Stevens-Johnson Syndrome & Toxic Epidermal Necrolysis

Meet the patient

A 56-year-old man started allopurinol six weeks ago for gout. He now has high fever, skin that burns to the touch, haemorrhagic crusting of the lips, conjunctivitis, and dusky purpuric macules coalescing on his trunk with sheet-like peeling over 15 per cent of his body surface.[1][6]

This is SJS-TEN overlap, and the clock is already running. Two acts decide his survival in the next hour: stop the allopurinol now (every additional day on the offending drug adds to the keratinocyte death toll) and transfer him to a burns unit or ICU because detachment has crossed 10 per cent BSA. Hold those two acts and the whole topic is structured.[1][2]

Two non-negotiable principles frame everything

First, immediately stop every potentially causative drug — the single most important intervention and the only one that has never been controversial. Withdraw every drug started in the preceding eight weeks; if one is essential, switch to a structurally unrelated alternative.[1]

Second, recognise the disease early and transfer to a burns unit or ICU when detachment exceeds 10 per cent BSA. The level of supportive care, the ophthalmology input, and the infection surveillance determine survival more than any specific immunomodulator. Ophthalmology from day one prevents the irreversible corneal scarring that is the most feared long-term complication of survivors.[1][2]

The spectrum — one disease, three BSA bands

The Bastuji-Garin consensus arranges SJS and TEN on a single continuum defined by the percentage of detached BSA, and the band carries prognostic weight: mortality climbs as detachment increases.[3]

[3]

The classic trap: erythema multiforme is a separate disease, not the mild end of SJS. EM has typical raised three-zone targets, an infection trigger (HSV, Mycoplasma), and near-zero mortality. SJS/TEN has flat purpuric atypical targets, a drug trigger, and high mortality. The rule: typical raised targets are EM; flat dusky macules with mucosal ulceration after a new drug are SJS/TEN.[9][11]

How common, and who is at risk

SJS and TEN are rare but catastrophic. The combined annual incidence is about 1 to 2 per million per year for SJS and 0.4 to 1.2 per million per year for TEN, drawn from the German national registry.[8]

[8]

Risk concentrates in slow acetylators, patients with HIV (a thousand-fold increased risk of sulfonamide reactions and a marked risk from nevirapine), systemic lupus erythematosus, active malignancy or chemotherapy, the elderly, and renal or hepatic impairment (impaired clearance prolongs the immune exposure). Crucially, specific HLA alleles confer very high genetic risk in particular populations, which is why pharmacogenomic screening before certain drugs is now a global guideline.[1][9]

The five drug families — and the latency that catches candidates

Drugs cause 80 to 95 per cent of SJS/TEN, and the latency is one to eight weeks after the drug is started. The five families every candidate must name: allopurinol (now the commonest single cause in Europe and the Americas), anticonvulsants (carbamazepine, lamotrigine, phenytoin, phenobarbital), sulphonamide antibiotics (cotrimoxazole), oxicam NSAIDs (piroxicam, meloxicam), and nevirapine.[9]

The classic trap: the causative drug is often not the most recently started one. A patient who began allopurinol eight weeks ago and an antibiotic two days ago will draw your eye to the antibiotic — but the allopurinol is the culprit. Review every drug of the preceding eight weeks, every time.[1]

The drug spectrum shifts by geography. In Europe and the Americas allopurinol leads, often started outside guideline indications for asymptomatic hyperuricaemia. In East and South-East Asia carbamazepine dominates, driven by high HLA-B asterisk 1502 carriage. In India and South Asia anticonvulsants, sulphonamides, and nevirapine lead, with allopurinol rising. In HIV cohorts nevirapine and cotrimoxazole dominate.[6][9]

Granulysin — and the HLA alleles that load the gun

SJS/TEN is a type IV hypersensitivity reaction mediated by drug-specific CD8-positive cytotoxic T cells that home to the epidermis and kill keratinocytes in a disseminated, confluent pattern. The offending drug is presented by HLA class I on the keratinocyte; the drug-specific T cell recognises the complex and releases its cytotoxic cargo.[4]

