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Biological Agents for Moderately to Severely Active Ulcerative Colitis: A Systematic Review and Network Meta-analysisBiological Agents for Ulcerative Colitis

Silvio Danese, MD, PhD; Gionata Fiorino, MD, PhD; Laurent Peyrin-Biroulet, MD, PhD; Ersilia Lucenteforte, ScD, PhD; Gianni Virgili, MD; Lorenzo Moja, MD, MSc, DrPH; and Stefanos Bonovas, MD, MSc, PhD
[+] Article and Author Information

From Inflammatory Bowel Disease Center, IRCCS Humanitas Research Hospital, University of Milan, IRCCS Galeazzi Orthopedic Institute, and Laboratory of Drug Regulatory Policies, IRCCS Mario Negri Institute for Pharmacologic Research, Milan, Italy; University Hospital of Nancy, Université de Lorraine, Vandoeuvre-lès-Nancy, France; University of Florence, Florence, Italy; and School of Medicine, University of Athens, Athens, Greece.

Grant Support: By the Centro Ricerca e Cura delle Malattie Infiammatorie Croniche Intestinali, IRCCS Istituto Clinico Humanitas.

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-2403.

Requests for Single Reprints: Silvio Danese, MD, PhD, Inflammatory Bowel Disease Center, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy; e-mail, silvio.danese@humanitas.it.

Current Author Addresses: Drs. Danese and Fiorino: Inflammatory Bowel Disease Center, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy.

Dr. Peyrin-Biroulet: Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy, Université de Lorraine, Vandoeuvre-lès-Nancy, France.

Dr. Lucenteforte: Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.

Dr. Virgili: Department of Specialised Surgical Sciences, University of Florence, Via le Morgagni 85, 50134 Florence, Italy.

Dr. Moja: Clinical Epidemiology Unit, IRCCS Orthopedic Institute Galeazzi, Via R. Galeazzi 4, 20161 Milan, Italy.

Dr. Bonovas: Department of Pharmacology, School of Medicine, University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece.

Author Contributions: Conception and design: S. Danese, G. Fiorino, L. Peyrin-Biroulet, L. Moja, S. Bonovas.

Analysis and interpretation of the data: S. Danese, E. Lucenteforte, G. Virgili, L. Moja, S. Bonovas.

Drafting of the article: S. Danese, L. Peyrin-Biroulet, L. Moja, S. Bonovas.

Critical revision of the article for important intellectual content: S. Danese, G. Fiorino, L. Peyrin-Biroulet, E. Lucenteforte, G. Virgili, L. Moja, S. Bonovas.

Final approval of the article: S. Danese, G. Fiorino, L. Peyrin-Biroulet, E. Lucenteforte, G. Virgili, L. Moja, S. Bonovas.

Provision of study materials or patients: G. Fiorino.

Statistical expertise: E. Lucenteforte, G. Virgili, S. Bonovas.

Administrative, technical, or logistic support: S. Danese.

Collection and assembly of data: S. Danese, G. Fiorino, S. Bonovas.


Ann Intern Med. 2014;160(10):704-711. doi:10.7326/M13-2403
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Background: Biological agents are emerging treatment options for the management of ulcerative colitis (UC).

Purpose: To assess the comparative efficacy and harm of biological agents in adult patients with moderately to severely active UC who are naive to biological agents.

Data Sources: MEDLINE, EMBASE, and Cochrane Library from inception through December 2013, without language restrictions, and ClinicalTrials.gov, European Medicines Agency, and U.S. Food and Drug Administration Web sites.

Study Selection: Randomized, placebo-controlled or head-to-head trials assessing biological agents as induction or maintenance therapy for moderately to severely active UC.

Data Extraction: Two reviewers independently abstracted study data and outcomes and rated each trial's risk of bias.

Data Synthesis: There were no head-to-head trials. There were 7 double-blind, placebo-controlled trials that were rated as low risk of bias and showed that all biological agents (adalimumab, golimumab, infliximab, and vedolizumab) resulted in more clinical responses, clinical remissions, and mucosal healings than placebo for induction therapy. The results of network meta-analysis suggested that infliximab is more effective to induce clinical response (odds ratio, 2.36 [95% credible interval, 1.22 to 4.63]) and mucosal healing (odds ratio, 2.02 [95% credible interval, 1.13 to 3.59]) than adalimumab. No other indirect comparison reached statistical significance. For maintenance, 6 double-blind, placebo-controlled trials that were rated high risk of bias showed that all biological agents have greater clinical efficacy than placebo. The occurrence of adverse events was not different between biological agents and placebo.

Limitation: Few trials, no head-to-head comparisons, and inadequate follow-up in maintenance trials.

Conclusion: Biological agents are effective treatments for UC, but head-to-head trials are warranted to establish the best therapeutic option.

Primary Funding Source: Centro Ricerca e Cura delle Malattie Infiammatorie Croniche Intestinali, IRCCS Istituto Clinico Humanitas. (PROSPERO registration number: CRD42013005459)

Figures

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Figure 1.

Summary of evidence search and selection.

MCS = Mayo Clinic score; RCT = randomized, controlled trial; UC = ulcerative colitis.

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Appendix Figure 1.

Summary of methodological characteristics of trials.

Induction phases are represented in blue, whereas maintenance phases are represented in green. ACT = Active Ulcerative Colitis Trial; ADA = adalimumab; eow = every other week; GLM = golimumab; IFX = infliximab; ITT-A3 = intention-to-treat population, after protocol amendment 3; ITT-E = intention-to-treat population, original protocol; IV = intravenous; PBO = placebo; PURSUIT-M = Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment–Maintenance; PURSUIT-SC = Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment–Subcutaneous; q8w = every 8 wk; q4w = every 4 wk; R = randomization; SC = subcutaneous; ULTRA = Ulcerative Colitis Long-Term Remission and Maintenance With Adalimumab; VDZ = vedolizumab.

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Figure 2.

Summary of risk-of-bias assessments for randomized, controlled trials of induction therapy.

Green circles signify low risk of bias. ACT = Active Ulcerative Colitis Trial; PURSUIT-SC = Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment–Subcutaneous; ULTRA = Ulcerative Colitis Long-Term Remission and Maintenance With Adalimumab.

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Appendix Figure 2.

Summary of risk-of-bias assessments for randomized, controlled trials of maintenance therapy.

Green circles indicate low risk of bias, and red circles signify high risk of bias. ACT = Active Ulcerative Colitis Trial; PURSUIT-M = Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment–Maintenance; ULTRA = Ulcerative Colitis Long-Term Remission and Maintenance With Adalimumab.

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Figure 3.

Network geometry for induction treatment.

Compared treatments are connected indirectly through the placebo, the “common comparator.” The number of independent randomized, controlled trials and number of patients who were naive to biological agents (in parenthesis) for each comparison in the induction treatment network are informed by head-to-head evidence. To calculate the numbers of patients, we considered only persons assigned to a dose as approved in the summary of product characteristics and those assigned to placebo. ADA = adalimumab; GLM = golimumab; IFX = infliximab; PBO = placebo; VDZ = vedolizumab.

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Appendix Figure 3.

Comparative efficacy of biological agents as induction therapy for moderately to severely active ulcerative colitis.

Treatment effect estimates come from Bayesian network meta-analysis. Odds ratios >1.0 favor the treatment in the left upper square. To obtain ORs for comparisons in the opposite direction, reciprocals should be calculated. ADA = adalimumab; CrI = credible interval; GLM = golimumab; IFX = infliximab; OR = odds ratio; VDZ = vedolizumab.

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