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General Inpatient Medicine




Infectious Disease








Outpatient & Preventative Medicine


Palliative Care




Pulmonary/Critical Care



Methotrexate Toxicity

Toxicities depend on whether patient is on low-dose MTX (e.g. for Rheumatoid Arthritis) vs high-dose (e.g. chemotherapy).
Keep in mind that MTX toxicity can still be present weeks after discontinuing the medication when there is sequestering in fluid reservoirs, with subsequent slow leakage over weeks.   Most common scenario where this happens is with pleural effusions and ascites.

Common:  GI symptoms (mucositis, nausea, dyspepsia, diarrhea), Skin (macular rash), Neurotoxicity, Macrocytosis.
More serious:
- Hepatotoxicity
- Pulmonary toxicity – both acute reactions and chronic pulmonary toxicity
- Renal toxicity – usually with high dose MTX – due to precipitation of MTX crystals and tubular injury
- Myelosuppression – this is the major dose-limiting side effect


- Common side effect of methotrexate
- Usually presents within 3-7 days after hi dose treatment initiation and lasts <2 wks (self-limited)
- Most complications come from dehydration and superinfection
- Risk for mucositis include poor dentition or preexisting dental infections
- Dental screening (by a Dentist) is recommended prior to methotrexate initiation
- Superinfections include candida > hsv


Role of folic acid and “Leucovorin Rescue”
MTX acts by interfering with cellular utilization of folic acid, mainly by inhibiting the enzyme Dihydrofolate Reductase, which catalyzes the reduction of Folic Acid to Folinic acid (Leucovorin).  Folic acid is a necessary cofactor in synthesis of thymidine, and thus MTX indirectly inhibits DNA synthesis.
All patients on MTX should be on daily folic acid supplementation at the least. 

Folinic acid (Leucovorin) is more effective than Folic acid in reversing/ameliorating many of the toxicities of MTX, due to the fact that Folinic acid bypasses the inhibition of Dihydrofolate Reducatase by MTX.  However, it is much more expensive than folic acid and thus is used if there is an unsatisfactory response to folic acid, or toxicities are severe.
For unclear reasons, addition of folic acid or Leucovorin does not seem to decrease the efficacy of MTX for cancer (mainly because Leucovorin is not easily transported into tumor cells); there is mixed data on whether or not it decreases the efficacy of MTX for Rheumatoid arthritis.



(Ellen Eaton MD, 7/12/10)

(Chanu Rhee MD, 12/16/10)