Skin & Subcutaneous Tissue

Stevens-Johnson syndrome and toxic epidermal necrolysis

Clinical Overview and When to Suspect SJS/TEN

— SJS: <10% BSA

— SJS/TEN overlap: 10–30% BSA

— TEN: >30% BSA

— Sulfonamides (TMP-SMX is the classic Step 3 culprit)

— Allopurinol (highest absolute risk in Europe/Asia)

— Tetracyclines, Tiotropium? no — anticonvulsants: carbamazepine, lamotrigine, phenytoin, phenobarbital

— Anti-gout (allopurinol), Antibiotics (β-lactams, fluoroquinolones)

— NSAIDs (oxicams), Nevirapine

— Also: sulfasalazine, abacavir, and immune checkpoint inhibitors (emerging cause)

Board pearl: Skin pain out of proportion to visible findings in a patient on a high-risk drug should trigger immediate SJS/TEN consideration — before sloughing appears. Stop the offending drug immediately; delay worsens mortality (SCORTEN-validated).

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe T-cell–mediated mucocutaneous reactions characterized by keratinocyte apoptosis, full-thickness epidermal necrosis, and sloughing — a dermatologic emergency with mortality up to 30–50% in TEN.

Classification by body surface area (BSA) of detached or detachable epidermis:

Pathophysiology: CD8+ cytotoxic T cells release granulysin, perforin, granzyme B, and soluble Fas ligand → widespread keratinocyte apoptosis. HLA-restricted drug presentation drives the immune response.

Most common triggers (mnemonic: "SATAN"):

Infectious triggers (especially in pediatrics): Mycoplasma pneumoniae, HSV, CMV — M. pneumoniae causes a distinct entity now called Mycoplasma-induced rash and mucositis (MIRM).

Timeline: Reaction typically begins 4–28 days after drug initiation (median 1–3 weeks); re-exposure can shorten this to hours.

When to suspect on Step 3: New drug + prodromal fever/malaise + painful skin + mucosal involvement (oral, ocular, genital) + dusky macules progressing to bullae.

Presentation Patterns and Key History

— Fever >39°C, malaise, myalgia, arthralgia, sore throat, conjunctival burning, photophobia, dysphagia, odynophagia

— Often misdiagnosed as viral URI — Step 3 question may show a patient sent home from clinic, returning 48 h later with rash

— Begins on face and trunk, then spreads symmetrically to extremities (palms/soles may be involved)

— Initial lesions: erythematous to dusky/purpuric macules with darker centers ("atypical targets" — only 2 zones, vs. true targets of erythema multiforme with 3 zones)

— Coalesce into flaccid bullae → epidermal detachment in sheets

— Oral: hemorrhagic crusting of lips, painful erosions

— Ocular: purulent conjunctivitis, pseudomembranes, corneal erosions

— Genitourinary: dysuria, vulvovaginal/penile erosions, urinary retention

— Respiratory/GI: tracheobronchial sloughing, esophagitis, diarrhea (poor prognostic signs)

— Complete medication review including new starts in past 8 weeks, OTC drugs, herbals, recent antibiotic courses

— Prior drug reactions, family history of severe cutaneous reactions

— HIV status (100-fold increased risk), recent radiation therapy, malignancy

— Ancestry: HLA-B15:02 (Han Chinese, Southeast Asian) → carbamazepine; HLA-B58:01 (Asian) → allopurinol; HLA-B*57:01 → abacavir

Key distinction: Erythema multiforme major has true 3-zone targets, acral predominance, usually HSV-triggered, minimal mucosal involvement, and benign course. SJS/TEN has atypical 2-zone targets, truncal onset, drug-triggered, severe mucosal disease, and high mortality. The 2018 international consensus considers EM and SJS/TEN separate entities, not a spectrum — a frequent Step 3 distractor.

Prodrome (1–3 days before rash):

Cutaneous eruption onset:

Mucosal involvement (>90% of cases, often precedes skin):

Key history to obtain:

Physical Exam Findings and Hemodynamic Assessment

— Document total BSA of detachment using rule of nines or palm method (patient's palm ≈ 1% BSA); include only detached or detachable skin, not erythema alone

— Nikolsky sign positive: lateral pressure on perilesional skin causes epidermal shearing — sensitive but not specific (also seen in pemphigus, SSSS)

— Asboe-Hansen sign: bulla extends laterally with pressure — confirms intraepidermal cleavage

— Lesion color progression: pink → dusky red → gray → frank necrosis with wrinkled, sloughing epidermis resembling "wet cigarette paper"

— Lip and oral cavity hemorrhagic crusts; assess airway patency

— Slit-lamp evaluation: fluorescein staining for corneal epithelial defects, symblepharon formation

— Genital exam: erosions, urethral involvement → may require Foley placement before swelling

— Temperature (often 38–40°C), HR, BP, urine output, mental status

— Massive insensible fluid losses through denuded skin → hypovolemia, prerenal AKI, electrolyte derangements

— Tachycardia and hypotension suggest sepsis or hypovolemic shock

— Respiratory rate, SpO₂, work of breathing — bronchial epithelial sloughing causes hypoxemia and ARDS-like picture (poor prognostic sign)

— Age >40, HR >120, malignancy, BSA detached >10%, BUN >28 mg/dL, glucose >252 mg/dL, bicarbonate <20 mEq/L

— Each = 1 point; mortality climbs from ~3% (0–1) to >90% (≥5)

Step 3 management: On initial exam, immediately discontinue all non-essential medications, especially any started in the last 4 weeks. Calculate SCORTEN, establish two large-bore IVs, place a Foley to track urine output (target 0.5–1 mL/kg/h), and request urgent dermatology, ophthalmology, and burn/ICU consultation before further workup.

