• Self-limited, but potentially recurrent, disease.

• Two forms: erythema multiforme (EM) major and EM minor (Table 16.1).

• Both forms have an abrupt onset of papular ‘target’ lesions that favor acrofacial sites.

• Two types of target lesions: (1) typical targets, with at least three different zones; (2) atypical papular targets, with only two different zones and/or a poorly defined border (Fig. 16.1).

• EM minor: typical > atypical papular target lesions, little or no mucosal involvement, and no systemic symptoms.

• EM major: typical > atypical papular target lesions, moderate to severe mucosal involvement, and some systemic symptoms (fever, asthenia, arthralgia).

• Preceding HSV infection is most common precipitating factor; less often other preceding infections, in particular Mycoplasma pneumoniae (Table 16.2; Fig. 16.2); rarely drug exposure.

• Diagnosis based on clinicopathologic correlation and not solely histopathologic findings.

• EM is a distinct disorder from Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) (see Table 16.1).

• EM does not progress to TEN.

• DDx: giant urticaria (Fig. 16.3; Table 16.3), morbilliform drug reaction (Fig. 16.4), multiple fixed drug eruption (FDE), acute hemorrhagic edema of infancy, Kawasaki disease, small vessel vasculitis, Rowell’s syndrome, GVHD, polymorphic light eruption (PMLE).

• Rx mild disease: symptomatic and supportive care, treat underlying infection if detected, ophthalmology consultation if ocular involvement.

• Rx recurrent disease: oral antiviral drug as prophylaxis for HSV infections, administered for at least 6 months (acyclovir 10 mg/kg/day, valacyclovir 500–1000 mg/day, or famciclovir 250 mg BID).

• Rx severe recurrent disease or failure to respond to prophylactic (anti-HSV) treatment: double the antiviral dose and if this fails, then consider referral to a dermatologist for possible immunosuppressive treatment.

• SJS and TEN are considered the same disease, but along a clinical spectrum of severity and distinct from EM (see Table 16.1).

• Most likely etiology for both is an adverse reaction to a medication.

• Most common culprit drugs (Table 16.4): NSAIDs, antibiotics (in particular, sulfonamides and penicillins), anticonvulsants, and allopurinol.

• In some patients there may be an underlying genetic predisposition, e.g.

– Allopurinol-induced SJS/TEN associated with HLA-B*58:01 allele.

– Carbamazepine-induced SJS associated with HLA-B*15:02 in Asian populations.

– Carbamazepine-induced SJS associated with HLA-A*31:01 allele in Europeans.

• HLA screening in these at-risk populations prior to beginning these medications has been shown to reduce SJS–TEN risk and has opened the door for the future identification of additional genetic risks.

• Mucocutaneous tenderness, erythema, and varying degrees of epidermal detachment are characteristic features.

• SJS is characterized by <10% body surface area (BSA) epidermal detachment, SJS–TEN overlap by 10–30% BSA epidermal detachment, and TEN by >30% BSA epidermal detachment (Fig. 16.5).

• Onset usually 7–21 days after starting culprit medication.

• Symptoms that typically precede skin findings by 1–3 days: prodromal flu-like syndrome, sore throat, fever, painful skin.

• Tender cutaneous lesions most prominent on trunk, followed by extension to face, neck, proximal extremities.

• Painful erythema and erosions of buccal, ocular, and genital mucosa in >90% of patients (Fig. 16.6).

• Morphologic progression of skin lesions: dusky red or purpuric macules (macular atypical targets) of various sizes and shapes that begin to coalesce (Fig. 16.7); the gray-colored centers become wrinkled and begin to slough due to the development of flaccid bullae and poor attachment of the necrotic epidermis (likened to wet cigarette paper) (Fig. 16.8); the result is raw, denuded, bright red dermis (scalding) (Fig. 16.9).

• Additional systemic findings: fever, lymphadenopathy, hepatitis, cytopenias, erosions of epithelium in the gastrointestinal and respiratory tracts.

• Unpredictable course; worse prognosis in the elderly and with increasing BSA involvement (Table 16.5).

• Mortality rate in SJS is 1–5% and in TEN, 25–35%.

• Most important factor in improving outcome is withdrawal of culprit medication.

• Epidermal detachment is due to extensive keratinocyte death via apoptosis, which is mediated by interaction of the death receptor-ligand pair Fas–Fas ligand; perforin, granzyme B, and granulysin also play a role.

• DDx: EM, drug-induced linear IgA bullous dermatosis (LABD), acute generalized exanthematous pustulosis (AGEP), severe acute GVHD, Rowell’s syndrome, paraneoplastic pemphigus; in children can consider staphylococcal scalded skin syndrome (SSSS) and Kawasaki disease.

• Rx: stop the culprit medication, rapid initiation of supportive care, specific therapy (no evidence-based treatment) (Fig. 16.10).

• Specific therapies that have the potential to block keratinocyte apoptosis, such as IVIg, may provide added benefit over supportive care (Fig. 16.11).