Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Methotrexate-induced lung injury

Robert A Balk, MD
Section Editors
Kevin R Flaherty, MD, MS
James R Jett, MD
Deputy Editors
Helen Hollingsworth, MD
Diane MF Savarese, MD


Methotrexate is an analogue of the vitamin folic acid; it inhibits cellular proliferation by inducing an acute intracellular deficiency of certain folate coenzymes (figure 1) [1-3]. This impairs the intracellular trafficking of single carbon groups and results in impaired synthesis of thymidine, deoxyribonucleic acid (DNA), and ribonucleic acid (RNA) [1,4]. In addition to its antiproliferative effects, methotrexate has antiinflammatory and immunomodulating properties [2,3,5-7]. It is used to treat a variety of malignancies, connective tissue diseases, and also psoriasis. Serious toxicity from methotrexate may affect the lungs, liver, and bone marrow [1,2,8-11].

This topic review will review the pulmonary injury that may result from methotrexate use. Other side effects of methotrexate therapy and an approach to pulmonary toxicity associated with antineoplastic agents are discussed separately. (See "Major side effects of low-dose methotrexate" and "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease" and "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment" and "Therapeutic use and toxicity of high-dose methotrexate", section on 'Overview of adverse effects' and "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Mechanism of action'.)


Lung toxicity most often occurs after weeks to months of low-dose oral methotrexate therapy (as is typically used for non-malignant disease), but can occur following relatively short term use of intravenous or intrathecal administration of higher doses [10,12-14]. In a literature review of 123 cases of methotrexate pneumonitis, about one-half arose in patients receiving therapy for rheumatoid arthritis (range 2.5 to 15 mg weekly), about 20 percent arose during intensification/consolidation treatment for leukemia (doses approximately 20 to 80 mg weekly), and 8 percent were in patients treated for other malignancies (weekly doses ranging from 15 to 1400 mg) (table 1) [10].

The precise frequency with which methotrexate pulmonary toxicity occurs is difficult to assess as some reports have included patients who were receiving other cytotoxic medications, had ongoing infectious diseases, or had underlying disease processes capable of involving the lungs and pleura [1]. In addition, impure preparations of methotrexate may have played a role in some of the earlier reports of toxicity [1]. Many series estimate that acute pulmonary toxicity develops in 1 to 8 percent of patients receiving methotrexate for rheumatologic condition, including rheumatoid arthritis, but some reports suggest an incidence as high as 33 percent [14-22]. On the other hand, others suggest that rates are much lower because not all cases of pneumonitis occurring in patients treated with methotrexate are directly attributable to the drug. The following examples show the frequency of pneumonitis among patients who received methotrexate for rheumatoid arthritis or other inflammatory diseases:

In a systematic literature review of 3463 patients with rheumatoid arthritis who were receiving methotrexate, 84 patients (2 percent) had some type of lung toxicity, but only 15 were felt to be definitive cases of pneumonitis attributable to methotrexate (0.43 percent) [23]. The mean duration of methotrexate use was 36.5 months and the average dose was 8.8 mg/week.