Skin examination — systematic approach:

Mucosal exam (mandatory at all sites):

Hemodynamic and systemic assessment:

SCORTEN parameters (assess on day 1 and day 3):

Diagnostic Workup — Initial Labs, Imaging, and Bedside Studies

— CBC with differential: anemia common; lymphopenia is characteristic (correlates with severity); neutropenia is a poor prognostic sign

— Comprehensive metabolic panel: BUN, creatinine (AKI from hypovolemia/tubular injury), glucose (hyperglycemia from stress/sepsis), electrolytes (hyponatremia, hypophosphatemia, hypomagnesemia)

— LFTs: transaminitis in 10–15%; hepatitis suggests overlap with DRESS syndrome

— Bicarbonate <20 is a SCORTEN criterion — reflects sepsis, AKI, or impending respiratory failure

— Coagulation panel: DIC can develop in severe TEN

— Blood and wound cultures at baseline and with any fever spike — S. aureus and Pseudomonas dominate

— Lactate, ABG/VBG if hemodynamically unstable or hypoxemic

— Mycoplasma pneumoniae IgM and PCR (especially in children/young adults with prominent mucositis, sparse skin involvement)

— HSV PCR of mucosal lesions if EM-like

— HIV testing — markedly elevated SJS/TEN risk

— Chest X-ray for pneumonia, ARDS, or Mycoplasma infiltrates

— ECG if electrolyte derangements or QT-prolonging drugs

— Urinalysis for hematuria/proteinuria suggesting urothelial sloughing

CCS pearl: On a CCS case, after stopping the offending drug, order in parallel: CBC, CMP, LFTs, coagulation, blood cultures × 2, lactate, CXR, urinalysis, and HIV — then advance the clock. Avoid ordering studies serially; CCS rewards efficient bundled workup. Re-check SCORTEN at 72 hours; it remains prognostically valid on day 3.

SJS/TEN is primarily a clinical diagnosis — labs guide severity, SCORTEN, and complication detection rather than confirm the diagnosis.

Essential initial laboratory panel:

Infectious workup when triggers are unclear:

Bedside studies:

Diagnostic Workup — Advanced and Confirmatory Studies

— Take two punch biopsies from a lesional edge: one for routine H&E and one for direct immunofluorescence (DIF) to exclude autoimmune blistering disease

— Frozen section can provide rapid (<1 h) diagnosis when bedside differential includes SSSS — particularly useful in pediatric ED

— Histology: full-thickness epidermal necrosis with subepidermal cleavage, scant dermal lymphocytic infiltrate, individual keratinocyte apoptosis

— DIF: negative (helps exclude pemphigus, bullous pemphigoid, paraneoplastic pemphigus, linear IgA dermatosis)

— SSSS: cleavage at granular layer (superficial), no full-thickness necrosis

— Pemphigus vulgaris: suprabasal acantholysis, DIF with intercellular IgG

— Bullous pemphigoid: subepidermal split, DIF with linear IgG/C3 at basement membrane

— ALDEN score (Algorithm of Drug Causality for Epidermal Necrolysis): scores timing, drug notoriety, presence in body at reaction, prior exposure, dechallenge response

— Score ≥4 = probable/very probable culprit — guides which drug to permanently avoid

— HLA-B*15:02 — carbamazepine-induced SJS/TEN in Han Chinese, Thai, Malay (FDA recommends pre-prescription screening in Asian ancestry)

— HLA-B*58:01 — allopurinol (screen in Korean CKD patients per ACR)

— HLA-B*57:01 — abacavir (mandatory screening before initiation)

Board pearl: A patient developing SJS on carbamazepine prompts lifelong avoidance of all aromatic anticonvulsants (carbamazepine, phenytoin, phenobarbital, lamotrigine, oxcarbazepine) due to 70–80% cross-reactivity. Safe alternatives: valproate, levetiracetam, topiramate, gabapentin.

Skin biopsy — the confirmatory test:

Differentiating biopsy patterns:

Drug causality assessment:

HLA testing (not for acute diagnosis, but for future avoidance and family screening):

Ophthalmology evaluation: slit-lamp with fluorescein, lid eversion, daily exams during acute phase to detect symblepharon and corneal melt.

Risk Stratification and First-Line Management Logic

— 0–1 points: 3.2% mortality

— 2 points: 12.1%

— 3 points: 35.3%

— 4 points: 58.3%

— ≥5 points: 90%

— SJS (<10% BSA), stable, SCORTEN 0–1: dermatology ward with close monitoring acceptable

— SJS/TEN overlap or TEN (≥10% BSA): transfer to burn unit or ICU — burn-unit care reduces mortality (retrospective data, but consistent)

— Any airway, ocular, or hemodynamic compromise → ICU regardless of BSA

— Airway: assess for mucosal involvement; early intubation if tracheobronchial sloughing or stridor

— Breathing: SpO₂, CXR; bronchoscopy if hypoxemic

— Circulation: IV crystalloid resuscitation — 2 mL/kg × %BSA detached in first 24 h (less than Parkland because losses are smaller than burns)

— Drug discontinuation: stop all suspect drugs immediately — single most important intervention

