• An acute self-limited hypersensitivity reaction involving the skin and sometimes the mucus membranes:
  • Erythema multiforme (also called the erythema multiforme Hebra) is a mild disease that appears as a pleomorphic rash and includes target lesions, but not large vesicles or petechia, affecting the skin with or without involving 1 mucus membrane site.
  • Three clinical subgroups have been identified:
    • Classical: A single episode as described;
    • Recurrent: Episodes recur, usually in synchrony with herpes simplex outbreaks
    • Persistent: Rare; only 23 cases having been reported in the world literature
• Acceptance of the diagnostic criteria for erythema multiforme is not universal. Much of the literature consists of reports of 1 or 2 cases with “an erythema multiform-like rash.” Many authors refer to episodes of Stevens-Johnson syndrome as erythema multiforme, or erythema multiforme major, and others describe patients with oral lesions but no rash as “atypical erythema multeforme.” Some authors consider erythema multeforme to be a mild form of Stevens-Johnson syndrome, but there appears to be a growing consensus that the 2 are unrelated (11).
• System(s) affected: Skin/Exocrine
• Synonym(s): Erythema exudativum multiforme

Incidence
The incidence in the US is not known. In Germany, the incidence of erythema multiforme major, Stevens Johnson syndrome, and toxic epidermal necrolysis combined appears to be 0.189/100,000 persons per year.

Prevalence

• Predominant age: Peak incidence in 20s and 30s; rare < age 3 and > age 50
• Predominant sex: Male > Female (3:2)

Previous history of erythema multiforme

Genetics
Possibly associated with HLA-B15

• Known or suspected etiologic agents should be avoided.
• Acyclovir may help prevent herpes-related erythema multiforme.
• Tamoxifen has been shown to prevent premenstrual-related disease.

• Most cases appear to be due to a preceding infection. Viral infections, particularly herpes simplex; also Epstein-Barr, Coxsackie, echovirus, varicella, mumps, and poliovirus
• Bacterial infections, including brucellosis, diphtheria, borreliosis
• Mycoplasma appears to more often precede Stevens-Johnson syndrome.
• Protozoan infections
• Fungal infection, including Trichophyton rubrum
• Collagen vascular diseases
• Malignancy
• Pregnancy
• Premenstrual hormone changes
• Consumption of beer
• Reiter syndrome
• Sarcoidosis
• Vaccines: Tetanus/Diphtheria, bacillus Calmette-Guérin, oral polio vaccine
• Medications: Drugs seem to be an infrequent cause of erythema
• The list of drugs that have been reported as being involved includes sulfonamides, penicillins, anticonvulsants, and salicylates, but most of these were actually associated with Stevens Johnson syndrome when it was considered to be a type of erythema nodosum major.

• Any of the infections or diseases listed under “Etiology”
• Alert skin biopsy

ALERT
Pregnancy Considerations
Reported as a possible etiologic condition

History
Appearance of an unusual rash, usually without itching, particularly in a patient who has herpes simplex.

ALERT
Because it is an immunologic reaction, drug-related erythema multiforme will not occur until 7–14 days after exposure to the offending agent, unless the patient has had the medication previously.

Physical Exam

• Typical pleomorphic eruption is a mixture of macules of various sizes and target lesions. These consist of a central inflamed and superficially necrotic area, surrounded by a halo of less inflamed skin, enclosed within an outer erythematous rim.
  • Purpuric lesions are uncommon, and vesicles may be related to antecedent herpes 1 infections.
  • Rash occurs on the palms, soles, dorsum of the hands, and extensor surface of the extremities and the face; often recurrent, following a viral infection.
• In erythema multiforme there may be involvement of one mucus membrane. This consists of target lesions of the lips or herpetic lesions without extensive necrosis. This may cause confusion with Stevens-Johnson syndrome in which two or more mucus membranes are involved, often with deep ulceration and necrosis.
• Corneal ulceration is a serious complication.

Lab
Initial Labs
No lab tests have been found to be useful in making the diagnosis or monitoring the progress of erythema multiforme.

