Pathogenesis

The pathogenesis of EM is unclear, but it may be a host-specific, cell-mediated immune response to an antigenic stimulus, resulting in damage to keratinocytes. HSV Pol1 gene expressed in HA-EM lesions upregulates/activates the transcription factor SP1 and inflammatory cytokines. These cytokines, released by activated mononuclear cells and keratinocytes, may contribute to epidermal cell death and constitutional symptoms.

Pathology

Microscopic findings in EM are variable but may aid in diagnosis. Early lesions typically show slight intercellular edema, rare dyskeratotic keratinocytes, and basal vacuolation in the epidermis and a perivascular lymphohistiocytic infiltrate with edema in the upper dermis. More mature lesions show an accentuation of these characteristics and the development of lymphocytic exocytosis and an intense, perivascular, and interstitial mononuclear infiltrate in the upper third of the dermis. In severe cases, the entire epidermis becomes necrotic.

Differential Diagnosis

The differential diagnosis of EM also includes bullous pemphigoid, pemphigus, linear immunoglobulin (Ig) A dermatosis, graft versus host disease, bullous drug eruption, urticaria, viral infections such as HSV, reactive arthritis syndromes, Kawasaki disease, Behçet disease, allergic vasculitis, erythema annulare centrifugum, and periarteritis nodosa. EM that primarily involves the oral mucosa may be confused with bullous pemphigoid, pemphigus vulgaris, vesiculobullous or erosive lichen planus, Behçet syndrome, recurrent aphthous stomatitis, and primary herpetic gingivostomatitis. Serum sickness-like reaction (SSLR) to cefaclor may also manifest as EM-like lesions; the lesions may develop a dusky to purple center, but in most cases, the eruption of cefaclor-induced SSLR is pruritic, transient, and migratory and is probably urticarial rather than true EM.

Treatment

Treatment of EM is supportive. Topical emollients, systemic antihistamines, and nonsteroidal anti-inflammatory agents do not alter the course of the disease but may provide symptomatic relief. No controlled, prospective studies support the use of corticosteroids in the management of EM. Rather, glucocorticoid therapy may be permissive of HSV replication and make EM episodes more frequent or continuous. Prophylactic oral acyclovir given for 6 mo may be effective in controlling recurrent episodes of HSV-associated EM. On discontinuation of acyclovir, both HSV and EM may recur, although episodes may be less frequent and milder.

Clinical Manifestations

Cutaneous lesions in Stevens-Johnson syndrome generally consist initially of erythematous macules that rapidly and variably develop central necrosis to form vesicles, bullae, and areas of denudation on the face, trunk, and extremities. The skin lesions are typically more widespread than in EM and are accompanied by involvement of two or more mucosal surfaces, namely the eyes, oral cavity, upper airway or esophagus, gastrointestinal tract, or anogenital mucosa (Fig. 646-3). A burning sensation, edema, and erythema of the lips and buccal mucosa are often the presenting signs, followed by development of bullae, ulceration, and hemorrhagic crusting. Lesions may be preceded by a flu-like upper respiratory illness. Pain from mucosal ulceration is often severe, but skin tenderness is minimal to absent in Stevens-Johnson syndrome, in contrast to pain in toxic epidermal necrolysis. Corneal ulceration, anterior uveitis, panophthalmitis, bronchitis, pneumonitis, myocarditis, hepatitis, enterocolitis, polyarthritis, hematuria, and acute tubular necrosis leading to renal failure may occur. Disseminated cutaneous bullae and erosions may result in increased insensible fluid loss and a high risk of bacterial superinfection and sepsis. New lesions occur in crops, and complete healing may take 4-6 wk; ocular scarring, visual impairment, and strictures of the esophagus, bronchi, vagina, urethra, or anus may remain. Nonspecific laboratory abnormalities in Stevens-Johnson syndrome include leukocytosis, elevated erythrocyte sedimentation rate, and, occasionally, increased liver transaminase levels and decreased serum albumin values. Toxic epidermal necrolysis is the most severe disorder in the clinical spectrum of the disease, involving considerable constitutional toxicity and extensive necrolysis of the mucous membranes and > 30% of the body surface area (Fig. 646-4).

Figure 646-3 Bullae are present on the conjunctivae (A) and in the mouth (B) with Stevens-Johnson syndrome. Sloughing, ulceration, and necrosis in the oral cavity interfere with eating (C). Genital lesions cause dysuria and interfere with voiding.

(From Habif TP, editor: Clinical dermatology, ed 4, Philadelphia, 2004, Mosby, p 631.)

Figure 646-4 A, Large sheets of full-thickness epidermis are shed. B, Toxic epidermal necrolysis begins with diffuse, hot erythema. In hours the skin becomes painful, and with slight thumb pressure, the skin wrinkles, slides laterally, and separates from the dermis (Nikolsky sign).

(From Habif TP, editor: Clinical dermatology, ed 4, Philadelphia, 2004, Mosby, p 633.)

Pathogenesis

Pathogenesis is related to drug-specific CD8+ cytotoxic T cells, with perforin/granzyme B and granulysin triggering keratinocyte apoptosis. This process is followed by expanded enactment of apoptosis involving the interaction of soluble Fas ligand with Fas receptor.

Differential Diagnosis

The differential diagnosis of Stevens-Johnson syndrome includes toxic epidermal necrolysis, urticaria, DRESS (drug rash [or reaction] with eosinophilia and systemic symptoms) syndrome (Chapter 637.2) and other drug eruptions and viral exanthems, including Kawasaki disease.

Treatment