Drug Eruptions: Stevens-Johnson Syndrome (SJS) & Toxic Epidermal Necrolysis (TEN)

1. Topic Overview (Clinical Overview)

Summary

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) represent severe, life-threatening mucocutaneous drug reactions characterised by widespread keratinocyte apoptosis leading to full-thickness epidermal necrosis and detachment. [1,2] They form a continuum of disease severity defined by percentage of Body Surface Area (BSA) affected: SJS (less than 10% BSA), SJS/TEN Overlap (10-30% BSA), and TEN (> 30% BSA). [1,3] The condition is predominantly drug-induced (> 80% of cases), with allopurinol, anticonvulsants (carbamazepine, lamotrigine, phenytoin), sulfonamide antibiotics, and NSAIDs being the most common culprits. [1,4]

The hallmark clinical features include a prodrome of fever and flu-like symptoms followed by targetoid or dusky erythematous macules that progress to flaccid blisters and sheet-like epidermal detachment. [1,2] The Nikolsky sign is positive (lateral pressure on uninvolved skin causes epidermal separation), reflecting the underlying full-thickness necrosis. [5] Mucosal involvement is almost universal, affecting oral, ocular, and genital surfaces with erosions, pseudomembranes, and haemorrhagic crusting. [1,6] Ocular complications can lead to permanent visual impairment or blindness if not managed aggressively. [7,8]

Immediate cessation of the causative drug is the single most critical intervention, with evidence showing that delayed withdrawal (> 7 days from symptom onset) significantly worsens mortality. [9] Patients require intensive supportive care in a burns unit or specialist dermatology high-dependency setting, focusing on fluid resuscitation (though less than standard burns formulae due to absence of capillary leak), wound care with non-adherent dressings, temperature control, nutritional support, and infection surveillance. [10,11] Daily ophthalmology review is mandatory for all patients with ocular involvement to prevent synechiae and scarring. [7,8]

SCORTEN (Severity-of-illness Score for Toxic Epidermal Necrolysis) is a validated 7-parameter prognostic tool calculated within 24 hours and at day 3, predicting mortality from 3% (score 0-1) to > 90% (score ≥5). [12] Overall mortality is 5-10% for SJS and 25-35% for TEN, with sepsis being the leading cause of death. [1,13] Adjunctive immunomodulatory therapies including intravenous immunoglobulin (IVIG), ciclosporin, and systemic corticosteroids remain controversial with limited high-quality evidence, though some centres use ciclosporin based on emerging data. [14,15]

Key Facts

• Definition Spectrum (By BSA Detachment): SJS (less than 10%), SJS/TEN Overlap (10-30%), TEN (> 30%). [1,3]
• Main Cause: Drug-induced (> 80%); rare cases from infections (Mycoplasma pneumoniae, HSV). [4,16]
• Culprit Drugs: Allopurinol, anticonvulsants (lamotrigine, carbamazepine, phenytoin, phenobarbital), sulfonamides (co-trimoxazole), NSAIDs (oxicam class). [1,4]
• Incidence: SJS 1-6 per million/year; TEN 0.4-1.2 per million/year. [1]
• Nikolsky Sign: Positive (epidermis separates from dermis with lateral pressure). [5]
• Mucosal Involvement: Oral (haemorrhagic crusting, erosions), ocular (conjunctivitis, pseudomembranes, risk of blindness), genital (erosions, urinary retention). [1,6,7]
• Mortality: SJS 5-10%, TEN 25-35%; predicted by SCORTEN score. [12,13]
• Pathophysiology: CD8+ T-cell-mediated cytotoxicity with granulysin as key effector molecule inducing keratinocyte apoptosis. [17,18]
• HLA Associations: HLA-B15:02 (carbamazepine in Han Chinese/SE Asians), HLA-B58:01 (allopurinol). [19,20]
• Management Cornerstones: Immediate drug withdrawal, burns unit supportive care, ophthalmology input, infection surveillance. [10,11]

Clinical Pearls

"Stop the Drug Immediately": Culprit drug identification and cessation within 24 hours is the single most important determinant of outcome. Drugs with long half-lives (allopurinol, phenobarbital) confer worse prognosis. [9]

"Nikolsky Sign = Emergency": Positive Nikolsky sign indicates full-thickness epidermal necrosis and differentiates SJS/TEN from other blistering disorders. Immediate admission to burns/HDU setting required. [5]

"Eyes, Eyes, Eyes": Ocular involvement occurs in 70-90% of cases. Daily ophthalmology review with aggressive lubrication, steroid drops, and mechanical lysis of synechiae prevents blindness. [7,8]

"SCORTEN is Your Friend": Calculate SCORTEN within 24 hours (age > 40, heart rate > 120, malignancy, BSA > 10%, urea > 10 mmol/L, bicarbonate less than 20 mmol/L, glucose > 14 mmol/L). Recalculate at day 3. [12]

"Less Fluid Than Burns": Unlike thermal burns, there is no significant capillary leak in TEN. Excessive fluid resuscitation increases mortality. Use approximately 50% of Parkland formula estimates. [10]

"Supportive Care is Paramount": No adjunctive immunomodulatory therapy (IVIG, ciclosporin, corticosteroids) has robust evidence from RCTs. The mainstay of treatment remains meticulous supportive care. [14,15]

Why This Matters Clinically

SJS/TEN are dermatological emergencies with high mortality and devastating long-term sequelae including blindness, chronic ocular surface disease, genital scarring, and psychological trauma. Early recognition (prodromal fever and malaise preceding rash, mucosal involvement, positive Nikolsky sign), immediate drug withdrawal, and transfer to specialist centres with burns unit capabilities save lives. Delayed diagnosis or inappropriate management (e.g., continuing the culprit drug, treating as minor drug eruption, inadequate ophthalmology input) results in exponentially increased morbidity and mortality. The condition represents a "test case" for drug safety vigilance, particularly in high-risk populations (HIV/AIDS patients have 100-fold increased risk) and those with known HLA risk alleles requiring pharmacogenetic screening before prescribing high-risk drugs.

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2. Epidemiology

Incidence and Prevalence

• SJS: 1-6 cases per million population per year. [1]
• TEN: 0.4-1.2 cases per million population per year. [1]
• SJS/TEN Overlap: Approximately 0.5-1 per million population per year. [3]
• Combined SJS/TEN: Estimated 2-7 cases per million population per year across all subtypes. [1,13]

Age Distribution

• Bimodal distribution: Peak incidence in young adults (20-40 years) and elderly (> 65 years). [1]
• Median age of onset: 46-63 years (TEN typically occurs in older patients than SJS). [13]
• Paediatric cases: Represent 10-15% of all cases; higher proportion associated with Mycoplasma pneumoniae infection rather than drugs. [16]

Sex Distribution

• Slight female predominance: Female:male ratio approximately 1.5:1 to 2:1 (may reflect higher drug exposure in women). [1,13]

Geographic and Ethnic Variation

• Global distribution: Occurs worldwide, but incidence varies based on drug prescribing patterns and genetic factors.
• Higher incidence in Asians: Related to higher frequency of risk alleles (HLA-B15:02, HLA-B58:01) and use of allopurinol/carbamazepine. [19,20]
• HIV-endemic regions: Higher incidence due to 100-fold increased risk in HIV/AIDS patients and frequent use of culprit drugs (co-trimoxazole, nevirapine). [21]

Risk Factors

Seasonal Variation

• No consistent seasonal pattern, though some studies suggest higher incidence in spring/summer (may relate to increased antibiotic/NSAID use). [1]
• Mycoplasma-associated cases: May show seasonal clustering (autumn/winter) reflecting Mycoplasma pneumoniae epidemiology. [16]

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3. Aetiology

Drugs (> 80% of Cases)

The latency period (time from drug initiation to symptom onset) is typically 1-3 weeks for most drugs, but can extend up to 8 weeks for anticonvulsants. [1,4] Reactions occurring within 24-48 hours of first exposure are extremely rare and should prompt consideration of prior occult exposure.

High-Risk Drugs (Most Common Culprits)

Moderate-Risk Drugs

• Antibiotics: Tetracyclines (minocycline, doxycycline), macrolides (azithromycin, rare).
• Antifungals: Fluconazole, voriconazole (rare).
• Immunosuppressants: Azathioprine (rare, case reports).
• Biologics: Anti-TNF agents (infliximab, adalimumab), immune checkpoint inhibitors (nivolumab, pembrolizumab) - rare but increasingly recognized. [23]

Lower-Risk but Documented Drugs

• Proton pump inhibitors (PPIs): Omeprazole, pantoprazole (rare, case reports).
• Antihypertensives: Hydralazine, captopril (rare).
• Analgesics: Paracetamol (acetaminophen) - extremely rare, usually confounded by co-administered NSAIDs.

