Short term effect of methotrexate in severe steroid-dependent asthma. The role of methotrexate in the management of steroid-dependent asthma. Methotrexate in the management of severe steroid dependent asthma. Lack of benefit of methotrexate in severe, steroid-dependent asthma. A double-blind, placebo-controlled study. Methotrexate in the treatment of corticosteroid-dependent asthma. A double-blind crossover study. Controlled trial of methotrexate in patients with severe chronic asthma. Methotrexate in the treatment of steroid-dependent asthma. Randomised, double-blind, placebo-controlled trial of methotrexate in steroid-dependent asthma. Comparison of methotrexate 30 mg per week with placebo in chronic steroid-dependent asthma: a 12-week double-blind, cross-over study. High-dose beclomethasone: oral steroid-sparing effect in severe asthmatic patients.
The steroid-sparing capacity of methotrexate in asthmatics is still being debated. The present study was undertaken to evaluate the effect of low-dose methotrexate on steroid consumption in patients with severe asthma, who require very high doses of systemic corticosteroids. We conducted a randomized, double-blind, parallel clinical trial in 24 patients with long-standing asthma. After a 3-week run-in period, patients received a 16-week course of either 15 mg of oral methotrexate weekly or matched placebo in addition to their previous asthma therapy. The daily steroid dose (at run-in 30 +/- 14 mg/day in the methotrexate group; 25 +/- 9 mg/day in the placebo group (NS)) decreased by 24% in the methotrexate group (p < 0.01) and by 5% in the placebo group (NS) during weeks 9-16 of the treatment period when compared with run-in values. However, there was no difference in steroid consumption between the two groups at any time. We conclude that in patients with severe asthma who require very high doses of systemic corticosteroids, short-term treatment with methotrexate allows only a marginal steroid reduction. Our study does not support the use of methotrexate as a steroid-sparing agent in asthmatics. Severe asthma often requires high-dose corticosteroid therapy. However, steroid therapy is fraught with many side effects. There are conflicting reports in the literature regarding the role of methotrexate in reducing the steroid requirements of these patients. This study examined the role of low-dose methotrexate in the management of steroid-dependent asthma. Eleven subjects with stable steroid-dependent asthma were enrolled in a placebo-controlled double-blind crossover trial. Patients received methotrexate, 15 mg/wk, or placebo each for two 12-week periods. There was significant improvement of pulmonary function and reduction of prednisone requirement in both placebo and methotrexate treatment periods. However, methotrexate was not superior to placebo. Only 3 of 11 patients responded to methotrexate. Although low-dose methotrexate therapy may have a role in a small select group of steroid-dependent asthmatics, it provided no additional benefit overall. This study was designed to assess the efficacy of low dose methotrexate, 15 mg weekly, as a steroid-sparing agent in asthmatic patients requiring long-term oral prednisone treatment.
                The study was a randomised, double blind, placebo controlled, cross over study of 48 weeks duration. Eleven patients with severe steroid-dependent asthma were included. A successful outcome was defined as a reduction in mean prednisone requirements of 7 mg daily compared to baseline requirements, during active treatment.
                Two patients were required to be withdrawn owing to methotrexate-related adverse effects. The mean prednisone dose for patients who completed the study was 14.4 mg per day (95% CI; 13.6, 15.1) during active treatment, and 12.9 mg per day (95% CI: 12.2, 13.6) during placebo treatment (NS). Only one patient reduced his individual dose requirements by more than 7 mg per day, whereas in three patients prednisone requirements actually increased during active treatment. There were no significant differences in symptom scores, pulmonary function data, and exacerbations between active and placebo treatments.
                No significant steroid-sparing effect was obtained using low dose methotrexate in this study. This negative outcome may be attributable to the small population of patients studied, low baseline FEV1, and the omission of a steroid minimisation run-in period. Our results highlight the importance of careful patient selection and a painstaking approach in the management of patients with steroid-dependent asthma. To determine the effect of low-dose methotrexate in asthmatic patients on steroid use, asthma symptom scores, pulmonary function, airway reactivity, blood cellular components, and immunoglobulin E levels.
                A randomized, double-blind, parallel, placebo-controlled, 13-week clinical trial with follow-up of patients in an open trial of methotrexate at the conclusion of the double-blind study.