— Environment: warmed room (28–32°C), reverse isolation, minimize handling

— Fluids/nutrition: early enteral feeding (NG tube if oral mucositis precludes intake)

— Non-adherent dressings (petrolatum gauze, silicone-coated, biosynthetic) — avoid silver sulfadiazine (sulfa risk)

— Do NOT debride detached but adherent epidermis — acts as biologic dressing; only remove frankly necrotic, dislodged skin

— Daily atraumatic dressing changes; warmed saline or chlorhexidine cleansing

Step 3 management: The three interventions proven to reduce mortality are (1) early withdrawal of the culprit drug, (2) transfer to a burn unit or experienced ICU, and (3) meticulous supportive care including fluid/electrolyte management and infection surveillance. No immunomodulatory therapy has robust mortality benefit in RCTs.

SCORTEN — validated mortality prediction (calculate within 24 h and again at 72 h):

Disposition decisions driven by SCORTEN and BSA:

Immediate priorities — "ABC-DEF" of TEN:

Wound care principles:

Pharmacotherapy — Disease-Modifying Therapy

— Dose: 3–5 mg/kg/day PO or IV divided BID × 7–10 days, then taper over 2 weeks

— Mechanism: inhibits calcineurin → blocks T-cell activation and granulysin release

— Observational data and meta-analyses suggest reduced mortality vs. supportive care alone (standardized mortality ratio ~0.5)

— Avoid in: severe renal impairment, uncontrolled hypertension, active infection, malignancy

— Monitor: BP, creatinine, magnesium, potassium, drug levels

— Single dose 50 mg SC, may repeat in 3 days

— RCT (Wang et al., 2018) showed faster re-epithelialization and trend toward reduced mortality vs. corticosteroids

— Avoid in active TB, sepsis, hepatitis B

— Controversial — older data suggested harm (increased infection, mortality), newer pulse regimens (methylprednisolone 1 g/day × 3 days) may help if started within 72 hours of onset

— Avoid prolonged courses

— Theoretical Fas-blockade rationale

— Meta-analyses show no mortality benefit; reserve for refractory cases or when other options contraindicated

— Risk: thrombosis, renal failure, hemolysis

— Analgesia: scheduled acetaminophen + IV opioids (PCA); avoid NSAIDs

— VTE prophylaxis: mechanical preferred; pharmacologic if no bleeding

— Stress ulcer prophylaxis with PPI

— Topical: petrolatum to lips, preservative-free artificial tears + topical antibiotic ointment to eyes

— No prophylactic systemic antibiotics — increases resistance and may select for fungal superinfection; treat documented infections only

Board pearl: Pick cyclosporine or etanercept over IVIG or steroids on a Step 3 question asking about disease-modifying therapy in TEN — current evidence base is strongest for those agents.

Immunomodulatory therapy remains controversial — no agent has demonstrated mortality benefit in adequately powered RCTs. Current practice individualizes therapy based on severity, timing, and contraindications.

Cyclosporine (most evidence-supported option):

Etanercept (TNF-α inhibitor) — emerging first-line:

Systemic corticosteroids:

IVIG (2–4 g/kg total over 3–5 days):

Supportive medications:

Procedures, Wound Care, and Multidisciplinary Interventions

— Early elective intubation if oropharyngeal/laryngeal mucositis, hoarseness, stridor, or BSA >30% with face involvement

— Anticipate difficult airway from mucosal sloughing and edema; consider awake fiberoptic intubation

— Bronchoscopy if hypoxemia or suspected tracheobronchial involvement — sloughed mucosa portends ARDS and high mortality

— Place lines through non-involved skin if possible; if unavoidable, suture into denuded skin and rotate every 72 h

— Arterial line for hemodynamic monitoring in TEN/ICU patients

— Conservative ("anti-shear") approach preferred: leave detached epidermis as biologic dressing

— Alternative aggressive approach: gentle debridement + biosynthetic coverings (Biobrane, Suprathel, allograft) — reserved for burn units

— Daily dressing changes under analgesia/sedation; chlorhexidine 0.05% or saline cleansing

— Avoid silver sulfadiazine (sulfa cross-reactivity) and adhesive dressings

— Lubricating drops every 1–2 h, topical antibiotic ointment, topical steroids per ophthalmology

— Amniotic membrane transplantation within 7 days for severe ocular involvement → reduces long-term blindness and symblepharon formation

— Lysis of forming symblephara with glass rod

— Oral rinses with saline, chlorhexidine, or "magic mouthwash" (viscous lidocaine + diphenhydramine + antacid)

— Early NG/Dobhoff feeding if oral intake impaired; high-calorie, high-protein (1.5–2 g/kg/day)

— Early Foley placement; gentle vaginal dilator use to prevent vulvovaginal adhesions in women

— Daily inspection and topical emollients

CCS pearl: Sequence on CCS: stop drug → IV access → fluids → labs/cultures → consult dermatology, ophthalmology, urology, burn surgery → transfer to burn unit → initiate cyclosporine or etanercept → wound care orders → amniotic membrane within 7 days. Documentation of culprit drug in problem list is critical for handoff.

