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Erythema multiforme - Anogenital in
See also in: Overview,Oral Mucosal Lesion
Other Resources UpToDate PubMed

Erythema multiforme - Anogenital in

See also in: Overview,Oral Mucosal Lesion
Contributors: Erin X. Wei MD, Jeffrey M. Cohen MD, Belinda Tan MD, PhD, Susan Burgin MD
Other Resources UpToDate PubMed


Erythema multiforme (EM) is a self-limited hypersensitivity reaction of the skin and mucous membranes characterized by the acute onset of fixed lesions of concentric color change (target lesions). Two subtypes exist: EM major and EM minor. Key differences between the EM subtypes include mucosal involvement and systemic symptoms such as fever, arthralgias, and asthenias seen in the major subtype. Prodromal symptoms occasionally can be associated.

Recurrent EM occurs in a subset of patients and has been variably defined as more than 1, more than 2, or more than 6 flares per year.

Persistent EM is uncommon and refers to chronic, continuous presence of EM or outbreaks separated by 15 days or less.

In adults, the primary trigger for EM is herpes simplex virus (HSV), which is estimated to incite about 90% of cases. EM has been reported with other infections including histoplasmosis, Epstein-Barr virus, and, most recently, COVID-19. Idiopathic cases have also been seen.

Typically, all cutaneous lesions appear within 24-72 hours and persist for 1-4 weeks before fading. The eruption recurs on repeated exposure to the inciting agent.


L51.9 – Erythema multiforme, unspecified

36715001 – Erythema multiforme

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Diagnostic Pearls

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Differential Diagnosis & Pitfalls

  • Stevens-Johnson syndrome / Toxic epidermal necrolysis – Histologic features may not differentiate EM from SJS/TEN. Clinically, however, look for irregularly shaped, dusky red macular or patch-like lesions on the trunk, face, and palms / soles. A positive Nikolsky sign can be found; there is mucosal involvement, including the eyes, lips, mouth, and genitalia. Look for hemorrhagic crusts, bullae, and denudation in these areas. Systemic symptoms are commonly present but not invariable. Lesions are more pronounced on the trunk than on the extremities. Precipitating factors are usually medications.
  • Reactive infectious mucocutaneous eruption (RIME) – Usually occurs secondary to mycoplasma infection (as evidenced by clinical pneumonia, imaging studies, and/or mycoplasma serologies), although Chlamydia pneumoniae, human parainfluenza virus 2, rhinovirus, adenovirus, enterovirus, human metapneumovirus, and influenza B virus have more recently been recognized to cause a similar clinical picture. There is pronounced oral and ocular mucositis with absent, spare, or mild cutaneous involvement. Cutaneous lesions are most often tense vesiculobullae. Target or targetoid lesions may be present. Cutaneous lesions do not erode or desquamate as seen in SJS/TEN. (Note: Erosion is seen in the genital and perianal skin, which are considered akin to mucosal surfaces.) Nikolsky sign is negative. Acute and convalescent mycoplasma titers may be employed to help establish this diagnosis in the correct clinical scenario.
  • Scabies
  • Generalized Fixed drug eruption – Look for erythematous plaques that develop on the lips, face, distal extremities, and genitalia 1-2 weeks after medication ingestions. The oral mucosa can be involved. Histology will differentiate a fixed drug eruption from EM.
  • Lichen planus – Very pruritic, sometimes associated with hepatitis C. Biopsy will differentiate EM from lichen planus.
  • Secondary syphilis – Scattered scaling papules and plaques; check rapid plasma reagin (RPR) and check for history of primary chancre and systemic symptoms.
  • Arthropod bite or sting
  • Bullous disorders (eg, Bullous pemphigoid or Pemphigus vulgaris)
  • Paraneoplastic pemphigus

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Management Pearls

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Drug Reaction Data

Below is a list of drugs with literature evidence indicating an adverse association with this diagnosis. The list is continually updated through ongoing research and new medication approvals. Click on Citations to sort by number of citations or click on Medication to sort the medications alphabetically.

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Last Reviewed:12/19/2022
Last Updated:02/10/2023
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Erythema multiforme - Anogenital in
See also in: Overview,Oral Mucosal Lesion
A medical illustration showing key findings of Erythema multiforme (Skin) : Scattered many
Clinical image of Erythema multiforme - imageId=30005. Click to open in gallery.  caption: 'Edematous and erythematous papules and plaques, some with a target-like appearance on the leg.'
Edematous and erythematous papules and plaques, some with a target-like appearance on the leg.
Copyright © 2024 VisualDx®. All rights reserved.