Methotrexate in the treatment of steroid-dependent asthma

A 63-year-old woman with refractory psoriatic arthritis and asthma, requiring intermittent steroid therapy, was treated with methotrexate (MTX). Her arthritis responded rapidly and it was noted that her asthma required no further steroid therapy. Six patients with established steroid-dependent asthma were then treated with 7.5 to 15.0 mg of MTX per week, after protocols used to treat psoriasis and rheumatoid arthritis. Five patients reduced their steroid usage while on MTX. Side effects were minimal while taking MTX. It was concluded that MTX may have a role in reducing cortisone requirements in steroid-dependent asthma.     

Methotrexate in the treatment of steroid-dependent asthma

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.     

Plasmapheresis in the treatment of steroid-dependent bronchial asthma

Background: Can plasmapheresis improve disease severity and lung function and reduce steroid doses in severe asthma patients dependent on oral corticosteroids? Methods: A pilot study with four asthma patients was undertaken using PEF (peak expiratory flow) symptom score, number of puffs of β₂-agonist, and dose of systemic steroids as disease variables. After at least an 8-week run-in, the patients were randomized to a crossover treatment regimen consisting of either 10 days of plasmapheresis or placebo treatment. Each treatment was succeeded by an 8–26-week follow-up period. Results: No patients achieved a significant effect of plasmapheresis treatment according to the established criteria, nor did anyone experience deterioration. Conclusions: Removing humoral factors extensively over a 10-day period did not significantly influence the clinical condition of the four steroid-dependent asthma patients studied. Circulating humoral factors seem to be of little importance for the maintenance of the established chronic allergic inflammation in these patients. Plasmapheresis does not seem to be a treatment option for this patient category.     

Fatal varicella in steroid-dependent asthma

Disseminated varicella infection is a potentially life-threatening complication of chronic high-dose corticosteroid (CS) or immunosuppressive therapy. A review of the literature indicates that, with one possible exception, this complication has not occurred in a CS-dependent subject with asthma. We present in this article the clinical features and autopsy findings of a steroid-dependent subject with asthma who died of acute, disseminated varicella. A 16-year-old poorly compliant, steroid-dependent subject with asthma received two courses of high-dose intravenous methylprednisolone during a 3-week period, followed by a tapering schedule of oral prednisone. During this time, she was exposed to chickenpox. She subsequently developed a classic varicella rash, sever back pain, rapidly progressive hepatic failure, pneumonitis, and encephalopathy. Death ensued 3 days after the onset of the rash. Evidence of disseminated varicella infection was confirmed at autopsy. This case illustrates that a small number of subjects with severe asthma receiving high-dose CS need to be considered as a separate, high-risk group for developing disseminated varicella. We recommend that the immune status of these patients to varicella-zoster virus be assessed by a serum titer. If these patients are nonimmune, they would be candidates for varicella-zoster immune globulin on exposure, and for acyclovir therapy should varicella dissemination occur.     

Immunologic analysis of steroid-dependent asthma

In order to analyze steroid-dependent asthma immunologically, IgE antibodies to mite (Dermatophagoides farinae), Candida albicans, and Aspergillus fumigatus were measured in 112 asthmatic patients. IgG and IgG subclass antibodies to mite were also measured. The rate of patients who were positive to candida IgE RAST was higher in atopic steroid-dependent patients than in atopic steroid-independent patients (P less than .01). The rate of mite-sensitive patients who had not received immunotherapy with mite or house dust was higher than in the atopic steroid-dependent patients than in atopic steroid-independent patients (P less than .05). IgG1 and IgG4 antibodies to mite were higher in mite-sensitive steroid-independent patients than in mite-sensitive steroid-dependent patients. IgE antibodies to A. fumigatus were detected only in patients with allergic bronchopulmonary aspergillosis (ABPA). Based on these results, we were encouraged to try immunotherapy with house dust mite or C. albicans if patients were steroid-dependent and sensitive to these allergens except when the patients had ABPA.     

