Stevens-Johnson Syndrome

Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson syndrome is characterized by keratinocyte necrosis and separation of the epidermis from the dermis. Patients will present with a flu-like prodrome, followed by cutaneous bullae and sloughing on the face, thorax, and mucous membranes. Stevens-Johnson syndrome is considered a medical emergency, and management is largely supportive. Withdrawal of the causative agent is required. Monitoring for, and treating, superinfection is essential due to the high risk of associated death in these patients.

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Overview

Classification

  • Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe mucocutaneous reactions. 
  • Considered a continuum of the same disease
  • Classified based on the percentage of body surface affected by blisters, erosions, and skin detachment:
Subtype Involved BSA

Stevens-Johnson syndrome

10% of BSA

Overlapping SJS/TEN

10%‒30% of BSA

Toxic epidermal necrolysis

30% of BSA

BSA: body surface area
SJS: Stevens-Johnson syndrome
TEN: toxic epidermal necrolysis

Epidemiology

  • Incidence: 
    • 1–7 cases per million people per year
    • Higher in patients with HIV and active cancer
    • SJS is more common.
  • Mortality rate: 
    • SJS: 10%
    • TEN: 50%
  • More common in women than men, with a ratio of 2:1
  • Can occur at any age

Etiology

  • Medications 
    • Approximately 70% of cases
    • Occurs within 8 weeks of medication onset
  • Infections 
    • 2nd-most common trigger
    • Frequent cause in children
  • Idiopathic
    • > 1/3 of cases
  • Genetics
    • Some HLA types are associated with an increased risk.
  • Other risk factors 
    • Malignancy 
    • Lupus 
    • Ultraviolet light stimulus 
    • Radiation therapy

The following table lists the major common medication and infectious causes of SJS/TEN:

Types Examples

Medications

Antiepileptics

Lamotrigine, phenobarbital, carbamazepine, valproate, phenytoin

Sulfa

Cotrimoxazole, sulfasalazine

Other antibiotics

Aminopenicillins, fluoroquinolones, cephalosporins

NSAIDs

Meloxicam, piroxicam

Antiretrovirals

Nevirapine

Miscellaneous

Allopurinol, chlormezanone

Infectious

Viral

Herpes simplex virus, HIV, coxsackievirus, hepatitis, influenza, mumps, Epstein-Barr virus, enteroviruses

Bacterial

Group A beta-hemolytic streptococci, brucellosis, mycobacteria, Mycoplasma pneumoniae, rickettsia, tularemia
NSAIDs: Nonsteroidal anti-inflammatory drugs

Pathogenesis

The exact mechanism is unknown, but there are several theories:

  1. Drug, or infectious, antigen in the skin tissue → stimulates cytotoxic T cells, natural killer T cells (NKT), and natural killer (NK) cells → granulysin release → keratinocyte death
  2. Apoptosis of keratinocytes → epidermal separation from the dermis → characteristic skin detachment of SJS/TEN
  3. Dying cells and necrosis → ↑ antigen load → triggers T cells to continue the inflammatory response → development of fluid-filled blisters 

This impaired skin integrity can lead to:

  • Water loss
  • Secondary bacterial infections and sepsis
Pathophysiology in Stevens-Johnson syndrome and toxic epidermal necrolysis

Schematic showing how a peptide antigen (in this case, from a drug) presented on keratinocytes can lead to a cytotoxic inflammatory response resulting in granulysin release, keratinocyte apoptosis and necrosis, detachment of the epidermis, and blister formation in SJS and TEN.

Image by Lecturio.

