¹University Medical Center Schleswig-Holstein, Rheumatology, Internal Medicine I, Kiel
²DLR, Clinical Air and Space Medicine, Cologne
³Kiel University, Institute of Epidemiology and Biobank popgen, Kiel
⁴University Medical Center Schleswig-Holstein, Internal Medicine I, Kiel
⁵Kiel University, Institute for Clinical Molecular Biology, Kiel
⁶Kiel University, Division of Food Technology, Human Nutrition and Food Science, Kiel

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Introduction: Interleukin 6 (IL-6) plays a central role in the pathogenesis of rheumatoid arthritis (RA). While classic IL-6 signalling involves membrane-bound IL-6 receptors (IL-6R), trans-signalling involves soluble IL-6 receptors (sIL6R) and membrane-bound glycoprotein 130 (gp130). Soluble gp130 (sgp130) inhibits IL-6 trans-signalling. Understanding how IL-6 signalling components respond to targeted therapies may offer mechanistic insights.

Methods: Serum samples were collected from patients with active arthritis at baseline and 3–6 months after treatment intensification with a targeted therapy. IL-6, sIL6R and sgp130 concentrations were measured by ELISA and correlated with treatment response (defined as SDAI decrease of ≥ 50% or achieving SDAI remission at follow-up).

Results: Fifty-four patients (39 female) were included: 44 with RA (31 seropositive), 8 with psoriatic arthritis, 1 with peripheral spondyloarthritis, and 1 with juvenile idiopathic arthritis. Median baseline SDAI was 17.4 (IQR 12.3–21.4). Treatments comprised TNFi (n=31), JAKi (n=18) and IL-6Ri (n=5). IL-6, sIL6R and sgp130 levels did not differ between SDAI responders and non-responders (all p > 0.05). However, IL-6 levels significantly increased (p < 0.01) after IL6Ri treatment, and sIL6R concentrations were significantly higher than in patients treated with TNFi (p < 0.001) and JAKi (p < 0.05). Conversely, sIL6R significantly decreased with JAKi treatment compared to baseline (p < 0.01).

Conclusion: In this pilot study, soluble IL-6 signalling components were not associated with treatment response, but therapy-specific effects were observed: IL6 and sIL6R were increased under IL6R blockade – likely due to feedback and reduced clearance, while sIL6R decreased under JAK inhibition, possibly reflecting lower receptor turnover. These findings suggest class-specific modulation of IL-6 signalling and warrant further investigation.

Funding: This study received financial support from the DGRh Forschungsinitiative and the Cluster of Excellence “Precision Medicine in Chronic Inflammation”.

Disclosures: JHS: None declared; UG: None declared; HK: None declared; BH: Speakers honorary (Chugai), GJ: None declared; JL: Scientific advisory board/speakers bureau: Abbvie, Amgen, AstraZeneca, BMS, Galapagos/Alfasigma, Janssen-Cilag, Lilly, Novartis, Sanofi, UCB, Research support: Abbott, Boehringer, Gilead, Novartis; SS: Consulting fees: AbbVie, Amgen, Arena, BMS, Biogen, Celltrion, Celgene, Falk, Fresenius Kabi, Galapagos, Gilead, Hikma, IMAB, Janssen, Lilly, MSD, Mylan, Pfizer, Protagonist Provention Bio, Takeda, Theravance and Ventyx, SW: None declared.