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.
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.
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.
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.