Association of Treatment Status with Cytokine and sCTLA-4 Profiles in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is triggered by dysregulated cytokine networks, but the distributional association of conventional synthetic (csDMARDs) and biologic DMARDs (bDMARDs) with circulating mediators has not been fully described. In this study, we aimed to investigate the treatment-associated modulation of TNF-α, IL-17, IL-13, and soluble CTLA-4 (sCTLA-4) in 64 RA patients (untreated, n = 14; csDMARD, n = 32; bDMARD ± csDMARD, n = 18) and 20 controls. ELISA was used to determine the serum levels, and Kruskal–Wallis tests and false discovery rate correction were used to determine the differences between groups, accompanied by DAS28- and CRP-adjusted quantile regression. Group-level analysis demonstrated that the levels of IL-17 were higher in patients treated with csDMARDs and bDMARDs than in the controls (FDR-adjusted p = 0.0009 and <0.0001, respectively), and the levels of IL-13 were higher in patients treated with bDMARDs than in the controls (p = 0.026). However, quantile regression did not reveal consistent treatment-related associations, suggesting that long-term pathway-specific immune responses and context-dependent regulation may be involved. Smoking independently predicted higher IL-13 at lower quantiles (β = 35.5; p < 0.0001), while TNF-α showed treatment-related increases only at the upper quantile in CRP-adjusted models (β = 323.7; p = 0.049). On the other hand, sCTLA-4 had the largest and most significant treatment-based increase (p < 0.0001), regardless of disease activity, and constant effects across mid-quantiles. Taken together, these findings suggest that sCTLA-4 shows therapy-responsive distributional changes, supporting its potential utility as a biomarker of biological efficacy. In contrast, the observed increases in IL-17 and IL-13 reflect ongoing immune activity and possible environmental influences. Distribution-sensitive biomarker profiling provides a nuanced approach to capturing immune response diversity in RA and may enhance precision in monitoring procedures.