What are the causes of erythema multiforme?

Causes of Erythema Multiforme

Herpes simplex virus (HSV) infection is the most common cause of erythema multiforme, followed by medications, with many cases also triggered by other infections including Mycoplasma pneumoniae.

Primary Causes

Infectious Causes

• Herpes simplex virus (HSV) infection is the predominant cause of erythema multiforme (EM), especially in recurrent cases 1, 2
• Mycoplasma pneumoniae is another significant infectious trigger, particularly common in children 3, 4
• Other infectious agents that can trigger EM include:
  • Hepatitis C virus 1
  • Epstein-Barr virus 1
  • Coxsackie virus 1

Medication-Related Causes

• Medications represent the second most common identifiable cause of EM 1, 5
• Common medication triggers include:
  • Anticonvulsants (phenobarbital, phenytoin, valproic acid) 1
  • Antibiotics (sulfonamides, penicillins, erythromycin, tetracyclines) 1
  • Allopurinol 1
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) including acetylsalicylic acid 1, 6
  • Statins 1
  • TNF-α inhibitors (adalimumab, infliximab, etanercept) 1

Newer Reported Triggers

• Vaccinations have been reported as potential triggers 1
• Immunotherapy for melanoma 1
• Topical medications such as imiquimod 1
• Anticancer agents can cause toxic erythema that may resemble EM 3

Clinical Differentiation from Similar Conditions

Distinguishing EM from Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN)

• EM typically presents with typical target lesions or raised atypical targets, predominantly on limbs and extremities 3
• SJS/TEN presents with widespread purpuric macules or flat atypical targets 3
• EM is mostly related to HSV infection, while SJS/TEN is usually triggered by drugs 3
• EM has lower mortality and better prognosis compared to SJS/TEN 3

Histopathological Features

• EM shows variable epidermal damage ranging from individual cell apoptosis to confluent epidermal necrosis 3
• Epidermal changes are associated with basal cell vacuolar degeneration and subepidermal vesicle or bulla 3
• Histopathology helps exclude other blistering dermatoses that may mimic EM 3

Special Presentations

Atypical Manifestations

• Lichenoid or granulomatous lesions can occur in atypical EM 1
• Lesional infiltrates of T cell lymphoma and histiocytes may be present in some cases 1
• Mycoplasma-induced EM, especially in children, may present with predominantly mucous membrane involvement with little or no cutaneous lesions (termed "Mycoplasma pneumoniae-associated mucositis") 3

Idiopathic Cases

• A significant proportion of EM cases have no identifiable cause despite thorough investigation 5, 6
• Recurrent EM without identifiable triggers may require empiric treatment approaches 5

Diagnostic Approach

Key Diagnostic Criteria

• Typical clinical presentation with target lesions having concentric zones of color change 2
• Predominant acral distribution of lesions 1
• History of preceding HSV infection or medication exposure 2
• Histopathological confirmation when clinical diagnosis is uncertain 3

Differential Diagnosis

• Important conditions to rule out include urticaria, fixed drug eruption, bullous pemphigoid, paraneoplastic pemphigus, and cutaneous small-vessel vasculitis 2
• Table 1 in the UK guidelines provides a comprehensive list of differential diagnoses for SJS/TEN that may also apply to EM 3

Understanding the causes of erythema multiforme is essential for proper management, as treatment approaches differ based on the identified trigger, with HSV-associated cases potentially benefiting from antiviral prophylaxis for recurrent episodes 5, 2.