Low-dose methotrexate-induced skin toxicity: Keratinocyte dystrophy as a histologic marker

J Am Acad Dermatol. 2015 Sep;73(3):484-90. doi: 10.1016/j.jaad.2015.06.015. Epub 2015 Jul 16.


Background: Skin toxicity during low-dose methotrexate therapy is rare, ill described, and reported to have nonspecific histologic characteristics. Thus, misdiagnosis is common in patients with mucosal ulcers and/or skin erosions related to low-dose methotrexate.

Objective: We sought to describe the features of skin toxicity induced by low-dose methotrexate.

Methods: We evaluated the clinical and histologic features in 5 patients who experienced skin toxicity induced by low-dose methotrexate between 2011 and 2013.

Results: All 5 patients had acute mucosal ulcers, 4 had moderately abnormal blood cell counts, and 3 had skin erosions. In 3 patients, methotrexate dosage or dosing-schedule errors were identified. No other contributing factors (eg, renal dysfunction or interacting drugs) were identified. Mucocutaneous biopsy specimens consistently showed multiple dystrophic keratinocytes.

Limitations: We studied only 5 patients and obtained no sensitivity or specificity data on the diagnostic value of keratinocyte dystrophy.

Conclusion: Keratinocyte dystrophy may help to diagnose skin toxicity of low-dose methotrexate, even in the absence of known risk factors or methotrexate administration errors. Studies of the diagnostic performance of this histologic sign are needed.

Keywords: keratinocyte dystrophy; methotrexate; pancytopenia; psoriasis; skin toxicity; ulcers.

MeSH terms

  • Administration, Oral
  • Aged
  • Aged, 80 and over
  • Arthritis, Rheumatoid / diagnosis
  • Arthritis, Rheumatoid / drug therapy
  • Biomarkers
  • Biopsy, Needle
  • Cohort Studies
  • Dose-Response Relationship, Drug
  • Drug Eruptions / etiology
  • Drug Eruptions / pathology
  • Female
  • Follow-Up Studies
  • Humans
  • Immunohistochemistry
  • Keratinocytes / drug effects
  • Keratinocytes / pathology*
  • Male
  • Methotrexate / adverse effects*
  • Methotrexate / therapeutic use
  • Middle Aged
  • Pemphigoid, Bullous / diagnosis
  • Pemphigoid, Bullous / drug therapy
  • Psoriasis / diagnosis
  • Psoriasis / drug therapy
  • Rare Diseases
  • Retrospective Studies
  • Risk Assessment
  • Skin Ulcer / chemically induced*
  • Skin Ulcer / pathology


  • Biomarkers
  • Methotrexate