Erythema Multiforme

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  • Erythema multiforme (EM) is relatively common, acute, recurrent, self-limiting inflammatory disease.
    • Mostly (~90% of cases) triggered by infectious agents (up to 50% by herpes simplex virus [HSV]-1 or -2), or less commonly, by drugs and vaccinations (1,2)
    • Skin lesions include acrally distributed, distinct targetoid lesions with concentric color variation, sometimes accompanied by oral, genital, or ocular mucosal lesions (1,3).
    • Flat, atypical lesions and macules with or without blisters are more suggestive of Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) (4,5).
  • There are no universal diagnostic criteria, but clinical history, clinical examination, skin biopsy, laboratory studies, and special consideration of persistent EM are all included in making a diagnosis.


  • Two subtypes, erythema multiforme minor (EMm) and erythema multiforme major (EMM), with the former involving none or one mucous membrane and the latter involving at least two mucous membrane sites. EMM is now separate from SJS and TEN.
  • Recurrent EM is defined as >3 attacks but has a mean number of 6 attacks (range 2 to 24) per year and a mean duration of 6 to 9.5 years (range 2 to 36) (1).


Annual U.S. incidence is estimated at <1% (1).

  • Peak incidence in 20s to 40s; rare <3 years and >50 years of age
  • Slight male predominance is observed.

Etiology and Pathophysiology

  • The exact pathophysiology of EM is incompletely understood but appears to be the result of a TH1-mediated immune response to an inciting event such as infection or drug exposure.
  • Genetic susceptibility can be a predisposing factor in some patients with EM. Different HLA alleles have been found to be consistent in patients with EM.
  • HSV containing a certain HSV pol, a polymerase associated with the HSV-triggered EM seems to involve autoimmune activation and a cell-mediated response (1).
  • With electron microscopy, there is evidence of lichenoid inflammatory infiltrate and epidermal necrosis including circulating immune complexes, deposition of C3, IgM, and fibrin around the upper dermal blood vessels.
  • SJS and TEN have an increased granulysin and perforin expression within T cells than in EM (4,5).
  • Previous viral infections, particularly; also Epstein-Barr, coxsackievirus, echovirus, varicella, mumps, poliovirus, hepatitis C, cytomegalovirus, HIV, molluscum contagiosum virus (1)
  • Bacterial infections, particularly Mycoplasma pneumoniae; other reported bacterial infections include Treponema pallidum, Mycobacterium tuberculosis, and Gardnerella vaginalis (1).
  • Medications, including NSAIDs, antibiotics, penicillin, sulfonamides, and antiepileptics (1,3)
  • Vaccines: stronger association with HPV, MMR, and small pox vaccines, but also associated with hepatitis B, meningococcal, pneumococcal, varicella, influenza, diphtheria-pertussis-tetanus, and Haemophilus influenzae (2)
  • Occupational exposures: herbicides (alachlor and butachlor), iodoacetonitrile
  • Radiation therapy
  • Premenstrual hormone changes (3)
  • Malignancy (3)

Strong association with HLA-DQB10301, particularly in herpes-related cases (1); possible association in recurrent cases with HLA-B35, -B62, -DR53

Risk Factors

Previous history of EM

General Prevention

  • Known or suspected etiologic agents should be avoided.
  • Acyclovir or valacyclovir may help prevent herpes-related recurrent EM.

Commonly Associated Conditions

See “Etiology and Pathophysiology” earlier.

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