Methotrexate-induced epidermal necrosis: A case series of 24 patients

J Am Acad Dermatol. 2017 Aug;77(2):247-255.e2. doi: 10.1016/j.jaad.2017.02.021. Epub 2017 May 10.


Background: Methotrexate-induced epidermal necrosis (MEN) is a rare but life-threatening cutaneous reaction that mimics Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

Objectives: To investigate the clinicopathology, risk factors, and prognostic factors of MEN.

Methods: We enrolled 24 patients with MEN and 150 controls and analyzed the demographics, pathology, and plasma concentrations of methotrexate (MTX).

Results: Patients with MEN showed extensive skin necrosis (mean, 33.2% total body surface area) but no target lesions. The histopathology displayed keratinocyte dystrophy. Early signs of MEN included painful skin erosions, oral ulcers, and leukopenia/thrombocytopenia. Although 79.2% patients received leucovorin treatment, there was 16.7% mortality. Risk factors for MEN included older age (>60 years), chronic kidney disease, and high initial dosage of MTX without folic acid supplementation. Renal insufficiency delayed MTX clearance. Severe renal disease and leukopenia predicted poor prognosis in MEN, but none of the SCORe of Toxic Epidermal Necrosis criteria were associated with mortality of MEN.

Limitations: The study was limited by the small sample size.

Conclusion: MEN exhibited distinct clinicopathologic features from SJS/TEN. Recognition of the early signs and prognostic factors is important, because the rapid institution of leucovorin may be helpful. To reduce the risk of MEN, physicians should avoid prescribing MTX to high-risk patients and titrate the dosage slowly upward with folic acid supplementation.

Keywords: cutaneous adverse reactions; methotrexate; skin necrosis.

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • Body Surface Area
  • Case-Control Studies
  • Drug Eruptions / diagnosis
  • Drug Eruptions / drug therapy
  • Drug Eruptions / etiology*
  • Drug Eruptions / pathology
  • Epidermis / pathology*
  • Female
  • Folic Acid Antagonists / administration & dosage
  • Folic Acid Antagonists / adverse effects*
  • Folic Acid Antagonists / blood
  • Humans
  • Leucovorin / therapeutic use
  • Male
  • Methotrexate / administration & dosage
  • Methotrexate / adverse effects*
  • Methotrexate / blood
  • Middle Aged
  • Necrosis / chemically induced
  • Prognosis
  • Renal Insufficiency, Chronic / complications
  • Survival Rate
  • Vitamin B Complex / therapeutic use


  • Folic Acid Antagonists
  • Vitamin B Complex
  • Leucovorin
  • Methotrexate