Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis

Abstract

Background: Serious infections are a major concern for patients considering treatments for rheumatoid arthritis. Evidence is inconsistent as to whether biological drugs are associated with an increased risk of serious infection compared with traditional disease-modifying antirheumatic drugs (DMARDs). We did a systematic review and meta-analysis of serious infections in patients treated with biological drugs compared with those treated with traditional DMARDs.

Methods: We did a systematic literature search with Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to Feb 11, 2014. Search terms included "biologics", "rheumatoid arthritis" and their synonyms. Trials were eligible for inclusion if they included any of the approved biological drugs and reported serious infections. We assessed the risk of bias with the Cochrane Risk of Bias Tool. We did a Bayesian network meta-analysis of published trials using a binomial likelihood model to assess the risk of serious infections in patients with rheumatoid arthritis who were treated with biological drugs, compared with those treated with traditional DMARDs. The odds ratio (OR) of serious infection was the primary measure of treatment effect and calculated 95% credible intervals using Markov Chain Monte Carlo methods.

Findings: The systematic review identified 106 trials that reported serious infections and included patients with rheumatoid arthritis who received biological drugs. Compared with traditional DMARDs, standard-dose biological drugs (OR 1.31, 95% credible interval [CrI] 1.09-1.58) and high-dose biological drugs (1.90, 1.50-2.39) were associated with an increased risk of serious infections, although low-dose biological drugs (0.93, 0.65-1.33) were not. The risk was lower in patients who were methotrexate naive compared with traditional DMARD-experienced or anti-tumour necrosis factor biological drug-experienced patients. The absolute increase in the number of serious infections per 1000 patients treated each year ranged from six for standard-dose biological drugs to 55 for combination biological therapy, compared with traditional DMARDs.

Interpretation: Standard-dose and high-dose biological drugs (with or without traditional DMARDs) are associated with an increase in serious infections in rheumatoid arthritis compared with traditional DMARDs, although low-dose biological drugs are not. Clinicians should discuss the balance between benefit and harm with the individual patient before starting biological treatment for rheumatoid arthritis.

Funding: Rheumatology Division at the University of Alabama at Birmingham.

Figure 1

PRISMA Diagram of selection of studies

Figure 2

Evidence networks for serious infection among populations. The width of the lines is proportional to the number of randomized controlled trials comparing each pair of treatments, and the size of each treatment node is proportional to the number of randomized participants (sample size). DMARD= disease-modifying anti-rheumatic drugs; MTX=methotrexate; RCT= randomized controlled trial

Figure 3

Summary of findings from traditional meta-analysis and network meta-analysis for serious infection among populations compared with traditional DMARD monotherapy. CI= confidence interval; CrI= Credible interval; DMARD= disease-modifying anti-rheumatic drugs; RCT= randomized controlled trial

Figure 4

Cumulative meta-analysis – Risk of serious infection among patients using standard dose biologics +/− traditional DMARD compared with traditional DMARD monotherapy DMARDs= disease-modifying anti-rheumatic drugs; RCT= randomized controlled trial