Erythema exsudativum multiforme

Ferdinand v. Hebra 1860

Erythema multiforme, EM, EEM, erythema multiforme of Hebra.

Acute, usually self-limiting, polyetiological disease characterised by target-like lesions.

• Incidence: unknown, but estimated to be well below 1% per annum
• Peak incidence: 20- 40 years of age
• M > F

• Minor form: no mucosal involvement. No systemic symptoms. No progression to toxic epidermal necrolysis (TEN).
• Major form: with mucosal involvement. Systemic symptoms, usually before the skin changes: Fever and asthenia, occasionally arthralgias and atypical pneumonia. No progression to TEN. 

• Possible triggers (combinations also possible)
• Infections
  • approx. 90% of all triggers
  • Viral
    • Herpes simplex virus (HSV) type I (most common trigger)
    • HSV type II
    • Orf virus
    • Parapox virus
    • Varicella zoster virus
    • Epstein-Barr virus
    • Parvovirus B19
    • Adenovirus
    • Cytomegalovirus
    • Coxsackie virus
    • Hepatitis B or C virus
    • HI virus
  • Bacteria
    • Mycoplasma pneumoniae (frequent trigger, especially in children)
    • Chlamydophila psittaci
    • Salmonella
  • Mycobacteria
    • Mycobacterium tuberculosis
  • Mycoses
    • Histoplasma capsulatum
    • Dermatophytes
• Medications (<10%)
  • NSAIDs
  • Sulfonamides
  • Antiepileptics
  • Antibiotics
• Neoplasias
• Autoimmune diseases
• Vaccinations
• UV-radiation (sunburn)
• Trauma
• Sarcoidosis
• Menstruation

• Possible genetic predisposition: HLA-DQw3, DRw53, AW33, HLA-DQB1*0301, B15(62), B35, and DQ3.
• HSV infection causes cellular immune reactions against viral antigens localised in the skin.

• EEM in general:

  • Typical target lesions: Two rings of contrasting erythema, smaller than 3cm, and central skin with signs of epidermal damage such as bulla or crusting.

  • There are usually erythematous, often pruritic or burning papules at localised sites, which transform exanthematously into cocardial and disc-shaped plaques with characteristic central vesicles. A linear arrangement may be detectable (Köbner phenomenon), but this is only active BEFORE the EEM.

  • The first skin changes usually appear after an incubation period of 2-3 days. In some cases, however, there can be up to 17 days between contact with the trigger and the first appearance of efflorescences.

• Prodromal symptoms can occur with EEM major:

  • ↓ AZ, fever, myalgias

  • Cough with M. pneumoniae infection

  • EEM major: Enanthema, painful erosions or vesicles appear on the mucous membranes. Usually only the oral cavity is affected, but in a few cases it can lead to involvement of the pharynx and upper respiratory organs.  In most cases, only the oral mucosa is affected. Involvement of the genital mucosa occurs in approx. 25% and ocular involvement in approx. 17%.

• The most important differential diagnosis is Steven Johnson syndrome: it produces dark red macules and atypical targets, as well as bullous lesions, and can develop into TEN with epidermal detachment of >30% of the body surface area.

• Most common false differential diagnosis is annular urticaria gigantea, also known as urticaria multiforme. Attention, EM lesions remain in place for 7 days, but urticaria only for 24 hours. Subcutaneous adrenaline does not affect EEM lesions, but urticaria disappears in 30 minutes. 

• Anamnesis (infections, herpes simplex, cough, medication intake)
• Clinic
• Laboratory:
  • Nonspecific
  • Optional: ↑BSG, leucocytosis, ↑transaminases, HSV PCR
• Urine
  • Mycoplasma pneumoniae
• Biopsy
  • Dermatopathology
  • Direct immunofluorescence

EEM minor: Mostly symmetrical on the extensor sides of the extremities, palmoplantar, elbows, face.

EEM major: Face, extremities and mucous membranes can be affected. The spread is centripetal.

Focal apoptosis of keratinocytes with interface dermatitis. Vacuolar degeneration of the stratum basale. Lymphocytic, perivascular infiltrates. In the advanced stage, confluent keratinocyte necrosis occurs.

Normally without sequelae. Eye damage with EEM major is rare.

In HSV-triggered EEM, a continuous HSV prophylaxis with valaciclovir can be indicated.

• Scarless healing, but in some cases with hyperpigmentation, within 2 weeks.
• Very few patients suffer from recurrences, some up to 6 times a year. The average duration of recurrences is 6-10 years.

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