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

By

Julia Benedetti

, MD, Harvard Medical School

Last full review/revision Jul 2020| Content last modified Jul 2020
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Stevens-Johnson syndrome and toxic epidermal necrolysis are severe cutaneous hypersensitivity reactions. Drugs, especially sulfa drugs, antiseizure drugs, and antibiotics, are the most common causes. Macules rapidly spread and coalesce, leading to epidermal blistering, necrosis, and sloughing. Diagnosis is usually obvious by appearance of initial lesions and clinical syndrome. Treatment is supportive care; cyclosporine, plasmapheresis or IV immune globulin, early corticosteroid therapy, and tumor necrosis factor-alpha inhibitors have been used. Mortality can be as high as 7.5% in children and 20 to 25% in adults but tends to be lower with early treatment.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are clinically similar except for their distribution. By one commonly accepted definition, changes affect < 10% of body surface area in SJS and > 30% of body surface area in TEN; involvement of 10 to 30% of body surface area is considered SJS/TEN overlap.

The disorders affect between 1 and 5 people/million. Incidence, severity, or both of these disorders may be higher in bone marrow transplant recipients, in Pneumocystis jirovecii–infected HIV patients, in patients with systemic lupus erythematosus, and in patients with other chronic rheumatologic diseases.

Etiology

Drugs precipitate over 50% of SJS cases and up to 95% of TEN cases. The most common drug causes include

  • Sulfa drugs (eg, cotrimoxazole, sulfasalazine)

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

  • Antiseizure drugs (eg, phenytoin, carbamazepine, phenobarbital, valproate, lamotrigine)

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

  • Antiretroviral drugs (eg, nevirapine)

  • Miscellaneous individual drugs (eg, allopurinol, chlormezanone)

Cases that are not caused by drugs are attributed to

  • Infection (mostly with Mycoplasma pneumoniae)

  • Vaccination

  • Graft-vs-host disease

Rarely, a cause cannot be identified.

Pathophysiology

The exact mechanism of Stevens-Johnson syndrome and toxic epidermal necrolysis is unknown; however, one theory holds that altered drug metabolism (eg, failure to clear reactive 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 theory 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 has been suggested.

Symptoms and Signs

Within 1 to 3 weeks after the start of the offending drug, patients develop a prodrome of malaise, fever, headache, cough, and keratoconjunctivitis. Macules, often in a target 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. 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 toxic epidermal necrolysis.

In severe cases of toxic epidermal necrolysis, large sheets of epithelium slide off the entire body at pressure points (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 up to 90% of cases. Bronchial epithelium may also slough, causing cough, dyspnea, pneumonia, pulmonary edema, and hypoxemia. Glomerulonephritis and hepatitis may develop.

Diagnosis

  • Clinical evaluation

  • Often skin biopsy

Diagnosis is often obvious from 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 multiple organ 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, drug history), and clinical suspicion of staphylococcal infection.

Prognosis

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. With early therapy, survival rates approach 90%. The severity-of-illness score for toxic epidermal necrolysis (see Table: 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.

Table
icon

Severity-of-Illness Score for Toxic Epidermal Necrolysis (SCORTEN)

Risk Factor*

Score

0

1

Age

< 40 years

40 years

Associated cancer

No

Yes

Heart rate (beats/minute)

< 120

120

Serum blood urea nitrogen

28 mg/dL (10 mmol/L)

> 28 mg/dL (10 mmol/L)

Detached or compromised body surface

< 10%

10%

Serum bicarbonate

≥ 20 mEq/L (≥ 20 mmol/L)

< 20 mEq/L (< 20 mmol/L)

Serum glucose

250 mg/dL (≤ 13.88 mmol/L)

> 250 mg/dL (> 13.88 mmol/L)

* More risk factors indicate a higher score and a higher mortality rate (%) as follows:

  • 0–1 = 3.2% (CI: 0.1 to 16.7)

  • 2 = 12.1% (CI: 5.4 to 22.5)

  • 3 = 35.3% (CI: 19.8 to 53.5)

  • 4 = 58.3% (CI: 36.6 to 77.9)

  • 5 => 90% (CI: 55.5 to 99.8)

CI = confidence interval.

Data from Bastuji-Garin S, Fouchard N, Bertocchi M, et al: SCORTEN: A severity-of-illness score for toxic epidermal necrolysis. Journal of Investigative Dermatology 115:149–153, 2000. doi: 10.1046/j.1523-1747.2000.00061.x

Treatment

  • Supportive care

  • Cyclosporine

  • Possibly corticosteroids, plasmapheresis, IV immune globulin (IVIG), or tumor necrosis factor (TNF)-alpha inhibitors

Treatment is most successful when Stevens-Johnson syndrome and toxic epidermal necrolysis are recognized early and treated in an inpatient dermatologic or intensive care unit setting; treatment in a burn unit may be needed for severe disease. Ophthalmology consultation and specialized eye care are mandatory for patients with ocular involvement. Potentially causative drugs 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 controversial and often avoided.

Drug treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis is controversial. Cyclosporine (3 to 5 mg/kg orally once/day) inhibits CD8 cells and has been shown to decrease the duration of active disease by 2 to 3 days in some instances and possibly decrease mortality. The use of systemic corticosteroids remains controversial. It had been thought by many experts to increase mortality because of increased rates of infection and the risk of masking sepsis. However, some reports show improved outcomes with early corticosteroid therapy.

Plasmapheresis can remove reactive drug metabolites or antibodies and can be considered. Early high-dose IVIG 2.7 g/kg over 3 days blocks antibodies and Fas ligand. However, despite some remarkable initial results using high-dose IVIG for toxic epidermal necrolysis, further clinical trials involving small cohorts have reported conflicting results, and a retrospective analysis has suggested no improvement or even higher than expected mortality (1).

The TNF-alpha inhibitors infliximab and etanercept can help reduce inflammation.

Thalidomide has also been tested but increases mortality and is now contraindicated.

Treatment reference

  • 1. Kirchhof MG, Miliszewski MA, Sikora S, et al: Retrospective review of Stevens-Johnson syndrome/toxic epidermal necrolysis treatment comparing intravenous immunoglobulin with cyclosporine. J Am Acad Dermatol 71(5):941–947, 2014. doi: 10.1016/j.jaad.2014.07.016

Key Points

  • Drugs cause > 50% of Stevens-Johnson syndrome (SJS) and up to 95% of toxic epidermal necrolysis (TEN) cases, but infection, vaccination, and graft-vs-host disease are also potential causes.

  • Confirm the diagnosis by biopsy (showing necrotic epithelium) if clinical characteristics (eg, target lesions progressing to bullae, ocular and mucous membrane involvement, Nikolsky sign, desquamation in sheets) are inconclusive.

  • Early treatment decreases the often high mortality rate.

  • Except for mild cases, treat SJS/TEN in a burn unit and with intensive supportive care.

  • Consult ophthalmology if the eyes are affected.

  • Consider cyclosporine and possibly plasmapheresis for severe cases.

Drugs Mentioned In This Article

Drug Name Select Trade
Gammagard S/D
TEGRETOL
No US brand name
AZULFIDINE
NEORAL, SANDIMMUNE
ZYLOPRIM
AMOXIL
THALOMID
LAMICTAL
ENBREL
REMICADE
VIRAMUNE
MOBIC
DILANTIN
FELDENE
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NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version
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