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Summary Table

Domain	Detail
Risk Factors	Recent drug exposure (within 1-3 weeks), HIV/AIDS, HLA-B1502 (carbamazepine in Southeast Asian populations), HLA-B5801 (allopurinol), immunocompromised states, active malignancy, slow acetylator phenotype
Etiology	Drug-induced in >80% of cases. Top offenders: allopurinol, sulfonamide antibiotics, anticonvulsants (carbamazepine, lamotrigine, phenytoin, phenobarbital), nevirapine, oxicam NSAIDs. Infections (Mycoplasma pneumoniae) account for most non-drug cases, particularly in children
Patient Presentation	1-3 day prodrome of fever, malaise, pharyngitis, and skin tenderness followed by rapidly progressive painful erythematous-to-dusky macules with central necrosis, widespread epidermal detachment, and mucosal erosions involving at least two mucosal sites
Classic Physical Exam	Targetoid lesions with dusky/necrotic centers (atypical flat targets), flaccid bullae, sheet-like skin sloughing, positive Nikolsky sign, hemorrhagic crusting of lips, conjunctival injection with pseudomembrane formation, genital erosions
Key Diagnostic Results	Skin biopsy: full-thickness epidermal necrosis with subepidermal detachment and sparse lymphocytic infiltrate at the dermal-epidermal junction. Labs: elevated ESR, lymphopenia, elevated transaminases, possible renal impairment
Management	Immediate withdrawal of the causative drug, transfer to burn unit or ICU, aggressive fluid and electrolyte replacement, wound care with non-adherent dressings, pain control, cyclosporine as emerging first-line immunomodulator, ophthalmology consultation
Keywords	"Sheet-like skin sloughing," "positive Nikolsky sign," "scalded skin appearance," "new drug started 1-3 weeks ago," "mucosal involvement at multiple sites," "targetoid lesions with necrotic centers," "full-thickness epidermal necrosis on biopsy"

1. Pathophysiology

SJS and TEN represent a continuum of the same disease rather than two distinct entities. The underlying mechanism is a drug-induced, immune-mediated cytotoxic reaction targeting keratinocytes. When a susceptible individual is exposed to a culprit drug, the drug or its reactive metabolite is presented by HLA class I molecules on keratinocyte surfaces. This triggers activation of drug-reactive cytotoxic CD8+ T lymphocytes and natural killer (NK) cells in the skin.

The key effector molecule driving keratinocyte death is granulysin, a cytolytic protein secreted by activated cytotoxic T cells and NK cells. Granulysin is the most critical mediator and has been shown to be present in blister fluid at concentrations far exceeding those of other cytotoxic molecules. It induces direct keratinocyte apoptosis in a non-cell-contact-dependent manner, meaning it can spread and cause widespread damage beyond the immediate area of immune cell infiltration. This explains the characteristically disproportionate amount of tissue destruction relative to the sparse inflammatory infiltrate seen on histopathology.

Additional apoptotic pathways contribute to keratinocyte death. The Fas-FasL interaction plays an important role: soluble FasL is upregulated and binds Fas receptors on keratinocytes, activating the caspase cascade and triggering apoptosis. The perforin-granzyme B pathway also participates, with cytotoxic granules directly puncturing keratinocyte membranes. The cumulative effect of these pathways results in confluent epidermal necrosis, where large sheets of epidermis detach from the underlying dermis at the level of the basement membrane zone.

The reason patients develop mucosal involvement is that mucosal epithelium shares the same keratinocyte biology as skin. The oral, ocular, and urogenital mucosae are all susceptible to the same cytotoxic immune attack. This explains why mucosal erosions at two or more sites are a hallmark of the disease and help distinguish SJS/TEN from other blistering disorders.

The genetic susceptibility component is clinically important. Certain HLA alleles dramatically increase the risk of SJS/TEN with particular drugs. HLA-B1502 is strongly associated with carbamazepine-induced SJS/TEN in Southeast Asian and East Asian populations, and HLA-B5801 predisposes to allopurinol-induced SJS/TEN across multiple ethnic groups. These HLA molecules present drug antigens with high efficiency to cytotoxic T cells, lowering the threshold for triggering the immune cascade. This is why pharmacogenomic screening before prescribing these drugs is now recommended in guideline-concordant practice.

2. Classification and Clinical Manifestation

The classification is based entirely on the percentage of body surface area (BSA) with epidermal detachment, which determines disease severity and prognosis.

