Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)

Medications precipitate most cases of SJS and TEN in adults. The most common medications precipitating SJS and TEN include:

• Sulfonamide antibiotics (eg, sulfasalazine)

• Other antibiotics (eg, aminopenicillins [usually ampicillin or amoxicillin], fluoroquinolones, cephalosporins)

• Antiseizure medications (eg, phenytoin, carbamazepine, phenobarbital, valproic acid and its derivatives, lamotrigine)

• Nonsteroidal anti-inflammatory drugs (eg, piroxicam, meloxicam)

• Antiretroviral medications (eg, nevirapine)

• Miscellaneous individual medications (eg, allopurinol, chlormezanone)

• Immune checkpoint inhibitors (1)

Cases that are not caused by medications are attributed to:

• Infection (mostly with Mycoplasma pneumoniae)

• Vaccination

• Graft-vs-host disease

In children with Stevens-Johnson syndrome, an infection is the most likely cause, and most of those are related to M. pneumoniae.

Rarely, a cause cannot be identified.

The exact underlying mechanism by which Stevens-Johnson syndrome and toxic epidermal necrolysis occur is poorly characterized. One hypothesis is that altered drug metabolism (eg, failure to clear reactive drug metabolites) in some patients triggers a T-cell–mediated cytotoxic reaction to drug antigens in keratinocytes. CD8+ T cells have been identified as important mediators of blister formation. Findings suggest that granulysin released from cytotoxic T cells and natural killer cells might play a role in keratinocyte death; granulysin concentration in blister fluid correlates with severity of disease. Interleukin-15 has also been found to be increased in patients with SJS/TEN and has been found to increase granulysin production.

Another hypothesis is that interactions between Fas (a cell-surface receptor that induces apoptosis) and its ligand, particularly a soluble form of Fas ligand released from mononuclear cells, lead to cell death and blister formation.

A genetic predisposition for SJS/TEN is well-established, with strong associations between specific HLA alleles and drug-induced severe cutaneous adverse reactions. Testing for the presence of certain HLA allelic variants before the administration of certain medications may be considered, particularly in certain Northern European or Asian populations (eg, HLA-B*58:01 for allopurinol, HLA-A*31:01, HLA-B*15:02 for carbamazepine) (1).

Within 1 to 3 weeks after the start of the offending medication, patients develop a prodrome of malaise, fever, headache, cough, and keratoconjunctivitis (1). Macules, often in a target configuration (bull's eye configuration), then appear suddenly, usually on the face, neck, and upper trunk. These macules simultaneously appear elsewhere on the body, coalesce into large flaccid bullae, and slough over a period of 1 to 3 days (1). Nails and eyebrows may be lost along with epithelium. The palms and soles may be involved. Skin, mucosal, and eye pain are common. In some cases, diffuse erythema is the first skin abnormality of TEN.

Stevens-Johnson Syndrome (SJS) (1)

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This photo shows an erythematous rash and blisters on the skin and on the mucosa of the eyes and mouth in this patient with SJS.

DR P. MARAZZI/SCIENCE PHOTO LIBRARY

Stevens-Johnson Syndrome (SJS) (2)

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This photo shows numerous erythematous to dusky macules and papules, some coalescing, with visible areas of epidermal detachment and denudation. Mucosal involvement includes erosions and ulceration of the lips and eyes.

DR M.A. ANSARY/SCIENCE PHOTO LIBRARY

Toxic Epidermal Necrolysis (Lyell Syndrome)

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This photo shows extensive necrosis and splitting and sloughing of the epidermis from the dermis secondary to drug-induced toxic epidermal necrolysis on the torso of a 60 year old woman. It is a rare but life-threatening skin condition.

PDC/SCIENCE PHOTO LIBRARY

In severe cases of TEN, large sheets of epithelium slide off the entire body at pressure points (ie, positive Nikolsky sign), exposing weepy, painful, and erythematous skin. Painful oral crusts and erosions, keratoconjunctivitis, and genital problems (eg, urethritis, phimosis, vaginal synechiae) accompany skin sloughing in most cases. Bronchial epithelium may also slough, causing cough, dyspnea, pneumonia, pulmonary edema, and hypoxemia. Glomerulonephritis and hepatitis may develop.

• Primarily history and physical examination

• Often skin biopsy

The diagnosis is usually clinically evident from the appearance of lesions and rapid progression of symptoms. Histologic examination of sloughed skin shows necrotic epithelium, a distinguishing feature.

