Description

• A generalized hypersensitivity reaction, usually to a drug, in which skin and mucous membrane lesions are an early manifestation
• Once considered on the same spectrum with erythema multiforme in which >1 mucosal surface is involved; Stevens-Johnson syndrome (SJS) is now considered to be a different disease with a more difficult course and more ominous prognosis.
• SJS exists on a continuum with toxic epidermal necrolysis (TEN).
• SJS presents with characteristic targetoid cutaneous lesions.
• When epidermal detachment is involved, the condition is considered to be SJS when <10% of the body surface area (BSA) is involved. 10–30% of BSA is considered an overlap between SJS and TEN. Involvement of >30% of BSA is TEN, which has a high morbidity and mortality.
• System(s) affected: cardiovascular, hematologic, lymphatic/immunologic, nervous, renal/urologic, skin/exocrine
• Synonym(s): ectodermosis erosiva pluriorificialis; febrile mucocutaneous syndrome; herpes iris; erythema polymorphe; TEN

Geriatric Considerations
TEN has a greater mortality in older patients.

Pediatric Considerations
Rare in children <3 years of age, more common from age 3 years to young adult

Pregnancy Considerations
Pregnancy is a possible predisposing condition.

Epidemiology

Incidence

• Incidence/prevalence of SJS in the United States is difficult to estimate due to the lack of a universally accepted case definition.
• 1 to 7 and 0.4 to 1.2 cases per 1 million person-years for SJS and TEN, respectively

Prevalence

• Predominant sex: female > male (2:1)
• Sex (females): 33–62% for SJS and 61–64% for TEN
• Age (average range): 25 to 47 years for SJS and 46 to 63 years for TEN; <10% of cases are children.

Etiology and Pathophysiology

• Up to 50% of cases are idiopathic; cross-reactivity between drug classes is suspected (1).
• Associated with abnormal metabolism and clearance of drugs and metabolites (2)
• Slow intrinsic acetylation rates
• 75% of cases involving SJS/TEN overlap with recent medication:
  • 50% of cases occur within 4 weeks and 90% occur within 8 weeks of an offending agent (1).
• Algorithm-based approach helps to assess probability of drug causality in SJS, TEN, or overlap (3)[B],(4).
• Frequently associated with upper respiratory tract infection and recent use of antibiotics
• Sulfonamides are the drugs most strongly associated with SJS and TEN. Others include:
  • Cephalosporins
  • Quinolones
  • Aminopenicillins
  • Tetracyclines
  • Macrolides
  • Imidazole antifungals
  • Antiretrovirals (e.g., protease inhibitors, efavirenz, abacavir, amprenavir, telaprevir, fosamprenavir, atazanavir, darunavir, etravirine)
  • Anticonvulsants, especially carbamazepine
  • NSAIDs, especially oxicam
  • Allopurinol, especially in patients of European/Israeli heritage
  • Acetaminophen
  • Vaccines: DPT, BCG, oral polio
  • Mycoplasma pneumoniae infection
• Erythematous papular lesions and keratinocyte necrosis are a consequence of cell-mediated immunity.
• Occurs 1 to 2 weeks after initial exposure to offending drugs and within 48 hours on rechallenge
• Drugs bind MHC class I and T-cell receptor, inducing drug-specific T-cell receptors and causing clonal expansion of cytotoxic T cells that kill keratinocytes, in a mechanism involving the release of cytolytic protein (granulysin).

Genetics
Associations with HLA-A*3101 in Northern Europeans; HLA-B*1501, HLA-B*1502, HLA-B*1511, HLA-B*5801 in patients of Asian ancestry, HLA-Bw44, HLA-B12, and HLA-DQB1*0601

Risk Factors

• Previous history of SJS
• Immunocompromised status, including active cancer, chronic viral infections (Epstein-Barr virus), and HIV (5)
• Patients with HIV infection may be predisposed to developing SJS in response to their medications:
  • HLA allele subtypes A, B, and D
  • Diseases that cause immune compromise (e.g., deficiencies, malignancy)
  • Possibly radiation therapy/ultraviolet light

General Prevention

Secondary prevention possible by avoiding exposure to offending medications/chemical agents

Commonly Associated Conditions

• SJS progressing to TEN is ominous prognostically.
• M. pneumoniae may be an infectious precursor.