Serum interleukin-38 is paradoxically elevated in rheumatoid arthritis and associated with disease activity and treatment intensity: a cross-sectional study

Abstract Background Interleukin-38 (IL-38), an anti-inflammatory IL-1 superfamily member, is paradoxically elevated in Rheumatoid Arthritis (RA). Whether this reflects pathogenic involvement or compensatory counter-regulation remains unresolved. Co-measuring Protein Tyrosine Phosphatase Non-Receptor ( PTPN22 ) expression offers a unique opportunity to determine whether IL-38 operates within the upstream molecular architecture of RA or merely co-varies with downstream inflammation. Methodology This cross-sectional study enrolled 140 individuals (70 RA, 70 controls) from rheumatology centers in Babylon, Iraq. Serum IL-38, Interleukin-6 (IL-6), Interleukin-17 A (IL-17 A), and tumor necrosis factor alpha (TNF-α) were quantified by sandwich enzyme linked immunosorbent assay (ELISA); (PTPN22) and Human Leukocyte Antigen DRB1 (HLA-DRB1) were quantified by quantitative real-time polymerase chain reaction (qRT-PCR) and expressed as relative fold change using the 2 − ΔΔCt method. Spearman correlation, Kruskal–Wallis with Dunn’s post hoc, and multivariable linear regression were applied. Results IL-38 was significantly elevated in RA (104.47 ± 37.82 pg/mL) versus controls (58.60 ± 16.73 pg/mL; p < 0.001), correlating strongly with DAS28-ESR (ρ = +0.722), CRP (ρ = +0.661), IL-6 (ρ = +0.587), and IL-17 A (ρ = +0.543). It showed a strong inverse correlation with PTPN22 (ρ = −0.664) but null correlation with HLA-DRB1 (ρ = −0.001). IL-38 was lowest in biologic-treated patients and highest in newly diagnosed cases (H = 39.56, p < 0.001) and remained independently significant in multivariable regression (adjusted β = 0.005, p = 0.025; multivariable R² = 0.818). Conclusions IL-38 is associated with disease activity, shows no association with HLA-DRB1 expression, and is lower among patients receiving more advanced pharmacological therapy — identifying it as a candidate pharmacodynamic biomarker in RA.