Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis

Timmer A, McDonald JW, MacDonald JK

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Summary

Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis

Studies of azathioprine and 6-mercaptopurine for maintenance treatment of ulcerative colitis.
Six studies were reviewed and provide the best evidence we have. Study quality was mostly poor. The studies tested 286 people over the age of eighteen who had ulcerative colitis. The subjects received oral azathioprine or 6-mercaptopurine, placebo (fake pills) or standard maintenance treatment (mesalazine or sulfasalazine). The studies lasted for at least 12 months.

What is ulcerative colitis and could azathioprine and 6-mercaptopurine work?
Ulcerative colitis is a chronic inflammatory disorder of the colon. The most common symptoms of ulcerative colitis are bloody diarrhea and abdominal pain. Azathioprine and 6-mercaptopurine are thought to reduce inflammation by blocking the immune system.

What did the studies show?
The studies showed that azathioprine was better than placebo for maintenance treatment (i.e. preventing the disease from coming back once the patient has responded to treatment). Fifty-six per cent of patients treated with azathioprine were disease free after one year of treatment compared to 35% of patients who received placebo.

How safe are azathioprine and 6-mercaptopurine?
The drugs were generally well tolerated and side effects occurred infrequently. However serious side effects such as acute pancreatitis (an inflammation of the pancreas that causes severe abdominal pain - a 2% risk) and bone marrow suppression (failure to make normal blood cells - a 4% risk) can occur. Patients taking these drugs should be regularly monitored for evidence of effectiveness and side effects.

What is the bottom line?
Given the established effectiveness and safety of aminosalicylates (i.e. mesalazine or sulfasalazine) for the maintenance of remission in ulcerative colitis, azathioprine and 6-mercaptopurine cannot be recommended as first line treatment to prevent the disease from coming back. However, azathioprine may be an effective maintenance treatment for patients who have failed or cannot tolerate mesalazine or sulfasalazine and for patients who require repeated courses of steroids.

This is a Cochrane review abstract and plain language summary, prepared and maintained by The Cochrane Collaboration, currently published in The Cochrane Database of Systematic Reviews 2010 Issue 1, Copyright © 2010 The Cochrane Collaboration. Published by John Wiley and Sons, Ltd.. The full text of the review is available in The Cochrane Library (ISSN 1464-780X).
This record should be cited as: Timmer A, McDonald JWD, MacDonald JK. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD000478. DOI: 10.1002/14651858.CD000478.pub2.

This version first published online: January 24. 2007

Abstract

Background

Maintenance of remission is a major issue in inflammatory bowel disease. In ulcerative colitis, the evidence for the effectiveness of azathioprine and 6-mercaptopurine for the maintenance of remission is still controversial.

Objectives

To assess the effectiveness and safety of azathioprine and 6-mercaptopurine for maintaining remission of ulcerative colitis.

Search strategy

The MEDLINE database was used to search literature from 1966 to 2006. A manual search was also performed using references from these articles as well as review articles, proceedings from major gastrointestinal meetings and data available from the Cochrane Collaboration database. Authors of maintenance trials were asked about unpublished studies.

Selection criteria

Randomized controlled trials of at least 12 months duration that compared azathioprine or 6-mercaptopurine with placebo or standard maintenance therapy (mesalamine) were included.

Data collection and analysis

Data were extracted by two raters using standard forms. Disagreements were solved by informal consent, including a third rater. Jadad scores were applied to assess study quality. Analyses were performed separately by type of control (placebo, or active comparator). Pooled odds ratios were calculated based on the fixed effects model unless heterogeneity was shown.

Main results

Six studies were identified including 286 patients with ulcerative colitis. The study quality was mostly poor. Azathioprine was shown to be superior for the maintenance of remission as compared to placebo based on four trials (failure to maintain remission: OR 0.41; 95% CI 0.24 to 0.70). Two trials that compared 6-mercaptopurine to mesalazine, or azathioprine to sulfasalazine showed significant heterogeneity. Both studies using active comparators were open label. Adverse effects occurred in 11 of 127 patients receiving azathioprine, including acute pancreatitis (3 cases) and significant bone marrow suppression (5 cases).

Authors' conclusions

Azathioprine may be an effective maintenance therapy for patients who have failed or cannot tolerate mesalazine or sulfasalazine and for patients who require repeated courses of steroids. More research is needed to evaluate superiority over standard maintenance therapy, especially in the light of a potential for adverse events from azathioprine.

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