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Erythema Multiforme


Julia Benedetti

, MD, Harvard Medical School

Last full review/revision Jul 2020| Content last modified Jul 2020
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Erythema multiforme is an inflammatory reaction, characterized by target or iris skin lesions. Oral mucosa may be involved. Diagnosis is clinical. Lesions spontaneously resolve but frequently recur. Erythema multiforme usually occurs as a reaction to an infectious agent such as herpes simplex virus or mycoplasma but may be a reaction to a drug. Suppressive antiviral therapy may be indicated for patients with frequent or symptomatic recurrence due to herpes simplex virus.

For years, erythema multiforme was thought to represent the milder end of a spectrum of drug hypersensitivity disorders that included Stevens-Johnson syndrome and toxic epidermal necrolysis, but it is now considered a different entity.

Etiology of Erythema Multiforme

The majority of cases are caused by

HSV-1 is more often a cause than HSV-2, although it is unclear whether erythema multiforme lesions represent a specific or nonspecific reaction to the virus. Current thinking holds that erythema multiforme is caused by a T-cell–mediated cytolytic reaction to HSV DNA fragments present in keratinocytes. A genetic disposition is presumed given that erythema multiforme is such a rare clinical manifestation of HSV infection, and several human leukocyte antigen subtypes have been linked with the predisposition to develop lesions.

Less commonly, cases are caused by drugs, vaccines, other bacterial or viral diseases (especially hepatitis C), or possibly systemic lupus erythematosus (SLE). Erythema multiforme that occurs in patients with SLE is sometimes referred to as Rowell syndrome.

Symptoms and Signs of Erythema Multiforme

Erythema multiforme manifests as the sudden onset of asymptomatic, erythematous macules, papules, wheals, vesicles, bullae, or a combination on the distal extremities (often including palms and soles) and face. The classic lesion is annular with a violaceous center and pink halo separated by a pale ring (target or iris lesion). Distribution is symmetric and centripetal, sometimes spreading to the trunk. Some patients have itching.

Manifestations of Erythema Multiforme

Oral lesions include target lesions on the lips and vesicles and erosions on the palate and gingivae.

Diagnosis of Erythema Multiforme

  • Clinical evaluation

Diagnosis of erythema multiforme is by clinical appearance; biopsy is rarely necessary.

Oral lesions must be distinguished from aphthous stomatitis, pemphigus, herpetic stomatitis, and hand-foot-and-mouth disease.

Patients with widely disseminated purpuric macules and blisters and prominent involvement of the trunk and face are likely to have Stevens-Johnson syndrome rather than erythema multiforme.

Treatment of Erythema Multiforme

  • Supportive care

  • Sometimes prophylactic antivirals

Erythema multiforme spontaneously resolves, so treatment is usually unnecessary. Topical corticosteroids and anesthetics and oral antihistamines may ameliorate symptoms and reassure patients. Recurrences are common, and empiric oral maintenance therapy with acyclovir 400 mg orally every 12 hours, famciclovir 250 mg orally every 12 hours, or valacyclovir 1000 mg orally every 24 hours can be attempted if symptoms recur more than 5 times/year and HSV association is suspected or if recurrent erythema multiforme is consistently preceded by herpes flares.

Key Points

  • Erythema multiforme is usually triggered by herpes simplex virus (HSV) but can be caused by a drug.

  • Target lesions and lesions on the palms and soles can be relatively specific findings.

  • Biopsy is rarely necessary.

  • Treat erythema multiforme supportively and consider prophylactic antiviral drugs if HSV is the suspected cause and recurrences are frequent.

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