Classification	BSA Detachment	Clinical Features	Mortality
SJS	<10%	Widespread erythematous-to-purpuric macules with atypical flat targets, limited epidermal detachment, involvement of at least two mucosal surfaces	1-5%
SJS-TEN Overlap	10-30%	Transitional zone; clinical features of both SJS and TEN coexist with intermediate extent of detachment	~10-30%
TEN	>30%	Extensive confluent erythema progressing to sheet-like epidermal sloughing, positive Nikolsky sign over large areas, "scalded" appearance, severe multi-organ involvement	25-50%

Clinical Manifestation by Phase

Phase	Timing	Manifestation
Prodromal phase	Days 1-3 after onset	Fever (often >39C), malaise, arthralgia, upper respiratory symptoms mimicking a viral syndrome, skin tenderness or burning sensation without visible rash
Acute cutaneous phase	Days 3-5	Erythematous or dusky macules appearing first on the trunk and face, rapidly coalescing; atypical flat targetoid lesions (unlike the raised, three-zone targets of erythema multiforme); progression to flaccid bullae and epidermal detachment
Mucosal phase	Often concurrent with skin	Painful oral erosions with hemorrhagic crusting of lips; bilateral conjunctival injection, pseudomembrane formation, corneal erosions; urogenital erosions causing dysuria; possible respiratory and GI tract involvement
Plateau/Extension phase	Days 5-14	Continued expansion of detachment; peak systemic complications including sepsis, acute respiratory distress, electrolyte derangements, acute kidney injury
Recovery phase	Weeks 2-4+	Re-epithelialization begins; scarring complications emerge (ocular synechiae, skin dyspigmentation, nail dystrophy, urogenital strictures)

Mucosal Involvement

Site	Frequency	Key Findings
Oral	~90%	Painful erosions on buccal mucosa, lips, tongue; hemorrhagic crusting of vermilion border; odynophagia limiting oral intake
Ocular	~80%	Bilateral purulent conjunctivitis, pseudomembrane formation, corneal ulceration, risk of long-term cicatrizing complications including symblepharon and visual impairment
Urogenital	~70%	Erosions of vulvar/vaginal mucosa or glans/urethral meatus; dysuria; risk of stricture formation
Respiratory	~25%	Bronchial epithelial sloughing can cause hypoxia, bronchial casts, and respiratory failure requiring mechanical ventilation

3. Diagnostic Workup

Test	Role	Expected Finding
Clinical assessment + drug history	Best initial step	Temporal correlation with culprit drug (onset 1-3 weeks for first exposure, 1-3 days for re-exposure); painful rash with mucosal involvement; Nikolsky sign
Skin biopsy (frozen section)	Confirmatory / gold standard	Full-thickness epidermal necrosis with subepidermal cleavage; sparse perivascular lymphocytic infiltrate; necrotic keratinocytes throughout all epidermal layers
CBC	Supportive	Lymphopenia (marker of severity), neutropenia, anemia
CMP (metabolic panel)	Supportive / prognostic	Elevated BUN/creatinine (renal involvement), elevated transaminases (hepatic involvement), electrolyte derangement from fluid losses, hypoalbuminemia
Blood cultures	Rule out sepsis	Obtained routinely due to high infection risk from loss of skin barrier
SCORTEN score	Prognostic scoring	Calculated within first 24 hours and at day 3 to predict mortality
Direct immunofluorescence (DIF)	Differentiating from autoimmune blistering	Negative in SJS/TEN (positive in pemphigus, bullous pemphigoid, linear IgA disease)
Chest X-ray	Baseline and monitoring	Evaluate for pulmonary involvement, bronchial epithelial sloughing, or secondary pneumonia
Ophthalmologic slit-lamp exam	Required early consultation	Assess for corneal ulceration, pseudomembranes, symblepharon formation

The diagnosis of SJS/TEN is fundamentally clinical, made at the bedside by recognizing the triad of recent drug exposure, painful cutaneous eruption with epidermal detachment, and mucosal involvement at two or more sites. The best initial step when you suspect SJS/TEN is a thorough drug history and clinical assessment including evaluation of BSA involvement.

The next step after clinical suspicion is skin biopsy, which serves as the confirmatory test. A punch biopsy taken from the edge of an active lesion (including both affected and unaffected skin) or a frozen section of sloughed epidermis should be sent for both standard histopathology and direct immunofluorescence. The histopathologic hallmark is full-thickness epidermal necrosis with a subepidermal split at the dermal-epidermal junction. The dermis shows only a sparse, predominantly lymphocytic infiltrate. This pattern of extensive epithelial destruction with minimal inflammation is the histologic signature and reflects the apoptosis-driven (rather than inflammation-driven) pathogenesis.

Direct immunofluorescence must be negative in SJS/TEN. This is a key test for ruling out autoimmune blistering diseases that can mimic TEN, such as paraneoplastic pemphigus, linear IgA bullous dermatosis, and bullous pemphigoid. If DIF shows IgG deposits along the basement membrane zone or intercellular deposits, the diagnosis shifts away from SJS/TEN.

