What are the typical causes, clinical presentation, and first‑line management of erythema multiforme?

Erythema Multiforme: Causes, Clinical Presentation, and First-Line Management

Erythema multiforme is an immune-mediated mucocutaneous reaction most commonly triggered by herpes simplex virus infection, presenting with characteristic targetoid lesions on the extremities that persist for at least 7 days, and is managed primarily with topical corticosteroids and treatment of the underlying cause. 1, 2

Typical Causes

Infectious Triggers (Most Common)

• Herpes simplex virus (HSV) is the most frequent cause of erythema multiforme, particularly in recurrent cases 1, 3, 2
• Mycoplasma pneumoniae is another significant infectious trigger, especially common in children, and carries a better prognosis 1, 4
  • May present as "Mycoplasma pneumoniae-associated mucositis" with predominantly mucous membrane involvement and minimal cutaneous lesions 1, 5
• Other infectious agents include hepatitis C virus, Coxsackie virus, and Epstein-Barr virus 4

Drug-Induced (Second Most Common)

• Medications constitute the second most frequently identified cause 1, 3, 2
• Implicated drugs include allopurinol, phenobarbital, phenytoin, valproic acid, antibacterial sulfonamides (including trimethoprim-sulfamethoxazole), penicillins, erythromycin, tetracyclines, statins, and TNF-α inhibitors 4, 6
• Document all medications taken in the previous 2 months, including over-the-counter and complementary therapies 7

Other Triggers

• Vaccinations (including HPV vaccine) have been reported as triggering factors 4, 8
• Immunotherapy for melanoma and topical drugs like imiquimod 4

Clinical Presentation

Lesion Characteristics

• Target or "iris" lesions consisting of three zones: central dark papule/vesicle, pale intermediate zone, and erythematous outer halo 1, 5
• Lesions are characterized by dusky red and white concentric rings with well-defined circular appearance 1
• Individual lesions persist for a minimum of 7 days, distinguishing erythema multiforme from urticaria where lesions resolve within 24 hours 1, 7, 2

Distribution Pattern

• Lesions typically begin on ankles, wrists, or forearms, then spread to palms, soles, arms, legs, and trunk 1
• Predominantly affects limbs and extremities (especially extensor surfaces), most often sparing the face 1, 5, 2
• Mucous membrane involvement may occur in more severe cases 5, 2

Timing

• Typically appears 10 days after viral infection 1
• Median time to onset is 4 weeks but can range from 2 to 150 weeks 9

Critical Differentiation from Stevens-Johnson Syndrome/TEN

This differentiation is crucial as it impacts mortality and management:

• Erythema multiforme: Typical target lesions or raised atypical targets, predominantly on limbs/extremities, mostly HSV-related, mortality <5%, better prognosis 1, 5
• Stevens-Johnson syndrome/TEN: Flat atypical targets or purpuric macules with epidermal detachment, positive Nikolsky sign, usually drug-triggered, mortality 5%-30% 1, 5
• Immediately evaluate for signs of Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS syndrome as these require immediate ICI interruption and specialist treatment 9

First-Line Management

Immediate Actions

1. Discontinue any suspected culprit medications immediately if drug-induced erythema multiforme is suspected 7
2. Examine all mucosal sites for involvement and document extent of skin involvement 7
3. Apply emollients and skin moisturizers to affected areas 7

Symptomatic Treatment

• Topical corticosteroids (e.g., hydrocortisone cream) for symptomatic relief of skin lesions 7, 3, 2
• Oral antihistamines for pruritus 3, 2
• Antiseptic or anesthetic solutions for mucosal involvement 3

Treating the Underlying Cause

• For HSV-associated erythema multiforme: Treat active infection; consider prophylactic antiviral therapy for recurrent cases 3, 2
• For Mycoplasma pneumoniae: Appropriate antibiotic therapy 1
• For drug-induced cases: Immediate discontinuation of the culprit drug is essential 7, 5

Monitoring and Escalation

• Reassess after 2 weeks of treatment 7
• If worsening or no improvement, escalate therapy to systemic corticosteroids 7
• Severe mucosal involvement may require hospitalization for intravenous fluids and electrolyte repletion 2

Recurrent Erythema Multiforme

• Prophylactic antiviral therapy is first-line for HSV-associated recurrent cases 3, 2
• For patients non-responsive to antivirals, consider dapsone, immunosuppressive agents, or newer options like JAK-inhibitors or apremilast 3, 4

Common Pitfalls

• Avoid confusing with urticaria: Erythema multiforme lesions remain fixed for ≥7 days versus <24 hours for urticaria 1, 2
• Do not miss Stevens-Johnson syndrome/TEN: Look for widespread purpuric macules, epidermal detachment, and positive Nikolsky sign 1, 5
• Document lesion evolution: Photograph and mark borders to track progression 1
• Avoid excessive cooling measures: Limit to 10 minutes, 4 times daily maximum to prevent tissue damage 7