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Jul 21, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Cooper JA Jr, White DA, Matthay RA. Drug-induced pulmonary disease. Part 1: Cytotoxic drugs. Am Rev Respir Dis 1986; 133:321.
  2. Cronstein BN. Molecular therapeutics. Methotrexate and its mechanism of action. Arthritis Rheum 1996; 39:1951.
  3. Lynch JP 3rd, McCune WJ. Immunosuppressive and cytotoxic pharmacotherapy for pulmonary disorders. Am J Respir Crit Care Med 1997; 155:395.
  4. Searles G, McKendry RJ. Methotrexate pneumonitis in rheumatoid arthritis: potential risk factors. Four case reports and a review of the literature. J Rheumatol 1987; 14:1164.
  5. Kremer JM. Methotrexate update. Scand J Rheumatol 1996; 25:341.
  6. Goodman TA, Polisson RP. Methotrexate: adverse reactions and major toxicities. Rheum Dis Clin North Am 1994; 20:513.
  7. Segal R, Yaron M, Tartakovsky B. Methotrexate: mechanism of action in rheumatoid arthritis. Semin Arthritis Rheum 1990; 20:190.
  8. Lateef O, Shakoor N, Balk RA. Methotrexate pulmonary toxicity. Expert Opin Drug Saf 2005; 4:723.
  9. Bedrosian CW. Iatrogenic and toxic injury. In: Pulmonary Pathology, Dail DH, Hammar SP (Eds), Springer Verlag, New York 1988. p.511.
  10. Imokawa S, Colby TV, Leslie KO, Helmers RA. Methotrexate pneumonitis: review of the literature and histopathological findings in nine patients. Eur Respir J 2000; 15:373.
  11. Acute lymphocytic leukemia in children: maintenance therapy with methotrexat administered intermittently. Acute Leukemia Group B. JAMA 1969; 207:923.
  12. Bernstein ML, Sobel DB, Wimmer RS. Noncardiogenic pulmonary edema following injection of methotrexate into the cerebrospinal fluid. Cancer 1982; 50:866.
  13. Le Guillou F, Dominique S, Dubruille V, et al. [Acute respiratory distress syndrome due to pneumonitis following intrathecal methotrexate administration]. Rev Mal Respir 2003; 20:273.
  14. Kremer JM, Alarcón GS, Weinblatt ME, et al. Clinical, laboratory, radiographic, and histopathologic features of methotrexate-associated lung injury in patients with rheumatoid arthritis: a multicenter study with literature review. Arthritis Rheum 1997; 40:1829.
  15. Rosenow EC 3rd, Myers JL, Swensen SJ, Pisani RJ. Drug-induced pulmonary disease. An update. Chest 1992; 102:239.
  16. Kinder AJ, Hassell AB, Brand J, et al. The treatment of inflammatory arthritis with methotrexate in clinical practice: treatment duration and incidence of adverse drug reactions. Rheumatology (Oxford) 2005; 44:61.
  17. Hilliquin P, Renoux M, Perrot S, et al. Occurrence of pulmonary complications during methotrexate therapy in rheumatoid arthritis. Br J Rheumatol 1996; 35:441.
  18. Hassell A, Dawes P. Serious problems with methotrexate? Br J Rheumatol 1994; 33:1001.
  19. Carroll GJ, Thomas R, Phatouros CC, et al. Incidence, prevalence and possible risk factors for pneumonitis in patients with rheumatoid arthritis receiving methotrexate. J Rheumatol 1994; 21:51.
  20. Rosenow EC 3rd. Drug-induced pulmonary disease. Dis Mon 1994; 40:253.
  21. Grove ML, Hassell AB, Hay EM, Shadforth MF. Adverse reactions to disease-modifying anti-rheumatic drugs in clinical practice. QJM 2001; 94:309.
  22. Saravanan V, Kelly C. Drug-related pulmonary problems in patients with rheumatoid arthritis. Rheumatology (Oxford) 2006; 45:787.
  23. Salliot C, van der Heijde D. Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research. Ann Rheum Dis 2009; 68:1100.
  24. Conway R, Low C, Coughlan RJ, et al. Methotrexate use and risk of lung disease in psoriasis, psoriatic arthritis, and inflammatory bowel disease: systematic literature review and meta-analysis of randomised controlled trials. BMJ 2015; 350:h1269.
  25. Conaghan PG, Quinn DI, Brooks PM, Day RO. Hazards of low dose methotrexate. Aust N Z J Med 1995; 25:670.
  26. Bedrossian CW, Miller WC, Luna MA. Methotrexate-induced diffuse interstitial pulmonary fibrosis. South Med J 1979; 72:313.
