Mucocutaneous toxicity in the form of necrosis, erosions, and ulcers can occur in patients taking low-dose or high-dose methotrexate (MTX). MTX-induced skin necrosis (MEN) is a rarer form of skin toxicity, which simulates Stevens-Johnson syndrome / toxic epidermal necrolysis (SJS/TEN) and may also be accompanied by mucosal ulceration.

Some risk factors for developing mucocutaneous toxicity include age older than 55 years; renal impairment; lack of folate supplementation or folate deficiency; taking incorrect MTX dosages; newly starting, increasing, or adjusting MTX dosages; low serum albumin; and concomitant use of medications such as NSAIDs or trimethoprim-sulfamethoxazole, among others.

The appearance of skin toxicity may indicate the impending onset of life-threatening pancytopenia and organ failure. Drug cessation typically results in rapid healing and recovery of mucocutaneous involvement; however, a few instances of MTX mucocutaneous toxicity have been associated with complications such as multiorgan failure, sepsis, pulmonary edema, and other life-threatening complications. Factors such as lack of folic acid supplementation, pancytopenia, and renal dysfunction have an increased association with mortality from MTX toxicity.