Stevens-Johnson syndrome

1. History

• Drug exposure timeline: Onset typically 4–28 days after continuous exposure to a new medication. Ask about every medication started in the past month, including OTC drugs, herbal remedies, and supplements. [1-2]
• Prodromal symptoms: Fever, malaise, myalgias, and "influenza-like" illness 1–3 days before skin findings. Skin pain and burning often precede visible lesions. [5-6]
• Mucosal symptoms: Painful swallowing, eye irritation/redness, dysuria, or genital pain — mucosal involvement precedes skin lesions in many cases and occurs in ~80% of patients. [1]
• Symptom progression: Rapid spread of rash (maximal within hours to 4 days), starting on face/trunk. Ask about blistering, skin sloughing, and worsening pain. [6]
• Prior episodes: History of prior SJS/TEN or drug allergy. Any family history of severe drug reactions.
• Infection history: Recent upper respiratory infection, especially in children (Mycoplasma pneumoniae is a recognized trigger). [1][7]

2. Alarm Features

• Rapidly progressive skin detachment — any blistering rash with positive Nikolsky sign and mucosal involvement [1][8]
• High fever (>38.5°C) with widespread painful erythema and skin tenderness
• Respiratory distress — bronchial epithelial involvement can cause dyspnea, cough, and hypoxia; pulmonary involvement is associated with higher mortality [1][5]
• Hemodynamic instability — suggests sepsis or massive fluid loss
• Ocular involvement — conjunctival hyperemia, pseudomembranes, corneal erosions; early ophthalmology consultation is critical [9-10]
• Genital/urologic erosions — can lead to strictures if untreated [11]
• Signs of sepsis — the leading cause of death in SJS/TEN [1][5]

3. Medications

High-risk causative drugs: [2][5][12]

• Antibiotics: Sulfonamides (TMP-SMX), beta-lactams, fluoroquinolones
• Anticonvulsants: Carbamazepine, phenytoin, lamotrigine, phenobarbital
• Allopurinol
• NSAIDs: Oxicam-type (piroxicam), ibuprofen, aspirin
• Nevirapine
• Immune checkpoint inhibitors (emerging cause) [13]

Treatment medications: [1][5][14-15]

• Systemic corticosteroids: IV methylprednisolone 1–2 mg/kg/day (controversial but widely used)
• Cyclosporine A: Growing evidence supporting use; inhibits IL-15/IL-17 pathways
• IVIG: 2 g/kg divided over 2–5 days (evidence mixed; meta-analysis showed no clear mortality benefit) [1]
• TNF-α inhibitors: Etanercept (single subcutaneous dose) — emerging data [14]
• Thalidomide is contraindicated — an RCT was stopped early due to increased mortality [16]

Key principle: Immediate withdrawal of the culprit drug is the single most important intervention and is associated with decreased mortality. [2][17]

4. Diet

• NPO or modified diet if severe oral mucosal involvement prevents safe swallowing
• Enteral nutrition via nasogastric tube preferred over parenteral when possible
• High-calorie, high-protein requirements similar to burn patients due to hypermetabolic state [18]
• Aggressive IV fluid resuscitation — fluid losses from denuded skin are significant; target resuscitation similar to burn protocols but typically at lower volumes (estimated at ~2/3 of burn resuscitation) [8][18]
• Electrolyte monitoring and repletion — hyponatremia, hypoalbuminemia common

5. Review of Systems

• Skin: Painful rash, blistering, skin peeling, burning sensation
• Eyes: Redness, tearing, photophobia, foreign body sensation, blurred vision [1][9]
• Oral: Odynophagia, oral pain, difficulty eating/drinking, lip crusting [1]
• Genitourinary: Dysuria, genital pain, urinary retention [11]
• Respiratory: Cough, dyspnea, chest tightness (bronchial epithelial involvement) [5]
• GI: Nausea, diarrhea (intestinal epithelial necrosis, rare) [1]
• Constitutional: Fever, malaise, arthralgias
• Psychiatric: Anxiety, acute stress (PTSD develops in a significant proportion of survivors) [1][19]

