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

Quiz

Question 1

Which HLA allele is strongly associated with carbamazepine induced SJS/TEN in Asian and East Indian patients?

A. HLA-B 5701
B. HLA-A 3101
C. HLA-B 1502
D. HLA-DQB1 0601

Question 2

Which medication is most strongly associated with HLA-B 5801 mediated SJS/TEN risk in Han Chinese patients?

A. Lamotrigine
B. Allopurinol
C. Abacavir
D. Nevirapine

Question 3

Which immune cell plays the central role in keratinocyte apoptosis in SJS/TEN?

A. B lymphocytes
B. CD8 positive cytotoxic T cells
C. Mast cells
D. Plasma cells

Question 4

Granulysin in SJS/TEN primarily causes which of the following?

A. Dermal fibrosis
B. Keratinocyte apoptosis
C. Melanocyte proliferation
D. Neutrophil chemotaxis

Question 5

Which population has an approximately 1000 fold increased risk of developing SJS/TEN?

A. Patients with psoriasis
B. Patients with AIDS
C. Patients with diabetes mellitus
D. Patients with atopic dermatitis

Question 6

Which anticonvulsant does NOT significantly cross react with other aromatic anticonvulsants in SJS/TEN?

A. Phenytoin
B. Phenobarbital
C. Carbamazepine
D. Valproic acid

Question 7

SJS most commonly develops within what time frame after initiation of the culprit medication?

A. Within 24 hours
B. 5 to 28 days
C. 3 to 6 months
D. More than 1 year

Question 8

Which serologic marker has high sensitivity and specificity for distinguishing SJS/TEN from uncomplicated drug eruptions?

A. ANA
B. Rheumatoid factor
C. Granulysin
D. Anti-dsDNA antibodies

Question 9

Which pathway contributes to apoptosis in SJS/TEN through CD95 signaling?

A. JAK-STAT pathway
B. FAS ligand and FAS receptor interaction
C. Complement activation pathway
D. IL-17 pathway

Question 10

Which NSAID subgroup is particularly associated with SJS/TEN?

A. Salicylates
B. Oxicams
C. COX-2 inhibitors
D. Propionic acid derivatives

Question 11

Which HLA allele is associated with abacavir hypersensitivity reactions including SJS/TEN?

A. HLA-B 1502
B. HLA-DQB1 0601
C. HLA-A 3101
D. HLA-B 5701

Question 12

What is the primary function of granulysin in the pathogenesis of SJS/TEN?

A. Blocking T cell activation
B. Stimulating collagen synthesis
C. Mediating widespread epidermal necrosis
D. Activating melanocytes

Question 13

Which of the following is an NNRTI associated with SJS/TEN?

A. Efavirenz
B. Methotrexate
C. Hydroxychloroquine
D. Cyclosporine

Question 14

Which HLA association increases risk of ocular complications in white patients with SJS/TEN?

A. HLA-B 1502
B. HLA-DQB1 0601
C. HLA-B 5701
D. HLA-A 3101

Question 15

Which mechanism increases susceptibility to SJS/TEN in slow acetylators?

A. Excess melanin production
B. Increased complement activation
C. Impaired detoxification of reactive drug metabolites
D. Excess neutrophil migration

Answers

1 C. HLA-B 1502
2 B. Allopurinol
3 B. CD8 positive cytotoxic T cells
4 B. Keratinocyte apoptosis
5 B. Patients with AIDS
6 D. Valproic acid
7 B. 5 to 28 days
8 C. Granulysin
9 B. FAS ligand and FAS receptor interaction
10 B. Oxicams
11 D. HLA-B 5701
12 C. Mediating widespread epidermal necrosis
13 A. Efavirenz
14 B. HLA-DQB1 0601
15 C. Impaired detoxification of reactive drug metabolites