Erythema Multiforme – Causes, Symptoms, Diagnosis, Treatment and Ongoing care


  • Erythema multiforme (EM) is an acute, self-limited hypersensitivity reaction:
    • Mostly triggered by infectious agents (more than 50% by herpes simplex virus [HSV]-1 or -2) or drugs (1,2)[B]
    • Involving the skin and sometimes the mucous membrane, most commonly the mouth
    • Skin lesions include typical target or “iris” lesions, flat or raised atypical lesions, macules with or without blisters.
  • Currently, there are no universal diagnostic criteria for EM. It was previously considered to be a spectrum of disease, consisting of EM, EM major, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). However, it appears to be a growing consensus that EM is a distinct condition from SJS and TEN due to the differences in clinical presentation, histopathology manifestation, patient demographics, possible etiology and pathogenesis, and treatment plan (1,2,3,4)[C].


  • Two subtypes, erythema multiforme minor (EMm) and erythema multiforme major (EMM), with the former involving none or 1 mucous membrane, and the latter involving at least 2 mucous sites (1)[C]
  • Recurrent EM has a mean number of 6 attacks (range 2–24) per year and a mean duration of 9.5 years (range 2–36) (1)[B].
  • System(s) affected: Skin/Exocrine
  • Synonym(s): Erythema polymorphe



The annual incidence in the US has been estimated at between 0.01 and 1% (4)[C].


  • Predominant age: Peak incidence in 20s and 40s; rare <age 3 and >age 50
  • Predominant sex: Male > Female (3:2 to 2:1) (1,2)[C]

Risk Factors

Previous history of erythema multiforme


Strong association with HLA-DQ3 in herpes-related cases. Possible association in recurrent cases with HLA-B15, -B35, -A33, -DR53, DQB1*0301, and DQW3 (1)[C]

General Prevention

  • Known or suspected etiologic agents should be avoided.
  • Acyclovir may help prevent herpes-related erythema multiforme (1,2)[B].


  • The exact pathophysiology of EM is unknown.
  • Possible immunologically mediated lymphocytic reaction to an infectious agent or a drug at the dermal-epithelial junction
  • HSV-triggered EM seems to involve CD4+ T-cell infiltration and associated IFN-γ activation.
  • Drug-triggered EM involves CD8+ T-cells and associated TNF-α activation (4)[C].


  • Most cases appear to be due to a preceding infection.
  • Viral infections, particularly herpes simplex (accounting for more than 50% of cases); also Epstein-Barr, coxsackie, echovirus, varicella, mumps, poliovirus, hepatitis C, cytomegalovirus, HIV, molluscum contagiosum virus
  • Bacterial infections, particularly Mycoplasma pneumoniae; other occasional reported bacterial infections include Treponema Pallidum and Gardnerella vaginalis
  • Fungal infection, including Histoplasma capsulatum and Coccidioides immitis
  • Medications, including sulfonamides, penicillins, barbiturates, hydantoins, nonsteroidal anti-inflammatory drugs (NSAIDs), phenothiazines. Other sparsely reported medications include candesartan, cilexetil, rofecoxib, metformin, bupropion, ciprofloxacin, sorafenib, gemfibrozil, risperidone, paclitaxel, metoprolol, adalimumab, etanercept, and infliximab.
  • Vaccines: Tetanus/diphtheria, bacillus Calmette-Guérin, oral polio, hepatitis B, human papillomavirus
  • Protozoan infections
  • Radiation therapy
  • Premenstrual hormone changes
  • Sarcoidosis

Commonly Associated Conditions

Any of the infections or diseases listed under Etiology

Herpes simplex virus, Herpes simplex, Erythema multiforme, Cutaneous condition, Stevens–Johnson syndrome, HLA-DQ3, erythema multiforme,


Diagnose clinically by careful review of the history and detailed physical examination. No specific labs are required for the diagnosis.


