Erythema multiforme (EM) is a self-limited hypersensitivity reaction of the skin and mucous membranes characterized by the acute onset of fixed lesions of concentric color change (target lesions). Two subtypes exist: EM major and EM minor. Key differences between the EM subtypes include mucosal involvement and systemic symptoms such as fever, arthralgias, and asthenias seen in the major subtype. Prodromal symptoms occasionally can be associated.

Recurrent EM occurs in a subset of patients and has been variably defined as more than 1, more than 2, or more than 6 flares per year.

Persistent EM is uncommon and refers to chronic, continuous presence of EM or outbreaks separated by 15 days or less.

The primary trigger for EM is herpes simplex virus (HSV), which is estimated to incite about 90% of cases. EM has been reported with other infections including histoplasmosis, Epstein-Barr virus, and, most recently, COVID-19. Medication can also be a trigger. In children, important additional triggers to consider include drugs (particularly penicillin), group A Streptococcus, and Epstein-Barr virus, among other viruses and bacteria. Idiopathic cases have also been seen.

Typically, all cutaneous lesions appear within 24-72 hours and persist for 1-4 weeks before fading. The eruption recurs on repeated exposure to the inciting agent.

Related topic: reactive infectious mucocutaneous eruption (RIME)