Objective: to assess the efficacy of the monoclonal antibody adalimumab (ADM) in the treatment of juvenile idiopathic arthritis-associated uveitis (JIA-U).
Design: multicentre double-blind randomised controlled trial.
Setting: 14 ophthalmology or rheumatology clinics in the United Kingdom (Bristol, Liverpool and London).
Trial population: adolescents and children aged more than 2 years with a diagnosis of active JIA-U that had been receiving stable treatment with methotrexate (10 to 20 mg/m2 of body surface area, maximum of 25 mg) for at least 3 months. The exclusion criteria were previous exposure to ADM or other biologic agents, receipt of more than 6 topical glucocorticoid drops per eye per day, and treatment with prednisone (or the equivalent) at a dose exceeding 0.2 mg/kg of body weight per day.
Intervention: between October 2011 and April 2015, out of 332 eligible patients, 242 were finally excluded because they did not meet the criteria. Sixty patients were randomly assigned to the group that received ADM (intervention group [IG]) via the subcutaneous route and every two weeks (at a dose of 20 mg in patients weighing less than 30 kg, or a dose of 40 mg in patients weighing 30 or more kg), and 30 patients to receive placebo (control group [CG]), which was also injected every 14 days. Fifteen percent of patients in the IG and 23% in the CG withdrew from the trial intervention for reasons other than treatment failure.
Outcome measurement: the primary endpoint was the time to treatment failure (assessed by determination of the grade of intraocular inflammation by slit-lamp biomicroscopy applying well-defined criteria). Ophthalmic assessments were performed at the time of randomisation and during scheduled visits at 4, 8 and 12 weeks and every 3 months thereafter until completion of 18 months of treatment or withdrawal from treatment, with a followup of six months in all patients after treatment completion or withdrawal. All patients that received at least 1 dose of ADM or placebo were included in the safety analyses (total adverse events and total severe adverse events). The statistical analysis was by intention to treat and primarily assessed the time to treatment failure by plotting Kaplan-Meier survival curves, comparing groups with the long-rank test and fitting a Cox proportional-hazards model. A sensitivity analysis tested the effects of missing data, participants who stopped the intervention protocol early, or participants that were incorrectly identified as having treatment failure.
Main results: the trial was stopped early owing to evidence that the risk of treatment failure was significantly lower in the IG compared to the CG (treatment failure in 27% compared to 60% of patients, respectively; hazard ratio [HR] of the IG versus CG of 0.25; 95% confidence interval [95 CI]: 0.12 to 0.49). Nine sensitivity analyses confirmed the conclusions of the primary analysis. There were differences in the adverse events experienced by each group: the rate of serious adverse events was greater in the IG (0.29 serious events graves per patient-year [95 CI: 0.15 to 0.43]) compared to the CG (0.19 events per patient-year [95 CI: 0.00 to 0.40]); the total number of events per patient-year was significantly greater in the IG (10.07; 95 CI: 9.26 to 10.89) compared to the CG (6.51; 95 CI: 5.26 to 7.77).
Conclusion: combining ADM with methotrexate seemed useful for the treatment of JIA-U, despite the significant increase in the incidence of adverse events (most of them mild).
Conflicts of interest: detailed in the full text of the article.
Funding source: grants from the National Institute for Health Research Health Technology Assessment Programme and Arthritis Research UK.