Airway management:

Vascular access:

Wound care protocol:

Ocular interventions (ophthalmology daily):

Oral and GI care:

Genitourinary:

Special Populations — Elderly and Renal/Hepatic Impairment

— Age >40 is a SCORTEN criterion; mortality climbs sharply with each decade

— Polypharmacy complicates culprit identification — review every medication, including OTC and recent short courses (e.g., TMP-SMX for UTI)

— Decreased physiologic reserve → faster decompensation; lower threshold for ICU/burn unit transfer

— Higher baseline rates of CKD, CHF, dementia influence fluid resuscitation goals — target euvolemia, not aggressive overfilling

— Pressure injury risk amplified by epidermal detachment; specialty bed (low-air-loss, fluidized) essential

— Allopurinol-induced SJS/TEN is dose-related and amplified by reduced GFR — dose-reduce allopurinol in CKD and consider HLA-B*58:01 testing in high-risk ancestries before initiation

— Cyclosporine is nephrotoxic — monitor creatinine daily; reduce dose 25–50% if rising creatinine; consider etanercept instead if eGFR <30

— Adjust all renally cleared medications (e.g., acyclovir, vancomycin, gabapentin for neuropathic pain)

— RRT may be required for severe AKI, hyperkalemia, or volume overload

— TEN itself can cause transaminitis; new hepatitis raises suspicion for DRESS overlap (eosinophilia, lymphadenopathy, facial edema)

— Cyclosporine hepatically metabolized — reduce dose in Child-Pugh B/C

— Acetaminophen safe up to 2 g/day in cirrhosis; avoid NSAIDs entirely

— Glucose >252 is a SCORTEN criterion; stress hyperglycemia common

— Hold oral hypoglycemics; use insulin infusion or sliding scale targeting 140–180 mg/dL

— Sulfonylureas (glyburide, glipizide) are sulfa-derivatives — switch permanently to non-sulfa agents (metformin, DPP-4 inhibitors) post-recovery

Key distinction: DRESS (drug reaction with eosinophilia and systemic symptoms) features facial edema, lymphadenopathy, eosinophilia, hepatitis, and reactivation of HHV-6 — but lacks epidermal detachment. Same culprits (allopurinol, anticonvulsants, sulfonamides), different syndrome, different therapy (high-dose steroids favored).

Elderly patients (>65):

Chronic kidney disease and AKI:

Hepatic impairment:

Diabetes:

Special Populations — Pregnancy and Pediatrics

— Lower overall mortality than adults (1–7% in SJS, 15–30% in TEN)

— Most common drug triggers: sulfonamides (TMP-SMX), anticonvulsants (lamotrigine — especially with valproate co-administration that raises lamotrigine levels), NSAIDs

— Mycoplasma pneumoniae is a leading non-drug trigger — distinct entity MIRM (Mycoplasma-induced rash and mucositis): prominent mucositis with sparse/absent skin involvement, better prognosis, treat underlying infection with macrolide (azithromycin)

— Fluid resuscitation: weight-based, more aggressive than adults given larger BSA-to-mass ratio

— Long-term ocular sequelae (dry eye, symblepharon, blindness) particularly devastating in children — mandate early ophthalmology and amniotic membrane transplant

— Lamotrigine dosing: must titrate slowly (over 6 weeks); rapid escalation markedly increases SJS risk

— Rare but reported; obstetric outcomes generally favorable if mother survives

— Stop offending drug; supportive care identical to non-pregnant patients

— Cyclosporine is pregnancy category C — used in transplant pregnancies, reasonable in severe TEN

— Etanercept crosses placenta in third trimester — limited safety data; avoid if alternative available

— IVIG generally considered safe in pregnancy

— Avoid systemic corticosteroids in first trimester if possible (oral cleft risk)

— Fetal monitoring per gestational age; maternal sepsis is greatest threat to fetus

— Live vaccines deferred during immunosuppression

— Document culprit drug in pediatric medical record and on MedicAlert bracelet

Board pearl: A child with painful mucositis, conjunctivitis, scant truncal target lesions, and a recent "walking pneumonia" — think MIRM, not classic drug-induced SJS. Treat Mycoplasma with azithromycin and provide supportive mucocutaneous care; prognosis is excellent.

Pediatric SJS/TEN:

Pregnancy:

Breastfeeding: Most immunomodulators concentrate minimally in breast milk; weigh maternal benefit vs. infant exposure.

Vaccination considerations post-recovery:

Complications and Adverse Outcomes

— Sepsis — leading cause of death; S. aureus (including MRSA) and Pseudomonas aeruginosa dominate; surveillance cultures from skin, blood, urine

— Hypovolemic shock and AKI from insensible losses

— ARDS and bronchiolitis obliterans from tracheobronchial sloughing

— GI hemorrhage from esophageal/intestinal involvement

— DIC, thromboembolism (PE, DVT) — bedbound + inflammatory state

— Hypothermia from impaired thermoregulation through denuded skin

— Electrolyte derangements: hypokalemia, hypophosphatemia, hypomagnesemia

— Chronic dry eye (severe, debilitating)

— Symblepharon, ankyloblepharon, trichiasis, entropion

— Corneal neovascularization, scarring, limbal stem cell deficiency

— Blindness in 5–10% of survivors

— Post-inflammatory hyper- or hypopigmentation

— Nail dystrophy or permanent loss

— Scarring alopecia

— Oral synechiae, dental caries, xerostomia

— Esophageal strictures requiring dilation

— Vulvovaginal adhesions, urethral stenosis, phimosis

— Anal strictures

Step 3 management: At every follow-up visit, systematically screen for ocular, oral, genitourinary, pulmonary, and psychiatric sequelae — survivors require multidisciplinary longitudinal care (dermatology, ophthalmology, gynecology/urology, pulmonology, psychiatry). Many sequelae are preventable with early intervention during the acute phase.