Infections (Minority of Cases, ~5-10%)

Distinguishing Drug-Induced vs Infection-Induced SJS/TEN

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4. Pathophysiology

Overview of Mechanism

SJS/TEN is a T-cell-mediated cytotoxic reaction targeting keratinocytes, leading to widespread apoptosis and full-thickness epidermal necrosis. [17,18] The process involves drug presentation, immune activation, and effector-mediated keratinocyte death.

Step-by-Step Pathogenesis

Key Cytotoxic Mediators

Granulysin (Primary Effector)

• Secreted by CTLs, NK cells, NKT cells.
• 15 kDa protein that forms pores in cell membranes.
• Directly induces keratinocyte apoptosis.
• Elevated in blister fluid and serum in SJS/TEN patients (> 1000-fold higher than controls). [18]
• Concentration correlates with disease severity and extent of epidermal necrosis.
• Potential diagnostic biomarker: Early elevation may precede clinical detachment.

Fas-Fas Ligand (FasL) Pathway

• Fas (CD95) expressed on keratinocytes.
• FasL expressed on activated CTLs.
• Fas-FasL binding triggers caspase 8 → caspase 3 apoptotic cascade.
• Soluble FasL (sFasL) elevated in serum of SJS/TEN patients. [17]

Perforin/Granzyme B

• Perforin forms pores in target cell membranes.
• Granzyme B (serine protease) enters through pores and activates caspases.
• Provides redundant cytotoxic pathway alongside granulysin and Fas-FasL.

Genetic Susceptibility: HLA Associations

Mechanism of HLA Associations:

• "Altered peptide repertoire" hypothesis: HLA-B*15:02/58:01 preferentially bind and present drug-modified peptides.
• "Altered TCR repertoire" hypothesis: Specific HLA alleles interact with restricted TCR Vβ usage, lowering activation threshold. [24]
• Direct drug-HLA-TCR interaction (p-i concept): Drug binds directly to HLA groove, creating neo-epitope recognized by TCR without peptide modification. [17,24]

Why Only a Minority with Risk Alleles Develop SJS/TEN?

• HLA allele is necessary but not sufficient: Positive predictive value of HLA-B15:02 for carbamazepine-SJS is only ~3% (i.e., 97% of HLA-B15:02+ individuals tolerate carbamazepine). [19]
• Additional co-factors required: Other genetic factors (non-HLA genes), viral infections (reactivation of herpesviruses may provide co-stimulatory signals), drug dosage, metabolic factors.
• Stochastic immune activation: Chance formation of high-affinity drug-HLA-TCR complexes in individuals with particular TCR repertoires.

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5. Classification

By Body Surface Area (BSA) of Epidermal Detachment

SJS, SJS/TEN Overlap, and TEN represent a single disease continuum differentiated by extent of epidermal detachment rather than distinct pathological entities. [1,3]

Calculating BSA:

• Rule of Nines (adults): Head/neck 9%, each arm 9%, anterior trunk 18%, posterior trunk 18%, each leg 18%, perineum 1%.
• Palmar method: Patient's palm (including fingers) ≈ 1% BSA. Useful for rapid bedside estimation.
• Lund-Browder chart: More accurate (accounts for age-related proportions), preferred in paediatric cases.

Key Point: BSA includes both areas of frank epidermal detachment (denuded skin) and areas of erythema with epidermal detachment on gentle pressure (positive Nikolsky sign areas). [1]

Relationship to Erythema Multiforme (EM)

Historically, SJS was considered part of the erythema multiforme (EM) spectrum. Current consensus treats them as distinct entities: [1,25]

Clinical Implication: Differentiating EM major from SJS is critical (EM is self-limiting; SJS is life-threatening). Key differentiators: Nikolsky sign, extent/depth of epidermal necrosis, drug vs infection history.

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6. Clinical Presentation

Timeline of Disease Evolution

Prodromal Symptoms (1-3 Days Before Rash)

Prodrome is non-specific and often mistaken for viral illness or reaction to underlying infection being treated. Diagnosis becomes apparent only with rash onset. [1]

Skin Manifestations

Early Lesions (First 24-48 Hours)

• Erythematous macules: Dusky red, round or oval, 1-3 cm diameter.
• Distribution: Initially face, trunk, proximal limbs. Spreads centrifugally.
• Atypical targets: Poorly defined, 2 zones (dusky centre + erythematous rim), unlike well-defined 3-zone targets of EM. [25]
• Confluence: Lesions coalesce to form sheets of erythema.

Blisters and Epidermal Detachment (Days 2-5)

Healed Lesions (Weeks 2-4)

• Post-inflammatory hyperpigmentation: Especially in darker skin types. Can be disfiguring.
• Post-inflammatory hypopigmentation: Patchy depigmentation.
• Scarring: Usually minimal on skin (unlike mucosal surfaces), but can occur in areas of secondary infection.

Mucosal Involvement (Present in > 90% of Cases)

Mucosal involvement is a defining feature of SJS/TEN and often precedes skin detachment by 1-2 days. [1,6]

Oral Mucosa (> 90% of Cases)

Ocular Involvement (70-90% of Cases)

Ocular complications are the LEADING CAUSE of long-term morbidity and can result in permanent visual impairment or blindness. [7,8]

Key Management Principle: Ophthalmology involvement from day 1. Daily or twice-daily examinations, aggressive lubrication, mechanical lysis of synechiae, and consideration of amniotic membrane grafting can prevent devastating chronic ocular surface disease. [7,8]

Genital Mucosa (50-70% of Cases)

Respiratory Tract Involvement (Rare, 5-10% of Severe TEN)

• Bronchial epithelium necrosis: Leads to bronchial casts, respiratory failure, ARDS.
• Clinical features: Dyspnoea, hypoxemia, wheezing.
• Management: Intubation/mechanical ventilation may be required. High mortality (> 50%) if respiratory failure develops. [1]

Systemic Features

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7. Diagnosis

Clinical Diagnosis (Primarily Clinical)

Diagnosis of SJS/TEN is primarily clinical, based on:

1. Recent drug exposure (1-8 weeks before symptom onset).
2. Prodrome of fever, malaise, skin tenderness.
3. Characteristic skin lesions: Dusky macules → flaccid blisters → epidermal detachment.
4. Positive Nikolsky sign. [5]
5. Mucosal involvement (≥2 sites: oral, ocular, genital). [1,6]
6. BSA of epidermal detachment less than 10% (SJS), 10-30% (overlap), > 30% (TEN). [1,3]

No single laboratory test is diagnostic. Skin biopsy provides histological confirmation but is not required for immediate management (clinical diagnosis suffices to initiate drug withdrawal and supportive care). [1]

Differential Diagnosis

Skin Biopsy (Confirmatory, Not Always Required)

Indications:

• Diagnostic uncertainty (differentiate from other blistering disorders).
• Medico-legal documentation.
• Research/registry purposes.

Timing: Ideally early in disease course (first 48 hours) from edge of blister or erythematous lesion.

Technique:

• Punch or incisional biopsy (4 mm punch sufficient).
• Biopsy edge of blister to include involved and uninvolved skin.
• Frozen section available in some centres (provides rapid confirmation within hours). [1]

Histopathological Findings

Immunohistochemistry (Research Setting):

• Granulysin staining: Elevated in epidermis and blister fluid (research biomarker). [18]
• CD8+ T-cell infiltrate: Confirm cytotoxic T-cell presence.

Laboratory Investigations

No specific diagnostic test exists. Investigations are for supportive care, prognostication (SCORTEN), and monitoring complications. [10,11,12]

Key Point: Do NOT delay management awaiting biopsy or lab results. Clinical diagnosis is sufficient to initiate drug withdrawal and supportive care. [1,10]

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8. SCORTEN Prognostic Score

SCORTEN (SCore of Toxic Epidermal Necrolysis) is a validated 7-parameter severity-of-illness score predicting mortality in SJS/TEN. [12] It was developed and validated by Bastuji-Garin et al. (2000) in a multicentre study of 165 TEN patients.

SCORTEN Parameters (Calculate at Admission and Day 3)

Each parameter present = 1 point (maximum score 7). [12]

SCORTEN Score and Predicted Mortality

Original validation study: Predicted mortality closely matched observed mortality across all score categories (excellent calibration). [12]

Subsequent validation studies: SCORTEN has been validated in multiple independent cohorts worldwide, consistently showing good predictive performance. [26]

Clinical Application

1. Calculate SCORTEN within 24 hours of admission (using admission parameters). [12]
2. Recalculate at Day 3: Allows dynamic risk assessment (worsening score indicates clinical deterioration).
3. Use for:
   • Prognostication: Inform patient/family discussions.
   • Triage: Guide level of care (HDU vs ICU).
   • Clinical trials: Stratification of patients.
   • Audit: Compare observed vs predicted mortality (assess quality of care).