  27. Kim YJ, Song M, Ryu JC. Inflammation in methotrexate-induced pulmonary toxicity occurs via the p38 MAPK pathway. Toxicology 2009; 256:183.
  28. St Clair EW, Rice JR, Snyderman R. Pneumonitis complicating low-dose methotrexate therapy in rheumatoid arthritis. Arch Intern Med 1985; 145:2035.
  29. Golden MR, Katz RS, Balk RA, Golden HE. The relationship of preexisting lung disease to the development of methotrexate pneumonitis in patients with rheumatoid arthritis. J Rheumatol 1995; 22:1043.
  30. Kim YJ, Song M, Ryu JC. Mechanisms underlying methotrexate-induced pulmonary toxicity. Expert Opin Drug Saf 2009; 8:451.
  31. Ohbayashi M, Suzuki M, Yashiro Y, et al. Induction of pulmonary fibrosis by methotrexate treatment in mice lung in vivo and in vitro. J Toxicol Sci 2010; 35:653.
  32. Morice AH, Lai WK. Fatal varicella zoster infection in a severe steroid dependent asthmatic patient receiving methotrexate. Thorax 1995; 50:1221.
  33. Weinblatt ME. Methotrexate in rheumatoid arthritis: toxicity issues. Br J Rheumatol 1996; 35:403.
  34. LeMense GP, Sahn SA. Opportunistic infection during treatment with low dose methotrexate. Am J Respir Crit Care Med 1994; 150:258.
  35. Kamel OW, van de Rijn M, Weiss LM, et al. Brief report: reversible lymphomas associated with Epstein-Barr virus occurring during methotrexate therapy for rheumatoid arthritis and dermatomyositis. N Engl J Med 1993; 328:1317.
  36. Salloum E, Cooper DL, Howe G, et al. Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases. J Clin Oncol 1996; 14:1943.
  37. Hoshida Y, Xu JX, Fujita S, et al. Lymphoproliferative disorders in rheumatoid arthritis: clinicopathological analysis of 76 cases in relation to methotrexate medication. J Rheumatol 2007; 34:322.
  38. Rizzi R, Curci P, Delia M, et al. Spontaneous remission of "methotrexate-associated lymphoproliferative disorders" after discontinuation of immunosuppressive treatment for autoimmune disease. Review of the literature. Med Oncol 2009; 26:1.
  39. Homsi S, Alexandrescu DT, Milojkovic N, et al. Diffuse large B-cell lymphoma with lung involvement in a psoriatic arthritis patient treated with methotrexate. Dermatol Online J 2010; 16:1.
  40. Kamiya Y, Toyoshima M, Suda T. Endobronchial Involvement in Methotrexate-associated Lymphoproliferative Disease. Am J Respir Crit Care Med 2016; 193:1304.
  41. Bologna C, Picot MC, Jorgensen C, et al. Study of eight cases of cancer in 426 rheumatoid arthritis patients treated with methotrexate. Ann Rheum Dis 1997; 56:97.
  42. Wolfe F, Michaud K. Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients. Arthritis Rheum 2004; 50:1740.
  43. Wolfe F, Michaud K. The effect of methotrexate and anti-tumor necrosis factor therapy on the risk of lymphoma in rheumatoid arthritis in 19,562 patients during 89,710 person-years of observation. Arthritis Rheum 2007; 56:1433.
  44. Alarcón GS, Kremer JM, Macaluso M, et al. Risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis. A multicenter, case-control study. Methotrexate-Lung Study Group. Ann Intern Med 1997; 127:356.
  45. Kremer JM. Toward a better understanding of methotrexate. Arthritis Rheum 2004; 50:1370.
  46. Furst DE, Koehnke R, Burmeister LF, et al. Increasing methotrexate effect with increasing dose in the treatment of resistant rheumatoid arthritis. J Rheumatol 1989; 16:313.
  47. Sany J, Anaya JM, Gutierrez M, et al. Predictive value of pulmonary function tests in methotrexate induced pneumonitis in rheumatoid arthritis. Arthritis Rheum 1992; 35:S147.
  48. The effect of age and renal function on the efficacy and toxicity of methotrexate in rheumatoid arthritis. Rheumatoid Arthritis Clinical Trial Archive Group. J Rheumatol 1995; 22:218.
  49. Hider SL, Bruce IN, Thomson W. The pharmacogenetics of methotrexate. Rheumatology (Oxford) 2007; 46:1520.
