Adalimumab in combination with methotrexate for refractory uveitis associated with juvenile idiopathic arthritis: a RCT
- PMID: 31033434
- PMCID: PMC6511891
- DOI: 10.3310/hta23150
Adalimumab in combination with methotrexate for refractory uveitis associated with juvenile idiopathic arthritis: a RCT
Abstract
Background: Children 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.
Objective: To 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.
Design: This 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.
Setting: The setting was tertiary care centres throughout the UK.
Participants: Patients aged 2-18 years inclusive, with persistently active JIA-associated uveitis (despite optimised MTX treatment for at least 12 weeks).
Interventions: All 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 measures: Primary 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.
Results: A 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.
Conclusions: Adalimumab 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 work: A 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 registration: Current Controlled Trials ISRCTN10065623 and European Clinical Trials Database number 2010-021141-41.
Funding: This 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.
Keywords: ADALIMUMAB; JUVENILE IDIOPATHIC ARTHRITIS; METHOTREXATE; OPHTHALMOLOGY; PAEDIATRIC; RANDOMISED CONTROLLED TRIAL; RHEUMATOLOGY; SAFETY; UVEITIS.
Plain language summary
Juvenile idiopathic arthritis (JIA) is one of the most common rheumatic diseases in children and young people, who are at risk of developing inflammation in an area of the eye called the uvea (called uveitis). The purpose of the study was to look at how effective the use of adalimumab in combination with methotrexate (MTX) is compared with using MTX alone to treat JIA-associated uveitis. A total of 90 children (aged 2–18 years) taking MTX with JIA-associated uveitis took part in the study. If the inflammation in a patient’s eye or eyes was not getting better during the 18 months, the patient was told to stop taking the study drug. It was found that those patients who were taking placebo and MTX in the trial stopped taking the study drug sooner than those who were taking adalimumab and MTX. This means that adalimumab and MTX was better at treating uveitis than MTX alone. It was found that more patients taking adalimumab and MTX together either reduced or stopped taking topical steroids than the patients taking placebo and MTX. It was found that patients taking adalimumab and MTX together experienced more side effects than those taking placebo with MTX. However, these were expected based on what was already known about adalimumab’s side effects. An economic evaluation was conducted to estimate whether or not adalimumab would represent value for money for the NHS for this condition. This included long-term effects based on information about patients’ clarity of vision. The analysis showed that adalimumab may not be cost-effective, as the additional costs of treatment may not be justified by the benefits. The final results show that although adalimumab used in combination with MTX does help to treat patients with JIA and uveitis, it may not represent good value for the NHS.
Conflict of interest statement
Athimalaipet V Ramanan reports grants from the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme and Arthritis Research UK during the conduct of the study and others from AbbVie Inc. (Ludwigshafen, Germany) and the University Hospitals Bristol NHS Foundation Trust, outside the submitted work. He has received speaker fees from AbbVie Inc. and lectured in symposia, sponsored by AbbVie Inc.. He has also been on an Advisory Board organised by AbbVie Inc. and has been supported by AbbVie Inc. to attend European and American Rheumatology Society meetings. Andrew D Dick reports other from data and revenue sharing outside the submitted work for consultancy work, paid to University of Bristol by AbbVie Inc., Ashley P Jones, Andrew McKay, Anna Rosala-Hallas, Ben Hardwick, Helen Hickey, Naomi Rainford, Graeme Hickey, Ruwanthi Kolamunnage-Dona and Paula R Williamson report grants from the NIHR HTA programme and Arthritis Research UK during the conduct of the study, other from AbbVie Inc. and University Hospitals Bristol NHS Foundation Trust and personal fees from University of Liverpool, outside the submitted work. In addition, Paula R Williamson is the Director of the Clinical Trials Research Centre, which is the Clinical Trials Unit that managed the day-to-day running of this trial. Dyfrig Hughes and Patricia Woo report grants from the NIHR HTA programme and Arthritis Research UK during the conduct of the study and other from AbbVie Inc., outside the submitted work. Giovanna Culeddu and Eifiona Wood report grants from Arthritis Research UK during the conduct of the study. Sandrine Compeyrot-Lacassagne reports grants from the NIHR HTA programme and Arthritis Research UK during the conduct of the study, and grants and others from AbbVie Inc., outside the submitted work. Clive Edelsten reports grants from the NIHR HTA programme and Arthritis Research UK during the conduct of the study, and others and personal fees from AbbVie Inc., outside the submitted work. Michael W Beresford reports grants from the NIHR HTA programme and Arthritis Research UK during the conduct of the study and others from AbbVie Inc. and the University Hospitals Bristol NHS Foundation Trust, outside the submitted work.