Multicenter study of flunisolide aerosol in adult patients with steroid-dependent asthma

Seventy-three adult, steroid-dependent asthmatic patients participated in a 16-wk, double-blind study testing the efficacy of flunisolide aerosol. Forty received flunisolide, and 33 received placebo. The mean daily prednisone requirement of patients receiving flunisolide fell 59.2% during the testing period, and that of the patients receiving placebo fell 19.7%. The median daily prednisone dose dropped 74.4% in the flunisolide group and 4.2% in the placebo group (p = 0.006). In the flunisolide group 75% tapered use of oral steroids 50% or more, and 27.5% stopped taking oral steroids completely. In the placebo group 36% tapered use of oral steroids 50% or more, and only 12% stopped taking them completely. Despite their reduction in systemic steroids, those patients receiving flunisolide achieved significantly greater reduction in the daily severity of wheezing (p = 0.014) and frequency of asthma attacks (p = 0.049) than did those receiving placebo. In the final evaluation of therapeutic response, 70% of patients receiving flunisolide were rated as having a very good or good response, and 30% were rated as having a fair or poor response. In contrast 33% of patients receiving placebo were rated as very good or good, and 67% were rated as fair or poor (p = 0.0009). No serious reactions were reported. Plasma cortisols showed an average increase of 42.9% in the flunisolide group but no change in the placebo group. Flunisolide aerosol is a well-tolerated and effective agent in the treatment of steroid-dependent asthma.     

Methotrexate in steroid-dependent asthma: long-term results

Treatment of 21 steroid-dependent asthmatic patients with methotrexate (MTX) 15 mg/week was prospectively evaluated for a mean of 14.7 (SD 3.7) months. Before MTX, therapy consisted of a mean prednisone dose of 16.6 (SD 9.2) mg, in addition to inhaled beclomethasone/budesonide (mean daily dose 1157 (SD 330) μg) and bronchodilators. Thirteen patients were weaned from all regular systemic steroid therapy, a 50% or more reduction was achieved in four patients, and a less than 50% reduction in four patients. Abnormal liver function tests were noted in six of the 21 patients; this resolved despite continuation of MTX in five. In one patient, MTX was stopped because of symptoms as well as a fivefold rise in serum transaminases, and a speedy resolution was noted. Gastrointestinal side-effects were reported in six patients but were resolved in five with intramuscular MTX. There were no hematologic or pulmonary complications. We conclude that MTX appears to be both safe and efficacious as a steroid-sparing agent in most steroid-dependent asthmatic patients when taken over a long period.     

Treatment of steroid-dependent asthma with recombinant interferon-gamma

We have recently reported that treatment of patients with severe atopic dermatitis with recombinant interferon-gamma (rIFN-gamma) resulted in clinical improvement as well as a reduction of circulating eosinophils. Since IgE-dependent late phase allergic reactions and eosinophilic infiltration are thought to play an important role in the pathogenesis of asthma, we conducted a two centre randomized double-blind placebo-controlled trial of rIFN-gamma in the treatment of steroid-dependent asthma. Patients were treated with daily subcutaneous injections of either 0.05 mg/m2 rIFN-gamma (n = 9) or placebo (n = 11) for 90 days. All patients completed the study without significant drug toxicity noted. Oral prednisone dose, forced expiratory volume in 1 second (FEV1), peak expiratory flow rates (PEFR) and circulating eosinophil counts were monitored throughout the trial. There was no significant difference between the two treatment groups in per cent reduction from baseline of daily prednisone (P = 0.51). There was also no significant difference between the two treatment groups in per cent change from baseline in FEV1 (P = 0.54) or in PEFR (P = 0.75). Total circulating eosinophil counts decreased by 31% in the rIFN-gamma group and increased by 8.5% in the placebo group (P = 0.09). We conclude that this treatment regimen was not effective in patients with steroid-dependent asthma.     

Troleandomycin: Effectiveness in steroid-dependent asthma and bronchitis

The steroid dose-reducing capacity of troleandomycin (Tao), a macrolide antibiotic, was substantiated by a double-blind crossover study of 74 corticosteroid-dependent asthmatic and bronchitic subjects. Fifty were marked responders, 13 probable responders, and 11 nonresponders. Responders also improved in their sputum production, pulmonary function measurements, need for aerosolized bronchodilators, and subjective evaluations. Tao was effective when used concomitantly with methylprednisone. At a dose of up to 16 mg. of methylprednisolone per day, along with 250 to 500 mg. of Tao per day, patients could either retain a normal serum cortisol level or increase this to normal values 24 to 48 hours after the last dose. Hepatic function abnormalities were usually mild and transient but 10 had increased alkaline phosphatase levels, prompting discontinuation in some patients. The mechanism of action is not known, but in 11 of 14 marked responders on Tao, the threshold dose of methacholine required to produce a 20 per cent fall in Fev₁ was substantially increased. The antibiotic property of Tao did not explain improvement.     

T and B lymphocytes in patients with steroid-dependent bronchial asthma during long-term treatment.

