Interleukin‐18 Levels Are Associated With Disease Course in Patients With Still Disease Treated With Interleukin‐1 Inhibitors

OBJECTIVE: To evaluate the prognostic utility of circulating interleukin-18 (IL-18) levels in predicting disease activity, macrophage activation syndrome (MAS), and disease course in patients with Still disease (SD) receiving first-line IL-1 inhibitors (IL-1i). METHODS: We retrospectively analyzed 66 biologic-naive patients with SD who received first-line treatment with IL-1i. Plasma IL-18 levels were measured at baseline and at 3, 6, and 12 months after IL-1i initiation. Associations between IL-18 levels and clinical outcomes were assessed using mixed-effects models, receiver operating characteristic (ROC) curve analysis, and multivariate logistic regression. RESULTS: Median baseline IL-18 levels were 61,425 pg/mL (interquartile range 16,194-235,746) and declined significantly after IL-1 blockade (P < 0.0001). Higher IL-18 levels persisted in patients with active disease (P < 0.0001). Baseline IL-18 >45,000 pg/mL predicted active disease at 12 months (area under the curve [AUC] 0.82; P = 0.0002), MAS development within 24 months (AUC 0.78; P = 0.01), and a chronic-persistent course (AUC 0.73; P = 0.007). In multivariate models, elevated baseline IL-18 and delayed IL-1i initiation for more than three months independently predicted adverse outcomes. Strikingly, at three months, IL-18 >15,000 pg/mL was a stronger predictor of chronic-persistent course (AUC 0.92; P < 0.0001), independent of clinical disease activity (odds ratio 25.6; P = 0.01), with the multivariate model explaining 67% of variance (AUC 0.95). CONCLUSION: In biologic-naive patients with SD, IL-18 levels, especially reassessed three months after IL-1i initiation, robustly predict long-term disease activity, MAS risk, and chronic-persistent trajectory. Early measurement and dynamic monitoring of IL-18 may enable risk stratification and guide timely therapeutic escalation or treatment adjustment to improve outcomes.