Dermatology · PANCE / PANRE

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

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) — 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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