Erythema Multiforme


  • Erythema multiforme (EM) is an uncommon, self-limiting, immune-mediated, mucocutaneous disease.
    • Approximately 90% of cases are triggered by infectious agents (herpes simplex virus [HSV] is most common, up to 50%), or less commonly, by drugs and vaccinations (1).
    • Characteristic skin lesions are acrally distributed, distinct, targetoid papules with concentric color variation (3 zones), occasionally accompanied by oral, genital, or ocular mucosal involvement.
    • EM needs to be differentiated from Steven-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which are characterized by truncal, flat lesions with or without blisters which can result in significant mortality (1).
  • There are no universal diagnostic criteria, but clinical history, clinical examination, skin biopsy, laboratory studies, and special consideration of persistent EM are all helpful in making a diagnosis.
  • Treatment focuses on supportive care in addition to treating the underlying etiology and discontinuing causative agents (1).


  • There are two subtypes of EM: erythema multiforme minor (EMm) which involves ≤1 mucosal site and erythema multiforme major (EMM), which involves ≥2 mucosal sites. EMM is now separate from SJS and TEN. Skin lesions that are predominantly truncal, flat (macular, nonpalpable), and atypical (less sharply demarcated with only two concentric zones) with or without blisters are more suggestive of SJS or TEN (1).
  • Recurrent EM is defined as ≥3 episodes but has a mean number of 6 episodes per year and a mean duration of 6 to 10 years.


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

Predominant in young adults from age 20 to 40 years; rare in <3 years and >50 years of age (1). Slight female predominance is observed. There is no apparent race predilection (1).

Etiology and Pathophysiology

  • Etiology (1)
    • Viral infections: HSV-1 (most common etiology) and HSV-2, Epstein-Barr, hepatitis C, coxsackievirus, echovirus, varicella, mumps, poliovirus, cytomegalovirus, HIV, molluscum contagiosum, COVID-19
    • Bacterial infections: Mycoplasma pneumoniae (2nd most common etiology), Treponema pallidum, Mycobacterium tuberculosis, and Gardnerella vaginalis
    • Drugs: NSAIDs, anti-epileptics, antibiotics (penicillin, sulfonamides, erythromycin, nitrofurantoin, tetracyclines), statin, tumor necrosis factor (TNF)-α inhibitors, and barbiturates
    • Vaccines: stronger association with HPV, MMR, and small pox vaccines, but also associated with hepatitis B, meningococcal, pneumococcal, varicella, influenza, diphtheria-pertussis-tetanus, Haemophilus influenzae, and COVID-19
    • Other causes: occupational exposures: herbicides (alachlor and butachlor), iodoacetonitrile, heavy metals; radiation therapy; premenstrual hormone changes; malignancy (e.g., lymphoma); inflammatory bowel disease
  • Pathogenesis of EM
    • In HSV-associated EM, peripheral mononuclear cells that phagocytose the virus transport fragmented HSV DNA to keratinocytes. Within the keratinocytes, the HSV DNA polymerase gene (pol) leads to a TH-1 mediated immune response. Activation of the HSV-specific CD4+ TH-1 cells then produces cytokines such as interferon (IFN)-γ and triggers an inflammatory cascade which leads to the mucocutaneous findings.
    • Development of EM from other inciting factors such as drugs and vaccinations is not completely understood, but it appears that the pathway involves TNF-α, perforin, and granzyme B rather than IFN-γ.

Genetic susceptibility may play a role in some patients with EM. There is a strong association with the HLA-DQB1*0301 allele found among patients with herpes-associated EM. In recurrent EM, there is an association with HLA-B35, -B62, and -DR53 alleles.

Risk Factors

Previous history of EM, age 20 to 40 years, use of causative agents or infection with causative pathogens

General Prevention

  • Known etiologic agents or those with potential for cross-reactivity should be avoided.
  • Oral acyclovir or valacyclovir may help prevent herpes-related recurrent EM (2).

Commonly Associated Conditions

See “Etiology and Pathophysiology.”

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