groups slowly increasing to Week 52 (54.7% CZP+MTX vs 39.4% PBO+MTX, p<0.001; figure 4C and see online supplementary figure S3). ACR20/50/70 response rates showed a separation of CZP+MTX treatment from PBO+MTX as early as Week 2 and was sustained to Week 52 for ACR50/70 (figure 5). From Week 6 onwards, there was no statistical difference between CZP+MTX and PBO+MTX in ACR20 response. Figure 5 Percentage of patients with American College of Rheumatology (ACR)20/50/70 response by visit. The results are shown for FAS and non-responder imputation was used for missing data; nominal p value between groups are estimated by logistic regression: *p≤0.05 at Weeks 2, 4 and 40 (ACR20); †p≤0.05 at Weeks 2, 4, 6, 8, 12, 20, 40 and 52 (ACR50); ‡p≤0.05 at all time points (ACR70). CZP, certolizumab pegol; FAS, full analysis set; MTX, methotrexate; PBO, placebo. A greater decrease in disease activity (measured by CFB in DAS28(ESR)) was observed for CZP+MTX compared with PBO+MTX as early as Week 2 (p<0.001) and continued to Week 52 (the mean CFB (SE) at Week 52: −3.6 (0.1), CZP+MTX vs −3.0 (0.1) PBO+MTX, p<0.001; mean DAS28(ESR) values are shown in table 2). Similar trends from Week 2 through Week 52 were observed in CDAI, SDAI, TJC, SJC, ESR and CRP (table 2). Table 2 Mean disease activity at key study visits

A greater decrease in disease activity (measured by CFB in DAS28(ESR)) was observed for CZP+MTX compared with PBO+MTX as early as Week 2 (p<0.001) and continued to Week 52 (the mean CFB (SE) at Week 52: −3.6 (0.1), CZP+MTX vs −3.0 (0.1) PBO+MTX, p<0.001; mean DAS28(ESR) values are shown in table 2). Similar trends from Week 2 through Week 52 were observed in CDAI, SDAI, TJC, SJC, ESR and CRP (table 2). Table 2 Mean disease activity at key study visits Baseline  Week 2   Week 12  Week 24   Week 52 DAS28(ESR) PBO+MTX (SD) 6.80 (0.91) 5.91 (1.28) 4.43 (1.46) 4.07 (1.44) 3.77 (1.68) CZP+MTX (SD) 6.70 (0.89) 5.06 (1.27) 3.88 (1.44) 3.54 (1.47) 3.11 (1.58) p Value (CFB) − <0.001 <0.001 <0.001 <0.001 CDAI PBO+MTX (SD) 42.64 (12.87) 31.52 (14.85) 17.20 (13.69) 14.11 (12.99) 13.08 (13.72) CZP+MTX (SD) 41.28 (12.52) 23.74 (12.87) 13.33 (11.99) 10.79 (11.27) 8.71 (11.65) p Value (CFB) − <0.001 <0.001 0.001 <0.001 SDAI PBO+MTX (SD) 44.79 (13.91) 33.38 (15.84) 18.32 (14.39) 15.08 (13.65) 14.05 (14.29) CZP+MTX (SD) 43.46 (13.56) 24.41 (13.08) 14.10 (12.63) 11.55 (12.00) 9.43 (12.41) p Value (CFB) − <0.001 <0.001 <0.001 <0.001 TJC PBO+MTX (SD) 16.22 (6.45) 12.37 (7.28) 6.20 (6.32) 5.08 (6.09) 4.76 (6.10) CZP+MTX (SD) 15.61 (6.48) 9.21 (6.76) 5.13 (5.86) 4.08 (5.63) 3.27 (5.39) p Value (CFB) − <0.001 0.055 0.060 0.002 SJC PBO+MTX (SD) 13.04 (5.64) 8.99 (6.02) 5.09 (5.38) 3.89 (4.58) 3.60 (4.51) CZP+MTX (SD) 12.37 (5.48) 6.77 (4.86) 3.25 (4.24) 2.61 (3.83) 2.06 (3.94) p Value (CFB) − <0.001 <0.001 <0.001 <0.001 ESR* PBO+MTX (min, max) 44.00 (10.0, 135.0) 41.00 (4.0, 140.0) 30.00 (1.0, 100.0) 30.00 (2.0, 137.0) 21.50 (2.0, 110.0) CZP+MTX (min, max) 42.00 (2.0, 150.0) 29.00 (1.0, 130.0) 22.00 (0.0, 150.0) 20.00 (0.0, 150.0) 17.00 (0.0, 150.0) p Value (CFB) − <0.001 <0.001 <0.001 <0.001 CRP* PBO+MTX (min, max) 10.51 (0.3, 243.2) 8.35 (0.3, 231.2) 4.69 (0.2, 157.8) 3.74 (0.2, 157.8) 3.96 (0.2, 157.8) CZP+MTX (min, max) 11.14 (0.2, 231.1) 2.17 (0.1, 237.2) 2.33 (0.1, 170.6) 2.05 (0.2, 251.8) 2.07 (0.1, 251.8) p Value (CFB) − <0.001 <0.001 <0.001 <0.001 *Median values; PBO+MTX n=213, CZP+MTX n=655; p values are nominal and describe the difference in CFB between the two study arms at each study visit; LOCF; FAS.

57.8) CZP+MTX (min, max) 11.14 (0.2, 231.1) 2.17 (0.1, 237.2) 2.33 (0.1, 170.6) 2.05 (0.2, 251.8) 2.07 (0.1, 251.8) p Value (CFB) − <0.001 <0.001 <0.001 <0.001 *Median values; PBO+MTX n=213, CZP+MTX n=655; p values are nominal and describe the difference in CFB between the two study arms at each study visit; LOCF; FAS. CFB, change from baseline; CDAI, Clinical Disease Activity Index; CRP, C reactive protein; CZP, certolizumab pegol; ESR, erythrocyte sedimentation rate; FAS, full analysis set; LOCF, last observation carried forward; MTX, methotrexate; PBO, placebo; SDAI, Simplified Disease Activity Index; SJC, swollen joint count; TJC, tender joint count. Subgroup analyses Analyses of subgroups defined by disease duration were carried out on the primary and secondary endpoints. For almost all endpoints, differences were in favour of CZP+MTX for patients with both ≤4 months (75.9% of patients) and >4 months (24.1% of patients) since RA diagnosis, although for ACR50 in the >4 months subgroup, no difference was observed between CZP+MTX and PBO+MTX. Forest plots demonstrated that patients in the ≤4 months subgroup had a greater response to CZP treatment (online supplementary figure S4 presents key categorical endpoints and forest plots; online supplementary figure S5 details mean changes from BL in mTSS; interpretation was limited due to the low number of patients in the >4 months subgroups).

t patients in the ≤4 months subgroup had a greater response to CZP treatment (online supplementary figure S4 presents key categorical endpoints and forest plots; online supplementary figure S5 details mean changes from BL in mTSS; interpretation was limited due to the low number of patients in the >4 months subgroups). According to the logistic regression model, improvements in sREM with CZP+MTX versus PBO+MTX differed by geographical region, with greater improvements seen in Europe and Australia (38.4% CZP+MTX vs 16.8% PBO+MTX; OR=3.07, 95% CI (1.77 to 5.34), p<0.001) than in Latin and North America (17.6% CZP+MTX vs 13.2% PBO+MTX; OR=1.43, 95% CI (0.75 to 2.70), p=0.28). Safety The incidence of AEs was similar for both treatment arms (table 3). The most frequently reported AEs in the CZP+MTX group were nausea, upper respiratory tract infection, urinary tract infection, nasopharyngitis, headache and increased levels of alanine aminotransferase (MedDRA preferred terms). Withdrawals due to AEs occurred for 57 (8.6%) CZP+MTX patients versus 20 (9.2%) PBO+MTX patients. The overall rates of SAEs were similar between treatment groups (CZP+MTX: 70 (10.6%); PBO+MTX: 20 (9.2%)). Table 3 Summary of AEs

Safety The incidence of AEs was similar for both treatment arms (table 3). The most frequently reported AEs in the CZP+MTX group were nausea, upper respiratory tract infection, urinary tract infection, nasopharyngitis, headache and increased levels of alanine aminotransferase (MedDRA preferred terms). Withdrawals due to AEs occurred for 57 (8.6%) CZP+MTX patients versus 20 (9.2%) PBO+MTX patients. The overall rates of SAEs were similar between treatment groups (CZP+MTX: 70 (10.6%); PBO+MTX: 20 (9.2%)). Table 3 Summary of AEs PBO+MTX n=217 CZP+MTX n=659 Total patient-years (PY) at risk (per 100 PY) Median exposure (days) 1.93 6.05 364.0 364.0 n (%) IR (95% CI) n (%) IR (95% CI) Any TEAE (≥5% in any SOC) 158 (72.8) 195.6 (166.3 to 228.7) 525 (79.7) 250.8 (229.8 to 273.2) Blood and lymphatic system disorders 13 (6.0) 6.9 (3.7 to 11.8) 45 (6.8) 7.8 (5.7 to 10.4) Eye disorders 13 (6.0) 7.0 (3.8 to 12.0) 24 (3.6) 4.1 (2.6 to 6.1) Gastrointestinal disorders 53 (24.4) 34.0 (25.5 to 44.5) 206 (31.3) 44.7 (38.8 to 51.3) General disorders and administration site conditions 27 (12.4) 15.4 (10.2 to 22.5) 108 (16.4) 20.2 (16.6 to 24.4) Infections and infestations 76 (35.0) 52.7 (41.5 to 66.0) 298 (45.2) 71.8 (63.9 to 80.4) Injury, poisoning and procedural complications 15 (6.9) 8.2 (4.6 to 13.5) 62 (9.4) 10.9 (8.4 to 14.0) Investigations 42 (19.4) 25.2 (18.2 to 34.1) 137 (20.8) 26.4 (22.1 to 31.2) Metabolism and nutrition disorders 12 (5.5) 6.5 (3.3 to 11.3) 57 (8.6) 10.0 (7.6 to 13.0) Musculoskeletal and connective tissue disorders 36 (16.6) 20.5 (14.4 to 28.4) 114 (17.3) 21.2 (17.5 to 25.5) Nervous system disorders 26 (12.0) 14.9 (9.7 to 21.8) 92 (14.0) 17.1 (13.8 to 20.9) Respiratory, thoracic and mediastinal disorders 22 (10.1) 12.3 (7.7 to 18.6) 76 (11.5) 13.6 (10.7 to 17.0) Skin and subcutaneous tissue disorders 31 (14.3) 18.2 (12.4 to 25.8) 119 (18.1) 22.5 (18.6 to 26.9) Vascular disorders 9 (4.1) 4.8 (2.2 to 9.2) 39 (5.9) 6.7 (4.8 to 9.2) Serious TEAEs, n (%) 20 (9.2) 10.7 (6.6 to 16.6) 70 (10.6) 12.1 (9.4 to 15.2) Infections and infestations 7 (3.2) 3.7 (1.5 to 7.6) 20 (3.0) 3.3 (2.0 to 5.2) Active tuberculosis (TB)* 0 (0.0) − 1 (0.2) 0.2 (0.0 to 0.9) Drug-related TEAEs 69 (31.8) − 278 (42.2) − TEAEs leading to discontinuation 20 (9.2) 10.6 (6.5 to 16.4) 57 (8.6) 9.6 (7.3 to 12.4) TEAEs requiring dose change of MTX 14 (6.5) − 73 (11.1) − TEAEs leading to death 1 (0.5) 0.5 (0.0 to 2.9) 2 (0.3) 0.3 (0.0 to 1.2) *Included both pulmonary TB and gastrointestinal TB in the same patient, diagnosis not confirmed by PCR. SS. n, number of patients reporting ≥1 AE in that category.

(8.6) 9.6 (7.3 to 12.4) TEAEs requiring dose change of MTX 14 (6.5) − 73 (11.1) − TEAEs leading to death 1 (0.5) 0.5 (0.0 to 2.9) 2 (0.3) 0.3 (0.0 to 1.2) *Included both pulmonary TB and gastrointestinal TB in the same patient, diagnosis not confirmed by PCR. SS. n, number of patients reporting ≥1 AE in that category. A TEAE was defined as an AE starting on or after the date of first study medication administration and up to 70 days after the last (most recent) CZP or PBO dose. AEs with a missing relationship to study medication were counted as related. MedDRA v17.0. AE, adverse event; CZP, certolizumab pegol; IR, incidence rate; MTX, methotrexate; PBO, placebo; SOC, system organ class; SS, safety set; TEAE, treatment emergent adverse event. The IR of infection was higher with CZP+MTX (71.8/100 PY, 95% CI (63.9 to 80.4)) than PBO+MTX (52.7/100 PY, 95% CI (41.5 to 66.0)), while the incidence of serious infection was similar in both groups (3.3/100 PY (2.0, 5.2) vs 3.7/100 PY (1.5, 7.6), respectively). The IR of opportunistic infections was higher in the CZP+MTX group (0.2/100 PY, 95% CI (0.0 to 0.9)) with no cases in the PBO+MTX group. One case of disseminated mycobacterium infection was reported in the CZP+MTX group. The mycobacterial strain was not characterised by PCR.

