Drug-induced severe mucocutaneous reaction with widespread keratinocyte apoptosis and epidermal detachment; life-threatening.
Also known as: SJS, TEN, Stevens-Johnson syndrome, toxic epidermal necrolysis, Lyell syndrome, SCAR
Overview
A spectrum of severe cutaneous adverse drug reactions characterized by widespread keratinocyte apoptosis with full-thickness epidermal detachment and mucosal involvement. Classified by BSA detachment: SJS <10%, SJS/TEN overlap 10-30%, TEN >30%.
Epidemiology
Rare: SJS 1-7/million person-years; TEN 0.4-1.5/million person-years. Higher in HIV (1000x), SLE, hematologic malignancy. Mortality: SJS ~10%, SJS/TEN overlap ~30%, TEN ~30-50%. SCORTEN score predicts mortality.
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Question 1DermatologyMedium
A 58-year-old man presents with a 2-day history of fever, painful skin, and burning eyes followed by dusky red macules on the face and trunk that are beginning to blister and slough. He has erosions on the lips and oral mucosa and conjunctival injection. Nikolsky sign is positive. His clinician suspects Stevens-Johnson syndrome and reviews his medication list, noting several drugs started over the past month. Which of the following recently started medications is the strongest risk factor for this condition?
AAllopurinol
BHydralazine
CClopidogrel
DFurosemide
EAtorvastatin
Reveal answer & full explanation
Correct answer: A — Allopurinol
AAllopurinol✓
BHydralazine
CClopidogrel
DFurosemide
EAtorvastatin
Why Allopurinol is correct
Drugs cause more than 80% of SJS/TEN cases, and allopurinol is currently the single most common drug culprit in many series, particularly when started within the prior 4-28 days.
Other high-risk culprit classes include aromatic anticonvulsants (carbamazepine, lamotrigine, phenytoin, phenobarbital), sulfonamide antibiotics, oxicam NSAIDs, and nevirapine; the recent new-drug exposure plus painful skin and multisite mucosal involvement points to a high-risk culprit.
HLA-B*58:01 strongly predisposes to allopurinol-induced SJS/TEN in Han Chinese, Thai, and Korean patients, and allopurinol should never be prescribed for asymptomatic hyperuricemia.
Why the others are wrong
Atorvastatin: statins are very commonly prescribed but are not recognized high-risk SJS/TEN triggers, and their cutaneous reactions are rare and usually mild.
Hydralazine: classically causes drug-induced lupus rather than the keratinocyte apoptosis and full-thickness epidermal detachment of SJS/TEN.
Clopidogrel: an antiplatelet agent that is not a recognized cause of SJS/TEN.
Furosemide — a loop diuretic with a sulfonamide group, which tempts students who equate any sulfa drug with SJS/TEN, but the high-risk sulfonamides are the antibiotics such as TMP-SMX, and loop diuretics are not recognized high-risk triggers.
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Genetic predisposition (pharmacogenomic): HLA-B*15:02 with carbamazepine (Han Chinese, Southeast Asian); HLA-B*58:01 with allopurinol (Han Chinese, Korean, Thai; testing also advised in African American patients). HLA-B*57:01 predicts abacavir hypersensitivity syndrome, a different reaction, not SJS/TEN
Mycoplasma pneumoniae and rare other infections (more often produce MIRM)
Pathophysiology
Drug or drug metabolite presented by HLA molecules → activation of cytotoxic CD8+ T-cells specific for drug-MHC complex → release of granulysin, perforin/granzyme, FasL → widespread keratinocyte apoptosis at the dermal-epidermal junction → full-thickness epidermal necrosis and detachment. Onset 4-28 days after starting offending drug.
Painful skin (burning, stinging) — often precedes visible rash
Eye discomfort, conjunctival injection
Oral, genital, respiratory pain
Signs / physical exam
Initial: dusky red/purple macules and atypical flat targets on face and trunk → centrifugal spread to extremities (NOTE: opposite distribution to EM)
Progression to flaccid bullae and full-thickness epidermal sloughing — wrinkles like 'wet cigarette paper' under pressure
Positive Nikolsky sign (lateral pressure shears epidermis) and Asboe-Hansen sign (bullae extend with pressure)
Severe mucosal involvement (≥2 sites in 90%): hemorrhagic crusted lips, painful oral erosions, purulent conjunctivitis with pseudomembranes/symblepharon, genital ulceration, urethritis, esophagitis, tracheobronchitis
Detachment: SJS <10% BSA, SJS/TEN overlap 10-30%, TEN >30%
Classic findings
Skin pain disproportionate to visible findings; widespread dusky targets; mucosal involvement at multiple sites; positive Nikolsky.
