Mucocutaneous toxicity in the form of necrosis, erosions, and ulcers can occur in patients taking low-dose or high-dose methotrexate (MTX). A rarer form of skin toxicity is that of methotrexate-induced skin necrosis (MEN). This simulates Stevens-Johnson syndrome / toxic epidermal necrolysis (SJS/TEN) and may also be accompanied by mucosal ulceration. MTX is commonly prescribed for inflammatory or autoimmune disorders like psoriasis or rheumatoid arthritis, and it is also used as a chemotherapeutic agent.

Some risk factors for developing mucocutaneous toxicity include age older than 55 years; renal impairment; folate deficiency; low serum albumin; an alteration in MTX dose, such as taking a higher dose of the medication; restarting MTX after a hiatus; or initiation of a high dose of MTX without concomitant folic acid. In a case series of patients with MEN, many patients had more than one risk factor, including older age, renal impairment, and initiation of high-dose MTX without folic acid. Additionally, the likelihood of developing skin erosions due to MTX therapy has been shown to increase with concomitant NSAID, aspirin, trimethoprim / sulfamethoxazole, allopurinol, and proton pump inhibitor use.

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; however, a few instances of MTX toxic skin eruptions have ended fatally.