What are the causes of Stevens-Johnson Syndrome (SJS)?

Causes of Stevens-Johnson Syndrome (SJS)

Stevens-Johnson Syndrome (SJS) is primarily caused by medications, with drugs responsible for approximately 90% of cases in adults, while in children both medications and infections are important triggers with up to 50% of pediatric cases attributed to infectious causes. 1, 2

Medication Causes

High-Risk Medications

• Anticonvulsants: Carbamazepine, lamotrigine, phenytoin, phenobarbital 1, 2
• Antibiotics: Sulfamethoxazole and other sulfonamides 1, 2
• Other high-risk medications:
  • Allopurinol 1, 2, 3
  • Nevirapine and other antiretrovirals 1, 2
  • Oxicam-type NSAIDs 1, 2
  • Sulfasalazine 1, 2

Allopurinol, phenytoin, and carbamazepine have been identified as the three strongest signals for SJS in pharmacovigilance data 3.

Medication Risk Factors

• Timing: Most reactions occur within 5-28 days after starting the medication 1, 2
• Previous exposure: Shorter latency period may occur in patients with previous exposure to the same drug 2
• Genetic factors:
  • HLA-B*1502 has a strong association with carbamazepine-induced SJS/TEN in patients of Southeast Asian ancestry 2, 4
  • HLA-A*3101 is associated with hypersensitivity reactions including SJS in patients of various ancestries taking carbamazepine 4

Infectious Causes

Particularly important in the pediatric population:

• Mycoplasma pneumoniae: Responsible for up to 50% of infection-related SJS cases in children 1, 5
• Herpes Simplex Virus (HSV) 1, 5
• Other respiratory infections 1

A specific variant of SJS/TEN secondary to respiratory infection has been described, involving predominantly mucous membranes with limited cutaneous lesions, termed "Mycoplasma pneumoniae-associated mucositis" or "Mycoplasma pneumoniae-induced rash and mucositis" 1.

Pathophysiological Mechanisms

SJS/TEN involves a cell-mediated cytotoxic reaction against keratinocytes leading to massive skin necrolysis 6. The immunopathologic mechanism includes:

• Immune synapse composed of cytotoxic T cells with drug-specific HLA class I restriction 6
• T cell receptor repertoire involvement 6
• Various cytotoxic proteins and cytokines as mediators:
  • Soluble granulysin
  • Perforin
  • Granzyme B
  • Interleukin-15
  • Fas ligand
  • Interferon-γ
  • Tumor necrosis factor-α 6

Risk Assessment Tools

The ALDEN algorithm has been developed to help define drug causality in SJS/TEN 1. Key parameters to consider include:

• Timeline of drug exposure relative to symptom onset
• Previous exposure and reactions
• Drug notoriety for causing SJS/TEN
• Presence of alternative causes

Special Considerations

Pediatric Population

• Both infections and drugs are important triggers 1
• Up to 50% of cases may be related to infections 1, 5
• Anticonvulsants and antibiotics are most commonly implicated medications 1
• Paracetamol and ibuprofen have unclear associations but may be confounders due to their use in treating prodromal symptoms 1

High-Risk Populations

• Patients with malignancy or stem cell transplantation have worse prognosis with drug-induced SJS/TEN 1
• Patients with specific HLA types (HLA-B1502, HLA-A3101) have increased risk with certain medications 2, 4

Common Pitfalls

• Failure to obtain a complete medication history including over-the-counter preparations
• Not considering infectious causes, particularly in children
• Delayed withdrawal of causative agents, which increases mortality risk
• Not recognizing genetic risk factors in specific populations
• Confusing SJS with other blistering disorders that require different management

Early recognition, immediate withdrawal of causative agents, and prompt referral to specialized care are essential for improving outcomes in SJS/TEN 1, 2, 6.