Gastroenterology

Gastroenterology

Volume 148, Issue 2, February 2015, Pages 344-354.e5
Gastroenterology

Original Research
Full Report: Clinical—Alimentary Tract
Comparative Effectiveness of Immunosuppressants and Biologics for Inducing and Maintaining Remission in Crohn's Disease: A Network Meta-analysis

https://doi.org/10.1053/j.gastro.2014.10.011Get rights and content

Background & Aims

There is controversy regarding the best treatment for patients with Crohn’s disease because of the lack of direct comparative trials. We compared therapies for induction and maintenance of remission in patients with Crohn’s disease, based on direct and indirect evidence.

Methods

We performed systematic reviews of MEDLINE, EMBASE, and Cochrane Central databases, through June 2014. We identified randomized controlled trials (N = 39) comparing methotrexate, azathioprine/6-mercaptopurine, infliximab, adalimumab, certolizumab, vedolizumab, or combined therapies with placebo or an active agent for induction and maintenance of remission in adult patients with Crohn’s disease. Pairwise treatment effects were estimated through a Bayesian random-effects network meta-analysis and reported as odds ratios (OR) with a 95% credible interval (CrI).

Results

Infliximab, the combination of infliximab and azathioprine (infliximab + azathioprine), adalimumab, and vedolizumab were superior to placebo for induction of remission. In pair-wise comparisons of anti–tumor necrosis factor agents, infliximab + azathioprine (OR, 3.1; 95% CrI, 1.4–7.7) and adalimumab (OR, 2.1; 95% CrI, 1.0–4.6) were superior to certolizumab for induction of remission. All treatments were superior to placebo for maintaining remission, except for the combination of infliximab and methotrexate. Adalimumab, infliximab, and infliximab + azathioprine were superior to azathioprine/6-mercaptopurine: adalimumab (OR, 2.9; 95% CrI, 1.6–5.1), infliximab (OR, 1.6; 95% CrI, 1.0–2.5), infliximab + azathioprine (OR, 3.0; 95% CrI, 1.7–5.5) for maintenance of remission. Adalimumab and infliximab + azathioprine were superior to certolizumab: adalimumab (OR, 2.5; 95% CrI, 1.4–4.6) and infliximab + azathioprine (OR, 2.6; 95% CrI, 1.3–6.0). Adalimumab was superior to vedolizumab (OR, 2.4; 95% CrI, 1.2–4.6).

Conclusions

Based on a network meta-analysis, adalimumab and infliximab + azathioprine are the most effective therapies for induction and maintenance of remission of Crohn’s disease.

Section snippets

Eligibility Criteria

We included all randomized controlled trials that assessed treatments (azathioprine/6-mercaptopurine, methotrexate, infliximab, adalimumab, certolizumab, and vedolizumab) alone or in combination in adult patients with Crohn’s disease. We included trials assessing induction of remission of immunosuppressants between 12 and 17 weeks. We included trials assessing the induction of remission of biologic therapy between 4 and 17 weeks because the onset of action of biologic therapies is more rapid.

Search Results, Trial Characteristics, and Risk of Bias

We included 39 trials from 35 articles (Figure 1).6, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 Four articles contained 2 trials each that were considered separately.6, 49, 50, 51 Excluded studies and the rationale for exclusion are shown in Supplementary Table 2. Characteristics of included trials are shown in Supplementary Table 1. Fifteen trials evaluated anti-TNF therapy, 4 trials evaluated

Discussion

We conducted a systematic review and network meta-analysis of randomized controlled trials of immunosuppressants and biologics for induction and maintenance of remission in adults with Crohn’s disease. Our systematic review identified a paucity of head-to-head trials in the Crohn’s disease literature, which are necessary to inform clinicians on the appropriate efficacious and safe treatment regimens for Crohn’s disease. By applying a network meta-analysis approach, our study integrated direct

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    This article has an accompanying continuing medical education activity on page e14. Learning Objective: Upon completion of the CME activity, successful learners will be able to compare different treatment strategies in managing Crohn's disease and understand the purpose of conducting a network meta-analysis.

    Conflicts of interest These authors disclose the following: Gilaad Kaplan has served as a speaker for Jansen, Merck, Schering-Plough, Abbott, and UCB Pharma, has participated in advisory board meetings for Jansen, Abbott, Merck, Schering-Plough, Shire, and UCB Pharma, and has received research support from Merck, Abbott, and Shire; Remo Panaccione has served as a speaker, a consultant, and an advisory board member for Abbott Laboratories, Merck, Schering-Plough, Shire, Centocor, Elan Pharmaceuticals, and Procter and Gamble, has served as a consultant and speaker for Astra Zeneca, has served as a consultant and an advisory board member for Ferring and UCB, has served as a consultant for Glaxo-Smith Kline and Bristol Meyers Squibb, has served as a speaker for Byk Solvay, Axcan, Jansen, and Prometheus, has received research funding from Merck, Schering-Plough, Abbott Laboratories, Elan Pharmaceuticals, Procter and Gamble, Bristol Meyers Squibb, and Millennium Pharmaceuticals, and has received educational support from Merck, Schering-Plough, Ferring, Axcan, and Jansen; Subrata Ghosh has served as a speaker for Merck, Schering-Plough, Centocor, Abbott, UCB Pharma, Pfizer, Ferring, and Procter and Gamble, has participated in ad hoc advisory board meetings for Centocor, Abbott, Merck, Schering-Plough, Proctor and Gamble, Shire, UCB Pharma, Pfizer, and Millennium, and has received research funding from Procter and Gamble, Merck, and Schering-Plough; Glen Hazlewood has received fellowship funding from UCB Pharma and honoraria and travel expenses from UCB Pharma and Abbott, and has participated in an advisory board meeting for Amgen; Ali Rezaie has received honoraria from Ferring Pharmaceuticals; Cynthia Seow has served as a speaker for Janssen, Merck, Schering-Plough, and Warner Chilcott, and has participated in advisory board meetings for Janssen, Abbott, Merck, and Schering-Plough; Corey Siegel has served on advisory boards for AbbVie, Given Imaging, Janssen, Prometheus, Salix, Takeda, and UCB, has received grant funding from AbbVie, Janssen, Salix, and UCB, and has presented CME activities for AbbVie, Merck, and Santarus; Gil Melmed has served as a speaker for Abbott and Prometheus Labs, has participated in ad hoc advisory board meetings for Luitpold, Janssen, Given Imaging, UCB, and AbbVie, and has received research funding from Pfizer and Prometheus. The remaining authors disclose no conflicts.

    Funding This research was supported by The Alberta IBD Consortium, which was funded by an AHFMR Interdisciplinary Team Grant (AHFMR is now Alberta Innovates–Health Solutions). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

    Author names in bold designate shared co-first authors.

    ∗

    Authors share co-first authorship.

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