Comparing Three Ways to Start Treatment for Patients with Polyarticular Juvenile Idiopathic Arthritis—The Stop-JIA Trial [Internet]

Excerpt

Background: Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic condition, affecting 1 to 4 of 1000 children. More than half have polyarticular JIA (pJIA) and experience poorer outcomes and quality of life. Many effective treatments for pJIA are now available, but there is significant treatment variation among pediatric rheumatologists, due in part to a lack of data comparing the effectiveness of different timing for starting biologic medication. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) has developed 3 standardized pJIA consensus treatment plans (CTPs) to be the subject of comparative effectiveness research (CER). By directly comparing clinical and patient-reported outcomes (PROs) in patients with pJIA treated with the 3 CTPs, the results of this study can provide critical information to assist physicians and patients in their treatment decisions.

Objectives: Our study, Start Time Optimization of biologics in Polyarticular-JIA (STOP-JIA), compared the effectiveness of the pJIA CTPs in real-life settings. We proposed the following specific aims: to compare (1) the clinical effectiveness of 3 different strategies for starting biologic therapy in untreated pJIA using clinically inactive disease (CID) at 12 months as the primary outcome, and (2) PROs and caregiver-reported outcomes as the secondary outcome.

Methods: STOP-JIA was a prospective observational cohort study conducted using the CARRA Registry that compared 3 CTPs:

1. Step Up. Nonbiologic disease-modifying antirheumatic drug (DMARD) monotherapy (such as methotrexate or sulfasalazine), adding biologic medication if needed after ≥3 months

2. Early Combination. DMARD and biologic medication are started together

3. Biologic First. Biologic monotherapy, adding DMARD medication later if needed

Children and their caregivers in consultation with their pediatric rheumatologist chose 1 of the 3 CTPs and were followed for 12 months. There was no randomization.

The primary outcome was the proportion of children achieving CID at 12 months off glucocorticoids (GCs). Secondary outcomes were the comparison of Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference and Mobility PROs that addressed variables identified as important in a caregiver survey and/or were recommended by the PCORnet PRO Common Measures Working Group (as part of the PCORI initiative to facilitate integration of electronic health record data into CER. The primary analysis was intention to treat.

Other secondary outcomes included the achievement of Juvenile Arthritis Disease Activity Score (JADAS) remission, time to achievement of JADAS remission and CID, adverse events, medication adverse effects, and time to discontinuation of GCs. Propensity score (PS) modeling was used to adjust for potential confounders, and multiple imputation (MI) was used to address missing data. Adjusted comparisons were also made using Bayesian models.

Results: We enrolled 401 children and adolescents with untreated pJIA at 56 CARRA Registry sites. One patient who did not have JIA was started on treatment but was subsequently excluded from the analysis, leaving 400 analyzable patients. In total, 257 (64%) patients were started on the Step Up CTP, 100 (25%) patients were started on the Early Combination CTP, and 44 (11%) patients were started on the Biologic First CTP. Twenty (5%) patients were lost to follow-up before the 12-month visit, and of the remaining 380 patients, 43 (11%) did not have a 12-month visit (28 Step Up, 12 Early Combination, and 3 Biologic First). Treatment choice was made through shared decision-making. There were significant baseline differences between the CTP groups in JIA categories, number of active joints, physician global assessment of disease activity, and 10-joint clinical JADAS (cJADAS10) scores. The unadjusted rates for achieving CID at 12 months (primary outcome) were 37% (95% CI, 27%-49%) in Early Combination, 32% (95% CI, 26%-39%) in Step Up, and 24% (95% CI, 12%-43%) in Biologic First. After PS weighting and MI, the rates were 47.3% (95% CI, 32.6%-62%) in Early Combination vs 37.8% (95% CI, 29.4%-46.2%) in Step Up (P = .17). The cJADAS10 remission (score ≤2.5) at 12 months (secondary outcome) favored Early Combination over Step Up (66.6% vs 42.4%, respectively; P = .02). No significant differences were observed in the 2 PROMIS measures of pain interference and mobility between groups, although both outcomes improved during the study.

Conclusions: The STOP-JIA study addressed a question of critical importance to children with pJIA, their caregivers, and their health care providers: When is the best time to begin biologic medications to achieve the optimal clinically reported outcomes and PROs? Our results indicate no significant differences between the 3 CTPs in achieving the primary outcome of CID at 12 months off GCs. The Early Combination CTP group did show improvement in a secondary outcome (cJADAS10 remission) compared with the Step Up group, but these results are limited by substantial missing data. This is the first use of CARRA standardized CTPs in an observational prospective study to determine comparative effectiveness.

Limitations: This is a diverse population of patients, and even though all patients had polyarticular forms of JIA, multiple categories of JIA were included. Because this was an observational study without randomization, there were baseline differences in the CTP groups, which required adjustments to reduce bias, but there is likely residual confounding. Small sample size, variation in CTP and medication adherence, missed visits, incomplete questionnaires, and missing data were also limitations. Last, fewer patients were enrolled in the Early Combination and Biologic First CTPs than was expected, limiting the power of some of the planned analyses.