Limitations:

• Developed in TEN cohort: Less validated in pure SJS (less than 10% BSA), though often applied.
• Does not guide specific treatment decisions (e.g., does not indicate which adjunctive therapy to use).
• Not designed for individual prediction: Probabilities are population-level; individual outcomes vary.
• BSA at Day 1 may be underestimated: Some patients continue to progress Day 2-5; rescoring at Day 3 addresses this.

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9. Management

Principles of Management

1. Immediate cessation of culprit drug(s).
2. Admission to specialist unit (burns unit, dermatology HDU, or ICU).
3. Meticulous supportive care (fluid resuscitation, wound care, temperature control, nutrition, pain management).
4. Daily ophthalmology review for ocular involvement.
5. Infection surveillance (cultures, early antibiotic therapy if sepsis develops).
6. Consider adjunctive immunomodulatory therapies (IVIG, ciclosporin) in selected cases, though evidence is limited.
7. Multidisciplinary team involvement (dermatology, burns/plastics, ophthalmology, critical care, pharmacy, nutrition, psychology).

1. Drug Withdrawal (MOST CRITICAL INTERVENTION)

"Time to drug withdrawal is the single most important modifiable factor influencing mortality." [9]

Practical Steps:

1. Obtain detailed drug history: All medications (prescription, over-the-counter, herbal), including start dates.
2. Calculate latency period: For each drug, determine time from initiation to symptom onset. Typical latency 1-3 weeks (up to 8 weeks for anticonvulsants). [1,4]
3. Identify most likely culprit(s):
   • Drugs started within 1-8 weeks of symptom onset.
   • High-risk drugs (allopurinol, anticonvulsants, sulfonamides, NSAIDs). [4]
4. Stop ALL suspected drugs immediately: If multiple suspects, stop all (unless life-sustaining, in which case seek alternatives immediately). [1,10]
5. Consider drug half-lives: Long half-life drugs (allopurinol [oxypurinol metabolite t½ 18-30 hours], phenobarbital [t½ 80-120 hours]) continue to exert effects for days after cessation → poorer prognosis. [9]
6. Avoid drug re-challenge: Never re-introduce culprit drug (near 100% recurrence risk, often more severe). Avoid structurally similar drugs (cross-reactivity). [1]

Example: Patient on carbamazepine (started 3 weeks ago), allopurinol (started 6 months ago), amlodipine (started 5 years ago), paracetamol (as needed). Action: STOP carbamazepine (high-risk drug, appropriate latency). STOP allopurinol (high-risk drug, can be stopped acutely). Continue amlodipine (started too long ago, not culprit). Continue paracetamol (very low risk).

2. Supportive Care (Burns Unit Principles)

Setting: Burns unit (preferred), dermatology HDU, or medical/paediatric ICU with dermatology input. [10,11]

Fluid Resuscitation

Key Difference from Thermal Burns: No significant capillary leak in TEN (unlike burns). Excessive fluid administration → pulmonary edema, increased mortality. [10]

Wound Care

Temperature Control

• Thermoregulatory dysfunction: Loss of epidermis → evaporative heat loss → hypothermia (especially in extensive TEN).
• Maintain ambient temperature 30-32°C (burn unit rooms often heated). [10]
• Use warming blankets if hypothermic.
• Monitor core temperature regularly.

Nutritional Support

Pain Management

• Severe pain (skin tenderness, oral erosions, dressing changes).
• Multimodal analgesia: Paracetamol (if not contraindicated), opioids (morphine, oxycodone), neuropathic pain agents (gabapentin, pregabalin) if needed. [10]
• Avoid NSAIDs (may have been culprit drug; also impair platelet function).
• Topical analgesia: Lidocaine gel for oral lesions, topical local anaesthetics before dressing changes.

Mouth Care

Genital Care

• Avoid catheterization if possible (increases infection risk, can cause urethral trauma). [10]
• If catheter required: Remove as soon as urinary retention resolves (typically 3-7 days). Consider suprapubic catheter if prolonged catheterization needed (reduces urethral stricture risk).
• Topical emollients to genital erosions (white soft paraffin).
• In females with extensive vulvovaginal involvement: Consider vaginal dilators during healing phase (prevents adhesions/stenosis). Gynaecology input if available. [1]

VTE Prophylaxis

• Moderate-high risk (immobility, systemic inflammation).
• Pharmacological prophylaxis: LMWH (enoxaparin 40 mg SC daily) or UFH (5000 units SC BD) unless contraindicated. [10]
• Mechanical prophylaxis: Intermittent pneumatic compression devices if pharmacological contraindicated.

3. Ophthalmology Care (MANDATORY for Ocular Involvement)

"Ophthalmology within 24 hours for all patients with ocular involvement." [7,8]

Long-term Ophthalmology Follow-up:

• Chronic ocular surface disease develops in 30-50% of patients despite optimal acute care. [7,8]
• Complications: Dry eye (aqueous and lipid deficiency), symblepharon, corneal scarring/neovascularization, trichiasis, entropion.
• Requires lifelong ophthalmology follow-up (every 3-6 months initially, then annually).
• Advanced therapies: Scleral contact lenses (vault over irregular cornea), keratoprosthesis (artificial cornea, end-stage cases).

4. Infection Surveillance and Management

Sepsis is the leading cause of death in SJS/TEN. [10,11]

5. Adjunctive Immunomodulatory Therapies (CONTROVERSIAL)

No immunomodulatory therapy has robust evidence from large RCTs. [14,15] Use varies by centre and is guided by retrospective data, case series, and expert opinion.

Intravenous Immunoglobulin (IVIG)

Proposed Mechanism: Blockade of Fas-FasL interaction (preventing keratinocyte apoptosis). [14]

Evidence:

• Cochrane Review (2022): No high-quality evidence of benefit. Included studies were retrospective, small, with high risk of bias. [15]
• Meta-analyses: Mixed results. Some suggest reduced mortality (particularly if high-dose IVIG ≥3 g/kg total dose); others show no benefit. [27]
• Concerns: Theoretical blockade of Fas-FasL not consistently demonstrated in vivo. Expensive. Adverse effects (aseptic meningitis, renal impairment, thromboembolism).

Current Practice:

• Some centres use IVIG 2-3 g/kg total dose (divided over 3-5 days) in severe TEN (> 30% BSA) or high SCORTEN (≥3). [1,14]
• Not standard of care; supportive care remains paramount.

Ciclosporin (Cyclosporine)

Mechanism: Inhibits T-cell activation (blocks calcineurin → prevents IL-2 production). [14,28]

Evidence:

• Retrospective cohort studies: Some show reduced mortality compared to supportive care alone (particularly if started early, less than 72 hours). [28]
• Prospective case series: Wang et al. (2020) showed improved outcomes with ciclosporin 3-5 mg/kg/day. [28]
• Cochrane Review (2022): Insufficient high-quality evidence to recommend, but emerging data more favourable than IVIG. [15]

Current Practice:

• Increasingly used in specialist centres, particularly in Europe and Asia.
• Dose: 3-5 mg/kg/day PO/IV for 7-10 days, then taper. [28]
• Preferred by some experts over IVIG (theoretical mechanism more sound, lower cost, some positive retrospective data).
• Caution: Renal impairment (many patients have pre-existing renal dysfunction), hypertension, infection risk.

Systemic Corticosteroids

Mechanism: Broad immunosuppression, anti-inflammatory.

Evidence:

• Controversial: Some retrospective studies suggest increased mortality (infection risk, delayed healing). [14,15]
• Others show no difference or potential benefit if short course, high-dose (e.g., pulse methylprednisolone 500 mg-1 g/day × 3 days). [14]
• Cochrane Review (2022): Insufficient evidence. [15]

Current Practice:

• NOT routinely recommended. [10,11]
• Some centres use short course high-dose pulse steroids in select cases (e.g., DRESS-TEN overlap with eosinophilia/hepatitis). [1]
• If used, requires careful infection surveillance.