Diagnostic Procedures/Other
Skin biopsy

Pathological Findings
A predominantly inflammatory pattern characterized by a lichenoid infiltrate, which is of high density and rich in T lymphocytes, and epidermal necrosis that mainly affects the basal layer

• Stevens-Johnson syndrome
• Urticaria
• Necrotizing vasculitis
• Drug eruptions
• Contact dermatitis
• Pityriasis rosea
• Secondary syphilis
• Ringworm
• Pemphigus vulgaris
• Pemphigoid
• Dermatitis herpetiformis
• Herpes gestationis
• Septicemia
• Serum sickness
• Viral exanthems
• Rocky Mountain spotted fever
• Collagen vascular diseases
• Mucocutaneous lymph node syndrome
• Meningococcemia
• Lichen planus
• Behçet syndrome
• Recurrent aphthous ulcers
• Herpetic gingivostomatitis
• Granuloma annulare

First Line

• Treatment of any underlying or causative disease
• Withdrawal of any drugs that might be the cause
• For mild cases, symptomatic treatment is sufficient.

Second Line

• Steroid use is controversial. Patients who have recurrent herpes-induced erythema mulitforme may benefit from acyclovir, which reduces the number of herpetic episodes. Other causative infections should be treated appropriately.
• Contraindications: Some underlying infections or health problems, such as diabetes, may contraindicate the use of steroids.
• Precautions: Refer to the manufacturer's profile of each drug.
• Significant possible interactions: Refer to the manufacturer's profile of each drug.

General Measures

• For more severe cases, be meticulous regarding wound care and the use of Burow's solution or Domeboro solution dressings.
• Oral lesions can be treated with mouthwashes with warm saline or a solution of diphenhydramine, lidocaine (Xylocaine), and Kaopectate to provide symptomatic relief and oral hygiene and to facilitate oral intake.

Initial Stabilization
Care at home, unless mouth lesions (i.e. herpes infection) preclude oral intake

As tolerated

Patient Monitoring

• The disease is self-limiting.
• Complications are rare with no mortality.

As tolerated with increased fluid intake

Patients should be reassured that the disease is self-limited, but that recurrences are possible. If it recurs, viral suppressive therapy with acyclovir may reduce the frequency of outbreaks.

• Rash evolves over 1–2 weeks and subsequently resolves within 2–3 weeks, generally without scarring or sequelae.
• Following resolution, there may be some postinflammatory hyperpigmentation.
• Risk of recurrence may be as high as 37%.

Corneal ulceration is reported as a serious complication of Stevens-Johnson syndrome. It is not clear whether this can occur in true erythema multiforme. Although there may be complications as a result of the underlying disease, there are no other complications of erythema multiforme.

Chen CW, Tsai TF, Chen YF, et al. Persistent erythema multiforme treated with thalidomide. Am J Clin Dermatol 2008;9:123–127.

Coté B, Wechsler J, Bastuji-Garin S, et al. Clinicopathologic correlation in erythema multiforme and Stevens-Johnson syndrome. Arch Dermatol 1995;131:1268–1272.

Paquet P, Piérard GE. Erythema multiforme and toxic epidermal necrolysis: a comparative study. Am J Dermatopathol 1997;19:127–132.

Tay YK, Huff JC, Weston WL. Mycoplasma pneumoniae infection is associated with Stevens-Johnson syndrome, not erythema multiforme (von Hebra). J Am Acad Dermatol 1996;35:757–760.

Vaness MJ, et al. Erythema multiforme-like reaction associated with radiotherapy. Australian Radiol 1996;40:334–347.

Wanner M, Pol-Rodriguez M, Hinds G et al. Persistent erythema multiforme and CMV infection. J Drugs Dermatol 2007;6:333–336.

Weston WL, Morelli JG, Rogers M. Target lesions on the lips: Childhood herpes simplex associated with erythema multiforme mimics Stevens-Johnson syndrome. J Am Acad Dermatol 1997;37:848–850.

Whorle S, et al. EMPACT syndrome. Journal der Deutchen Dermatol Ges 2005;3(1):39–43.

See Also (Topic, Algorithm, Electronic Media Element)
Cutaneous Drug Reactions; Dermatitis Herpetiformis; Herpes Gestationalis; Urticaria

695.10 Erythema multiforme, unspecified

36715001 erythema multiforme (disorder)

Lewis C. Rose, MD

Figure 18-8

Erythema multiforme minor. This patient has a recurrent herpes simplex virus infection. Note the drying crust of the herpetic "cold sore" on his lower lip and the target-like lesions on his palm.

Figure 18-9

Erythema multiforme major. Extensive hemorrhagic crusting on mucous membranes is noted in a patient with fever and extensive erythematous lesions.

1. Assier H, Bastuji-Garin S, Revuz J, et al. Erythema multiforme with mucous membrane involvement and Stevens-Johnson syndrome are clinically different disorders with distinct causes. Arch Dermatol 1995;131:539–543.  [PMID:7741539]