Erythema Multiforme, SJS & TEN

A high-yield spectrum of immune-mediated mucocutaneous reactions. Two ends are biologically distinct: erythema multiforme (EM) is usually an infection-triggered (HSV) reaction with target lesions, while Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) form a single drug-induced, life-threatening continuum separated only by body-surface-area (BSA) detachment. NEET PG loves the BSA cut-offs, culprit drugs, Nikolsky sign and the SCORTEN score.

The big concept: two different diseases, three names

The most common exam trap is lumping EM with SJS/TEN. Older literature called EM-minor/major and SJS a continuum; modern (Bastuji-Garin) classification separates EM from SJS/TEN entirely.

• EM = mostly acral, raised typical targets, HSV/Mycoplasma trigger, benign, recurrent.
• SJS–TEN = truncal, atypical flat targets + dusky macules, drug trigger, mucosa-dominant, sheet-like epidermal necrosis, high mortality.

High-yield: EM and SJS/TEN are NOT the same disease. EM is infection-driven and acral; SJS/TEN is drug-driven, truncal and potentially fatal. The unifying histology is keratinocyte (epidermal) apoptosis/necrosis.

Classification by BSA detachment (the single most-tested table)

Entity	Epidermal detachment (BSA)	Typical lesions	Usual trigger	Mortality
Erythema multiforme	Minimal/none	Typical raised 3-zone targets, acral	HSV (90%), Mycoplasma	<1%
SJS	< 10%	Atypical flat targets, dusky macules, truncal	Drugs	~5-10%
SJS–TEN overlap	10-30%	Confluent macules	Drugs	~30%
TEN	> 30%	Sheets of epidermal sloughing	Drugs	~30-50%

High-yield: SJS = <10%**, overlap = **10-30%**, TEN = **>30% BSA detachment. This single number distinguishes the three and is asked almost every year.

Etiology

EM

• Herpes simplex virus (HSV-1 > HSV-2) — the commonest cause; herpes-associated EM (HAEM) is the recurrent form.
• Mycoplasma pneumoniae — especially in children; may cause Mycoplasma-induced rash and mucositis (MIRM) with prominent mucosa but sparse skin.
• Other: histoplasmosis, EBV, orf, drugs (less common in EM than in SJS/TEN).

SJS / TEN — drugs dominate (>80%)

A useful mnemonic for the high-risk drugs: "SATAN" → Sulfonamides (cotrimoxazole), Allopurinol, Tegretol (carbamazepine) & other anticonvulsants, Antibiotics (aminopenicillins, quinolones), NSAIDs (oxicams).

The classic culprits to memorise:

Drug class	Examples
Sulfonamides	Cotrimoxazole, sulfasalazine
Anticonvulsants	Carbamazepine, phenytoin, phenobarbitone, lamotrigine
Anti-gout	Allopurinol (commonest single cause in many series)
NSAIDs	Oxicams (piroxicam, meloxicam)
Antibiotics	Aminopenicillins, cephalosporins, quinolones
Antiretrovirals	Nevirapine
Others	Sulfonamide antibiotics, antimalarials

High-yield: Allopurinol is one of the most frequent causes of SJS/TEN worldwide. Latency is typically 4-28 days after starting the drug (longer than urticaria). A drug started in the last 1-3 weeks is the prime suspect.

Genetic associations (favourite single-best-answer)

• HLA-B*15:02 → carbamazepine-induced SJS/TEN in Han Chinese / South-East Asian populations. Screen before prescribing.
• HLA-B*58:01 → allopurinol-induced SJS/TEN.
• HLA-B*57:01 → abacavir hypersensitivity (related drug-reaction concept).

Pathophysiology

SJS/TEN is a CD8+ cytotoxic T-cell-mediated reaction against keratinocytes bearing drug-altered self-antigens, leading to widespread keratinocyte apoptosis and full-thickness epidermal necrosis with dermo-epidermal separation.

Key mediators:

• Granulysin — the dominant cytotoxic protein found in blister fluid; correlates with severity (high-yield molecule).
• Fas–Fas ligand (FasL) interaction → apoptosis.
• Perforin/granzyme B.

Flow of pathogenesis:

Culprit drug/metabolite binds MHC-I + alters self-peptide → CD8+ T-cell activation → release of granulysin + FasL + perforin/granzyme → massive keratinocyte apoptosis → full-thickness epidermal detachment → mucocutaneous failure (fluid/electrolyte loss, sepsis).

In EM, the mechanism is a delayed (Type IV) hypersensitivity with HSV DNA polymerase gene fragments transported to keratinocytes triggering a CD4+ Th1 / interferon-γ response — hence its milder, more localised pattern.

Clinical features

Erythema multiforme

• Typical target ("iris") lesion = the diagnostic hallmark: three concentric zones — central dusky/blistered disc, surrounding pale oedematous ring, outer erythematous halo.
• Acral and symmetric: dorsa of hands, palms, extensor forearms, knees, elbows, face.
• EM minor: little or no mucosal involvement, no systemic upset.
• EM major: ≥2 mucosal sites involved + targets, but still acral and lacking extensive detachment.
• Recurrent episodes point to HSV.