Clinical Presentation

Clinical manifestations

Prodrome: 

  • Fever (often > 39°C)
  • Myalgia and arthralgia
  • Keratoconjunctivitis (inflammation of the cornea and conjunctiva)
  • Sore throat
  • Headache
  • Malaise

Acute phase: 

  • 1‒3 days after the prodrome
  • Lasts 8‒12 days
  • Cutaneous lesions
    • Begin as ill-defined, coalescing macules with purpuric centers or diffuse erythema
      • Start on the face and thorax, then spread symmetrically
      • Typically spare scalp, palms, and soles
      • Tender to touch
    • Vesicles and bullae form as the disease progresses
    • Skin begins to slough within days
    • Nikolsky’s sign: extension of skin sloughing by applying pressure
  • Mucosal lesions 
    • Occur in approximately 90% of cases
    • Includes oral, pharyngeal, ocular, and urogenital erosions

Complications

  • Significant fluid loss 
    • Severe dehydration 
    • Hypovolemic shock 
    • Renal failure
  • Bacterial infection 
    • Sepsis and septic shock are the main cause of death in SJS/TEN patients.
    • Most often caused by Staphylococcus aureus and Pseudomonas aeruginosa
  • Tracheobronchial epithelial involvement  
    • Pneumonia 
    • Interstitial pneumonitis 
    • Acute respiratory distress syndrome 
  • Protein loss: edema
  • Electrolyte imbalances
  • Epithelial necrosis of the gastrointestinal tract  
    • Diarrhea 
    • Melena 
    • Colonic perforation 
    • Small bowel intussusception

Diagnosis

The diagnosis is clinical, based on history and physical exam findings.

  • Skin biopsy 
    • Not required for diagnosis, but can confirm and rule out other conditions
    • Keratinocyte necrosis is the hallmark finding.
      • Can be partial or full-thickness
      • Apoptotic keratinocytes are scattered in the basal layer of the epidermis in early lesions.
      • Full-thickness epidermal necrosis and subepidermal bullae later in the disease
    • Lymphocytic inflammatory infiltration
    • Direct immunofluorescence is negative.
  • Supporting workup 
    • Aids in monitoring treatment and complications
    • Basic metabolic panel → evaluate for electrolyte imbalance and renal failure
    • Complete blood count → significant leukocytosis may signal an infection
    • Bacterial and fungal cultures → bacterial superinfection and sepsis
    • Chest radiograph → pneumonia or interstitial pneumonitis
Curcumin in stevens-johnsons syndrome culprit or bystander1

Histopathology of a skin biopsy taken from a patient with SJS/TEN showing characteristic epidermal detachment and lymphocyte infiltration in the dermis

Image: “Curcumin in stevens-johnsons syndrome: culprit or bystander?” by Irani C, Haddad F, Maalouly G, Nemnoum R. License: CC BY 2.0

Treatment

  • Immediate hospital admission
    • Patients typically require intensive care or a burn unit.
    • SCORTEN score (score of toxic epidermal necrolysis) is calculated to determine severity, prognosis, and appropriate setting for management (see table below).
  • Withdrawal of causative agent is required.
  • Supportive care:
    • Wound care 
      • Debridement 
      • Moisturizers 
      • Antibacterial ointments
    • Fluid and electrolyte management
    • Nutritional support 
      • Parenteral nutrition for those with dysphagia and odynophagia 
      • Transition to oral feeds when tolerated
    • Ocular care 
      • Ophthalmology consultation
      • Corticosteroid and antibiotic eye drops 
      • Artificial tears for lubrication 
    • Temperature management
    • Pain control 
      • Acetaminophen and ibuprofen for mild pain 
      • Opioids for severe pain
    • Monitoring and treatment of superinfections 
      • Bacterial and fungal cultures of blood, wounds, and mucosal lesions
      • Appropriate antibiotics and antifungals, as necessary
    • Education on future drug avoidance, including closely related agents
  • Controversial treatments:
    • Cyclosporine
    • Systemic corticosteroids
    • Plasmapharesis
    • Intravenous immunoglobulin (IVIG)
Table: SCORTEN score
Prognostic factorsScore

Age ≥ 40 years

1

Malignancy present

1

Body surface area detached ≥ 10%

1

Tachycardia ≥ 120/min

1

Serum urea > 10 mmol/L

1

Serum glucose > 14 mmol/L

1

Serum bicarbonate < 20 mmol/L

1

The SCORTEN score is used to help determine the severity, prognosis, and appropriate setting for management in SJS/TEN patients.

