Methotrexate is another immunosuppressive agent. Low-dose oral administration has been shown to be both effective and relatively nontoxic in other immunologically mediated diseases, such as rheumatoid arthritis and psoriasis. An early trial in MS showed some reduction in the relapse rate but no benefit in patients with progressive disease.

In another study, 60 ambulatory patients with progressive MS and moderate to severe disability were treated with methotrexate in a dosage of 7.5 mg weekly or placebo for two years. Patients receiving active treatment showed significantly reduced worsening according to a composite measure of outcome that included the EDSS and tests of arm function, the maximal benefit occurring relatively early in the study. However, the effect of this treatment was not significant when a traditional outcome measure such as the EDSS was used. The effect on MRI activity also was marginal. This low dose of methotrexate was well tolerated, and none of the patients discontinued treatment because of side-effects. Several small studies have been published indicating that methotrexate, when added to one of the interferons, may reduce disease activity, but these reports are not definitive.

Prolonged use of methotrexate may cause mucosal irritation, gastrointestinal symptoms, hepatotoxicity, pulmonary fibrosis, and bone marrow suppression.

In the opinion of the Committee, the benefit of methotrexate has not been proven, and further studies are needed. Low-dose therapy seems to be well tolerated.