Drug Safety

, Volume 15, Issue 4, pp 283–290 | Cite as

A Risk-Benefit Assessment of Methotrexate in Corticosteroid-Dependent Asthma

  • Tiberiu R. Shulimzon
  • Robert J. Shiner
Review Article Risk-Benefit Assessment


Methotrexate is a folic acid antagonist with proven anti-inflammatory properties. This originally led to its use in the therapy of some rheumatic and dermatological inflammatory disorders and, since the early 1980s, as a corticosteroid-sparing agent in the therapy of bronchial asthma.

Although the exact anti-inflammatory mechanism is not known, it appears that in some patients with severe corticosteroid-dependent bronchial asthma, a reduction of at least 50% in the maintenance corticosteroid dosage can be achieved.

Controversies regarding methotrexate efficacy may be a result of the small size and heterogeneity of the patient populations studied and the variable definition of corticosteroid ‘dependence’.

Although the potential for serious short and long term adverse effects resulting from methotrexate therapy cannot be ignored, overall, methotrexate appears to be well tolerated at low dosages. Hepatic and pulmonary toxicity are the main adverse effects of concern.

The ‘lesser evil’ approach is logical, but it is imperative to administer the drug for at least 3 months to adequately assess its efficacy in a specific patient.


Asthma Methotrexate Allergy Clin Immunol Peak Expiratory Flow Rate Methotrexate Therapy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Weinblatt ME, Coblyn JS, Fox DA, et al. Efficacy of low dose methotrexate in rheumatoid arthritis. N Engl J Med 1985; 312: 818–22PubMedCrossRefGoogle Scholar
  2. 2.
    Giannini EH, Brewer EJ, Kuzmina N, et al. Methotrexate in resistant juvenile rheumatoid arthritis: results of the USA/USSR double blind placebo controlled trial. N Engl J Med 1990; 326: 1043–9CrossRefGoogle Scholar
  3. 3.
    Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn’s disease. N Engl J Med 1995; 332: 292–7PubMedCrossRefGoogle Scholar
  4. 4.
    Gubner R, August S, Ginsberg V, et al. Therapeutic suppression of tissue reactivity I: effect of aminopterin in rheumatoid arthritis and psoriasis. Am J Med Sci 1951; 221: 176–82PubMedCrossRefGoogle Scholar
  5. 5.
    Kaplan RL, Waite DH. Progressive interstitial lung disease from prolonged methotrexate therapy. Arch Dermatol 1978; 114: 1800–2PubMedCrossRefGoogle Scholar
  6. 6.
    Kremer JM. The mechanism of action of methotrexate in rheumatoid arthritis, the search continues. J Rheumatol 1994; 21: 1–5PubMedGoogle Scholar
  7. 7.
    Cronstein BN, Naime D, Ostad E. The antiinflammatory mechanism of methotrexate: increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation. J Clin Invest 1993; 92: 2675–82PubMedCrossRefGoogle Scholar
  8. 8.
    Reid DJ, Segars LW. Methotrexate for the therapy of chronic steroid dependent asthma. Clin Pharm 1993; 12: 762–7PubMedGoogle Scholar
  9. 9.
    Glynn-Barnhart ASC, Erzurum SC, Leff JA, et al. Effect of low dose methotrexate on the disposition of glucocorticosteroids and theophylline. J Allergy Clin Immunol 1991; 88/2: 180–6CrossRefGoogle Scholar
  10. 10.
    Mullarkey MF, Blumenstein BA, Andrade WP. et al. Methotrexate in the treatment of corticosteroid dependent asthma. N Engl J Med 1988; 318: 603–7PubMedCrossRefGoogle Scholar
  11. 11.
    Shiner RJ, Nunn AJ, Chung KF, et al. Randomised, double blind, placebo controlled trial of methotrexate in steroid dependent asthma. Lancet 1990; 336: 137–40PubMedCrossRefGoogle Scholar
  12. 12.