Acute complications:

Ocular sequelae (occur in 50–90%, the most disabling long-term complications):

Mucocutaneous sequelae:

Pulmonary: chronic bronchiolitis obliterans, restrictive lung disease, bronchiectasis

Renal: chronic tubular dysfunction, CKD progression

Psychiatric: PTSD, depression, anxiety — high prevalence in survivors; screen at follow-up and refer for mental health support

Long-term increased mortality: TEN survivors have elevated mortality for at least 1 year post-discharge, independent of acute mortality.

When to Escalate — ICU, Burn Unit, and Consult Triage

— BSA detachment ≥10% (any SJS/TEN overlap or TEN)

— SCORTEN ≥2 (mortality ≥12%)

— Airway compromise, hoarseness, stridor, or tracheobronchial involvement

— Hemodynamic instability, ongoing fluid resuscitation needs

— Septic shock or suspected sepsis

— Severe ocular involvement requiring frequent intervention

— Inadequate experience at receiving facility — transfer earlier rather than later

— Dermatology: diagnosis confirmation, biopsy, wound-care guidance, drug causality

— Ophthalmology: daily slit-lamp exams, lubrication, amniotic membrane decision

— Burn surgery / wound care: dressing strategy, debridement decisions

— Critical care / pulmonology: airway management

— Urology and/or gynecology: GU mucosal involvement, prevention of adhesions

— Otolaryngology: if oropharyngeal/laryngeal involvement

— Nutrition: early enteral nutrition planning

— Pharmacy: medication reconciliation, drug causality (ALDEN scoring), future avoidance documentation

— Pain management: multimodal analgesia

— Psychiatry / social work: acute stress, family support

— Stabilize airway and hemodynamics before transport

— Wrap denuded areas in non-adherent dressings, warmed blankets

— Maintain ambient temperature in transport vehicle

— Send copies of medication list, ALDEN assessment, photographs of lesions, and biopsy slides

— Re-epithelialization >50%, no new lesions × 48 h

— Hemodynamic stability without vasopressors

— Tolerating enteral nutrition

— No active infection requiring IV antibiotics

CCS pearl: On any CCS case with BSA ≥10%, order transfer to burn unit early — this single decision improves outcomes more than any pharmacotherapy. Document SCORTEN in the chart at 24 h and 72 h; both timepoints are independently prognostic.

Indications for immediate burn unit or ICU transfer:

Specialty consultations required from day 1:

Transfer logistics:

De-escalation criteria from ICU/burn unit:

Key Differentials — Severe Cutaneous and Blistering Disorders

— Mediated by exfoliative toxins A/B targeting desmoglein 1

— Predominantly infants and young children; rare in adults except with renal failure

— Spares mucous membranes (key Step 3 distinction)

— Superficial cleavage at granular layer on biopsy

— Treatment: anti-staphylococcal antibiotics (nafcillin, vancomycin)

— True 3-zone target lesions, acral predominance

— HSV-triggered in >90% of cases

— Minimal or absent mucosal involvement; benign course

— Treat: antiviral suppression (acyclovir) if recurrent

— Autoimmune, anti-desmoglein 3 antibodies

— Flaccid bullae, severe oral erosions, Nikolsky positive

— Chronic course, not acute drug reaction

— DIF: intercellular IgG ("chicken-wire" pattern)

— Treat: high-dose steroids, rituximab

— Severe polymorphous mucositis + skin lesions in patient with lymphoproliferative malignancy (CLL, NHL, Castleman disease)

— DIF positive with multiple antibody patterns

— Elderly patients, tense bullae on erythematous base, intense pruritus

— Mucosal involvement uncommon (10–30%, mild)

— Anti-BP180/BP230 antibodies

— Vancomycin-induced classically

— "String of pearls" arrangement; DIF with linear IgA at BMZ

— Drug-induced (β-lactams, macrolides); fever + diffuse non-follicular sterile pustules on erythematous base

— Resolves in days after drug withdrawal; low mortality

Key distinction: SSSS spares mucosa and affects children; SJS/TEN involves mucosa heavily and is drug-induced. If a Step 3 stem shows a febrile toddler with Nikolsky-positive perioral and flexural skin sloughing but clear, uninvolved lips and mouth, choose SSSS and treat with anti-staphylococcal antibiotics.

Staphylococcal scalded skin syndrome (SSSS):

Erythema multiforme major:

Pemphigus vulgaris:

Paraneoplastic pemphigus:

Bullous pemphigoid:

Linear IgA bullous dermatosis:

Acute generalized exanthematous pustulosis (AGEP):

DRESS syndrome: fever, facial edema, lymphadenopathy, eosinophilia, hepatitis, no epidermal detachment

Key Differentials — Non-Dermatologic Mimics

— Fever, hypotension, diffuse macular erythroderma (sunburn-like), desquamation occurring 1–2 weeks after acute illness

— Multi-organ dysfunction: AKI, hepatitis, encephalopathy

— Strep TSS often with necrotizing soft tissue infection

— No epidermal detachment in acute phase; desquamation is delayed

— Treat: source control, clindamycin + β-lactam, IVIG (strep TSS)

— Fever ≥5 days + conjunctivitis, oral changes (strawberry tongue, lip cracking), polymorphous rash, extremity changes, cervical lymphadenopathy