Other Therapies (Limited Data)

Bottom Line: Supportive care is the cornerstone of management. Adjunctive therapies (IVIG, ciclosporin) may be considered in severe cases at specialist centres, but evidence is limited. Do NOT delay supportive care while pursuing adjunctive therapies. [10,11,14,15]

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10. Complications

Acute Complications (During Hospitalization)

Chronic Complications (Long-term Sequelae)

Key Point: Long-term multidisciplinary follow-up (dermatology, ophthalmology, gynaecology if needed, psychology) is essential for all SJS/TEN survivors. Chronic ocular surface disease is often progressive and requires lifelong monitoring. [7,8]

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11. Prognosis

Mortality

Factors Associated with Increased Mortality: [1,9,12,13]

1. Higher SCORTEN score (strongest predictor). [12]
2. Delayed drug withdrawal (> 7 days from symptom onset). [9]
3. Older age (> 40 years, especially > 65 years). [12]
4. Extensive BSA detachment (> 30%, i.e., TEN). [1,12]
5. Underlying malignancy. [12]
6. Neutropenia (less than 1000/μL). [1]
7. Renal impairment (elevated urea). [12]
8. Sepsis / Multiorgan failure. [10,11]
9. Culprit drug with long half-life (allopurinol/oxypurinol, phenobarbital). [9]

Factors Associated with Improved Outcomes:

1. Early drug withdrawal (less than 24 hours). [9]
2. Care in specialist burn/dermatology unit. [10,11]
3. Multidisciplinary team approach. [10,11]
4. Aggressive ophthalmology input (reduces chronic ocular morbidity, not mortality). [7,8]

Long-term Quality of Life

• Physical sequelae: Chronic ocular surface disease (30-50%), skin pigmentation (70-90%), genital scarring (10-20%). [1,7,8]
• Psychological sequelae: PTSD (20-40%), depression (30-50%). [1]
• Return to work: Many patients experience prolonged disability (median time to return to work 6-12 months). Some never return to previous employment due to chronic complications. [1]
• Quality of life scores: Significantly reduced in survivors compared to general population, particularly if chronic ocular disease. [1,7]

Key Message for Patients: "SJS/TEN is a severe condition with significant acute mortality and long-term complications. However, with early recognition, immediate drug withdrawal, and intensive supportive care, most patients survive. Lifelong follow-up is needed for eye care and management of other chronic issues." [1,10,11]

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12. Differential Diagnosis: DRESS Syndrome

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is another severe drug reaction that can occasionally overlap with or be confused with SJS/TEN. [30]

Comparison: DRESS vs SJS/TEN

Key Differentiator: Presence of eosinophilia + hepatitis + lymphadenopathy = DRESS. Presence of Nikolsky sign + extensive epidermal detachment = SJS/TEN. [1,30]

Overlap Cases: Rare patients have features of both (drug-induced epidermal necrosis + eosinophilia + hepatitis). Management requires both supportive wound care (as for SJS/TEN) and systemic immunosuppression (as for DRESS). [1]

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13. Prevention Strategies

Primary Prevention (Avoiding SJS/TEN)

Secondary Prevention (Preventing Recurrence)

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14. Evidence & Guidelines

Key Guidelines

Landmark Studies

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15. Exam Scenarios

Scenario 1: SJS/TEN Overlap Diagnosis

Stem: A 45-year-old man with newly diagnosed epilepsy started on carbamazepine 3 weeks ago presents with fever (39.2°C), malaise, and widespread painful rash for 48 hours. On examination, he has haemorrhagic crusting of lips, bilateral conjunctivitis, and erythematous dusky macules over 20% of his trunk and limbs with areas of epidermal detachment. Nikolsky sign is positive.

Questions:

1. What is the most likely diagnosis?
2. What is the first critical management step?
3. What prognostic score should be calculated?
4. Which specialist should be involved within 24 hours?

Answers:

1. SJS/TEN Overlap (carbamazepine-induced). BSA 10-30% (here ~20%). [1,3]
2. Immediate cessation of carbamazepine. [9,10]
3. SCORTEN (calculate within 24 hours and at day 3). [12]
4. Ophthalmology (for bilateral conjunctivitis; daily review required to prevent symblepharon and chronic ocular complications). [7,8]

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Scenario 2: SCORTEN Calculation

Stem: A 68-year-old woman with TEN (40% BSA detachment, allopurinol-induced) is admitted to burns unit. Parameters: Age 68, HR 130 bpm, no malignancy, BSA detachment 40%, urea 14 mmol/L, bicarbonate 18 mmol/L, glucose 16 mmol/L.

Question: Calculate her SCORTEN score and predicted mortality.

Answer:

• Age > 40: 1 point
• HR > 120: 1 point
• Malignancy: 0 points
• BSA > 10%: 1 point
• Urea > 10 mmol/L: 1 point
• Bicarbonate less than 20 mmol/L: 1 point
• Glucose > 14 mmol/L: 1 point

SCORTEN = 6 points → Predicted mortality ≥90% (score ≥5). [12]

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Scenario 3: Drug Withdrawal Timing

Stem: Which of the following interventions has the STRONGEST evidence for reducing mortality in SJS/TEN? A) Intravenous immunoglobulin (IVIG) B) Systemic corticosteroids C) Ciclosporin D) Immediate cessation of culprit drug within 24 hours E) Plasmapheresis

Answer: D) Immediate cessation of culprit drug within 24 hours. [9] This is the only intervention with consistent high-quality evidence for reducing mortality. Delayed withdrawal (> 7 days) significantly increases mortality. Adjunctive therapies (IVIG, ciclosporin, steroids) lack robust RCT evidence. [14,15]

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Scenario 4: Chronic Ocular Complications

Stem: A 30-year-old woman had TEN 6 months ago (lamotrigine-induced, recovered). She now complains of persistent dry, gritty eyes and reduced vision. On slit-lamp examination, you note corneal scarring and adhesions between the palpebral and bulbar conjunctiva.

Questions:

1. What is the chronic ocular complication shown?
2. What is the incidence of chronic ocular complications post-SJS/TEN?
3. What management is required?

Answers:

1. Symblepharon (conjunctival adhesions) and corneal scarring (chronic ocular surface disease). [7,8]
2. 30-50% of SJS/TEN patients develop chronic ocular complications despite optimal acute care. 3-10% have severe visual impairment or blindness. [7,8]
3. Lifelong ophthalmology follow-up (every 3-6 months). Preservative-free lubricants multiple times daily. Autologous serum eye drops. Scleral contact lenses (vault over irregular cornea). In severe cases, keratoprosthesis (artificial cornea). Symblepharon may require surgical lysis, though recurrence common. [7,8]

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Scenario 5: HLA Screening

Stem: A 35-year-old Han Chinese man with new-onset epilepsy requires anticonvulsant therapy. His neurologist is considering carbamazepine.

Questions:

1. What genetic test should be performed BEFORE starting carbamazepine in this patient?
2. If the test is positive, what is the implication?
3. What alternative anticonvulsants are considered safer?

Answers:

1. HLA-B*15:02 screening. [19] Mandatory in Han Chinese, Thai, Malaysian, Filipino populations before carbamazepine (FDA/EMA guidelines).
2. If HLA-B*15:02 positive: Do NOT prescribe carbamazepine (OR 2504 for SJS/TEN). [19] Use alternative anticonvulsant.
3. Levetiracetam, valproate, gabapentin, pregabalin (no HLA association, lower SJS/TEN risk). [1] Avoid other aromatic anticonvulsants (phenytoin, phenobarbital, oxcarbazepine: cross-reactivity).

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Scenario 6: Mycoplasma-Induced vs Drug-Induced SJS

Stem: A 12-year-old boy presents with fever, cough, and rash. He has widespread oral erosions, bilateral conjunctivitis, and minimal skin involvement (less than 5% BSA with few targetoid lesions). He has no recent drug exposure (only paracetamol for fever). Chest X-ray shows right lower lobe consolidation.

Questions:

1. What is the most likely diagnosis?
2. How does this differ from typical drug-induced SJS?
3. What investigation would confirm the diagnosis?

Answers:

1. Mycoplasma-Induced Rash and Mucositis (MIRM) (subset of Mycoplasma pneumoniae-associated SJS). [16]
2. Differences: Age (children/young adults), no drug exposure, prominent respiratory symptoms (pneumonia), less extensive skin involvement (less than 10% BSA), severe mucosal involvement (often \u003e 2 sites). Drug-induced SJS typically occurs in adults with recent drug exposure. [16]
3. Mycoplasma pneumoniae serology (IgM positive in acute infection) or PCR from respiratory secretions (nasopharyngeal swab, sputum). [16]

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Scenario 7: Fluid Management in TEN

Stem: A 55-year-old woman with TEN (50% BSA detachment) is transferred to burns unit. The admitting burns surgeon suggests using Parkland formula (4 mL/kg/% BSA over 24 hours) for fluid resuscitation.

Question: Is the Parkland formula appropriate for TEN? What modification is required?

Answer: [10]

NO, the standard Parkland formula is NOT appropriate for TEN.

