Management of Erythema Multiforme
Immediately discontinue any suspected culprit medications and initiate topical corticosteroids for symptomatic relief, with emollients as first-line therapy for most cases. 1
Initial Assessment and Immediate Actions
Document all medications taken in the previous 2 months, including over-the-counter and complementary therapies, as drugs are the second most common cause after infections 1, 2. Stop any suspected causative medications immediately 1.
Examine all mucosal sites and document the extent of skin involvement, specifically looking for typical target lesions starting on acral surfaces (hands, feet) progressing proximally 1, 3. This distribution pattern helps distinguish EM from other conditions 4.
Distinguish EM from Stevens-Johnson syndrome (SJS), as these require completely different management approaches 3. EM presents with discrete targetoid lesions and patients remain constitutionally well, whereas SJS shows widespread erythematous or purpuric macules with blisters and systemic illness 3, 4. Critically, EM does not progress to SJS/TEN 3.
First-Line Treatment Algorithm
For Acute EM (Single Episode)
Apply topical corticosteroids such as hydrocortisone cream to affected skin areas for symptomatic relief 1, 5. High-potency topical corticosteroids are recommended for more severe cutaneous involvement 5.
Use emollients and skin moisturizers liberally to all affected areas 1. This forms the foundation of supportive care 5.
Consider topical antihistamines for pruritus if present 5, 4.
For mucosal involvement, use antiseptic or anesthetic solutions for symptomatic relief 5. Severe mucosal disease may require hospitalization for intravenous fluids and electrolyte repletion 4.
For Recurrent EM
Initiate prophylactic antiviral therapy if herpes simplex virus (HSV) is the identified trigger, as HSV is the most common cause of recurrent EM 5, 2. However, evidence shows variable response: only 16 of 33 patients (48%) achieved partial or complete disease suppression with continuous antiviral treatment 6.
If antiviral therapy fails after adequate trial, consider switching to an alternative antiviral agent before abandoning this approach 2. Topical acyclovir prophylaxis does not prevent further episodes 2.
Second-Line Therapies for Refractory Cases
Mycophenolate mofetil demonstrated the best response among immunosuppressants, with 6 of 8 patients (75%) achieving partial or complete response 6. This represents the strongest evidence for second-line therapy in recalcitrant cases.
Dapsone may be considered in patients non-responsive to antiviral agents 2.
Systemic corticosteroids are frequently used (77% of patients in one series), though evidence for efficacy is limited and should not be first-line for mild disease 6.
Newer agents including JAK-inhibitors and apremilast have been reported as potential options for resistant cases, though evidence remains limited 2.
Monitoring Protocol
Reassess after 2 weeks of treatment 1. If worsening or no improvement occurs, escalate therapy according to the algorithm above 1.
Individual lesions remain fixed for minimum 7 days, which helps differentiate EM from urticaria where lesions resolve within 24 hours 4. This timeline guides expectations for treatment response.
Common Pitfalls to Avoid
Do not confuse EM with SJS/TEN, as this leads to inappropriate escalation of care 3, 4. EM patients remain constitutionally well and make good recovery without specialized burn unit care 3.
Do not rely solely on antiviral prophylaxis for recurrent EM - more than half of recurrent EM cases have no identifiable cause, and HSV is found less frequently than historically reported 6. In one series, 58% had unknown etiology and only 23% were HSV-related 6.
Recognize features predicting recalcitrant disease: inability to identify specific cause, lack of improvement with continuous antiviral therapy, severe oral involvement, and need for multiple immunosuppressive agents 6. These patients may require earlier escalation to immunosuppressive therapy.
Consider non-HSV infectious triggers, particularly Mycoplasma pneumoniae in children, as well as hepatitis C, Coxsackie virus, and Epstein-Barr virus 2, 7. Treatment should target the identified pathogen.