Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Epidemiology and Pathogenesis

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Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Epidemiology and Pathogenesis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, severe, immune mediated mucocutaneous reactions that are almost always drug induced and occur at an incidence of approximately 5 cases per million people annually. They occur more frequently in elderly patients and show a female predominance. Genetic susceptibility plays a major role, including increased risk in slow acetylators and strong associations with specific HLA alleles that confer drug specific risk. HLA-B 1502 is associated with a markedly increased risk in Asian and East Indian patients exposed to carbamazepine, with a reported 220 fold increase. HLA-A 3101 increases risk in European patients exposed to carbamazepine, HLA-B 5701 confers risk with abacavir exposure, HLA-B 5801 increases risk in Han Chinese patients exposed to allopurinol, and HLA-DQB1 0601 is associated with increased risk and ocular complications in white patients. Patients with AIDS have an approximately 1000 fold increased risk due to loss of protective CD4 positive, CD25 positive, and regulatory T cells. Pathogenesis begins when a culprit drug binds to the MHC I complex, leading to activation of cytotoxic CD8 positive T cells. Granulysin is a primary mediator of keratinocyte apoptosis and can be detected serologically with high sensitivity and specificity, along with high mobility group protein B1, aiding differentiation from uncomplicated drug eruptions. Additional apoptotic signaling occurs through FAS ligand binding to the FAS death receptor on keratinocytes, resulting in caspase activation and widespread apoptosis. Stevens-Johnson syndrome typically develops 5 to 28 days after drug initiation, with anticonvulsant associated cases occurring within the first 2 months. Common culprit drugs include allopurinol, anticonvulsants, sulfonamides, NSAIDs particularly oxicams, sulfasalazine, and NNRTIs such as abacavir, nevirapine, and efavirenz.

Epidemiology

  • Stevie J’s = Stevens-Johnson syndrome and toxic epidermal necrolysis
  • Elderly waitress = Higher incidence in the elderly
  • Female waitress = Female predominance

Genetic Risk Factors

  • Acetylating cashier with a scanner = Slow acetylators have higher risk
  • Asian and East Indian customers in a car with $15 meal for 2 = HLA-B 1502 increases risk in Asian and East Indian patients exposed to carbamazepine with 220 fold increased risk
  • European man with $31 meal for 1 = HLA-A 3101 increases risk in European patients exposed to carbamazepine
  • Happy meal with $0.57 and 1 magic wand = HLA-B 5701 increases risk when exposed to abacavir
  • Chinese kid with pure aloe for $0.58 = HLA-B 5801 increases risk in Han Chinese exposed to allopurinol
  • White man wearing 6-shaped glasses = HLA-DQB1 0601 increases risk of SJS and ocular complications in white patients

High Risk Populations

  • Large first aid kit = AIDS patients have a 1000 fold increased risk due to loss of protective immune cells
  • Skater without protective padding who fell and scraped skin = Markedly increased SJS and TEN risk in AIDS patients

Pathogenesis

  • MHC Mickey D’s #1 fan holding a medication bottle = Drug binding to MHC I complex initiates pathogenesis
  • Grandma security guard stopping Mickey D’s fan = Granulysin mediates apoptosis
  • Grandma popping Mickey D balloon = Granulysin induced keratinocyte apoptosis
  • Beakers = Serologic tests for granulysin with 80% sensitivity and 95% specificity
  • High mobility hummingbird = High mobility group protein B1
  • Fast car with CD95 license plate = FAS ligand CD95L
  • Fast car binding to parking spot = FAS ligand binding to FAS death receptor on keratinocytes
  • Bottle cap under car tire = Caspase activation leading to apoptosis

Timing

  • Monthly special advertisement = SJS occurs 5 to 28 days after starting the culprit drug
  • 2 shaky shakes = SJS can occur within the first 2 months after starting anticonvulsants

Culprit Medications

  • Pure aloe = Allopurinol
  • Car in the parking lot = Carbamazepine
  • Lama in the parking lot = Lamotrigine
  • VIP chain on lama = Valproic acid does not cross react with other anticonvulsants
  • Tow truck with barbed wire = Phenytoin and phenobarbital
  • Smelly sulfur eggs = Sulfonamides
  • Anti-inflammatory fire extinguishers = NSAIDs particularly oxicam
  • Waiter holding sulfur salt = Sulfasalazine
  • Abra cadabra happy meal toy = Abacavir
  • Pine tree = Nevirapine
  • Elf waiter = Efavirenz