Abstract: Two studies (n = 101 patients) were included in the review. One study (n = 67) compared oral methotrexate 12.5 mg/week) to placebo. The other study (n = 34) compared oral methotrexate (15 mg/week) to 6-mercaptopurine (1.5 mg/kg/day) and 5-aminosalicylic acid (3 g/day). The placebo-controlled study was judged to be at low risk of bias. The other study was judged to be at high risk of bias due to an open-label design. There was no statistically significant difference in clinical remission rates between methotrexate and placebo patients. Forty-seven per cent (14/30) of methotrexate patients achieved clinical remission and complete withdrawal from steroids during the study period compared to 49% (18/37) of placebo patients (RR 0.96, 95% CI 0.58 to 1.59. A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data (32 events). There were no statistically significant differences in the proportion of patients who achieved clinical remission and withdrawal from steroids in the study comparing oral methotrexate to 6-mercaptopurine and 5-aminosalicylic acid. At 30 weeks, 58% (7/12) of methotrexate patients achieved clinical remission and withdrawal from steroids compared to 79% (11/14) of 6-mercaptopurine patients (RR 0.74, 95% CI 0.43 to 1.29) and 25% of 5-aminosalicylic acid patients (RR 2.33, 95% CI 0.64 to 8.49). GRADE analyses indicated that the overall quality of the evidence was very low due to very sparse data (18 and 9 events respectively) and and high risk of bias. In the placebo-controlled trial two patients (7%) were withdrawn from the methotrexate group due to adverse events (leucopenia, migraine) compared to one patient (3%) who had a rash in the placebo group (RR 2.47, 95% CI 0.23 to 25.91). Adverse events experienced by methotrexate patients in the active comparator study included nausea and dyspepsia, mild alopecia, mild increase in aspartate aminotransferase levels, peritoneal abscess, hypoalbuminemia, severe rash and atypical pneumonia. Although methotrexate was well-tolerated, the studies showed no benefit for methotrexate over placebo or active comparators. The results for efficacy outcomes between methotrexate and placebo, methotrexate and 6-mercaptopurine and methotrexate and 5-aminosalicylic acid were uncertain. Whether a higher dose or parenteral administration would be effective for induction therapy is unknown. At present there is no evidence supporting the use of methotrexate for induction of remission in active ulcerative colitis. A trial in which larger numbers of patients receive a higher dose of oral methotrexate should be considered. Currently there are two large ongoing placebo-controlled trials (METEOR and MERIT-UC) assessing the efficacy and safety of intramuscular or subcutaneous methotrexate in patients with active UC which may help resolve the evidence supporting the use of methotrexate as therapy for active of ulcerative colitis.

Plain-language summary: The researchers identified two studies that included a total of 101 participants. One was a high quality study (67 participants) that compared oral methotrexate (12.5 mg/week) to a placebo (a sugar pill or fake medicine). The other study (34 participants) compared oral methotrexate (15 mg/week) against 6-mercaptopurine (an immunosuppressive drug at a dose of 1.5 mg/kg/day) and against 5-aminosalicylic acid (an anti-inflammatory drug at a dose of 3 g/day). In the high quality study, there was no difference between the methotrexate and placebo treatment groups for the number of people who achieved remission and were able to stop taking steroids. This suggests that, when used at this low dose (12.5 mg/week), methotrexate does not produce remission from ulcerative colitis. However, this result is uncertain because of the small number of people who were assessed. The other, smaller study showed no differences between methotrexate and the other treatments in the proportion of participants who experienced remission and were able to stop taking steroids. This result is also uncertain due to poor study design and the low number of participants. The side effects reported in the two studies included leucopenia (a decrease in the number of white blood cells), migraine, rash, nausea and dyspepsia (indigestion), mild alopecia (hair loss), mild increase in levels of an enzyme found in the liver (aspartate aminotransferase), a collection of pus in the abdominal tissue (peritoneal abscess), abnormally low levels of the protein albumin in the blood (hypoalbuminemia), and pneumonia. At present, the results from medical trials do not support the use of low dose oral methotrexate (12.5 mg to 15 mg/week) for the production of remission in active ulcerative colitis. It is not known whether a higher dose of oral methotrexate, or giving methotrexate by a different route (e.g. by injection), would increase the likelihood of remission. In future, researchers should consider organising a study with a larger number of participants who receive a higher dose of oral methotrexate. Currently, there are two large studies being run that compare a higher dose of methotrexate – given by injection – with placebo in people with active ulcerative colitis (the METEOR and MERIT-UC studies). The results of these studies may resolve the uncertainty surrounding the use of methotrexate for the treatment of active ulcerative colitis.