Interleukin-40 in Systemic Sclerosis: A Treatment-Sensitive Marker of Immune Modulation Rather Than Disease Activity

Interleukin-40 (IL-40) is a recently identified cytokine primarily produced by activated B cells and implicated in immune regulation across several autoimmune diseases. Although B cell-driven immune dysregulation plays a central role in systemic sclerosis (SSc), the circulating behavior and clinical relevance of IL-40 in this disease remain poorly defined. To characterize serum IL-40 levels in patients with SSc and to explore their associations with immunosuppressive treatment exposure, disease subsets, clinical manifestations, and disease activity. Serum IL-40 levels were measured by ELISA in 41 patients with SSc and 29 age- and sex-matched healthy controls. Patients were stratified according to immunosuppressive treatment status at the time of serum sampling. Clinical features, organ involvement, and disease activity were recorded. Serum IL-40 levels differed significantly among immunosuppressed SSc patients, untreated SSc patients, and healthy controls (p < 0.001). Patients receiving immunosuppressive therapy exhibited markedly lower IL-40 concentrations compared with both untreated SSc patients and healthy controls. In contrast, untreated SSc patients showed IL-40 levels comparable to controls. Serum IL-40 levels were not significantly associated with cutaneous disease subtype, interstitial lung disease, dysphagia, or disease activity status. Stratified analyses demonstrated that lower IL-40 levels in treated patients were observed irrespective of disease activity. Lower circulating IL-40 levels were observed in immunosuppressed patients irrespective of disease phenotype, organ involvement, or disease activity. These findings support an association between treatment exposure and circulating IL-40 levels, although longitudinal studies are needed to clarify causality.