What is the best management approach for erythema multiforme?

Management of Erythema Multiforme

Erythema multiforme is a self-limited immune-mediated condition requiring symptomatic treatment with topical corticosteroids or antihistamines, identification and treatment of the underlying trigger (most commonly herpes simplex virus or Mycoplasma pneumoniae), and prophylactic antiviral therapy for recurrent herpes-associated cases. 1

Critical Distinction from Stevens-Johnson Syndrome

Erythema multiforme is fundamentally different from Stevens-Johnson syndrome/toxic epidermal necrolysis and does not progress to these severe conditions 2. Key distinguishing features include:

• Erythema multiforme: Typical target lesions starting on acral surfaces (hands, feet, elbows, knees) progressing proximally; patients are constitutionally well; good recovery expected; rarely causes long-term complications 2
• Stevens-Johnson syndrome: Widespread erythematous or purpuric macules with blisters; significant mucosal involvement; systemic illness with potential multiorgan failure 2

This distinction is critical because misclassification leads to inappropriate management strategies 2.

Immediate Assessment and Workup

Rule Out Mycoplasma Pneumoniae Immediately

Test for Mycoplasma pneumoniae infection urgently, as this requires specific antibiotic treatment 3. This is particularly important in children, where M. pneumoniae is a common trigger 4, 5.

Identify the Triggering Agent

• Herpes simplex virus is the most common cause (23% of cases) 6, 4
• Mycoplasma pneumoniae, especially in pediatric patients 4, 3
• Other infections: Hepatitis C, Coxsackie virus, Epstein-Barr virus 4
• Medications: Allopurinol, phenobarbital, phenytoin, valproic acid, sulfonamides, penicillins, erythromycin, tetracyclines, NSAIDs, statins, TNF-α inhibitors 4
• Note: 58% of cases remain idiopathic despite thorough workup 6

Clinical Examination

• Skin lesions: Fixed target or iris lesions (lasting minimum 7 days, unlike urticaria which resolves within 24 hours) distributed symmetrically on extremities, especially extensor surfaces 1, 5
• Mucosal involvement: Present in 63% of cases, most commonly oral mucosa; assess severity of pain and ability to maintain oral intake 6, 1
• Constitutional symptoms: Patients are typically well, unlike Stevens-Johnson syndrome 2

Acute Management

Symptomatic Treatment

Topical corticosteroids are first-line for skin lesions 1. Apply to affected areas to reduce inflammation and pruritus.

Antihistamines for symptomatic relief of pruritus 1.

Systemic corticosteroids (prednisone) are indicated for severe erythema multiforme, particularly with extensive mucosal involvement 7, 6. In the Mayo Clinic series, 77% of patients with recurrent disease required systemic corticosteroids 6.

Severe Mucosal Involvement

Hospitalize patients who cannot maintain adequate oral intake due to severe oral mucosal involvement 1. Management includes:

• Intravenous fluids for hydration 1
• Electrolyte repletion 1
• Pain control to facilitate oral intake 1

Etiologic Treatment

If herpes simplex virus is identified: Treat the active infection with antivirals (acyclovir, valacyclovir, or famciclovir) 4, 3.

If Mycoplasma pneumoniae is identified: Initiate appropriate antibiotics immediately 3.

If medication-induced: Discontinue the offending agent 4.

Management of Recurrent Erythema Multiforme

First-Line: Prophylactic Antiviral Therapy

For herpes simplex virus-associated recurrent erythema multiforme, prescribe continuous antiviral therapy 1, 6. In the Mayo Clinic series, 16 of 33 patients (48%) receiving continuous antiviral treatment achieved partial or complete disease suppression 6.

Important caveat: Topical acyclovir prophylaxis does not prevent recurrences; systemic therapy is required 4. If one antiviral fails, switch to an alternative agent 4.

Second-Line: Immunosuppressive Therapy

When continuous antivirals fail or for non-herpes-associated recurrent disease:

Mycophenolate mofetil showed the best response in recalcitrant cases, with 6 of 8 patients achieving partial or complete response 6.

Dapsone may be considered in patients non-responsive to antivirals 4.

Novel agents: JAK inhibitors or apremilast have shown promise in case reports for refractory cases 4.

Features Predicting Recalcitrant Disease

Patients with the following characteristics often require more aggressive management 6:

• No identifiable cause despite thorough workup
• Lack of improvement with continuous antiviral therapy
• Severe oral involvement
• Need for extensive corticosteroid therapy
• Requirement for multiple immunosuppressive agents

Common Pitfalls to Avoid

Do not confuse erythema multiforme with Stevens-Johnson syndrome – this leads to inappropriate escalation of care and unnecessary anxiety about prognosis 2.

Do not rely on topical acyclovir for prevention of recurrent herpes-associated erythema multiforme – it is ineffective 4.

Do not miss Mycoplasma pneumoniae – this requires specific antibiotic treatment and is particularly common in children 3, 4.

Do not assume all cases are herpes-related – only 23% are HSV-associated, and 58% remain idiopathic despite workup 6.