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

Studies of azathioprine and 6-mercaptopurine for maintenance treatment of ulcerative colitis.
Seven studies were reviewed and provide the best evidence we have. Study quality was mostly poor. The studies tested 302 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 diarrhoea 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 (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?
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.

Authors' conclusions: 

Azathioprine therapy appears to be more effective than placebo for maintenance of remission in ulcerative colitis. Azathioprine or 6-mercaptopurine may be effective as 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. This review updates the existing review of azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis which was published in the Cochrane Library (September 2012).

Read the full 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, EMBASE and Cochrane Library databases were searched from inception to 30 July 2015. Both full randomized controlled trials and associated abstracts were included.

Selection criteria: 

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

Data collection and analysis: 

Two authors independently extracted data using standard forms. Disagreements were solved by consensus including a third author. Study quality was assessed using the Cochrane risk of bias tool. The primary outcome was failure to maintain clinical or endoscopic remission. Secondary outcomes included adverse events and withdrawal due to adverse events. Analyses were performed separately by type of control (placebo, or active comparator). Pooled risk ratios were calculated based on the fixed-effect model unless heterogeneity was shown. The GRADE approach was used to assess the overall quality of evidence for pooled outcomes.

Main results: 

Seven studies including 302 patients with ulcerative colitis were included in the review. The risk of bias was high in three of the studies due to lack of blinding. Azathioprine was shown to be significantly superior to placebo for maintenance of remission. Fourty-four per cent (51/115) of azathioprine patients failed to maintain remission compared to 65% (76/117) of placebo patients (4 studies, 232 patients; RR 0.68, 95% CI 0.54 to 0.86). A GRADE analysis rated the overall quality of the evidence for this outcome as low due to risk of bias and imprecision (sparse data). Two trials that compared 6-mercaptopurine to mesalazine, or azathioprine to sulfasalazine showed significant heterogeneity and thus were not pooled. Fifty per cent (7/14) of 6-mercaptopurine patients failed to maintain remission compared to 100% (8/8) of mesalazine patients (1 study, 22 patients; RR 0.53, 95% CI 0.31 to 0.90). Fifty-eight per cent (7/12) of azathioprine patients failed to maintain remission compared to 38% (5/13) of sulfasalazine patients (1 study, 25 patients; RR 1.52, 95% CI 0.66 to 3.50). One small study found that 6-mercaptopurine was superior to methotrexate for maintenance of remission. In the study, 50% (7/14) of 6-mercaptopurine patients and 92% (11/12) of methotrexate patients failed to maintain remission (1 study, 26 patients; RR 0.55, 95% CI 0.31 to 0.95). One very small study compared azathioprine with cyclosporin and found that there was no significant difference between patients failing remission on azathioprine (50%, 4/8) or cyclosporin (62.5%, 5/8) (1 study, 16 patients, RR 0.80 95% CI 0.33 to 1.92). When placebo-controlled studies were pooled with aminosalicylate-comparator studies to assess adverse events, there was no statistically significant difference between azathioprine and control in the incidence of adverse events. Nine per cent (11/127) of azathioprine patients experienced at least one adverse event compared to 2% (3/130) of placebo patients (5 studies, 257 patients; RR 2.82, 95% CI 0.99 to 8.01). Patients receiving azathioprine were at significantly increased risk of withdrawing due to adverse events. Eight per cent (8/101) of azathioprine patients withdrew due to adverse events compared to 0% (0/98) of control patients (5 studies, 199 patients; RR 5.43, 95% CI 1.02 to 28.75). Adverse events related to study medication included acute pancreatitis (3 cases, plus 1 case on cyclosporin) and significant bone marrow suppression (5 cases). Deaths, opportunistic infection or neoplasia were not reported.

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