Two- and 3-Year Outcomes of the Childhood Arthritis and Rheumatology Research Alliance FiRst Line Options for sJIA Treatment (FROST) Trial

Background: Systemic juvenile idiopathic arthritis (sJIA) is a severe autoinflammatory disease associated with substantial morbidity, including macrophage activation syndrome (MAS), sJIA-associated lung disease, and glucocorticoid (GC)-related toxicity. CARRA’s FiRst Line Options for sJIA Treatment (FROST) study demonstrated favorable short-term outcomes with early biologic therapy, but long-term outcomes have not yet been described. Methods: Patients with new-onset sJIA enrolled in FROST (2016–2019) were followed longitudinally through the CARRA Registry. Four consensus treatment plans (CTPs) were evaluated, including biologic (IL-1 or IL-6 inhibitors) and non-biologic approaches. Long-term follow-up occurred through 36 months. The primary outcome was achievement of clinically inactive disease (CID) by Wallace/ACR provisional criteria without concurrent GC use at 24 and 36 months. Secondary outcomes included CID irrespective of GC use, cJADAS-10 ≤ 2.5 without fever, medication utilization, and safety events. Adverse events were expressed as events per 100 person-years. Results: Seventy-three patients were enrolled; 87.6% initiated biologic therapy. At 24 and 36 months, 41 and 32 patients, respectively, had evaluable data for the primary outcome. CID without GC use was achieved by 58.5% of patients at 24 months and 65.5% at 36 months. At both time points, over 80% of patients achieved cJADAS-10 ≤ 2.5 without fever and without GC use. Nearly all patients were off GCs at 24 and 36 months (> 90%). The cumulative proportion of patients achieving CID at any time during follow-up increased to 78.8% by 24 months and 87.6% by 36 months. At last follow-up, 42.5% of the cohort was off all DMARDs. Over 228.2 person-years of observation, serious adverse events occurred at a rate of 6.6 per 100 person-years; MAS was the most common SAE. No cases of sJIA-associated lung disease were identified. Conclusions: Patients with sJIA enrolled in FROST demonstrated continued clinical improvement during long-term follow-up, with increasing rates of clinically inactive disease and high rates of glucocorticoid discontinuation. Serious adverse events were uncommon and largely related to disease activity. These findings support early biologic therapy as an effective and durable first-line strategy for sJIA.