The dominant mediator is granulysin. Chung and colleagues showed granulysin is present in SJS/TEN blister fluid at concentrations far higher than perforin or granzyme B, and that injecting granulysin into mouse skin reproduces the necrosis. The other three pathways — perforin-granzyme B, Fas-FasL, and TNF-alpha — amplify the signal. The histological correlate is full-thickness epidermal necrosis with a sparse infiltrate — "many dead keratinocytes, few inflammatory cells" — the opposite of the cell-rich interface dermatitis of EM.[4][11]

[1]

The pharmacogenomics that saves lives: HLA-B asterisk 1502 presents carbamazepine to cytotoxic T cells in Han Chinese and South-East Asians — the US FDA recommends screening before carbamazepine in Asian-ancestry patients, and it is mandatory in Taiwan and Hong Kong. HLA-B asterisk 5801 presents allopurinol and its metabolite oxypurinol, with an odds ratio over 100 in Han Chinese, Thai, and Korean cohorts — screen before allopurinol in these groups. These are not mere associations: the peptide-binding groove of the HLA molecule physically accommodates the drug.[5][6]

What you see at the bedside

The course unfolds in two phases. Phase 1 is the prodrome — one to three days of high fever, malaise, arthralgia, upper-respiratory symptoms, and a burning, stinging sensation of the skin and eyes that precedes any visible rash (a cardinal clue easily misread as a viral illness). Phase 2 is the eruptive phase — dusky purpuric atypical target lesions (flat, two-zone, dark-centred macules with a red halo) appear first on the trunk and proximal limbs, then coalesce; flaccid bullae form over the dusky macules and lateral pressure shears the epidermis off in sheets.[1][2]

Mucosal involvement is the rule, in over 90 per cent and at at least two sites. The oral mucosa is earliest and most often hit, with painful haemorrhagic crusting of the lips that is almost pathognomonic. Ocular involvement is the single most important site to manage aggressively — it decides long-term vision. Genital and urethral mucositis cause dysuria and retention; tracheobronchial and oesophageal involvement predict respiratory and feeding compromise. Unlike staphylococcal scalded skin syndrome, which spares mucosae, SJS/TEN always involves them — a key bedside discriminator.[1][10]

The Nikolsky sign — the bedside manoeuvre that anchors the diagnosis

The direct (lateral) Nikolsky: apply firm sliding pressure with a thumb to unblistered skin beside a lesion; positive when the epidermis shears off, leaving a moist glistening base. The indirect (Asboe-Hansen) Nikolsky: press vertically on an intact blister roof; positive when the blister extends sideways. A positive Nikolsky means the entire epidermis is necrotic and loose — the histology of TEN. It is also positive in pemphigus vulgaris and SSSS, so it confirms "epidermolysis" but not the cause; the mucosal involvement, drug history, and atypical targets then separate SJS/TEN.[1][9]

[1]

The face-off — SJS/TEN against its blistering mimics

The differential of an acute blistering or skin-sloughing rash with mucositis is short, but the management of each diverges sharply. Name the four examiners expect, with the discriminating feature.[9][11]

[9]

The one-line discriminator: mucosae spared and a superficial split = SSSS; mucosae involved and full-thickness necrosis = SJS/TEN; tense bullae and Nikolsky negative = bullous pemphigoid.[1]

Confirm on biopsy and grade with SCORTEN

SJS/TEN is fundamentally a clinical diagnosis, but a punch biopsy confirms it and SCORTEN grades it. Send FBC, U&E, LFTs, glucose, bicarbonate, lactate, CRP, and blood cultures before antibiotics; a chest radiograph screens for aspiration and pulmonary involvement.[1]