.2) vs 3.7/100 PY (1.5, 7.6), respectively). The IR of opportunistic infections was higher in the CZP+MTX group (0.2/100 PY, 95% CI (0.0 to 0.9)) with no cases in the PBO+MTX group. One case of disseminated mycobacterium infection was reported in the CZP+MTX group. The mycobacterial strain was not characterised by PCR. There were two deaths reported in the CZP+MTX group: one stroke, not considered related to study medication, and one case of disseminated, non-characterised, mycobacterium infection (reported above) primarily localised in the peritoneum (peritonitis with extensive granulomas which stained positive for acid-fast bacillus) with acute respiratory distress, considered by the investigator to be study medication related. Notably, the BL chest X-ray and QuantiFERON test were both negative. The one death in the PBO+MTX group was not considered to be related to study medication (respiratory failure).

ich stained positive for acid-fast bacillus) with acute respiratory distress, considered by the investigator to be study medication related. Notably, the BL chest X-ray and QuantiFERON test were both negative. The one death in the PBO+MTX group was not considered to be related to study medication (respiratory failure). Discussion C-EARLY is the first report of a double-blind, randomised PBO-controlled study assessing the efficacy and safety of CZP+optimised MTX in DMARD-naïve patients with early RA with poor prognostic factors, using a stringent primary outcome of sREM. These data demonstrate that CZP+MTX combination therapy results in a significantly higher proportion of patients achieving sREM than those treated with PBO+MTX, even when using a ‘treat-to-tolerance’ dosing strategy for MTX. Significant improvements in physical function and inhibition of structural damage were observed for CZP+MTX patients. Consequently, for patients with poor prognostic factors for severe disease progression, treating early and aggressively may represent a unique opportunity to achieve maximal clinical benefit.

y for MTX. Significant improvements in physical function and inhibition of structural damage were observed for CZP+MTX patients. Consequently, for patients with poor prognostic factors for severe disease progression, treating early and aggressively may represent a unique opportunity to achieve maximal clinical benefit. Advances in the treatment options for RA, including DMARDs and biologic DMARDs/anti-TNFs, have made clinical remission and radiographic non-progression an achievable target.12 In this study, MTX titration was an important component of treatment and ensured that each patient received the maximum-tolerated MTX dose within the first 8 weeks (between ≥15 and ≤25 mg/week), which we refer to as optimised MTX. To our knowledge, there are no previous studies in MTX-naïve or DMARD-naïve patients with RA where MTX doses have been optimised per-protocol to the levels achieved in C-EARLY. This optimisation may have been responsible, in part, for the response observed for the PBO+MTX and CZP+MTX arms. Optimisation of MTX is not specifically stated in treat-to-target guidelines; however, the mean doses achieved are consistent with international recommendations.13

rotocol to the levels achieved in C-EARLY. This optimisation may have been responsible, in part, for the response observed for the PBO+MTX and CZP+MTX arms. Optimisation of MTX is not specifically stated in treat-to-target guidelines; however, the mean doses achieved are consistent with international recommendations.13 In addition to sREM, this study also evaluated the rate of remission using alternative remission criteria, including DAS28(ESR), CDAI, SDAI and ACR/EULAR criteria, with superior results consistently observed for CZP+MTX over PBO+MTX, supporting the reliability of the recently validated ACR/EULAR remission definition.14 In the C-EARLY trial, despite receiving optimised MTX, a significant proportion of patients were not in remission at Week 52 and an even smaller proportion achieved the primary outcome of sREM. Although patients generally responded well to MTX, which is expected in a DMARD-naïve population of patients, they responded significantly better to CZP, confirming the clinical relevance of our findings.

n of patients were not in remission at Week 52 and an even smaller proportion achieved the primary outcome of sREM. Although patients generally responded well to MTX, which is expected in a DMARD-naïve population of patients, they responded significantly better to CZP, confirming the clinical relevance of our findings. Treatment of patients very early in the pathogenesis of disease is associated with significantly reduced joint destruction and better clinical outcomes.15 The analysis of radiographic data in C-EARLY demonstrates that CZP+MTX therapy can inhibit structural damage significantly more than MTX alone—the percentage of patients with radiographic non-progression was significantly higher in the CZP+MTX group compared with the PBO+MTX group. These results are consistent with the C-OPERA trial in Japanese patients with early RA, which showed that CZP+MTX treatment results in greater inhibition of structural damage and higher clinical remission rates than PBO+MTX.9 While DAS(ESR)<2.6 is a validated measure of clinical remission, consensus has not yet been reached on what constitutes sREM. Until now, the two RA clinical trials that have used sREM as the primary endpoint chose two different definitions. These trials were an open-label study evaluating etanercept tapering6 and an open-label study evaluating abatacept withdrawal.16 We defined sREM as DAS(ESR) <2.6 at Weeks 40 and 52 of treatment. The use of two time points 12 weeks apart was meant to reflect RA management goals used in real-world clinical practice.3

ns. These trials were an open-label study evaluating etanercept tapering6 and an open-label study evaluating abatacept withdrawal.16 We defined sREM as DAS(ESR) <2.6 at Weeks 40 and 52 of treatment. The use of two time points 12 weeks apart was meant to reflect RA management goals used in real-world clinical practice.3 The rates of sREM observed in C-EARLY (28.9% for the CZP+MTX arm) were lower than those initially estimated in the power analysis, which were based on Week 52 remission rates of the etanercept COMET trial (50%).17 This is most likely a consequence of the use of sREM, which is a more rigorous endpoint than clinical remission; this is supported by C-EARLY Week 52 remission rates (42% for the CZP+MTX arm), which were comparable with the remission rates observed in COMET. Overall, the results from C-EARLY suggest that it is possible to achieve sREM more frequently with combined CZP+MTX treatment than with MTX alone in DMARD-naïve patients with RA. Consistent with our results, other studies have demonstrated greater efficacy of anti-TNFs in combination with MTX in early RA. These have included infliximab+MTX,18 adalimumab+MTX,19 etanercept+MTX17 20 and golimumab+MTX.21

frequently with combined CZP+MTX treatment than with MTX alone in DMARD-naïve patients with RA. Consistent with our results, other studies have demonstrated greater efficacy of anti-TNFs in combination with MTX in early RA. These have included infliximab+MTX,18 adalimumab+MTX,19 etanercept+MTX17 20 and golimumab+MTX.21 No new safety signals for CZP+MTX were observed and there was no increase in infection relative to other anti-TNFs in equivalent patient populations with RA.7 8 No increase in overall AEs, SAEs or serious infection events (SIEs) in patients treated with CZP+MTX was seen compared with PBO+MTX. As patients were DMARD-naïve (including MTX) at study entry, their tolerance to MTX treatment could not be anticipated. Thus, the incidence of AEs observed in this study may be partly attributed to the optimised MTX dose. The IR of SIEs with CZP+MTX in this study (3.3/100 PY) was comparable with those reported for other anti-TNFs in combination with MTX in similar patient populations with early RA: adalimumab+MTX (2.9/100 PY)19 and infliximab+MTX (5.4/100 PY).22 The single CZP-related death in this study occurred in a 65-year-old patient of Indian origin, with hypertension and diabetes mellitus. The patient died of cardiorespiratory failure and acute respiratory distress syndrome, secondary to septic shock caused by bowel perforations. Acid-fast bacillus stains of the gut and saliva were positive. This, in conjunction with the gut pathology, led to a diagnosis of disseminated, non-characterised, mycobacterium infection; the QuantiFERON test was negative and there was no PCR confirmation of TB.

, secondary to septic shock caused by bowel perforations. Acid-fast bacillus stains of the gut and saliva were positive. This, in conjunction with the gut pathology, led to a diagnosis of disseminated, non-characterised, mycobacterium infection; the QuantiFERON test was negative and there was no PCR confirmation of TB. We conclude that there is a positive benefit–risk ratio associated with CZP treatment in combination with MTX as initial therapy in DMARD-naïve patients within a year of diagnosis of severe, active RA. The beneficial effect of earlier treatment with biologics specifically in patients with poor prognostic factors may be an important consideration in determining the timing of treatment initiation in specific subgroups of patients. Of note, an aggressive combination of CZP with a ‘treat-to-tolerance’ strategy for MTX at an early stage of disease may contribute to overcome the currently perceived ‘efficacy ceiling’ for anti-TNFs. Correction notice: This article has been corrected since it was published Online First. In the penultimate paragraph of the Discussion section the ‘IR of SIEs with CZP+MTX in this study’ has been corrected to ‘(3.3/100 PY)’. We thank the patients and their caregivers in addition to the investigators and their teams who contributed to this study. The authors acknowledge ‘Matladi N. Ndlovu, PhD, UCB Pharma, Brussels, Belgium, for publication critical review coordination and Costello Medical Consulting, UK, for writing and editorial assistance, which was funded by UCB Pharma.

regivers in addition to the investigators and their teams who contributed to this study. The authors acknowledge ‘Matladi N. Ndlovu, PhD, UCB Pharma, Brussels, Belgium, for publication critical review coordination and Costello Medical Consulting, UK, for writing and editorial assistance, which was funded by UCB Pharma. Contributors: All the authors made substantial contributions to the evaluation of the study results and to the development and review of the manuscript. Funding: UCB Pharma sponsored the study and the development of the manuscript. In addition to content approval by the authors, UCB signed off on the manuscript following a full review to ensure that the data presented in the publication are scientifically, technically and medically supportable and did not contain any information which has the potential to damage the intellectual property of UCB. Additionally, UCB ensured that the publication complies with applicable laws, regulations, guidelines and good industry practice.

presented in the publication are scientifically, technically and medically supportable and did not contain any information which has the potential to damage the intellectual property of UCB. Additionally, UCB ensured that the publication complies with applicable laws, regulations, guidelines and good industry practice. Competing interests: PE received consultancy and speaker's fee from Pfizer, MSD, AbbVie, UCB Pharma, Roche, Bristol-Myers Squibb, Schering-Plough, Novartis and Samsung. COBIII received consultancy fees from UCB Pharma. GRB received consultancy fees from AbbVie, MSD, Pfizer, Roche and UCB Pharma. DEF received research grants from Abbott, Actelion, Amgen, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, NIH, Novartis, Pfizer, Roche/Genentech and UCB Pharma; consultancy fees from Abbott, Actelion, Amgen, Bristol-Myers Squibb, Biogen IDEC, Janssen, Gilead, GlaxoSmithKline, NIH, Novartis, Pfizer, Roche/Genentech and UCB Pharma and other fees from Abbott, Actelion, Amgen, Bristol-Myers Squibb, Biogen, IDEC, Janssen, Gilead, NIH, Roche/Genentech, Abbott, Actelion and UCB Pharma. XM received research grants from Pfizer, GlaxoSmithKline and Roche and consultancy fees from Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Roche, UCB Pharma and Sanofi-Aventis. DvdH received consultancy fees from AbbVie, Amgen, AstraZeneca, Augurex, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GlaxoSmithKline, Janssen, Merck, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB Pharma and Vertex; research grants from AbbVie, Amgen, AstraZeneca, Augurex, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GlaxoSmithKline, Janssen, Merck, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB Pharma and Vertex and is Director of Imaging at Rheumatology BV. RvV received research support from AbbVie, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Roche and UCB Pharma and consultancy fees from AbbVie, Biotest, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Eli-Lilly, Merck, Pfizer, Roche, UCB Pharma and Vertex. CA is an employee of UCB Pharma. IM is an employee of UCB Pharma. OP is an employee of UCB Pharma. DT is an employee of UCB Pharma. BV is an employee of UCB Pharma.

B Pharma and consultancy fees from AbbVie, Biotest, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Eli-Lilly, Merck, Pfizer, Roche, UCB Pharma and Vertex. CA is an employee of UCB Pharma. IM is an employee of UCB Pharma. OP is an employee of UCB Pharma. DT is an employee of UCB Pharma. BV is an employee of UCB Pharma. MEW received research grants from Amgen, Bristol-Myers Squibb, Crescendo Bioscience and UCB Pharma and consultancy fees from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Crescendo Bioscience, Eli-Lilly, MedImmune, Merck, Novartis, Pfizer, Roche and UCB Pharma. Ethics approval: This study was conducted in accordance with the current version of the applicable regulatory and International Conference on Harmonisation (ICH)-Good Clinical Practice (GCP) requirements, the ethical principles that have their origin in the principles of the Declaration of Helsinki and the local laws of the countries involved. Provenance and peer review: Not commissioned; externally peer reviewed.

Introduction Etanercept is a recombinant human tumour necrosis factor (TNF) receptor p75Fc fusion protein. Etanercept is well established and has been widely used in clinical practice for about 15 years, with a well-characterised pharmacological, efficacy and safety profile.1–5 Originally licensed for use in moderate to severe rheumatoid arthritis (RA), the therapeutic indications have been stepwise extended and comprise treatment of patients with polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis and also paediatric psoriasis. Recently, etanercept has been also approved for use in non-radiographic axial spondyloarthritis by the European Medicines Agency (EMA).6 A biosimilar is a biological medicinal product that contains a version of the active substance of an already authorised original biological medicinal product (reference medicinal product). A biosimilar demonstrates similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise.7–9

of the active substance of an already authorised original biological medicinal product (reference medicinal product). A biosimilar demonstrates similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise.7–9 SB4 has been developed as a biosimilar to the reference product etanercept (ETN). SB4 is produced by recombinant DNA technology in Chinese hamster ovary mammalian cell expression system. Similar structural, physicochemical and biological activities of SB4 and ETN have been shown using state-of-the-art analytical methods including peptide mapping, TNF-α binding assay and TNF-α neutralisation cell-based assay. Equivalence in the pharmacokinetics (PK) between SB4 and ETN was demonstrated in a phase I study conducted in healthy male subjects.10 The objective of this study was to compare the efficacy, safety, PK and immunogenicity of SB4 and ETN in patients with RA.

