Methotrexate is another antimetabolite that has beneficial effects in a number of chronic inflammatory diseases, including Crohn’s disease and rheumatoid arthritis , and in cancer . Methotrexate may be given orally, subcutaneously, or intramuscularly. Reported oral bioavailabil-ity is 50–90% at doses used in chronic inflammatory diseases. Intramuscular and subcutaneous methotrexate exhibit nearly complete bioavailability.
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 anti-proliferative effects may not be evident. Methotrexate may inter-fere with the inflammatory actions of interleukin-1. It may also stimulate increased release of adenosine, an endogenous anti-inflammatory autacoid. Methotrexate may also stimulate apopto-sis and death of activated T lymphocytes.
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 satisfac-tory response is achieved within 8–12 weeks, the dose is reduced to 15 mg/wk.
At higher dosage, methotrexate may cause bone marrow depres-sion, 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 impair-ing 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 accumula-tion and toxicity.