Comparative risk of systemic autoimmune diseases in juvenile idiopathic arthritis treated with TNF-α or IL-6 inhibitors

Objective: This study aimed to compare the risk of developing systemic autoimmune diseases (SADs) among pediatric patients with juvenile idiopathic arthritis (JIA) treated with tumor necrosis factor inhibitors (TNFi) versus interleukin-6 inhibitors (IL-6i), based on real-world data. Methods: We conducted a retrospective real-world cohort study using the TriNetX Research Network, which contains data from over 122 million patients. Individuals ≤18 years of age with a diagnosis of JIA who initiated TNFi or IL-6i therapy between January 1, 2013, and December 31, 2024, were included. Propensity score matching (1:1) was performed to balance baseline characteristics. The primary outcome was the incidence of SADs. Hazard ratios (HRs) were estimated using Cox proportional hazards models, and subgroup and sensitivity analyses were conducted to assess robustness. Results: After matching, 1,192 patients were included in each cohort. The TNFi group demonstrated a significantly lower incidence of SADs than the IL-6i group (17 vs. 45 events; HR = 0.37, 95% CI: 0.20–0.63). Subgroup analyses showed consistent protective effects of TNFi across age, sex, and concomitant medication strata. Sensitivity analyses across three adjusted models confirmed the robustness of the findings, yielding HRs ranging from 0.28 to 0.46. Conclusion: Among pediatric patients with JIA, TNF inhibitor therapy was associated with a substantially lower risk of developing systemic autoimmune diseases compared with IL-6 inhibitor therapy. These findings may inform biologic selection and long-term safety considerations in pediatric rheumatologic practice.