— Coronary artery aneurysm risk

— Treat: IVIG + aspirin

— Group A strep pharyngitis + sandpaper rash, strawberry tongue, Pastia lines

— Desquamation after rash resolves

— Treat: penicillin or amoxicillin

— Recurs at same sites with re-exposure; usually limited BSA

— Common culprits: sulfonamides, NSAIDs, tetracyclines

— Exposure history; sharp demarcation following splash pattern

— No mucosal involvement unless inhalation injury

— Post-allogeneic transplant; can mimic TEN clinically and histologically

— Concurrent hepatitis, diarrhea help distinguish

— Rare; ANA, anti-dsDNA, multi-system features

— Sun-exposed distribution, history of photosensitizer (doxycycline, voriconazole, HCTZ)

Board pearl: When a Step 3 stem describes diffuse erythroderma + hypotension + multi-organ dysfunction without epidermal detachment or atypical targets, especially in a menstruating young woman with tampon use or a patient with surgical wound, think toxic shock syndrome, not TEN. The presence (TEN) or absence (TSS) of frank skin sloughing during the acute febrile phase is the key discriminator.

Toxic shock syndrome (staphylococcal or streptococcal):

Kawasaki disease (pediatric):

Scarlet fever:

Generalized fixed drug eruption (bullous variant):

Chemical or thermal burns:

Graft-versus-host disease (acute cutaneous):

Acute lupus erythematosus / TEN-like lupus:

Viral exanthems with mucositis: enterovirus, EBV, primary HIV — usually milder, no full-thickness necrosis

Severe sunburn / phototoxic drug reaction:

Secondary Prevention, Discharge Medications, and Long-Term Plan

— Add to allergy list in EHR with reaction descriptor "SJS/TEN — life-threatening, do not rechallenge"

— Provide patient with written allergy list and MedicAlert bracelet

— Educate patient and family verbally and with printed materials

— Notify primary care, all subspecialists, and pharmacy

— Report to FDA MedWatch (voluntary but encouraged)

— Aromatic anticonvulsants (carbamazepine ↔ phenytoin ↔ phenobarbital ↔ oxcarbazepine ↔ lamotrigine) — 70–80% cross-reactivity

— Sulfonamides: antibiotic sulfonamides (TMP-SMX, sulfasalazine) cross-react; non-antibiotic sulfonamides (furosemide, thiazides, sulfonylureas, celecoxib) have low cross-reactivity but most clinicians avoid all sulfa-containing drugs in SJS/TEN survivors

— NSAIDs: if oxicam-induced (meloxicam, piroxicam), avoid all oxicams; cross-reactivity to other NSAID classes is lower but caution warranted

— Allopurinol: switch to febuxostat for gout (note FDA cardiovascular warning; weigh risks)

— First-degree relatives sharing high-risk HLA alleles are at elevated risk

— Counsel about HLA-B15:02 (carbamazepine), HLA-B58:01 (allopurinol), HLA-B*57:01 (abacavir) testing before relevant drug exposures

— Avoid the culprit drug class in relatives when possible

— Catch up on missed vaccines; live vaccines deferred until 3 months after immunosuppression

— Annual influenza, pneumococcal per age

— Dermatology: 2 weeks, then 1, 3, 6, 12 months

— Ophthalmology: weekly × 1 month, then monthly × 6 months minimum

— Primary care: 1–2 weeks for medication reconciliation

— Gynecology/urology, pulmonology, psychiatry as indicated

Step 3 management: The single most important discharge intervention is unambiguous documentation of the culprit drug and its cross-reactive class on the EHR allergy list, the patient's wallet card, and communication to all current and future providers. Failure of this transition-of-care step causes preventable re-exposure and recurrent (often fatal) SJS/TEN.

Permanent documentation of culprit drug:

Cross-reactive drug avoidance:

Family screening:

Vaccinations post-recovery:

Specialist follow-up scheduling at discharge:

Follow-Up, Monitoring, and Rehabilitation Counseling

— Re-epithelialization >90%, no new lesions × 1 week

— Tolerating oral nutrition, off IV fluids

— Pain controlled on oral analgesics

— Mucosal lesions healing

— Ophthalmologic plan in place

— Mental health screening completed

— Discharge to home with caregiver support, SNF, or rehab as needed

— Primary care: 1–2 weeks — medication reconciliation, allergy documentation, mood screening (PHQ-9), wound assessment

— Dermatology: 2 weeks, then 1/3/6/12 months — scarring, pigmentation, nail recovery

— Ophthalmology: weekly × 4 weeks, then monthly × 6 months — symblepharon, dry eye, vision testing; scleral lenses if severe dry eye

— Gynecology/urology: 1 month, then as needed — vaginal/urethral adhesions

— Pulmonology: 1–3 months if any pulmonary involvement — PFTs to detect bronchiolitis obliterans (obstructive pattern, reduced FEV1)

— Psychiatry/psychology: 4–6 weeks — PTSD, depression screening; CBT or pharmacotherapy as indicated

— Lab follow-up at 2–4 weeks: CBC, CMP, LFTs (residual cytopenias, renal/hepatic recovery)

— Thyroid function at 3 months (autoimmune thyroiditis reported)

— If cyclosporine was used and continued: BP, creatinine, magnesium, drug levels

— Sun protection — affected areas hyperpigment with UV exposure; SPF 30+ daily

— Skin care: bland emollients, fragrance-free; avoid harsh soaps

— Eye care: preservative-free artificial tears every 1–2 h, lid hygiene

— Recognize and report early signs of any drug reaction — fever + new rash within 4 weeks of new drug → ED immediately

— Carry allergy documentation at all times

— Physical therapy for deconditioning, joint contractures

— Occupational therapy for ADLs if scarring/contractures

— Nutrition follow-up — protein-calorie repletion may take months

— Return to work/school: typically 1–3 months depending on severity and occupation

Board pearl: Up to 50% of TEN survivors develop chronic ocular surface disease, and ophthalmologic follow-up is the single most underutilized longitudinal intervention. Step 3 stems frequently test recognition of late symblepharon or trichiasis — the answer is referral, not topical treatment alone.

