Comparison of oral pulse methotrexate with placebo in the treatment of severe glucocorticosteroid-dependent asthma

doi:10.1016/0091-6749(94)90204-6

Journal of Allergy and Clinical Immunology

Volume 94, Issue 3, Part 1, September 1994, Pages 482-489

https://doi.org/10.1016/0091-6749(94)90204-6 Get rights and content

Abstract

Background: This study compared the efficacy of weekly oral administration of methotrexate and placebo in treatment of 24 subjects with chronic glucocorticosteroid-dependent asthma. Methods: The 33-week randomized, double-blind, placebo-controlled crossover trial compared once weekly 15 mg doses of methotrexate with placebo. At the time of entry, the subjects' mean dosage of prednisone was 23.8 mg/day (range, 12.5 to 85 mg) and glucocorticosteroid therapy had been used continuously for a mean duration of 78 months (range, 5 to 360 months). Results: Of the 21 subjects who completed the study, 13 tolerated lower daily prednisone doses during methotrexate treatment compared with placebo. When treated with methotrexate, subjects required 14.2% less prednisone than when treated with placebo (p = 0.0447), their subjective symptom scores improved 21.4% (p < 0.05), and mean forced expiratory volume in 1 second values tended to improve. Mean serum theophylline levels did not change significantly between the methotrexate and placebo arms of the study. Adverse effects were minimal, with nausea and headache occurring twice as often during methotrexate therapy compared with placebo. Conclusion: Short-term, low-dose, pulse therapy with orally administered methotrexate results in a decrease in the daily glucocorticosteroid requirement in a majority of subjects with severe asthma and is accompanied by improvement in subjective symptom scores without unacceptable side effects or deterioration of pulmonary function. (J ALLERGY CLIN IMMUNOL 1994;94:482-9.)

Section snippets

Subject selection

Twenty-four subjects between the ages of 18 and 70 years were enrolled. All had chronic reversible airway disease, defined as recurring airway obstruction of sufficient severity to require therapy. This was documented by history and at least 15% improvement in forced expiratory volume in 1 second (FEV ₁) after inhalation of a β-adrenergic aerosol. Atopic status was documented by history and skin testing during visit 2 (week 0).

Twenty-three subjects were GCS-dependent as defined by an average

RESULTS

Three of the 24 subjects withdrew before completion of the study. One withdrew because of concern over the possibility of side effects from MTX. A second participant withdrew after a severe asthma exacerbation, which required hospitalization and a significant increase in GCS dose. The third subject did not comply with study visits and was ultimately lost to follow-up. All three subjects were in the placebo treatment arm at the time of withdrawal from the study.

As shown in Table III, of the 24

DISCUSSION

Most studies of MTX in asthma have reported a moderate to great reduction (33% to 76%) in GCS requirements accompanied by improvement in subjective symptom scores (Table V). Two studies have shown significant GCS reductions in both MTX and placebo groups without a significant difference between the two groups.4, 5 Those subjects were examined at weekly intervals, which probably improved compliance and facilitated a decrease in GCS doses during treatment with placebo. In one of the studies with

Acknowledgements

We thank Lederle Laboratories, Pearl River, New York, for providing methotrexate and placebo tablets for use in this study. We also thank Dr. Samuel C. Bukantz for reviewing the manuscript.

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The duration of treatment ranged from 12 to 24 weeks with no long-term follow-up, with the exception of the study by Comet et al.63 where MTX was given for 12 months. For 3 of these studies,59,62,63 a significant reduction in OCS dose with MTX was reported, whereas in the remaining 6 studies no significant change between MTX and placebo was observed.55–58,60,61 An important placebo effect was noted in most studies with significant reductions in OCS use, that could be attributed to the increased multiple follow-ups and patient education.
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^☆: From the Division of Allergy and Clinical Immunology, The University of South Florida and James A. Haley Veterans Hospital, Tampa.

^☆☆: Supported by The Division of Allergy and Clinical Immunology, The University of South Florida, Tampa.

^★: Reprint requests: Dennis K. Ledford, MD, University of S. Florida College of Medicine, c/o James A. Haley V.A. Hospital, 13,000 Bruce B. Downs Blvd. (VAR 111D), Tampa, FL 33612.

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Comparison of oral pulse methotrexate with placebo in the treatment of severe glucocorticosteroid-dependent asthma☆,☆☆,★,★★

Abstract

Section snippets

Subject selection

RESULTS

DISCUSSION

Acknowledgements

Lancet

J ALLERGY CLIN IMMUNOL

Chest

J ALLERGY CLIN IMMUNOL

J ALLERGY CLIN IMMUNOL

Am J Med

Lancet

Lancet

Lancet

J ALLERGY CLIN IMMUNOL

Methotrexate in the treatment of corticosteroid-dependent asthma — a double-blind cross-over study

N Engl J Med

Lack of benefit of methotrexate in severe, steroid-dependent asthma. A double-blind, placebo-controlled study

Ann Intern Med

Long-term methotrexate treatment in corticosteroid-dependent asthma

Ann Intern Med

Systemic chemotherapy for psoriasis

A national survey. Arch Dermatol

Pneumocystis carinii pneumonia following methotrexate therapy for rheumatoid arthritis [Letter]

Arthritis Rheum