A 4 mm punch biopsy of the advancing erythematous border shows the signature: full-thickness epidermal necrosis with a sub-epidermal split and a sparse superficial perivascular lymphocytic infiltrate — "many dead cells, few inflammatory cells". Direct immunofluorescence is negative or non-specific, excluding pemphigus vulgaris (intercellular fishnet IgG) and bullous pemphigoid (linear basement-membrane IgG or C3). Frozen-section histology at the bedside can confirm TEN within an hour when the differential is genuinely uncertain.[1][9]

The resuscitation bundle — four acts in parallel

The resuscitation phase decides whether the patient survives the first week. Four non-negotiable elements run in parallel.[1][2]

[1]

Stop the causative drug the moment SJS/TEN is suspected, not after biopsy. Withdraw every drug of the preceding eight weeks; switch an essential drug to a structurally unrelated alternative. Early withdrawal shortens progression and reduces mortality.[1]

Decide the level of care by BSA detached. Over 10 per cent detachment (overlap and TEN), rapidly progressive SJS, airway involvement, renal failure, or a high SCORTEN mandates transfer to a burns unit or ICU.[1][2]

Fluid and electrolyte resuscitation — reduce, do not copy, the burn formula. The denuded dermis loses fluid like a burn, but the dermis is intact, so insensible loss is less than a comparable thermal burn. Give roughly two-thirds of a standard burn-formula volume — about 1.5 mL per kg per per cent BSA in the first 24 hours versus 2 to 4 in the Parkland formula — titrated to a urine output of 0.5 to 1.0 mL per kg per hour. Over-resuscitation causes pulmonary oedema and worsens outcome.[1][2]

Analgesia and airway. Skin denudation is exquisitely painful — give intravenous morphine, titrated or patient-controlled. Address the airway: tracheobronchial involvement can slough epithelium and cause respiratory failure, requiring intubation by an experienced operator (the friable mucosa bleeds).[1]

Burns-level supportive care — the organs that decide survival

Beyond the resuscitation bundle, definitive management is burns-level supportive care plus organ-specific protection; specific immunomodulators are controversial and adjunctive, not definitive.[1][7]

Wound care. Dress the denuded skin like a partial-thickness burn: gentle debridement of necrotic epidermis, non-adherent dressings (paraffin gauze, silicone), and biological or synthetic skin substitutes (allograft, amniotic membrane, Biobrane) for large areas. Topical silver sulfadiazine 1 per cent twice daily is widely used but controversial — sulphonamide absorption through denuded skin can itself provoke reactions, so many units prefer petroleum-based emollients or biosynthetic dressings. Warm the environment to combat massive heat loss.[1][2]

Nutrition. SJS/TEN is profoundly catabolic. Early enteral feeding via a nasogastric tube within 24 to 48 hours is preferred over parenteral nutrition — it maintains gut mucosal integrity, reduces bacterial translocation, and avoids line-infection risk. Caloric targets follow burns formulas (about 1.5 times basal metabolic rate).[1][2]

Eye care — the organ that decides the survivor's life. Daily ophthalmology review from day one is mandatory and is the single most important determinant of long-term vision. The bundle is topical preservative-free lubricants hourly, topical antibiotics (chloramphenicol or ofloxacin), and topical corticosteroids (prednisolone 0.5 per cent). For severe disease, early amniotic membrane transplantation within the first few days covers the denuded conjunctival and corneal surface, suppresses inflammation, and dramatically reduces symblepharon, fornix shortening, dry eye, and corneal opacity.[10]

Mucosal care. Oral hygiene with chlorhexidine 0.2 per cent mouthwash, topical anaesthetic mouthwashes (lidocaine viscous) for pain, and topical corticosteroids (triamcinolone in Orabase) for erosions. A urinary catheter is usually needed for urethral mucositis; stool softeners prevent anal fissure.[1]

