Stevens-Johnson syndrome / Toxic epidermal necrolysis

Rare but devastating: incidence ~1–6 cases per million per year. Women slightly > men. Markedly elevated risk in HIV-positive patients (up to 100× baseline) and in specific HLA contexts. Children: less common; when it occurs, Mycoplasma-associated mucositis (MIRM) overlaps clinically but is now considered a distinct entity with better prognosis.

Drug or metabolite binds an MHC class I–restricted T-cell receptor on CD8+ cells → granulysin and Fas-ligand-mediated keratinocyte apoptosis → full-thickness epidermal necrosis. Strong HLA associations:

• HLA-B\*15:02 — carbamazepine-induced SJS/TEN in Han Chinese, Southeast Asian populations. Test before prescribing in at-risk groups.
• HLA-B\*57:01 — abacavir hypersensitivity; mandatory pre-prescription screening.
• HLA-B\*58:01 — allopurinol-induced SJS/TEN, especially Han Chinese, Thai, Korean populations.
• HLA-A\*31:01 — carbamazepine in European populations.

Common culprits: sulfonamides (TMP-SMX), allopurinol, anticonvulsants (carbamazepine, lamotrigine, phenytoin, phenobarbital), nevirapine, oxicam NSAIDs (meloxicam, piroxicam), beta-lactams.

Latency: 4–28 days from first drug exposure (longer than morbilliform drug eruption at 4–14 days).

Prodrome (1–3 days): fever, malaise, URI-like symptoms, painful/burning skin.

Eruption: begins on the trunk/face, spreading to extremities. Initial lesions are dusky or erythematous macules with central purpura, often atypical targets. Lesions coalesce; flaccid bullae form; Nikolsky sign (lateral pressure → epidermal shear) develops.

Mucosal involvement: required for diagnosis (≥2 sites in most cases). Oral erosions (hemorrhagic crusted lips, painful oral ulcers), ocular (conjunctivitis → pseudomembrane → symblepharon), genitourinary (painful urination, genital erosions), respiratory, esophageal.

Systemic: fever 39–40°C, tachycardia, hypotension, transaminitis, electrolyte derangements.

Recognition is harder and frequently delayed in Fitzpatrick V–VI — a clinically and medicolegally serious issue.

• Early erythema is attenuated or absent. Look for dusky, grey-purple, violaceous macules rather than red.
• Skin pain out of proportion to visible findings is a reliable cross-tonal sign — take it seriously regardless of whether erythema is visible.
• Nikolsky sign, flaccid bullae, and sheet-like detachment are tone-independent physical findings — elicit them when the history raises suspicion.
• Mucosal erosions (lips, oral, ocular, genital) are visible in all skin tones and must be actively examined.
• Dusky macules may look like bruising in very dark skin; do not dismiss as trauma when there is also mucosal involvement and drug history.
• Post-inflammatory hyperpigmentation can be severe and prolonged; counsel survivors early.
• Delayed presentation is a documented disparity — if dermatology consult threshold is 'red rash + mucosa,' darker-skinned patients with dusky-rather-than-red presentations will be triaged later. Adjust your threshold.

• SJS: <10% BSA epidermal detachment.
• SJS/TEN overlap: 10–30% BSA.
• TEN: >30% BSA.
• Mycoplasma-induced rash and mucositis (MIRM): prominent mucositis with sparse cutaneous involvement; distinct from classic SJS, better prognosis.
• Generalized bullous fixed drug eruption: can mimic SJS/TEN but typically lacks systemic symptoms, mucosal involvement, and shows classic recurrent locations.
• DRESS (drug reaction with eosinophilia and systemic symptoms): overlapping drug list (especially anticonvulsants, allopurinol), different phenotype (morbilliform with facial edema, eosinophilia, hepatitis, lymphadenopathy, longer latency 2–8 weeks). Can rarely coexist.

• Erythema multiforme major — classic targets, distal limbs, infection (HSV, Mycoplasma) more than drug; limited mucosal involvement; much lower mortality.
• Staphylococcal scalded skin syndrome (SSSS) — toxin-mediated, superficial split (subcorneal), spares mucosa, typically young children.
• Acute generalized exanthematous pustulosis (AGEP) — pustular, latency <4 days, fewer than 1% mortality.
• Generalized bullous fixed drug eruption — recurrent pattern, less mucosal, fewer systemic features.
• Paraneoplastic pemphigus — severe mucositis, associated malignancy, different pathology.
• Acute GvHD (post-transplant) — diarrhea, hepatitis, skin mottling.
• Pemphigus vulgaris — slower, intact blisters, distinct histology and DIF.

