Stevens-Johnson Syndrome

First described in 1922, Stevens-Johnson syndrome (SJS) is an immune-complex–mediated hypersensitivity complex that is a severe expression of erythema multiforme. It is known by some as erythema multiforme major, but disagreement exists in the literature. Most authors and experts consider Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) different manifestations of the same disease. For that reason, many refer to the entity as SJS/TEN. SJS typically involves the skin and the mucous membranes. While minor presentations may occur, significant involvement of oral, nasal, eye, vaginal, urethral, GI, and lower respiratory tract mucous membranes may develop in the course of the illness. GI and respiratory involvement may progress to necrosis. SJS is a serious systemic disorder with the potential for severe morbidity and even death. Missed diagnosis is common.
Although several classification schemes have been reported, the simplest breaks the disease down as follows:¹

• Stevens-Johnson syndrome - A "minor form of TEN," with less than 10% body surface area (BSA) detachment
• Overlapping Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) - Detachment of 10-30% BSA
• Toxic epidermal necrolysis - Detachment of more than 30% BSA

Pathophysiology

Stevens-Johnson syndrome is an immune-complex–mediated hypersensitivity disorder that may be caused by many drugs, viral infections, and malignancies. Cocaine recently has been added to the list of drugs capable of producing the syndrome. Additionally, the antidepressant mirtazapine and tumor necrosis factor (TNF) – alpha antagonists infliximab, etanercept, and adalimumab have been reported as causes. In up to half of cases, no specific etiology has been identified.
Although not currently relevant to the practice of emergency medicine, research into the pathophysiology of SJS/TEN may soon allow for the development of tests to aid in the diagnosis as well as to identify those at risk.  

Pathologically, cell death results causing separation of the epidermis from the dermis. The death receptor, Fas, and its ligand, FasL, have been linked to the process, as has TNF-alpha. Researchers have found increased soluble FasL levels in the sera of patients with SJS/TEN before skin detachment or inset of mucosal lesions.²

Others have also linked inflammatory cytokines to the pathogenesis.

A "killer effector molecule" has been identified that may play a role in the activation of cytotoxic lymphocytes.³

There is also strong evidence for a genetic predisposition to severe cutaneous adverse drug reactions such as SJS. The US FDA and Health Canada advise screening for a human leukocyte antigen, HLA-B*1502, in patients of southeastern Asian ethnicity before starting treatment with carbamazepine. (The risk is much lower in other ethnic populations, making screening impractical in them). Another HLA antigen, HLA-B*5801, confers a risk of allopurinol-related reactions. Pretreatment screening is not readily available.⁴

Frequency

United States

Cases tend to have a propensity for the early spring and winter.

For overlapping SJS and TEN, oxicam NSAIDs (piroxicam, meloxicam, tenoxicam) and sulfonamides are most commonly implicated in the United States and other western nations.⁴

International

SJS occurs with a worldwide distribution similar in etiology and occurrence to that in the United States.

In contrast to the drugs most often implicated in western nations, allopurinol is the most common offending agent in Southeast Asian nations, including Malaysia, Singapore, Taiwan, and Hong Kong.⁴

Mortality/Morbidity

• Mortality is determined primarily by the extent of skin sloughing. When BSA sloughing is less than 10%, the mortality rate is approximately 1-5%. However, when more than 30% BSA sloughing is present, the mortality rate is between 25% and 35%, and may be as high as 50%.^5,4 Bacteremia/sepsis may also contribute to mortality.⁶
• See SCORTEN for a more complete discussion of severity of illness and mortality.
• Lesions may continue to erupt in crops for as long as 2-3 weeks. Mucosal pseudomembrane formation may lead to mucosal scarring and loss of function of the involved organ system. Esophageal strictures may occur when extensive involvement of the esophagus exists. Mucosal shedding in the tracheobronchial tree may lead to respiratory failure.
• Ocular sequelae may include corneal ulceration and anterior uveitis. Blindness may develop secondary to severe keratitis or panophthalmitis in 3-10% of patients. Vaginal stenosis and penile scarring have been reported. Renal complications are rare.