The SCORTEN prognostic score should be calculated within 24 hours of admission and recalculated at day 3. It includes seven independent risk factors, each scored as 0 or 1:

SCORTEN Parameter	Criterion (1 point each)
Age	> 40 years
Heart rate	> 120 bpm
Malignancy	Active cancer present
BSA detachment	> 10% on day 1
Serum urea	> 10 mmol/L (BUN > 28 mg/dL)
Serum bicarbonate	< 20 mmol/L
Serum glucose	> 14 mmol/L (> 252 mg/dL)

SCORTEN	Predicted Mortality
0-1	3%
2	12%
3	35%
4	58%
5+	> 90%

4. Management and Treatment

Phase	Intervention	Details
Immediate (Hour 0)	Withdraw the offending drug	Identify and stop ALL potentially causative medications immediately; earlier withdrawal correlates with better survival
Acute supportive care	Transfer to burn unit/ICU	Patients with >10% BSA detachment should be managed in a burn center; reverse isolation to minimize infection risk
Fluid resuscitation	IV crystalloid	Fluid requirements are lower than typical burn patients; start with approximately 0.7 mL/kg per percent BSA affected; titrate to urine output 0.5-1 mL/kg/hr
Wound care	Non-adherent dressings	Gentle debridement of necrotic epidermis vs. conservative approach (leaving detached epidermis as biologic dressing); avoid silver sulfadiazine in sulfonamide-triggered cases
Temperature management	Maintain ambient temperature 30-32C	Thermoregulatory failure from skin loss; hypothermia prevention is essential
Pain control	IV opioids, acetaminophen	Avoid NSAIDs if suspected trigger; mucosal pain requires systemic analgesia, not just topical
Nutritional support	Enteral nutrition via NG tube	Early initiation within 24 hours; caloric needs calculated similarly to burn patients at ~25-30 kcal/kg/day
Immunomodulation	Cyclosporine A	3-5 mg/kg/day in divided doses for 10-14 days with taper; emerging evidence supports this as the preferred systemic agent
Ophthalmologic care	Immediate and ongoing	Preservative-free lubricants, topical corticosteroid drops, daily pseudomembrane lysis with glass rod, amniotic membrane transplantation for severe ocular involvement
Infection prevention	Cultures, no prophylactic antibiotics	Monitor closely for signs of sepsis; systemic antibiotics only when infection is documented, not prophylactically
VTE prophylaxis	Low-molecular-weight heparin	Standard thromboprophylaxis for immobilized patients

Drug withdrawal is the single most important intervention and the answer to "what is the most important first step" on an exam vignette. The mortality benefit of drug withdrawal is time-dependent: drugs with short half-lives (e.g., sulfonamides) that are stopped early carry a better prognosis than drugs with long half-lives (e.g., allopurinol, phenobarbital) stopped late. Every hour of delay in withdrawing the causative agent worsens outcomes. When multiple drugs are suspect, stop all potentially causative agents, not just the most likely one.

Supportive care in a burn unit is the backbone of treatment. Fluid resuscitation follows principles similar to burn care but at reduced volumes (roughly two-thirds of standard Parkland formula estimates) because the dermal vasculature is less damaged in SJS/TEN than in thermal burns. Electrolytes, renal function, and serum albumin must be monitored frequently. Albumin replacement may be needed for significant hypoalbuminemia.

Regarding immunomodulatory therapy, the evidence landscape has shifted considerably. Cyclosporine A at a dose of 3-5 mg/kg/day divided into two doses for 10-14 days followed by a taper is now considered the most evidence-supported systemic agent based on multiple observational studies and a randomized trial showing improved re-epithelialization time and reduced mortality. Cyclosporine works by inhibiting T-cell activation and reducing the cytotoxic immune response driving keratinocyte death. It is contraindicated in patients with uncontrolled infections, severe renal impairment, or uncontrolled hypertension. Monitor renal function and blood pressure closely during treatment.

Systemic corticosteroids remain controversial. Short-course, high-dose pulse corticosteroids (dexamethasone 1.5 mg/kg IV over 3 days) have shown benefit in some studies when given very early. However, prolonged corticosteroid use is associated with increased infection risk, delayed wound healing, and higher mortality, and most current guidelines advise against prolonged courses.

IVIG was historically used but has not shown consistent survival benefit in well-designed studies and is no longer considered first-line. If used, the theoretical mechanism is blockade of Fas-FasL interaction by anti-Fas antibodies present in pooled immunoglobulin. The dose studied is typically 0.2-0.5 g/kg/day for 3-4 consecutive days (total dose ~1-2 g/kg).