6. Collateral History and Family History

• Complete medication reconciliation from pharmacy records, family, and other providers — critical for identifying the culprit drug
• ALDEN score (Algorithm of Drug Causality for Epidermal Necrolysis) can help identify the most likely causative agent when multiple drugs are involved [2]
• Family history of severe drug reactions — genetic predisposition via HLA alleles is well-established [1][20]
• Ethnic background: HLA associations are population-specific (e.g., HLA-B15:02 in Southeast Asian populations for carbamazepine; HLA-B58:01 for allopurinol, particularly in those of African, Southeast Asian, or Korean descent) [1][21-22]
• HIV status: Increased risk of SJS/TEN, particularly with sulfonamide exposure [4]

7. Risk Factors

• Medications — the most common trigger (~80–95% of cases) [5][7]
• HIV/AIDS — 100-fold increased incidence [4]
• Active malignancy — independent risk factor for both SJS/TEN and mortality [23-24]
• Immune dysregulation — autoimmune disease, organ transplant recipients [23]
• Genetic predisposition: [1][21-22]
  • HLA-B15:02 → carbamazepine-induced SJS/TEN (Han Chinese, Southeast Asian)
  • HLA-B58:01 → allopurinol-induced SJS/TEN (multiple populations)
  • HLA-A31:01 → carbamazepine-induced SCARs (Northern European, Japanese)
  • HLA-A34:02 → allopurinol-induced SCARs (US populations) [22]
• Slow acetylator phenotype
• Female sex (slight predominance, F:M ~1.3:1) [12]
• Infections: Mycoplasma pneumoniae (especially in children), viral infections [1][7]

8. Differential Diagnosis

• Erythema multiforme major (EMM): Typical target lesions on extremities, usually post-infectious (HSV, Mycoplasma), benign course — distinct from SJS despite mucosal erosions [6][11]
• Generalized fixed drug eruption: Well-demarcated, round, dusky patches recurring at same sites; can mimic SJS when widespread [1]
• Staphylococcal scalded skin syndrome (SSSS): Superficial epidermal cleavage (subcorneal), no mucosal involvement, primarily in children <5 years; biopsy distinguishes
• Linear IgA bullous dermatosis: Drug-induced or spontaneous; positive direct immunofluorescence (linear IgA at BMZ) [1]
• Acute graft-versus-host disease: Post-transplant context [1]
• Autoimmune blistering diseases: Pemphigus vulgaris, bullous pemphigoid — immunofluorescence differentiates
• Thermal/chemical burns: History of exposure
• Reactive infectious mucocutaneous eruption (RIME): Mycoplasma-associated, predominantly mucosal, minimal skin detachment — increasingly recognized as distinct from SJS in children [7]

9. Past Medical History

• Prior SJS/TEN episode — absolute contraindication to re-exposure to the culprit drug and structurally related drugs
• Epilepsy or gout — common conditions requiring high-risk medications (anticonvulsants, allopurinol)
• HIV/AIDS — dramatically increased risk
• Chronic kidney disease — impaired drug clearance, increased risk
• Autoimmune conditions (e.g., SLE) — associated with TEN-like presentations [1]
• Malignancy — independent risk factor and SCORTEN parameter [17][24]

10. Physical Exam

• Vital signs: Fever (often >39°C), tachycardia (HR >120 bpm is a SCORTEN parameter and independent mortality predictor) [24-25]
• Skin:
  • Erythematous, irregularly shaped, dusky-red macules — initially on face and upper trunk [1][6]
  • Atypical target lesions with dark necrotic centers (not the classic three-ring targets of EM) [1]
  • Flaccid blisters, confluent epidermal necrosis, large sheets of detached epidermis [1]
  • Nikolsky sign: Positive — lateral pressure on erythematous skin causes epidermal sloughing [1-2]
  • Assess and document % BSA detachment (detached + detachable skin) [1-2]
• Mucous membranes (involved in ~80% of cases): [1]
  • Oral: Hemorrhagic erosions, pseudomembranes, crusted lips
  • Ocular: Conjunctival hyperemia, chemosis, pseudomembranes, corneal erosions [1][9]
  • Genital/anal: Erosions, crusting
• Respiratory: Auscultate for crackles, wheezing (bronchial involvement)

