Clinician Article

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

  • Singh JA
  • Cameron C
  • Noorbaloochi S
  • Cullis T
  • Tucker M
  • Christensen R, et al.
Lancet. 2015 Jul 18;386(9990):258-65. doi: 10.1016/S0140-6736(14)61704-9. Epub 2015 May 11. (Review)
PMID: 25975452
Read abstract Read evidence summary
  • Family Medicine (FM)/General Practice (GP)
    Relevance - 6/7
    Newsworthiness - 6/7
  • General Internal Medicine-Primary Care(US)
    Relevance - 6/7
    Newsworthiness - 6/7
  • Infectious Disease
    Relevance - 6/7
    Newsworthiness - 5/7
  • Rheumatology
    Relevance - 6/7
    Newsworthiness - 5/7
  • Internal Medicine
    Relevance - 5/7
    Newsworthiness - 5/7


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.

Clinical Comments

Family Medicine (FM)/General Practice (GP)

Most primary care clinicians do not prescribe these biologic agents. However, primary care clinicians will undoubtedly care for patients who are candidates for them, in addition to caring for patients who are currently receiving them. Primary care clinicians need to be aware of this new information to better inform patients of the risks, and to be attuned to possible infections when they occur.

General Internal Medicine-Primary Care(US)

Good to know that my clinical experience of biologics increasing risk for infection, at least in usual and high doses, bears up in in this meta-analysis.

General Internal Medicine-Primary Care(US)

Useful meta-analysis with a pretty high increased incidence (~5%) of serious infections with high-dose biologics.

General Internal Medicine-Primary Care(US)

An excellent paper evaluating the risk for serious infections occurring in RA patients treated with biologic agents compared with patients treated with traditional disease-modifying agents. The advantages of this meta-analysis over previous studies is the inclusion of more randomised trials with a larger patient exposure, stratifying patients based on previous DMARD or anti-TNF therapy exposure, and also stratifying patients based on whether they used low-, standard-, or high-dose biologic treatment. The results clearly show an increased risk for serious infections attributed to biologic therapies in patients receiving standard or high-dose biologic therapy, but not in those receiving low-dose biologic treatment. Patients who had received traditional DMARDs or anti-TNF therapies had a higher risk than those who were methotrexate naive. Clinicians can now give patients an absolute risk of serious infections related to biologic therapies to balance the benefits of these agents.

General Internal Medicine-Primary Care(US)

This meta-analysis, the most recent and comprehensive to date, provides important new insights: there are small but significantly increased risks for infection associated with biologic mediators for treatment of RA, which rise sharply in methotrexate- or biologic mediator-experienced patients and with high-dose therapy.

Infectious Disease

Interesting analysis involving a network analysis to compare different agents.

Infectious Disease

The paper fine-tunes the info regarding serious infections associated with different doses of biologic drugs with or without prior exposure to DMARDs. Such info was not previously available.

Infectious Disease

A large comprehensive meta-analysis of the risk for infection associated with biologic therapy for rheumatoid arthritis that refines the absolute risk for infectious complications by biologic therapy dose and other patient- and therapy-level risk factors.

Internal Medicine

Drugs are commonly used now and internists need to have heightened awareness about the infection rates.

Internal Medicine

This is a highly useful paper in that it is based on five times as many participants compared with the previous large study, and it provides data we can share with our patients on the risk of therapy. Its weakness is that, in older studies, tuberculin skin testing was not done before treatment. The data suggest the risk for infection is less in more recent studies. This is the best study to date to share with our patients on infection risk.

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