Mechanism of action: The principal mechanism of action is inhibition of dihydrofolate reductase, an enzyme important in the production of thymidine and purines. At the high doses used for chemotherapy, methotrexate inhibits cellular proliferation. However, at the low doses used in the treatment of inflammatory bowel disease (12–25 mg/wk), the antiproliferative effects may not be evident. Methotrexate may interfere with the inflammatory actions of interleukin-1. It may also stimulate increased release of adenosine, an endogenous antiinflammatory autacoid. Methotrexate may also stimulate apoptosis and death of activated T lymphocytes.
Clinical Uses: Methotrexate is used to induce and maintain remission in patients with Crohn’s disease. Its efficacy in ulcerative colitis is uncertain. To induce remission, patients are treated with 15–25 mg of methotrexate once weekly by subcutaneous injection. If a satisfactory response is achieved within 8–12 weeks, the dose is reduced to 15 mg/wk.
Adverse Effects: At higher dosage, methotrexate may cause bone marrow depression, megaloblastic anemia, alopecia, and mucositis. At the doses used in the treatment of inflammatory bowel disease, these events are uncommon but warrant dose reduction if they do occur. Folate supplementation reduces the risk of these events without impairing the anti-inflammatory action. In patients with psoriasis treated with methotrexate, hepatic damage is common; however, among patients with inflammatory bowel disease and rheumatoid arthritis, the risk is significantly lower. Renal insufficiency may increase risk of hepatic accumulation and toxicity.
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