    Dyer PD, Vaughan TR, Weber RW. Methotrexate in the treatment of steroid-dependent asthma. J Allergy Clin Immunol 1991; 88: 208–12PubMedCrossRefGoogle Scholar
  13. 13.
    Stewart II GE, Diaz JD, Lockey RF, et al. Comparison of oral pulse methotrexate with placebo in the treatment of severe glucocorticosteroid dependent asthma. J Allergy Clin Immunol 1994; 94: 482–9PubMedCrossRefGoogle Scholar
  14. 14.
    Trigg CJ, Davies RJ. Comparison of methotrexate 30 mg/week with placebo in chronic steroid dependent asthma: a 12 week double blind crossover study. Respir Med 1993; 87: 211–6PubMedCrossRefGoogle Scholar
  15. 15.
    Coffey MJ, Sanders G, Eschenbacher WL. The role of methotrexate in the management of steroid dependent asthma. Chest 1994; 105: 117–21PubMedCrossRefGoogle Scholar
  16. 16.
    Erzurum S, Leff JA, Evans Cochran J. Lack of benefit of methotrexate in severe steroid dependent asthma. Ann Int Med 1991; 114:353–60PubMedGoogle Scholar
  17. 17.
    NIH International Consensus Report on diagnosis and therapy of asthma. Washington, DC: US Government Printing Office, 1991; 92: 3091Google Scholar
  18. 18.
    Shiner RJ, Geddes DM. Corticosteroids in asthma. Chest 1990; 97: 1021PubMedCrossRefGoogle Scholar
  19. 19.
    Mullarkey MF, Webb DR, Pardee NE. Methotrexate in the treatment of steroid dependent asthma. Ann Allergy 1986; 56: 347–50PubMedGoogle Scholar
  20. 20.
    Mullarkey MF, Lammert JK, Blumenstein BA. Long term methotrexate therapy in corticosteroid dependent asthma. Ann Intern Med 1990; 112: 577–81PubMedGoogle Scholar
  21. 21.
    Shiner RJ, Katz I, Shulimzon T, et al. Methotrexate in steroid dependent asthma: long term results. Allergy 1994; 49: 565–8PubMedCrossRefGoogle Scholar
  22. 22.
    Domingo CH, Ferrer A, Torremorell MD, et al. Methotrexate as a steroid sparing agent in bronchial asthma: preliminary results [abstract]. Chest 1994; 106 Suppl.: 108CrossRefGoogle Scholar
  23. 23.
    Felleti R, Cerri E, Mangano A, et al. Follow up in a larger group of patients: methotrexate treatment in corticosteroid dependent asthma patients [abstract]. Eur Respir J 1992; 5: Suppl. 15: 13Google Scholar
  24. 24.
    Kimura I, Tada S. Methotrexate in the treatment of bronchial asthma. Kokyu To Junkan 1991; 10: 566–70Google Scholar
  25. 25.
    Bardin PG, Johnston SL, Holgate ST. Antiinflammatory strategies for the treatment of asthma. S Afr Med J 1992; 81: 303–9PubMedGoogle Scholar
  26. 26.
    Edward N, Squire JR, Lombardo FA. If methotrexate fails to control asthma other regimens do too. J Allergy Clin Immunol 1993; 91: 168Google Scholar
  27. 27.
    Edward N, Squire JR, Lombardo FA. Methotrexate may successfully control severe asthma when hydroxychloroquine and/or troleandomycin fail but not vice versa. J Allergy Clin Immunol 1992; 89: 286Google Scholar
  28. 28.
    Moss RB. Alternative pharmacotherapies for steroid dependent asthma. Chest 1995; 107: 817–25PubMedCrossRefGoogle Scholar
  29. 29.
    Hill JM, Tattersfield AE. Corticosteroid sparing agents in asthma. Thorax 1995; 50: 577–82PubMedCrossRefGoogle Scholar
  30. 30.
    Stempel DA, Lammert J, Mullarkey MF. Use of methotrexate in the treatment of steroid dependent adolescent asthmatics. Ann Allergy 1991; 67: 346–8PubMedGoogle Scholar
  31. 31.
    Guss S, Portnoy J. Methotrexate treatment of severe asthma in children. Pediatrics 1992; 89: 635–9PubMedGoogle Scholar
  32. 32.
    Fertel D, Wanner A. Methotrexate: does it treat or induce asthma? Am Rev Respir Dis 1991; 143: 1–2PubMedGoogle Scholar
  33. 33.
