Smarter Decisions,
Better Care

UpToDate synthesizes the most recent medical information into evidence-based practical recommendations clinicians trust to make the right point-of-care decisions.

  • Rigorous editorial process: Evidence-based treatment recommendations
  • World-Renowned physician authors: over 5,100 physician authors and editors around the globe
  • Innovative technology: integrates into the workflow; access from EMRs

Choose from the list below to learn more about subscriptions for a:

Subscribers log in here

Major side effects of low-dose methotrexate


Potentially life-threatening hepatotoxicity, pulmonary damage, and myelosuppression are sometimes seen with use of methotrexate (MTX) and can occur with either high-dose therapy as used for malignant diseases (eg, cyclic use of 1 gram or more) or with low-dose therapy (eg, weekly doses of 7.5 to 25 mg) as used in other disorders such as rheumatoid arthritis and psoriasis.

The most commonly observed side effects of MTX (at doses typically used for the treatment of rheumatoid arthritis, as opposed to the high doses used in malignancy) are never life-threatening. Nevertheless, they may become clinically significant if they result in premature discontinuation of a drug that is the best therapeutic alternative for a given individual. It is therefore important to learn the effective management of common toxicities in order to achieve optimal utilization MTX.

The major side effects of low-dose MTX are discussed here. The clinical use of high-dose MTX and related adverse effects are discussed separately. (See "Therapeutic use and toxicity of high-dose methotrexate".)


Hepatotoxicity due to methotrexate (MTX) may result from direct damage to hepatocytes; or, in patients with concomitant viral hepatitis, MTX may enhance viral damage. Screening for hepatitis B and hepatitis C virus infection before initiating long-term MTX therapy allows for detection and a decision whether to avoid the use of MTX, to try to eradicate the viral infection before initiating therapy, or to suppress viral replication during immunosuppressive therapy. Periodic monitoring of aminotransaminase and albumin (eg, every four to eight weeks) is suggested to detect hepatotoxicity during chronic treatment with MTX [1,2]. Early studies in Scandinavian psoriatic patients on MTX indicated that alcohol ingestion was a clear risk factor for hepatotoxicity [3]. As no one has studied the amount of alcohol which might be safe with MTX, a general recommendation would be to avoid or minimize alcohol intake while on the drug. (See "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease" and "Hepatitis B virus reactivation associated with immunosuppression".)


