Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are mucocutaneous drug-induced or idiopathic reaction patterns characterized by skin tenderness and erythema of skin and mucosa, followed by extensive cutaneous and mucosal epidermal necrosis and sloughing. They are potentially life-threatening due to multisystem involvement. Synonym: TEN: Lyell's syndrome.

Definition Not clearly defined. SJS is considered by most a maximal variant of EM (major) and TEN a maximal variant of SJS. Both can start with target-like lesions; however, about 50% of TEN cases do not, and in these the condition evolves from diffuse erythema to immediate necrosis and epidermal detachment. SJS <10% epidermal detachment SJS/TEN overlap 10% to 30% epidermal detachment. TEN >30% epidermal detachment.

Epidemiology Age of Onset Any age, but most common in adults >40 years. Equal sex incidence. Overall Incidence TEN: 0.4 to 1.2 per million person-years. SJS: 1.2 to 6 per million person-years. Risk Factors Systemic lupus erythematosus, HLA-B12, HIV disease.

Etiology and Pathogenesis Polyetiologic reaction pattern, but drugs are clearly the leading causative factor. TEN: 80% of cases have strong association with specific medication (Table 7-2); <5% of patients report no drug use. Also: chemicals, Mycoplasma pneumonia, viral infections, immunization. SJS: 50% are associated with drug exposure; etiology often not clear-cut.

Table 7-2 Drugs Associated with Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Drugs Most Frequently Associated* Sulfadoxine Sulfadiazine Sulfasalazine Co-trimoxazole Hydantoins Carbamazepine Barbiturates Benoxaprofen Phenylbutazone Isoxicam Piroxicam Chlormezanone Allopurinol Amithiozone Aminopenicillins

Drugs Also Associated Cephalosporins Fluoroquinolones Vancomycin Rifampin Ethambutol Fenbufen Tenoxicam Tiaprofenic acid Diclofenac Sulindac Ibuprofen Ketoprofen Naproxen Thiabendazole

Together these drugs account for approximately two-thirds of the cases attributed to drugs in large series in France, Germany, and the United States. This drug is no longer marketed.
SOURCE:

JC Roujeau et al: N Engl J Med 331:1272, 1994.

Pathogenesis of SJS-TEN is only partially understood. It is viewed as a cytotoxic immune reaction aimed at the destruction of keratinocytes expressing foreign (drug-related) antigens. Epidermal injury is based on the induction of apoptosis. Drug-specific activation of T cells has been shown in vitro on peripheral blood mononuclear cells of patients with drug eruptions. The nature of the antigens that drive the cytotoxic cellular immune reaction is not well understood. Drugs or their metabolites act as haptens and render keratinocytes antigenic by binding to their surfaces. Cutaneous drug eruptions have been linked to a defect of the detoxification systems of liver and skin, which results in direct toxicity or alteration of antigenic properties of keratinocytes. Cytokines produced by activated mononuclear cells and keratinocytes probably contribute to local cell death, fever, and malaise.

History Time from first drug exposure to onset of symptoms: 1 to 3 weeks. Occurs more rapidly with rechallenge. Occurs after days of ingestion of the drug; newly added drug is most suspect. Prodromes: fever, influenza-like symptoms 1 to 3 days prior to mucocutaneous lesions. Mild to moderate skin tenderness, conjunctival burning or itching, then skin pain, burning sensation, tenderness, paresthesia. Mouth lesions are painful, tender. Impaired alimentation, photophobia, painful micturition, anxiety.

Physical Examination Skin Lesions Prodromal Rash Is morbilliform, EM-like; diffuse erythema (Fig. 7-23). Figure 7-23

Stevens-Johnson syndrome Generalized eruption of lesions that initially had a target-like appearance but then became confluent, brightly erythematous, showed a crinkled surface and became bullous. If these lesions are touched, the epidermis will be dislodged and erosions will appear (Nikolsky sign). The patient had extensive mucous membrane involvement and tracheobronchitis. Early Necrotic epidermis first appears as macular areas with crinkled surface that enlarge and coalesce (Fig. 7-23). Sheetlike loss of epidermis. Raised flaccid blisters (Figs. 7-23 and 7-24) that spread with lateral pressure (Nikolsky sign) on erythematous areas. With trauma, full-thickness epidermal detachment yields exposed, red, oozing dermis (Fig. 7-24) resembling a second-degree thermal burn. Figure 7-24

Toxic epidermal necrolysis Generalized, macular eruption with some target-like lesions which rapidly developed epidermal necrosis, positive Nikolsky sign, bulla formation, and denuded erosive areas. On the back this eruption looks like scalding. It was due to a sulfonamide.

