Methotrexate related cutaneous adverse drug reactions: a systematic literature review

J Basic Clin Physiol Pharmacol. 2021 Oct 27;33(5):549-565. doi: 10.1515/jbcpp-2021-0165. eCollection 2022 Sep 1.


Objectives: Recently, there is an increased number of reports being published on Methotrexate (MTX) related cutaneous manifestations. We aimed to identify and critically appraise descriptive studies describing the MTX related skin manifestations, treatment approach, and their outcomes.

Methodology: An extensive literature search was performed in the PubMed, Embase, and Scopus databases from inception to April 2021 without any restrictions along with the bibliographic search of included studies, grey literature search, and a snowball search was performed in Google and Google Scholar to identify the relevant literature. Descriptive studies reporting MTX related cutaneous manifestations were considered for the review. The study selection, data extraction, and quality assessment were conducted by two independent reviewers and any disagreements were settled by consensus with the third reviewer.

Results: 31 out of 8,365 descriptive studies including 38 patients (22 females and 16 males) aged between 12 and 78 years prescribed for the management of rheumatoid arthritis, ankylosing spondylitis, and psoriasis were included in this review. Toxic epidermal necrolysis (TEN), papular eruption, vasculitis, erosions of psoriasis, ulcerated psoriatic plaques, local reactions, keratinocyte dystrophy, erythema multiforme, drug rash with eosinophilia and systemic symptoms, Steven Johnson syndrome and photosensitive dermatitis were the majority of MTX induced cutaneous reactions. Immediate withdrawal of MTX, providing appropriate care with anti-inflammatory, topical steroids, and supplementation with folic acid were reported to be effective for the management of the MTX related cutaneous manifestations.

Conclusions: Clinicians and healthcare professionals should be aware of possible acute cutaneous drug reactions induced by MTX to avoid further consequences and fatal conditions. Immediate withdrawal of MTX and supportive care were reported as an efficacious therapeutic management of acute cutaneous drug reactions.

Prospero registration number: CRD42020220038.

Keywords: adverse effect; case report; cutaneous reaction; methotrexate; skin manifestation; systematic review.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Arthritis, Rheumatoid*
  • Child
  • Female
  • Folic Acid / therapeutic use
  • Humans
  • Male
  • Methotrexate / adverse effects
  • Middle Aged
  • Psoriasis* / drug therapy
  • Spondylitis, Ankylosing* / chemically induced
  • Spondylitis, Ankylosing* / drug therapy
  • Young Adult


  • Folic Acid
  • Methotrexate