Pulmonary toxicity of methotrexate (MTX) is seen with both high- and low-dose treatment and may present with acute or chronic symptoms. Either symptomatic or asymptomatic radiographic lung damage may be due to inflammation, infection, or MTX-related neoplasia. We recommend that a chest radiograph be obtained prior to initiating MTX treatment [4]. Pulmonary toxicity is discussed in detail separately. (See "Methotrexate-induced lung injury".)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2014. | This topic last updated: Aug 19, 2014.
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 ©2014 UpToDate, Inc.
  1. Kremer JM, Alarcón GS, Lightfoot RW Jr, et al. Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. American College of Rheumatology. Arthritis Rheum 1994; 37:316.
  2. Guidelines for monitoring drug therapy in rheumatoid arthritis. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum 1996; 39:723.
  3. Nyfors A. Liver biopsies from psoriatics related to methotrexate therapy. 3. Findings in post-methotrexate liver biopsies from 160 psoriatics. Acta Pathol Microbiol Scand A 1977; 85:511.
  4. 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.
  5. Weinblatt ME, Fraser P. Elevated mean corpuscular volume as a predictor of hematologic toxicity due to methotrexate therapy. Arthritis Rheum 1989; 32:1592.
  6. Gutierrez-Ureña S, Molina JF, García CO, et al. Pancytopenia secondary to methotrexate therapy in rheumatoid arthritis. Arthritis Rheum 1996; 39:272.
  7. Ortiz Z, Shea B, Suarez-Almazor ME, et al. The efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis. A metaanalysis of randomized controlled trials. J Rheumatol 1998; 25:36.
  8. van Ede AE, Laan RF, Rood MJ, et al. Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum 2001; 44:1515.
  9. Montecucco C, Caporali R, Rossi S, Porta C. Allopurinol mouthwashes in methotrexate-induced stomatitis. Arthritis Rheum 1994; 37:777.
  10. 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.
  11. Quinn CT, Kamen BA. A biochemical perspective of methotrexate neurotoxicity with insight on nonfolate rescue modalities. J Investig Med 1996; 44:522.
  12. Bernini JC, Fort DW, Griener JC, et al. Aminophylline for methotrexate-induced neurotoxicity. Lancet 1995; 345:544.
  13. Alarcón GS, Tracy IC, Strand GM, et al. Survival and drug discontinuation analyses in a large cohort of methotrexate treated rheumatoid arthritis patients. Ann Rheum Dis 1995; 54:708.
  14. 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.
  15. Hornung N, Ellingsen T, Stengaard-Pedersen K, Poulsen JH. Folate, homocysteine, and cobalamin status in patients with rheumatoid arthritis treated with methotrexate, and the effect of low dose folic acid supplement. J Rheumatol 2004; 31:2374.
  16. Ortiz Z, Shea B, Suarez Almazor M, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev 2000; :CD000951.
  17. Shea B, Swinden MV, Tanjong Ghogomu E, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev 2013; 5:CD000951.
  18. Shea B, Swinden MV, Ghogomu ET, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. J Rheumatol 2014; 41:1049.
  19. Khanna D, Park GS, Paulus HE, et al. Reduction of the efficacy of methotrexate by the use of folic acid: post hoc analysis from two randomized controlled studies. Arthritis Rheum 2005; 52:3030.
  20. Shiroky JB, Neville C, Esdaile JM, et al. Low-dose methotrexate with leucovorin (folinic acid) in the management of rheumatoid arthritis. Results of a multicenter randomized, double-blind, placebo-controlled trial. Arthritis Rheum 1993; 36:795.
  21. Weinblatt ME, Maier AL, Coblyn JS. Low dose leucovorin does not interfere with the efficacy of methotrexate in rheumatoid arthritis: an 8 week randomized placebo controlled trial. J Rheumatol 1993; 20:950.
  22. Joyce DA, Will RK, Hoffman DM, et al. Exacerbation of rheumatoid arthritis in patients treated with methotrexate after administration of folinic acid. Ann Rheum Dis 1991; 50:913.
  23. Tishler M, Caspi D, Fishel B, Yaron M. The effects of leucovorin (folinic acid) on methotrexate therapy in rheumatoid arthritis patients. Arthritis Rheum 1988; 31:906.
  24. Rodenhuis S, Kremer JM, Bertino JR. Increase of dihydrofolate reductase in peripheral blood lymphocytes of rheumatoid arthritis patients treated with low-dose oral methotrexate. Arthritis Rheum 1987; 30:369.
  25. Menke DM, Griesser H, Moder KG, et al. Lymphomas in patients with connective tissue disease. Comparison of p53 protein expression and latent EBV infection in patients immunosuppressed and not immunosuppressed with methotrexate. Am J Clin Pathol 2000; 113:212.
  26. Mariette X, Cazals-Hatem D, Warszawki J, et al. Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France. Blood 2002; 99:3909.
  27. 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.
  28. Bachman TR, Sawitzke AD, Perkins SL, et al. Methotrexate-associated lymphoma in patients with rheumatoid arthritis: report of two cases. Arthritis Rheum 1996; 39:325.
  29. Moseley AC, Lindsley HB, Skikne BS, Tawfik O. Reversible methotrexate associated lymphoproliferative disease evolving into Hodgkin's disease. J Rheumatol 2000; 27:810.
  30. Yamakawa N, Fujimoto M, Kawabata D, et al. A clinical, pathological, and genetic characterization of methotrexate-associated lymphoproliferative disorders. J Rheumatol 2014; 41:293.
  31. Merrill JT, Shen C, Schreibman D, et al. Adenosine A1 receptor promotion of multinucleated giant cell formation by human monocytes: a mechanism for methotrexate-induced nodulosis in rheumatoid arthritis. Arthritis Rheum 1997; 40:1308.
  32. Pfeilschifter J, Diel IJ. Osteoporosis due to cancer treatment: pathogenesis and management. J Clin Oncol 2000; 18:1570.
  33. Schwartz AM, Leonidas JC. Methotrexate osteopathy. Skeletal Radiol 1984; 11:13.
  34. Buckley LM, Leib ES, Cartularo KS, et al. Effects of low dose methotrexate on the bone mineral density of patients with rheumatoid arthritis. J Rheumatol 1997; 24:1489.
  35. Ide M, Suzuki Y, Ichikawa Y, et al. Influence of long-term low-dose methotrexate therapy on periarticular and generalized osteoporosis in rheumatoid arthritis. Jap J Rheumatol 1999; 9:75.
  36. Turner SL, Slevin NJ, Gupta NK, Swindell R. Radical external beam radiotherapy for 333 squamous carcinomas of the oral cavity--evaluation of late morbidity and a watch policy for the clinically negative neck. Radiother Oncol 1996; 41:21.
  37. O'Dell J, Gilg J, Palmer W, et al. Pneumococcal vaccination in rheumatoid arthritis patients on methotrexate. (abstract) Arthritis Rheum 1992; 35:S197.
  38. Mease PJ, Ritchlin CT, Martin RW, et al. Pneumococcal vaccine response in psoriatic arthritis patients during treatment with etanercept. J Rheumatol 2004; 31:1356.
  39. Peponis V, Kyttaris VC, Chalkiadakis SE, et al. Ocular side effects of anti-rheumatic medications: what a rheumatologist should know. Lupus 2010; 19:675.