Recovery Regrowth of epidermis begins within days; completed in 3 weeks. Pressure points and periorificial sites exhibit delayed healing. Skin that is not denuded acutely is shed in sheets, especially palms/soles. Nails and cilia may shed. Distribution Initial erythema on face, extremities, becoming confluent over a few hours or days. Epidermal sloughing may be generalized, resulting in large denuded areas (Fig. 7-24). Scalp, palms, soles may be less severely involved or spared. SJS: widely distributed with prominent involvement of trunk and face. TEN: generalized, universal (Fig. 7-24). Mucous Membranes 90% of patients have mucosal lesions, i.e., erythema, painful erosions: lips, buccal mucosa, conjunctiva, genital and anal skin. Eyes 85% have conjunctival lesions: hyperemia, pseudomembrane formation; synechiae between eyelids and conjunctiva; keratitis, corneal erosions. Hair and Nails Eyelashes and nails may be shed in TEN.

General Findings Fever usually higher in TEN (>38C) than in SJS. Usually mentally alert. In distress due to severe pain. Tubular necrosis. Acute renal failure; erosions in lower respiratory tract, gut. Epithelial erosions of trachea, bronchi, gastrointestinal (GI) tract.

Laboratory Examinations Hematology Anemia, lymphopenia; eosino-philia uncommon. Neutropenia correlates with poor prognosis.

Dermatopathology Early Vacuolization/necrosis of basal keratinocytes and individual cell necrosis throughout the epidermis. Late Full-thickness epidermal necrosis and detachment with formation of subepidermal split above basement membrane. Little or no inflammatory infiltrate in dermis. Immunofluorescence studies unremarkable, ruling out other blistering disorders.

Diagnosis and Differential Diagnosis Early Exanthematous drug eruptions, EM major, scarlet fever, phototoxic eruptions, toxic shock syndrome, GVHD. Fully Evolved EM major (see typical target-like lesions, predominantly on extremities), GVHD (may mimic TEN; less mucosal involvement), thermal burns, phototoxic reactions, staphylococcal scaldedskin syndrome (in young children, rare in adults), generalized bullous fixed drug eruption, exfoliative dermatitis.

Course and Prognosis Average duration of progression is <4 days. Course similar to that of extensive thermal burns. Prognosis related to extent of skin necrosis. Transcutaneous fluid loss large and varies with area of denudation; associated electrolyte abnormalities. Prerenal azotemia common. Bacterial colonization common and associated with sepsis. Other complications include hypermetabolic state and diffuse interstitial pneumonitis. Mortality rate for TEN is 30%, mainly in elderly; for SJS, 5%. Mortality related to sepsis, GI hemorrhage, fluid/electrolyte imbalance. If the patient survives the first episode of SJS or TEN, reexposure to the causative drug may be followed by recurrence within hours to days, more severe than the initial episode.

Sequelae Skin: Scarring, irregular pigmentation, eruptive nevomelanocytic nevi, abnormal regrowth of nails. Eyes: Common, including Sjgren-like sicca syndrome with deficiency of mucin in tears; entropion, trichiasis, squamous metaplasia, neovascularization of conjunctiva and cornea; symblepharon, punctate keratitis, corneal scarring; persistent photophobia, burning eyes, visual impairment, blindness. Anogenitalia: Phimosis, vaginal synechiae.

Management Acute SJS/TEN Early diagnosis and withdrawal of suspected drug(s) are very important. Patients are best cared for in an intermediate or intensive care unit. Manage replacement of IV fluids and electrolytes as for patient with a third-degree thermal burn. Systemic glucocorticoids early in the disease are reported helpful in reducing morbidity or mortality but this has not been proven. Some claim beneficial effects, particularly if glucocorticoids are given in high doses and early. High-dose IV immunoglobulins halt progression of TEN if administered early. Pentoxifylline IV by continuous drip early on in the eruption has been anecdotally reported to be beneficial. With oropharyngeal involvement, suction frequently to prevent aspiration pneumonitis. Debride only frankly necrotic skin. Diagnose and treat complicating infections, including sepsis (fever, hypotension, change in mental status). Treat eye lesions early with erythromycin ointment. Prevention The patient must be aware of the likely offending drug and that other drugs of the same class can cross-react. These drugs must never be readministered. Patient should wear a medical alert bracelet.