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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: Erin X. Wei MD, Jeffrey M. Cohen MD, Belinda Tan MD, PhD, Susan Burgin MD
Other Resources UpToDate PubMed

Synopsis

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. Medication can also be a trigger. 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.

The following points should be kept in mind when a diagnosis of EM is being considered:
  • Herpes labialis may typically precede development of EM but may sometimes 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 and 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 Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) and confers no risk of progressing to TEN.
  • EM major refers to the presence of significant mucosal involvement in a case of EM, whereas in EM minor, mucosal involvement is absent or minimal.
The presence of erythema multiforme-like lesions in a patient with lupus, along with a speckled pattern of antinuclear antibody (ANA), positive anti-Ro/SSA or anti-La/SSB, and positive rheumatoid factor (RF) is known as Rowell syndrome. This syndrome has been described in patients with discoid lupus erythematosus (DLE), subacute cutaneous lupus erythematosus (SCLE), and systemic lupus erythematosus (SLE). Its existence as a distinct entity has been debated in the literature; some authors believe the association is coincidental. Prednisone with or without hydroxychloroquine, dapsone, or immunosuppressive drugs such as cyclosporin have been cited as therapy.

Codes

ICD10CM:
L51.9 – Erythema multiforme, unspecified

SNOMEDCT:
36715001 – Erythema multiforme

Look For

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Diagnostic Pearls

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Differential Diagnosis & Pitfalls

  • Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) – 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.
  • 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 multiforme – 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, there are no systemic symptoms, and 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.
  • SCLE – Antinuclear antibodies (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), and 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
  • Cocaine levamisole toxicity
  • Kawasaki disease
  • Autoimmune progesterone dermatitis
  • Paraneoplastic pemphigus
Differential diagnosis of hemorrhagic crusting of both lips:

Best Tests

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Management Pearls

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Therapy

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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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References

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Last Reviewed:12/19/2022
Last Updated:04/03/2023
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Erythema multiforme in Adult
See also in: Anogenital,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.
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