Comparative effectiveness of biological medicines in rheumatoid arthritis: systematic review and network meta-analysis including aggregate results from reanalysed individual patient data

Abstract

Objective: To assess the comparative effectiveness of biological medicines in rheumatoid arthritis in sufficiently similar patient populations, based on the current definitions of key outcomes.

Design: Systematic review and network meta-analysis including aggregate results from reanalysed individual patient data.

Data sources: Clinical study reports and aggregate results from reanalyses of individual patient data on key outcomes for rheumatoid arthritis provided by study sponsors for studies conducted up to 2017, and several databases and registries from inception up to February 2017.

Eligibility criteria for selecting studies: Randomised controlled trials investigating patient relevant outcomes in adults with rheumatoid arthritis treated with biological medicines in combination with methotrexate after methotrexate failure for at least 24 weeks.

Results: 45 eligible trials were identified. Combining data from clinical study reports and aggregate results from reanalyses of individual patient data allowed extensive analyses yielding sufficiently similar populations and homogeneous study results for network meta-analyses, including up to 35 studies on eight biological medicines combined with methotrexate. These analyses showed few statistically significant differences between the combination treatments. For example, anakinra showed less benefit than almost all the other seven biological medicines regarding clinical remission or low disease activity (clinical disease activity index ≤2.8 or ≤10, respectively) and certolizumab pegol showed more harm than the other seven biological medicines regarding serious adverse events or infections. Some outcomes had very wide 95% confidence intervals, potentially implying unidentified differences between the eight biological medicines, but wide 95% confidence intervals were less prominent for low disease activity, serious adverse events, and infections. Owing to a lack of head-to-head trials, results were mainly based on indirect comparisons with a limited number of studies, and recently approved Janus kinase inhibitors could not be included.

Conclusions: For patients with rheumatoid arthritis after methotrexate failure, only minor differences in benefits and harms were seen between biological medicines in combination with methotrexate. However, the analysis was hampered by a lack of long term direct comparisons. The substantial information gain achieved by the reanalysis of individual patient data calls for the routine availability of individual patient data.

Fig 1

Evidence search and study selection. *Records excluded in screening of title, abstract, or full text (reasons for exclusion in title/abstract screening: violation of minimum inclusion criteria (that is, wrong indication or intervention), not studying people, or no secondary publication (n=709); reasons for exclusion in full text screening: wrong population (n=28), intervention (n=113), comparator (n=26) or study design (n=694); no full publication (n=96); wrong study duration (n=39) or language (n=5); and no patient relevant outcome (n=0)). †Infliximab/methotrexate versus placebo/methotrexate. ‡One study each for following comparisons: adalimumab/methotrexate versus etanercept/methotrexate, tocilizumab/methotrexate versus etanercept/methotrexate. §One study each for following comparisons: adalimumab/methotrexate versus placebo/methotrexate, tocilizumab/methotrexate versus placebo/methotrexate. ¶Etanercept/methotrexate versus other synthetic disease modifying antirheumatic drugs. HTA=health technology assessment; MTX=methotrexate

Fig 2

Network plots of treatment comparisons for clinical remission, low disease activity, serious adverse events, infections, pain, and physical function in patients with rheumatoid arthritis. Network plots include the number of trials and the number of included patients for each comparison. CDAI=clinical disease activity index; HAQ-DI=health assessment questionnaire-disability index; MTX=methotrexate; n=number of included patients; VAS=visual analogue scale