Clinical Reference / Therapeutic Strategies / Erythema Multiforme

Erythema Multiforme

Key Points

  • Erythema multiforme (EM) is a clinical syndrome marked by either target lesions and/or mucosal erosions. It may be idiopathic or seen in association with infections or medications.
  • EM has been reported in association with herpes simplex infection, mycoplasma pneumonial infection, contact dermatitis, medications, and radiation.
  • There is considerable controversy in the literature regarding the proper classification and terminology of erythema multiforme. EM may be subdivided into EM minor and major, connoting distinct associations, although many investigators and consensus groups no longer distinguish between the two entities. In general, EM minor is associated with infections (classically, herpes simplex virus) and is typically a self-limited process. EM major, according to some authors, may be synonymous with Stevens-Johnson syndrome (SJS) and entails a more severe clinical syndrome with more atypical target lesions and pronounced mucosal involvement at two anatomic sites. EM major occurs in association with many different infections or as an adverse reaction to medications, and requires hospitalization.


The presence of annular lesions, often acrally distributed, with a central target or bulla, is characteristic of erythema multiforme (EM). True target lesions are tri-partite and consist of sharply marginated circular or polycyclic lesions with central dusky erythema, concentric edematous blanching, rimmed by a macular erythematous border. The central portion may be bullous. Mucosal lesions are seen in 25% of cases and typically affect the oral mucosa. EM may be seen in association with herpes simplex infection, mycoplasma pneumonial infection, contact dermatitis, medications, radiation, or be idiopathic.

The classification and terminology of EM in the literature is controversial, and at times, confusing. EM may be clinically subdivided into EM minor and EM major, connoting distinct disease associations. EM minor is typified by minimal skin and/or mucosal disease, with minimal systemic symptoms, in association with either herpes simplex virus (HSV) or mycoplasma pneumonial infection. Therapy is generally not required or helpful for EM minor (limited to skin and/or one mucosal surface without systemic symptoms), which is a self-limited process. Because this form of erythema multiforme invariably follows infection and is self-limited, usually lasting only days to weeks, in the majority of cases the therapeutic strategy is symptom control or no treatment at all. EM major (sometimes alternatively termed infection or drug-related EM or Stevens-Johnson syndrome), however, requires in-patient management because of significant systemic symptoms and involvement of one and usually more mucosal surfaces. Unfortunately, specific therapy does not exist, and administration of systemic steroids may cause complications. Fortunately, like EM minor, the disease is self-limited regardless of severity and supportive care is the mainstay of treatment.

Initial Evaluation

Differential diagnosis

Herpes simplex virus, oral

Lyell’s syndrome

Pemphigus vulgaris, oral and ocular only


Initial therapy

First-line treatment is supportive care. Diagnostic management should entail consideration of a skin biopsy and a reasonable search for potential triggers that can be eliminated or treated. Diagnostic considerations include: viral direct fluorescence antibody (DFA) testing, viral culture, herpes serologies, mycoplasma serologies or cold agglutinins, and chest X-ray.

  • For bullous skin lesions, aluminum acetate compresses (such as Domeboro’s or Burow’s soak compresses, made by dissolving one packet or tablet in one cup of tap water) applied b.i.d. for 10-20 minutes followed by applications of silver sulfadiazine (Silvadene) cream b.i.d. Silvadene should be avoided if there is any concern for a sulfa drug related EM or SJS.
  • For oral lesions, an antiseptic mouthwash or hydrogen peroxide 30%, diluted 1:10, should be used t.i.d. Pain-alleviating mouthwash containing viscous lidocaine, diphenhydramine and aluminum and magnesium hydroxide can be used b.i.d. to t.i.d.
  • For ocular lesions, the most devastating potential complication of EM and/or Stevens-Johnson syndrome, ophthalmology referral is paramount. There currently is no evidence that either systemic or intraocular steroids can prevent progression of ocular disease. Note: Sulfa-containing eye drops should be avoided if there is any concern for a sulfa drug related EM or SJS.

When to refer to a dermatologist

  • When the diagnosis of erythema multiforme is not clear.
  • If EM is recurrent or if a diagnostic evaluation cannot clearly identify an underlying cause.
  • If a patient presents with widespread lesions (i.e., >25% body surface area) or if the patient is developing progressive lesions concerning for evolution to TEN.
  • For management of EM associated with contact dermatitis, radiation, or drug.

Clinical Cases

Case 1

  • 24-year-old woman with history of recurrent orolabial herpes infection
  • Presents with asymptomatic lesions on the palms (approximately 8 on each hand) and soles (approximately 4-5 on each foot) that developed one day after new vesicles developed on her lips
  • This is the first time she has developed skin lesions in association with her orolabial herpes
  • She reports no fever, respiratory or gastrointestinal symptoms

Initial evaluation

  • Exam reveals target lesions, approximately 1 cm in size on the palms and soles
  • Four small erosions on the lower left lip with hemorrhagic crusting
  • A diagnosis of HSV-associated EM minor is rendered
  • Since it has been several days since her orolabial herpetic flare, no antiviral therapy is given; the patient is counseled that if she develops frequent HSV recurrences with EM minor, she should return to the clinic for consideration of viral suppressive therapy
  • She is also counseled to use photoprotection, especially over the lips, to avoid triggering recurrent herpetic flares

Case 2

  • 17-year-old teenage boy presents with scattered skin lesions, oral erosions, eye pain, and 4 days’ history of cough
  • He has had subjective fevers and malaise over the past week
  • He denies taking any regular or occasional medications

Initial evaluation

  • The patient has fever, mild tachycardia, slight hypotension, with increased breathing rate and a slightly reduced oxygen saturation
  • Exam reveals scattered target lesions (approximately 5% body surface area) on the trunk, arms, legs; there are extensive superficial erosions on the lips and buccal mucosa with hemorrhagic crusting; he has marked conjunctival erythema and chemosis
  • Respiratory exam reveals reduced breath sounds throughout; a chest X-ray reveals diffuse pulmonary infiltrates and cold agglutinins done at the clinic bedside are positive
  • A diagnosis of mycoplasma-associated SJS is rendered
  • The patient is admitted to the hospital and there he is evaluated by infectious disease and ophthalmology, who confirm that he has mycoplasma pneumonia with mild ocular complications; later serologic testing confirms that he has active infection with Mycoplasma pneumoniae
  • The patient is hospitalized with supportive care and is given a course of antibiotics for mycoplasma pneumonia; skin and eye care are implemented; he is discharged two days later to home


Shah KN, Honig PJ, Yan AC (2007). “Urticaria multiforme: a case series and review of acute annular urticarial hypersensitivity syndromes in children,” Pediatrics, 119; e1177.

Hughey SL (2011). Approach to the hospitalized patient with targetoid lesions, Dermatologic Therapy, 24(2): 196-206.