Stevens-Johnson Syndrome (SJS)

Stevens-Johnson syndrome is a rare, life-threatening, delayed-type hypersensitivity reaction characterized by <10% body surface area (BSA) epidermal detachment with mucosal erosions, most commonly triggered by medications.[1-2] SJS and toxic epidermal necrolysis (TEN) exist on a spectrum: SJS (<10% BSA), SJS-TEN overlap (10–30%), and TEN (>30%).[1-2] Incidence is approximately 1–6 cases per million per year, with mortality of ~10% for SJS and up to 50% for TEN.[2-3]

The following figure illustrates the clinical classification spectrum from erythema multiforme to TEN:

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

• 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

• 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

• 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)

• 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

• 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

• 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

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

Mucosal care

• 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)

• 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

• 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

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

18. Follow Up / Return Precautions

Follow-up timing

• 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

References

1. Severe Cutaneous Adverse Reactions to Drugs. — Duong TA, Valeyrie-Allanore L, Wolkenstein P, Chosidow O. Lancet. 2017.

2. Worldwide Prevalence of Antibiotic-Associated Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Systematic Review and Meta-analysis. — Lee EY, Knox C, Phillips EJ. JAMA Dermatology. 2023.

3. Stevens-Johnson syndrome/­toxic epidermal necrolysis. — National Library of Medicine (MedlinePlus) 2020.

4. Correlations Between Clinical Patterns and Causes of Erythema Multiforme Majus, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis: Results of an International Prospective Study. — Auquier-Dunant A, Mockenhaupt M, Naldi L, et al. Archives of Dermatology. 2002.

5. Current Perspectives on Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. — Lerch M, Mainetti C, Terziroli Beretta-Piccoli B, Harr T. Clinical Reviews in Allergy & Immunology. 2018.

6. Severe Adverse Cutaneous Reactions to Drugs. — Roujeau JC, Stern RS. The New England Journal of Medicine. 1994.

7. Infantile Stevens Johnson syndrome and toxic epidermal necrolysis: A systematic review of clinical features and outcomes in children ages 12 months and under. — Iriarte C, Karim SA, Nassim JS, Grenier PO, Massey KJ. Pediatric Dermatology. 2022.

8. High Risk and Low Prevalence Diseases: Stevens Johnson Syndrome and Toxic Epidermal Necrolysis. — van Nispen C, Long B, Koyfman A. The American Journal of Emergency Medicine. 2024.

9. Updates on the Ocular Manifestations and Treatment of SJS/­TEN. — Sotozono C, Ueta M. Allergology International : Official Journal of the Japanese Society of Allergology. 2025.

10. Japan: Diagnosis and Management of Stevens-Johnson Syndrome/­Toxic Epidermal Necrolysis With Severe Ocular Complications. — Sotozono C, Ueta M, Kinoshita S. Frontiers in Medicine. 2021.

11. Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Standard Reporting and Evaluation Guidelines: Results of a National Institutes of Health Working Group. — Maverakis E, Wang EA, Shinkai K, et al. JAMA Dermatology. 2017.

12. Drug-Induced Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Ten-Year Retrospective Study of 103 Cases. — Zhou L, Lu Y, Zou Y, et al. Clinical and Experimental Dermatology. 2025.

13. Management of Immune Checkpoint Inhibitor-Related Toxicities. — Updated 2025-10-23. National Comprehensive Cancer Network.

14. Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Review of Current Management and Innovative Therapies. — Martinez Villarreal JD, Cardenas-de la Garza JA, Ionescu MA, et al. International Journal of Dermatology. 2025.

15. Recent Developments in the Research of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Pathogenesis, Diagnosis and Treatment. — Yao LM, Su X, Liu LL, et al. European Journal of Medical Research. 2025.

16. Systemic Interventions for Treatment of Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and SJS/­TEN Overlap Syndrome. — Jacobsen A, Olabi B, Langley A, et al. The Cochrane Database of Systematic Reviews. 2022.

