1866: Erythema Multiforme (EM) was first described by Ferdinand von Hebra
Definition: “multiforme” refers to various skin manifestations (although most patients have similar lesions at a specific point in time, morphology of lesions may vary between patients and may evolve over time in a single patient)
Epidemiology: association with Herpes Simplex Virus (HSV)
Clinical Features: acral (peripheral) skin lesion, consisting of target lesions, edematous papules, and/or plaques without mucosal involvement
1922: Stevens-Johnson Syndrome (SJS) was described a pediatric febrile mucocutaneous disorder with febrile erosive stomatitis, severe conjunctivitis, and disseminated cutaneous eruption
1948: first description of Toxic Epidermal Necrolysis (TEN)
1950: Thomas proposed the subclassification of EM
Erythema Multiforme Minor: acute, self-limited condition with characteristic red papular skin lesions
Erythema Multiforme Major: applied to patients who also displayed oral mucosal involvement
Note: this subset included patients with SJS/TEN (and some Dermatologists confusingly use this term and SJS/TEN interchangeably)
Current State of Understanding
Strong association between HSV and EM
SJS is more commonly associated with exogenous agents (such as drugs)
Studies of IL-13 and other cytokines suggest that SJS and TEN are related, while EM is a distinct disorder
Current Classification Schema (Based on 1993 Classification)
Hemorrhagic crusting of lips (also may be seen in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis, HSV, Pemphigus Vulgaris, and Paraneoplastic Pemphigus)
Dense superficial dermal lymphohistiocytic infiltrate around blood vessels and the dermoepidermal junction
Papillary dermal edema and red blood cell extravasation may be evident (especially in early lesions)
Subepidermal clefting and vesiculation (due to extensive basal cell vacuolar degeneration) are present in some specimens
Biopsy of Mucosal Lesions: similar histologic features to those of cutaneous lesions
More prominent spongiosis and intracellular edema and vesiculation may be present
Choice of Biopsy Site: may influence histopathology
While specimens from the dusky central portions of lesions may reveal subepidermal separation with necrotic keratinocytes, biopsies from the peripheral portions often show predominantly dermal changes, such as papillary dermal edema, vascular dilation, and a perivascular mononuclear cell infiltrate
Direct Immunofluorescence: usually non-specific (although one study found granular deposits of C3 and IgM at the dermoepidermal junction and around superficial dermal blood vessels, fibrin around dermal blood vessels and in a band-like distribution at the dermoepidermal junction in regions of necrosis or blister formation)
Direct and indirect immunofluorescence aid in the exlclusion of Bullous Pemphigoid and Paraneoplastic Pemphigus
Lack of Neutrophilic Infiltrate: aids in the exclusion of Sweet’s syndrome
Clinical
Prodromal Syndrome
Including fever/malaise/myalgias
Uncommon in mild EM, but may be seen in cases with mucosal involvement
Dermatologic Manifestations
Skin Lesions
Lesions often begin as round erythematous papules, which evolve into acrally (peripherally)-distributed target lesions on extensor surfaces of extremities -> spread centripetally
Lesions usually appear over 3-5 days and resolve within 2 weeks
Post-inflamatory hyperpigmentation may occur in some patients with dark skin (but scarring is usually not seen)
Note: target lesions are not necessary to make the diagnosis of EM
Typical Target Lesions (3 components): dusky central area or blister, dark red inflammatory zone surrounded by a pale ring of erythema, and an outer erythematous halo
Atypical Target Lesions: raised edematous lesions with two zones of color change and poorly defined border
Face/neck/palms/soles/trunk may also be involved
Lesions may cluster on elbows and knees
Lesions may occur at sites of trauma or sunburn
Erythema and swelling of nail folds may occur
Most lesions are asymptomatic, but some patients experience pruritus or burning
Limited Extent of Skin Detachment
Hemorrhagic Crusting of Lips: also may be seen in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis, Herpes-Simplex Virus, Pemphigus Vulgaris, and Paraneoplastic Pemphigus)
Mucosal Involvement (component of Erythema Multiforme Major): mucous membrane involvement usually occurs in association with skin lesions (however, there have been cases reported with isolated mucous membrane involvement)
Oral Lesions (common mucosal site, can be present in up to 70% of EM cases)
May onvolve vermilion lip, buccal mucosa, labial mucosa, non-attached gingiva, and tongue
Diagnosis: Laboratory abnormalities including hypocomplementemia and circulating immune complexes also can occur, but are not found in all affected patients
Clinical: widespread papulonecrotic or bullous lesions
Mucosal Lesions: variable
Recurrent Erythema Multiforme
Epidemiology
A subset of patients experience recurrent episodes of EM
Average Frequency of Recurrence: 6 episodes per year
Mean Duration of Disease: 6 to 10 years
Etiology
Benzoic Acid Ingestion: used as a preservative
Complex Aphthosis
Herpes Simplex Virus (61-100% of cases) (see Herpes Simplex Virus, [[Herpes Simplex Virus]])