Discuss adverse drug reaction .management of Ten and SJS IN 10 marks format for 3rd yr dermatology post graduate theory examination

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"Stevens-Johnson syndrome" OR "toxic epidermal necrolysis" management

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Adverse Drug Reactions (ADR) — Management of TEN and SJS

3rd Year Dermatology PG Theory — 10 Marks

I. ADVERSE DRUG REACTIONS (ADR) — Overview

An adverse drug reaction is any unintended, harmful response to a drug administered at a normal therapeutic dose. The classic Rawlins & Thompson classification divides ADRs into:

Type	Description	Examples
Type A (Augmented)	Predictable, dose-dependent, pharmacologic	Cushing's with steroids, hypoglycemia with insulin
Type B (Bizarre)	Unpredictable, dose-independent, immunologic/idiosyncratic	SJS, TEN, DRESS, anaphylaxis
Type C (Chronic)	Related to long-term use	Adrenal suppression
Type D (Delayed)	Appear after discontinuation	Teratogenesis, carcinogenesis
Type E (End-of-dose)	Withdrawal effects	Rebound hypertension
Type F (Failure)	Therapeutic failure	Drug resistance

Severe Cutaneous Adverse Reactions (SCARs) — the most dangerous Type B ADRs — include:

Stevens-Johnson Syndrome (SJS)
Toxic Epidermal Necrolysis (TEN)
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
Acute Generalized Exanthematous Pustulosis (AGEP)

II. STEVENS-JOHNSON SYNDROME (SJS) AND TOXIC EPIDERMAL NECROLYSIS (TEN)

A. Definition and Classification

SJS and TEN represent a spectrum of the same disease, classified by percentage of body surface area (BSA) of epidermal detachment:

Condition	BSA Detachment	Mortality
SJS	< 10%	~5–10%
SJS/TEN overlap	10–30%	~30%
TEN	> 30%	25–35%

They are nearly always drug-induced, resulting in extensive keratinocyte cell death causing separation of skin at the dermal-epidermal junction — clinically resembling scalded skin.

B. Common Causative Drugs (High-Risk)

Anticonvulsants: carbamazepine, phenytoin, lamotrigine, phenobarbitone
Antibiotics: sulfonamides (cotrimoxazole), penicillins, fluoroquinolones
Anti-gout: allopurinol (most common cause in Asia)
NSAIDs: oxicam class (meloxicam, piroxicam)
Antiretrovirals: nevirapine
Oncology: checkpoint inhibitors

C. Pathogenesis

Keratinocyte apoptosis occurs via two primary mechanisms:

Granulysin pathway: Activated cytotoxic CD8+ T cells and NK cells secrete granulysin (a key mediator), as well as TNF-α, TRAIL, and perforin-granzyme B → keratinocyte necrosis. Serum granulysin levels correlate with disease severity.
Fas-FasL pathway: Soluble Fas ligand (sFasL) binds Fas (CD95/death receptor) on keratinocytes → apoptosis. sFasL is elevated in TEN and correlates with BSA involvement.

Genetic susceptibility: HLA-B1502 (carbamazepine → SJS in Han Chinese) and HLA-B5801 (allopurinol → SJS/TEN in Asians) — pharmacogenomic screening is recommended in high-risk populations.

D. Clinical Features

Prodrome (1–3 days): Fever, malaise, sore throat, conjunctivitis — mimicking upper respiratory infection.

