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.

Efficacy and Safety of Anti-TNFα Therapy for Uveitis Associated with Juvenile Idiopathic Arthritis: A Systematic Review and Meta-Analysis

“…of participants, F/M) Control group (no. of participants, F/M) Age, years Length of follow-up (months) Control of intraocular inflammation (TG vs CG) Visual acuity Corticosteroid sparing (TG vs CG) AEs and SAEs (TG vs CG) Ramanan, et al [ 27 ] (EudraCT number, 2010–021,141-41) RCT, DB 90 ADA (60, 47/13) 20 mg/0.8 ml for participants weighing < 30 kg or 40 mg/0.8 ml for participants weighing ≥ 30 kg Placebo (30, 23/7) 8.9 18 Number of participants failing treatment (14/60 vs 17/30) (RR 0.40, 95% CI 0.23–0.72; P = 0.002) NA 4/7vs2/2 AEs 59 vs 26 The rate of AEs (10.60 per PY, 95% CI 9.77–11.44 per PY)vs (7.12 per PY, 95% CI 5.89–8.53 per PY) SAEs 13 vs 2 The rate of SAEs (0.29 per PY vs 0.19 per PY) Quartier et al [ 28 ] (Trial registration number: NCT01385826) RCT, DB 31 ADA (16, 15/1) 24 mg/m 2 in patients aged < 13 years, 40 mg in the others, every other week Placebo (15, 13/2) 9.5 (4.9–29.1) 12 30% reduction of Inflammation on LFP: 9/16 vs 3/15 (P = 0.038, χ 2 test; RR = 2.81, 95% CI 0.94–8.45; RD = 36.3%, 95% CI 2.1–60.6); logMAR: 0.1 (− 0.2 to 1.3) to 0.15 (− 0.10 to 1.10) NA NA Janine A. Smith et al [ 29 ] (Trial registration number: NCT00012506) RCT, DB 12 ETA (7, 4/3) 0.4 mg/kg to a maximum of 25 mg subcutaneously twice weekly for 6 months Placebo (5, 5/0) 11 (6–15) 6 AC cells to 0 or topical corticosteroid < 3 times/day or 50% reduction in number or dose of other anti-inflammatory medications: 3 (95% CI 0.10–0.82) vs 2 (95% CI 0.05–0.85) ( P = 1.0) NA 0/2vs0/2 …”

“…Regarding three RCTs, a study conducted by Ramanan et al [ 27 ] had a low risk of bias in all items. The other two studies [ 28 , 29 ] had an unclear risk of bias in allocation concealment and blinding of outcome assessment.…”

“…RCT conducted by Ramanan, et al [ 27 ] indicated that the AE rate of ADA treatment (10.60 per Patient Year (PY), 95% CI 9.77 to 11.44 per PY) was statistically different from that of the control group (7.12 per PY, 95% CI 5.89 to 8.53 per PY) and the most common AEs of ADA were infections and infestations (83%); while the rate of SAEs was low (0.29 per PY). The five SAEs in ADA were cataracts, injection site reactions, glaucoma, arthralgia and arthritis.…”

“…Their results are also in line with those of the meta-analysis. Significant efficacy was revealed for ADA treatment in two RCTs [ 27 , 28 ], but not for ETA in another RCT[ 29 ]. There is no RCT exploring the efficacy of IFX in the treatment of JIA-U so far.…”

Efficacy and Safety of Immunosuppressant Therapy for Noninfectious Uveitis: A Systematic Review and Meta-Analysis

“…Two RCTs (trials SYCAMORE and ADJUVITE) confirmed clinical efficacy of anti-TNF- α antibody for uveitis associated with juvenile idiopathic arthritis (JIA) [ 15 , 20 ], and they were also included in this study. Meta-analysis illustrated that compared with placebo or other drugs, immunosuppressant therapy for noninfectious uveitis had clinical efficacy to some extent, whereas there was moderate heterogeneity among studies.…”