Abstract: Three trials (165 patients) fulfilled the inclusion criteria. One study compared oral methotrexate (12.5 mg/week) to placebo, another compared oral methotrexate (15 mg/week) to 6-mercaptopurine (6-MP, 1.5 mg/kg/day) or 5-aminosalicylic acid (5-ASA, 3 g/day) and the other compared methotrexate (15 mg/week) in combination sulfasalazine (3 g/day) to sulfasalazine. The placebo-controlled study was rated as low risk of bias. The study comparing methotrexate to 6-MP and 5-ASA was rated as high risk of bias and the study assessing methotrexate and sulfasalazine was rated as unclear risk of bias for sequence generation, allocation concealment and blinding. The placebo-controlled study found no statistically significant differences in the proportion of patients who maintained remission. At nine months, 36% (5/14) of methotrexate patients maintained remission compared to 54% (10/18) of placebo patients (RR 0.64, 95% CI 0.28 to 1.45). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (15 events). The study comparing combination therapy to sulfasalazine found no statistically significant difference in the proportion of patients who maintained remission. At 12 months, 100% (14/14) of patients in the combination group maintained remission compared to 75% (9/12) of sulfasalazine patients (RR 1.32, 95% CI 0.94 to 0.86), A GRADE analysis indicated that the overall quality of the evidence for this outcome was very low due to unknown risk of bias and very sparse data (23 events). There were no statistically significant differences in maintenance of remission rates between methotrexate and 6-MP or between methotrexate and 5-ASA. At 76 weeks, 14% (1/7) of methotrexate patients maintained remission compared to 64% (7/11) of 6-MP patients (RR 0.22, 95% CI 0.03 to 1.45) and 0% (0/2) of 5-ASA patients (RR 1.13, 95% CI 0.06 to 20.71). A GRADE analysis indicated that the overall quality of the evidence from this study was very low due to high risk of bias and very sparse data. Adverse events reported in these studies included transient leucopenia, migraine, nausea and dyspepsia, mild alopecia, mild increase in aspartate aminotransferase levels, peritoneal abscess, hypoalbuminemia, severe rash and atypical pneumonia The results for efficacy and safety outcomes between methotrexate and placebo, methotrexate and sulfasalazine, methotrexate and 6-mercaptopurine and methotrexate and 5-aminosalicylic acid were uncertain. Whether a higher dose or parenteral administration of methotrexate would be effective in quiescent ulcerative colitis is unknown. At present there is no evidence supporting the use of methotrexate for maintenance of remission in ulcerative colitis. More studies are needed to determine the efficacy and safety of methotrexate maintenance therapy in patients with quiescent ulcerative colitis. Large scale methodologically rigorous randomized controlled trials are needed. These studies should investigate higher doses of methotrexate (e.g. 15 to 25 mg/week) and parenteral administration.

Plain-language summary: The researchers identified three studies that included a total of 165 patients. One study (67 patients) compared oral methotrexate (12.5 mg/week) to placebo (e.g. a sugar pill or fake medicine), one study (26 patients) compared oral methotrexate (15 mg/week) and sulfasalazine (3 g/day) to sulfasalazine alone, and one study (72 patients in total; of which, 34 had ulcerative colitis ) compared oral methotrexate (15 mg/week) to 6-mercaptopurine (1.5 mg/kg/day) or 5-aminosalicylic acid (3 g/day). Two studies were judged to be of very low quality and the placebo-controlled study was judged to be of high quality. There was no difference between the methotrexate and placebo treatment groups for the number of people who maintained remission at nine months. This suggests that, when used at this low dose (12.5 mg/week) methotrexate does not maintain remission in patients with inactive ulcerative colitis. However, this result is uncertain due to the small number of people who were assessed There was no difference between the combination therapy (methotrexate plus sulfasalazine) and sulfasalazine treatment groups for the number of people who maintained remission at 12 months. This result is uncertain due to poor study design and the low number of participants. The other, small study showed no differences between methotrexate and the other treatments (6-mercaptopurine and 5-aminosalicylic acid) in the proportion of participants who were able to maintain remission. These results are uncertain due to poor study design and the low number of participants. The side effects reported in the 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 maintenance of remission in people with inactive 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 be effective for maintenance of remission in people with inactive ulcerative colitis. In future, researchers should consider organizing a study with a larger number of participants who receive a higher dose of methotrexate (15 to 25 mg/week). Future studies should also investigate methotrexate given by injection. The results of such studies may resolve the uncertainty surrounding the use of methotrexate as maintenance therapy in people with inactive ulcerative colitis.