SJS / TEN

• Prodrome (1-3 days): fever >39°C, malaise, sore throat, stinging eyes, dysphagia — often misdiagnosed as a viral URTI before the rash.
• Skin: ill-defined dusky-red macules with purpuric centres, starting on the trunk/face and spreading; atypical flat targets; coalescence into sheets; then flaccid blisters and sheet-like detachment ("wet wallpaper / wet cigarette paper" peeling).
• Skin pain and tenderness out of proportion is an early warning sign.
• Mucosal involvement in ≥90% — at least two sites:
  • Oral: haemorrhagic crusting of lips, painful erosions.
  • Ocular: purulent conjunctivitis, pseudomembranes, risk of symblepharon and blindness (ophthalmology referral is mandatory).
  • Urogenital/anal erosions.
• Respiratory epithelium sloughing → bronchial casts, ARDS.

High-yield: Mucosal (especially two-site: oral + ocular/genital) involvement with skin pain and dusky macules in a patient on a new drug = think SJS/TEN until proven otherwise.

Nikolsky sign

• Positive Nikolsky sign: lateral shearing pressure on perilesional skin causes the epidermis to slide off → seen in TEN (and pemphigus).
• Asboe-Hansen (bulla spread) sign: pressing a blister extends it laterally — also positive.

High-yield: Nikolsky sign is positive in TEN. Remember it is negative in bullous pemphigoid (sub-epidermal, tense blisters) — a classic distractor.

Investigations

SJS/TEN is largely a clinical + histological diagnosis. The single confirmatory test of choice is skin biopsy.

Test	Finding / purpose
Skin biopsy (investigation of choice)	Full-thickness epidermal necrosis with subepidermal split; sparse dermal infiltrate; frozen section gives rapid answer
Direct immunofluorescence (DIF)	Negative — excludes autoimmune blistering disease (pemphigus, BP)
Granulysin (blister fluid)	Research/severity marker
CBC, electrolytes, glucose, urea, bicarbonate	For SCORTEN and fluid management
Cultures (skin, blood)	Monitor for sepsis (do not give prophylactic antibiotics)
Mycoplasma serology / HSV PCR	When EM/MIRM suspected

High-yield: Frozen-section skin biopsy showing full-thickness epidermal necrosis is the rapid confirmatory test; DIF is negative, distinguishing SJS/TEN from pemphigus.

SCORTEN — the prognostic score (must-know)

A severity-of-illness score for TEN, calculated within the first 24 hours (and ideally repeated on day 3). One point each for:

1. Age ≥ 40 years
2. Malignancy present
3. Heart rate ≥ 120/min (tachycardia)
4. Initial BSA detached > 10%
5. Serum urea (BUN) > 28 mg/dL (>10 mmol/L)
6. Serum bicarbonate < 20 mmEq/L
7. Serum glucose > 252 mg/dL (>14 mmol/L)

Mnemonic for the 7 parameters: "A MTV BBG" → Age, Malignancy, Tachycardia, BSA (Very >10%), Bicarbonate low, BUN/urea high, Glucose high.

SCORTEN	Predicted mortality
0-1	~3%
2	~12%
3	~35%
4	~58%
≥5	≥90%

High-yield: SCORTEN has 7 parameters; each scores 1. A score of ≥5 predicts >90% mortality. Glucose cut-off >252 mg/dL, urea >28 mg/dL, bicarbonate <20 mEq/L, HR ≥120 — these exact numbers are testable.

Management

The cornerstone is immediate withdrawal of the culprit drug and supportive ICU/burns-unit care — analogous to managing a major burn.

Stepwise approach:

1. Identify and STOP the offending drug immediately (single most important step; early withdrawal reduces mortality).
2. Transfer to a burns unit / ICU for SJS-TEN overlap and TEN.
3. Fluid & electrolyte resuscitation — losses are large; titrate to urine output (~0.5-1 mL/kg/hr). Requirements are less than thermal burns of equal area.
4. Temperature control, nutrition (high-protein, often via NG tube), and analgesia.
5. Wound care — non-adherent dressings; antiseptic; avoid routine debridement of detached but adherent epidermis (acts as a biological dressing).
6. Specialist referrals: ophthalmology (mandatory, early) to prevent symblepharon/blindness; urology/gynaecology for genital adhesions; dentistry for oral care.
7. Infection surveillance: cultures, NO prophylactic systemic antibiotics (only treat proven sepsis).

Drug of choice / specific immunomodulation

This is controversial and a favourite of examiners.

• Ciclosporin (3-5 mg/kg/day) — increasingly the preferred immunomodulator in TEN; evidence suggests it halts disease progression and may reduce mortality. Often the "best answer" in current questions.
• Systemic corticosteroids — short-course early high-dose is used by some; benefit unproven and may increase sepsis if late.
• IVIG — blocks Fas–FasL; evidence mixed.
• Etanercept (anti-TNF) — emerging, promising in trials.