Discharge readiness criteria:

Follow-up schedule (Step 3 favorite):

Monitoring parameters:

Patient education topics:

Rehabilitation considerations:

Ethical, Legal, and Patient Safety Considerations

— Report serious adverse drug reactions to FDA MedWatch (voluntary for clinicians but strongly recommended); mandatory for manufacturers

— Document culprit drug clearly in EHR allergy module, problem list, and discharge summary

— Provide patient with written and electronic allergy documentation

— When restarting a related drug class is medically necessary (e.g., antiepileptic in a survivor of phenytoin-SJS), document risk-benefit discussion, alternatives considered, and patient understanding — ideally with dermatology and pharmacy input

— In incapacitated patients, surrogate decision-makers should be informed of any high-risk drug initiation; obtain HLA testing pre-prescription where indicated

— Allergy documentation lost during EHR transitions or paper-to-electronic conversion → re-prescription of culprit drug

— Pharmacist/prescriber should perform medication reconciliation against allergy list at every transition (ED → admission, ICU → ward, ward → discharge, discharge → primary care)

— Use clinical decision support alerts for cross-reactive drugs (sulfa, aromatic anticonvulsants, allopurinol)

— Discharge summary must explicitly list culprit drug and prohibited drug classes

— FDA recommends HLA-B15:02 testing before carbamazepine in patients of Asian ancestry; HLA-B57:01 testing mandatory before abacavir

— Cost, insurance coverage, and turnaround time can delay therapy — consider alternative non-cross-reactive drugs when testing unavailable

— Counsel about implications for family members

— Failure to recognize early skin pain on a high-risk drug, delayed drug discontinuation, and inadequate allergy documentation are recurrent malpractice themes

— Re-prescription of a documented culprit drug is a never event

— In TEN with SCORTEN ≥5 (mortality >90%), engage palliative care early for symptom management, family support, and goals-of-care discussions in parallel with aggressive care

Step 3 management: The single most preventable cause of recurrent SJS/TEN is failure of allergy documentation during transitions of care. Always perform medication reconciliation against the allergy list at every handoff, and update the EHR with the specific drug and reaction phenotype (e.g., "TMP-SMX — SJS/TEN") rather than vague terms like "rash."

Mandatory reporting and documentation:

Informed consent edge cases:

Transition-of-care risks (high-yield Step 3 patient safety):

HLA pharmacogenomic testing — equity and access:

Liability and malpractice considerations:

Resource allocation and goals of care:

Research ethics: SJS/TEN patients are commonly enrolled in registries; ensure informed consent or surrogate consent.

High-Yield Associations and Rapid-Fire Facts

— HLA-B*15:02 → carbamazepine SJS/TEN in Han Chinese, Thai, Malay, Filipino

— HLA-B*58:01 → allopurinol SJS/TEN in Han Chinese, Korean, Thai

— HLA-B*57:01 → abacavir hypersensitivity (not classic SJS/TEN, but mandatory screening)

— HLA-A*31:01 → carbamazepine SJS/TEN/DRESS in European/Japanese

Board pearl: A young Han Chinese patient started on carbamazepine 2 weeks ago presenting with fever, conjunctivitis, hemorrhagic lip crusting, and dusky truncal macules → SJS/TEN; stop carbamazepine, calculate SCORTEN, transfer to burn unit, consider cyclosporine, lifelong avoidance of all aromatic anticonvulsants, and family HLA-B*15:02 counseling.

Top drug causes (memorize): sulfonamide antibiotics, allopurinol, aromatic anticonvulsants (carbamazepine, phenytoin, lamotrigine, phenobarbital), NSAIDs (oxicams), nevirapine, abacavir, sulfasalazine, dapsone, immune checkpoint inhibitors

Time to onset: 4–28 days from first exposure; hours on re-exposure

HLA associations:

Risk factors: HIV (100×), SLE, malignancy, recent radiotherapy, slow acetylator phenotype, female sex (slightly)

SCORTEN parameters (memorize all 7): age >40, HR >120, malignancy, BSA detached >10%, BUN >28, glucose >252, bicarbonate <20

Histopathology: full-thickness epidermal necrosis with subepidermal cleavage; scant lymphocytic infiltrate; negative DIF

Biomarkers of severity: elevated serum granulysin, soluble Fas ligand, IL-15

Mortality: SJS 1–10%; SJS/TEN overlap 10–30%; TEN 25–50%

Re-epithelialization: 2–4 weeks in survivors

Long-term blindness: 5–10% of TEN survivors

MIRM: Mycoplasma-induced; prominent mucositis, sparse skin; treat with macrolide

Distinguishing EM major from SJS: 3-zone vs. 2-zone targets; acral vs. truncal; HSV vs. drug; benign vs. severe

