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). 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 is similar to that of extensive burns, including fluid resuscitation, wound care, and pain management. SJS and TEN are associated with a high mortality as a result of hypovolemic and/or septic 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 ^[1][2][3]

• Medications (most common): risk is highest within the first 8 weeks of treatment ; ^[1]
  • Antibiotics: sulfonamides (e.g., TMP/SMX), aminopenicillins, rifampicin, quinolones, cephalosporins, tetracyclines, macrolides
  • Antiepileptics: lamotrigine, carbamazepine, phenobarbital, phenytoin
  • Nevirapine
  • Oxicam NSAIDs (e.g., piroxicam)
  • Allopurinol
  • Sulfasalazine
• Rare causes
  • Infections: Mycoplasma pneumoniae infection, herpesvirus infection, URIs, HIV, hepatitis A ^[4]
  • Vaccinations

Risk factors ^[4][5]

• HIV ^[6]
• Connective tissue disease (e.g., SLE)
• Age > 60 years
• Certain HLA phenotypes
• Certain CYP polymorphisms

• 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

Prodrome ^[4][7]

Onset: 1–3 weeks after trigger

• Fever
• Malaise
• Sore throat
• Myalgias, arthralgias
• Headaches

Mucocutaneous lesions ^[4][7]

Onset: 1–3 days after the prodrome

• Cutaneous lesions: affect all patients; progress throughout the illness
  • Initial painful erythematous macules with purpuric centers (atypical target lesions) on the face and trunk
  • Rapid spread and coalescence into bullae with positive Nikolsky sign
  • Expansion to extensive epidermal necrosis
  • Dermal-epidermal dissociation and sloughing of the epidermis
  • Reepithelialization 1–2 weeks after epidermal sloughing
• Mucosal lesions: occur in > 90% of patients ^[4]
  • Oral: stomatitis, cheilitis, ulcers
  • Ocular: conjunctivitis, keratitis, iritis, anterior uveitis
  • GU: genital erosions (e.g., of the glans penis, vulva, vagina), urethral erosions

Systemic involvement ^[4]

Systemic involvement is less common than mucocutaneous involvement and can affect multiple organ systems.

• GI: esophageal ulcerations, hepatocellular necrosis, cholestasis
• Renal: acute kidney injury, acute tubular necrosis, glomerulonephritis
• Pulmonary: ulceration and necrosis of the bronchial epithelium, pulmonary edema, respiratory failure

Approach ^[8]

• Make a clinical diagnosis of SJS based on history and mucocutaneous lesions.
• Obtain a skin biopsy to confirm the diagnosis.
• Rule out differential diagnoses of SJS, e.g., blistering skin diseases.

Mucosal involvement differentiates SJS from staphylococcal scalded skin syndrome.

Laboratory studies ^[7][9][10]

Possible findings include:

• CBC: lymphopenia, neutropenia, thrombocytopenia
• BMP: electrolyte abnormalities, acute kidney injury (↑ BUN)
• LFTs: ↑ transaminases
• Microbiological studies (if applicable): pathogen detection in cultures of blood, skin, mucous membranes, and urine

Findings on skin biopsy include:

• Keratinocyte necrosis
• Apparent subepidermal split
• Eosinophilic infiltration with minimal infiltration of lymphocytes and histiocytes around blood vessels

See also “Overview of blistering skin diseases” and “Rash.”

• 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 can be used to confirm the diagnosis.
• Erythema multiforme (EMF)
  • EMF minor does not typically 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.
• Severe acute cutaneous lupus erythematosus
• Severe acute graft-versus-host disease

The differential diagnoses listed here are not exhaustive.

Management involves a multidisciplinary team of specialists (e.g., dermatology, ophthalmology, gynecology).

Initial management and supportive care ^[7][8][11]

• Discontinue the offending drug.
• Consult dermatology, ophthalmology, and/or gynecology.
• Supportive management is similar to that of extensive burns, including:
  • Goal-directed IV fluid therapy: See “Strategies for IV fluid therapy.”
  • Pain management: See “Oral analgesics” and “Parenteral analgesics” for dosages.
  • Wound care ^[8]
  • Mucosal care (e.g., oral care)
  • Specialized nutrition support
  • Adequate glycemic control
  • See also “Supportive care for burn injury.”
• Pharmacotherapy : Consider in consultation with specialists. ^[12]

Disposition and monitoring ^[8][11]

• ICU admission is typically required; consider transfer to a burn center.
• Monitor for acute complications, including:
  • Infection, septic shock
  • Hypovolemic shock
  • Pleural effusion, respiratory failure ^[13]
• Treat complications, e.g., with:
  • Respiratory support
  • Electrolyte repletion
  • Rewarming techniques
  • Antibiotics for sepsis

Only administer antibiotics if there are signs of infection, e.g., fever, worsening skin pain. ^[11]

• Acute: dehydration and hypovolemic shock; , secondary infection, sepsis, and septic shock
• Ophthalmologic: ocular scarring and vision loss (most common), keratoconjunctivitis sicca, trichiasis ^[7][13]
• Dermatologic: hyperpigmentation, hypopigmentation, alopecia, nail loss ^[13]
• Urogenital: urethral stenosis, vaginal adhesions, dyspareunia, phimosis, sexual dysfunction ^[11]
• Gastrointestinal: stenosis, strictures, dysphagia ^[4]

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

• Mortality rate ^[14]
  • SJS: 5.4%
  • SJS/TEN overlap: 14.4%
  • TEN: overall, 15.3%
• Severity-of-illness score for toxic epidermal necrolysis (SCORTEN) ^[15]
  • Risk factors
    • Age ≥ 40 years
    • Heart rate ≥ 120 bpm
    • Malignancy
    • > 10% epidermal detachment on day 1
    • BUN > 28 mg/dL
    • Bicarbonate < 20 mmol/L
    • Glucose > 252 mg/dL
  • Interpretation: Mortality increases for every additional risk factor present at admission; rates of up to 90% have been reported for patients with ≥ 5 risk factors. ^[14][15][16]
• Recurrence: SJS and/or TEN may reoccur with the use of the same or closely related offending drug.