The immunomodulators — and the Cochrane verdict

No specific therapy is proven over supportive care. The 2022 Cochrane review of systemic interventions for SJS, TEN, and overlap concluded the evidence is insufficient to recommend IVIG, ciclosporin, corticosteroids, thalidomide, or TNF-alpha inhibitors over supportive care alone. This is the single most important evidence statement to reproduce at viva.[7]

[1]

The practical consequence: supportive care is the standard, and specific therapy is adjunctive, selected case by case (often IVIG or ciclosporin), never a substitute for stopping the drug and burns-level support.[7]

The scenarios that change the plan

Mycoplasma-induced rash and mucositis (MIRM or RIME) in children. An SJS-like illness one to two weeks after Mycoplasma pneumoniae respiratory infection, with prominent mucositis and minimal skin lesions. Drug cause is absent or weak. Manage with supportive care plus a macrolide (azithromycin or clarithromycin); the prognosis is better than drug-induced SJS but ocular complications still occur. Biopsy shows an interface dermatitis rather than confluent necrosis.[11]

Allopurinol-induced SJS and HLA-B asterisk 5801. Allopurinol is now the commonest single cause in Europe and the Americas; the reaction begins two to eight weeks after starting, and the risk is dose- and renal-function-related (oxypurinol accumulates in renal impairment). Screen HLA-B asterisk 5801 before allopurinol in Han Chinese, Thai, and Korean populations. Safe prescribing: start low (100 mg/day, lower in renal impairment) and titrate slowly, and never initiate allopurinol for asymptomatic hyperuricaemia outside guidelines.[6][9]

Carbamazepine-induced SJS and HLA-B asterisk 1502. Concentrated in Han Chinese and South-East Asians due to high HLA-B asterisk 1502 carriage. The US FDA recommends screening before carbamazepine in Asian-ancestry patients; it is mandatory in Taiwan and Hong Kong. Oxcarbazepine, phenytoin, and lamotrigine carry cross-reactivity.[5]

DRESS — the mimic most often confused with SJS. Onset two to eight weeks after a drug; features are a morbilliform rash, facial oedema, fever, lymphadenopathy, eosinophilia, hepatitis, and HHV-6 reactivation. DRESS has no sheet-like necrosis, no positive Nikolsky, and typically no mucosal ulceration. Treat with systemic corticosteroids (prednisolone 1 mg/kg/day tapering).[9]

Complications — sepsis kills acutely, the eye kills chronically

Sepsis is the commonest cause of death — usually gram-positive (Staphylococcus aureus) or gram-negative bacteraemia from denuded skin, central lines, or lungs — followed by acute respiratory distress syndrome, acute kidney injury, gastrointestinal bleeding, electrolyte disturbances, and venous thromboembolism (prophylaxis is essential).[1][2]

In survivors, the eye dominates long-term morbidity: dry eye, symblepharon, fornix shortening, trichiasis, corneal scarring, corneal opacity, and blindness affect up to a third to a half without optimal early eye care. Mucosal sequelae include oesophageal, urethral, and anal strictures; cutaneous sequelae include post-inflammatory pigment change, scarring, and nail dystrophy. Lifelong ophthalmology follow-up is essential.[10]

Prognosis and disposition

Mortality is driven by detachment extent and comorbidity, captured by SCORTEN — calculate it at admission and again at 72 hours, since the 72-hour score is the more accurate predictor. Mortality bands are 3.2 per cent for 0 to 1, 12.1 per cent for 2, 35.8 per cent for 3, 58.4 per cent for 4, and over 90 per cent for 5 or more. In general, SJS mortality is 1 to 5 per cent, overlap 5 to 15 per cent, and TEN 25 to 35 per cent; survivors re-epithelialise over two to six weeks.[3]