    Jones G, Mierins E, Karsh J. Methotrexate induced asthma. Am Rev Respir Dis 1991; 143: 179–81PubMedGoogle Scholar
  34. 34.
    Chung KF, Geddes DM, Shiner RJ. Methotrexate: does it treat or induce asthma [letter]. Am Rev Respir Dis 1992; 733Google Scholar
  35. 35.
    Taylor DR, Flannery EM, Herbison JP. Methotrexate in the management of severe steroid dependent asthma. NZ Med J 1993; 106:409–11Google Scholar
  36. 36.
    Lock SH, Kay AB, Barnes NC. Double blind, placebo controlled study of cyclosporin A as a corticosteroid-sparing agent in cortico steroid dependent asthma. Am J Respir Crit Care Med 1996; 153:509–14PubMedGoogle Scholar
  37. 37.
    Vallerand H, Cossart C, Milosevic D, et al. Fatal Pn. carini pneumonia in asthmatic patient treated with methotrexate [letter]. Lancet 1992; 339: 1551PubMedCrossRefGoogle Scholar
  38. 38.
    Shulimzon T, Weiss P, Shiner RJ, et al. Long term methotrexate treatment (up to six years) in steroid dependent asthma [abstract]. European Respiratory Society Annual Congress: 1996 Sep 7–11; StockholmGoogle Scholar
  39. 39.
    Alarcon GS, Tracy IC, Blackburn WD. Methotrexate in rheumatoid arthritis: toxic effects as the major factor in limiting long term treatment. Arthritis Rheum 1989; 32: 671–6PubMedCrossRefGoogle Scholar
  40. 40.
    Tishler M, Caspi D, Rosenbach TO. Methotrexate in rheumatoid arthritis. Ann Rheum Dis 1988; 47: 654–9PubMedCrossRefGoogle Scholar
  41. 41.
    Kremer JM, Lee JK. The safety and efficacy of the use of methotrexate in long term therapy of rheumatoid arthritis. Arthritis Rheum 1986; 29: 822–31PubMedCrossRefGoogle Scholar
  42. 42.
    Tugwell P, Bennett K, Gent M. Methotrexate in rheumatoid arthritis indications, contraindications, efficacy and safety. Ann Intern Med 1987; 107: 358–66PubMedGoogle Scholar
  43. 43.
    Jurgens H, Gobell U. Pharmacology, toxicology and drug interaction methotrexate. Rheumatology 1986; 9: 6–19Google Scholar
  44. 44.
    Health and Public Policy Committee, American College of Physicians. Methotrexate in rheumatoid arthritis. Ann Intern Med 1987; 107: 518–9Google Scholar
  45. 45.
    Geddes DM. Methotrexate in asthma. Clin Exp Allergy 1991; 21: 541–3PubMedCrossRefGoogle Scholar
  46. 46.
    Sostman HD, Matthay RA. Methotrexate induced pneumonia. Medicine 1976; 55: 371–88PubMedCrossRefGoogle Scholar
  47. 47.
    Wollner A, Mohle-Boetani J, Lambert RE, et al. Pn. carinii and low dose methotrexate. Thorax 1991; 46: 205–7PubMedCrossRefGoogle Scholar
  48. 48.
    Kuitert LM, Harrison AC. Pneumocystis carinii pneumonia as a complication of methotrexate therapy of asthma. Thorax 1991; 46: 936–7PubMedCrossRefGoogle Scholar
  49. 49.
    Altz-Smith M, Kendall LG, Stamm AM. Cryptococcosis associated with low dose methotrexate for arthritis. Am J Med 1987; 83: 179–81PubMedCrossRefGoogle Scholar
  50. 50.
    Keegan JM, Byrd JW. Nocardiosis associated with low dose methotrexate for rheumatoid arthritis [letter]. J Rheumatol 1988; 15: 1585–6PubMedGoogle Scholar
  51. 51.
    Nyfors A, Jensen H. Frequency of malginant neoplasms in 248 long term methotrexate treated psoratics. Dermatologica 1983; 167:260–1PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1996

Authors and Affiliations

  • Tiberiu R. Shulimzon
    • 1
    • 2
  • Robert J. Shiner
    • 1
    • 2
  1. 1.Department of Clinical Respiratory PhysiologyInstitute of Respiratory Medicine, The Chaim Sheba Medical CenterTel HashomerIsrael
  2. 2.Sackler School of MedicineTel-Aviv UniversityIsrael

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