Clinical characteristics and risk factors for low dose methotrexate toxicity: a cohort of 28 patients

Autoimmun Rev. 2014 Nov;13(11):1109-13. doi: 10.1016/j.autrev.2014.08.027. Epub 2014 Aug 27.


Objective: Low dose (10-25 mg/week) methotrexate is widely used for the management of systemic inflammatory diseases, and is considered to be relatively safe. Toxicity due to low dose MTX has been reported but is poorly characterized. We describe the clinical features, risk factors, and outcomes of low dose MTX toxicity in a large case series at our center.

Patients and methods: We conducted a retrospective case series of all adult (>18 years) patients hospitalized at Sheba Medical Center, between 2005 and 2012 for low dose MTX toxicity.

Results: We identified 28 patients (age: 70.4±13.7 years, range: 33-88; 20 (71%) females) hospitalized for low dose MTX toxicity. Indications for MTX therapy included: rheumatoid arthritis (39.2%), psoriasis±arthritis (21.5%), polymyalgia rheumatica (10.8%) and other inflammatory conditions (28.5%). Pancytopenia was the most common manifestation of low dose MTX toxicity detected in 78.5% of the patients. Potential risk factors included acute renal failure, hypoalbuminemia, concurrent use of drugs known to interact with MTX, and dose errors. Serum MTX concentrations (n=20, mean 0.04±0.07 μg/mL range: 0-0.3) did not correlate with the degree of either neutropenia (r=-0.36; p=0.18) or thrombocytopenia (r=0.44; p=0.10). Seven (25%) patients died, all from pancytopenia followed by sepsis. Serum MTX concentrations did not differ between the patients who died from MTX toxicity (n=6; mean: 0.05±0.04 μg/mL) and those who survived the toxicity (n=14 mean 0.04±0.08; p=0.45).

Conclusions: Low-dose MTX toxicity can be life threatening, mainly due to myelosuppression. There is no rationale for MTX therapeutic drug monitoring in the setting of low-dose toxicity.

Keywords: Drug toxicity; Methotrexate; Pancytopenia; Psoriasis arthritis; Rheumatoid arthritis.

Publication types

  • Review

MeSH terms

  • Antirheumatic Agents / administration & dosage
  • Antirheumatic Agents / adverse effects
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / drug therapy*
  • Humans
  • Methotrexate / administration & dosage
  • Methotrexate / adverse effects
  • Methotrexate / therapeutic use*
  • Retrospective Studies
  • Risk Factors
  • Treatment Outcome


  • Antirheumatic Agents
  • Methotrexate