                An asthma care outpatient clinic.
                From February 1988 to March 1990, 19 patients with severe, steroid-dependent asthma were enrolled in the study. Two of these patients were excluded from analysis.
                Patients were administered methotrexate or placebo intramuscularly, to assure complete absorption, once weekly during the 13-week study.
                Patients on methotrexate and placebo both significantly decreased their steroid dose by 39.6% (95% CI, 25.1% to 54.1%, P = 0.001) and 40.2% (CI, 17.9% to 67.4%, P = 0.003), respectively. Pulmonary function did not differ significantly between the methotrexate and placebo groups. In addition, airway reactivity and symptom scores were unchanged on methotrexate or placebo. No significant toxicities were seen during the course of the 13-week blinded study, but one patient on methotrexate and prednisone in the follow-up period developed Pneumocystis carinii pneumonia and died. Despite continuing methotrexate for up to 1 year, and increasing methotrexate to 30 mg weekly, no significant benefit of methotrexate on asthma control could be shown.
                Our study does not support the use of methotrexate in the treatment of severe asthma. To test our previous observation that methotrexate reduces corticosteroid requirements of patients with severe asthma, we studied 14 patients with corticosteroid-dependent bronchial asthma in a 24-week randomized double-blind crossover trial comparing a low dosage of methotrexate (15 mg per week) with placebo. At base line the mean dosage of prednisone was 173.5 mg per week (range, 70 to 420). On the average, 36.5 percent less prednisone was required when patients received methotrexate than when they received placebo (P = 0.01). Measurement of forced vital capacity and forced expiratory volume in one second showed that there was no deterioration in the condition of patients in whom the dosage of prednisone was reduced. The patients' subjective assessment of breathing ability indicated significant improvement (P = 0.01). The adverse effects of methotrexate were limited to transient nausea in three patients and an evanescent rash in one patient. Nine patients are still receiving methotrexate 3 to 10 months after the study's conclusion. The dosages of steroids have been further reduced in each of these patients, and prednisone has been discontinued in four. We conclude from this preliminary study that the use of methotrexate allows a significant reduction in the use of corticosteroids in patients with severe asthma without deterioration of pulmonary function. The aim of this study was to investigate the efficacy and adverse effects of methotrexate (MTX) in the treatment of severe chronic asthma in 12 patients with severe asthma requiring continuous treatment with oral steroids at the Outpatient Department of Helsinki University Central Hospital. The study was a randomised, double-blind placebo-controlled trial of methotrexate treatment 15 mg weekly on a crossover basis over 24 weeks. During the 2 weeks baseline phase the mean dose of oral steroids administered was 10.9 (3.2-28) mg.day-1, and the mean dose of inhaled steroids administered was 2.3 (1.6-3.2) mg budesonide or beclomethasone. The average dose of oral steroids administered was 12.8 mg.day-1 during the last 2 placebo weeks but only 7.9 mg.day-1 during the last 2 weeks with MTX treatment. The reduction in daily dose of oral steroids was 38%, while daily bronchodilator use was reduced by 22%. During MTX treatment the patients experienced significantly less wheezing, dyspnoea and coughing. Nine out of 12 patients reported better asthma control during MTX treatment. The peak expiratory flow rate (PEF) 1-s forced expiratory volume (FEV1) values did not differ between MTX and placebo treatments. There was no statistical correlation between serum MTX concentration and clinical improvement. No serious adverse effects of MTX were found during the study. It was concluded that low-dose MTX may be beneficial for severe chronic asthma and that this therapy is well tolerated by patients. A double-blind, placebo-controlled, crossover study was designed to compare steroid requirements between placebo and methotrexate (MTX) treatment in subjects with corticosteroid-requiring asthma. Subjects began with a steroid taper and then were randomized to a 3-month trial of drug or placebo therapy. Subjects received 15 mg of MTX a week or identical placebo. A 1-month washout period was completed before the crossover trial. Symptom scores, peak flow rates, spirometry, and beta-agonist frequency were closely monitored. Ten subjects completed the study. The average dose of prednisone during the placebo-treatment