Methotrexate toxicity


  • Methotrexate blocks dihydrofolate reductase (DHFR) → blocks conversion of folate to folinic acid
  • Used in treatment of Non-Hodgkin's lymphoma, acute lymphocytic leukemia, certain other malignancies, psoriasis and other dermatological conditions, rheumatoid arthritis (as a DMARD)
  • Folate supplementation is often given with methotrexate, and ↓ risk of toxicity[1]
  • Absorbed by saturable transporter in GI tract[2]
    • Single large oral dose will have lower bioavailability/toxicity than multiple small doses or chronic toxicity.

Clinical Features[1]

  • Nausea/vomiting
  • Folate deficiency
  • Myelosuppression, pancytopenia
  • Hepatotoxicity
    • Acutely - transaminitis
    • Chronic - cirrhosis/fibrosis
  • Pulmonary toxicity
  • Renal injury (ATN) secondary to precipitation of methotrexate crystals[2]
  • Cutaneous injury (stomatitis, mucositis, ulcerations, SJS and TEN, etc.)

Differential Diagnosis



Early initiation of therapy is important, so begin treatment once MTX toxicity is strongly suspected

  • Folinic Acid (Leucovorin)[1]
    • 20mg IV or IM q6h until MTX serum level <10−8 M
  • Glucarpidase
    • Works by enzymatic cleaving of MTX into metabolites
  • Hydration and urine alkalinization
    • Bicarbonate drip at 1.5-2x maintenance rate to maintain urine pH of >7.5
    • MTX is excreted renally


  • Admit

See Also


  1. Weidmann A, Foulkes AC, Kirkham N, Reynolds NJ. Methotrexate Toxicity During Treatment of Chronic Plaque Psoriasis: A Case Report and Review of the Literature. Dermatology and Therapy. 2014;4(2):145-156. doi:10.1007/s13555-014-0056-z.
  2. Schmiegelow K. Advances in individual prediction of methotrexate toxicity: a review. Br J Haematol. 2009 Sep;146(5):489-503. doi: 10.1111/j.1365-2141.2009.07765.x.
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