High-yield: Stopping the culprit drug is the single most important intervention. Among immunomodulators, ciclosporin is the most favoured agent in recent guidance; supportive care in a burns/ICU setting determines survival.

EM management

• EM minor: symptomatic — antihistamines, topical steroids; self-limiting.
• HSV-associated recurrent EM: prophylactic oral aciclovir/valaciclovir for 6 months (treating an active episode with aciclovir does NOT abort the EM, but suppression prevents recurrences).
• Mycoplasma-related: treat with macrolides.

Complications

• Acute: fluid/electrolyte derangement, hypovolaemic shock, sepsis (commonest cause of death — Staph aureus, Pseudomonas), ARDS, multi-organ failure, thermoregulatory failure.
• Ocular (long-term, important): symblepharon, entropion/trichiasis, corneal scarring, dry-eye, blindness.
• Cutaneous: dyspigmentation, scarring, nail dystrophy.
• Mucosal: oesophageal/vaginal/urethral strictures, phimosis.
• SMART syndrome / late sequelae, chronic photophobia.

High-yield: Sepsis is the leading cause of death in TEN; ocular scarring/blindness is the most feared long-term complication — hence early ophthalmology referral.

Key differential diagnoses

Condition	Distinguishing features
Staphylococcal scalded skin syndrome (SSSS)	Children/neonates; toxin-mediated; subcorneal/superficial split (intra-epidermal at granular layer); mucosa SPARED; biopsy = superficial cleavage, not full-thickness
Pemphigus vulgaris	Flaccid bullae, oral erosions, Nikolsky +, but DIF positive (intercellular IgG, "fish-net"); chronic course
Bullous pemphigoid	Elderly, tense bullae, Nikolsky negative, DIF linear C3/IgG at BMZ
Acute generalized exanthematous pustulosis (AGEP)	Drug-induced; numerous tiny sterile pustules, rapid onset, fever, neutrophilia; resolves with desquamation
DRESS / DiHS	Drug reaction with eosinophilia + systemic symptoms; facial oedema, lymphadenopathy, eosinophilia, organ (liver) involvement, longer latency (2-6 wks)
Erythema multiforme	Acral, typical raised targets, HSV trigger, minimal detachment

High-yield: SSSS spares mucosa and splits at the granular layer (superficial); TEN involves mucosa and causes full-thickness necrosis. This biopsy-level distinction (granular vs dermo-epidermal split) is a classic SBA.

Recently asked / exam angle

• BSA cut-offs distinguishing SJS (<10%), overlap (10-30%) and TEN (>30%) — repeatedly asked.
• SCORTEN parameters and the value linked to each (urea >28, glucose >252, bicarbonate <20, HR ≥120) — image/match-type questions.
• Granulysin as the chief cytotoxic mediator in blister fluid.
• HLA-B*15:02 + carbamazepine and HLA-B*58:01 + allopurinol pharmacogenomics.
• Nikolsky sign positive in TEN; DIF negative (differentiating from pemphigus).
• Most common cause: drugs for SJS/TEN (allopurinol, sulfonamides, anticonvulsants); HSV for EM.
• Ciclosporin as the preferred immunomodulatory drug; stop the drug as the first step.
• Investigation of choice: skin biopsy (frozen section) with full-thickness epidermal necrosis.
• MIRM (Mycoplasma) as a paediatric mimic with prominent mucositis.
• Identifying the target lesion on a clinical photograph.

Rapid revision

1. EM = acral + typical 3-zone targets + HSV trigger; SJS/TEN = truncal, atypical flat targets, drug trigger.
2. SJS <10%, overlap 10-30%, TEN >30% BSA epidermal detachment.
3. Commonest cause of EM = HSV; commonest cause of SJS/TEN = drugs (SATAN: Sulfonamides, Allopurinol, Tegretol/anticonvulsants, Antibiotics, NSAIDs).
4. Allopurinol and cotrimoxazole are top single culprits; latency 1-4 weeks.
5. HLA-B*15:02 → carbamazepine, HLA-B*58:01 → allopurinol SJS/TEN.
6. Granulysin is the key cytotoxic mediator; CD8+ T-cell + Fas-FasL apoptosis.
7. Nikolsky sign POSITIVE in TEN; DIF NEGATIVE (vs pemphigus DIF positive).
8. Investigation of choice = skin biopsy (full-thickness epidermal necrosis, frozen section for speed).
9. SCORTEN = 7 parameters, each 1 point; score ≥5 → >90% mortality; calculate in first 24 h.
10. First and most important step = STOP the culprit drug; manage in burns unit/ICU; ciclosporin is the favoured immunomodulator.
11. Mandatory early ophthalmology referral — ocular scarring/blindness is the dreaded sequela; sepsis is the leading cause of death.
12. SSSS spares mucosa, splits at granular layer; recurrent HSV-EM → prophylactic aciclovir for 6 months.