TNF-α binding assay and TNF-α neutralisation cell-based assay. Equivalence in the pharmacokinetics (PK) between SB4 and ETN was demonstrated in a phase I study conducted in healthy male subjects.10 The objective of this study was to compare the efficacy, safety, PK and immunogenicity of SB4 and ETN in patients with RA. Methods Patients Patients aged 18–75 years who have been diagnosed with RA according to the revised 1987 American College of Rheumatology (ACR) criteria for ≥6 months and ≤15 years prior to screening were eligible for the study. Patients had to have active disease defined as ≥6 swollen and ≥6 tender joints and either erythrocyte sedimentation rate (ESR) ≥28 mm/h or serum C reactive protein (CRP) ≥1.0 mg/dL despite methotrexate (MTX) treatment for ≥6 months (stable dose of 10–25 mg/week for ≥4 weeks prior to screening). Non-steroidal anti-inflammatory drugs and oral glucocorticoids (equivalent to ≤10 mg prednisolone) were permitted if received at a stable dose for ≥4 weeks prior to randomisation. Major exclusion criteria consisted of previous treatment with any biological agents, history of lymphoproliferative disease, congestive heart failure (New York Heart Association Class III/IV) or demyelinating disorders, diagnosis of active tuberculosis (TB) and pregnancy or breast feeding at screening. Additional eligibility criteria are listed in online supplementary appendix 1.

Major exclusion criteria consisted of previous treatment with any biological agents, history of lymphoproliferative disease, congestive heart failure (New York Heart Association Class III/IV) or demyelinating disorders, diagnosis of active tuberculosis (TB) and pregnancy or breast feeding at screening. Additional eligibility criteria are listed in online supplementary appendix 1. Study design This phase III, randomised, double-blind, parallel-group study was conducted at 73 centres across 10 countries in Europe, Latin America and Asia. Patients were randomised in a 1:1 ratio to receive 50 mg of either SB4 or ETN (see online supplementary appendix 2). Patients self-administered SB4 or ETN once weekly for up to 52 weeks via subcutaneous injection. All patients had to take MTX (10–25 mg/week) and folic acid (5–10 mg/week) during the study. This study is currently ongoing, and this report represents efficacy data up to 24 weeks of treatment and safety data up to the 24-week interim report data cut-off point (21 July 2014). Study endpoints The primary endpoint was the ACR20 response rate at week 24. Other efficacy endpoints were the ACR50 and ACR70 responses, the numeric index of the ACR response (ACR-N), change in the disease activity score in 28 joints (DAS28) based on ESR, the area under the curve (AUC) of the ACR-N, AUC of the change in DAS28 and the European League Against Rheumatism (EULAR) response. Safety endpoints included incidence of adverse events (AEs) and serious adverse events (SAEs).

CR response (ACR-N), change in the disease activity score in 28 joints (DAS28) based on ESR, the area under the curve (AUC) of the ACR-N, AUC of the change in DAS28 and the European League Against Rheumatism (EULAR) response. Safety endpoints included incidence of adverse events (AEs) and serious adverse events (SAEs). PK analyses were performed in the PK population, which included a subset of patients from pre-designated study sites. Key PK endpoints included serum trough concentration (Ctrough) and area under the concentration–time curve during the dosing interval (AUCτ) at steady state. Serum concentrations were determined using a validated ELISA, and PK parameters were calculated by non-compartmental analyses (WinNonlin V.5.2 or higher, Pharsight, Mountain View, California, USA). Immunogenicity was measured in all patients. The immunogenicity endpoints were incidence of antidrug antibodies (ADAs) and neutralising antibodies (NAbs). A single-assay approach with SB4 tag was used to assess immunogenicity. ADAs were measured using validated electrochemiluminescence immunoassays, and NAbs were measured using a competitive ligand-binding assay. Details on the serum measurement and ADA detection assay can be found in online supplementary appendix 3.

Immunogenicity was measured in all patients. The immunogenicity endpoints were incidence of antidrug antibodies (ADAs) and neutralising antibodies (NAbs). A single-assay approach with SB4 tag was used to assess immunogenicity. ADAs were measured using validated electrochemiluminescence immunoassays, and NAbs were measured using a competitive ligand-binding assay. Details on the serum measurement and ADA detection assay can be found in online supplementary appendix 3. Statistical analyses Sample size was determined using the historical data for the equivalence test. The expected ACR20 response rate at week 24 for both SB4 and ETN was expected to be 60% from the previous ETN pivotal studies.11–13 Based on the expected response rate, the equivalence margin of −15% to 15% at week 24 for ACR20 response rate was calculated in line with the US Food and Drug Administration Guidance for Industry Non-Inferiority Clinical Trials and the Committee for Medicinal Products for Human Use Guideline on the Choice of the Non-inferiority Margin and was also agreed with the regulatory agencies.14 15 Given a two-sided α level of 0.05 and 80% power, the two-sided 15% equivalence margin required 438 patients for the per-protocol set (PPS). Assuming 20% loss of patients from the PPS, the study required a minimum of 548 randomised patients.

Statistical analyses Sample size was determined using the historical data for the equivalence test. The expected ACR20 response rate at week 24 for both SB4 and ETN was expected to be 60% from the previous ETN pivotal studies.11–13 Based on the expected response rate, the equivalence margin of −15% to 15% at week 24 for ACR20 response rate was calculated in line with the US Food and Drug Administration Guidance for Industry Non-Inferiority Clinical Trials and the Committee for Medicinal Products for Human Use Guideline on the Choice of the Non-inferiority Margin and was also agreed with the regulatory agencies.14 15 Given a two-sided α level of 0.05 and 80% power, the two-sided 15% equivalence margin required 438 patients for the per-protocol set (PPS). Assuming 20% loss of patients from the PPS, the study required a minimum of 548 randomised patients. The primary efficacy analysis for ACR20 response at week 24 was performed on the PPS in which patients completed week 24 visit, received 80–120% of both the expected number of study drug administrations and the expected sum of MTX doses, and did not have any major protocol deviations affecting the efficacy assessment. To declare the equivalence between the two treatment groups, the 95% CI of the adjusted treatment difference had to be entirely contained within the equivalence margin of −15% to 15%. The 95% CI of the difference of ACR20 response rates was estimated non-parametrically using the Mantel–Haenszel weights for region while adjusting for the baseline CRP. As a sensitivity analysis, the same analysis was repeated for the full analysis set (FAS) with missing data at week 24 considered as non-responses to explore the robustness of the results. Similar analyses were performed for ACR50 and ACR70 responses at week 24. Other secondary endpoints are summarised descriptively.

. As a sensitivity analysis, the same analysis was repeated for the full analysis set (FAS) with missing data at week 24 considered as non-responses to explore the robustness of the results. Similar analyses were performed for ACR50 and ACR70 responses at week 24. Other secondary endpoints are summarised descriptively. In addition, the exponential time–response model for ACR20 response rate was used to investigate the treatment difference during the time course of the study up to week 24.16 Details on the time–response model are provided in online supplementary appendix 4. Safety and immunogenicity endpoints were analysed descriptively on the safety set that included all patients who received at least one dose of study drug. PK endpoints were summarised descriptively on the PK population who had at least one PK sample collected. The analyses were performed using SAS V.9.2 software (SAS Institute, Cary, North Carolina, USA). Results Patient disposition and baseline characteristics Patient screening began in June 2013, and the 24-week evaluation of the last patient occurred in April 2014. Overall, 777 patients were screened, of whom 596 patients were randomised. A total of 551 patients completed 24 weeks of treatment and 481 (80.7%) patients were included in the PPS (75 patients were excluded from the PPS due to protocol deviations, see online supplementary table S1). Patients withdrew before week 24 mainly due to AEs (3.7%) and withdrawal of consent (2.7%) (figure 1). The demographic and baseline disease characteristics were comparable between treatment groups (table 1).

the PPS (75 patients were excluded from the PPS due to protocol deviations, see online supplementary table S1). Patients withdrew before week 24 mainly due to AEs (3.7%) and withdrawal of consent (2.7%) (figure 1). The demographic and baseline disease characteristics were comparable between treatment groups (table 1). Table 1 Baseline demographics and disease characteristics

the PPS (75 patients were excluded from the PPS due to protocol deviations, see online supplementary table S1). Patients withdrew before week 24 mainly due to AEs (3.7%) and withdrawal of consent (2.7%) (figure 1). The demographic and baseline disease characteristics were comparable between treatment groups (table 1). Table 1 Baseline demographics and disease characteristics SB4 50 mg ETN 50 mg Total N=299 N=297 N=596 Age (years), mean (SD) 52.1 (11.72) 51.6 (11.63) 51.8 (11.67) Age group, n (%) <65 years 253 (84.6) 262 (88.2) 515 (86.4) ≥65 years 46 (15.4) 35 (11.8) 81 (13.6) Gender n (%) Male 50 (16.7) 44 (14.8) 94 (15.8) Female 249 (83.3) 253 (85.2) 502 (84.2) Race, n (%) White 279 (93.3) 273 (91.9) 552 (92.6) American Indian or Alaskan Native 5 (1.7) 7 (2.4) 12 (2.0) Asian 11 (3.7) 13 (4.4) 24 (4.0) Other 4 (1.3) 4 (1.3) 8 (1.3) Weight (kg), mean (SD) 72.5 (15.93) 71.0 (14.63) 71.8 (15.30) Height (cm), mean (SD) 164.4 (8.78) 164.4 (8.55) 164.4 (8.66) BMI (kg/m2), mean (SD) 26.8 (5.51) 26.3 (5.30) 26.6 (5.41) Disease duration (years), mean (SD) 6.0 (4.20) 6.2 (4.41) 6.1 (4.30) Duration of MTX use (months), mean (SD) 48.2 (39.87) 47.1 (40.77) 47.7 (40.29) MTX dose (mg/week), mean (SD) 15.6 (4.52) 15.5 (4.60) 15.5 (4.56) Swollen joint count (0–66), mean (SD) 15.4 (7.48) 15.0 (7.30) 15.2 (7.39) Tender joint count (0–68), mean (SD) 23.5 (11.90) 23.6 (12.64) 23.5 (12.26) HAQ-DI (0–3), mean (SD) 1.49 (0.553) 1.50 (0.560) 1.50 (0.556) Physician global assessment VAS (0–100), mean (SD) 62.2 (15.09) 63.2 (14.76) 62.7 (14.92) Subject global assessment VAS (0–100), mean (SD) 61.7 (18.97) 63.0 (17.70) 62.4 (18.35) Subject pain assessment VAS (0–100), mean (SD) 61.8 (20.22) 62.3 (19.22) 62.1 (19.71) DAS28 (ESR), mean (SD) 6.5 (0.91) 6.5 (0.88) 6.5 (0.89) C reactive protein (mg/dL), mean (SD) 1.5 (2.00) 1.3 (1.60) 1.4 (1.81) Erythrocyte sedimentation rate (mm/h), mean (SD) 46.5 (22.10) 46.4 (22.62) 46.5 (22.34) Rheumatoid factor positive, n (%) 237 (79.3) 231 (77.8) 468 (78.5) BMI, body mass index; DAS28, disease activity score in 28 joints; ETN, reference product etanercept; ESR, erythrocyte sedimentation rate; HAQ-DI, Health Assessment Questionnaire-Disability Index; MTX, methotrexate; VAS, visual analogue scale.

.5 (22.34) Rheumatoid factor positive, n (%) 237 (79.3) 231 (77.8) 468 (78.5) BMI, body mass index; DAS28, disease activity score in 28 joints; ETN, reference product etanercept; ESR, erythrocyte sedimentation rate; HAQ-DI, Health Assessment Questionnaire-Disability Index; MTX, methotrexate; VAS, visual analogue scale. Figure 1 Summary of patient disposition. A total of 777 patients were screened and 181 patients were excluded mainly due to meeting the exclusion criteria. Multiple screening failure reasons were possible. All patients randomised were included in the full analysis set and the safety set. Of the 551 patients who completed 24 weeks of treatment, 481 patients were included in the per-protocol set. ETN, reference product etanercept. Efficacy The ACR20 response rate at week 24 in the PPS was 78.1% for SB4 and 80.3% for ETN. The 95% CI of the adjusted difference (SB4—ETN) in ACR20 response rate was within the predefined equivalence margin of −15% to 15% in both the PPS (95% CI −9.41% to 4.98%) and FAS (95% CI −5.24% to 9.07%), indicating therapeutic equivalence between SB4 and ETN (figure 2). The time–response models of SB4 and ETN up to week 24 in the PPS were estimated to be equivalent since the treatment difference in terms of the two-norm difference was 12.7 and the 95% CI was −4.6 to 30.0, where the upper limit 30.0 was less than the pre-specified equivalence margin of 83.28 (figure 3).

