DESCRIPTION

• Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe, potentially fatal, mucocutaneous reactions, typically caused by medications. Clinically, they are characterized by epidermal necrosis involving skin and at least two mucous membranes.
• The cutaneous necrosis leads to widespread epidermal detachment and loss of skin barrier function.
• Given the potential risk for infection and fluid and electrolyte imbalances with widespread denudation, SJS and TEN are considered medical emergencies.

EPIDEMIOLOGY

• Overall annual risk of 0.5 to 1.9 per million in the general population
• The precise incidence in children is unknown.
• Patients with HIV have a 1,000-fold increased risk.

ETIOLOGY

• <5% of cases have no known cause.
• Medications
  • >100 medications have been implicated in causing SJS/TEN.
  • High-risk drugs include aromatic amine anticonvulsants such as carbamazepine, phenobarbital and phenytoin, lamotrigine, β-lactam antibiotics, sulfa medications (including trimethoprim-sulfamethoxazole and sulfasalazine), minocycline, cephalosporins, quinolones, nonsteroidal anti-inflammatory drugs (NSAIDs) (especially peroxicam and meloxicam), allopurinol, and nevirapine. Lamotrigine has an up-titration dosing schedule to reduce the risk for SJS/TEN.
• Acetaminophen (very rare)
  • The U.S. Food and Drug Administration (FDA) issued a warning about the risk of acetaminophen-related SJS/TEN.
  • Although SJS/TEN is a very rare occurrence in patients taking acetaminophen, the ubiquity of acetaminophen in prescription and over the counter products prompted the requirement for new labeling.
• A greater risk of developing SJS/TEN is seen in the first 8 weeks of treatment with these medications, with the highest risk being 1 to 3 weeks after exposure.
• There is scant evidence that vaccines, neoplastic syndromes, and autoimmune disease such as systemic lupus erythematosus (SLE) may play a role in etiology.
• Distinction should be made between drug-induced epidermal necrolysis (DEN) and reactive infectious mucocutaneous eruption (RIME). RIME refers to reactive mucocutaneous eruptions due to an infectious trigger. Clinically, RIME tends to display a paucity of skin lesions but impressive mucositis, usually in the setting of preceding upper respiratory tract symptoms. The clinical course tends to be less severe as compared to DEN.

RISK FACTORS

• Exposure to inciting medications
• Infection with HIV
• Genetic background
• Coexistence of cancer
• Concomitant radiotherapy

GENERAL PREVENTION

Once SJS/TEN has occurred, the inciting medication and any cross-reacting medications should be avoided.

PATHOPHYSIOLOGY

• Widespread keratinocyte and mucosal cell death occurs secondary to CD8+ T-cell–mediated apoptosis via Fas and Fas ligand pathways and/or direct granulysin secretion. Fas receptors are located on keratinocytes and, when activated with Fas ligand, induce apoptosis and therefore necrosis of epidermal cells. Granulysin is released from cytotoxic T cells and induces apoptosis by creating holes in target cell membranes.
• The exact mechanism by which the implicated drug or infection triggers activation of cytotoxic T cells, and the upregulation of the Fas and Fas ligand pathway is unknown.
• Soluble Fas ligand is increased in patients with SJS/TEN.