11. Lab Studies

Recommended labs: [5][8][25]

• CBC with differential: Leukocytosis (or leukopenia suggesting sepsis), anemia
• BMP/CMP: Serum glucose >252 mg/dL, BUN >28 mg/dL, bicarbonate <20 mmol/L — all SCORTEN parameters [24-25]
• LFTs: Transaminase elevation common; hepatic involvement is frequent [5][12]
• Serum creatinine: Elevated creatinine is an independent mortality predictor [26]
• Coagulation studies: DIC occurs in ~21% of cases [27]
• Blood cultures: Rule out sepsis — the leading cause of death [1][5]
• Lactate: If sepsis suspected
• Procalcitonin: May help differentiate infection from sterile inflammation
• Skin biopsy: Full-thickness epidermal necrosis with negative direct immunofluorescence is mandatory for definitive diagnosis [1]

12. Imaging

• Chest X-ray: Baseline and if respiratory symptoms present — evaluate for pneumonia, ARDS, bronchial epithelial sloughing [5][8]
• CT chest: If significant respiratory compromise or concern for pulmonary complications
• Imaging is not diagnostic for SJS/TEN but assists in identifying complications [8]
• Imaging is unnecessary in uncomplicated early presentations without respiratory symptoms

13. Special Tests

• SCORTEN (Severity-of-Illness Score for TEN): The most widely used prognostic tool — should be calculated within 24 hours of admission and again at day 3. Seven parameters: age >40, malignancy, HR >120, initial BSA detachment >10%, serum urea >28 mg/dL, glucose >252 mg/dL, bicarbonate <20 mmol/L. Predicted mortality ranges from 3.2% (score 0–1) to 90% (score ≥5). [25][28]
• ABCD-10 score: Alternative model (age, bicarbonate, cancer, dialysis, 10% BSA) — SCORTEN remains superior in most validation studies [29-30]
• ALDEN score: Algorithm to identify the most likely culprit drug when multiple drugs are involved [2]
• Skin biopsy with direct immunofluorescence: Distinguishes SJS/TEN (negative DIF, full-thickness necrosis) from autoimmune blistering diseases [1][13]
• HLA testing: Pre-prescription screening recommended for specific drug-population combinations: [11][21]
  • HLA-B15:02 before carbamazepine in patients of Southeast Asian descent
  • HLA-B58:01 before allopurinol in at-risk populations
  • HLA-A31:01 before carbamazepine in Northern European/Japanese patients

14. ECG

• No pathognomonic ECG findings for SJS/TEN
• ECG indicated to evaluate for tachycardia (HR >120 is a SCORTEN parameter) [24-25]
• Monitor for myocardial involvement: Case reports of myocardial infarction during acute SJS/TEN [27]
• SJS/TEN survivors have elevated long-term cardiovascular risk — increased risk of ischemic heart disease (HR ~3-fold in first year) and cerebrovascular events (HR ~5-fold in first year) persisting for 4–7 years [27]
• Continuous telemetry monitoring recommended in ICU/burn unit setting given hemodynamic instability risk

15. Assessment

• SJS/TEN is a medical emergency requiring immediate recognition and action [5][8]
• Classification by BSA detachment: SJS (<10%), overlap (10–30%), TEN (>30%) [1-2]
• Typical presentation: Prodromal flu-like illness → painful mucocutaneous eruption → progressive epidermal detachment over hours to days [1][6]
• Atypical presentations: Mucosal-only disease (especially Mycoplasma-associated in children), drug-free cases (~30%), immune checkpoint inhibitor-associated SJS/TEN [1][13]
• Complications to anticipate: Sepsis (leading cause of death), fluid/electrolyte derangements, ARDS, renal failure, DIC, ocular sequelae [1][5][27]
• Long-term sequelae affect >80% of survivors: cutaneous (>80%), ocular (~60%), oral mucosal (~50%), psychological (depression/anxiety ~45%) [19]