  • Score 0‒1: 94% survival, may be treated in non-specialized wards
  • Score 2: 87% survival, should be transferred to an intensive care unit, burn unit, or specialized dermatology unit
  • Score 3: 53% survival, should be transferred to an intensive care unit, burn unit, or specialized dermatology unit
  • Score 4: 25% survival, should be transferred to an intensive care unit, burn unit, or specialized dermatology unit
  • Score 5‒7: 17% survival, should be transferred to an intensive care unit, burn unit, or specialized dermatology unit

Differential Diagnosis

  • Erythema multiforme: an acute, immune-mediated skin eruption with typical targetoid lesions; may be accompanied by systemic symptoms and mucosal involvement. Etiology is usually due to infection from the herpes simplex virus, unlike SJS/TEN, which is usually caused by a medication. Diagnosis is clinical and will differentiate this condition from SJS. Treatment includes supportive care.
  • Staphylococcal scalded skin syndrome (SSSS): presents with a painful, desquamative skin rash, especially around the nose, mouth, and anus. The condition results from a staphylococcal toxin, and is usually seen in children. Unlike SJS/TEN, there is no mucosal involvement. Diagnosis is clinical and confirmed with bacterial cultures. A biopsy will show noninflammatory, superficial splitting of the epidermis. Treatment includes antibiotics, wound care, and supportive care.
  • Exfoliative dermatitis: a generalized, symmetric, erythematous rash caused by an underlying cutaneous disease (psoriasis, atopic dermatitis), medications, and malignancy (lymphoma). The condition can mimic the early stages of SJS; however, there is no mucosal involvement (which will differentiate the condition from SJS). Diagnosis is made clinically, and treatment focuses on treating the underlying cause, withdrawal of implicated medications, and supportive care.
  • Toxic shock syndrome: a systemic syndrome caused by staphylococcus or streptococcus endotoxins. Patients present with fever, shock, and multisystem organ dysfunction. Cutaneous manifestations include a diffuse, erythematous rash and desquamation. Diagnosis is based on blood culture results, clinical history, and exam, which will differentiate this condition from SJS. Treatment includes hemodynamic support, fluid resuscitation, and antibiotics.
  • Pemphigus vulgaris: an autoimmune disorder causing intraepidermal blistering and erosions of the skin and mucous membranes. Patients will have cutaneous bullae appearing on normal-appearing skin and painful mucocutaneous erosions. Diagnosis involves a biopsy with immunofluorescence testing showing immunoglobulin G (IgG) antibodies against keratinocytes, differentiating this condition from SJS. Treatment includes corticosteroids, immunosuppressants, and IVIG.
  • Bullous pemphigoid: an autoimmune skin disorder causing pruritus, erythematous plaques, and tense, bullous lesions. Mucous membrane involvement is rare. Triggers include medications, trauma, skin conditions, and systemic disease. Biopsy with immunofluorescence shows IgG and complement deposits along the basement membrane, which differentiates the condition from SJS. Treatment includes steroids, immunosuppressants, and anti-inflammatory medications.

References

  1. High, W.A. (2019). Stevens-Johsnon syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis. In Corona, R. (Ed.), Uptodate. Retrieved November 7, 2020, from https://www.uptodate.com/contents/stevens-johnson-syndrome-and-toxic-epidermal-necrolysis-pathogenesis-clinical-manifestations-and-diagnosis
  2. High, W.A. (2020). Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae. In Corona, R. (Ed.), Uptodate. Retrieved November 7, 2020, from https://www.uptodate.com/contents/stevens-johnson-syndrome-and-toxic-epidermal-necrolysis-management-prognosis-and-long-term-sequelae
  3. Benedetti, J. (2020). Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). MSD Manual Professional Edition. Retrieved November 7, 2020, from https://www.msdmanuals.com/professional/dermatologic-disorders/hypersensitivity-and-inflammatory-skin-disorders/stevens-johnson-syndrome-sjs-and-toxic-epidermal-necrolysis-ten
  4. Foster, C.S, Ba-Abbad, R., Letko, E., and Parillo, S.J. (2019). Stevens-Johnson syndrome. In Dahl, A.A. (Ed.), Medscape. Retrieved November 7, 2020, from https://emedicine.medscape.com/article/1197450-overview

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