Key Difference from Thermal Burns:

• Thermal burns: Significant capillary leak → massive third-space losses → requires aggressive fluid resuscitation (Parkland formula: 4 mL/kg/% BSA/24h).
• TEN: NO significant capillary leak despite extensive epidermal loss. Excessive fluid administration → pulmonary edema, ARDS, increased mortality. [10]

Appropriate Fluid Management:

• Use approximately 50% of Parkland formula estimate.
• Adult: 1.5-2 mL/kg/% BSA/24 hours (vs 4 mL/kg in burns).
• Child: 2-3 mL/kg/% BSA/24 hours.
• Titrate to urine output: 0.5-1 mL/kg/hour (adult), 1-2 mL/kg/hour (child). [10]
• Monitor carefully: CVP, lactate, hourly urine output.

Example: 70 kg patient with 50% BSA TEN:

• Thermal burn (Parkland): 4 × 70 × 50 = 14,000 mL/24h (14 L)
• TEN (modified): 1.5-2 × 70 × 50 = 5,250-7,000 mL/24h (5-7 L)

Exam Point: Over-resuscitation in TEN is a common error that increases mortality. Always emphasize "less fluid than burns" in exams. [10]

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Scenario 8: Re-challenge Medicolegal Case

Stem: A 60-year-old man had documented SJS from carbamazepine 2 years ago (confirmed by skin biopsy, HLA-B*15:02 positive). He now develops new-onset trigeminal neuralgia. A junior doctor prescribes carbamazepine, unaware of the allergy history (not documented in EMR allergy list).

Questions:

1. What is the medicolegal issue?
2. What is the expected outcome if the patient takes carbamazepine?
3. What systems should be in place to prevent this?

Answers:

1. Medicolegal negligence: Prescribing a drug that caused previous SJS/TEN is absolute contraindication. Failure to document drug allergy in EMR and prescribe culprit drug = breach of duty of care. [1]

2. Near 100% recurrence risk if re-exposed to carbamazepine. Recurrent episode often more severe (higher BSA, faster progression, higher mortality). [1] Patient would likely develop TEN (not just SJS) on re-exposure.

3. Systems to prevent re-challenge: [1]

   • EMR allergy alert: Drug allergy MUST be documented in electronic medical record with severity level ("anaphylaxis/SJS/TEN" – highest alert).
   • Patient allergy card/bracelet: Patient carries card listing culprit drug and cross-reactive drugs.
   • Pharmacy flags: Automated alerts when culprit drug prescribed.
   • Discharge summary: Prominent documentation of drug allergy.
   • GP communication: Inform primary care of drug allergy immediately.
   • Family counselling: HLA-B*15:02 positive → first-degree relatives may share allele (offer testing).

Alternative for trigeminal neuralgia: Gabapentin, pregabalin, baclofen, lamotrigine (though lamotrigine also carries SJS risk – avoid if possible), surgical options (microvascular decompression). NEVER re-challenge with carbamazepine. [1]

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16. Triage: When to Refer

Key Triage Principle: Any patient with positive Nikolsky sign and mucosal involvement requires IMMEDIATE hospital admission to specialist unit (burns/dermatology HDU/ICU). This is a life-threatening emergency. [1,10]

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17. Patient/Layperson Explanation

What is SJS/TEN?

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are very serious skin reactions, almost always caused by medications. The skin blisters and peels off (like a severe burn), and the mouth, eyes, and genitals also develop sores. It is a medical emergency that requires treatment in hospital (often in a burns unit).

What causes it?

• Medications cause SJS/TEN in over 80% of cases. Common culprits:
  • Antibiotics (especially sulfa drugs like co-trimoxazole)
  • Seizure medications (carbamazepine, lamotrigine, phenytoin)
  • Gout medication (allopurinol)
  • Pain relievers (certain NSAIDs like piroxicam)
• The reaction typically starts 1-3 weeks after starting the medication (though can be up to 8 weeks).
• Rarely, infections (like Mycoplasma pneumonia) can cause a similar reaction, especially in children.

What are the symptoms?

Early symptoms (1-3 days before rash):

• High fever
• Feeling very unwell (fatigue, aches)
• Sore throat, painful swallowing

Rash and skin peeling:

• Red patches appear on the face and body
• Blisters form and burst, leaving raw, painful skin
• Skin peels off in sheets when touched gently (Nikolsky sign: a warning sign)

Mouth, eyes, and genitals:

• Mouth: Painful sores, bleeding, crusted lips
• Eyes: Red, watery, gritty (can lead to permanent vision problems if not treated)
• Genitals: Painful sores, difficulty urinating

How is it treated?

1. Stop the medication immediately: This is the most important step. The sooner the drug is stopped, the better the outcome.
2. Hospital care (usually in a burns unit):
   • Fluids through a drip (to replace what's lost through damaged skin)
   • Wound care (special dressings to protect raw skin)
   • Pain relief
   • Eye care (eye drops, daily checks by eye doctors to prevent scarring and blindness)
   • Nutrition (feeding tube if mouth sores make eating impossible)
   • Infection prevention (skin is vulnerable to infection; antibiotics if needed)
3. Specialist care: Dermatologists, burns specialists, eye doctors, and intensive care doctors work together.

Controversial treatments: Some hospitals use medicines like IVIG (antibody infusions) or ciclosporin (immune-suppressing drug), but evidence for benefit is limited. The cornerstone of treatment is supportive care.

What is the outlook?

• Mortality: 5-10% for SJS (less severe), 25-35% for TEN (more severe). Deaths are usually from infection or organ failure.
• Recovery: Skin typically heals in 2-4 weeks, though pigmentation changes can last months-years.
• Long-term problems:
  • "Eyes: 30-50% of people have chronic dry eyes or scarring; 3-10% have severe vision loss or blindness."
  • "Skin: Pigment changes (darker or lighter patches), rarely scarring."
  • "Genitals: Women may develop vaginal scarring (10-20%); men rarely develop urinary strictures."
  • "Psychological: Many survivors experience PTSD, depression, or anxiety."

Key Points to Remember

1. Never take the drug that caused SJS/TEN again: It will almost certainly cause another (often worse) reaction. Carry an allergy card and tell ALL doctors/dentists/pharmacists.
2. Avoid related drugs: Your doctor will advise which drugs to avoid (e.g., if carbamazepine caused it, avoid related seizure medications).
3. Eye care forever: Even if your eyes seemed OK in hospital, see an eye doctor regularly (every 6-12 months) for life.
4. Family members: If you had SJS/TEN from carbamazepine or allopurinol, tell family members (they may share your genetic risk).
5. Seek help early: If you ever develop a rash with fever and mouth sores after starting a new medication, stop the drug and go to A&E immediately.

Counselling Points (Doctor to Patient)

Drug Avoidance: "You must never take [DRUG NAME] again. It caused a life-threatening reaction. I will give you a list of drugs to avoid (including related ones). Carry this list with you always and show it to any doctor treating you."

Allergy Alert: "We will mark your medical records with a drug allergy alert. Always tell healthcare professionals about this allergy before receiving any medication."

Eye Monitoring: "Your eyes may have been affected, even if they seem fine now. You need lifelong eye checks (every 6-12 months) to monitor for dry eyes and scarring. Use lubricating eye drops daily if advised."

Genetic Testing: "We may test you for genetic markers (HLA-B*15:02 or HLA-B*58:01) to confirm your risk and advise family members."

Psychological Support: "Many people feel anxious or traumatized after SJS/TEN. If you have flashbacks, nightmares, or feel low, please tell us. We can arrange counselling or treatment."

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18. Special Populations and Considerations

SJS/TEN in Children

SJS/TEN in Pregnancy

Extremely rare (case reports only). Key considerations: [1]

SJS/TEN in HIV/AIDS Patients

100-fold increased risk of SJS/TEN in HIV-positive patients compared to general population. [21]

SJS/TEN in Elderly (> 65 Years)

SJS/TEN Associated with Biologics and Immunotherapies

Emerging issue with increasing use of biologics and immune checkpoint inhibitors (ICIs). [23]

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19. Multidisciplinary Team (MDT) Approach

SJS/TEN requires coordinated multidisciplinary care. Key specialties and roles: [10,11]

MDT Meetings: Weekly multidisciplinary rounds in burns unit/HDU to review progress, complications, discharge planning. [10,11]

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20. Medicolegal and Ethical Considerations

Drug Rechallenge

ABSOLUTE CONTRAINDICATION: Never rechallenge with culprit drug. [1]

• Recurrence risk near 100% if re-exposed.
• Recurrent episodes often more severe (higher BSA, faster progression, higher mortality).
• Medicolegal risk: Prescribing known culprit drug after documented SJS/TEN is negligence.
• Exception: None. Even if drug is "life-saving" (e.g., only effective anticonvulsant), alternatives must be found.

