Gastroenterology

Gastroenterology

Volume 145, Issue 4, October 2013, Pages 758-765.e2
Gastroenterology

Original Research
Full Report: Clinical—Alimentary Tract
Early Administration of Azathioprine vs Conventional Management of Crohn's Disease: A Randomized Controlled Trial

https://doi.org/10.1053/j.gastro.2013.04.048Get rights and content

Background & Aims

Immunomodulator therapy is effective for patients with Crohn’s disease (CD) but has not been shown to affect disease progression, presumably because it is given too late after diagnosis. We compared the efficacy of early treatment (within 6 months after diagnosis) with azathioprine versus conventional management of patients at high risk for disabling disease.

Methods

We performed an open-label trial of adults with a diagnosis of CD for less than 6 months who were at risk for disabling disease. From July 2005 to November 2010, patients at 24 French centers were randomly assigned to treatment with azathioprine (2.5 mg ∙ kg−1 ∙ day−1, n = 65) or conventional management (azathioprine only in cases of corticosteroid dependency, chronic active disease with frequent flares, poor response to corticosteroids, or development of severe perianal disease) (n = 67). The primary end point was the proportion of trimesters spent in corticosteroid-free and anti–tumor necrosis factor (TNF)—free remission during the first 3 years after inclusion.

Results

During the 3-year follow-up period, 16 patients in the azathioprine group were switched to mercaptopurine or methotrexate therapy because of intolerance or poor efficacy. Forty-one patients in the conventional management group required immunosuppressant therapy (61%; median time to first prescription, 11 months). In the azathioprine group, a median 67% of trimesters were spent in remission (interquartile range, 11%–85%) compared with 56% in the conventional management group (interquartile range, 29%–73%) (P = .69). Among secondary outcomes, a higher cumulative proportion of patients in the azathioprine group were free of perianal surgery than in the conventional management group (96% ± 3% and 82% ± 6% at month 36, respectively; P = .036). The cumulative proportion of patients free of intestinal surgery and anti-TNF therapy did not differ between groups.

Conclusions

Based on results from a clinical trial, administration of azathioprine within 6 months of diagnosis of CD was no more effective than conventional management in increasing time of clinical remission. Clinicaltrials.gov, Number NCT00546546.

Section snippets

Study Design and Patients

This 3-year, randomized, parallel, open-label trial (Résultat de l'Adjonction Précoce d'ImmunoDépresseurs; RAPID) compared early prescription of azathioprine (within the first 6 months after diagnosis) with conventional step-care strategy in patients at high risk for disabling CD.

Eligible patients were at least 18 years of age and had been diagnosed with CD according to validated criteria within 6 months before screening. Patients were considered at high risk for disabling disease based on the

Patient Characteristics and Disposition

Recruitment began on July 12, 2005, and ended on November 30, 2010, because the sample size was reached. Of the 147 randomly assigned patients, 72 were assigned to the early azathioprine group and 75 to the conventional management group (Supplementary Figure 1). Five patients were excluded immediately after randomization for screening failure or withdrawal of consent. Eight other patients declined further participation within the first 3 months; 5 withdrew consent, and 3 in the early

Discussion

This study, performed in adult patients with a high risk of disabling CD, failed to show that early treatment with azathioprine within 6 months of diagnosis was more effective than conventional management for increasing the duration of remission over the next 36 months. Among the secondary efficacy measures, only the development of fewer perianal complications and less need for perianal surgery was associated with early azathioprine use.

The efficacy of azathioprine for maintenance of remission

Acknowledgments

A list of investigators and study centers appears in the Appendix.

The authors thank Patricia Détré, Julie Demolin, and Gaëlle Brillault for their technical help and remember our friend Prof Marc Lémann, who initiated this study.

References (27)

  • J. Cosnes et al.

    Impact of the increasing use of immunosuppressants in Crohn's disease on the need for intestinal surgery

    Gut

    (2005)
  • P.L. Lakatos et al.

    Has there been a change in the natural history of Crohn's disease? Surgical rates and medical management in a population-based inception cohort from Western Hungary between 1977-2009

    Am J Gastroenterol

    (2012)
  • A.V. Ramadas et al.

    Natural history of Crohn's disease in a population-based cohort from Cardiff (1986-2003): a study of changes in medical treatment and surgical resection rates

    Gut

    (2010)

    • Cited by (0)

    This article has an accompanying continuing medical education activity on page e14. Learning Objective: Upon completion of these exercises, successful learners will be able to discuss the advantages and limits of early prescription of azathioprine (and other classical immunosuppressants) compared with conventional management in patients diagnosed with Crohn's disease.

    Conflicts of interest The authors disclose the following: Jacques Cosnes has served as a paid consultant for Abbott Laboratories. David Laharie has received fees for lectures and advisory boards for Abbott Laboratories and MSD. Yoram Bouhnik has served as a paid consultant for Bristol-Myers Squibb, Shire, Sanofi, Norgine Pharma, MSD, Abbott Laboratories, and AstraZeneca and received honoraria from Bristol-Myers Squibb, MSD, Abbott Laboratories, Teva, Ferring, Solvay Pharma, Vifor Pharma, and HAC. Matthieu Allez has received honoraria for consulting or teaching activities from Abbott Laboratories and MSD. Guillaume Savoye received lecture fees from Ferring, Abbott Laboratories, MSD, Vifor, and HAC Pharma. Jean-Frédéric Colombel has served as a paid consultant for Abbott Laboratories, Amgen, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Cellerix SL, ChemoCentryx, Centocor, Cosmo Technologies, Elan Pharmaceuticals, Genentech, Giuliani SPA, Given Imaging, GlaxoSmithKline, Immune Pharmaceuticals, Merck, Millennium Pharmaceuticals, Neovacs SA, Ocera Therapeutics (previously Renovia), Pfizer, Prometheus, Sanofi, Schering-Plough, Shire Pharmaceuticals, Synta Pharmaceuticals, Takeda, Teva Pharmaceuticals, Therakos, TxCell, UCB Pharma (previously Celltech Therapeutics), and Wyeth Pharmaceuticals; received speaker’s fees from Abbott Laboratories, Centocor, Falk Pharma, Ferring, Given Imaging, Merck, Schering-Plough, Shire Pharmaceuticals, and UCB Pharma; received financial support for research from Abbott Laboratories, Ferring, Schering-Plough, UCB Pharma, and Giuliani SPA; and is a shareholder in Intestinal Biotech Development. The remaining authors disclose no conflicts.

    Funding Supported by the Association François Aupetit and the Société Nationale Française de Gastroentérologie.

    View full text
    Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.