Is methotrexate appropriate for treating ulcerative colitis refractory to 5‑aminosalicylic acid agents, corticosteroids, and azathioprine?

Methotrexate Should Not Be Used for Ulcerative Colitis

Methotrexate is not recommended for treating ulcerative colitis, whether refractory to conventional therapy or otherwise, as it has shown no benefit over placebo for either induction or maintenance of remission. 1

Evidence Against Methotrexate in Ulcerative Colitis

Induction of Remission

• The most recent 2025 British Society of Gastroenterology guidelines explicitly state that methotrexate is not suggested for induction and maintenance of remission in patients with moderate to severe ulcerative colitis (conditional recommendation, low certainty evidence). 1
• Placebo-controlled trials showed no statistically significant difference in clinical remission rates between methotrexate (12.5 mg/week oral) and placebo (RR=1.19,95% CI 0.72 to 1.96). 1
• The 2015 Toronto Consensus and 2020 AGA guidelines both recommend against using methotrexate monotherapy for induction of remission (strong recommendation, low-quality evidence). 1

Maintenance of Remission

• There was no statistically significant difference in maintaining remission between methotrexate and placebo (RR=1.06; 95% CI 0.79 to 1.43). 1
• The pivotal MERIT study found no difference at week 48, with 27% of methotrexate patients and 30% of placebo patients maintaining steroid-free clinical remission. 1
• The 2020 AGA guidelines recommend against methotrexate monotherapy for maintenance of remission (conditional recommendation, low-quality evidence). 1

What to Use Instead

For Patients Refractory to 5-ASA, Corticosteroids, and Azathioprine

• Biologic therapy is the appropriate next step, specifically infliximab or vedolizumab as first-line options, which have superior efficacy compared to other biologics in biologic-naïve patients. 2
• The AGA recommends early use of biologic agents with or without immunomodulator therapy rather than gradual step-up after conventional therapy failure. 2, 3
• Consider combination therapy with a biologic plus thiopurine or methotrexate (see limited role below) rather than biologic monotherapy for enhanced efficacy. 2, 4

The Only Limited Role for Methotrexate in UC

As an Adjunct to Anti-TNF Therapy

• Methotrexate may have a role in combination with anti-TNFα monoclonal antibodies to reduce immunogenicity in patients who have contraindications to or are intolerant of thiopurines (azathioprine/6-mercaptopurine). 1
• This is based on pharmacokinetic principles and extrapolation from Crohn's disease data, not direct evidence in UC. 4
• The typical dose would be 10-12.5 mg/week subcutaneously when used for this purpose. 1

Critical Safety Considerations

Teratogenicity Warning

• Methotrexate is contraindicated in women who are actively family planning due to very high risk of miscarriage and teratogenicity. 1
• Female patients of childbearing age must be advised about teratogenic risks and counseled to use suitable contraception. 1

For Patients Already on Methotrexate

• If a patient is already established on methotrexate monotherapy for UC, hold an individualized discussion about discontinuation, as remission may be spontaneously maintained with 5-ASA monotherapy. 1
• Do not abruptly discontinue without shared decision-making. 1

Common Pitfalls to Avoid

• Do not use methotrexate as monotherapy for UC in any scenario—induction, maintenance, or steroid-dependent disease. 1
• Do not delay biologic therapy in patients with moderate-to-severe UC who have failed conventional therapy, as this increases risk of complications, hospitalization, and colectomy. 2, 3
• Do not confuse UC with Crohn's disease—methotrexate is effective in Crohn's disease but not in UC. 5
• Do not continue 5-ASA once remission is achieved with biologics and/or immunomodulators, as it provides no additional benefit. 2, 3