The role of methotrexate in the management of steroid-dependent asthma. Methotrexate in the management of severe steroid dependent asthma. Short term effect of methotrexate in severe 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. Methotrexate in the treatment of steroid-dependent asthma. Randomised, double-blind, placebo-controlled trial of methotrexate in steroid-dependent asthma. A placebo-controlled multicenter study of auranofin in the treatment of patients with corticosteroid-dependent asthma. Auranofin Multicenter Drug Trial. Controlled trial of methotrexate in patients with severe chronic asthma. Methotrexate in the treatment of corticosteroid-dependent asthma. A double-blind crossover study. Methotrexate in chronic active Crohn's disease: a double-blind, randomized, Israeli multicenter trial.
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                Two patients were required to be withdrawn owing to methotrexate-related adverse effects.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. 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. 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. 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. Previous clinical studies have demonstrated that injectable gold salts and the oral gold compound, auranofin, possess significant steroid-sparing effects in the treatment of asthma.
                The objectives of this investigation were to determine whether auranofin could reduce oral corticosteroid requirements and to evaluate the safety of auranofin in the treatment of chronic corticosteroid-dependent asthma.
                Patients with asthma were eligible if they required at least 10 mg of prednisone per day for control and prevention of asthma exacerbations. Two hundred seventy-nine patients with chronic corticosteroid-dependent asthma (requiring > or = 10 mg/day) were randomized to receive auranofin, 3 mg twice daily, or placebo during an 8-month clinical trial, which was divided into three phases including: a 4-week baseline period (phase I), a 6-month double-blind treatment and steroid reduction period (phase II), and a 4-week posttreatment observation period during which steroid and auranofin doses or placebo doses were maintained at levels achieved by the end of phase II (phase III). The primary efficacy variable was "therapeutic success" or reduction of daily corticosteroid use by 50% or more.
                The proportion of patients in the auranofin group achieving therapeutic success (41%) was significantly higher than that in the placebo group (27%) (p = 0.01). This effect was greatest in patients requiring 10 to 19 mg of oral prednisone per day at baseline (p < 0.001). In all treated patients, including those who did and did not complete the trial, significant reduction (> or = 50% of baseline) in oral corticosteroid dosage was achieved in the auranofin group (60%) compared with the placebo group (32%) (p < 0.001). There were no significant differences between treatment groups in symptoms, concomitant medication use, or lung function. Mean serum total IgE levels decreased significantly from baseline in the auranofin group (-44.63 IU/ml) compared with the placebo group (p = 0.001). Gastrointestinal and cutaneous adverse events were greater in the auranofin group.
                Auranofin demonstrated a steroid-sparing effect without concomitant worsening of symptoms or lung function and appeared to be more effective in patients dependent on 10 to 19 mg of prednisone per day. Therefore this study has demonstrated that auranofin is useful as a steroid-sparing agent in the treatment of chronic corticosteroid-dependent asthma. 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. 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. At present only one large controlled study has indicated that parenteral methotrexate may be effective in chronic active Crohn's disease (CD).
                To evaluate the effectiveness of oral methotrexate in chronic steroid-dependent CD.
                Patients with active CD, who have received steroids and/or immunosuppressives for at least 4 months during the preceding 12 months and with a current Harvey-Bradshaw index of > or = 7 were studied.
                Methotrexate (12.5 mg weekly) or 6-mercaptopurine (50 mg daily), or placebo were given during the 9 months of the trial in addition to steroids and 5-aminosalicylic acid as clinically indicated.
                Eighty-four patients were included (methotrexate, 26 patients; 6-mercaptopurine, 32 patients; placebo, 26 patients). The proportion of patients entering first remission as well as the proportions of patients relapsing after first remission were not significantly different between the groups. The mean Harvey-Bradshaw index and the mean monthly steroid dose were also similar. However, when each patient was evaluated as his or her own control, the reduction in steroid dose, the general well being, and the reduction in abdominal pain were significantly better in the methotrexate treated patients.
                Methotrexate at a weekly oral dose of 12.5 mg was found to be moderately better than 6-mercaptopurine and placebo in patients with chronic active CD.
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.