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Erythema multiforme

Last updated: September 5, 2020

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Erythema multiforme (EM) is a rare, acute hypersensitivity reaction most commonly triggered by herpes simplex virus (HSV) infections. Other triggers include M. pneumoniae infection, certain drugs, and immunizations. EM is mainly seen in adults between 20–40 years of age. Clinical features include a rash of varied appearance, beginning as macules and papules, which evolve into characteristic target lesions. The rash first appears on the dorsal aspect of the hands and feet then extends proximally. If mucous membrane involvement and systemic symptoms occur, the condition is defined as EM major. The diagnosis is often clear on history and physical examination, whereas serology for underlying infectious causes and/or skin biopsy may be necessary in doubtful or recurrent cases. EM is usually self-limiting and resolves spontaneously within a month; symptomatic treatment with NSAIDs, antihistamines, and topical steroids is generally sufficient. In severe cases of EM major, hospitalization to treat dehydration, severe pain, and possible bacterial superinfection may be necessary.

  • Incidence: < 1% per year
  • Age: mainly adults 20–40 years
  • Sex: slight male predominance


Epidemiological data refers to the US, unless otherwise specified.

Erythema multiforme is a type IV hypersensitivity reaction; which can be triggered by the following.


  • Rash
  • Distribution
    • Symmetrical distribution
    • Affects backs of hands and feet first → spreads proximally and can affect the entire body, including palms and soles
    • Mucous membrane involvement
      • EM minor: no/minimal involvement of mucus membranes
      • EM major: painful ulcers of the oral (most common), ocular, genital mucosa
  • Further symptoms: fever, myalgia, and arthralgia in cases of EM major


The diagnosis is mainly clinical and should be suspected (especially) if there is a history of recurrent labial herpes, recent drug intake, or immunizations.



The differential diagnoses listed here are not exhaustive.

In most cases of EM, no treatment is necessary because the condition is self-limiting.

  • General: stop the offending drug or treat the underlying infection
  • Mild cases: symptomatic treatment
  • Severe cases: (EM major): hospitalize and treat as thermal burns
  • Recurrent EM: oral acyclovir for 4 months; if no recurrence, then taper and stop


  • EM is usually self-limiting; rash spontaneously disappears within a month
  • Some patients may have a recurrence of EM.


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