Biologics for rheumatoid arthritis: an overview of Cochrane reviews

Abstract

Background: The biologic disease-modifying anti-rheumatic drugs (DMARDs) are very effective in treating rheumatoid arthritis (RA), however there is a lack of head-to-head comparison studies.

Objectives: To compare the efficacy and safety of abatacept, adalimumab, anakinra, etanercept, infliximab, and rituximab in patients with RA.

Methods: This 'Overview of Reviews' was done by including all Cochrane Reviews on Biologics for RA available in The Cochrane Library. We included only data on standard dosing regimens for these biologic DMARDs from placebo-controlled trials. The primary efficacy and safety outcomes were ACR50 and withdrawals due to adverse events. We calculated Risk Ratios (RR) for efficacy, Odds Ratio (OR) for safety and combined estimates of events across the placebo groups as the expected Control Event Rate (CER). Indirect comparisons of biologics were performed for efficacy and safety using a hierarchical linear mixed model incorporating the most important study-level characteristic (i.e. type of biologic) as a fixed factor and study as a random factor; reducing the between study heterogeneity by adjusting for the interaction between the proportion of patients responding on placebo and the duration of the trial.

Main results: From the six available Cochrane reviews, we obtained data from seven studies on abatacept, eight on adalimumab, five on anakinra, four on etanercept, four on infliximab, and three on rituximab.The indirect comparison estimates showed similar efficacy for the primary efficacy outcome for all biologics with three exceptions. Anakinra was less efficacious than etanercept with a ratio of RRs (95% CI; P value) of 0.44 (0.23 to 0.85; P = 0.014); anakinra was less efficacious than rituximab, 0.45 (0.22 to 0.90; P = 0.023); and likewise adalimumab was more efficacious than anakinra, 2.34 (1.32 to 4.13; P = 0.003).In terms of safety, adalimumab was more likely to lead to withdrawals compared to etanercept, with a ratio of ORs of 1.89 (1.18 to 3.04; P = 0.009); anakinra more likely than etanercept, 2.05 (1.27 to 3.29; P = 0.003); and likewise etanercept less likely than infliximab, 0.37 (0.19 to 0.70; P = 0.002).

Authors' conclusions: Based upon indirect comparisons, anakinra seemed less efficacious than etanercept, adalimumab and rituximab and etanercept seemed to cause fewer withdrawals due to adverse events than adalimumab, anakinra and infliximab. Significant heterogeneity in characteristics of trial populations imply that these finding must be interpreted with caution. These findings can inform physicians and patients regarding their choice of biologic for treatment of RA.

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Study Selection Flow Chart

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Comparison of each biologic to placebo for benefit (defined as a 50% improvement in patient‐ and physician‐reported criteria of the American College of Rheumatology [ACR50]). A value greater than 1.0 indicates a benefit from the biologic. CI = confidence interval. For details of studies included for each biologic, refer to Appendix. I² values for the studies are presented in Figure 7. Every square represents the individual study’s effect measure with 95% CI indicated by horizontal lines. Square sizes are proportional to the precision of the estimate.

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Forest plots for ACR50 (grouped by drug)

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Indirect comparison of each biologic to each other for benefit (ACR50). CI = confidence interval. I² values for the studies are presented in Figure 7.

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Comparison of each biologic to placebo for safety (determined by number of withdrawals because of adverse events). A value less than 1.0 indicates a benefit from the biologic. CI = confidence interval. For details of the studies included for each biologic, refer to Appendix. I² values for the studies are presented in Figure 9. Every square represents the individual study’s effect measure with 95% CI indicated by horizontal lines. Square sizes are proportional to the precision of the estimate.

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Indirect comparison of biologics to each other for safety (determined by number of withdrawals because of adverse events). CI = confidence interval. I² values for the studies are presented in Figure 9.

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Forest plots for All withdrawals (grouped by drug)

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Forest plots for ACR20 (grouped by drug)

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Forest plots for ACR70 (grouped by drug)

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Forest plots for Withdrawals due to adverse events (grouped by drug)