DRESS clue: fever + facial edema + lymphadenopathy + eosinophilia + hepatitis, NO sloughing

AGEP clue: sterile pustules on erythema, β-lactam trigger, resolves quickly

Don't use in TEN wound care: silver sulfadiazine (sulfa), adhesive dressings

Don't choose for first-line therapy on boards: systemic steroids alone, IVIG monotherapy (no proven benefit)

Best evidence-supported therapy: cyclosporine 3–5 mg/kg/day or etanercept 50 mg SC

Burn unit transfer: standard of care for BSA ≥10%

Board Question Stem Patterns

Board pearl: When in doubt on a Step 3 SJS/TEN question, the highest-yield single answer is discontinue the offending drug immediately — it appears as the correct first step more often than any specific therapy.

Pattern 1 — Drug identification: "A 58-year-old man started on TMP-SMX for UTI 10 days ago presents with fever, painful skin, conjunctivitis, and dusky macules with epidermal detachment on 15% of BSA. Most appropriate next step?" → Stop TMP-SMX, transfer to burn unit, supportive care.

Pattern 2 — Mortality prediction: "Calculate SCORTEN for a 65-year-old woman with HR 130, BUN 45, glucose 280, bicarbonate 18, BSA detached 25%, no malignancy." → Answer: 6 of 7 criteria → mortality >90%.

Pattern 3 — Differentiating SSSS from SJS/TEN: "A 2-year-old with fever, perioral and flexural erythema, Nikolsky-positive sloughing, but clear oral mucosa and lips." → SSSS; treat with nafcillin or vancomycin.

Pattern 4 — MIRM in pediatrics: "A 12-year-old with 1 week of cough and fever now has severe oral, ocular, and genital mucositis with only 2–3 truncal target lesions." → Mycoplasma-induced rash and mucositis; azithromycin + supportive care.

Pattern 5 — Cross-reactivity counseling: "A patient survived phenytoin-induced TEN and now needs an antiepileptic. Which is safest?" → Valproate or levetiracetam (avoid carbamazepine, lamotrigine, phenobarbital).

Pattern 6 — Pharmacogenomic screening: "Before initiating carbamazepine in a Han Chinese patient, which test is recommended?" → HLA-B*15:02.

Pattern 7 — DRESS vs. TEN distinction: "Three weeks after allopurinol, a patient has fever, facial edema, lymphadenopathy, eosinophilia 25%, transaminitis, and a morbilliform rash without sloughing." → DRESS; stop allopurinol, systemic steroids.

Pattern 8 — Wound care selection: "Which topical agent should be avoided in TEN?" → Silver sulfadiazine (sulfa).

Pattern 9 — Ocular intervention: "TEN patient on day 5 with corneal epithelial defects and forming symblepharon. Best intervention?" → Amniotic membrane transplantation.

Pattern 10 — CCS sequence: Order: stop drug → 2 large-bore IVs → fluid resuscitation → labs/cultures → CXR → SCORTEN → derm/ophth/burn consults → transfer to burn unit → cyclosporine or etanercept → daily wound care, slit-lamp, mucosal care → mental health and PT/OT pre-discharge → comprehensive allergy documentation.

Pattern 11 — Transition-of-care safety: "Survivor of TMP-SMX SJS receives furosemide and develops a mild rash — what counseling?" → Non-antibiotic sulfonamides have low cross-reactivity, but document carefully and individualize.

One-Line Recap

Stevens-Johnson syndrome and toxic epidermal necrolysis are T-cell–mediated, drug-induced mucocutaneous emergencies defined by epidermal detachment (<10% SJS, 10–30% overlap, >30% TEN) whose outcomes hinge on immediate withdrawal of the culprit drug, prompt transfer to a burn unit, meticulous supportive and mucosal care, and rigorous lifelong documentation of the offending drug class.

Diagnosis: clinical — painful dusky macules + ≥1 mucosal site + drug exposure 4–28 days prior; confirm with biopsy (full-thickness epidermal necrosis, negative DIF); calculate SCORTEN (age >40, HR >120, malignancy, BSA >10%, BUN >28, glucose >252, HCO₃ <20) at 24 and 72 hours.

Management: stop the drug (single most important step) → IV fluids (2 mL/kg × %BSA) → burn unit transfer for BSA ≥10% → consider cyclosporine 3–5 mg/kg/day or etanercept 50 mg SC as disease-modifying therapy → conservative wound care (no silver sulfadiazine) → daily ophthalmology + amniotic membrane within 7 days for severe ocular disease → multidisciplinary consults (derm, ophth, urology/gyn, burn, pulm, psych).

Differentials to nail: SSSS spares mucosa and affects children; EM major has true 3-zone targets and is HSV-driven; DRESS has fever/eosinophilia/hepatitis without sloughing; MIRM is Mycoplasma-induced in children with prominent mucositis and minimal skin disease; TSS causes erythroderma without acute detachment.

Long-term: EHR allergy documentation with specific drug/phenotype + cross-reactive class avoidance (aromatic anticonvulsants 70–80% cross-react; allopurinol → febuxostat; sulfonamide antibiotics → avoid all) + MedicAlert bracelet + family HLA counseling (HLA-B15:02, B58:01) + ophthalmology, dermatology, pulmonary, and psychiatric follow-up; transition-of-care medication reconciliation prevents lethal re-exposure.