  50. Dawson JK, Graham DR, Desmond J, et al. Investigation of the chronic pulmonary effects of low-dose oral methotrexate in patients with rheumatoid arthritis: a prospective study incorporating HRCT scanning and pulmonary function tests. Rheumatology (Oxford) 2002; 41:262.
  51. Camus P. Interstitial lung disease from drugs, biologics, and radiation. In: Interstitial lung disease, 5th, Schwarz MI, King TE Jr (Eds), People's Medical Publishing House, Shelton, CT 201. p.637.
  52. van der Veen MJ, Dekker JJ, Dinant HJ, et al. Fatal pulmonary fibrosis complicating low dose methotrexate therapy for rheumatoid arthritis. J Rheumatol 1995; 22:1766.
  53. Sostman HD, Matthay RA, Putman CE. Cytotoxic drug-induced lung disease. Am J Med 1977; 62:608.
  54. Diagnosis of Diseases of the Chest, 3rd ed, Fraser RG, Pare JAP, Pare PD, et al (Eds), WB Saunders, Philadelphia 1991. p.2433.
  55. High-resolution CT of the Lung, 2nd ed, Webb WR, Muller NL, Naidich DP (Eds), Lippincott-Raven, Philadelphia 1996. p.125.
  56. Biederer J, Schnabel A, Muhle C, et al. Correlation between HRCT findings, pulmonary function tests and bronchoalveolar lavage cytology in interstitial lung disease associated with rheumatoid arthritis. Eur Radiol 2004; 14:272.
  57. Padley SP, Adler B, Hansell DM, Müller NL. High-resolution computed tomography of drug-induced lung disease. Clin Radiol 1992; 46:232.
  58. Arakawa H, Yamasaki M, Kurihara Y, et al. Methotrexate-induced pulmonary injury: serial CT findings. J Thorac Imaging 2003; 18:231.
  59. Leonel D, Lucia C, A M, et al. Pulmonary function test: its correlation with pulmonary high-resolution computed tomography in patients with rheumatoid arthritis. Rheumatol Int 2012; 32:2111.
  60. Beyeler C, Jordi B, Gerber NJ, Im Hof V. Pulmonary function in rheumatoid arthritis treated with low-dose methotrexate: a longitudinal study. Br J Rheumatol 1996; 35:446.
  61. Dayton CS, Schwartz DA, Sprince NL, et al. Low-dose methotrexate may cause air trapping in patients with rheumatoid arthritis. Am J Respir Crit Care Med 1995; 151:1189.
  62. Khadadah ME, Jayakrishnan B, Al-Gorair S, et al. Effect of methotrexate on pulmonary function in patients with rheumatoid arthritis--a prospective study. Rheumatol Int 2002; 22:204.
  63. Wall MA, Wohl ME, Jaffe N, Strieder DJ. Lung function in adolescents receiving high-dose methotrexate. Pediatrics 1979; 63:741.
  64. Saravanan V, Kelly CA. Reducing the risk of methotrexate pneumonitis in rheumatoid arthritis. Rheumatology (Oxford) 2004; 43:143.
  65. Cottin V, Tébib J, Massonnet B, et al. Pulmonary function in patients receiving long-term low-dose methotrexate. Chest 1996; 109:933.
  66. White DA, Rankin JA, Stover DE, et al. Methotrexate pneumonitis. Bronchoalveolar lavage findings suggest an immunologic disorder. Am Rev Respir Dis 1989; 139:18.
  67. Schnabel A, Richter C, Bauerfeind S, Gross WL. Bronchoalveolar lavage cell profile in methotrexate induced pneumonitis. Thorax 1997; 52:377.
  68. Margagnoni G, Papi V, Aratari A, et al. Methotrexate-induced pneumonitis in a patient with Crohn's disease. J Crohns Colitis 2010; 4:211.
  69. Carson CW, Cannon GW, Egger MJ, et al. Pulmonary disease during the treatment of rheumatoid arthritis with low dose pulse methotrexate. Semin Arthritis Rheum 1987; 16:186.
  70. Rondon F, Mendez O, Spinel N, et al. Methotrexate-induced pulmonary toxicity in psoriatic arthritis (PsA): case presentation and literature review. Clin Rheumatol 2011; 30:1379.
  71. Dijkmans BA. Folate supplementation and methotrexate. Br J Rheumatol 1995; 34:1172.
  72. Morgan SL, Baggott JE, Vaughn WH, et al. The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 1990; 33:9.
  73. Morgan SL, Baggott JE, Vaughn WH, et al. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial. Ann Intern Med 1994; 121:833.
  74. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 Update. Arthritis Rheum 2002; 46:328.