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 of SJS and TEN
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)
Rarely, a cause cannot be identified.
Pathophysiology of SJS and TEN
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 of SJS and TEN
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 of SJS and TEN
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 Erythema Multiforme Erythema multiforme is an inflammatory reaction, characterized by target or iris skin lesions. Oral mucosa may be involved. Diagnosis is clinical. Lesions spontaneously resolve but frequently... read more , 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 Toxic Shock Syndrome (TSS) Toxic shock syndrome is caused by staphylococcal or streptococcal exotoxins. Manifestations include high fever, hypotension, diffuse erythematous rash, and multiple organ dysfunction, which... read more (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)
Paraneoplastic pemphigus Pemphigus Vulgaris Pemphigus vulgaris is an uncommon, potentially fatal, autoimmune disorder characterized by intraepidermal blisters and extensive erosions on apparently healthy skin and mucous membranes. Diagnosis... read more (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 Staphylococcal Scalded Skin Syndrome Staphylococcal scalded skin syndrome is an acute epidermolysis caused by a staphylococcal toxin. Infants and children are most susceptible. Symptoms are widespread bullae with epidermal sloughing... read more . 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 for SJS and TEN
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) Severity-of-Illness Score for Toxic Epidermal Necrolysis (SCORTEN) Stevens-Johnson syndrome and toxic epidermal necrolysis are severe cutaneous hypersensitivity reactions. Drugs, especially sulfa drugs, antiseizure drugs, and antibiotics, are the most common... read more ) 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.
Treatment of SJS and TEN
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 Treatment Burns are injuries of skin or other tissue caused by thermal, radiation, chemical, or electrical contact. Burns are classified by depth (superficial and deep partial-thickness, and full-thickness)... read more 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 Plasmapheresis Apheresis refers to the process of separating the cellular and soluble components of blood using a machine. Apheresis is often done on donors where whole blood is centrifuged to obtain individual... read more 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 Treatment reference Stevens-Johnson syndrome and toxic epidermal necrolysis are severe cutaneous hypersensitivity reactions. Drugs, especially sulfa drugs, antiseizure drugs, and antibiotics, are the most common... read more ).
The TNF-alpha inhibitors infliximab and etanercept can help reduce inflammation.
Thalidomide has also been tested but increases mortality and is now contraindicated.
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
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.