ETN (figure 2). The time–response models of SB4 and ETN up to week 24 in the PPS were estimated to be equivalent since the treatment difference in terms of the two-norm difference was 12.7 and the 95% CI was −4.6 to 30.0, where the upper limit 30.0 was less than the pre-specified equivalence margin of 83.28 (figure 3). Figure 2 American College of Rheumatology (ACR) response rates at week 24. The adjusted treatment difference and its 95% CI were analysed with baseline C reactive protein as a covariate and stratified by region. (A) ACR 20% (ACR20) response rates of SB4 and etanercept (ETN) in the per-protocol set and full analysis set. (B) ACR50 response rates of SB4 and ETN in the per-protocol set and full analysis set. (C) ACR70 response rates of SB4 and ETN in the per-protocol set and full analysis set. *One patient from the SB4 group was excluded from the FAS due to missing efficacy data at baseline. Figure 3 Estimated time–response curves of American College of Rheumatology 20% (ACR20) response rate up to week 24 in the per-protocol set. For details of the estimation process, please refer to the main text. ETN, reference product etanercept. The ACR50 and ACR70 response rates at week 24 in the PPS and FAS were equivalent between SB4 and ETN. The ACR50 response rate was 46.6% vs 42.3%, and the ACR70 response rate was 25.5% vs 22.6% in the PPS for SB4 and ETN, respectively, as shown in figure 2.

Figure 3 Estimated time–response curves of American College of Rheumatology 20% (ACR20) response rate up to week 24 in the per-protocol set. For details of the estimation process, please refer to the main text. ETN, reference product etanercept. The ACR50 and ACR70 response rates at week 24 in the PPS and FAS were equivalent between SB4 and ETN. The ACR50 response rate was 46.6% vs 42.3%, and the ACR70 response rate was 25.5% vs 22.6% in the PPS for SB4 and ETN, respectively, as shown in figure 2. Subgroup analyses on the ACR response rates in PPS showed comparable results regardless of ADA status. The proportion of patients who achieved ACR20 response rate in patients with ADA-negative results was 78.0% in SB4 and 81.5% in ETN (95% CI −11.12% to 3.99%) (see online supplementary table S2). The mean improvement in DAS28 from baseline was 2.6 and 2.5 at week 24 in SB4 and ETN, respectively (95% CI −0.14 to 0.28) (figure 4A). The proportion of patients achieving good or moderate EULAR response (figure 4B), low-disease activity score or remission (figure 4C) at week 24 according to DAS28 were similar between SB4 and ETN. The ACR-N at week 24 was 45.0% in SB4 and 43.7% in ETN. The AUC of ACR-N up to week 24 (5822.2 vs 5525.0) and the AUC of change in DAS28 from baseline up to week 24 (358.3 vs 343.5) were comparable between SB4 and ETN.

tivity score or remission (figure 4C) at week 24 according to DAS28 were similar between SB4 and ETN. The ACR-N at week 24 was 45.0% in SB4 and 43.7% in ETN. The AUC of ACR-N up to week 24 (5822.2 vs 5525.0) and the AUC of change in DAS28 from baseline up to week 24 (358.3 vs 343.5) were comparable between SB4 and ETN. Figure 4 Changes over time in the disease activity score in 28 joints (DAS28) and European League Against Rheumatism (EULAR) responses at week 24 in the full analysis set. (A) Change in DAS28 up to week 24. (B) EULAR response based on DAS28. (C) Proportion of patients achieving low-disease activity score (LDAS) defined as DAS28 ≤3.2 and remission defined as DAS28 ≤2.6. ETN, reference product etanercept. Safety Overall, 165 (55.2%) patients in SB4 and 173 (58.2%) patients in ETN reported at least one treatment-emergent adverse event (TEAE). Frequently occurring TEAEs by preferred term are shown in table 2, and the most frequently reported TEAE were upper respiratory tract infection (7.0%) and alanine aminotransferase increased (5.0%) in the SB4 and injection site erythema (11.1%), upper respiratory tract infection (5.1%) and nasopharyngitis (5.1%) in ETN. Most of the TEAEs were mild to moderate in severity, and TEAEs considered related to the study drug were reported in 83 (27.8%) and 106 (35.7%) patients for SB4 and ETN, respectively. Serious TEAEs were reported in 13 patients each in SB4 and ETN and 34 patients discontinued treatment due to TEAE (15 (5.0%) patients vs 19 (6.4%) patients).

e mild to moderate in severity, and TEAEs considered related to the study drug were reported in 83 (27.8%) and 106 (35.7%) patients for SB4 and ETN, respectively. Serious TEAEs were reported in 13 patients each in SB4 and ETN and 34 patients discontinued treatment due to TEAE (15 (5.0%) patients vs 19 (6.4%) patients). Table 2 Treatment-emergent adverse events reported in ≥2% patients by preferred term, n (%)

e mild to moderate in severity, and TEAEs considered related to the study drug were reported in 83 (27.8%) and 106 (35.7%) patients for SB4 and ETN, respectively. Serious TEAEs were reported in 13 patients each in SB4 and ETN and 34 patients discontinued treatment due to TEAE (15 (5.0%) patients vs 19 (6.4%) patients). Table 2 Treatment-emergent adverse events reported in ≥2% patients by preferred term, n (%) Preferred term SB4 50 mg ETN 50 mg N=299 N=297 Upper respiratory tract infection 21 (7.0) 15 (5.1) Alanine aminotransferase increased 15 (5.0) 14 (4.7) Nasopharyngitis 14 (4.7) 15 (5.1) Headache 13 (4.3) 8 (2.7) Hypertension 10 (3.3) 10 (3.4) Aspartate aminotransferase increased 7 (2.3) 8 (2.7) Viral infection 7 (2.3) 5 (1.7) Injection site erythema 6 (2.0) 33 (11.1) Rheumatoid arthritis 6 (2.0) 9 (3.0) Bronchitis 6 (2.0) 6 (2.0) Diarrhoea 5 (1.7) 7 (2.4) Pharyngitis 4 (1.3) 8 (2.7) Urinary tract infection 4 (1.3) 7 (2.4) Lymphocyte count decreased 4 (1.3) 6 (2.0) Cough 3 (1.0) 10 (3.4) Erythema 2 (0.7) 10 (3.4) Dizziness 2 (0.7) 7 (2.4) Injection site rash 2 (0.7) 6 (2.0) Injection site reaction 1 (0.3) 7 (2.4) A total of 25 patients (13 patients for SB4 and 12 patients for ETN) were diagnosed at screening with latent TB but entered the study after completing at least 30 days of treatment for latent TB and while receiving treatment. None of these patients or any other patients developed active TB during the study. Other serious infections were reported in one (0.3%) patient in SB4 and four (1.3%) patients in ETN. Malignancies were reported in three (1.0%) patients in SB4 (basal cell carcinoma, breast cancer and lung cancer metastatic) and in one (0.3%) patient in ETN (invasive ductal breast carcinoma).

ctive TB during the study. Other serious infections were reported in one (0.3%) patient in SB4 and four (1.3%) patients in ETN. Malignancies were reported in three (1.0%) patients in SB4 (basal cell carcinoma, breast cancer and lung cancer metastatic) and in one (0.3%) patient in ETN (invasive ductal breast carcinoma). Injection site reactions (ISRs), counted by the high-level group term of administration site reactions, occurred in fewer patients in SB4 compared with ETN. There were 22 ISRs reported in 11 (3.7%) patients vs 156 ISRs reported in 51 (17.2%) patients in SB4 and ETN, respectively (p<0.001). Most of the ISRs occurred early (between weeks 2 and 8) and were mild in severity. The incidence of ISR for SB4 and ETN were 3.7% vs 17.1% in ADA-negative patients and 0.0% vs 17.9% in ADA-positive patients, respectively (see online supplementary table S3). One death was reported in the SB4 treatment group due to cardiorespiratory failure, which was not considered related to the study drug. Pharmacokinetics PK analyses were performed on 79 patients (41 patients in SB4 and 38 patients in ETN). Ctrough were comparable at each time point between SB4 (ranging from 2.419 to 2.886 μg/mL in weeks 2–24) and ETN (ranging from 2.066 to 2.635 μg/mL in weeks 2–24) (see online supplementary figure S2). The AUCτ at week 8 was 676.4 vs 520.9 μg h/mL and the inter-subject variability (CV%) was 37.7% vs 50.1% in SB4 and ETN, respectively (see online supplementary figure S3).

B4 (ranging from 2.419 to 2.886 μg/mL in weeks 2–24) and ETN (ranging from 2.066 to 2.635 μg/mL in weeks 2–24) (see online supplementary figure S2). The AUCτ at week 8 was 676.4 vs 520.9 μg h/mL and the inter-subject variability (CV%) was 37.7% vs 50.1% in SB4 and ETN, respectively (see online supplementary figure S3). Immunogenicity The incidence of ADA was significantly lower in SB4 compared with ETN. Two (0.7%) patients in SB4 and 39 (13.1%) patients in ETN tested positive at least once up to week 24 (p<0.001), and only one sample from the ETN group had neutralising capacity. The ADAs appeared early (between weeks 2 and 8), and most of the ADAs disappeared after week 12 (see online supplementary appendix 9). Discussion In this randomised, double-blind, parallel-group, multicentre study, the efficacy, safety, PK and immunogenicity of SB4 were compared with those of ETN in patients with moderate to severe RA despite MTX treatment. Equivalence of efficacy between SB4 and ETN was demonstrated and the safety of SB4 was generally comparable to ETN.

andomised, double-blind, parallel-group, multicentre study, the efficacy, safety, PK and immunogenicity of SB4 were compared with those of ETN in patients with moderate to severe RA despite MTX treatment. Equivalence of efficacy between SB4 and ETN was demonstrated and the safety of SB4 was generally comparable to ETN. The primary endpoint at week 24 was met: the 95% CI of the adjusted treatment difference between SB4 and ETN in ACR20 response rate was within the predefined equivalence margin of −15% to 15%. The ACR20 responses observed in this study (73.8% for SB4 and 71.7% for ETN in FAS) were within the range of ACR20 response rates reported in pivotal studies with ETN (49–86%)4 11–13 17–19 but slightly higher than what was assumed (60%). Since active treatment is used in both groups, biosimilar studies tend to show higher ACR20 response rates20–22 compared with pivotal controlled studies.

ETN in FAS) were within the range of ACR20 response rates reported in pivotal studies with ETN (49–86%)4 11–13 17–19 but slightly higher than what was assumed (60%). Since active treatment is used in both groups, biosimilar studies tend to show higher ACR20 response rates20–22 compared with pivotal controlled studies. As the primary efficacy assessment (ACR20 response at week 24) was evaluated at a time point in the therapeutic plateau, various efficacy endpoints and statistical methods were applied to detect any non-equivalence in efficacy and to support the robustness of the primary efficacy analysis. The ACR20 response rate, ACR-N and DAS28 were measured at several different time points early in the treatment period. The time–response curves of SB4 and ETN up to week 24 showing the ACR20 response over time were estimated to be equivalent, and the AUC of ACR-N up to week 24 and AUC of the change in DAS28 (ESR) from baseline up to week 24 were comparable between SB4 and ETN, indicating that the efficacy of SB4 over time was similar to ETN.

me–response curves of SB4 and ETN up to week 24 showing the ACR20 response over time were estimated to be equivalent, and the AUC of ACR-N up to week 24 and AUC of the change in DAS28 (ESR) from baseline up to week 24 were comparable between SB4 and ETN, indicating that the efficacy of SB4 over time was similar to ETN. Overall, the safety profile of SB4 was comparable with that of ETN and was similar to those observed in the pivotal trials with ETN. There were no cases of active TB and only one patient in SB4 and four patients in ETN reported serious infection, which is lower than 6.3% shown in ETN product information.6 Malignancies were reported in three (1.0%) patients in SB4 and one (0.3%) patient in ETN. The incidence of malignancy observed in this study is similar to the previously conducted studies.4 23 24 Interestingly, ISRs were reported in fewer patients from SB4 compared with ETN (3.7% vs 17.2%). The proportion of patients who experienced at least one ISR from ETN group in this study (17.2%) is in line with recently conducted studies with 50 mg once weekly ETN,13 and most ISRs occurred in the first month, which is in accordance with the reference product label.6 26 Although it is unclear why the incidence of ISR was lower in SB4 compared with ETN, the difference in drug product formulation and container closure system may have contributed to the lower ISR. The only difference in drug composition between SB4 and ETN is the absence of L-arginine in SB4. It has not been shown that L-arginine is associated with increased risk of ISR; however, we cannot preclude the sole difference in formulation (absence of L-arginine) as the cause of ISR. In addition, natural rubber latex known to cause hypersensitivity reactions has not been used in the needle shield of SB4. There appears to be no correlation between ISR and ADA development, which is consistent with previously conducted studies.25

e difference in formulation (absence of L-arginine) as the cause of ISR. In addition, natural rubber latex known to cause hypersensitivity reactions has not been used in the needle shield of SB4. There appears to be no correlation between ISR and ADA development, which is consistent with previously conducted studies.25 In this study, Ctrough and steady state PK was investigated in a subset of population to provide supporting evidence to the phase I comparative PK study in healthy subjects, which demonstrated similar PK behaviour. In the phase III study, the Ctrough values were comparable between SB4 and ETN at each time point and AUCτ at steady state was relatively higher in SB4 compared with ETN; however, the numerical difference is likely due to an inherent high inter-subject variability (37.7% vs 50.1%).

ch demonstrated similar PK behaviour. In the phase III study, the Ctrough values were comparable between SB4 and ETN at each time point and AUCτ at steady state was relatively higher in SB4 compared with ETN; however, the numerical difference is likely due to an inherent high inter-subject variability (37.7% vs 50.1%). The incidence of ADA shown in the ETN group of this study (13.1%) is seemingly higher compared with what has been reported in the previous studies.6 In this study, the assay used to detect immunogenicity was more sensitive and immunogenicity was measured more frequently; most of the ADAs were detected at week 4 in this study while immunogenicity was not measured at these time points in the previous studies and could have resulted in higher overall incidence of ADA in this study.13 25 27 The characteristics of antibodies detected in this study were generally transient and non-neutralising, which is in accordance with those established with ETN in previous studies.6 25 Since SB4 tagged single-assay approach was used to detect immunogenicity, the assay method does not seem to have caused the lower incidence of ADA observed in SB4 compared with ETN (0.7% vs 13.1%). There are product-specific factors known to affect immunogenicity, such as product origin (foreign or human), product aggregates, impurities, container closure system;28–31 however, factors contributing to lower immunogenicity of SB4 are to be further investigated. Yet, according to the EMA guideline on biosimilars7 the lower immunogenicity of SB4 does not preclude classification as biosimilar since clinical efficacy of SB4 and ETN were equivalent in patients with ADA-negative results and no apparent correlation between ADA and clinical response or safety was observed.7 25 32 33

Yet, according to the EMA guideline on biosimilars7 the lower immunogenicity of SB4 does not preclude classification as biosimilar since clinical efficacy of SB4 and ETN were equivalent in patients with ADA-negative results and no apparent correlation between ADA and clinical response or safety was observed.7 25 32 33 To date, this is the first global, multicentre study comparing an ETN biosimilar to reference product ETN. Confirmed equivalence of SB4 and ETN in this study may provide an alternative treatment option for RA and allow better access to biologics for patients. Conclusions SB4 was shown to be equivalent in terms of clinical efficacy when compared with ETN. SB4 was well tolerated with a comparable safety profile to ETN.