Differential diagnosis
Erythema multiforme major — Acral typical 3-zone targets, HSV-triggered, no significant skin detachment, low mortality
Staphylococcal scalded skin syndrome (SSSS) — Young children, no mucosal involvement, cleavage in granular layer (superficial), positive Nikolsky on inflamed skin only
Drug-induced linear IgA bullous dermatosis — String-of-pearls bullae, less systemic; DIF linear IgA at BMZ
Acute generalized exanthematous pustulosis (AGEP) — Sterile pustules on erythema, fever, neutrophilia; resolves in days after drug stopped
DRESS / DIHS — Drug Reaction with Eosinophilia and Systemic Symptoms — fever, facial edema, morbilliform rash, lymphadenopathy, eosinophilia, hepatitis; 2-8 weeks after drug
Calculate SCORTEN within 24 h and at 72 h (7 variables: age >40, malignancy, HR >120, BSA >10%, BUN >10 mmol/L, glucose >14 mmol/L, bicarbonate <20 mmol/L) — predicts mortality
SJS / SJS-TEN overlap / TEN spectrum classification.
Treatment
First-line
IMMEDIATELY discontinue all suspected offending medications — single most important intervention
Transfer to specialized burn unit or ICU — improved survival vs general ward
Supportive care (analogous to severe burns):
• Fluid resuscitation (less than burn formulas; ~2/3 of standard burn fluids) — IV access through non-lesional skin (peripheral preferred; central line only if needed), urine output 0.5-1 mL/kg/h
• Temperature regulation (ambient 28-30°C)
• Nutritional support — enteral feeding preferred
• Wound care: non-adherent dressings, avoid debridement of detached epidermis (acts as biologic dressing)
• Pain control
• Prevent infection — surveillance cultures; antibiotics ONLY if documented infection, not prophylactic
Cyclosporine 3-5 mg/kg/day for 7-10 days — most evidence-supported; reduces mortality in observational studies
Etanercept 50 mg SC × 1-2 doses — emerging evidence; possibly improved time to re-epithelialization
IVIG — formerly used, evidence mixed; no longer routinely recommended
Systemic corticosteroids — controversial; high-dose pulse early may benefit, prolonged courses associated with sepsis and worse outcome
Second-line / adjunct
Document the offending drug clearly in medical record and provide patient with allergy alert/MedicAlert bracelet
Pharmacogenomic counseling for family members (HLA-B*15:02, HLA-B*58:01)
Counsel patient to AVOID re-exposure to the offending drug and structurally related compounds (e.g., aromatic anticonvulsant cross-reactivity)
Complications
Acute (days to weeks):
• Sepsis and bacteremia (leading cause of mortality)
• Pneumonia, ARDS
• Hypovolemic shock, acute kidney injury
• GI hemorrhage, intestinal perforation
• Thromboembolism, hepatic dysfunction
Chronic (months to lifelong):
• Ocular: chronic dry eye, symblepharon, trichiasis, corneal scarring, vision loss (chronic ocular sequelae in roughly one-third or more of survivors; severe visual loss is less common)
• Cutaneous: post-inflammatory dyspigmentation, scarring, nail dystrophy, alopecia
Painful skin disproportionate to visible findings + new drug exposure in past month = SJS/TEN until proven otherwise.
Allopurinol is currently the most common single drug culprit in many series — never prescribe for asymptomatic hyperuricemia.
HLA-B*15:02 testing is recommended before starting carbamazepine in patients of Han Chinese or Southeast Asian descent; HLA-B*58:01 testing is recommended before allopurinol in patients of Southeast Asian descent (Han Chinese, Korean, Thai) and African American patients (ACR 2020 gout guideline).
Cyclosporine is the immunomodulator with the most consistent mortality benefit; IVIG and high-dose steroids are NOT routinely recommended.
Survivors require lifelong ophthalmology follow-up and pharmacogenomic counseling for themselves and first-degree relatives.
References
SDH 2020 — Society of Dermatology Hospitalists Supportive Care Guidelines for the Management of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis in Adults (Seminario-Vidal et al., J Am Acad Dermatol 2020;82(6):1553-1567)
Bastuji-Garin SCORTEN — SCORTEN: A Severity-of-Illness Score for Toxic Epidermal Necrolysis (Bastuji-Garin et al., J Invest Dermatol 2000)
BAD 2016 — UK Guidelines for the Management of Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis in Adults (Creamer et al., Br J Dermatol 2016)
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