Disposition follows severity. Mild SJS (under 10 per cent BSA, low SCORTEN, no organ failure) may be managed on a dermatology ward with daily review. Overlap and TEN (over 10 per cent BSA, any organ failure, or SCORTEN of 3 or more) go to a burns unit or ICU. Discharge when re-epithelialisation is underway, sepsis is controlled, nutrition is established enterally, and ophthalmology and mucosal care plans are in place. Survivors need lifelong ophthalmology follow-up, strict avoidance of the causative drug and structurally related drugs (documented in the record and a medical-alert bracelet), and HLA screening of first-degree relatives when a high-risk allele is identified.[1][10]

Ward-round test

A patient on allopurinol for six weeks presents with fever, painful burning skin, haemorrhagic lip crusting, conjunctivitis, and sheet-like peeling over 15 per cent BSA. What is the diagnosis, the single most important immediate act, and the SCORTEN variables already accumulating?

SJS-TEN overlap — 15 per cent BSA detachment, atypical targets, mucositis at oral and ocular sites, one to eight weeks after allopurinol. The single most important act is stop the allopurinol immediately and review every drug of the preceding eight weeks, then transfer to a burns unit or ICU (over 10 per cent BSA). SCORTEN is already accumulating: age over 40 (1 point), heart rate over 120 if tachycardic, and initial detachment over 10 per cent BSA (1 point) — with serum urea, bicarbonate, glucose, and malignancy status still to check. Add daily ophthalmology from day one, amniotic membrane for severe eyes, modified (reduced) fluid resuscitation, and early enteral nutrition.[1][3]

Why are fluid volumes in SJS/TEN lower than the Parkland formula for a burn of the same size?

Because the dermis is intact in SJS/TEN — the split is at the dermo-epidermal junction, so insensible fluid loss is less than in a thermal burn where the full thickness is destroyed. Give roughly two-thirds of a standard burn-formula volume (about 1.5 mL/kg/per cent BSA in the first 24 hours), titrated to a urine output of 0.5 to 1.0 mL/kg/hour. Over-resuscitation causes pulmonary oedema and worsens outcome — which is why burn-formula fluid volumes must be reduced, not copied, for SJS/TEN.[1][2]

A febrile child has severe oral and ocular mucositis with sparse skin lesions, one week after a respiratory illness. What is the likely diagnosis, and how does management differ from drug-induced SJS?

Reactive infectious mucocutaneous eruption (RIME), formerly mycoplasma-induced rash and mucositis (MIRM) — prominent mucositis with minimal skin lesions one to two weeks after Mycoplasma pneumoniae. The drug cause is absent or weak, and the biopsy shows an interface dermatitis rather than confluent necrosis. Management is supportive care plus a macrolide (azithromycin or clarithromycin) for the underlying Mycoplasma; ophthalmology input is still essential because ocular complications occur. The prognosis is better than drug-induced SJS.[11]

References

1. [1]Frantz R, Huang S, Are A, Motaparthi K. Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Review of Diagnosis and Management Medicina (Kaunas), 2021.PMID 34577817
2. [2]Meledathu S, Gordon M, Thornton M, Ashinoff R. Management of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis: A Case Report and Literature Review J Drugs Dermatol, 2023.PMID 37943271
3. [3]Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis J Invest Dermatol, 2000.PMID 10951229
4. [4]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.PMID 19029983
5. [5]Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome Nature, 2004.PMID 15057820
6. [6]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.PMID 15743917
7. [7]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.PMID 35274741
8. [8]Naegele D, Sekula P, Paulmann M, Mockenhaupt M. Incidence of Epidermal Necrolysis: Results of the German Registry J Invest Dermatol, 2020.PMID 32353449
9. [9]Mockenhaupt M. Bullous Drug Reactions Acta Derm Venereol, 2020.PMID 32039459
10. [10]Akgun Z, Can GD, Selver OB. Ocular involvement in Stevens-Johnson syndrome and toxic epidermal necrolysis: A review of current management and changing trends Indian J Ophthalmol, 2025.PMID 41288622
11. [11]Chang WC, Abe R, Anderson P, et al. SJS/TEN 2019: From science to translation J Dermatol Sci, 2020.PMID 32192826