Cutaneous lesions:

Dusky erythematous macules — initially on trunk and face, spreading within hours
Atypical target lesions (macular, flat center) — unlike the raised 3-zone targets of EM
Flaccid bullae → epidermal detachment (Nikolsky sign positive)
"Wet cigarette paper" appearance of detached epidermis

Mucosal involvement (≥2 surfaces, characteristically severe):

Oral: hemorrhagic erosions, pseudomembranes, dysphagia
Ocular: conjunctivitis, pseudomembrane formation, corneal erosions — photophobia
Genital/urethral: dysuria, erosions
Respiratory: cough, erosions in tracheobronchial tree

E. Histopathology

Early: Scattered apoptotic keratinocytes in basal/suprabasal layers; minimal dermal infiltrate
Late: Subepidermal blister with full-thickness confluent epidermal necrosis; sparse perivascular lymphocytic infiltrate
CD8+ T cells in epidermis, CD4+ T cells in papillary dermis
DIF negative (excludes autoimmune bullous disease)

III. SEVERITY ASSESSMENT — SCORTEN

SCORTEN (SCORe of Toxic Epidermal Necrolysis) is calculated on Day 1 and Day 3 of admission:

Prognostic Factor	Points
Age ≥ 40 years	1
Heart rate ≥ 120 bpm	1
Cancer / hematologic malignancy	1
BSA involved on Day 1 > 10%	1
Serum urea > 10 mmol/L	1
Serum bicarbonate < 20 mmol/L	1
Serum glucose > 14 mmol/L	1

SCORTEN	Predicted Mortality
0–1	3.2%
2	12.1%
3	35.8%
4	58.3%
≥ 5	90%

IV. MANAGEMENT OF SJS/TEN

Management requires a multidisciplinary approach (dermatology, ophthalmology, ICU/burns unit, nutrition, nephrology).

Step 1 — Immediate Measures

Identify and withdraw the causative drug immediately — earlier withdrawal is associated with lower mortality; every day of continued exposure worsens prognosis
Admit to ICU or specialized burns unit — mandatory when BSA detachment ≥ 10–20%
Calculate SCORTEN on Day 1 and Day 3 to predict mortality and guide escalation

Step 2 — Supportive Care (Cornerstone of Management)

Supportive care mirrors severe thermal burn management and targets the primary causes of mortality: hypovolemia, sepsis, electrolyte imbalance, and respiratory failure.

a) Fluid and Electrolyte Management

IV fluid resuscitation to maintain urine output ≥ 0.5 mL/kg/hr
Correct electrolyte imbalances (hyponatremia, bicarbonate loss)
Enteral nutrition via nasogastric tube (high caloric demand, as in burns)

b) Wound Care (daily, performed by/with dermatologist)

Controlled-pressure, thermoregulated bed; aluminum survival sheet
Non-detached skin: kept dry, not manipulated
Detached/denuded areas: covered with Vaseline gauze or silicone non-adherent dressings until re-epithelialization (average ~3 weeks)
All manipulations done sterilely; venous catheters placed in non-involved skin
Silver nitrate 0.5% solution for macerated anogenital/interdigital areas

c) Mucosal Care

Oral: rinse with isotonic saline + antifungal suspension; antibiotic ointment around mouth
Ocular: ophthalmology review daily; isotonic saline cleansing; antibiotic + corticosteroid eye drops; lysis of early symblepharon with glass rod; amniotic membrane transplantation in severe cases
Nasal: sterile cotton swab cleaning + mupirocin ointment
Genital: daily saline cleansing; Foley catheterization for dysuria

d) Infection Control

Prophylactic systemic antibiotics are NOT recommended (increase risk of drug reaction and sepsis with resistant organisms)
Culture wounds/blood regularly; treat proven infections with narrow-spectrum agents
Avoid NSAIDs and drugs that can exacerbate reaction

e) Pain and Supportive

IV opioid analgesia (morphine/fentanyl) — pain is a cardinal feature
Anti-histamines for pruritus
Nutritional support (high protein, high calorie)
DVT prophylaxis; monitor for stress ulcers

