Treatment of Erythema Multiforme
For erythema multiforme, immediately discontinue any suspected culprit medications, apply topical corticosteroids (hydrocortisone cream) for symptomatic relief, and initiate antiviral prophylaxis if herpes simplex virus is the identified trigger. 1, 2
Immediate Assessment and Management
Discontinue all suspected medications immediately and document every medication taken in the previous 2 months, including over-the-counter drugs and complementary therapies. 1
Examine all mucosal sites (oral, ocular, genital) for involvement and document the extent of skin involvement, specifically noting the presence and distribution of target lesions. 1
Apply emollients and skin moisturizers to all affected areas as initial supportive care. 1
Treatment Algorithm by Severity
Mild to Moderate Disease (Skin-Predominant)
Topical corticosteroids (hydrocortisone cream) should be applied to skin lesions for symptomatic relief. 1 This represents first-line therapy for isolated cutaneous involvement. 2
Topical antihistamines can be added for pruritus control if needed. 2
Supportive care includes adequate hydration and monitoring for disease progression. 3
Severe Mucosal Involvement
Hospitalization is required when severe mucosal involvement compromises oral intake, requiring intravenous fluids and electrolyte repletion. 2
Systemic corticosteroids (prednisone) are indicated for severe erythema multiforme, as the FDA label specifically lists "severe erythema multiforme (Stevens-Johnson syndrome)" as an approved indication. 4 While the evidence base is limited, systemic corticosteroids are commonly used in clinical practice for severe cases. 5, 6
Antiseptic or anesthetic solutions should be used for symptomatic relief of oral mucosal lesions. 6
Etiologic-Specific Treatment
Herpes Simplex Virus-Associated EM
Prophylactic antiviral therapy is the cornerstone of management for recurrent HSV-associated erythema multiforme. 2, 7
Continuous antiviral treatment (acyclovir, valacyclovir, or famciclovir) provides partial or complete disease suppression in approximately 50% of patients. 5 However, topical prophylactic acyclovir does not prevent recurrent episodes. 7
If resistance develops to one antiviral agent, switch to an alternative antiviral medication. 7
Mycoplasma pneumoniae-Associated EM
Treat the underlying infection with appropriate antibiotics, particularly in pediatric patients where Mycoplasma is a common trigger. 7
Drug-Induced EM
Permanent avoidance of the implicated medication is essential. Common culprits include allopurinol, phenobarbital, phenytoin, valproic acid, sulfonamides, penicillins, and NSAIDs. 7
Recurrent Erythema Multiforme
First-Line Therapies
Continuous antiviral prophylaxis should be initiated even without confirmed HSV infection, as approximately 23% of recurrent cases are HSV-associated. 5
High-potency topical corticosteroids for cutaneous lesions. 6
Second-Line Therapies (Antiviral-Refractory Cases)
Mycophenolate mofetil provides partial or complete response in 75% of patients (6 of 8) who fail antiviral therapy, making it the preferred second-line immunosuppressant. 5
Dapsone should be considered in patients non-responsive to antiviral agents. 7
Novel agents including JAK inhibitors or apremilast may be considered for refractory cases, though evidence is limited. 7
Systemic corticosteroids are frequently used (77% of patients in one series) but should not be relied upon as monotherapy due to side effect profile with chronic use. 5
Follow-Up and Monitoring
Reassess after 2 weeks of treatment. If the condition is worsening or showing no improvement, escalate therapy to the next level. 1
Monitor for recurrence patterns to identify triggers and optimize prophylactic strategies. 5
Critical Patient Counseling Points
Avoid ice water immersion and continuous fan use despite the temptation to cool affected areas, as these can cause tissue damage, ulcerations, and paradoxical worsening of symptoms. 8 Limit cooling measures to 10 minutes, 4 times daily maximum. 8
Individual lesions persist for at least 7 days, distinguishing EM from urticaria where lesions resolve within 24 hours. 2 This helps patients understand the expected disease course.
The condition is self-limiting in most acute cases, typically resolving within 2-4 weeks with appropriate treatment. 3
Recurrent disease affects approximately 20-25% of patients, particularly those with HSV association, requiring long-term prophylactic strategies. 5
Common Pitfalls
Do not confuse EM with Stevens-Johnson syndrome. SJS presents with widespread erythematous or purpuric macules with blisters and more extensive mucosal involvement, representing a more severe condition requiring different management. 2
Recalcitrant cases are characterized by inability to identify a specific cause, lack of improvement with continuous antiviral therapy, severe oral involvement, and requirement for multiple immunosuppressive agents. 5 These patients warrant early referral to dermatology.
More than half of recurrent EM cases have no identifiable cause, and HSV is found less frequently than historically reported, so empiric antiviral therapy may not always be successful. 5