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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Risk of serious infections during rituximab, abatacept and anakinra treatments for rheumatoid arthritis: meta-analyses of randomised placebo-controlled trials

C Salliot, M Dougados, and L Gossec.

Review published: 2009.

CRD summary

This review evaluated the effects of biological agents on the risk of serious infections in patients with rheumatoid arthritis, concluding that rituximab or abatacept treatment did not increase the risk of serious infections, although high doses of anakinra may increase the risk, especially in patients with comorbidities. Some reporting limitations make it difficult to determine the reliability of these conclusions.

Authors' objectives

To determine whether biological agents increase the risk of serious infections in patients with rheumatoid arthritis.


PubMed, EMBASE, and the Cochrane Library were searched up to December 2007. Search terms were reported. The proceedings of relevant conferences from 2004 to 2006 were also searched for further studies. US and European drug regulatory bodies and relevant manufacturers were also contacted. The search was limited to studies published in English, French or Spanish.

Study selection

Randomised placebo-controlled trials (RCTs) evaluating rituximab, abatacept or anakinra in adult patients with rheumatoid arthritis (as defined by American College of Rheumatology criteria) were eligible for inclusion. Treatments could be provided as monotherapy or in combination with concomitant biological or non-biological disease modifying antirheumatic drugs (DMARDS).

Included trials evaluated rituximab (500 and 1000mg), abatacept (0.5, 2 and 10mg) and anakinra (0.04 to 2 mg/kg and 30 to 150 mg). These trials followed-up patients for 12 to 48 weeks. Eighty-one percent of participants were women with a mean age ranging from 46 to 57 years at inclusion and a mean duration of rheumatoid arthritis of 9.2 years (range 3.4 to 12.1).

One reviewer selected studies for inclusion.

Assessment of study quality

Trials were assessed in terms of blinding, intention-to-treat analysis, and completeness of follow-up.

One reviewer performed the validity assessment.

Data extraction

Data were extracted on key study characteristics by a single reviewer.

Methods of synthesis

The Mantel-Haenszel method was used to estimate a fixed-effects pooled odds ratio and associated 95% confidence interval (CI) for the rate of serious infections for each biological agent. Separate subgroup analyses were conducted for high- and low-dose treatment groups. Sensitivity analyses to exclude potential confounding factors were also conducted.

Results of the review

Twelve placebo-controlled RCTs were included in the review: three rituximab trials (n=1,143), five abatacept trials (n=2,945) and four anakinra trials (n=2,771). All the trials were double-blind and performed an intention-to-treat analysis. Ninety-four percent of the included participants were followed-up.

Meta-analyses indicated that overall risk of serious infection was not significantly increased by rituximab (odds ratio 1.45, 95% CI: 0.56, 3.73), abatacept (odds ratio 1.35, 95% CI: 0.79, 2.32), or anakinra (odds ratio 2.75, 95% CI: 0.90, 8.35). The risk was significantly increased for high-dose anakinra (i.e. 100mg or more) relative to placebo (odds ratio 3.40, 95% CI: 1.11, 10.46) and low-dose anakinra (odds ratio 9.63, 95% CI: 1.31, 70.91), but these results were not significant after excluding participants with comorbidity factors.

None of the investigated factors (age, concomitant steroid intake, rheumatoid factor status) appeared to be confounding factors of infections.

Authors' conclusions

The meta-analyses did not indicate a significant increase in the risk of serious infections during rituximab or abatacept treatment in patients with rheumatoid arthritis but high doses of anakinra may increase this risk, especially when patients have comorbidity factors.

CRD commentary

The review question was clearly defined in terms of the participants, interventions, comparators and study designs of interest. Attempts were made to identify relevant evidence from a variety of sources but, as only published data were included, there remains the potential for publication bias. The statistical methods used to pool trials appeared largely appropriate but some details, such as the degree of statistical heterogeneity between included trials, was not reported. The authors did not indicate any attempts to minimise the potential for errors or bias in the selection, extraction and assessment of trials in the review. These limitations make it difficult to determine the reliability of the authors' conclusions.

Implications of the review for practice and research

Practice: The authors stated that use of biological agents in patients with rheumatoid arthritis require careful monitoring, especially in patients with comorbidities and concomitant treatments, such as steroids.

Research: The authors stated that large post-marketing studies are needed to confirm the safety profile of rituximab, abatacept and anakinra.


Not stated.

Bibliographic details

Salliot C, Dougados M, Gossec L. Risk of serious infections during rituximab, abatacept and anakinra treatments for rheumatoid arthritis: meta-analyses of randomised placebo-controlled trials. Annals of the Rheumatic Diseases 2009; 68(1): 25-32. [PMC free article: PMC2596305] [PubMed: 18203761]

Indexing Status

Subject indexing assigned by NLM


Antibodies, Monoclonal /adverse effects; Antibodies, Monoclonal, Murine-Derived; Antirheumatic Agents /adverse effects; Arthritis, Rheumatoid /drug therapy /microbiology; Bacterial Infections /complications; Dose-Response Relationship, Drug; Female; Humans; Immunoconjugates /adverse effects; Interleukin 1 Receptor Antagonist Protein /adverse effects; Male; Middle Aged; Odds Ratio; Randomized Controlled Trials as Topic; Risk; Tumor Necrosis Factor-alpha /antagonists & inhibitors



Database entry date


Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 18203761


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