To date, this is the first global, multicentre study comparing an ETN biosimilar to reference product ETN. Confirmed equivalence of SB4 and ETN in this study may provide an alternative treatment option for RA and allow better access to biologics for patients. Conclusions SB4 was shown to be equivalent in terms of clinical efficacy when compared with ETN. SB4 was well tolerated with a comparable safety profile to ETN. Supplementary Material Web supplement The authors thank the patients who were involved in this study, the study personnel who made this work possible and the study investigators: Bulgaria: Goranov I, Geneva-Popova M, Shimbova K, Mihaylova M, Nestorova R, Stoilov R, Todorov S, Dimitrov E; Colombia: Vargas F, Londoño J; Czech Republic: Podrazilova L, Mosterova Z, Sedlackova M, Simkova G, Brabcova H, Urbanova Z, Kopackova J, Vitek P, Stejfova Z; Hungary: Nagy M, Sulyok G, Kranicz A, Sillo A, Simoncsics E; Republic of Korea: Choe J, Lee S, Lee S, Kang S, Bae S, Kim J; Lithuania: Lietuvininkiene V, Kausiene R, Stropuviene S, Kriauciuniene V; Mexico: Garcia de la Torre I; Poland: Janecka I, Rychlewska-Hanczewska A, Lis-Studniarska D, Zielinska A, Daniluk S, Hilt J, Glogowska-Szelag J, Kolczewska A, Sliwowska B, Rell-Bakalarsk M, Grabowicz-Waśko B, Marcinkiewicz J, Ruzga Z, Hajduk-Kubacka S; Ukraine: Ignatenko G, Vatutin M, Gasanov Y, Gnylorybov A, Shevchuk S, Rekalov D, Povoroznyuk V, Yatsyshyn R, Petrov A, Stanislavchuk M; UK: Haigh R. The authors also thank the study team for assistance with the logistic management and reporting of the study, specifically Ilsun Hong (lead clinical study manager) and Evelyn Eubene Hong (scientific solutions for writing and editorial support).

alov D, Povoroznyuk V, Yatsyshyn R, Petrov A, Stanislavchuk M; UK: Haigh R. The authors also thank the study team for assistance with the logistic management and reporting of the study, specifically Ilsun Hong (lead clinical study manager) and Evelyn Eubene Hong (scientific solutions for writing and editorial support). Correction notice: This article has been corrected since it was published Online First. Several minor textual changes have been made and the author affiliations altered. Contributors: PE, JG and SYC were involved in the conception or design of the work, or the acquisition, analysis or interpretation of data, drafting the work or revising it critically for important intellectual content, final approval of the version published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. JV, AS, PL, WP, AB, VT, VZ, BS, RM and AB were involved in acquisition of data, drafting the work or revising it critically for important intellectual content, and final approval of the version published. Funding: This study was funded by Samsung Bioepis Co., Ltd.

Contributors: PE, JG and SYC were involved in the conception or design of the work, or the acquisition, analysis or interpretation of data, drafting the work or revising it critically for important intellectual content, final approval of the version published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. JV, AS, PL, WP, AB, VT, VZ, BS, RM and AB were involved in acquisition of data, drafting the work or revising it critically for important intellectual content, and final approval of the version published. Funding: This study was funded by Samsung Bioepis Co., Ltd. Competing interests: All authors received funding for clinical research from Samsung Bioepis: PE received consulting fees; JV, AS, PL, WP, AB, VT, VMZ, BS, RM, and AABR received research grants; SYC and JG are full-time employee of Samsung Bioepis. In addition, PE reports receiving grant/research support from AbbVie, Pfizer and consultancy fee from AbbVie, BMS, Pfizer, USB, MSD, Roche, Novartis, Takeda, Lilly; JV served on speakers bureau for USB, Pfizer, AbbVie, MSD; PL reports receiving grant/research support from Roche, MSD, Janssen, Novo-Nordisk, UCB, Pfizer, Novartis, GSK, BM, served as paid instructor for Novo-Nordisk, and served on speakers bureau for MSD, UCB, Roche, Amgen; AB reports receiving grant/research support from AbbVie. Patient consent: Obtained.

Competing interests: All authors received funding for clinical research from Samsung Bioepis: PE received consulting fees; JV, AS, PL, WP, AB, VT, VMZ, BS, RM, and AABR received research grants; SYC and JG are full-time employee of Samsung Bioepis. In addition, PE reports receiving grant/research support from AbbVie, Pfizer and consultancy fee from AbbVie, BMS, Pfizer, USB, MSD, Roche, Novartis, Takeda, Lilly; JV served on speakers bureau for USB, Pfizer, AbbVie, MSD; PL reports receiving grant/research support from Roche, MSD, Janssen, Novo-Nordisk, UCB, Pfizer, Novartis, GSK, BM, served as paid instructor for Novo-Nordisk, and served on speakers bureau for MSD, UCB, Roche, Amgen; AB reports receiving grant/research support from AbbVie. Patient consent: Obtained. Ethics approval: This study was conducted in compliance with the Declaration of Helsinki and Good Clinical Practice Guidelines established by the International Conference Harmonisation. The protocol was reviewed and approved by the institutional review board or the independent ethics committee of each investigational centre. Provenance and peer review: Not commissioned; externally peer reviewed.

Introduction The tumour necrosis factor inhibitor etanercept was the first approved biologic disease-modifying antirheumatic drug and allowed for a major advance in the treatment of rheumatoid arthritis (RA).1 Eighteen years since its approval, etanercept continues to play a key role in RA management, having demonstrated efficacy and a manageable safety profile in both clinical trial and real-world settings.1 Other current indications for etanercept include juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis (European Union only), plaque psoriasis and paediatric psoriasis (USA only).2 3 SB4 (Benepali, Samsung Bioepis UK Limited, Surrey, UK; Brenzys, Samsung Bioepis, Republic of Korea) is a biosimilar of reference etanercept (ETN). The structural, physicochemical and biological quality attributes of SB4 have been shown to be highly similar to ETN in a comprehensive comparability exercise designed as part of the European Medicines Agency’s rigorous approval pathway.4 A phase 1 study in healthy subjects demonstrated pharmacokinetic equivalence between SB4 and ETN5; a phase 3 study (NCT01895309; EudraCT 2012-005026-30) in patients with moderate to severe RA despite treatment with methotrexate (MTX) demonstrated equivalent efficacy in terms of American College of Rheumatology 20% response rate (ACR20) at the 24-week interim analysis (SB4, 78.1%; ETN, 80.3%)6 and at week 52 (SB4, 80.8%; ETN, 81.5%).7 Safety was generally comparable between SB4 and ETN.6 7

erate to severe RA despite treatment with methotrexate (MTX) demonstrated equivalent efficacy in terms of American College of Rheumatology 20% response rate (ACR20) at the 24-week interim analysis (SB4, 78.1%; ETN, 80.3%)6 and at week 52 (SB4, 80.8%; ETN, 81.5%).7 Safety was generally comparable between SB4 and ETN.6 7 SB4 has been approved for treatment of RA, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis and plaque psoriasis in the European Union.8 9 However, an important consideration for prescribing physicians is whether switching from ETN to SB4, which may occur in clinical practice, can be achieved without detriment to safety and efficacy. We analysed data from the open-label extension period of the phase 3 study to evaluate the efficacy, safety and immunogenicity of continuing SB4 (SB4/SB4) versus switching from ETN to SB4 (ETN/SB4). Long-term safety and efficacy were assessed up to week 100.

ce, can be achieved without detriment to safety and efficacy. We analysed data from the open-label extension period of the phase 3 study to evaluate the efficacy, safety and immunogenicity of continuing SB4 (SB4/SB4) versus switching from ETN to SB4 (ETN/SB4). Long-term safety and efficacy were assessed up to week 100. Methods Study design and patients Patients with moderate to severe RA despite treatment with MTX were eligible to enrol in this phase 3, randomised, double-blind, multicentre study, which included an open-label extension period. Detailed patient inclusion/exclusion criteria were previously published.6 During the double-blind period, patients were randomised 1:1 to receive subcutaneous SB4 50 mg or ETN 50 mg once weekly for 52 weeks. Patients in the Czech Republic or Poland who completed the scheduled 52-week visit were enrolled in the open-label, single-arm extension period. During the extension period, patients from the SB4 group continued to receive SB4 (SB4/SB4), and patients from the ETN group switched to SB4 50 mg (ETN/SB4) once weekly for an additional 48 weeks. All patients took a stable dose of MTX (10–25 mg/week) from 4 weeks before screening until the end-of-treatment visit for the extension period. For patients who entered the extension period, efficacy was assessed at weeks 52, 76 and 100, and safety was assessed at all visits during treatment and at 4 weeks after treatment (or after the early termination visit).

25 mg/week) from 4 weeks before screening until the end-of-treatment visit for the extension period. For patients who entered the extension period, efficacy was assessed at weeks 52, 76 and 100, and safety was assessed at all visits during treatment and at 4 weeks after treatment (or after the early termination visit). Endpoints Efficacy endpoints for the extension period included ACR20/50/70 response (≥20%/50%/70% improvement, respectively, from baseline in ACR response criteria), European League Against Rheumatism (EULAR) response and disease activity score based on a 28-joint count (DAS28). Physical function was assessed using the Health Assessment Questionnaire-Disability Index (HAQ-DI). For patients who entered the extension period, radiographs of the hands and feet obtained at weeks 0, 52 and 100 were evaluated by a single reader to determine the modified Total Sharp Score (mTSS), which is the sum of the joint erosion and joint space narrowing (JSN) scores.10 Post hoc assessments included the proportions of patients achieving low disease activity (LDA) and remission based on the Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI) and DAS28 and the proportions achieving Boolean-based remission (defined as ≤1 swollen and ≤1 tender joint, C-reactive protein ≤1 mg/dL and patient global visual analogue scale score ≤1 using a 0–10 scale). Safety endpoints included the incidence of treatment-emergent adverse events (TEAEs) and adverse events (AEs) of special interest (serious infections and active tuberculosis). Immunogenicity was assessed by determining the incidence of antidrug antibodies (ADAs) and neutralising antibodies; ADAs were detected in serum samples using an electrochemiluminescence bridging assay (Meso Scale Discovery, Maryland, USA), double-antigen format with acid dissociation and neutralising antibodies were measured using a competitive ligand-binding assay.6

cidence of antidrug antibodies (ADAs) and neutralising antibodies; ADAs were detected in serum samples using an electrochemiluminescence bridging assay (Meso Scale Discovery, Maryland, USA), double-antigen format with acid dissociation and neutralising antibodies were measured using a competitive ligand-binding assay.6 Statistical analysis All data were analysed descriptively. Efficacy and safety data were analysed in the extended population, which comprised all patients who provided informed consent for the open-label extension period and received ≥1 dose of study medication in the open-label extension period. Efficacy data obtained up to week 52 were analysed retrospectively in this population. No imputation was made for missing data. Analyses were performed using SAS software, V.9.2 or higher (SAS Institute, Cary, North Carolina, USA). Results Patients A total of 245 patients, including 126 who continued on SB4 and 119 who switched to SB4 from ETN, enrolled in the extension period. All patients received ≥1 dose of study drug during the extension period and were included in this analysis. Patient disposition is shown in figure 1; 94.7% of patients (232/245) who entered the extension period completed 100 weeks of treatment, with 5.6% of patients in the SB4/SB4 group and 5.0% of patients in the ETN/SB4 group withdrawing before week 100. Patient demographic and clinical characteristics were well balanced between the two groups (table 1). Table 1 Patient baseline demographics and disease characteristics at baseline and week 52 (extended population)

