Erythema multiforme (EM) was first described by Ferdinand von Hebra in 1860 as a benign, self-limited, symmetrical, polymorphous erythematous rash confined to the skin.¹,² In 1922, Stevens and Johnson³ described a severe acute febrile illness characterized as a new eruptive cutaneous disorder associated with stomatitis and ophthalmia. In 1950, Thomas⁴ combined these two entities as EM and suggested a division into two forms: EM minor (von Hebra) and EM major (Stevens-Johnson syndrome [SJS]) as distinct clinical forms along the same disease spectrum.⁵ Subsequently, the term SJS became considered to be a more severe form of EM.⁶

In 1956, Lyell⁷ described a clinical condition characterized by extensive epidermal loss, which he termed toxic epidermal necrolysis (TEN). Later studies showed that both SJS and TEN shared many characteristics, such as similar inciting drugs, the development of epidermal necrosis in more severe cases of SJS, and atypical cutaneous and mucosal target-like lesions.⁸,⁹,¹⁰ Subsequently, EM, SJS, and TEN were all considered to be variants along a clinical spectrum.¹¹

However, in 1993, based on the distribution of lesions, morphological criteria, and inciting factors, an international consensus classification defined five related severe bullous skin conditions that included the major form of EM, as well as SJS and TEN.¹² They proposed a novel classification with EM designated as a different entity from SJS/TEN, with its own etiology, pathophysiology, and clinical course. Later, pediatric EM was characterized as a separate entity, based on epidemiological, etiological, clinical, laboratory, and treatment characteristics.¹³

In EM, children are mostly affected and the inciting factor is predominantly infectious. In SJS and TEN, adults are most commonly affected, and inciting factors are usually drug related, although in children infectious causes are more frequent.¹⁴ Skin detachment is rare in EM but involves more than 30% of the body surface area in TEN. In EM, the typical skin lesions are raised, sharply demarcated, and target shaped with three concentric rings and are nonprogressive. In SJS and TEN, they are less well defined, flat, and atypical, with only two concentric rings around a central epidermal lesion, and may be confluent.¹² It is still unclear whether EM and SJS should be considered separate diseases or variations along a single disease spectrum. But since both have distinctive clinical characteristics, we will treat them in separate chapters in this volume.

EM is an acute, self-limited, or recurrent, immune-mediated disorder that affects the skin and mucous membranes.¹⁵,¹⁶,¹⁷,¹⁸ It is characterized by target or iris-shaped, erythematous papules, preferentially localized on the skin of the extremities and trunk.¹⁹,²⁰,²¹ Mucous membranes can also be involved, primarily seen on the oral mucosa and less frequently, the conjunctiva.

EM occurs worldwide with an estimated prevalence rate of 0.01% to 1%,¹⁷,²² and the disease can show a peak incidence in the spring or fall.²³ It affects patients at any age but is seen more frequently in young adults aged 20 to 40 years,¹⁵ with only about 20% of cases occurring in children.¹⁷,²⁴ The condition is slightly more common in women than in men with a M:F ratio of 1.5:1.¹⁵,²⁵

Clinically, EM is classified as EM minor and EM major based on the distribution of lesions, severity of the inflamation, and extent of mucosal involvement.²⁶,²⁷ EM minor is typically infectious in origin and is usually seen in young adults. Skin lesions occupy less than 10% of the body surface area and have a symmetric distribution mostly on the extensor (acral) surfaces of the extremities.¹⁵ Circular, erythematous plaques, 2 to 20 mm in size, are seen in a
concentric target-shaped pattern with three distinct rings. Mucosal lesions are uncommon. When present, they are seen only on a single mucosal area and are usually mild, occurring most often on the oral mucosa, gingiva, and palate, and on the vermilion border of the lips. The conjunctiva is very rarely involved. Occasionally, EM minor can be isolated to the oral mucosa alone, without skin involvement.¹⁵ Both skin and mucosal lesions usually heal without scarring within 1 to 4 weeks.

In EM major, two or more mucosal sites are severely involved, most often the oral, buccal, and labial mucosa as well as the conjunctiva.¹¹,²⁸ Less frequently, the floor of the mouth, palate, and gingiva are involved.¹⁵ Typical target skin lesions occupy less than 10% of the body but are larger than in EM minor. Mild systemic symptoms, such as fever or chills, may also be seen.