  • Absent or mild prodromal symptoms.
  • Preceding HSV infection (over 50% of cases) 10–15 days before the skin eruptions (1,2)[B]
  • Rash involving the skin and sometimes the mucous membrane, most commonly the mouth

Physical Exam

  • Skin pleomorphic eruption with a mixture of macules, papules of various sizes, and target lesions:
    • Typical target lesions: Raised and cyanotic center, edematous light intermediate ring and bright erythematous border (three zones)
    • Flat or raised atypical target lesions: 2 zones only (center and intermediate ring) with poorly defined border
    • Symmetrically distributed rash, mainly on the palms, soles, dorsum of the hands, and extensor surface of the extremities and the face
    • Lesions may coalesce and become generalized.
    • Body surface area with epidermal detachment <10% (1,2,3,4)[B]
  • Mucosal involvement:
    • Minimal involvement in EM minor; if present, most commonly involves the mouth
    • At least 2 mucosal sites involved in EM major, including eyes (conjunctivitis, keratitis), mouth (stomatitis, cheilitis), and probable trachea, bronchi, gastrointestinal tract, or genital tract (balanitis and valvulitis)
    • Multiple papules and vesicles, superficial irregular erosions, shallow painful ulcers with erythematous margin (1)[C]

Diagnostic Tests & Interpretation


  • No specific lab test is indicated to make the diagnosis of EM (1,2,3,4)[B].
  • Skin biopsy of lesional and perilesional tissue in equivocal conditions (1,2,3,4)[C]
  • Direct and indirect immunofluorescence to differentiate EM from other vesiculobullous diseases (1)[C]. Indirect immunofluorescence is detected on a biopsy of perilesional skin, and direct immunofluorescence is detected from a blood sample.
  • HSV tests in recurrent EM (serologic tests, swab culture, or tests using skin biopsy sample to check HSV antigens or DNA in keratinocytes by immunofluorescence or polymerase chain reaction (PCR)) (4)[C]
  • Antibody staining to IFN-γ and TNF-α to differentiate HSV-associated EM and drug-associated EM (4)[C]
  • Elevated M. pneumonia antibody titer in M. pneumonia infection–associated EM (1)[C]


Initial approach

No specific imaging studies are indicated in most cases.

Follow-Up & Special Considerations

Chest x-ray may be necessary if an underlying pulmonary infection (M. pneumoniainfection) is suspected.

Pathological Findings

  • A predominantly perivascular inflammatory infiltrate with CD4+ T lymphocytes and histocytes in papillary dermis and the epidermal-dermal junction
  • Focal necrotic keratinocytes mainly in the basal layer
  • Dermal edema (1,2,4)[C]

Differential Diagnosis

  • Stevens-Johnson syndrome (3)[C]:
    • Different pattern and location of the skin lesions. No typical target lesion. Atypical flat target lesions or macules, generalized or mainly in the trunk
    • Blisters and skin detachment less than 10% of the total body surface area
    • Usually with systemic complications (i.e., Central Nervous System, lung, gastrointestinal system, kidney)
    • 1–5% mortality rate
  • Toxic epidermal necrolysis (1,3)[C]:
    • Blisters and skin detachment more than 30% of the total body surface area
    • 10–30% mortality rate
  • Urticaria
  • Necrotizing vasculitis
  • Drug eruptions
  • Contact dermatitis
  • Pityriasis rosea
  • Herpes simplex
  • 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 (1,2)[B]
  • Withdrawal of any drugs that might be the cause (1,2)[B]
  • Symptomatic treatment with oral antihistamines and topical corticosteroids for mild cases (1,2)[B]
  • Early treatment with acyclovir may lessen the number and duration of cutaneous lesions for patients with coexisting or recent HSV infection (2)[B]:
    • Acyclovir for adults: 200 mg, 5 times a day for 7–10 days in the onset of EM
    • For pediatric patients: 10 mg/kg or 500 mg/s2, 3 times a day for 7–10 days
  • Recurrent EM may be treated with oral acyclovir (400 mg 2 times per day), even if HSV infection has not been confirmed (2)[B].
  • Valacyclovir (Valtrex, 500–1,000 mg per day) and famciclovir (Famvir, 125–250 mg per day) may be tried in patients who are resistant to acyclovir (2)[C]:
    • Reduce the dosage once the patient is recurrence-free for 4 months, and eventually discontinue the drug.