Results Patients A total of 245 patients, including 126 who continued on SB4 and 119 who switched to SB4 from ETN, enrolled in the extension period. All patients received ≥1 dose of study drug during the extension period and were included in this analysis. Patient disposition is shown in figure 1; 94.7% of patients (232/245) who entered the extension period completed 100 weeks of treatment, with 5.6% of patients in the SB4/SB4 group and 5.0% of patients in the ETN/SB4 group withdrawing before week 100. Patient demographic and clinical characteristics were well balanced between the two groups (table 1). Table 1 Patient baseline demographics and disease characteristics at baseline and week 52 (extended population) Variable SB4/SB4 (n=126) ETN/SB4 (n=119) Age, years 49.9 (12.05) 52.1 (10.91) Women, n (%) 107 (84.9) 100 (84.0) White, n (%) 126 (100.0) 118 (99.2) BMI, kg/m2 26.7 (5.80) 26.1 (5.05) Disease duration, years 5.7 (3.94) 5.8 (4.18) Duration of MTX use, months 46.0 (35.63) 43.9 (39.81) Weekly dose of MTX, mg 16.9 (4.92) 16.5 (4.91) Swollen joint count (0–66) Baseline 14.4 (7.25) 14.4 (7.74) Week 52 2.9 (4.84) 2.8 (4.30) Tender joint count (0–68) Baseline 21.0 (9.96) 21.4 (11.08) Week 52 5.0 (7.11) 5.6 (7.86) Physician VAS (0–100) Baseline 62.4 (16.35) 63.6 (15.25) Week 52 16.8 (14.47) 18.8 (15.27) Patient VAS (0–100) Baseline 58.9 (19.75) 61.5 (18.08) Week 52 24.9 (20.97) 26.8 (19.62) Patient pain VAS (0–100) Baseline 59.0 (21.38) 60.5 (20.22) Week 52 25.8 (21.86) 27.0 (21.32) HAQ-DI (0–3) Baseline 1.38 (0.555) 1.45 (0.597) Week 52 0.68 (0.585) 0.74 (0.651) DAS28 Baseline 6.22 (0.908) 6.26 (0.877) Week 52 3.40 (1.179) 3.49 (1.119) SDAI Baseline 37.01 (12.037) 37.65 (12.052) Week 52 10.04 (8.589) 10.38 (8.713) CDAI Baseline 35.85 (11.586) 36.45 (11.672) Week 52 9.41 (8.249) 10.01 (8.670) CRP, mg/L Baseline 11.5 (15.71) 12.0 (16.35) Week 52 6.2 (15.84) 3.8 (5.47) ESR, mm/h Baseline 41.9 (23.26) 41.7 (19.53) Week 52 24.5 (18.63) 22.2 (16.21) Rheumatoid factor positive, n (%) 99 (78.6) 89 (74.8) Values represent mean (SD) unless otherwise specified.

1.586) 36.45 (11.672) Week 52 9.41 (8.249) 10.01 (8.670) CRP, mg/L Baseline 11.5 (15.71) 12.0 (16.35) Week 52 6.2 (15.84) 3.8 (5.47) ESR, mm/h Baseline 41.9 (23.26) 41.7 (19.53) Week 52 24.5 (18.63) 22.2 (16.21) Rheumatoid factor positive, n (%) 99 (78.6) 89 (74.8) Values represent mean (SD) unless otherwise specified. BMI, body mass index; CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; DAS28, disease activity score based on a 28-joint count; ESR, erythrocyte sedimentation rate; ETN, reference etanercept; HAQ-DI, Health Assessment Questionnaire-Disability Index; MTX, methotrexate; SDAI, Simplified Disease Activity Index; VAS, visual analogue scale. Figure 1 Patient disposition. AE, adverse event; ETN, reference etanercept.

BMI, body mass index; CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; DAS28, disease activity score based on a 28-joint count; ESR, erythrocyte sedimentation rate; ETN, reference etanercept; HAQ-DI, Health Assessment Questionnaire-Disability Index; MTX, methotrexate; SDAI, Simplified Disease Activity Index; VAS, visual analogue scale. Figure 1 Patient disposition. AE, adverse event; ETN, reference etanercept. Efficacy ACR responses were comparable between the SB4/SB4 and ETN/SB4 groups and were maintained from weeks 52 through 100, with 79.2%/52.0%/38.4% and 82.4%/53.8%/32.8% of patients achieving ACR20/50/70 in each group, respectively, at week 52% and 77.9%/59.8%/42.6% and 79.1%/60.9%/41.7% of patients achieving ACR20/50/70 in each group, respectively, at week 100 (figure 2). ACR responses were also comparable between the two groups in the retrospective analysis of this population during the initial 52-week treatment period. Other efficacy results at week 100 are shown in table 2. At this time point, the proportion of patients who had moderate or good EULAR responses; the proportion who achieved LDA and remission based on DAS28, SDAI or CDAI criteria and the proportion who achieved Boolean-based remission were comparable between the SB4/SB4 and ETN/SB4 groups. Further, throughout the study, DAS28, SDAI, CDAI and HAQ-DI scores were also comparable between the two groups (see figure in the online supplementary material 1). The main factor driving the improvement in DAS28 score was the reduction in swollen and tender joint counts; these components demonstrated the largest percentage improvements from baseline during the extension period. At week 100, radiographic progression was comparable and minimal (figure 3), with mean (SD) change from baseline mTSS values of 0.48 (4.053) for the SB4/SB4 group and 1.00 (5.563) for the ETN/SB4 group (table 2). Summary of structural joint damage for each visit can be found in table S1 in the online supplementary material 1.

100, radiographic progression was comparable and minimal (figure 3), with mean (SD) change from baseline mTSS values of 0.48 (4.053) for the SB4/SB4 group and 1.00 (5.563) for the ETN/SB4 group (table 2). Summary of structural joint damage for each visit can be found in table S1 in the online supplementary material 1. 10.1136/annrheumdis-2017-211591.supp1Supplementary material 1 Table 2 Efficacy results at week 100 (extended population) SB4/SB4 (n=126) ETN/SB4 (n=119) EULAR response, n/N* (%) Good 59/121 (48.8) 63/115 (54.8) Moderate 54/121 (44.6) 40/115 (34.8) No response 8/121 (6.6) 12/115 (10.4) DAS28 Improvement from baseline, mean (SD) 2.9 (1.5) 3.0 (1.5) Disease activity, n/N* (%) Low (≤3.2) 60/122 (49.2) 63/115 (54.8) Remission (<2.6) 37/122 (30.3) 40/115 (34.8) SDAI score Improvement from baseline, mean (SD) 27.4 (15.5) 28.7 (14.6) Disease activity, n/N* (%) Low (>3.3 and≤11) 41/123 (33.3) 44/115 (38.3) Remission (≤3.3) 38/123 (30.9) 39/115 (33.9) CDAI score Improvement from baseline, mean (SD) 26.8 (15.0) 27.9 (14.1) Disease activity, n/N* (%) Low (>2.8 and≤10) 38/123 (30.9) 46/115 (40.0) Remission (≤2.8) 40/123 (32.5) 33/115 (28.7) Boolean-based remission, n/N* (%) 31/123 (25.2) 23/115 (20.0) Radiographic results† Change from baseline in JSN score, mean (SD) 0.19 (1.98) 0.39 (2.86) Change from baseline in joint erosion score, mean (SD) 0.28 (2.57) 0.61 (3.08) Change from baseline in mTSS, mean (SD) 0.48 (4.05) 1.0 (5.56) *Number of patients with available data at each time point.

31/123 (25.2) 23/115 (20.0) Radiographic results† Change from baseline in JSN score, mean (SD) 0.19 (1.98) 0.39 (2.86) Change from baseline in joint erosion score, mean (SD) 0.28 (2.57) 0.61 (3.08) Change from baseline in mTSS, mean (SD) 0.48 (4.05) 1.0 (5.56) *Number of patients with available data at each time point. †Based on number of patients who completed week 100 visit with available radiographic assessment results at weeks 0 and 100 (SB4/SB4, n=108; ETN/SB4, n=104). CDAI, Clinical Disease Activity Index; DAS28, disease activity score based on a 28-joint count; ETN, reference etanercept; EULAR, European League Against Rheumatism; JSN, joint space narrowing; mTSS, modified Total Sharp Score; SDAI, Simplified Disease Activity Index. Figure 2 American College of Rheumatology (ACR) response rates up to week 100 (extended population). ACR20/50/70=American College of Rheumatology 20%/50%/70% response criteria; ETN, reference etanercept. Figure 3 Cumulative probability of mTSS change from baseline at week 100 (extended population). Data based on patients with available radiographic assessment results at each visit. ETN, reference etanercept; mTSS, modified Total Sharp Score.

Figure 2 American College of Rheumatology (ACR) response rates up to week 100 (extended population). ACR20/50/70=American College of Rheumatology 20%/50%/70% response criteria; ETN, reference etanercept. Figure 3 Cumulative probability of mTSS change from baseline at week 100 (extended population). Data based on patients with available radiographic assessment results at each visit. ETN, reference etanercept; mTSS, modified Total Sharp Score. Safety Safety after week 52 was generally comparable between the SB4/SB4 and ETN/SB4 groups (table 3). This extension study was not adequately powered to showsimilar safety and imbalance might be expected as shown in the incidence of serious TEAEs, RA, viral infection, laryngitis and hypertension. Serious infection was reported in one patient in each treatment group, and there were no reports of active tuberculosis. Also during the extension period, no injection-site reactions were reported. One patient in the SB4/SB4 group died of hepatic cancer, which was considered to be related to the study drug. One patient in each treatment group developed non-neutralising ADAs after week 52 (see table S2 in the online supplementary material 1). Both patients had a low titre, and the ADAs did not affect efficacy. The patient in the SB4/SB4 group tested positive at week 100 with a titre of 1 and achieved an ACR50 response at week 100. The patient from the ETN/SB4 group tested positive at week 76 with a titre of <1 and achieved an ACR70 response at week 100. Table 3 Safety after week 52 (extended population)

Safety Safety after week 52 was generally comparable between the SB4/SB4 and ETN/SB4 groups (table 3). This extension study was not adequately powered to showsimilar safety and imbalance might be expected as shown in the incidence of serious TEAEs, RA, viral infection, laryngitis and hypertension. Serious infection was reported in one patient in each treatment group, and there were no reports of active tuberculosis. Also during the extension period, no injection-site reactions were reported. One patient in the SB4/SB4 group died of hepatic cancer, which was considered to be related to the study drug. One patient in each treatment group developed non-neutralising ADAs after week 52 (see table S2 in the online supplementary material 1). Both patients had a low titre, and the ADAs did not affect efficacy. The patient in the SB4/SB4 group tested positive at week 100 with a titre of 1 and achieved an ACR50 response at week 100. The patient from the ETN/SB4 group tested positive at week 76 with a titre of <1 and achieved an ACR70 response at week 100. Table 3 Safety after week 52 (extended population) n (%) SB4/SB4 (n=126) ETN/SB4 (n=119) ≥1 TEAE 60 (47.6) 58 (48.7) Frequently reported TEAEs (≥3%) Upper respiratory tract infection 10 (7.9) 9 (7.6) Pharyngitis 9 (7.1) 5 (4.2) Rheumatoid arthritis 7 (5.6) 3 (2.5) Bronchitis 6 (4.8) 7 (5.9) Nasopharyngitis 6 (4.8) 5 (4.2) Viral infection 4 (3.2) 1 (0.8) Laryngitis 4 (3.2) 0 (0.0) Hypertension 1 (0.8) 5 (4.2) ≥1 serious TEAE 6 (4.8) 2 (1.7) TEAE leading to study drug discontinuation 4 (3.2) 2 (1.7) Serious infection 1 (0.8) 1 (0.8) Active tuberculosis 0 (0.0) 0 (0.0) Injection-site reaction* 0 (0.0) 0 (0.0) Malignancy† 1 (0.8) 0 (0.0) Death† 1 (0.8) 0 (0.0) *TEAE with high-level group term of administration site reaction.

) ≥1 serious TEAE 6 (4.8) 2 (1.7) TEAE leading to study drug discontinuation 4 (3.2) 2 (1.7) Serious infection 1 (0.8) 1 (0.8) Active tuberculosis 0 (0.0) 0 (0.0) Injection-site reaction* 0 (0.0) 0 (0.0) Malignancy† 1 (0.8) 0 (0.0) Death† 1 (0.8) 0 (0.0) *TEAE with high-level group term of administration site reaction. †Hepatic cancer, which was considered related to study drug. ETN, reference etanercept; TEAE, treatment emergent adverse event. Discussion This open-label extension period of a phase 3, randomised, double-blind study evaluated the long-term efficacy, safety and immunogenicity of SB4 in patients with moderate to severe RA despite MTX treatment and compared outcomes between patients who continued SB4 (n=126) and those who switched from ETN to SB4 (n=119). Results showed SB4 to be effective and well tolerated over 2 years. In patients who switched from ETN to SB4, comparable efficacy to the SB4/SB4 group was observed, with no new safety signals identified. Among the patients entering the extension period, 94.4% in the SB4/SB4 group and 95.0% in the ETN/SB4 group completed an additional 48 weeks of SB4 treatment. The discontinuation rate due to lack of efficacy or TEAEs was very low, which suggests the long-term tolerability of SB4 treatment.

