Stevens-Johnson syndrome

Stevens-Johnson syndrome (SJS) is a rare, immune-mediated, skin reaction that results in blistering of skin and extensive epidermal detachment. SJS is generally triggered by medications (e.g., certain antibiotics and antiepileptics). The patient presents 1–3 weeks after exposure to a medication with fever and other flu-like symptoms. Painful, vesiculobullous skin lesions develop and eventually denude to form extensive skin erosions, resembling large, superficial burns. The mucous membranes are also characteristically affected and the patient presents with oral ulcers, genital ulcers, and/or severe conjunctivitis. When > 30% of the skin is affected, the condition is referred to as toxic epidermal necrolysis (TEN). SJS and TEN are associated with a high mortality as a result of hypovolemic and/or septic shock. The diagnosis is primarily clinical, but skin biopsies can be used to support the diagnosis and rule out other causes of vesiculobullous lesions. The most important therapeutic measure is to discontinue the offending drug. Supportive care (e.g., fluid resuscitation, antibiotics) may be required to treat shock.

• A rare, immune-mediated skin reaction that leads to extensive epidermal detachment and is associated with a high mortality.
• SJS and TEN (toxic epidermal necrolysis) are the same entity but differ in terms of disease severity (based on surface area of skin involved).
  • < 10% – SJS
  • 10–30% – SJS/TEN overlap
  • > 30% – Toxic epidermal necrolysis (severe SJS)

• Annual incidence: ∼ 5 cases per 1,000,000 individuals
• Age of onset: any age
• Sex: ♀ > ♂ (5:3)

Epidemiological data refers to the US, unless otherwise specified.

• Triggers
  • Drugs (most common trigger, ∼ 80% of cases)
    • Antibiotics: sulfonamides (e.g., TMP/SMX), aminopenicillins, rifampicin
    • Corticosteroids
    • Antiretroviral drugs (e.g., nevirapine)
    • Antiepileptics: phenytoin, phenobarbital, lamotrigine, valproic acid, carbamazepine, ethosuximide
    • Oxicam NSAIDs (e.g., piroxicam)
    • Allopurinol
    • Sulfasalazine
  • Infections: mycoplasma pneumonia, CMV, herpes
  • Rarely: vaccinations, graft-versus-host disease
  • Idiopathic
• Risk factors
  • HIV infection
  • Certain HLA phenotypes
  • Polymorphism in genes that code for CYP enzymes

• The pathogenesis is not completely understood but is thought to involve a delayed hypersensitivity reaction (type IV): ↑ activity of drug-specific cytotoxic T cells → release of granulysin; (a cytolytic protein) by an unknown mechanism → damage to keratinocytes

• Prodromal phase (begins 1–3 weeks after the intake of medication): high fever (usually > 39°C or 102°F), malaise, sore throat, myalgia and/or arthralgia
• Mucocutaneous lesions appear 1–3 days after the onset of prodromal symptoms
  • Cutaneous manifestation sequence
    1. Painful, erythematous/purpuric macules
       • May have a targetoid appearance (cockade lesions)
       • Typically seen over the face and trunk
    2. Lesions form bullae and/or vesicles; positive Nikolsky sign
    3. Extensive, full-thickness epidermal necrosis and sloughing (resembling large superficial burns)
    4. Healing by re-epithelialization: begins 1–2 weeks after epidermal sloughing and is completed within a few weeks
  • Mucosal membranes: almost always involved
    • Oral and pharyngeal mucosa: stomatitis, cheilitis, oral ulcers, odynophagia
    • Severe conjunctivitis, corneal ulcers: photophobia, eye pain
    • Urethritis, genital ulcers, and/or perianal ulcers
    • Esophageal ulcers and/or strictures (less common): dysphagia
    • Tracheal involvement (less common)
    • Small bowel, colon involvement (rare): diarrhea, melena, intussusception, bowel perforation
• Shock may develop

The involvement of mucous membranes differentiates SJS from staphylococcal scalded skin syndrome (SSSS) in which mucous membranes are spared!

SJS is primarily a clinical diagnosis (based on history of medications and infections, especially HIV) that is supported by skin tests and laboratory findings

• Skin biopsy
  • Keratinocyte necrosis
  • Apparent subepidermal split
  • Eosinophilic infiltration with minimal infiltration of lymphocytes and histiocytes around blood vessels
• Leukopenia
• ↑ BUN
• Hyperglycemia
• ↑ AST, ALT

• Erythema multiforme (EMF)
  • EMF minor does not involve mucous membranes
  • Lesions of EMF (both major and minor) are more acrally distributed and have limited skin detachment
  • While the triggers for both EMF and SJS are essentially the same, the former is more commonly associated with infections such as herpes and Mycoplasma, while the latter is most commonly associated with drugs.
• Staphylococcal scalded skin syndrome (SSSS)
  • Mucous membranes are typically not involved in SSSS.
  • SSSS is also much more commonly seen in a younger age group (especially infants).
  • Skin biopsy and exfoliative cytology can be used to confirm the diagnosis.
• See differential diagnoses of severe exfoliative skin conditions.

The differential diagnoses listed here are not exhaustive.

• Discontinue any offending drug
• Supportive therapy: similar to that of burns (see “Therapy” in burns)
  • Fluid resuscitation and replacement of ongoing fluid loss
  • Wound management
  • Antibiotic therapy in the case of sepsis
  • Cyclosporin may slow progression.
• Seek an urgent dermatological and ophthalmological consult

No definitive therapy exists. Early discontinuation of the drug and adequate supportive care are associated with better outcomes!

• Pneumonia, interstitial pneumonitis
• Irregular skin pigmentation, alopecia
• Ophthalmological complications: keratoconjunctivitis sicca (dry eyes), trichiasis, synechiae between the bulbar and palpebral conjunctiva, loss of vision
• Malnutrition
• Genital complications in females: vaginal stenosis, atrophic vaginitis, dyspareunia

We list the most important complications. The selection is not exhaustive.

• Mortality rate ^[1]
  • SJS: ∼ 25%
  • SJS/TEN overlap: ∼ 40%
  • TEN: ∼ 50%
• Factors associated with a poor prognosis
  • Old age (> 70 years)
  • Intestinal involvement
  • Pulmonary involvement
• Recurrence: SJS and/or TEN may recur with the use of the same or closely related offending drug.