Key messages
• Azathioprine and 6-mercaptopurine seem to be more effective than placebo (fake pills) for the long-term treatment of ulcerative colitis, which is an inflammatory disorder of the large bowel.
• There is not enough evidence to evaluate the effect of azathioprine or 6-mercaptopurine in combination with other drugs.
What is ulcerative colitis, and could azathioprine and 6-mercaptopurine work?
Ulcerative colitis is a chronic inflammatory disorder of the large bowel. The rising number of affected people makes it a growing healthcare burden worldwide. The most common symptoms of ulcerative colitis are bloody diarrhea and abdominal pain. Azathioprine and 6-mercaptopurine are two drugs of the type known as thiopurines, that are thought to reduce the inflammation caused by this disease. Newer drugs have recently been developed, but in many countries thiopurines are still the preferred first treatment for ulcerative colitis. This review aims to explore the value of thiopurines compared to other current treatments.
What did we want to find out?
We wanted to find out whether azathioprine or 6-mercaptopurine are better than a placebo (fake pills) in preventing symptoms from reoccurring in people with treated ulcerative colitis. We also wanted to assess the use of combining them with other drugs for a more effective treatment.
What did we do?
We searched for studies that sorted people into treatment groups at random and compared oral azathioprine or 6-mercaptopurine to placebo (fake pills) or other treatments (mesalazine, 5-aminosalicylate, methotrexate, cyclosporin, granulocyte-monocyte adsorption apheresis).
What did we find?
We found 10 studies that included a total of 468 people over 18 years old with ulcerative colitis. Two studies used azathioprine in combination with other drugs (allopurinol, infliximab). All studies lasted for at least 12 months.
Main results
The studies showed that azathioprine or 6-mercaptopurine may be better than placebo for preventing the disease from returning once the person has responded to treatment (maintenance treatment).
We are uncertain whether azathioprine treatment causes more people to stop treatment because of side effects compared to people taking placebo.
The evidence hints that 6-mercaptopurine is better than 5-aminosalicylate at keeping people free from ulcerative colitis, but we have little confidence in this evidence because it came from one small study. There was no information available to compare the safety of 6-mercaptopurine against 5-aminosalicylate.
How safe are azathioprine and 6-mercaptopurine?
The people taking these drugs did not have many side effects. However, serious side effects can occur, such as pancreatitis (inflammation of the pancreas that causes severe abdominal pain) and bone marrow suppression (failure to make normal blood cells). People taking these drugs should be regularly monitored for evidence of effectiveness and side effects.
What are the limitations of the evidence?
Our confidence in the evidence is mainly low as the studies were small, and some of the assessed studies did not report all the data we were interested in.
How up to date is this evidence?
The evidence is up to date to May 2023.
Low-certainty evidence suggests that azathioprine or 6-mercaptopurine therapy may be more effective than placebo for the maintenance of remission in ulcerative colitis. More research is needed to evaluate the value of therapeutic drug monitoring and the effects of various treatment modalities on long-term safety.
Maintenance of remission is essential in inflammatory bowel disease (IBD) in terms of disease course and long-term prognosis. The thiopurines azathioprine and 6-mercaptopurine have longstanding merit in ulcerative colitis, but more therapeutic options have been developed. This review is an update and extension of a review last published in 2016.
To assess the effectiveness and safety of azathioprine and 6-mercaptopurine in monotherapy or combined therapy regimens compared to placebo or active controls for the maintenance of remission in ulcerative colitis.
We searched Cochrane Central Register of Controlled Trials (until May 2023), ClinicalTrials.gov (until May 2023), Embase (until August 2022), MEDLINE (until May 2023), and WHO ICTRP (until May 2023). We checked reference lists of the included studies and, if needed, contacted the authors to request more data or information.
Randomized controlled trials (RCTs) of at least 24 weeks' duration comparing azathioprine or 6-mercaptopurine with placebo or any other medication, or comparing different treatment modalities of azathioprine or 6-mercaptopurine, in persons of any age with quiescent ulcerative colitis were eligible. We only considered studies with mixed IBD populations or with a preceding induction period if separate results on participants with ulcerative colitis in remission were available or could be calculated. The primary outcome was failure to maintain clinical or endoscopic remission (relapse). Secondary outcomes included change in disease activity, quality of life, hospitalization, need for surgery, days off work, adverse events, and withdrawal due to adverse events.
Two authors independently extracted data using standard forms, resolved any disagreements by consensus, and assessed study quality using the Cochrane risk of bias tool (RoB 2). We conducted separate analyses by type of control, calculated pooled risk ratios (RRs) or risk differences (RDs) using the fixed-effect model unless heterogeneity was likely, and assessed the certainty of evidence using the GRADE approach.
We included 10 studies in the review, including 468 adult participants with ulcerative colitis. The risk of bias across these was low for most outcomes, but we considered some outcomes to have some concerns or high risk of bias due to insufficient information on concealment of allocation and outcome measurement.
Based on five placebo-controlled studies, azathioprine or 6-mercaptopurine may reduce the risk of failing to maintain remission. In the thiopurine group, 45% (64/143) of participants failed to maintain remission compared to 67% (96/143) of participants receiving placebo (RR 0.66, 95% confidence interval (CI) 0.54 to 0.82; 5 studies, 286 participants; low-certainty evidence).
Three studies reported withdrawals due to adverse events. Among participants on azathioprine, 4% (3/80) withdrew due to adverse events compared to 0% (0/82) of placebo participants (RD 0.04, 95% CI −0.02 to 0.09; 3 studies, 162 participants; low-certainty evidence).
The evidence is of low certainty when comparing 6-mercaptopurine to 5-aminosalicylate. Based on one three-armed trial, 27% (3/11) of 6-mercaptopurine participants failed to maintain remission compared to 100% (2/2) of 5-aminosalicylate participants (RR 0.35, 95% CI 0.13 to 0.97; 1 study, 13 participants; low-certainty evidence). This trial also involved an induction phase; we only included the results for participants in remission.
The single trial comparing 6-mercaptopurine to 5-aminosalicylate did not report separate data on adverse events and withdrawals due to adverse events for the subgroup with successful induction of remission, so we could not analyze these outcomes for this comparison.