Original article
Systematic reviews and meta-analyses
Biologic Therapies and Risk of Infection and Malignancy in Patients With Inflammatory Bowel Disease: A Systematic Review and Network Meta-analysis

https://doi.org/10.1016/j.cgh.2016.04.039Get rights and content

Background & Aims

Safety issues are a major concern for patients considering treatments for inflammatory bowel disease (IBD). We performed a systematic review and meta-analysis to determine whether biologic agents affect the risk of infection or malignancy in adults with IBD.

Methods

We searched PubMed, Embase, Scopus, Cochrane IBD Group Specialized Trials Register, World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov through March 2016 for randomized placebo-controlled or head-to-head trials of biologic agents approved for treatment of adults with IBD (ie, adalimumab, certolizumab, golimumab, infliximab, natalizumab, or vedolizumab). Two reviewers independently extracted study data and outcomes (serious infections, opportunistic infections, tuberculosis, any infection, and malignancies) and rated each trial’s risk of bias. We used conventional meta-analysis to synthesize direct evidence and a network meta-analysis for adjusted indirect treatment comparisons.

Results

We identified 49 randomized placebo-controlled studies comprising 14,590 participants. Synthesis of the evidence indicated that patients treated with biologics had a moderate increase in risk of any infection (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.10–1.29) and a significant increase in risk of opportunistic infections (OR, 1.90; 95% CI, 1.21–3.01). Risk of serious infections was not increased in patients treated with biologics (OR, 0.89; 95% CI, 0.71–1.12). On the contrary, biologics appeared to significantly reduce risk of serious infections in studies with low risk of bias (OR, 0.56; 95% CI, 0.35–0.90). We did not find an increased risk of malignancy with use of biologic agents (OR, 0.90; 95% CI, 0.54–1.50), but data were insufficient in terms of exposure and follow-up times. None of the indirect comparisons, either among the individual agents or between the anti–tumor necrosis factor and anti-integrin classes, reached significance for any of the outcomes analyzed.

Conclusions

On the basis of a systematic review and meta-analysis, biologic agents increase the risk of opportunistic infections in patients with IBD, but not the risk of serious infections. It is necessary to continue to monitor the comparative and long-term safety profiles of these drugs.

Section snippets

Methods

Our protocol11 is registered with an international prospective register of systematic reviews (PROSPERO). The work was performed in accordance with the Cochrane Handbook,12 the ISPOR network meta-analysis guidance,13, 14 and the preferred reporting items for systematic reviews and meta-analyses (PRISMA) extension statement for reporting of systematic reviews incorporating network meta-analyses.15

Search Results

A summary of the evidence search and selection process is shown in Figure 1 (flow diagram). Forty-one full-text publications31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 reported results of 46 RCTs. Two more studies72, 73 had their results posted at ClinicalTrials.gov, and 1 additional study was initially identified through ClinicalTrials.gov and later in full-text publication.74

Discussion

In this systematic review and meta-analysis of RCTs assessing biologics for adult patients with IBD, we synthesized evidence from 49 studies reporting the occurrence of infectious AEs and malignancies as a safety (secondary) end point; none of those were head-to-head comparisons of biologic therapies. To the best of our knowledge, this study is the most comprehensive meta-analysis on the topic.

Overall, we detected a significant 19% increase in the odds of developing any infection among patients

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    Conflicts of interest These authors disclose the following: Gionata Fiorino has served as a consultant and advisory board member for MSD, Takeda, AbbVie, and Janssen. Laurent Peyrin-Biroulet has received consulting fees from Merck, Abbott, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Shire, Therakos, Pharmacosmos, Pilège, BMS, UCB-pharma, Hospira, Celltrion, Takeda, Biogaran, Boehringer-Ingelheim, Lilly, Pfizer, and HAC-pharma and lecture fees from Merck, Abbott, Takeda, Janssen, Ferring, Norgine, Tillots, Vifor, Therakos, and HAC-pharma. Silvio Danese has served as a speaker, consultant, and advisory board member for Schering-Plough, Abbott Laboratories, Merck, UCB-pharma, Ferring, Cellerix, Millenium Takeda, Nycomed, Pharmacosmos, Actelion, Danone, Alpha Wasserman, Genentech, Grunenthal, Pfizer, Astra Zeneca, Novo Nordisk, Cosmo Pharmaceuticals, Vifor, and Johnson & Johnson. The remaining authors disclose no conflicts.

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