Discussion This open-label extension period of a phase 3, randomised, double-blind study evaluated the long-term efficacy, safety and immunogenicity of SB4 in patients with moderate to severe RA despite MTX treatment and compared outcomes between patients who continued SB4 (n=126) and those who switched from ETN to SB4 (n=119). Results showed SB4 to be effective and well tolerated over 2 years. In patients who switched from ETN to SB4, comparable efficacy to the SB4/SB4 group was observed, with no new safety signals identified. Among the patients entering the extension period, 94.4% in the SB4/SB4 group and 95.0% in the ETN/SB4 group completed an additional 48 weeks of SB4 treatment. The discontinuation rate due to lack of efficacy or TEAEs was very low, which suggests the long-term tolerability of SB4 treatment. Efficacy outcomes in the extended population were comparable between the SB4/SB4 and ETN/SB4 groups at all visits up to week 100, sustained from weeks 52 to 100 and unaffected by switching. Comparable inhibition of radiographic progression was previously reported after 52 weeks of treatment with SB4 or ETN (mean change in mTSS: 0.45 for SB4 vs 0.74 for ETN).7 In both groups, continued inhibition of radiographic progression was observed with an additional year of SB4 treatment, with mean changes from baseline in joint space narrowing and joint erosion of <1. This is consistent with historical results from randomised studies of etanercept with or without MTX in patients with RA.11–13 Two-year radiographic findings in patients with early RA continuing ETN+MTX therapy from year 1 showed a mean Sharp/van der Heijde score change of −0.02 and an improvement in mean 28-swollen joint count from 1.7 to 1.3.11 Similarly, 2-year data from the Canadian Methotrexate and Etanercept Outcome study showed that patients continuing ETN+MTX therapy after the first 6 months had mean changes from baseline in mTSS and JSN of 0.0 at month 24 and those switching to ETN monotherapy had mean changes from baseline in mTSS and JSN of <1.12 Lastly, the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) demonstrated mean changes from baseline in mTSS, joint erosion scores and JSN of <1 at years, 1, 2 and 3 of treatment with ETN+MTX.13

and those switching to ETN monotherapy had mean changes from baseline in mTSS and JSN of <1.12 Lastly, the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) demonstrated mean changes from baseline in mTSS, joint erosion scores and JSN of <1 at years, 1, 2 and 3 of treatment with ETN+MTX.13 In the extension period, SB4 demonstrated a safety profile similar to that observed in the pivotal etanercept trials.11–13 There were no reports of active tuberculosis or injection-site reactions. One patient in each group reported a serious infection and one patient in the SB4/SB4 group died from hepatic cancer. After week 52, one patient in each group developed non-neutralising ADAs. The low incidence of non-neutralising ADAs observed in the study was expected given the low rates reported in short-term and long-term studies of etanercept-treated patients with RA (0%–6%).14–16 The ADAs developed prior to switching did not affect the efficacy or safety of SB4 in the ETN/SB4 group.

-neutralising ADAs. The low incidence of non-neutralising ADAs observed in the study was expected given the low rates reported in short-term and long-term studies of etanercept-treated patients with RA (0%–6%).14–16 The ADAs developed prior to switching did not affect the efficacy or safety of SB4 in the ETN/SB4 group. Results from this extended-period switching study showed maintenance of response after switching from ETN to SB4 with no newly identified safety issues (eg, no increase in immunogenicity or immune-related TEAEs of anaphylaxis, hypersensitivity or injection-site reactions). In extensions of PLANETRA (Program evaLuating the Autoimmune Disease iNvEstigational Drug cT-p13 in RA Patients)17 and PLANETAS (Program evaLuating the Autoimmune Disease iNvEstigational Drug cT-p13 in AS patients)18 which had similar study designs with the present study, switching from reference infliximab to the biosimilar infliximab CT-P13 was not associated with diminished efficacy or change in safety profile. These results are further corroborated by findings from the randomised, non-inferiority NOR-SWITCH study which demonstrated that switching to CT-P13 is not inferior to continued treatment with reference infliximab.19 In addition, data from the DANBIO registry where a nationwide switch took place, disease activity was not affected by the non-medical switch from the reference infliximab or ETN to CT-P13 or SB4, respectively.20 21 Observations from these studies provide data relevant to clinical practice and support switching of reference products to biosimilars for non-medical reasons.

tionwide switch took place, disease activity was not affected by the non-medical switch from the reference infliximab or ETN to CT-P13 or SB4, respectively.20 21 Observations from these studies provide data relevant to clinical practice and support switching of reference products to biosimilars for non-medical reasons. A retrospective analysis of our data was conducted for any potential anaphylaxis cases using related AEs (eg, pruritus, flushing, dyspnoea, hypotonia, syncope, incontinence, vomiting) and blood pressure (systolic blood pressure <90 mm Hg or >30% decrease from baseline), as defined in the National Institute of Allergy and Infectious Diseases/Food Allergy Anaphylaxis Network criteria.22 No cases of potential anaphylaxis were identified based on this analysis.

ypotonia, syncope, incontinence, vomiting) and blood pressure (systolic blood pressure <90 mm Hg or >30% decrease from baseline), as defined in the National Institute of Allergy and Infectious Diseases/Food Allergy Anaphylaxis Network criteria.22 No cases of potential anaphylaxis were identified based on this analysis. The open-label nature of the extension period is a study limitation. Because patients were required to have completed the 52-week visit of the randomised, double-blind period in order to enrol in the extension, there was the potential for selection bias. However, baseline demographic and clinical characteristics were well balanced between the treatment groups and were representative of those in the core study. Moreover, disease activity at week 52 for patients who enrolled in the extension period was comparable with that of patients who did not enrol in the extension period (see table S3 in the online supplementary material 1), suggesting no selection bias towards patients who responded well to treatment. This switching study was designed to evaluate approximately 100 patients in each group to allow detection of an increase in the risk for injection site reactions to 1% or more. Therefore, the two countries with the largest number of enrolled patients (Poland and the Czech Republic) were selected to participate in the extension period. Although the extension period was not designed to compare equivalence statistically, it provides valuable data on switching from ETN to SB4 in patients with RA.

Therefore, the two countries with the largest number of enrolled patients (Poland and the Czech Republic) were selected to participate in the extension period. Although the extension period was not designed to compare equivalence statistically, it provides valuable data on switching from ETN to SB4 in patients with RA. Conclusions SB4 was well tolerated and effective over 2 years in patients with RA. Switching from ETN to SB4 was not associated with treatment-emergent issues such as loss of efficacy or increases in TEAEs or immunogenicity. Postmarketing surveillance and registry studies are ongoing to monitor the efficacy and safety of SB4 in various indications. The authors thank the patients who were involved in this extension study, the study personnel who made this work possible and the study investigators. From the Czech Republic, this included L Podrazilova, M Sedlackova, G Simkova, H Brabcova, Z Urbanova, J Kopackova, P Vitek, and Z Stejfova. From Poland, this included I Janecka, A Rychlewska-Hanczewska, A Zielinska, S Daniluk, J Glogowska-Szelag, B Sliwowska, M Rell-Bakalarsk and B Grabowicz-Waśko. Editorial support for development of this manuscript was provided by Nicole Strangman, PhD, of C4 MedSolutions, LLC (Yardley, Pennsylvania, USA), a CHC Group company and funded by Samsung Bioepis Co., Ltd. Results included in this manuscript have been previously presented at the 2016 EULAR Congress and 2016 ACR/ARHP Annual Meeting. Handling editor: Tore K Kvien

Editorial support for development of this manuscript was provided by Nicole Strangman, PhD, of C4 MedSolutions, LLC (Yardley, Pennsylvania, USA), a CHC Group company and funded by Samsung Bioepis Co., Ltd. Results included in this manuscript have been previously presented at the 2016 EULAR Congress and 2016 ACR/ARHP Annual Meeting. Handling editor: Tore K Kvien Contributors: PE, SYC, and JG contributed to the study conception and design, analysis and interpretation of data and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. JV, AS, PL, WP, BS, JH and ZM contributed to the acquisition of data. All the authors equally contributed to the drafting the manuscript and revising it critically for important intellectual content, final approval of the version published. Funding: This study was funded by Samsung Bioepis Co., Ltd.

Contributors: PE, SYC, and JG contributed to the study conception and design, analysis and interpretation of data and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. JV, AS, PL, WP, BS, JH and ZM contributed to the acquisition of data. All the authors equally contributed to the drafting the manuscript and revising it critically for important intellectual content, final approval of the version published. Funding: This study was funded by Samsung Bioepis Co., Ltd. Competing interests: All authors received funding for clinical research from Samsung Bioepis. PE received consulting fees; JV, AS, PL, WP, BS, JH, and ZM received research grants and SYC and JG are full-time employee of Samsung Bioepis. In addition, PE reports receiving grant/research support from AbbVie and Pfizer and consultancy fees from AbbVie, Bristol-Myers Squibb, Pfizer, UCB, Merck Sharp & Dohme, Roche, Novartis, Takeda and Lilly; JV served on speakers bureaus for UCB, Pfizer, AbbVie and Merck Sharp & Dohme; PL received grant/research support from Roche, Merck Sharp & Dohme, Janssen, Novo-Nordisk, UCB, Pfizer, Novartis, GlaxoSmithKline, Bristol-Myers Squibb, served as paid instructor for Novo-Nordisk and served on speakers bureaus for Merck Sharp & Dohme, UCB, Roche and Amgen. Patient consent: Obtained.

Competing interests: All authors received funding for clinical research from Samsung Bioepis. PE received consulting fees; JV, AS, PL, WP, BS, JH, and ZM received research grants and SYC and JG are full-time employee of Samsung Bioepis. In addition, PE reports receiving grant/research support from AbbVie and Pfizer and consultancy fees from AbbVie, Bristol-Myers Squibb, Pfizer, UCB, Merck Sharp & Dohme, Roche, Novartis, Takeda and Lilly; JV served on speakers bureaus for UCB, Pfizer, AbbVie and Merck Sharp & Dohme; PL received grant/research support from Roche, Merck Sharp & Dohme, Janssen, Novo-Nordisk, UCB, Pfizer, Novartis, GlaxoSmithKline, Bristol-Myers Squibb, served as paid instructor for Novo-Nordisk and served on speakers bureaus for Merck Sharp & Dohme, UCB, Roche and Amgen. Patient consent: Obtained. Ethics approval: This study was conducted in accordance with the Declaration of Helsinki and International Council for Harmonisation Good Clinical practice guidelines. Protocols were reviewed and approved by the independent ethics committee or institutional review board for each study centre. All patients provided written informed consent. Provenance and peer review: Not commissioned; externally peer reviewed.

Introduction The European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) recommend clinical remission or low disease activity (LDA) if remission is unlikely to be obtained, as the treatment goal for rheumatoid arthritis (RA).1 2 Conventional synthetic disease-modifying antirheumatic drugs (DMARDs), particularly methotrexate (MTX), are recommended as part of an initial treatment strategy. If disease activity has not improved at 3 months, or the clinical target is not attained within 6 months and the patient has unfavourable prognostic markers, addition of a biological DMARD (bDMARD), such as a tumour necrosis factor inhibitor (TNFi), is recommended.1 2 This analysis evaluated the treat-to-target strategy by assessing whether patients with early RA who started on MTX monotherapy, followed by addition of adalimumab on treatment failure, had a similar or worse outcomes compared with patients who started on adalimumab+MTX combination therapy.

Introduction The European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) recommend clinical remission or low disease activity (LDA) if remission is unlikely to be obtained, as the treatment goal for rheumatoid arthritis (RA).1 2 Conventional synthetic disease-modifying antirheumatic drugs (DMARDs), particularly methotrexate (MTX), are recommended as part of an initial treatment strategy. If disease activity has not improved at 3 months, or the clinical target is not attained within 6 months and the patient has unfavourable prognostic markers, addition of a biological DMARD (bDMARD), such as a tumour necrosis factor inhibitor (TNFi), is recommended.1 2 This analysis evaluated the treat-to-target strategy by assessing whether patients with early RA who started on MTX monotherapy, followed by addition of adalimumab on treatment failure, had a similar or worse outcomes compared with patients who started on adalimumab+MTX combination therapy. Methods Study design OPTIMA was a 78-week, randomised, double-blind, phase 4, two-period study.3 4 In period 1, patients received MTX monotherapy weekly or adalimumab 40 mg every other week plus MTX weekly for 26 weeks.3 The protocol defined stable LDA as 28-joint modified Disease Activity Score based on C reactive protein (DAS28(CRP)) <3.2 at weeks 22 and 26. In period 2, patients with stable LDA continued MTX monotherapy or were rerandomised to adalimumab+MTX continuation or adalimumab withdrawal (MTX only).4 Patients who did not achieve stable LDA in period 1 continued open-label MTX+adalimumab (adalimumab carry-on) or received open-label adalimumab added to MTX monotherapy (adalimumab rescue). All patients remained blinded to their initial treatment allocation in period 1.4

ntinuation or adalimumab withdrawal (MTX only).4 Patients who did not achieve stable LDA in period 1 continued open-label MTX+adalimumab (adalimumab carry-on) or received open-label adalimumab added to MTX monotherapy (adalimumab rescue). All patients remained blinded to their initial treatment allocation in period 1.4 Post hoc populations A ‘merged adalimumab continuation’ group (including the ADA continuation arm, adjusted with a scaling factor based on the total number of patients in the adalimumab continuation and adalimumab withdrawal arms, so that both arms contributed equally) was combined with the adalimumab carry-on arm, comprising the total population randomised to adalimumab+MTX at baseline (online supplementary figure 1). The MTX monotherapy and adalimumab rescue arms were combined. These two main groupings allowed comparison of the validity of the EULAR and ACR recommendations of starting with MTX monotherapy followed by addition of a TNFi in patients who do not achieve the treatment target versus starting with TNFi+MTX. 10.1136/annrheumdis-2017-211871.supp1Supplementary file 1

Post hoc populations A ‘merged adalimumab continuation’ group (including the ADA continuation arm, adjusted with a scaling factor based on the total number of patients in the adalimumab continuation and adalimumab withdrawal arms, so that both arms contributed equally) was combined with the adalimumab carry-on arm, comprising the total population randomised to adalimumab+MTX at baseline (online supplementary figure 1). The MTX monotherapy and adalimumab rescue arms were combined. These two main groupings allowed comparison of the validity of the EULAR and ACR recommendations of starting with MTX monotherapy followed by addition of a TNFi in patients who do not achieve the treatment target versus starting with TNFi+MTX. 10.1136/annrheumdis-2017-211871.supp1Supplementary file 1 Efficacy assessments The main assessments were the proportion of patients who achieved DAS28(CRP) <3.2, normal function and no radiographic progression at weeks 52 and 78. Normal function was defined as Disability Index of the Health Assessment Questionnaire (HAQ-DI) <0.5 and radiographic non-progression as change in modified total Sharp score (ΔmTSS) ≤0.5. We also assessed Boolean-based remission,5 Simplified Disease Activity Index (SDAI) remission (≤3.3), response rates for 20%/50%/70% improvements in ACR criteria and patient-reported outcomes (global assessment, pain, Functional Assessment of Chronic Illness Therapy and EuroQoL-5 dimensions).