period was 11.97 mg/day compared to 8.37 mg/day while subjects were taking MTX. This was a 30% reduction in daily steroid requirement (p less than 0.01). Symptom scores and spirometry did not differ between the crossover trials, and overall clinical status was not altered. Complications from MTX were mild and included anorexia, alopecia, and stomatitis. All complications resolved with dose reduction or when MTX was stopped at the end of the study. No subjects withdrew from the study because of MTX complications. Low-dose MTX significantly reduced the steroid requirement in this group of subjects with steroid-dependent asthma. This reduction in steroid requirement was obtained without altering clinical status and without significant complication. 69 patients with steroid-dependent asthma (mean daily prednisolone dose 14.2 [SD 6.1] mg) took part in a randomised, double-blind, placebo-controlled study of 24 weeks' treatment with methotrexate 15 mg weekly. The patients were seen every 4 weeks by the same physician, who reduced the daily prednisolone dose by 2.5 mg if the daily diary card variables and measurements of lung function were unchanged or improved. All other treatment remained unchanged. After 24 weeks of treatment the prednisolone dose had been reduced by a significantly greater proportion in the methotrexate than in the placebo group (50% vs 14%) and the reduction was not sustained after the study treatment stopped. There were substantial abnormalities in liver function tests in 5 of the 38 patients taking methotrexate. Methotrexate has been shown to have a steroid-sparing effect in chronic steroid-dependent asthmatics at a dose of 15 mg week-1. The aim of this study was to investigate the steroid-sparing activity and adverse events profile of methotrexate 30 mg week-1 in severe steroid-dependent asthma. Eighteen patients who had required 10-50 mg week-1 prednisolone for at least 6 months were asked to participate in a randomized, double-blind, placebo-controlled cross-over study lasting 24 weeks. Daily diary cards of symptoms, peak expiratory flow rate and medication requirements were kept and the patients attended for a chest X-ray, spirometry, lung volumes and gas transfer at commencement and after each 12-week treatment period. Every 3 weeks, adverse events were noted and blood taken for full blood count, urea and electrolytes and liver function tests. Twelve patients completed the trial. Withdrawals were due to non-compliance in two patients, pneumonia in two patients, depression in one patient (on placebo) and severe nausea in one patient. Adverse events were common, probably as a consequence of the higher dosage. Prednisolone requirements were not significantly reduced on methotrexate. Lung function improved on methotrexate with a significant rise in maximal mid-expiratory flow rate and a trend towards improvement in FEV1. One hundred and twenty four patients with severe asthma requiring maintenance treatment with oral corticosteroids were included in a multicentre, double-blind, randomized study comparing the effects of inhaled beclomethasone dipropionate (BDP) (250 micrograms.puff-1), beginning with 1,000 micrograms daily, vs placebo (P). Pulmonary function was assessed and dosage of prednisone and BDP (or P) were adjusted every 15 days according to a clinical score. Our results showed, after 3 months: 1) A greater drop-out rate in the P group than in the BDP group (36 vs 6%, respectively, p less than 0.01); 2) A total weaning from prednisone in 76% of patients in the BDP group (mean BDP dosage = 1,270 +/- 340 micrograms.day-1, mean +/- SD), vs 34% in the P group (p less than 0.001). The mean daily dosage of prednisone was reduced from 17 +/- 7.5 mg to 3.1 +/- 7.4 mg in the BDP group vs 15.6 +/- 7.7 mg to 9.1 +/- 9.4 mg in the P group (p less than 0.001) without any relationship between the steroid-sparing effect and the initial dosage of prednisone; 3) Mean change in forced expiratory volume in one second (FEV1) was +7 +/- 21% from the initial value in the BDP group vs -6 +/- 20% in the P group; p less than 0.01. Thus, in patients with severe asthma requiring oral corticosteroids, high-dose BDP has an important oral steroid-sparing effect not related to the initial dosage of oral steroids and allows a better control of airway obstruction than oral corticosteroids alone.
Methotrexate may have a small steroid sparing effect in adults with asthma who are dependent on oral corticosteroids. However, the overall reduction in daily steroid use is probably not large enough to reduce steroid-induced adverse effects. This small potential to reduce the impact of steroid side-effects is probably insufficient to offset the adverse effects of methotrexate.