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Excess Serum Interleukin-18 Distinguishes Patients with Pathogenic Mutations in PSTPIP1. OBJECTIVE: Dominantly-inherited PSTPIP1 mutations cause a spectrum of autoinflammatory manifestations epitomized by Pyogenic Arthritis, Pyoderma gangrenosum, and Acne (PAPA) syndrome. The connections between PSTPIP1 and PAPA are poorly understood, although evidence suggests pyrin-inflammasome activation. Interleukin (IL)-18 is an inflammasome-activated cytokine associated with susceptibility to Macrophage Activation Syndrome (MAS), but its association with PAPA is unclear. METHODS: Clinical and genetic data, and serum samples were obtained from patients referred with symptoms concerning for PAPA syndrome. Serum Interleukin-18 (IL-18), IL-18 Binding Protein (IL-18BP), and CXCL9 were assessed by bead-based assay, and free IL-18 was assessed by ELISA. RESULTS: PSTPIP1-positive PAPA patients' symptoms overlapped with those of mutation-negative PAPA-like patients, but mutation-positive patients had earlier onset and more arthritis. We found uniform elevation of total serum IL-18 in treated PAPA patients at levels nearly as high as NLRC4-associated autoinflammation with infantile enterocolitis (AIFEC) patients and well above levels in most Familial Mediterranean Fever patients. IL-18 elevation in PAPA patients' serum persisted despite fluctuations in disease activity. The soluble IL-18 antagonist IL-18BP was modestly elevated, and PAPA patients had detectable free IL-18. PAPA syndrome was rarely associated with elevation of CXCL9, an indicator of Interferon-gamma activity, but no PAPA patients had histories of MAS. CONCLUSION: PAPA syndrome is a refractory and often disabling monogenic autoinflammatory disease associated with chronic and unopposed elevation of serum IL-18 but not risk for MAS. These findings affect our understanding of the diseases in which IL-18 is over-produced and suggest a link between pyrin-inflammasome activation, IL-18, and autoinflammation without susceptibility to MAS.