A prospective, randomized, double-blind, placebo-controlled, crossover trial was performed. Prior to administration of methotrexate or placebo, all patients were initially followed up for 4 to 10 weeks during which their pulmonary function was optimized with maximal conventional asthma therapy, including high dose inhaled steroids. Oral steroid dosage was increased initially to attain optimum pulmonary function and then oral steroid dosages were tapered slowly maintaining pulmonary function. In this way we established the minimum steroid dosage that was necessary to maintain optimal pulmonary function. Patients were seen by a pulmonary physician at least every 2 weeks and often weekly during this period. At the end of the initial period, baseline studies, including spirometry, FEVr FVC, peak flow rate measurements, chest radiograph, complete blood cell count and differential, platelets, serum urea nitrogen, creatinine, liver function tests, and a 24-h creatinine clearance were performed. In addition, all patients were asked to record peak flowmeter readings before and after bronchodilator therapy each morning and complete a daily diary card documenting their asthma medications and symptom score of 1 to 4 (1 = no problems; 2 = minor difficulty; 3 = moderate difficulty; 4 = severe difficulty breathing). canadianfamilypharmacy
After the initialization phase, when the pulmonary function was maximized while patients were receiving the lowest steroid dose, they were randomized into either the methotrexate phase or the placebo phase for 12 weeks. Patients taking methotrexate were started at a dose of 7.5 mg/wk given as a single oral dose. After 2 weeks at this level, the dose was increased by 2.5 mg/wk every 2 weeks until a dosage of 15 mg/wk. Subjects were maintained at 15 mg/wk of methotrexate. If side effects occurred, the methotrexate dose was stopped or reduced to 7.5 mg/wk and then gradually increased as described above. The minimum cumulative methotrexate dose was 150 mg. Following 12 weeks of therapy with either methotrexate or placebo, patients were crossed over to the second 12-week phase using the dosing schedule described above. Patients receiving methotrexate switched to placebo and visa versa, each subject acting as his/her own control. The steroid dose at the beginning of each phase was not the same dose but the minimum dose that maintained maximal function. During the first 5 weeks of each phase, patients were evaluated weekly by a physician blinded to the protocol who screened them for symptoms and signs of toxic reactions. Bone marrow, hepatic, and renal function tests were performed weekly for 5 weeks and biweekly thereafter. If a patient developed significant signs of toxicity during the protocol, a physician not involved in direct patient contact was unblinded. The pulmonologist was blinded to the protocol and reviewed the patients at a minimum every 2 weeks and often weekly. Pulmonary function tests were performed biweekly during both phases of the study. The oral steroid dose was adjusted by the pulmonologist depending on pulmonary function data and clinical assessment. Each patient’s steroid taper was individualized but as a general guideline, patients receiving 20 mg of prednisone a day or greater were tapered at a rate of 5 mg/wk; below 20 mg a day at a rate of 2.5 mg/wk.