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Am Fam Physician. 1998;57(4):817-818

Airway inflammation is a key component in the pathogenesis of asthma. Consequently, anti-inflammatory therapies, primarily corticosteroids, are the cornerstone of therapy for patients with severe asthma. Alternative anti-inflammatory therapies, including methotrexate, have been evaluated in numerous studies, but the results have been discrepant. Marin performed a meta-analysis of 11 studies published between 1988 and 1996 to determine whether low-dose methotrexate decreased the amount of steroids needed to maintain clinical stability in adults with steroid-dependent asthma. He also attempted to determine whether the steroid-sparing effect of methotrexate was related to the vigor with which steroids were tapered and whether methotrexate therapy improved pulmonary function.

Ninety articles were reviewed, and 11 were ultimately included in the meta-analysis. These studies included a total of 199 patients. All patients had received therapy with prednisone or methylprednisolone in varying dosages. The majority of the studies examined short-term use of methotrexate (three to four months). Three studies evaluated methotrexate therapy for six months or longer. With one exception, the methotrexate dosage was 15 mg per week.

In six studies, methotrexate was not found to have a steroid-sparing effect, but in five studies it was associated with a decrease in the steroid dosage of an average of 4.37 mg per day (23.7 percent of the initial dosage). The average steroid dosage for all of the studies pooled together was 8.24 mg per day, and the average dosage at initiation of the protocols was 18.40 mg per day. Six of the studies included a “run-in” period in which the steroid dosage was first reduced to the lowest level needed for clinical stability. None of the 11 studies reported an improvement in pulmonary function based on forced expiratory volume in one second (FEV1). No life-threatening side effects or serious adverse events resulting from methotrexate therapy were reported in any of the studies.

The author concludes that low-dose methotrexate has a statistically significant steroid-sparing effect in patients with steroid-dependent asthma. Efficacy is most pronounced in patients who receive methotrexate for 24 weeks. Therapy should not be started until the patient is taking the lowest possible dose of oral steroids.

In an accompanying editorial, Mullarkey cites data supporting the use of methotrexate early in the course of the asthma, similar to its use in the treatment of rheumatologic and dermatologic conditions. He believes that the risk-benefit profile clearly favors methotrexate over prednisone. His usual prescribing practice is to reduce the steroid dosage to the lowest effective level, begin methotrexate therapy, and then continue it for six months after the patient has been fully weaned from prednisone. Patients should continue to receive their usual asthma medication. He calls for additional controlled studies of methotrexate in chronic asthma as well as the development of additional steroid-sparing drugs.

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