• Athimalaipet V Ramanan, Andrew D Dick, Ashley P Jones, Dyfrig A Hughes, Andrew McKay, Anna Rosala-Hallas, Paula R Williamson, Ben Hardwick, Helen Hickey, Naomi Rainford, Graeme Hickey, Ruwanthi Kolamunnage-Dona, Giovanna Culeddu, Catrin Plumpton, Eifiona Wood, Sandrine Compeyrot-Lacassagne, Patricia Woo, Clive Edelsten, and Michael W Beresford.
• Department of Paediatric Rheumatology, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
• Health Technol Assess. 2019 Apr 1; 23 (15): 1-140.

BackgroundChildren with juvenile idiopathic arthritis (JIA) are at risk of uveitis. The role of adalimumab (Humira®; AbbVie Inc., Ludwigshafen, Germany) in the management of uveitis in children needs to be determined.ObjectiveTo compare the efficacy, safety and cost-effectiveness of adalimumab in combination with methotrexate (MTX) versus placebo with MTX alone, with regard to controlling disease activity in refractory uveitis associated with JIA.DesignThis was a randomised (applying a ratio of 2 : 1 in favour of adalimumab), double-blind, placebo-controlled, multicentre parallel-group trial with an integrated economic evaluation. A central web-based system used computer-generated tables to allocate treatments. A cost-utility analysis based on visual acuity was conducted and a 10-year extrapolation by Markov modelling was also carried out.SettingThe setting was tertiary care centres throughout the UK.ParticipantsPatients aged 2-18 years inclusive, with persistently active JIA-associated uveitis (despite optimised MTX treatment for at least 12 weeks).InterventionsAll participants received a stable dose of MTX and either adalimumab (20 mg/0.8 ml for patients weighing < 30 kg or 40 mg/0.8 ml for patients weighing ≥ 30 kg by subcutaneous injection every 2 weeks based on body weight) or a placebo (0.8 ml as appropriate according to body weight by subcutaneous injection every 2 weeks) for up to 18 months. A follow-up appointment was arranged at 6 months.Main Outcome MeasuresPrimary outcome - time to treatment failure [multicomponent score as defined by set criteria based on the Standardisation of Uveitis Nomenclature (SUN) criteria]. Economic outcome - incremental cost per quality-adjusted life-year (QALY) gained from the perspective of the NHS in England and Personal Social Services providers. Full details of secondary outcomes are provided in the study protocol.ResultsA total of 90 participants were randomised (adalimumab, n = 60; placebo, n = 30). There were 14 (23%) treatment failures in the adalimumab group and 17 (57%) in the placebo group. The analysis of the data from the double-blind phase of the trial showed that the hazard risk (HR) of treatment failure was significantly reduced, by 75%, for participants in the adalimumab group (HR 0.25, 95% confidence interval 0.12 to 0.51; p < 0.0001 from log-rank test). The cost-effectiveness of adalimumab plus MTX was £129,025 per QALY gained. Adalimumab-treated participants had a much higher incidence of adverse and serious adverse events.ConclusionsAdalimumab in combination with MTX is safe and effective in the management of JIA-associated uveitis. However, the likelihood of cost-effectiveness is < 1% at the £30,000-per-QALY threshold.Future WorkA clinical trial is required to define the most effective time to stop therapy. Prognostic biomarkers of early and complete response should also be identified.Trial RegistrationCurrent Controlled Trials ISRCTN10065623 and European Clinical Trials Database number 2010-021141-41.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 15. See the NIHR Journals Library website for further project information. This trial was also funded by Arthritis Research UK (grant reference number 19612). Two strengths of adalimumab (20 mg/0.8 ml and 40 mg/0.8 ml) and a matching placebo were manufactured by AbbVie Inc. (the Marketing Authorisation holder) and supplied in bulk to the contracted distributor (Sharp Clinical Services, Crickhowell, UK) for distribution to trial centres.

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