Sharp score (ΔmTSS) ≤0.5. We also assessed Boolean-based remission,5 Simplified Disease Activity Index (SDAI) remission (≤3.3), response rates for 20%/50%/70% improvements in ACR criteria and patient-reported outcomes (global assessment, pain, Functional Assessment of Chronic Illness Therapy and EuroQoL-5 dimensions). Statistical analyses Outcomes were assessed using the last observation carried forward method, except radiographic analyses used multiple imputation (missing values imputed in 10 steps, Markov chain Monte Carlo method).6 Categorical outcomes were compared using the Pearson χ2 test4 and continuous outcomes using one-sample or two-sample t-tests.

mes were assessed using the last observation carried forward method, except radiographic analyses used multiple imputation (missing values imputed in 10 steps, Markov chain Monte Carlo method).6 Categorical outcomes were compared using the Pearson χ2 test4 and continuous outcomes using one-sample or two-sample t-tests. Results As reported previously,3 a significantly greater proportion of patients receiving adalimumab+MTX, compared with those starting on MTX only, achieved LDA, normal function and radiographic non-progression at week 26. However, after therapy adjustment at week 26 in patients who failed to attain LDA, the proportions achieving LDA at weeks 52 and 78 and normal function were similar between the groups (figure 1A,B). Results were independent of glucocorticoid use (online supplementary figure 2). Moreover, the proportion of patients with radiographic non-progression (from week 0) remained stable from weeks 26 to 52 and 78, indicating that as soon as adalimumab rescue therapy began at week 26, progression of joint damage stopped (figure 1C). Likewise, the proportion of patients with radiographic non-progression from week 26 (‘reset’ baseline) to week 52 or 78 was similar between the groups (figure 1D). Moreover, the proportion of MTX monotherapy responders without radiographic progression at week 26 remained stable (ΔmTSS ≤0.5: 89/109 (81.7%) at week 52, 85/109 (78.0%) at week 78). Although significantly greater proportions of patients starting with adalimumab+MTX also achieved Boolean-based remission at weeks 26 and 52 and SDAI remission at week 26 versus patients starting with MTX monotherapy, the differences were no longer significant subsequently (data not shown). Mean changes in clinical, functional and radiographic scores were significantly better in patients starting with adalimumab+MTX (P<0.001) from baseline to week 26, whereas mean changes (except radiographic scores) were significantly better in patients starting with MTX monotherapy (P<0.001) from week 26 to weeks 52 and 78 (ie, after possible addition of adalimumab; data not shown). Mean changes in patient-reported outcomes from week 26 to weeks 52 and 78 were similar in the two groups (data not shown).

xcept radiographic scores) were significantly better in patients starting with MTX monotherapy (P<0.001) from week 26 to weeks 52 and 78 (ie, after possible addition of adalimumab; data not shown). Mean changes in patient-reported outcomes from week 26 to weeks 52 and 78 were similar in the two groups (data not shown). Figure 1 Percentage of patients with clinical, functional and radiographic outcomes stratified by initial treatment regimen. (A) LDA based on DAS28(CRP) <3.2 at weeks 26, 52 and 78. (B) Normal function based on HAQ-DI <0.5 at weeks 26, 52 and 78. (C) Radiographic non-progression based on ΔmTSS ≤0.5 at weeks 26, 52 and 78. (D) Radiographic nonprogression based on ΔmTSS ≤0.5 from week 26 to 52 and from week 26 to 78. *This analysis group included the ADA continuation arm (n=105) and, after scaling to yield a proportional equivalent number of patients, the ADA withdrawal arm (n=102). †P<0.001, χ2 test. Missing DAS28(CRP) and HAQ-DI data were imputed using last observation carried forward; missing ΔmTSS data were imputed using multiple imputation. ADA, adalimumab; CRP, C reactive protein; DAS28, 28-joint modified Disease Activity Score; HAQ-DI, Disability Index of the Health Assessment Questionnaire; LDA, low disease activity; mTSS, modified total Sharp score; MTX, methotrexate; PBO, placebo.

ed forward; missing ΔmTSS data were imputed using multiple imputation. ADA, adalimumab; CRP, C reactive protein; DAS28, 28-joint modified Disease Activity Score; HAQ-DI, Disability Index of the Health Assessment Questionnaire; LDA, low disease activity; mTSS, modified total Sharp score; MTX, methotrexate; PBO, placebo. ACR response rates from baseline to week 26 were higher on starting with adalimumab+MTX versus starting with MTX monotherapy, whereas in those starting with MTX monotherapy, the ACR rates were higher from week 26 to weeks 52 and 78 (figure 2). However, response rates were similar between groups from week 52 to week 78 or baseline to week 78. Figure 2 Response rates for patients achieving (A) 20%, (B) 50% and (C) 70% improvement in ACR criteria over the course of 78 weeks. *This analysis group included the ADA continuation arm (n=105) and, after scaling to yield a proportional equivalent number of patients, the ADA withdrawal arm (n=102). †Percentage improvement was assessed from week 26. ‡Percentage improvement was assessed from week 52. Missing data were imputed using last observation carried forward. ACR, American College of Rheumatology; ADA, adalimumab; MTX, methotrexate.

a proportional equivalent number of patients, the ADA withdrawal arm (n=102). †Percentage improvement was assessed from week 26. ‡Percentage improvement was assessed from week 52. Missing data were imputed using last observation carried forward. ACR, American College of Rheumatology; ADA, adalimumab; MTX, methotrexate. Discussion This post hoc analysis of patients with early, active RA (disease duration: ~4 months3) compared 78-week outcomes in patients initially treated with MTX monotherapy, followed by addition of adalimumab if treatment target was not achieved, versus patients initially treated with adalimumab+MTX combination therapy. Patients initially treated with MTX monotherapy had similar clinical, functional and patient-reported outcomes at weeks 52 and 78 as patients initially treated with adalimumab+MTX. Although initial adalimumab+MTX combination therapy resulted in minimally superior radiographic outcomes at a group level compared with initial MTX monotherapy, these mean differences were not deemed clinically relevant because, per an established formula, this 1-point difference on the radiographic scale translates to a negligible extent of irreversible functional impairment at the group level (0.01 HAQ points).7 Also, patients starting with adalimumab+MTX had higher ACR response rates in period 1 than patients starting with MTX monotherapy, but this pattern was reversed at week 52 when the baseline was ‘reset’ to week 26, so overall ACR response rates were similar by week 78. Thus, at a population level, starting with MTX monotherapy followed by addition of adalimumab in patients with early RA who did not respond to MTX within 6 months conveyed almost identical clinical, functional and quality of life (but not radiological) results at weeks 52 and/or 78 versus starting with adalimumab+MTX.

Thus, at a population level, starting with MTX monotherapy followed by addition of adalimumab in patients with early RA who did not respond to MTX within 6 months conveyed almost identical clinical, functional and quality of life (but not radiological) results at weeks 52 and/or 78 versus starting with adalimumab+MTX. EULAR and ACR recommend starting with MTX monotherapy or MTX+glucocorticoids1 2 8 but not with a bDMARD+MTX, in all patients with RA. In patients who do not achieve a treatment target of at least LDA and who have unfavourable prognostic factors (as in OPTIMA), adding a bDMARD is recommended. Our data fully validate this treat-to-target strategy2 by showing that the overall population of patients starting on MTX monotherapy, over time, fared as well in clinical, functional and structural respects as those starting on adalimumab+MTX. Furthermore, among those starting on MTX monotherapy, 24% achieved stable LDA at week 26,3 with little or no radiographic progression and mostly normative physical function thereafter; thus, the treat-to-target strategy allows for a good outcome without the need for a bDMARD, despite negative prognostic factors, and prevents overtreatment of one in four patients with active RA. Overall, by applying this strategy, approximately two of three patients with early RA achieve LDA or remission, the major therapeutic targets, within 1 year with essentially no or minimal joint damage.

for a bDMARD, despite negative prognostic factors, and prevents overtreatment of one in four patients with active RA. Overall, by applying this strategy, approximately two of three patients with early RA achieve LDA or remission, the major therapeutic targets, within 1 year with essentially no or minimal joint damage. To our knowledge, no previous study has addressed whether rapid addition of TNFi after MTX failure leads to different disease outcomes compared with an initial combination of TNFi+MTX. A further strength is the prospective design of this study. Limitations include the inherent bias of post hoc analyses and that the target was defined a priori as DAS28(CRP) <3.2, rather than a more stringent response. Patients were also not allowed alterations in glucocorticoids as recommended in treatment guidelines.1 2 8 Additionally, all patients who failed to achieve a clinical target received adalimumab and MTX, without comparisons with other rescue treatment options (eg, triple DMARD therapy and another bDMARD). The adalimumab+MTX population was not treated-to-target, unlike the MTX monotherapy population, since no treatment adjustment was made in patients who did not achieve stable LDA with adalimumab+MTX at week 26. Nonetheless, many adalimu-mab+MTX patients had further clinical/functional improvements and maintained the halt of radiographic progression. Furthermore, treatment was switched to MTX monotherapy in a subset of patients starting with adalimumab+MTX who had LDA at weeks 22 and 26; no equivalent removal of a therapeutic component was allowed in patients starting with MTX monotherapy who achieved stable LDA. Finally, rescue therapy was open label, which could have biased patient responses, particularly for the more subjective endpoints (eg, HAQ-DI); however, the initial treatment allocation remained blinded throughout the trial.

peutic component was allowed in patients starting with MTX monotherapy who achieved stable LDA. Finally, rescue therapy was open label, which could have biased patient responses, particularly for the more subjective endpoints (eg, HAQ-DI); however, the initial treatment allocation remained blinded throughout the trial. Conclusions Consistent with current treatment recommendations, starting with MTX monotherapy and optimising treatment by adding adalimumab after treatment failure at 26 weeks allowed patients with early RA to achieve comparable long-term clinical, functional and disease activity outcomes with patients who started with initial adalimumab+MTX combination therapy. This strategy also prevented potential overtreatment of approximately 25% of patients with early RA. Medical writing support was provided by Amanda Sheldon, PhD, Patrick Little, PhD, Katherine Groschwitz, PhD, Maria Hovenden, PhD, and Michael J. Theisen, PhD, of Complete Publication Solutions, LLC; this support was funded by AbbVie Inc. AbbVie and the authors would like to thank the patients who participated in the clinical trial and all study investigators for their contributions. Handling editor: Tore K Kvien Contributors: All authors have contributed to the work and approve the presented findings. Funding: AbbVie sponsored the study (OPTIMA; M06-810; NCT00420927) and analysis; contributed to their design and was involved in the collection, analysis and interpretation of the data. AbbVie was involved in the writing, review and approval of the manuscript.

Contributors: All authors have contributed to the work and approve the presented findings. Funding: AbbVie sponsored the study (OPTIMA; M06-810; NCT00420927) and analysis; contributed to their design and was involved in the collection, analysis and interpretation of the data. AbbVie was involved in the writing, review and approval of the manuscript. Competing interests: AK has provided remunerated expert advice to and received grant/research support for his institution from AbbVie. RFvV has received grants and research support from AbbVie, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Roche and UCB, and consulting fees and honoraria from AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, Crescendo, GlaxoSmithKline, Centocor-Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB and Vertex. RF provided remunerated expert advice to and received grant support from AbbVie. PE has received research grants and/or consulting fees from AbbVie, Bristol-Myers Squibb, Lilly, Merck, Novartis, Pfizer, Roche, Sandoz and UCB. SF, IS and SC are employees of AbbVie and may hold stock or stock options. BG is a former employee of AbbVie and may hold stock or stock options. HK is an employee of AbbVie Deutschland GmbH & Co KG and may hold stock or stock options. JSS has provided remunerated expert advice to and received grant/research support for his institution from AbbVie. Ethics approval: A central institutional review board or independent ethics committee approved the study at each of the 161 study sites. Provenance and peer review: Not commissioned; externally peer reviewed.