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

Erythema multiforme in Adult

See also in: Anogenital,Oral Mucosal Lesion
Contributors: 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.

In the past, the conditions EM, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) were considered a continuum, but it is now recognized that EM does not progress to TEN. Therefore, EM is now considered a distinct hypersensitivity eruption, which can be distinguished from SJS/TEN based on the presence of target lesions, papular (rather than macular) atypical target lesions, and an acral distribution.

In adults, the primary trigger for EM is herpes simplex virus (HSV), which is estimated to incite about 90% of cases. In children, important additional triggers to consider include drugs (particularly penicillin), mycoplasma pneumonia, group A Streptococcus, and Epstein-Barr virus. Importantly, mycoplasma pneumonia-induced EM is associated with prominent mucositis and absent or sparse cutaneous findings, which, if present, tend to have atypical morphology, including vesicles, bullae, targetoid lesions, and atypical targets / macules. The distinct cutaneous features seen in hypersensitivity eruptions due to mycoplasma pneumonia have led to the term "mycoplasma pneumonia-induced rash and mucositis," or MIRM, which some argue should be used to refer to any severe mucocutaneous eruption associated with mycoplasma pneumonia, abandoning the previous practice of classifying mycoplasma pneumonia-associated eruptions as EM, SJS, incomplete SJS, or mycoplasma pneumonia-associated mucositis. Many other infectious agents, both viruses and bacteria, have been associated with the development of EM.

Typically, all cutaneous lesions appear within 24-72 hours and persist for 2 weeks before fading. The eruption recurs on repeated exposure to the inciting agent. While HSV is the most common etiology associated with recurrent EM, several viruses have been associated as triggers, too.

The following points should be kept in mind when a diagnosis of EM is being considered:
  • Herpes labialis may precede, develop concomitantly, or manifest after the onset of EM. In almost half of all cases, herpes labialis precedes EM.
  • Although a strong association exists with HSV and EM, a direct immunofluorescence test or viral culture for HSV will be negative in EM lesions.
  • Classical target lesions are well-defined circular lesions that are less than 3 cm in diameter, have 3 distinct color zones, and a central zone that has a bulla or crust.
  • Atypical target lesions are palpable, poorly defined, circular lesions that have 2 distinct color zones. Raised atypical targets are a subtype of atypical targets that have a vesicle or bulla centrally.
  • EM can demonstrate classical target lesions, raised atypical target lesions, or both concomitantly.
  • EM is not considered within the same disease spectrum as SJS/TEN and confers no risk in progressing to TEN.


L51.9 – Erythema multiforme, unspecified

22972008 – Erythema multiforme, dermal type

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Diagnostic Pearls

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Differential Diagnosis & Pitfalls

  • Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) – Histological 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 crust, 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.
  • Mycoplasma pneumonia-induced rash and mucositis (MIRM) – Occurs secondary to mycoplasma infection as evidenced by clinical pneumonia, imaging studies, and/or mycoplasma serologies. 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 to establish this diagnosis in the correct clinical scenario.
  • Generalized fixed drug eruption – Look for erythematous plaques that develop on the lips, face, distal extremities, and genitalia 1-2 weeks after medication ingestions. Oral mucosa can be involved. Histology will differentiate fixed drug eruption from EM.
  • Urticaria – New lesions appear daily; lesions are transient and last less than 24 hours, associated with edema of lips, face, hands, and feet. No evidence of epidermal damage in the center of urticarial lesions. Subcutaneous epinephrine injections will clear urticarial lesions but not EM lesions.
  • Erythema annulare centrifugum (EAC) – Erythematous, annular patches and plaques that are idiopathic in nature; can last from days to months, no systemic symptoms, lesions commonly appear on hips and thighs. Biopsy will differentiate EAC and EM.
  • Lichen planus – Very pruritic, sometimes associated with hepatitis C. Biopsy will differentiate EM from lichen planus.
  • Subacute cutaneous lupus erythematosus (SCLE) – ANA will be positive in the majority of lupus patients. SCLE is characterized by annular plaques with raised borders and central clearing or papulosquamous lesions that are restricted to sun-exposed skin.
  • Secondary syphilis – Scattered scaling papules and plaques; check rapid plasma reagin (RPR), check for history of primary chancre and systemic symptoms.
  • Leukocytoclastic vasculitis (LCV) – Palpable purpura is the most common finding, consisting of nonblanching 1-3 mm, violaceous, round papules, characteristically involving the lower extremities. Biopsy will differentiate fixed LCV from EM.
  • Arthropod bites – Haphazard distribution of erythematous papules.
  • Viral exanthem
  • Erythema nodosum
  • Bullous disorders (eg, bullous pemphigoid or pemphigus vulgaris)
  • Cocaine levamisole toxicity

Best Tests

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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 Updated:05/07/2019
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Erythema multiforme in Adult
See also in: Anogenital,Oral Mucosal Lesion
Erythema multiforme : Bullae, Painful skin lesions, Palms and soles, Scattered many, Smooth plaque, Tense vesicles
Clinical image of Erythema multiforme
Copyright © 2021 VisualDx®. All rights reserved.