Differential diagnosis in Stevens-Johnson syndrome (SJS) and early toxic epidermal necrolysis (TEN) includes erythema multiforme, viral exanthems, and other drug rashes; SJS/TEN can usually be differentiated clinically as the disorder evolves and is characterized by significant pain and skin sloughing. In later stages of TEN, differential diagnosis includes the following:

• Toxic shock syndrome (usually has more prominent multiorgan involvement and different cutaneous manifestations, such as macular rash on palms and soles that evolves to desquamation over about 2 weeks)

• Exfoliative erythroderma (usually spares mucous membranes and is not as painful)

• Paraneoplastic pemphigus (sometimes with different mucocutaneous findings or in patients with evidence of cancer)

In children, TEN is less common and must be distinguished from staphylococcal scalded skin syndrome. Characteristics of staphylococcal scalded skin syndrome usually include sparing of mucous membranes, absence of risk factors for TEN (eg, medication history), and clinical suspicion of staphylococcal infection.

(See also table Severity-of-Illness Score for Toxic Epidermal Necrolysis (SCORTEN).)

• Supportive care

• Cyclosporine or tumor necrosis factor (TNF) inhibitors

• Possibly other agents (eg, glucocorticoids, plasmapheresis, IV immune globulin [IVIG])

The treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) involves early recognition and inpatient management with immediate discontinuation of the causative drug, and intensive supportive care (including fluids, wound care, infection control, nutritional, and ophthalmologic management). The role of systemic immunomodulatory therapy is uncertain and supported by limited evidence. Cyclosporine and some TNF inhibitors (eg, etanercept) may decrease mortality (1). Other immunomodulatory therapies that have been used include intravenous immunoglobulin (IVIG), glucocorticoids, and plasmapheresis. Outcomes are optimal when SJS/TEN is recognized early and treated in an inpatient dermatologic or intensive care unit setting; treatment in a burn unit may be needed for severe disease (2). Ophthalmology consultation and specialized eye care are mandatory for patients with ocular involvement.

Medications suspected to have triggered SJS/TEN should be stopped immediately. Patients are isolated to minimize exposure to infection and are given fluids, electrolytes, blood products, and nutritional supplements as needed. Skin care includes prompt treatment of secondary bacterial infections and daily wound care as for severe burns. Prophylactic systemic antibiotics are not routinely recommended in the absence of clinical evidence of infection, but can be given when bacterial infection or sepsis is suspected.

Pharmacotherapy of SJS/TEN is controversial. Immunomodulatory agents may be considered (1). Cyclosporine (3 to 5 mg/kg orally once/day) inhibits CD8 T cells and has been shown to decrease the duration of active disease (eg, by 2 to 3 days in some instances) and possibly decrease mortality (3). Limited evidence supports the use of the TNF. inhibitors infliximab and etanercept in reducing inflammation; etanercept can additionally reduce disease-specific mortality. The use of systemic glucocorticoids remains controversial. Many experts thought systemic glucocorticoids increased mortality because of increased rates of infection and the risk of masking sepsis. However, some reports have shown improved outcomes with early glucocorticoid therapy (4). Early IVIG (typically 1 to 2 g/kg total, administered over 2 to 5 days) blocks Fas-receptor and ligand (Fas-FasL) interaction through antibodies that target Fas (CD95). However, despite some remarkable initial results using high-dose IVIG for TEN, further clinical trials involving small cohorts have reported conflicting results, and a retrospective analysis has suggested no improvement or even higher than expected mortality (5) JAK inhibitors are an emerging treatment option for TEN; early clinical experience suggests benefit, although evidence remains limited (6).

Plasmapheresis can remove reactive drug metabolites or antibodies and can be considered.

Severe toxic epidermal necrolysis is similar to extensive burns; patients are acutely ill, may be unable to eat or open their eyes, and suffer massive fluid and electrolyte losses. They are at high risk of infection, multiorgan failure, and death.

Mortality risk generally depends on age, clinical severity of disease, and extent of body surface involvement (eg, higher in TEN than SJS). Mortality can be as high as 25 to 35% in adults but is usually lower in children and with early treatment (1).

With early therapy, survival rates for TEN approach 90%. The Severity-of-Illness Score for Toxic Epidermal Necrolysis (SCORTEN) systematically scores 7 independent risk factors within the first 24 hours of presentation to the hospital to determine the mortality rate for a particular patient.

In survivors, long-term physical and psychological sequelae can develop. Observational data have shown significantly higher rates of cutaneous, ocular, oral mucosal and psychological comorbidities (2).