The following figure shows the frequency of long-term sequelae in SJS/TEN survivors:

16. Treatment Plan

Immediate stabilization: [5][8][31]

• Stop the culprit drug immediately — the single most important intervention [2][17]
• Airway assessment — early intubation if oropharyngeal/laryngeal involvement
• Fluid resuscitation — crystalloid, targeting ~2/3 of Parkland formula for equivalent BSA burns [8][18]
• Thermoregulation — ambient temperature 30–32°C to reduce insensible losses [18]

Wound care: [14][31]

• Non-adherent dressings; avoid debridement of intact blisters
• Silver-containing topical agents for denuded areas
• Manage as a burn-equivalent wound

Mucosal care: [11][31]

• Eyes: Urgent ophthalmology consultation; preservative-free lubricants, topical corticosteroid drops (0.1% betamethasone within 4 days of onset reduces sequelae), amniotic membrane transplantation for severe cases [9-10]
• Oral: Antiseptic mouthwash, topical anesthetics, soft diet
• Genital/urologic: Urology evaluation; topical care to prevent adhesions [11]

Systemic therapy (no consensus on optimal agent): [1][14-15][31]

• Cyclosporine A (3–5 mg/kg/day): Growing evidence for benefit; may reduce time to re-epithelialization
• Systemic corticosteroids (IV methylprednisolone 1–2 mg/kg/day): Widely used; controversial — some data suggest prolonged disease course [1]
• IVIG (2 g/kg over 2–5 days): Mixed evidence; meta-analysis showed no mortality benefit [1]
• Etanercept (single SC dose): Emerging data showing promise [14]
• Pain management: Opioid analgesia often required; avoid NSAIDs if implicated

Infection prevention: [5][8]

• Avoid prophylactic antibiotics
• Surveillance cultures; treat documented infections with broad-spectrum antibiotics
• Central line and Foley catheter care per burn unit protocols

17. Disposition

All patients with suspected SJS/TEN require inpatient admission: [5][8][11]

• Transfer to a burn center or ICU with dermatology, ophthalmology, and critical care availability [8][23]
• SCORTEN ≥3: High mortality risk — ICU-level care mandatory [25][28]
• TEN (>30% BSA): Burn unit admission [8][18]
• SJS (<10% BSA) without hemodynamic compromise: May be managed on a dermatology ward with close monitoring, but burn center transfer is still recommended [8]

Specialist consultations: [11][13]

• Dermatology (urgent)
• Ophthalmology (urgent — within 24 hours)
• Burn surgery
• Urology/OB-GYN
• Pulmonology (if respiratory involvement)

18. Follow Up / Return Precautions

Follow-up timing: [1][11][31]

• Ophthalmology: Outpatient follow-up for all patients — ocular sequelae develop in up to 65% at the chronic stage; severe dry eye, limbal stem cell deficiency, and corneal scarring are common [1][9][32]
• Dermatology: 2–4 weeks post-discharge, then ongoing as needed for cutaneous sequelae (dyspigmentation, photosensitivity, nail changes) [1]
• Urology/Gynecology: Follow-up for genital adhesions/strictures [11]
• Psychiatry/Psychology: Screen for PTSD, depression, and anxiety — affects ~45% of survivors [19]
• Cardiovascular surveillance: SJS/TEN survivors have elevated cardiovascular mortality risk persisting 4–7 years [27]

Return precautions / patient counseling:

• Strict lifelong avoidance of the culprit drug and structurally related medications — document allergy prominently in medical records and provide a medical alert card/bracelet
• Return immediately for any new blistering, skin peeling, mouth sores, eye redness, or fever after starting any new medication
• Pharmacogenomic testing should be considered before prescribing high-risk drugs in at-risk populations (HLA-B15:02 for carbamazepine, HLA-B58:01 for allopurinol) [11][21-22]
• Expected recovery: Re-epithelialization typically begins ~1 week after disease onset and lasts up to 3 weeks [1]
• Photosensitivity may persist — sun protection counseling