Conventional medical management of crohn's disease: Methotrexate

Methotrexate (MTX) is a useful treatment option for Crohn's disease. The principal pharmacological action of MTX is the reversible competitive inhibition of dihydrofolate reductase (DHFR). However, it is not clear to what extent the anti-inflammatory actions of MTX depend on DHFR inhibition. There are five randomized controlled trials which report on using MTX in the induction of remission in chronic active, steroid-dependent Crohn's disease. The largest trial by Feagan et al. [N Engl J Med 332:292–297, 1995] reported substantial benefit after 16 weeks treatment with intramuscular 25 mg weekly MTX. Several trials with smaller numbers reported on the use of oral MTX at lower doses and failed to show benefit. This likely relates to oral administration and inadequate dose of the drug being used. Another large study by Feagan et al. [N Engl J Med 342:1627–1632, 2000] showed that 15–25 mg of intramuscular MTX was successful in sustaining remission in patients who have already entered remission with MTX. The subcutaneous route has been shown to be as efficacious as intramuscular and is better tolerated by patients [Brooks et al. Arthritis Rheum 33:91–94, 1990; Egan et al. Clin Pharmacol Ther 65:29–39, 1999]. Adverse effects include myelosuppression, idiosyncratic reactions, and hepatotoxicity. Some studies suggest that patients with inflammatory bowel disease (IBD) may be at a lower risk of developing hepatic fibrosis and cirrhosis than patients with psoriasis [Te et al. Am J Gastroenterol 95:3150–3156, 2000; Lemann et al. Am J Gastroenterol 95:1730–1734, 2000]. Patients at risk of developing MTX-induced hepatotoxicity include those with a high alcohol intake and obesity, and such patients are at a high risk of developing hepatic fibrosis. Therefore, MTX is not advised in those patients. The anti-inflammatory effect of MTX may be offset at higher doses by MTX-induced enterotoxicity [Gwavava et al. J Clin Pathol 34:790–795, 1981; Pinkerton et al. J Clin Pathol 35, 1272–1277, 1982]. In summary, MTX has been proven to be effective for the induction of remission in patients with chronically active, steroid-dependent Crohn's disease and for the maintenance of remission in patients who enter remission with this drug with acceptable risk of toxicity, provided patients are selected and monitored appropriately.