Since corticosteroids are known to be a potent factor redistributing the peripheral blood lymphocytes to other body compartments, we estimated the sub-populations of T and B lymphocytes in peripheral blood of steroid dependent asthma patients. In twenty steroid-treated asthma patients and eighteen healthy blood donors the percentage and absolute number of lymphocytes forming spontaneous rosettes with sheep red blood cells ("early" and "late" T lymphocyte marker) and mouse red blood cells (B lymphocyte marker) were determined. The asthma patients were treated with 40 or 60 mg of triamcinolone acetonide (Kenalog) i.m. for at least one year or more prior to the study. No statistically significant differences were observed in lymphocyte subpopulations between steroid-treated asthma patients and healthy blood donors.     

Treatment of steroid-dependent asthma with triamcinolone acetonide aerosol.

Corticosteroids, originally developed as topical agents, have proved effective in aerosol form in the treatment of asthma. Of 33 chronic bronchial asthmatic patients dependent on oral corticosteroids, 16 were randomly selected for treatment with triamcinolone acetonide aerosol and 17 for treatment with triamcinolone acetonide aerosol and 17 for treatment with placebo to determine the effectiveness of the active drug and the feasibility of eliminating or reducing oral steroids. Aerosol dosages of 800 g daily continued for 12 weeks. The patients improved about 30, 50 and 60% in mean FVC, FEV1, and FEF25 75, respectively. Their mean oral steroid dose dropped 77%, with 13 of the 16 discontinuing oral steroids entirely, and their asthma symptoms decreased about 30%. Placebo patients showed minimal or no improvement in these areas. The clinical results indicated that 14 of 16 active aerosol and 4 of 17 placebo aerosol patients improved over baseline. No side effects or fungal infections appeared and only two patients experienced oral-steroid withdrawal symptoms.     

Use of methotrexate in the treatment of steroid-dependent adolescent asthmatics

Five children 10 to 16 years of age with steroid-dependent asthma were treated with methotrexate. All were able to reduce their doses of prednisone and all had improvement in their clinical status. No significant side effects were noted in patients treated 1 to 3 years. This open study suggests that methotrexate should be considered in the treatment of older children with severe asthma and morbidity from their steroid therapy.     

Clinical studies on steroid-dependent intractable asthma. Comparison between early and late onset of asthma

The various components making for severe intractable asthma were clinically and allergo-immunologically studied in 90 patients with bronchial asthma, by comparison between early onset and late onset groups. 1. In the early onset asthma group, cases with low serum IgE levels showed a stronger tendency toward severe intractable asthma. 2. Late onset asthma cases with negative skin tests and negative specific IgE antibodies to house dust tended more often to be severe intractable cases. 3. There was no correlation between sensitization by specific antigens (house dust and Candida), especially Candida, and a tendency toward severe intractable asthma. 4. Severe intractable asthma might be caused by bronchospasm in cases under 30 years of age, by bronchospasm plus hypersecretion in cases between 31 and 40 years of age, and by bronchospasm plus bronchiolar obstruction in cases over 40 years of age.     

Comparison of the bronchodilator effects of nebulized bitolterol mesylate and isoproterenol hydrochloride in steroid-dependent asthma

This study of 183 ambulatory patients with steroid-dependent asthma was conducted to evaluate the efficacy and safety of nebulized bitolterol mesylate solution (0.2%) compared to isoproterenol hydrochloride solution (0.3%). A double-blind, randomized, parallel-group, repetitive-dose design was followed at nine centers for 3 months. Patients received either 1.0 mg of bitolterol or 1.5 mg of isoproterenol three times a day with a closed, intermittent-flow nebulization system. Pulmonary function was evaluated on four 8-hour office visits at approximately 30-day intervals. Efficacy was based on a 15% increase in FEV1 over baseline. Both medications resulted in bronchodilatation within 5 minutes, whereas nebulized bitolterol was statistically superior (p less than 0.05) to nebulized isoproterenol in terms of duration of action and area under the curve. The mean FEV1 response to bitolterol therapy remained greater than 15% over baseline for 5 to 8 hours on the four test days compared to 2 to 4.75 hours for isoproterenol therapy. Both medications were well tolerated. Adverse reactions were transient, and most were mild to moderate. Tremor was the most frequent side effect occurring in approximately 30% of the patients in both groups. There were no clinically significant laboratory changes or electrocardiographic findings. Nebulized bitolterol mesylate was found to be a safe and effective bronchodilator in steroid-dependent patients with asthma.