Erythema Multiforme

Erythema multiforme (EM) is an acute hypersensitivity reaction characterized by targetoid skin lesions with multiple rings and dusky centers. Lesions may be accompanied by systemic symptoms (e.g., fever) and mucosal lesions (e.g., bullae). The majority of patients with EM have a history of recent viral (especially herpes simplex virus) or bacterial infection (usually Mycoplasma pneumoniae). Erythema multiforme is diagnosed clinically and treatment is directed toward the causative agent and alleviation of symptoms.

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Overview

Epidemiology

  • Global incidence of 1.6–2 million cases per year
  • More common in young adults (< 30 years of age)
  • Men > women

Etiology

Erythema multiforme (EM) is a cell-mediated immune reaction (type IV reaction) directed against the antigens of the offending agent, which deposit in the skin.

ClassificationEtiologiesExamples
Infectious causes (most common)Bacterial
  • Mycoplasma pneumonia
  • Rickettsia
Viral
  • Herpes simplex virus (HSV) types 1 and 2
    • Most common cause
    • Approximately 50% of cases
  • Infectious mononucleosis
FungalHistoplasmosis
Noninfectious causesDrugs
  • Penicillins
  • Sulfonamide
  • Anticonvulsant drugs
  • Nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Barbiturates
Malignancy
  • Leukemia
  • Lymphoma
Miscellaneous
  • Sarcoidosis
  • Systemic lupus erythematosus
  • Polyarteritis nodosa

Classification

Erythema multiforme is classified based on the presence of mucosal lesions and systemic symptoms into EM minor and major.

Cutaneous lesionsMucosal involvementSystemic symptoms
EM minor
EM major

Clinical Presentation

Erythema multiforme usually resolves spontaneously within 1 month, with no long-term sequelae. Rarely, EM may recur, up to 6 times/year for 10 years (usually associated with HSV infection).

Cutaneous lesions

  • Begin as erythematous macules that develop over 35 days into papulestarget lesions with 3 different zones 
    • Central zone: dark and erythematous 
    • Middle zone: pale surrounding ring
    • Peripheral zone: erythematous outer ring with well-defined margins 
  • Symmetrical, acral distribution (i.e., hands, feet, and face)
  • Centripetal spread (distal to proximal)
  • Rounded, < 3 cm in diameter
  • Pruritus or burning sensation can be present.

Mucosal lesions

  • Bullous → painful erosions/ulcers
  • 3 locations:
    • Oral mucosa (most common)
    • Ocular mucosa
    • Genital mucosa

Systemic symptoms

  • Fever 
  • Malaise 
  • Myalgia 
  • Arthralgia/arthritis
Erythema multiform clinical presentation

Target lesions with a regular, round shape and 3 concentric zones: a central, darker-red area; a paler pink zone; and a peripheral red ring

Image: “Erythema multiforme” by Pediatric Unit, Maternal & Infant Department, S. Chiara University-Hospital, Via Roma 67, Pisa 56126, Italy. License: CC BY 2.0, edited by Lecturio.

Diagnosis and Management

Diagnosis

  • Usually diagnosed clinically 
  • Serologic testing to identify potential causes: M. pneumoniae in patients with respiratory symptoms, HSV in patients with recurrent EM
  • In uncertain cases, skin biopsy may show:
    • Vacuolated degeneration of basal cells
    • Scattered keratinocyte necrosis
    • Inflammation and edema

Management

  • Erythema multiforme is often self-limiting and does not require treatment.
  • Management is directed toward the causative agent and alleviation of symptoms. 
    • Elimination of the causative agent (e.g., drug, allergen)
    • Symptomatic therapy: topical corticosteroid/oral antihistamines for pruritus and anesthetic mouthwash for painful oral lesions
  • Specific treatment
    • Location dependent:
      • Ocular lesions: referral to an ophthalmologist 
      • Severe oral lesions: admission for pain management and hydration 
    • Recurrent EM: continuous acyclovir for 6 months (suppressive therapy)
Epidermal Changes in Erythema Multiforme

Epidermal changes in EM with vacuolated degeneration of basal cells (arrow) and scattered individual keratinocyte necrosis (arrowhead)

Image: “Epidermal Changes in Erythema Multiforme” by Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan. License: CC BY 2.5

Differential Diagnosis

  • Urticaria: a self-limiting disease consisting of superficial, erythematous, pruritic lesions resulting from mast cell activation and histamine release in the dermis. Lesions may last < 24 hours up to > 6 weeks. Commonly caused by viral infections or by allergic reactions to drugs or food, other infections, stress, cold/heat, and autoimmune disorders. Treatment, besides addressing the underlying condition, includes antihistamines and steroids.
  • Bullous pemphigoid: an immune-mediated condition characterized by the destruction of extracellular adhesive proteins (e.g., hemidesmosomes) by immunoglobulin G autoantibodies. Patients present with urticaria and eczematous papules during the prodromal stage. After that, cutaneous, tense bullae develop. This may last months to years, and treatment is focused on supportive, symptomatic care with steroids and antihistamines. 
  • Stevens-Johnson syndrome (SJS): a life-threatening immune-mediated hypersensitivity reaction that involves the mucous membranes and skin (< 10% of body surface area). Patients generally have a history of taking certain medications (e.g., sulfa drugs) or recent infection. Clinical presentation involves macular skin lesions with 2 zones of color change, vesicles, bullae, and systemic symptoms (e.g., fever). Treatment comprises supportive skin and eye care and symptom control. 
  • Toxic epidermal necrolysis (TEN): a life-threatening immune-mediated hypersensitivity disease process that is an extension of SJS. Toxic epidermal necrolysis is an immune-mediated hypersensitivity reaction with mucocutaneous involvement (> 30% of body surface area). Mortality rate depends on severity in both SJS and TEN, at approximately 10% for SJS and up to 50% for TEN. Both conditions require admission to a burn unit for skin care.

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