title: Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis.
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.
  
  
  OBJECTIVE
  To assess the effectiveness and safety of azathioprine and 6-mercaptopurine for maintaining remission of ulcerative colitis.
  
  
  METHODS
  The MEDLINE, EMBASE and Cochrane Library databases were searched from inception to June 2012. A manual search was also performed using references from these articles as well as review articles, and proceedings from major gastrointestinal meetings. Authors of maintenance trials were asked about unpublished studies.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  Six studies including 286 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 mesalamine 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). All of the studies which used active comparators were open label. When placebo and active comparator studies were pooled 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) and significant bone marrow suppression (5 cases). Deaths, opportunistic infection or neoplasia were not reported.
  
  
  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 (Issue 1, 2007).
authors.affiliation: Clinical Epidemiology, BIPS Institute for Epidemiology and Prevention Research, Bremen,Germany. timmer@bips.uni-bremen.de.
authors.forename: Antje
authors.initials: A
authors.lastname: Timmer
authors.forename: John W D
authors.initials: JW
authors.lastname: McDonald
authors.forename: David J
authors.initials: DJ
authors.lastname: Tsoulis
authors.forename: John K
authors.initials: JK
authors.lastname: Macdonald
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000627:therapeutic use; D000963:Antimetabolites / Q000009:adverse effects / Q000627:therapeutic use*; D001379:Azathioprine / Q000009:adverse effects / Q000627:therapeutic use*; D003093:Colitis, Ulcerative / Q000188:drug therapy*; D006801:Humans; D060046:Maintenance Chemotherapy / Q000379:methods*; D015122:Mercaptopurine / Q000009:adverse effects / Q000627:therapeutic use*; D019804:Mesalamine / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D055502:Secondary Prevention; D012460:Sulfasalazine / Q000627:therapeutic use
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000963:Antimetabolites; D012460:Sulfasalazine; D019804:Mesalamine; D015122:Mercaptopurine; D001379:Azathioprine