Erythema Multiforme

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.

Classification

Erythema multiforme is classified based on the presence of mucosal lesions and systemic symptoms into EM minor and 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 3–5 days into papules → target 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

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)

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.