Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
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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Risk factors
- Drugs (>80% of cases): allopurinol, anticonvulsants (lamotrigine, carbamazepine, phenytoin, phenobarbital), sulfonamide antibiotics (TMP-SMX, sulfasalazine), NSAIDs (especially oxicams — piroxicam, meloxicam), nevirapine, abacavir, sertraline, immune checkpoint inhibitors
- Genetic predisposition (pharmacogenomic): HLA-B*15:02 with carbamazepine (Han Chinese, Southeast Asian); HLA-B*58:01 with allopurinol (Han Chinese, Thai, Korean); HLA-B*57:01 with abacavir
- HIV (1000x increased risk)
- Active malignancy, autoimmune disease, recent radiation therapy + phenytoin (EMPACT syndrome)
- 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.
Clinical presentation
Symptoms
- Prodrome 1-3 days: fever ≥38°C, malaise, sore throat, photophobia, dysphagia, cough
- 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
- Paraneoplastic pemphigus — Painful mucositis, polymorphous skin lesions, underlying malignancy; positive desmoplakin antibodies
- Generalized bullous fixed drug eruption — Recurs at same sites with rechallenge, fewer mucosal sites, lower mortality
Diagnostic workup
Diagnostic criteria
Clinical + histopathologic confirmation; SJS/TEN spectrum defined by BSA epidermal detachment.
Labs
- CBC (cytopenias common), CMP (renal/hepatic dysfunction), CRP, glucose, bicarbonate, urea
- 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
- Skin biopsy: full-thickness epidermal necrosis with subepidermal blister; minimal dermal inflammation
- Direct immunofluorescence (negative — helps distinguish from autoimmune bullous diseases)
- Cultures (blood, skin, urine) to identify sepsis
- Mycoplasma serology and HIV testing
Imaging
- Chest X-ray — pneumonitis or aspiration
- Bronchoscopy if airway involvement suspected
Diagnostic algorithm
| Parameter | SJS | SJS/TEN Overlap | TEN |
|---|---|---|---|
| BSA detachment | <10% | 10-30% | >30% |
| Typical mortality | ~10% | ~30% | ~30-50% |
| Lesion morphology | Atypical flat targets + macules + bullae | Mixed | Confluent erythema with sheet-like detachment |
| Mucosal involvement | Severe, ≥2 sites | Severe | Severe, ≥2 sites |
| Main triggers | Drugs (>80%) — allopurinol, anticonvulsants, sulfa, NSAIDs | Drugs | Drugs |
| Setting of care | Specialized burn/ICU | Burn/ICU | Burn/ICU |
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) — central line, 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
- • Ophthalmology consultation daily — lubrication, topical steroids, amniotic membrane
- • Urology/gynecology consultation for genital involvement
Immunomodulatory therapy (controversial, evidence limited)
- 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*57:01, 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 (occurs in 35% of TEN survivors)
- • Cutaneous: post-inflammatory dyspigmentation, scarring, nail dystrophy, alopecia
- • Mucosal: oral synechiae, esophageal/vaginal strictures, urethral stenosis, anal stenosis
- • Pulmonary: bronchiolitis obliterans
- • Psychiatric: PTSD, depression, anxiety
PANCE pearls
- 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.
- 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
- FDA / AAAAI — Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis Clinical Practice Statements (AAD/AAAAI guidance)
- 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)
- AAD 2024 — Severe Cutaneous Adverse Reactions to Drugs (AAD work group)
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