Step 3 — Specific / Immunomodulatory Therapy

There is no universal consensus on the optimal immunomodulatory agent. Options include:

a) Etanercept (TNF-α inhibitor) ← Currently most evidence-supported

Dose: 50 mg SC single dose (or 25 mg twice weekly × 2 weeks)
A prospective RCT (96 patients) showed shorter skin healing time (14 vs 19 days, p=0.01) and less GI hemorrhage compared to IV prednisolone
Mechanism: blocks TNF-α, a key cytokine in keratinocyte death

b) Cyclosporine

Dose: 3–6 mg/kg/day in divided doses
Most favored in Europe
Mechanism: blocks T-cell activation; inhibits granulysin-mediated keratinocyte apoptosis
A meta-analysis of 256 patients showed significantly improved survival; however, a monocentric study of 174 patients showed no advantage over supportive care alone — conflicting evidence
Should be started early and tapered rapidly to avoid prolonged immunosuppression

c) Intravenous Immunoglobulin (IVIg)

Dose: 0.75–1 g/kg/day × 4 days (total ≥ 2 g/kg; doses < 2 g/kg may be insufficient)
Mechanism: IVIG contains anti-Fas antibodies that block sFasL binding to Fas, halting keratinocyte apoptosis
Higher doses (≥2 g/kg) correlate with increased survival
Relative contraindications: IgA deficiency, hypercoagulable states
Favored in the USA

d) Systemic Corticosteroids

Long controversial; risk of sepsis and impaired wound healing
May be beneficial when given early as pulse therapy: IV dexamethasone 1.5 mg/kg/day × 3 consecutive days
A 2021 network meta-analysis suggests corticosteroids + IVIg combination may reduce mortality in SJS/TEN overlap and TEN
Topical/systemic steroids for ocular involvement may improve outcomes

e) Combination therapy: Corticosteroids + IVIg is a reasonable option for severe TEN based on recent meta-analysis data.

f) Agents NOT recommended:

Thalidomide: a controlled trial was stopped early due to excess mortality in the treatment arm
Prophylactic antibiotics: increase risk of sepsis

Step 4 — Ophthalmologic Emergency Management

Ocular involvement is the single most important determinant of long-term morbidity:

Acute: topical antibiotic, steroid eye drops; glass rod lysis of early symblepharon
Subacute: amniotic membrane transplantation to prevent corneal scarring
Chronic: scleral contact lenses (Boston lens) for sicca syndrome; surgical correction of entropion, trichiasis

V. COMPLICATIONS AND SEQUELAE

System	Acute Complications	Chronic Sequelae
Cutaneous	Sepsis, hypothermia	Scarring, dyspigmentation, nail dystrophy, eruptive nevi
Ocular	Corneal ulceration	Symblepharon, entropion, trichiasis, blindness, sicca syndrome
Oral	Stomatitis, dysphagia	Esophageal stricture, altered taste
Genital	Dysuria, urinary retention	Vaginal/urethral stenosis
Respiratory	Pneumonia, ARDS	Bronchiolitis obliterans
Systemic	Septicemia, SIRS	—

VI. PREVENTION AND FUTURE PROTECTION

Re-exposure to causative drug is absolutely contraindicated — re-challenge carries near-100% recurrence risk
Document allergy clearly and provide the patient with a card/letter listing the offending drug(s) and all cross-reactive agents
HLA screening before prescribing carbamazepine in South/Southeast Asian patients (HLA-B1502) and allopurinol (HLA-B5801)
Avoid same chemical class (e.g., avoid all sulfonamides, all oxicam NSAIDs)

Summary Table — SJS vs TEN

Feature	SJS	TEN
BSA detachment	< 10%	> 30%
Mucosal involvement	Prominent (≥2 sites)	Less prominent
Nikolsky sign	Positive	Positive
Mortality	~5–10%	~25–35%
Primary treatment	Supportive ± Cyclosporine/IVIg	ICU + Etanercept / Cyclosporine / IVIg

Sources: Dermatology 2-Volume Set 5e (Weedon/Callen/James), p. 419–420; Andrews' Diseases of the Skin, p. 139–140; Fitzpatrick's Dermatology (8th ed)

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