Informed Consent for High-Risk Drugs

Ethical obligation to warn patients about SJS/TEN risk when prescribing high-risk drugs in high-risk populations: [19,20]

Pharmacovigilance and Reporting

SJS/TEN is a reportable adverse drug reaction in most countries: [1]

• Yellow Card Scheme (UK): Report to MHRA (Medicines and Healthcare products Regulatory Agency).
• FDA MedWatch (USA): Report to FDA.
• European databases: EudraVigilance.
• Purpose: Identify new drug associations, refine risk estimates, support pharmacovigilance.

Clinician Responsibility: Report ALL cases of suspected SJS/TEN to national pharmacovigilance systems. [1]

End-of-Life Care and Palliative Discussions

In patients with SCORTEN ≥5 (predicted mortality ≥90%), palliative care discussions are appropriate if patient deteriorates despite maximal therapy: [12]

• Involve palliative care team early if SCORTEN ≥5 or multi-organ failure develops.
• Goals of care discussion with patient (if conscious) and family: Balance aggressive life-sustaining interventions vs comfort-focused care.
• Escalation decisions: Intubation/mechanical ventilation, renal replacement therapy, vasopressor support.
• Cultural sensitivity: Approach varies by culture/religion; involve chaplaincy/family as appropriate.

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21. Quality Markers: Audit Standards

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22. Advanced Topics for Postgraduate Examinations

Pathophysiology Deep Dive: Immunological Mechanisms

Question: Describe the immunological cascade leading to keratinocyte apoptosis in SJS/TEN.

Answer Framework (MRCP/FRACP viva): [17,18,24]

1. Drug Presentation:

   • Drug/metabolite binds to HLA class I molecules (particularly HLA-B15:02, HLA-B58:01).
   • "Pharmacological interaction with immune receptors" (p-i concept): Drug directly occupies HLA-B peptide-binding groove, creating neo-antigen without requiring intracellular processing.
   • Alternative: Drug acts as hapten (covalently binds self-proteins), creating immunogenic drug-protein complex.

2. T-Cell Activation:

   • Drug-HLA complex presented on keratinocyte surface.
   • CD8+ cytotoxic T-cells (CTLs) recognize drug-HLA-TCR tripartite complex.
   • Oligoclonal T-cell expansion: Restricted TCR Vβ usage (e.g., Vβ11 in carbamazepine-SJS/TEN). [19]
   • CTLs traffic to epidermis and dermis.

3. Cytotoxic Mediator Release:

   • Activated CTLs release:
     • Granulysin (15 kDa cytotoxic protein): Forms membrane pores → mitochondrial damage → apoptosis. Primary effector (levels 1000-fold elevated in blister fluid). [18]
     • Fas Ligand (FasL): Binds Fas (CD95) on keratinocytes → caspase 8/3 activation → apoptosis. [17]
     • Perforin/Granzyme B: Perforin creates pores; granzyme B (serine protease) enters and cleaves caspases.
     • TNF-α: Proinflammatory cytokine, contributes to keratinocyte apoptosis via TNFR1.
   • Natural Killer (NK) cells and NKT cells also recruited, amplifying cytotoxic response.

4. Keratinocyte Death:

   • Widespread apoptosis at all epidermal layers (basal, spinous, granular).
   • Histology: "Full-thickness epidermal necrosis" with preserved dermis.
   • Loss of intercellular adhesion (desmosomes) and basement membrane adhesion (hemidesmosomes).

5. Epidermal Detachment:

   • Dead keratinocytes separate as intact necrotic sheet from underlying dermis.
   • Subepidermal blister formation (split at dermo-epidermal junction).
   • Clinical: Positive Nikolsky sign, sheet-like epidermal detachment.

Key Exam Points:

• Granulysin is the MAJOR effector (most important molecule to mention in exams). [18]
• HLA-restricted (explains genetic susceptibility and ethnic variation). [19,20]
• CTL-mediated (not antibody-mediated; direct immunofluorescence negative). [1]
• Fas-FasL pathway provided rationale for IVIG (blocks Fas-FasL interaction), but efficacy not proven in RCTs. [15,17]

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Clinical Reasoning Case: Drug Causality Assessment

Scenario: 52-year-old woman with TEN (35% BSA). Drug history: Allopurinol (started 4 weeks ago for gout), Amlodipine (5 years), Atorvastatin (3 years), Omeprazole (6 months), Ibuprofen (taken 3 days before rash for headache).

Question: Which drug is most likely culprit? How do you assess drug causality?

Answer Framework:

Drug Causality Assessment Algorithm: [4]

Conclusion: Allopurinol is the most likely culprit (appropriate latency, highest-risk drug). Stop allopurinol immediately. Consider stopping ibuprofen also (though less likely if no prior exposure).

Exam Tip: In SJS/TEN cases, always consider drugs started 1-8 weeks before symptom onset. Drugs started years ago or days ago are unlikely culprits (unless recurrent exposure in case of recent drugs). [1,4]

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Differential Diagnosis Challenge: Blistering Disorders

Question: How would you differentiate TEN from Staphylococcal Scalded Skin Syndrome (SSSS) clinically and histologically?

Answer: [1]

Key Differentiator for Exams: Absence of mucosal involvement + young age (less than 5 years) + superficial histological split = SSSS, not TEN. [1]

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Pharmacogenetics in Practice

Question: A 40-year-old Han Chinese man requires anticonvulsant therapy for new-onset epilepsy. Discuss the role of pharmacogenetic testing.

Answer: [19,20]

Scenario Analysis:

1. Carbamazepine is effective anticonvulsant but carries SJS/TEN risk in Han Chinese.
2. HLA-B*15:02 prevalence in Han Chinese: ~10-15%.
3. Risk in HLA-B*15:02 positive individuals: OR 2504 for carbamazepine-SJS/TEN (i.e., > 2500-fold increased risk). [19]
4. Risk in HLA-B*15:02 negative individuals: SJS/TEN risk reduced to near-baseline (NPV > 99%).

Clinical Decision:

• MANDATORY HLA-B*15:02 screening before prescribing carbamazepine (FDA/EMA guidelines). [19]
• If HLA-B*15:02 POSITIVE: DO NOT prescribe carbamazepine. Use alternative:
  • Levetiracetam, Valproate, Gabapentin, Pregabalin (no HLA association).
  • Avoid oxcarbazepine (cross-reactivity with carbamazepine).
• If HLA-B*15:02 NEGATIVE: Carbamazepine can be prescribed (but still counsel patient about rare SJS/TEN risk; screen does not reduce risk to zero).

Cost-Effectiveness:

• HLA-B*15:02 screening in Han Chinese populations is cost-effective (prevents catastrophic SJS/TEN cases; screening cost ~£50-100 vs hospitalization cost £50,000-100,000 + mortality/morbidity). [19]
• Not recommended in Caucasian populations (HLA-B*15:02 prevalence less than 1%; positive predictive value too low).

Alternative HLA Associations:

• HLA-A*31:01: Associated with carbamazepine-SJS/TEN in Europeans and Japanese (OR 12-25, lower than HLA-B*15:02 in Asians). Screening considered but not universally implemented (lower sensitivity/specificity). [19]
• HLA-B*58:01: Associated with allopurinol-SJS/TEN (OR 580 in Han Chinese, OR 80 in Europeans). Screening recommended in Asian populations before allopurinol; consider in Caucasians with renal impairment. [20]

Exam Tip: Always mention HLA-B*15:02 and carbamazepine together (most well-established pharmacogenetic association in dermatology). [19]

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Management Controversies: Adjunctive Therapies

Question: Discuss the evidence for systemic immunomodulatory therapies in SJS/TEN.

Answer: [14,15]

Therapies Evaluated:

1. Intravenous Immunoglobulin (IVIG):

   • Proposed Mechanism: Blockade of Fas-FasL interaction (prevents keratinocyte apoptosis). Contains anti-Fas antibodies. [17]
   • Evidence:
     • Cochrane Review (2022): No high-quality evidence of benefit. Included studies retrospective, small, high risk of bias. [15]
     • Meta-analyses: Mixed results. Some suggest mortality benefit with high-dose IVIG (≥3 g/kg total); others no benefit. [27]
     • Concerns: Expensive (£5,000-10,000 per treatment course). Adverse effects (aseptic meningitis, renal impairment, thromboembolism). Theoretical mechanism not consistently demonstrated in vivo.
   • Current Use: Some centres use in severe TEN (> 30% BSA) or high SCORTEN (≥3). Not standard of care; supportive care paramount. [14,15]

2. Ciclosporin (Cyclosporine):

   • Mechanism: Inhibits T-cell activation (blocks calcineurin → prevents IL-2 transcription → prevents CTL proliferation). [28]
   • Evidence:
     • Retrospective cohort studies: Some show reduced mortality vs supportive care alone (particularly if started early, less than 72 hours). [28]
     • Wang et al. (2018) prospective study: Etanercept (anti-TNF) showed benefit, but ciclosporin arm not included. [28]
     • Cochrane Review (2022): Insufficient evidence, but emerging data more favorable than IVIG. [15]
   • Current Use: Increasingly used in specialist centres (Europe, Asia). Dose: 3-5 mg/kg/day PO or IV for 7-10 days, then taper. [28]
   • Concerns: Renal impairment (many TEN patients have pre-existing renal dysfunction). Hypertension. Infection risk.
   • Preference by some experts: More sound theoretical mechanism than IVIG (directly inhibits pathogenic T-cells). Lower cost.

