Methotrexate is a structural analogue of folic acid that competitively inhibits its binding to its receptors and has demonstrated effectiveness for treating several autoimmune diseases,  including rheumatoid arthritis and psoriasis.  Possible mechanisms of its anti-inflammatory action include increased concentrations of adenosine, inhibition of methylation functions necessary for cell replication, and apoptosis of T cells. A randomized placebo-controlled trial evaluating the use of intramuscular methotrexate for induction therapy in patients with active Crohn’s disease showed a significant benefit in inducing clinical remission at 16 weeks (39 %  versus 19 %), as well as a reduction in prednisone dosing. Adverse events leading to discontinuation occurred in 17 % of the methotrexate group, primarily due to serum aminotransferase elevations or nausea.  Patients who achieved clinical remission in this study were then re-randomized to a maintenance trial of continued methotrexate 15 mg weekly versus placebo for 40 more weeks.

Those who received maintenance methotrexate were more likely to remain in remission and less likely to require steroids,  compared with those who received placebo (65 % versus 39 %).

In a few small, randomized controlled trials, oral methotrexate monotherapy has not shown any benefit for treatment of Crohn’s.

In addition to nausea and liver function test abnormalities,  side effects of methotrexate can include stomatitis, diarrhea, headache, hair loss, infections, bone marrow depression, and interstitial pneumonitis. Hepatic fibrosis has been seen with long-term methotrexate use and requires vigilant monitoring of liver enzymes with dose reduction or discontinuation of methotrexate if hepatotoxicity occurs .

Methotrexate is highly teratogenic,  so women of childbearing capacity should be counseled about this risk and are advised to use highly effective contraception while on methotrexate. Additionally, methotrexate can induce a reversible oligospermia and the safety of male partner methotrexate use during conception is unknown. Consequently, men are counseled to discontinue methotrexate at least 3 months in advance of trying to conceive a pregnancy. 

Folic acid supplementation is recommended uniformly to prevent folate deficiency and reduce side effects. In recognition of the lack of high quality data and the slow onset of action, methotrexate is not currently endorsed as a first line option for induction of remission in Crohn’s disease, but may have a role in treating patients who have failed other options .  In current practice, methotrexate is more commonly used in combination with anti-TNF agents, and its use in this capacity will be discussed later in this review. 

### R. A. Fausel , MD
T. L. Zisman , MD, MPH
Division of Gastroenterology, University of Washington Medical Center , 1959 NE Pacific Street, Box 356424 , Seattle , WA 98195 , USA

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