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- A generalized hypersensitivity reaction, usually to a drug, in which skin and mucous membrane lesions are an early manifestation
- A severe form of erythema multiforme in which >1 mucosal surface is involved; many now consider it to be a different disease with a more difficult course and a more ominous prognosis.
- Stevens-Johnson syndrome (SJS) exists on a continuum with toxic epidermal necrolysis (TEN).
- SJS presents with characteristic targetoid cutaneous lesions when <10% of the body surface area (BSA) is involved.
- Targetoid cutaneous lesion involvement of 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 up to 70% 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
Patients with discrete skin lesions and >10% epidermal detachment are at risk of rapid progression to TEN.
TEN has a greater mortality in older patients.
Rare in children <3 years of age, more common from age 3 years to young adult
Pregnancy is a possible predisposing condition.
- Incidence/prevalence of SJS in the United States is difficult to estimate due to the lack of a universally accepted case definition.
- 1.1 to 7.1 and 0.4 to 1.2 cases/1 million person-years for SJS and TEN, respectively
- Predominant sex: male > female (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
- 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:
- 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
- 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
- Accumulation and binding of reactive drug metabolites to mucocutaneous epithelial cells as haptens (3)
- Drug haptens signal drug-specific CD8+ T lymphocyte and macrophages, which infiltrate and express interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α), and interferon-γ, leading to keratinocyte activation.
- Cytokines enhance keratinocyte expression of soluble Fas ligand and Fas receptors, leading to apoptosis.
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
- Previous history of SJS
- Immunocompromised status, including chronic viral infections with 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
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.