3. Systemic Corticosteroids:

   • Mechanism: Broad immunosuppression, anti-inflammatory.
   • Evidence:
     • Controversial: Some retrospective studies suggest increased mortality (infection risk, delayed wound healing). Others show no difference or potential benefit with short-course high-dose pulse (e.g., methylprednisolone 500 mg-1 g/day × 3 days). [14,15]
     • Cochrane Review (2022): Insufficient evidence. [15]
   • Current Use: NOT routinely recommended by most guidelines. [10,11]
   • Exception: Some centres use in DRESS-TEN overlap (if eosinophilia + hepatitis + epidermal necrosis coexist). [1]

4. Etanercept (Anti-TNF):

   • Mechanism: Neutralizes TNF-α (proinflammatory cytokine implicated in keratinocyte apoptosis).
   • Evidence: Wang et al. (2018) RCT showed reduced mortality vs supportive care (though small study, needs replication). [28] Other data limited to case series.
   • Current Use: Rarely used (limited availability, cost, need for more evidence).

5. Plasmapheresis:

   • Mechanism: Removes circulating drug/metabolites, cytokines, antibodies.
   • Evidence: Case reports only. No clear benefit. Labor-intensive, expensive. [14]
   • Current Use: Not recommended.

6. Thalidomide:

   • Mechanism: Anti-TNF-α, immunomodulatory.
   • Evidence: RCT (Wolkenstein et al. 1998) showed INCREASED MORTALITY vs placebo. [29] Study terminated early.
   • Current Use: CONTRAINDICATED. NEVER USE in SJS/TEN. [29]

Conclusion for Exams: [14,15]

• "Supportive care is the cornerstone of SJS/TEN management. No adjunctive immunomodulatory therapy has robust evidence from large RCTs."
• "IVIG and ciclosporin may be considered in severe cases (TEN > 30% BSA, SCORTEN ≥3) at specialist centres, but evidence is limited and supportive care remains paramount."
• "Thalidomide is CONTRAINDICATED (increased mortality in RCT)."
• "Do NOT delay drug withdrawal and supportive care while pursuing adjunctive therapies."

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23. Common Exam Questions and Model Answers

Question 1: SCORTEN Calculation (MRCP/FRACP Data Interpretation)

Stem: A 72-year-old man with TEN (allopurinol-induced, 45% BSA detachment) is admitted to ICU. Blood results on Day 1:

• Heart rate: 135 bpm
• Urea: 18 mmol/L
• Bicarbonate: 16 mmol/L
• Glucose: 17 mmol/L
• Medical history: Chronic lymphocytic leukaemia (CLL) on watchful waiting.

Calculate SCORTEN score and predicted mortality.

Answer:

• Age > 40 years: 1 point (age 72)
• Heart rate > 120 bpm: 1 point (135 bpm)
• Malignancy: 1 point (CLL)
• BSA detachment > 10% at Day 1: 1 point (45%)
• Serum urea > 10 mmol/L: 1 point (18 mmol/L)
• Serum bicarbonate less than 20 mmol/L: 1 point (16 mmol/L)
• Serum glucose > 14 mmol/L: 1 point (17 mmol/L)

SCORTEN = 7 points → Predicted mortality ≥90%. [12]

(Maximum score is 7; patient has all 7 risk factors. Prognosis extremely poor despite maximal supportive care.)

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Question 2: Drug Withdrawal Timing (MRCP/FRACP SBA)

Question: Which of the following interventions has the STRONGEST evidence for reducing mortality in Stevens-Johnson syndrome/toxic epidermal necrolysis?

A) Intravenous immunoglobulin 3 g/kg total dose over 3 days
B) Ciclosporin 5 mg/kg/day for 10 days
C) Systemic corticosteroids (prednisolone 1 mg/kg/day)
D) Immediate cessation of culprit drug within 24 hours of symptom onset
E) Plasmapheresis (3 sessions over 5 days)

Answer: D) Immediate cessation of culprit drug within 24 hours of symptom onset. [9]

Rationale: García-Doval et al. (2000) demonstrated that delayed drug withdrawal (> 7 days from symptom onset) significantly increases mortality in TEN. Each additional day of exposure to the culprit drug increases mortality risk. Early withdrawal (less than 24 hours) is associated with lowest mortality, approaching SCORTEN-predicted baseline. [9] This is the ONLY intervention with consistent high-quality evidence for mortality reduction. Adjunctive therapies (IVIG, ciclosporin, corticosteroids) lack robust RCT evidence (Cochrane Review 2022). [15]

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Question 3: HLA Screening (MRCOG/FRANZCOG, Paediatrics)

Scenario: A 9-year-old Thai girl with newly diagnosed epilepsy is being considered for carbamazepine therapy.

Question: What genetic test should be performed before starting carbamazepine, and why?

Answer: [19]

HLA-B*15:02 screening should be performed BEFORE prescribing carbamazepine.

Rationale:

1. HLA-B*15:02 is strongly associated with carbamazepine-induced SJS/TEN (OR 2504 in Han Chinese; Thai populations have similar prevalence ~10-15%). [19]
2. Prevalence in Thai population: ~10-15% carry HLA-B*15:02 allele.
3. Screening is MANDATORY before carbamazepine in Asian populations including Thai (FDA/EMA guidelines). [19]
4. If HLA-B*15:02 POSITIVE: DO NOT prescribe carbamazepine. Use alternative anticonvulsant (levetiracetam, valproate, gabapentin).
5. If HLA-B*15:02 NEGATIVE: Carbamazepine can be prescribed (but patient still counselled about rare SJS/TEN risk; NPV > 99%).

Exam Tip: Always mention Thai, Han Chinese, Malaysian, Filipino as high-risk populations for HLA-B*15:02. Screening NOT indicated in Caucasians (prevalence less than 1%). [19]

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Question 4: Ocular Complications (FRCOphth, MRCP PACES)

Scenario: A 35-year-old woman presents to ophthalmology clinic 8 months after recovering from TEN (lamotrigine-induced). She complains of bilateral dry, gritty eyes and reduced vision. Examination shows corneal scarring, conjunctival keratinization, and adhesions between palpebral and bulbar conjunctiva.

Question: a) What is the diagnosis?
b) What is the incidence of this complication?
c) What management should have been undertaken in the acute phase to prevent this?

Answer: [7,8]

a) Diagnosis: Chronic ocular surface disease secondary to SJS/TEN, comprising:

• Symblepharon (conjunctival adhesions between palpebral and bulbar conjunctiva)
• Corneal scarring and neovascularization
• Conjunctival keratinization (squamous metaplasia)
• Severe dry eye syndrome (aqueous and lipid deficiency due to lacrimal and Meibomian gland destruction)

b) Incidence: 30-50% of SJS/TEN patients develop chronic ocular complications despite optimal acute care. 3-10% have severe visual impairment or blindness. [7,8]

c) Acute-phase management to prevent chronic sequelae: [7,8]

1. Daily (or twice-daily) ophthalmology review throughout acute phase (first 2-4 weeks).
2. Preservative-free lubricants every 1-2 hours (hypromellose, carbomer gel).
3. Topical corticosteroid drops (prednisolone 0.5-1%) 4× daily to reduce inflammation.
4. Mechanical lysis of synechiae: CRITICAL intervention. Use glass rod or silicone rod to sweep conjunctival fornices twice daily during first 10-14 days. Breaks forming adhesions between palpebral and bulbar conjunctiva (prevents symblepharon). [7,8]
5. Amniotic membrane transplantation (AMT) in severe cases (within first week). Promotes epithelialization, reduces scarring. [7]
6. Topical antibiotics if epithelial defects (prevent secondary keratitis).

Current management (chronic phase): Lifelong ophthalmology follow-up (every 3-6 months), autologous serum eye drops, scleral contact lenses (vault over irregular cornea), punctal plugs (if aqueous deficiency), keratoprosthesis (artificial cornea, end-stage cases). [7,8]

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Question 5: DRESS vs SJS/TEN (MRCP/FRACP, Dermatology)

Question: A 45-year-old man started on phenytoin 3 weeks ago presents with fever (38.9°C), facial swelling, and widespread morbilliform rash. Bloods show eosinophils 3500/μL (normal less than 500), ALT 450 U/L (normal less than 40). Nikolsky sign is negative. No mucosal involvement. What is the most likely diagnosis, and how would you manage?

