What are the causes of Erythema Multiforme (EM)?

From the Guidelines

Erythema multiforme is primarily caused by infections, with herpes simplex virus (HSV) being the most common trigger, and medications, including antibiotics and anticonvulsants. The condition is regarded as a reactive mucocutaneous disorder that is distinct from Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) 1. Infections such as Mycoplasma pneumoniae, Epstein-Barr virus, cytomegalovirus, and various bacterial infections can also trigger erythema multiforme. Medication-induced erythema multiforme commonly results from antibiotics (particularly sulfonamides, penicillins, and cephalosporins), anticonvulsants (phenytoin, carbamazepine, lamotrigine), and NSAIDs.

The pathophysiology involves a delayed hypersensitivity reaction where the body's immune system responds inappropriately to these triggers, leading to cytotoxic T-cell activation and inflammatory damage to the skin and mucous membranes. This immune dysregulation causes the characteristic target-like lesions on the skin. Less commonly, erythema multiforme can be triggered by vaccines, radiotherapy, autoimmune diseases, or malignancies. In some cases, no specific cause can be identified, and these are classified as idiopathic. It is essential to differentiate erythema multiforme from other skin conditions, such as erythema migrans, which is a characteristic lesion of Lyme disease 1.

Key points to consider in the diagnosis and management of erythema multiforme include:

• Identifying the underlying trigger, whether infectious or medication-related
• Recognizing the characteristic target-like lesions on the skin
• Distinguishing erythema multiforme from other skin conditions, such as SJS/TEN and erythema migrans
• Providing supportive care and treating the underlying cause, if identified.

From the FDA Drug Label

Allergic Reactions:Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis, allergic myocarditis, erythema multiforme, exfoliative dermatitis, angioedema, drug fever, chills, Henoch-Schoenlein purpura, serum sickness-like syndrome, generalized allergic reactions, generalized skin eruptions, photosensitivity, conjunctival and scleral injection, pruritus, urticaria, rash, periarteritis nodosa, systemic lupus erythematosus, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized erythematous pustulosis (AGEP), and acute febrile neutrophilic dermatosis (AFND) Dermatologic Diseases Pemphigus Bullous dermatitis herpetiformis Severe erythema multiforme (Stevens-Johnson syndrome)

Erythema multiforme is listed as an adverse reaction to sulfonamides 2 and as a condition that can be treated with prednisone 3. The exact cause of erythema multiforme is not specified in the provided drug labels. However, it is associated with drug reactions and allergic responses.

From the Research

Erythema Multiforme Causes

• Infections are a major cause of erythema multiforme, with herpes simplex virus being the most common cause 4, 5, 6, 7, 8
• Other infectious agents that may trigger erythema multiforme include:
  • Mycoplasma pneumoniae 4, 6, 7, 8
  • Hepatitis C virus 4
  • Coxsackie virus 4
  • Epstein Barr virus 4
• Drugs are the second most frequently identified cause of erythema multiforme, with examples including:
  • Allopurinol 4
  • Phenobarbital 4
  • Phenytoin 4
  • Valproic acid 4
  • Antibacterial sulfonamides 4
  • Penicillins 4
  • Erythromycin 4
  • Nitrofurantoin 4
  • Tetracyclines 4
  • Chlormezanone 4
  • Acetylsalicylic acid 4
  • Statins 4
  • TNF-α inhibitors such as adalimumab, infliximab, and etanercept 4
• Other potential causes of erythema multiforme include:
  • Vaccination 4
  • Immunotherapy for melanoma 4
  • Topical drugs like imiquimod 4
  • Autoimmune diseases 6