Gastroenterology

Gastroenterology

Volume 128, Issue 7, June 2005, Pages 1812-1818
Gastroenterology

Clinical-alimentary tract
A Randomized, Double-Blind, Controlled Withdrawal Trial in Crohn’s Disease Patients in Long-term Remission on Azathioprine

https://doi.org/10.1053/j.gastro.2005.03.031Get rights and content

Background & Aims: An open study reported that patients with Crohn’s disease in remission who have taken azathioprine for longer than 3.5 years are at low risk of relapse when azathioprine is discontinued. To confirm this observation, we performed a multicenter, double-blind, noninferiority withdrawal study. Methods: Patients who were in clinical remission on azathioprine for ≥42 months were randomized to continue azathioprine or to receive an equivalent placebo for 18 months. The primary end point was clinical relapse at 18 months. Results: Forty patients were randomly assigned to receive azathioprine and 43 to receive placebo. Characteristics of patients at entry were similar in the 2 study groups. At 18 months, 3 patients had a relapse in the azathioprine group, and 9 had a relapse in the placebo group. Kaplan-Meier estimates of the relapse rate at 18 months were 8% ± 4% and 21% ± 6%, respectively. The hypothesis that placebo was inferior to azathioprine was not rejected (P = .195). Among the baseline variables, C-reactive protein level >20 mg/L, time without steroids <50 months, and hemoglobin level <12 g/dL were found to be predictive of relapse in the multivariate analysis. Conclusions: This study shows that azathioprine withdrawal is not equivalent to continued therapy with azathioprine for maintenance of remission in patients with Crohn’s disease who have been in remission on azathioprine for ≥3.5 years. Thus, azathioprine maintenance therapy should be continued beyond 3.5 years.

Section snippets

Patients

The study was performed at 11 sites in France and 1 site in Belgium, all of which are members of the Groupe d’Etude Thérapeutique des Affections Inflammatoires du tube Digestif (GETAID). Recruitment of patients took place from October 1995 to November 1999.

Eligible patients were at least 18 years old and had Crohn’s disease according to established clinical, endoscopic, radiological, and histological criteria. Criteria for inclusion in the study were (1) continuous treatment with azathioprine

Baseline Characteristics of the Study Patients

Between October 1995 and November 1999, a total of 83 patients were enrolled; 43 patients were randomly assigned to receive placebo, and 40 were randomly assigned to receive azathioprine. Demographic and other baseline characteristics were similar in the 2 study groups (Table 1). One patient in the azathioprine group never took study medication. Five patients discontinued the study for reasons other than relapse. Three patients withdrew their consent, 2 at month 9 (1 patient in each treatment

Discussion

Controlled trials, 1, 2, 3 a meta-analysis, 25 and a Cochrane review 26 have shown that azathioprine and 6-mercaptopurine are effective in Crohn’s disease, both for maintaining remission and as steroid-sparing agents in chronic, active, steroid-dependent cases. However, there has been no consensus about the duration of the treatment once remission has been obtained. Because thiopurines only suppress disease activity, the issue of when to stop the drug is a difficult clinical decision and is

References (38)

  • J.D. Lewis et al.

    Azathioprine for maintenance of remission in Crohn’s diseasebenefits outweigh the risk of lymphoma

    Gastroenterology

    (2000)
  • G.A. Dayharsh et al.

    Epstein-Barr virus-positive lymphoma in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine

    Gastroenterology

    (2002)
  • J. Cosnes et al.

    Smoking cessation and the course of Crohn’s diseasean intervention study

    Gastroenterology

    (2001)
  • D.P. O’Donoghue et al.

    Double-blind withdrawal of azathioprine as maintenance treatment for Crohn’s disease

    Lancet

    (1978)
  • S. Candy et al.

    A double blind controlled study of azathioprine in the treatment and maintenance of remission in CD

    Gut

    (1995)
  • D.H. Present et al.

    Treatment of Crohn’s disease with 6-mercaptopurine. A long-term, randomized, double-blind study

    N Engl J Med

    (1980)
  • A.G. Fraser et al.

    The efficacy of azathioprine for the treatment of inflammatory bowel diseasea 30 year review

    Gut

    (2002)
  • A.G. Fraser et al.

    Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine

    Aliment Pharmacol Ther

    (2002)
  • D.H. Present et al.

    6-Mercaptopurine in the management of inflammatory bowel diseaseshort and long term toxicity

    Ann Intern Med

    (1989)
  • Cited by (0)

    This study was initiated, designed, and conducted by GETAID. It was funded by grant supports from the Société Nationale Française de Gastroentérologie and by the Association François Aupetit. Drugs were provided by GlaxoSmithKline. All data analysis and writing were performed independently by GETAID, without the involvement of representatives of GlaxoSmithKline.

    View full text