Ab1160 Il-40 Elevation in Systemic Sclerosis: Unravelling a Link to Disease Activity, Gastrointestinal Involvement, Immune Regulation and Fibrotic Processes

Background: Interleukin 40 (IL-40) is an emerging cytokine implicated in malignancies and autoimmune rheumatic disorders. Recent studies described an association between IL-40 and fibrotic mediators. Since inflammation and fibrosis are pivotal elements of systemic sclerosis (SSc), we aimed to analyse the implication of IL-40 in SSc. Objectives: The aim of our study was to investigate the role of IL-40 in SSc. Methods: IL-40 expression was determined in dermal biopsies of SSc patients and healthy controls (HC) by immunohistochemistry (n=6). IL-40 was analysed in the serum of the cross-sectional cohort of 93 SSc patients and 145 HC. IL-40 levels were determined in 37 individuals at risk of SSc (VEDOSS, very early diagnosis of SSc). Twenty-four patients from the VEDOSS cohort were divided into progressors* (n=11) and non-progressors** (n=13) (mean follow-up 3.5 years, Table 1A). Serum IL-40 was analysed in 24 SSc patients with progressive skin thickening and/or arthritis and/or interstitial lung disease non-responsive to methotrexate, mycophenolate or cyclophosphamide who were treated with 2 (n=24) or 3 (n=16) series of rituximab (RTX†) (baseline, 6 and 12 months). The disease activity was assessed by European Scleroderma Study Group (ESSG) index. Clinical characteristics are shown in Table 1A. The effect of recombinant IL-40 on peripheral blood mononuclear cells (PBMCs) from SSc patients (n=5-9) and HC (n=3) was determined in vitro. The expression of selected molecules was analysed by immunoassays and qPCR. Results: IL-40 was expressed in the skin of SSc and HC individuals, in the fraction of dermal fibroblasts and round-shaped immune infiltrates. Serum IL-40 was increased in patients with SSc compared to HC (3.89 vs. 1.49 ng/ml; p<0.0001) and associated with disease activity (ESSG; r=0.365, p=0.0006), gastrointestinal involvement (GI; p<0.05). Furthermore, IL-40 positively correlated with serum IL-8 (r=0.270, p=0.019) and TGF-β1 (r=0.301, p=0.020). In the RTX cohort, no significant changes in serum IL-40 were observed upon treatment; nevertheless, both baseline and change in IL-40 levels upon RTX therapy were associated with a change in several clinical parameters (Table 1B). Serum IL-40 was elevated in VEDOSS compared to HC (2.49 vs. 1.53 ng/ml; p=0.0009). No significant changes were observed in progressors vs non-progressors; however, IL-40 was associated with capillaroscopy findings (p<0.05). IL-40 induced up-regulation of IL-6 (p<0.001), MCP-1 (p<0.05) and IL-10 (p<0.01) in PBMCs from SSc patients and HC in vitro. Conclusion: Our results show that IL-40 was up-regulated in SSc patients, associated with disease activity, GI involvement and fibrotic mediators. In addition, our in vitro data indicate that IL-40 might be involved in the regulation of immune response and fibrotic processes in SSc. REFERENCES: NIL. Acknowledgements: MHCR023728, GAUK114122, SVV260638, BBMRI-CZ LM2023033. Disclosure of Interests: None declared.