Answer: [30]

Diagnosis: DRESS Syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms).

Differentiating DRESS from SJS/TEN:

Management of DRESS: [30]

1. Stop phenytoin immediately (culprit drug).
2. Admit for monitoring (hepatitis can progress to fulminant hepatic failure; myocarditis risk).
3. Systemic corticosteroids: Prednisolone 0.5-1 mg/kg/day PO (or IV methylprednisolone if severe hepatitis). DRESS responds to steroids (unlike SJS/TEN where steroids controversial). [30]
4. Slow taper (over 6-12 weeks; flares common if tapered too quickly).
5. Monitor LFTs, renal function, troponin (cardiac involvement), viral reactivation (HHV-6, EBV PCR).
6. Avoid structurally similar drugs: Phenytoin, carbamazepine, phenobarbital (cross-reactivity). Use alternative anticonvulsant (levetiracetam, valproate).

Prognosis: Mortality 5-10% (deaths from fulminant hepatitis, myocarditis). Course prolonged (weeks to months). [30]

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19. Historical Context

Key Milestones in SJS/TEN History

Eponyms and Alternative Names

• Stevens-Johnson Syndrome (SJS): Named after Albert Mason Stevens and Frank Chambliss Johnson (American pediatricians, 1922).
• Toxic Epidermal Necrolysis (TEN): Named by Alan Lyell (Scottish dermatologist, 1956).
• Lyell Syndrome: Alternative name for TEN (eponymous to Alan Lyell).
• Erythema Multiforme Major: Older, now-obsolete term for SJS (currently, EM and SJS considered distinct).
• Mycoplasma-Induced Rash and Mucositis (MIRM): Modern term for Mycoplasma pneumoniae-associated SJS (recognizes distinct entity). [16]

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20. References

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2. Charlton OA, Harris V, Phan K, et al. Toxic Epidermal Necrolysis and Steven-Johnson Syndrome: A Comprehensive Review. Adv Wound Care (New Rochelle). 2020;9(7):426-439. doi:10.1089/wound.2019.0977

3. Bastuji-Garin S, Rzany B, Stern RS, et al. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol. 1993;129(1):92-96. PMID: 8420497

4. Sekula P, Dunant A, Mockenhaupt M, et al. Comprehensive survival analysis of a cohort of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. J Invest Dermatol. 2013;133(5):1197-1204. doi:10.1038/jid.2012.510

5. Wetter DA, Camilleri MJ. Clinical, etiologic, and histopathologic features of Stevens-Johnson syndrome during an 8-year period at Mayo Clinic. Mayo Clin Proc. 2010;85(2):131-138. doi:10.4065/mcp.2009.0379

6. Lerch M, Mainetti C, Terziroli Beretta-Piccoli B, Harr T. Current Perspectives on Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Clin Rev Allergy Immunol. 2018;54(1):147-176. doi:10.1007/s12016-017-8654-z

7. Ueta M. Stevens-Johnson syndrome/toxic epidermal necrolysis with severe ocular complications. Expert Rev Clin Immunol. 2020;16(3):283-294. doi:10.1080/1744666X.2020.1729128

8. Ueta M, Sotozono C, Kinoshita S. Pathogenesis of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis With Severe Ocular Complications. Front Med (Lausanne). 2021;8:651247. doi:10.3389/fmed.2021.651247

9. García-Doval I, LeCleach L, Bocquet H, et al. Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death? Arch Dermatol. 2000;136(3):323-327. PMID: 10724193

10. Harr T, French LE. Toxic epidermal necrolysis and Stevens-Johnson syndrome. Orphanet J Rare Dis. 2010;5:39. doi:10.1186/1750-1172-5-39

11. Seminario-Vidal L, Kroshinsky D, Malachowski SJ, et al. Society of Dermatology Hospitalists supportive care guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults. J Am Acad Dermatol. 2020;82(6):1553-1567. doi:10.1016/j.jaad.2020.02.066

12. Bastuji-Garin S, Fouchard N, Bertocchi M, et al. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol. 2000;115(2):149-153. doi:10.1046/j.1523-1747.2000.00061.x

13. Houschyar KS, Tapking C, Ahluwalia J, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis of drug causality and a comparison between Japanese and other Asian populations. J Wound Care. 2021;30(12):1012-1022. doi:10.12968/jowc.2021.30.12.1012

14. Zimmermann S, Sekula P, Venhoff M, et al. Systemic Immunomodulating Therapies for Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Systematic Review and Meta-analysis. JAMA Dermatol. 2017;153(6):514-522. doi:10.1001/jamadermatol.2016.5668

15. Jacobsen A, Olabi B, Langley A, et al. Systemic interventions for treatment of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap syndrome. Cochrane Database Syst Rev. 2022;3(3):CD013130. doi:10.1002/14651858.CD013130.pub2

16. Canavan TN, Mathes EF, Frieden I, Shinkai K. Mycoplasma pneumoniae-induced rash and mucositis as a syndrome distinct from Stevens-Johnson syndrome and erythema multiforme: a systematic review. J Am Acad Dermatol. 2015;72(2):239-245. doi:10.1016/j.jaad.2014.06.026

17. Viard I, Wehrli P, Bullani R, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science. 1998;282(5388):490-493. doi:10.1126/science.282.5388.490

18. Chung WH, Hung SI, Yang JY, et al. Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. Nat Med. 2008;14(12):1343-1350. doi:10.1038/nm.1884

19. Ko TM, Chung WH, Wei CY, et al. Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome. J Allergy Clin Immunol. 2011;128(6):1266-1276.e11. doi:10.1016/j.jaci.2011.08.013

20. Hung SI, Chung WH, Liou LB, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A. 2005;102(11):4134-4139. doi:10.1073/pnas.0409500102

21. Coopman SA, Johnson RA, Platt R, Stern RS. Cutaneous disease and drug reactions in HIV infection. N Engl J Med. 1993;328(23):1670-1674. doi:10.1056/NEJM199306103282304

22. Pejcic AV, Jankovic SM, Milosavljevic MN, et al. Amoxicillin-associated Stevens-Johnson syndrome or toxic epidermal necrolysis: systematic review of reports in the literature. J Chemother. 2023;35(2):81-93. doi:10.1080/1120009X.2022.2051128

23. Zhou J, Huang Y, Tian X, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis associated with immune checkpoint inhibitors: A systematic review. Front Immunol. 2024;15:1414136. doi:10.3389/fimmu.2024.1414136

24. Wei CY, Chung WH, Huang HW, et al. Direct interaction between HLA-B and carbamazepine activates T cells in patients with Stevens-Johnson syndrome. J Allergy Clin Immunol. 2012;129(6):1562-1569.e5. doi:10.1016/j.jaci.2011.12.990

25. Auquier-Dunant A, Mockenhaupt M, Naldi L, et al. Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol. 2002;138(8):1019-1024. PMID: 12164739

26. Strużyna J, Zarzecka A, Nesterowicz M, et al. Accuracy of SCORTEN in predicting mortality in toxic epidermal necrolysis. BMC Med Inform Decis Mak. 2022;22(1):272. doi:10.1186/s12911-022-02013-2

27. Huang YC, Li YC, Chen TJ. The efficacy of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis: a systematic review and meta-analysis. Br J Dermatol. 2012;167(2):424-432. doi:10.1111/j.1365-2133.2012.10940.x

28. Wang CW, Yang LY, Chen CB, et al. Randomized, controlled trial of TNF-α antagonist in CTL-mediated severe cutaneous adverse reactions. J Clin Invest. 2018;128(3):985-996. doi:10.1172/JCI93349

29. Wolkenstein P, Latarjet J, Roujeau JC, et al. Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis. Lancet. 1998;352(9140):1586-1589. doi:10.1016/S0140-6736(98)02197-7

30. Husain Z, Reddy BY, Schwartz RA. DRESS syndrome: Part I. Clinical perspectives. J Am Acad Dermatol. 2013;68(5):693.e1-693.e14. doi:10.1016/j.jaad.2013.01.033

31. Stevens AM, Johnson FC. A new eruptive fever associated with stomatitis and ophthalmia: report of two cases in children. Am J Dis Child. 1922;24:526-533.

32. Lyell A. Toxic epidermal necrolysis: an eruption resembling scalding of the skin. Br J Dermatol. 1956;68(11):355-361. PMID: 13373699

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Last Reviewed: 2026-01-09 | MedVellum Editorial Team

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Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. SJS/TEN is a medical emergency – seek immediate medical attention if suspected. Content is evidence-based but does not replace clinical judgment or local protocols.