Compared to placebo, treatment with azathioprine and 6-mercaptopurine does not significantly improve clinical remission rates in patients with active Crohn’s disease.

Previous studies involving the use of antimetabolite therapy for Crohn’s disease has produced conflicting and sometimes controversial results. In order to assess the safety and efficacy of these therapies, an updated meta-analysis was performed which included randomized controlled trials that compared oral azathioprine or 6-mercaptopurine to placebo or active therapy in adults with active disease. The main outcomes of the study included clinical remission and improvement, fistula improvement/healing, steroid sparing, adverse events and withdrawals due to side effects. Thirteen studies were included in the analysis and overall quality of evidence was assessed using the GRADE criteria. 

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Based on the results of five studies, no statistically significant difference in clinical remission rates was seen between azathioprine or 6-mercaptopurine and placebo (48% vs. 37%; 5 studies, 380 patients; RR 1.23, 95% CI 0.97 to 1.55). In addition, compared to placebo, there was no statistically significant difference in clinical improvement rates with azathioprine or 6-mercaptopurine (36% vs. 48%; 8 studies, 434 patients; RR 1.26, 95% CI 0.98 to 1.62). 

With regards to steroid sparing, a statistically significant difference was noted between the antimetabolites and placebo, with 64% of azathioprine patients reducing their prednisone dose to less than 10mg/day compared to 46% of patients in the placebo group (RR 1.34, 95% CI 1.02 to 1.77). Between the treatment and placebo groups, the number of patients who withdrew due to adverse events was not significantly different (10% vs. 5%; 8 studies, 510 patients; RR 1.70, 95% CI 0.94 to 3.08); serious side effects were reported in 14% of azathioprine patients versus 4% of placebo patients ( (2 studies, 216 patients; RR 2.57, 95% CI 0.92 to 7.13). 

In studies comparing antimetabolite treatment to active therapy, azathioprine was shown to be significantly inferior to infliximab for induction of steroid-free clinical remission (30% vs. 44%; 1 study, 339 patients; RR 0.68, 95% CI 0.51 to 0.90), however,  the combination of azathioprine and infliximab was found to be superior to infliximab monotherapy (60% vs. 48%; 2 studies, 383 patients; RR 1.23, 95% CI 1.02 to 1.47).  Compared to methotrexate, azathioprine or 6-mercaptopurine were found to be no better at inducing steroid free clinical remission (RR 1.13, 95% CI 0.85 to 1.49); similar outcomes were noted with 5-aminosalicylate or sulfasalazine (RR 1.24, 95% CI 0.80 to 1.91).  Withdrawal due to adverse events was not statistically significantly different between the antimetabolite groups and patients receiving an active comparator.

The authors conclude that while antimetabolite therapy offers no advantage over placebo with regards to clinical remission or improvement, it could allow Crohn’s disease patients to reduce their use of steroids. 

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