Second Line

  • Recurrent EM cases nonresponsive to antiviral therapy could also try dapsone (100–150 mg per day), azathioprine (Imuran, 100–150 mg per day), thalidomide (100–200 mg per day), mycophenolate mofetil (CellCept <2 g daily), hydroxychloroquine (<400 mg daily), colchicine (<1.2 mg daily) (25)[C].
  • Cyclosporine given intermittently (4 mg/kg per day for a week) may also be used for recurrent EM (2)[C].
  • Systemic steroid use is controversial, because it may decrease the patient’s resistance to HSV and increase recurrent HSV infection (1,2)[C].
  • Precautions: Refer to the manufacturer’s profile of each drug.
  • Significant possible interactions: Refer to the manufacturer’s profile of each drug.

Additional Treatment

General Measures

  • Meticulous wound care and Burow’s solution or Domeboro solution dressings for severe cases with epidermal detachment
  • Mouth washes with warm saline or a solution of diphenhydramine, lidocaine (Xylocaine), and Kaopectate for oral lesions to provide symptomatic relief and oral hygiene, and to facilitate oral intake

In-Patient Considerations

Admission Criteria

  • Care at home
  • Hospitalization needed for fluid, electrolyte management if patient with severe mucous membrane involvement, impaired oral intake and dehydration.
  • IV antibiotics if secondary infection develops

Ongoing Care

Follow-Up Recommendations

Patient Monitoring

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


As tolerated with increased fluid intake

Patient Education

  • The disease is self-limiting. However, the recurrence risk may be 30%.
  • Antiviral therapy with acyclovir may reduce the duration and frequency of outbreaks.
  • Avoid any identified etiological agents.


  • Rash evolves over 1–2 weeks and subsequently resolves within 2–6 weeks, generally without scarring or sequelae.
  • Following resolution, there may be some postinflammatory hyper- or hypopigmentation.


Secondary infection


1. Al-Johani KA, Fedele S, Porter SR. Erythema multiforme and related disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007.

2. Lamoreux MR, Sternbach MR, Hsu WT. Erythema multiforme. Am Fam Physician. 2006;74:1883–8.

3. Auquier-Dunant A, Mockenhaupt M, Naldi L, et al. Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol. 2002;138:1019–24.

4. Aurelian L, Ono F, Burnett J. Herpes simplex virus (HSV)-associated erythema multiforme (HAEM): a viral disease with an autoimmune component.Dermatol Online J. 2003;9:1.

5. Wetter DA, Davis MD et al. Recurrent erythema multiforme: clinical characteristics, etiologic associations, and treatment in a series of 48 patients at Mayo Clinic, 2000 to 2007. J Am Acad Dermatol. 2010;62:45–53.

Additional Reading

Chen M, Doherty SD, Hsu S et al. Innovative uses of thalidomide. Dermatol Clin. 2010;28:577–86.

Nikkels AF, Pièrard GE. Treatment of mucocutaneous presentations of herpes simplex virus infections. Am J Clin Dermatol. 2002;3:475–87.

Williams PM, Conklin RJ. Erythema multiforme: a review and contrast from Stevens-Johnson syndrome/toxic epidermal necrolysis. Dent Clin North Am.2005;49:67–76, viii.

See Also (Topic, Algorithm, Electronic Media Element)

Cutaneous Drug Reactions; Dermatitis Herpetiformis; Herpes Gestationalis; Urticaria; Stevens-Johnson Syndrome; Toxic Epidermic Necrotisis



695.10 Erythema multiforme, unspecified


36715001 Erythema multiforme (disorder)

Clinical Pearls

  • EM is diagnosed clinically by careful review of the history, through detailed physical examination, and by excluding other similar disorders. No lab tests are required for the diagnosis.
  • Typical lesions are pleomorphic macules, papules, and characteristic target or “iris” lesions
  • Lesions are symmetrically distributed on palms, soles, dorsum of the hands, and extensor surfaces of extremities and face. Mucosal involvement is minimal.
  • Management of EM involves determining the etiology when possible. The first step is to treat the suspected infection or discontinue the causative drug.
  • Complications are rare. Most cases are self-limited. However, the recurrence risk may be as high as 30%.
  • Recurrent cases often are secondary to herpes simplex infection. Antiviral therapy may be beneficial.

Jean-Paul Marat

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