Clinical research study
The Comparative Safety of Tumor Necrosis Factor Inhibitors in Rheumatoid Arthritis: A Meta-analysis Update of 44 Trials

https://doi.org/10.1016/j.amjmed.2014.06.012Get rights and content

Abstract

Objective

The study objective was to evaluate and update the safety data from randomized controlled trials of tumor necrosis factor inhibitors in patients treated for rheumatoid arthritis.

Methods

A systematic literature search was conducted from 1990 to May 2013. All studies included were randomized, double-blind, controlled trials of patients with rheumatoid arthritis that evaluated adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab treatment. The serious adverse events and discontinuation rates were abstracted, and risk estimates were calculated by Peto odds ratios (ORs).

Results

Forty-four randomized controlled trials involving 11,700 subjects receiving tumor necrosis factor inhibitors and 5901 subjects receiving placebo or traditional disease-modifying antirheumatic drugs were included. Tumor necrosis factor inhibitor treatment as a group was associated with a higher risk of serious infection (OR, 1.42; 95% confidence interval [CI], 1.13-1.78) and treatment discontinuation due to adverse events (OR, 1.23; 95% CI, 1.06-1.43) compared with placebo and traditional disease-modifying antirheumatic drug treatments. Specifically, patients taking adalimumab, certolizumab pegol, and infliximab had an increased risk of serious infection (OR, 1.69, 1.98, and 1.63, respectively) and showed an increased risk of discontinuation due to adverse events (OR, 1.38, 1.67, and 2.04, respectively). In contrast, patients taking etanercept had a decreased risk of discontinuation due to adverse events (OR, 0.72; 95% CI, 0.55-0.93). Although ORs for malignancy varied across the different tumor necrosis factor inhibitors, none reached statistical significance.

Conclusions

These meta-analysis updates of the comparative safety of tumor necrosis factor inhibitors suggest a higher risk of serious infection associated with adalimumab, certolizumab pegol, and infliximab, which seems to contribute to higher rates of discontinuation. In contrast, etanercept use showed a lower rate of discontinuation. These data may help guide clinical comparative decision making in the management of rheumatoid arthritis.

Section snippets

Data Sources and Searches

Study selection, assessment of eligibility criteria, data extraction, and statistical analysis were performed on the basis of a predefined, peer-reviewed protocol according to the Cochrane Collaboration guidelines (http://www.cochrane.org/resources/handbook/index.html).

We undertook a systematic literature search including randomized controlled trials that selected adult patients with rheumatoid arthritis. We searched studies using MEDLINE via OVID and PubMed, the Cochrane databases, Google

Study Selection

We identified a total of 268 titles and abstracts, from which 195 were excluded on the basis of title and abstract review and 31 were excluded on the basis of article review (Figure 1). Reasons for exclusion included no drug of interest; patients without rheumatoid arthritis; lack of randomization, blinding, or a control group; or a study duration <12 weeks (Appendix 2, available online shows a list of excluded studies). A total of 44 studies, including 3 studies obtained from PubMed Auto Alert

Discussion

Our objective was to systematically update major safety profiles reported in the randomized controlled trials of all approved tumor necrosis factor inhibitors to date to inform the field. Our findings indicate a higher risk of serious infection associated with adalimumab, certolizumab pegol, and infliximab, which seems to contribute to higher rates of discontinuation. A similar trend was observed with golimumab plus methotrexate combination therapy, but not golimumab monotherapy. In contrast,

Conclusions

Our meta-analysis of randomized controlled trials to date indicates potential important differences in the safety profile among all currently available tumor necrosis factor inhibitors. The risk of serious infection is increased among adalimumab-, certolizumab pegol–, or infliximab-treated patients. In turn, patients taking these agents had an increased risk of discontinuation due to adverse events. Etanercept-treated patients instead showed a decreased risk. Our null findings on malignancy

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    Funding: This research was supported by the National Institutes of Health (RC1AR058601).

    Conflict of Interest: None.

    Authorship: All authors had access to the data and played a role in writing this manuscript.

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