Ocular management deserves emphasis because ocular complications are the leading cause of long-term morbidity. Daily slit-lamp examinations during the acute phase, aggressive lubrication with preservative-free tears, topical corticosteroids (e.g., prednisolone acetate 1% every 2-4 hours), and mechanical lysis of forming synechiae are essential. In severe cases, amniotic membrane transplantation within the first 1-2 weeks can prevent cicatricial complications including symblepharon, trichiasis, and corneal opacification.

5. Differential Diagnosis and Distractors

Differential Diagnosis	Why It Is Similar	Key Discriminator
Staphylococcal Scalded Skin Syndrome (SSSS)	Widespread skin sloughing, positive Nikolsky sign, "scalded" appearance	SSSS occurs in young children/neonates, has NO mucosal involvement, biopsy shows cleavage within the granular layer (superficial split) rather than full-thickness necrosis, and is caused by exfoliative toxins from S. aureus
Erythema Multiforme Major	Targetoid lesions, mucosal erosions, often drug-related	EM has raised, three-zone "typical" targets (not the flat, atypical targets of SJS); distribution is acral (hands, feet, elbows, knees) rather than truncal; limited BSA involvement; often triggered by HSV, not drugs
Autoimmune Blistering Diseases (Pemphigus vulgaris, Bullous pemphigoid)	Flaccid bullae, mucosal erosions, positive Nikolsky sign (in pemphigus)	Autoimmune blistering diseases have positive direct immunofluorescence (intercellular IgG in pemphigus, linear IgG/C3 at BMZ in BP); chronic course without drug temporal relationship; no full-thickness epidermal necrosis on biopsy
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)	Drug-induced, fever, skin eruption, occurs 2-8 weeks after drug exposure	DRESS presents with facial edema, morbilliform exanthema (not epidermal detachment), marked eosinophilia, atypical lymphocytosis, internal organ involvement (hepatitis, nephritis, myocarditis); no Nikolsky sign, no mucosal erosions typically
Acute Generalized Exanthematous Pustulosis (AGEP)	Drug-induced, fever, acute skin eruption	AGEP shows hundreds of small non-follicular sterile pustules on an edematous erythematous base, not bullae or epidermal detachment; neutrophilia (not lymphopenia); rapid resolution within 1-2 weeks after drug withdrawal
Toxic Shock Syndrome	Acute onset, high fever, diffuse erythroderma, skin desquamation, multi-organ dysfunction	TSS desquamation occurs 1-2 weeks after onset (late finding), not acutely; diffuse blanching "sunburn-like" erythroderma rather than targetoid lesions or bullae; no mucosal erosions; positive blood/wound cultures for toxin-producing organisms
Paraneoplastic Pemphigus	Severe mucosal erosions, skin blistering, can mimic TEN histologically	PNP has polymorphic skin lesions, positive DIF with combined intercellular and BMZ staining, underlying neoplasm (usually lymphoproliferative), anti-plakin antibodies, and lichenoid interface changes on biopsy alongside acantholysis

6. Traps and High-Yield Pearls

The most common way students lose points on SJS/TEN questions is failing to distinguish SJS from Erythema Multiforme Major. Test writers exploit this by presenting a patient with targetoid lesions and oral erosions. The critical discriminator is the morphology of the targets and the distribution: EM has raised, typical three-zone targets on the extremities (acral distribution), whereas SJS has flat, atypical targets concentrated on the trunk. Additionally, EM is most commonly triggered by HSV infection, while SJS is almost always a drug reaction. If the vignette mentions a recent herpes outbreak and acral targets, think EM. If it mentions a new medication started 1-3 weeks ago and truncal involvement with mucosal erosions, think SJS.

A second common trap involves SSSS vs. TEN in a pediatric patient. Both present with widespread skin sloughing and a positive Nikolsky sign. The discriminator tested is mucosal involvement: SSSS spares the mucosa, while SJS/TEN always involves it. Additionally, the biopsy cleavage plane differs fundamentally: SSSS splits superficially within the granular layer (intraepidermal), while TEN shows full-thickness epidermal necrosis with subepidermal detachment.

Students also frequently miss the "Next Best Step" logic in management questions. When a vignette presents an acute SJS/TEN case, the answer to "what is the most important first step" is always immediate withdrawal of the offending drug, not starting IVIG, not transferring to a burn unit, and not ordering a biopsy. Drug withdrawal is both the first and highest-yield intervention.

Finally, be alert for pharmacogenomic screening questions. If a vignette describes a Southeast Asian patient about to start carbamazepine, the next step before prescribing is HLA-B1502 testing. If the vignette describes any patient about to start allopurinol (particularly in Southeast Asian or African American populations), the next step is HLA-B5801 testing. This represents the tested competency of preventing SJS/TEN through pre-prescription genetic screening, which is increasingly emphasized as a testable concept.

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