For years, erythema multiforme was thought to represent the milder end of a spectrum of drug hypersensitivity disorders that included Stevens-Johnson syndrome Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) Stevens-Johnson syndrome and toxic epidermal necrolysis are severe cutaneous hypersensitivity reactions. Drugs, especially sulfa drugs, antiseizure drugs, and antibiotics, are the most common... read more 
and toxic epidermal necrolysis Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) Stevens-Johnson syndrome and toxic epidermal necrolysis are severe cutaneous hypersensitivity reactions. Drugs, especially sulfa drugs, antiseizure drugs, and antibiotics, are the most common... read more , 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.
Oral lesions include target lesions on the lips and vesicles and erosions on the palate and gingivae.
Diagnosis of Erythema Multiforme
Diagnosis of erythema multiforme is by clinical appearance; biopsy is rarely necessary.
Differential diagnosis includes essential urticaria Urticaria Urticaria consists of migratory, well-circumscribed, erythematous, pruritic plaques on the skin. Urticaria also may be accompanied by angioedema, which results from mast cell and basophil activation... read more 
, vasculitis Overview of Vasculitis Vasculitis is inflammation of blood vessels, often with ischemia, necrosis, and organ inflammation. Vasculitis can affect any blood vessel—arteries, arterioles, veins, venules, or capillaries... read more 
, bullous pemphigoid Bullous Pemphigoid Bullous pemphigoid is a chronic autoimmune skin disorder resulting in generalized, pruritic, bullous lesions in older patients. Mucous membrane involvement is rare. Diagnosis is by skin biopsy... read more 
, pemphigus, linear IgA dermatosis Linear Immunoglobulin A (IgA) Disease Linear immunoglobulin A (IgA) disease is an uncommon bullous disease distinguished from bullous pemphigoid and dermatitis herpetiformis by linear deposits of IgA in the basement membrane zone... read more 
, acute febrile neutrophilic dermatosis Acute Febrile Neutrophilic Dermatosis Acute febrile neutrophilic dermatosis is characterized by tender, indurated, dark-red papules and plaques with prominent edema in the upper dermis and dense infiltrate of neutrophils. The cause... read more 
, and dermatitis herpetiformis Dermatitis Herpetiformis Dermatitis herpetiformis is an intensely pruritic, chronic, autoimmune, papulovesicular cutaneous eruption strongly associated with celiac disease. Typical findings are clusters of intensely... read more 
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Oral lesions must be distinguished from aphthous stomatitis Recurrent Aphthous Stomatitis Recurrent aphthous stomatitis is a common condition in which round or ovoid painful ulcers recur on the oral mucosa. Etiology is unclear. Diagnosis is clinical. Treatment is symptomatic and... read more 
, pemphigus, herpetic stomatitis, and hand-foot-and-mouth disease Hand-Foot-and-Mouth Disease (HFMD) Hand-foot-and-mouth disease (HFMD) is a febrile disorder usually caused by coxsackievirus A16, enterovirus 71, or other enteroviruses. Infection causes a vesicular eruption on the hands, feet... read more 
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Patients with widely disseminated purpuric macules and blisters and prominent involvement of the trunk and face are likely to have Stevens-Johnson syndrome Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) Stevens-Johnson syndrome and toxic epidermal necrolysis are severe cutaneous hypersensitivity reactions. Drugs, especially sulfa drugs, antiseizure drugs, and antibiotics, are the most common... read more rather than erythema multiforme.
Treatment of Erythema Multiforme
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
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Erythema multiforme is usually triggered by herpes simplex virus (HSV) but can be caused by a drug.
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Target lesions and lesions on the palms and soles can be relatively specific findings.
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Biopsy is rarely necessary.
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Treat erythema multiforme supportively and consider prophylactic antiviral drugs if HSV is the suspected cause and recurrences are frequent.