17. Assessment of Treatment Approaches and Outcomes in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Insights From a Pan-European Multicenter Study. — Kridin K, Brüggen MC, Chua SL, et al. JAMA Dermatology. 2021.

18. Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome: A Review. — Gerull R, Nelle M, Schaible T. Critical Care Medicine. 2011.

19. Long-term Physical and Psychological Outcomes of Stevens-Johnson Syndrome/­Toxic Epidermal Necrolysis. — Hoffman M, Chansky PB, Bashyam AR, et al. JAMA Dermatology. 2021.

20. Updates on the Immunopathology and Genomics of Severe Cutaneous Adverse Drug Reactions. — Gibson A, Deshpande P, Campbell CN, et al. The Journal of Allergy and Clinical Immunology. 2023.

21. Clinical Pharmacogenomic Testing and Reporting: A Technical Standard of the American College of Medical Genetics and Genomics (ACMG). — Tayeh MK, Gaedigk A, Goetz MP, et al. Genetics in Medicine : Official Journal of the American College of Medical Genetics. 2022.

22. HLA-B*58:01 and Risk of Allopurinol-Induced Severe Cutaneous Adverse Reactions in the US. — Campbell CN, Krantz MS, Yu A, Phillips EJ, Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) Survivor Study Collaborators. JAMA Dermatology. 2025.

23. Diagnosis and Management of Stevens-Johnson Syndrome/­Toxic Epidermal Necrolysis. — Noe MH, Micheletti RG. Clinics in Dermatology. 2020.

24. Predictive Value of a Severity-of-Illness Score for Toxic Epidermal Necrolysis (SCORTEN) Factors for in-Hospital Mortality in Stevens-Johnson Syndrome/­Toxic Epidermal Necrolysis. — Nikitina E, Dushkin A, Streltsov Y, et al. Frontiers in Medicine. 2025.

25. Improvement of Mortality Prognostication in Patients With Epidermal Necrolysis: The Role of Novel Inflammatory Markers and Proposed Revision of SCORTEN (Re-SCORTEN). — Koh HK, Fook-Chong SMC, Lee HY. JAMA Dermatology. 2022.

26. SCORTEN and Novel Prognostic Markers in Stevens-Johnson Syndrome/­Toxic Epidermal Necrolysis: A Systematic Review and Meta-Analysis. — Liu ZF, Yang H, Lin L, et al. The Australasian Journal of Dermatology. 2026.

27. Risk of Cardiovascular Morbidity and Mortality in Stevens-Johnson Syndrome/­Toxic Epidermal Necrolysis Survivors. — Chiu HY, Chiu YM. JAMA Dermatology. 2025.

28. Accuracy of SCORTEN to Predict the Prognosis of Stevens-Johnson Syndrome/­Toxic Epidermal Necrolysis: A Systematic Review and Meta-Analysis. — Torres-Navarro I, Briz-Redón Á, Botella-Estrada R. Journal of the European Academy of Dermatology and Venereology : JEADV. 2020.

29. Assessment and Comparison of Performance of ABCD-10 and SCORTEN in Prognostication of Epidermal Necrolysis. — Koh HK, Fook-Chong S, Lee HY. JAMA Dermatology. 2020.

30. Performance of ABCD-10 and SCORTEN Mortality Prediction Models in a Cohort of Patients With Stevens-Johnson Syndrome/­Toxic Epidermal Necrolysis. — Duplisea MJ, Roberson ML, Chrisco L, et al. Journal of the American Academy of Dermatology. 2021.

31. Diagnosing and Managing Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Adults: Review of Evidence 2017-2023. — Ingen-Housz-Oro S, Matei I, Gaillet A, et al. The Journal of Investigative Dermatology. 2025.

32. Chronic Ocular Complications in Stevens-Johnson Syndrome/­Toxic Epidermal Necrolysis: Clinical Features and Surgical Management in a Brazilian Tertiary Center. — de Alcântara RJA, Wakamatsu TH, Hirai FE, et al. Cornea. 2025.