• Drug history with specific dates — every drug started, resumed, or dose-changed in the preceding 2 months. Write the table yourself.
• SCORTEN on admission and day 3: Age >40 (1), Malignancy (1), HR >120 (1), Initial BSA >10% (1), BUN >28 mg/dL (1), Glucose >252 mg/dL (1), Bicarbonate <20 mEq/L (1). Score 0–1: ~3% mortality; 5+: ~90%.
• ALDEN score for drug causality assessment.
• Skin biopsy (including frozen section for rapid dx) — full-thickness epidermal necrosis, subepidermal split, scant dermal inflammation. Distinguishes SSSS (superficial split).
• Labs: CBC, BMP, LFTs, albumin, lactate, ABG, cultures (blood, skin, urine) — but empirical antibiotics only if confirmed infection.
• Imaging: CXR for aspiration/pneumonia.
• Consults: dermatology (STAT), ophthalmology (within 24 h — essential for long-term vision), urology/gyn for genital involvement, ENT if airway concern.
• HLA testing consideration for survivors and first-degree relatives with at-risk genotypes (B\*15:02, B\*58:01).

Immediate:

• Stop the culprit drug and every other non-essential medication started in the latency window. Document reason.
• Transfer to a burn unit or specialized ICU if TEN or SCORTEN ≥ 2. Early transfer correlates with lower mortality.
• Supportive care is the foundation:

- Fluid resuscitation (less than burn formula — typically 2–3 mL/kg/%BSA/24h Parkland-modified).

- Electrolyte correction, nutrition (enteral preferred).

- Thermoregulation (warm room, warming blankets; febrile but with impaired barrier).

- Wound care: nonadherent dressings (e.g., nanocrystalline silver, Biobrane, petrolatum gauze); avoid sulfadiazine (cross-reaction risk with SJS/TEN-causing sulfonamides).

- Ophthalmologic care: amniotic membrane graft if severe; lubrication; daily eyelid sweeping.

- Urogenital dilator/barrier care to prevent stricture.

- Pain control, DVT prophylaxis, stress ulcer prophylaxis, infection surveillance.

• Avoid prophylactic antibiotics. Treat only documented infection.

No single agent is universally endorsed. Decisions are case-by-case, institution-dependent:

• Cyclosporine 3–5 mg/kg/day for 7–10 days — most consistent mortality-reduction evidence in recent cohorts.
• TNF-α inhibitors (etanercept single dose, infliximab) — emerging evidence, good safety profile, increasingly used.
• IVIG 2–4 g/kg total dose — historically used; evidence mixed, likely no mortality benefit at lower doses.
• Systemic corticosteroids — controversial; early short course may reduce progression, but prolonged steroids increase infection risk.
• Plasmapheresis — last-line, limited evidence.

Consult derm + ICU + burn team. Most centers now default to cyclosporine or TNF-α inhibitor when adjunctive therapy is used.

Acute mortality tracks SCORTEN. Survivors face significant morbidity:

• Ocular: symblepharon, dry eye, trichiasis, meibomian gland loss, visual impairment, blindness — up to 50% have chronic ocular sequelae. Lifelong ophthalmology follow-up.
• Mucosal: esophageal strictures, vaginal stenosis, urethral strictures.
• Cutaneous: pigmentary changes (especially PIH in SoC), scarring, nail dystrophy/loss, vitiligo.
• Pulmonary: bronchiolitis obliterans (rare but devastating).
• Psychological: PTSD, chronic pain syndromes.
• Recurrence: occurs with re-exposure to the culprit or a cross-reactive agent. Lifelong avoidance is mandatory. Provide drug allergy documentation, alert bracelet, and counsel first-degree relatives.

• Skin pain out of proportion to visible findings is the earliest and most tone-independent sign. Trust it.
• In darker skin, look for dusky/grey rather than red. Do not require visible erythema to escalate.
• Mucosa + drug + pain = admit, stop drugs, consult derm.
• Every drug started in the 2 months before presentation is a suspect. Build the timeline yourself.
• Biopsy (even frozen section) quickly excludes SSSS — matters because management differs (antistaph abx vs. drug withdrawal).
• Do not prescribe sulfasalazine-containing wound care — risk of cross-reactive flare.
• SCORTEN on day 1 and day 3 — serial scoring is more predictive than single point.
• Counsel about cross-reactors: carbamazepine → phenytoin, lamotrigine, phenobarbital; sulfonamide antibiotics vs. non-antibiotic sulfonamides (less cross-reactivity than historically taught).
• HLA screening (B\*15:02, B\*58:01, B\*57:01) before prescribing respective drugs in at-risk populations is standard of care.

You have had a severe drug reaction. Recovery takes weeks to months. You must never take [culprit drug] or closely related drugs again — this could be fatal. You will receive a written list and an alert bracelet. Long-term follow-up with dermatology, ophthalmology, and (if involved) urology/gynecology is important. Color changes in the skin will fade but may take 6–12 months or longer. Emotional recovery is also a process — ask for mental-health support; it is part of healing. First-degree relatives may share genetic susceptibility and should know this history before starting similar medications.