This is the first overview of updated Cochrane systematic reviews of biologics at the approved doses for rheumatoid arthritis. We systematically extracted data from the existing reviews, updated older reviews to May 2009 and performed a network meta-analysis in accordance with the 2008 Cochrane Handbook.8
We made 2 observations that add to current knowledge and deserve further discussion. First, these network indirect comparisons confirm the lower rates of benefit (compared with placebo) with anakinra than with other biologics. Second, these analyses confirm the higher rate of withdrawals because of adverse events with infliximab, anakinra and adalimumab compared with placebo or etanercept (indirect comparison).
Physicians and patients must choose among these expensive medications while not knowing which biologic is more effective and safe. Because all 5 biologics examined, excluding anakinra, seemed equally efficacious in terms of relative measures, the choice may depend on cost to patients and health care systems, frequency of administration (e.g., etanercept taken twice weekly v. adalimumab taken every other week), preferences for route of administration (subcutaneous injection for etanercept and adalimumab; intravenous administration for abatacept, infliximab and rituximab) and safety aspects (etanercept was associated with a lower rate of withdrawals because of adverse events than were adalimumab, anakinra or infliximab).
This overview has some limitations. These biologics have been available only for a few years, and the duration of the trials was too short to assess the long-term benefits and harms. Furthermore, delayed and rare effects would not be detected by these controlled trials. The placebo group was somewhat heterogeneous because of the continuing use of disease-modifying antirheumatic drugs for some patients and the use of methotrexate versus other disease-modifying antirheumatic drugs versus another biologic in some studies.50,51
Methotrexate is the standard of care for treatment of rheumatoid arthritis, and most randomized controlled trials currently examine new therapies in patients who are taking methotrexate.
The included reviews consist of randomized controlled trials that differed in patient population characteristics, such as the duration of rheumatoid arthritis disease, prior failed therapy, concomitant methotrexate use and trial duration. For some reviews and subsequent stratified analyses, we were limited in that only 3–5 studies were available, which made our analyses susceptible to type II error (i.e., missing a difference when one exists because of small sample size). Thus, even though we performed indirect comparisons of the 6 biologics to each other using valid statistical approaches, these results should be interpreted with caution. The findings from the stratified and subgroup analyses are hypothesis-generating at best, susceptible to type II error with 2 studies each for comparisons of disease-modifying antirheumatic drugs, use of multiple biologics and long-term trial duration. It is reassuring that both patients with and without methotrexate use and those for whom previous biologic treatment had failed or succeeded responded better to biologics than to placebo.
Comparisons with other studies
The lower benefit of anakinra compared with anti–tumour necrosis factor biologics in indirect comparisons in our study confirms similar findings from a previous meta-analysis7
and a qualitative review.52
Our estimates of the number needed to treat for ACR50 were similar to those reported earlier53,54
from simple estimation from the placebo trials, thus adding to the robustness of these estimates
Two meta-analyses of randomized controlled trials of all doses of biologics found no significant differences in the ACR50 rates between 4 biologics (etanercept, infliximab, anakinra, adalimumab) in randomized controlled trials that lasted for 6 or more months55
and between all 6 biologics7
using indirect comparisons. In contrast, the ACR50 rate was significantly lower for etanercept than for adalimumab (p
< 0.0001) in one study that included only 3 randomized controlled trials of ≥ 50-week duration in an analysis that used a modified Bucher approach (i.e., an approach that only implicitly adjusts for varying placebo response rates across trials).56
Our findings of significantly higher ACR50 rates with etanercept and adalimumab than with anakinra disagree slightly with previous reports.7,55
The difference is likely because of our inclusion of 3–14 more studies for efficacy and 11 more studies for safety (up to May 2009, compared with 20067
), limiting our analyses to approved doses and the inclusion of all 6 biologics used commonly to treat rheumatoid arthritis.
Our findings of significantly lower rates of withdrawals because of adverse events with etanercept than with adalimumab, anakinra or infliximab add to the current findings and confirm a similar observation in a previous study.56
Withdrawals related to adverse events were lower with etanercept than with adalimumab (relative risk 0.38, 95% CI 0.17–0.86, p
= 0.02) in a meta-analysis of 3 randomized controlled trials.56
No differences were reported between the 6 biologics when data from randomized controlled trials were combined with the observational data gathered by Gartlehner and colleagues.7
Our overview provides indirect comparisons of the benefit and safety of 6 biologics for rheumatoid arthritis from double-blind, placebo-controlled trials in the absence of head-to-head studies. Because of differences in the study population characteristics between the trials, these findings must be interpreted with caution. There is a need for longer comparative effectiveness studies of biologics to provide data about the relative and absolute benefit and safety of biologics during various stages of rheumatoid arthritis (early, established and late), the various levels of functional limitation (mild, moderate and severe limitation) and the nature of prior treatment (traditional disease-modifying antirheumatic drugs v. biologics v. both). This information will help patients and clinicians make informed decisions about these therapies in the ever expanding area of new, effective therapies for rheumatoid arthritis.
Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library (www.thecochranelibrary.com
) should be consulted for the most recent version of the review. Journal club and podcast of the Cochrane review is available at www.cochranejournalclub.com/biologics