Neutrophils predominate as IL1B-expressing cells in Schnitzler syndrome: Insights from the SCan study

Schnitzler syndrome (SchS) is a late-onset autoinflammatory disease characterized by urticarial rash and monoclonal gammopathy. SchS shares clinical features with cryopyrin-associated periodic syndrome, which is driven by gain-of-function mutations in NLRP3, and while IL-1β-targeted therapies have shown efficacy, the underlying pathogenesis of SchS remains unclear. During a multicenter, single-arm, open-label, investigator-initiated trial evaluating the efficacy and safety of canakinumab in five Japanese patients with SchS (named the SCan Study after SchS and Canakinumab), based on a similar study conducted in Germany, we measured 32 cytokines/chemokines and 11 complement-related factors in plasma and analyzed their correlations with changes in clinical symptoms during treatment. Furthermore, in two cases, single-cell RNA sequencing of peripheral blood and spatial transcriptomic analysis of lesional skin were performed to identify IL1B-expressing cells. The improvement in clinical symptoms and quality of life was maintained for 48 weeks following canakinumab treatment. Notably, these changes in clinical symptoms strongly correlated with WBC count, neutrophil count, CRP, and serum amyloid A levels, which were used as evaluation parameters in this study. In contrast, IL-1β and most other cytokines/chemokines exhibited distinct patterns and were not useful as markers of disease activity. IgM levels remained stable without an upward trend. Additionally, IL1B-expressing cells were predominantly neutrophils in both peripheral blood and lesional skin. Furthermore, neutrophil counts in peripheral blood decreased following canakinumab administration. This study demonstrated that the primary source of IL1B-expressing cells in SchS is neutrophils. Moreover, canakinumab improves clinical symptoms by regulating neutrophil dynamics in peripheral blood.