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Methotrexate - low dose

Classification: C

Drug products: Ebetrex, Injexate, Maxtrex, Metex, Methotrexate Orion, Methotrexate Orion Pharma, Methotrexate Pfizer, Methotrexate Sandoz, Methotrexate Teva, Metoject, Metojectpen, Metotab, Nordimet

ATC code: L04AX03


Although methotrexate can have good effect in men and women, the effect has been shown to be better in men with rheumatoid arthritis. Studies suggest a better response to methotrexate in men with rheumatoid arthritis than women. Methotrexate can cause teratogenic effects when administrated to a pregnant woman. For Swedish users, more information can be found in Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Additional information

Pharmacokinetics and dosing

One study of methotrexate pharmacokinetics in children showed no differences between boys and girls [1]. No other studies with significant sex differences in pharmacokinetics have been found. No studies with a clinically relevant sex analysis regarding the dosing of methotrexate have been found.


A randomized controlled trial in patients with new-onset rheumatoid arthritis (RA) treated with methotrexate (87 men, 318 women) showed that women were less likely to respond to methotrexate (odds ratio 0.50), measured both with ACR and EULAR criteria [2]. Similar results have been shown in another study in patients with either new-onset RA (47 men, 139 women) [3] or established RA (122 men, 289 women) [4]. Treatment response to methotrexate has been analyzed in patients with idiopathic inflammatory myopathy in a retrospective cohort study (40 men, 73 women). Complete response to methotrexate was found in 8 of 24 men but only in 1 of 31 women [5]. A Swedish observational study (252 men, 446 women) showed that fewer women than men with RA receiving anti-rheumatic agents (mainly sulfasalazine or methotrexate) were in remission at follow-up at 2 and 5 years. Women had a higher doctor-assessed disease activity at baseline. After treatment, disease activity decreased less in women than in men [6].

Adverse effects

The risk of cancer associated with methotrexate compared with other biologic disease-modifying anti-rheumatic drugs have been examined in patients with RA in an observational study (1591 men, 5215 women). Men had a higher risk of any cancer (hazard ratio for female 0.50) [7].Sex differences in the incidence of liver test abnormalities  in patients with RA treated with low-dose methotrexate (71 men, 92 women) have been found. Toxic elevations in transaminases were seen more frequently in women [8]. Another study including patients with RA or psoriasis shows similar results (374 men, 435 women). Women were more likely to have liver enzyme elevation from long-term treatment with methotrexate (hazard ratio 1.43) [9]. The incidence of liver toxicity compared to clinical response of methotrexate in juvenile idiopathic arthritis has been analyzed in a retrospective cohort study (48 boys, 172 girls). One cohort received initial high-dose of methotrexate (>0.5 mg/kg/week) and one cohort received initial low-dose methotrexate (< 0.5 mg/kg/week). Girls receiving high-dose had a greater risk of liver toxicity at 12 months compared to girls on low-dose (odds ratio 3.7). Boys receiving high-dose had no increased risk of toxicity. However, this finding could be due to the relatively small number of boys in the cohort [10].

Reproductive health issues

Methotrexate is contraindicated in pregnant women and breastfeeding mothers. Methotrexate can cause fetal harm when administered to a pregnant woman. It is recommended that pregnancy should be avoided if either partner is receiving methotrexate. For male patients, their female partner should avoid pregnancy during therapy and for a minimum of three months after therapy. For female patients, pregnancy should be avoided during and for at least one ovulatory cycle after therapy [11]. Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Other information

Sex-specific differences in treatment of severe psoriasis have been analyzed using data from national surveys including 4.1 million men and 4.4 million women. Of patients receiving methotrexate, 79% of the men and 18 % of the women were 50 years old or younger.. For patients older than 50 years, women were more likely than men to receive intensive treatment.  For patients younger than 50 years, men were three times more likely than women to receive intensive treatment. This observation might be explained by a reluctance to use potentially teratogenic drugs in women of childbearing potential [12]. Despite the risk of teratogenic effects of methotrexate, one study found no sex difference in methotrexate use in teenagers with Crohn disease or ulcerative colitis [13].

Updated: 2022-02-03

Date of litterature search: 2015-07-10


  1. Madanat F, Awidi A, Shaheen O, Othman S, Al-Turk W. Effects of food and gender on the pharmacokinetics of methotrexate in children. Res Commun Chem Pathol Pharmacol. 1987;55:279-82. PubMed
  2. Saevarsdottir S, Wallin H, Seddighzadeh M, Ernestam S, Geborek P, Petersson IF et al. Predictors of response to methotrexate in early DMARD naive rheumatoid arthritis: results from the initial open-label phase of the SWEFOT trial. Ann Rheum Dis. 2011;70:469-75. PubMed
  3. Wessels JA, van der Kooij SM, le Cessie S, Kievit W, Barerra P, Allaart CF et al. A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent-onset rheumatoid arthritis. Arthritis Rheum. 2007;56:1765-75. PubMed
  4. Hoekstra M, van Ede AE, Haagsma CJ, van de Laar MA, Huizinga TW, Kruijsen MW et al. Factors associated with toxicity, final dose, and efficacy of methotrexate in patients with rheumatoid arthritis. Ann Rheum Dis. 2003;62:423-6. PubMed
  5. Joffe MM, Love LA, Leff RL, Fraser DD, Targoff IN, Hicks JE et al. Drug therapy of the idiopathic inflammatory myopathies: predictors of response to prednisone, azathioprine, and methotrexate and a comparison of their efficacy. Am J Med. 1993;94:379-87. PubMed
  6. Forslind K, Hafström I, Ahlmén M, Svensson B, BARFOT Study Group. Sex: a major predictor of remission in early rheumatoid arthritis?. Ann Rheum Dis. 2007;66:46-52. PubMed
  7. Solomon DH, Kremer JM, Fisher M, Curtis JR, Furer V, Harrold LR et al. Comparative cancer risk associated with methotrexate, other non-biologic and biologic disease-modifying anti-rheumatic drugs. Semin Arthritis Rheum. 2014;43:489-97. PubMed
  8. Leonard PA, Clegg DO, Carson CC, Cannon GW, Egger MJ, Ward JR. Low dose pulse methotrexate in rheumatoid arthritis: an 8-year experience with hepatotoxicity. Clin Rheumatol. 1987;6:575-82. PubMed
  9. Amital H, Arnson Y, Chodick G, Shalev V. Hepatotoxicity rates do not differ in patients with rheumatoid arthritis and psoriasis treated with methotrexate. Rheumatology (Oxford). 2009;48:1107-10. PubMed
  10. Becker ML, Rosé CD, Cron RQ, Sherry DD, Bilker WB, Lautenbach E. Effectiveness and toxicity of methotrexate in juvenile idiopathic arthritis: comparison of 2 initial dosing regimens. J Rheumatol. 2010;37:870-5. PubMed
  11. Trexall (methotrexate). DailyMed [www]. US National Library of Medicine. [updated 2015-04-01, cited 2015-07-10]. länk
  12. Hotard RS, Feldman SR, Fleischer AB. Sex-specific differences in the treatment of severe psoriasis. J Am Acad Dermatol. 2000;42:620-3. PubMed
  13. Lee GJ, Kappelman MD, Boyle B, Colletti RB, King E, Pratt JM et al. Role of sex in the treatment and clinical outcomes of pediatric patients with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2012;55:701-6. PubMed
  14. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2015 [cited 2016-04-05.] länk

Authors: Linnéa Karlsson Lind, Desirée Loikas

Reviewed by: Mia von Euler, Karin Schenck-Gustafsson

Approved by: Karin Schenck-Gustafsson