What are the causes, clinical presentation, diagnostic criteria, and management of Stevens‑Johnson syndrome?

Stevens-Johnson Syndrome: Causes, Clinical Presentation, Diagnosis, and Management

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening drug-induced mucocutaneous reactions requiring immediate drug withdrawal and transfer to a specialized intensive care or burn unit, with mortality ranging from <10% for SJS to 30% for TEN. 1

Etiology and Causative Agents

Drug-Induced Cases (Most Common in Adults)

The most critical intervention is immediate discontinuation of the culprit drug, as this single action most significantly impacts survival. 2

High-risk medications include: 1, 3, 4

• Anticonvulsants: carbamazepine, phenytoin, phenobarbital, lamotrigine
• Antibiotics: sulfonamides (especially trimethoprim-sulfamethoxazole), aminopenicillins, cephalosporins, quinolones
• Allopurinol
• NSAIDs: particularly oxicam-type
• Nevirapine
• Anti-cancer agents (emerging concern) 1

Paracetamol and ibuprofen have unclear causal relationships and are likely confounders, as they are frequently used to treat prodromal symptoms; however, reports of both causing SJS exist, and one series showed higher complication rates in children receiving ibuprofen. 1

Infection-Induced Cases (Up to 50% in Children)

• Mycoplasma pneumoniae (accounts for up to 50% of infection-related cases in children) 1, 5
• Herpes simplex virus 1, 5, 3
• Other respiratory pathogens 1

Genetic Susceptibility

• HLA-B*1502 strongly associated with carbamazepine-induced SJS in Han Chinese populations; genetic testing should be performed before initiating carbamazepine in Southeast Asian patients 1, 3, 4

Clinical Presentation

Prodromal Phase (4-28 Days After Drug Initiation)

Severe cutaneous pain preceding visible skin changes is a critical red-flag symptom demanding urgent assessment for incipient epidermal necrolysis. 1, 6, 7

Additional prodromal features: 1, 7

• Fever and malaise
• Upper respiratory tract symptoms
• Ocular inflammation (may precede skin lesions)

Cutaneous Manifestations

Initial lesions: 1, 6

• Atypical flat target lesions or purpuric macules with dark-red centers surrounded by pink rings
• Begin on upper torso, proximal limbs, and face
• Spread to trunk, distal limbs, palms, and soles

Progressive features: 1, 6

• Lesions expand and coalesce, reaching maximum extent at 5-7 days
• Large confluent erythematous areas develop
• Positive Nikolsky sign: gentle lateral pressure causes epidermal peeling (helpful but not specific—also positive in pemphigus) 1, 6
• Flaccid bullae form as necrotic epidermis separates from dermis
• Extensive sheet-like epidermal detachment exposes denuded dermis that exudes serum, bleeds readily, and becomes secondarily infected 1, 6

Mucosal Involvement (Early and Prominent)

Erosive and hemorrhagic mucositis affecting eyes, oral cavity, nose, and genitalia is usually an early feature. 1, 6

• Oral mucositis may require enteral feeding support 6
• In Mycoplasma-associated cases, mucosal involvement may predominate with minimal cutaneous lesions (termed "respiratory infection-induced rash and mucositis") 1, 6

Diagnostic Criteria and Classification

Classification by Body Surface Area (BSA) Involvement

Documentation must include both extent of erythema AND percentage of epidermal detachment (detachable epidermis may appear as dusky erythema before frank blistering). 6

• SJS: <10% BSA detachment plus widespread purpuric macules or flat atypical targets 1, 6
• SJS-TEN overlap: 10-30% BSA detachment 1, 6
• TEN: >30% BSA detachment 1, 6

Histopathology

Skin biopsy should be performed to confirm diagnosis and exclude other blistering dermatoses. 1, 6

Key histologic features: 1, 6

• Spectrum from isolated keratinocyte apoptosis to confluent full-thickness epidermal necrosis
• Basal cell vacuolar degeneration with subepidermal vesicle/bulla formation
• Mild predominantly perivascular lymphocytic and histiocytic dermal infiltrate
• Occasional adnexal involvement

Critical Differential Diagnoses

Staphylococcal scalded skin syndrome (SSSS) in children: 1, 5

• Key distinction: SSSS lacks mucosal involvement
• Histology shows intraepidermal cleavage (vs. subepidermal in SJS/TEN)
• Frozen section of blister roof definitively distinguishes these conditions

Erythema multiforme major: 1, 6

• Shows raised target lesions predominantly on limbs and extremities
• SJS has flat atypical targets with wider distribution

Other differentials include pemphigus, pemphigoid, other immunobullous disorders, acute generalized exanthematous pustulosis, and disseminated fixed bullous drug eruption 1, 3, 4

Management

Immediate Actions

Calculate SCORTEN within 24 hours to predict mortality risk (scores 0-7). 2

Withdraw all suspected medications immediately—this decreases mortality risk. 1, 2

Transfer and Level of Care

Delayed transfer to specialized care significantly increases mortality—transfer within hours, not days. 2

For SJS (<10% BSA): 2, 6

• Transfer to center with multidisciplinary team experienced in SJS/TEN
• Admit to intensive care or burn unit if comorbidities exist or mechanical ventilation required

For overlap SJS-TEN (10-30% BSA) or TEN (>30% BSA): 2, 6

• Immediate transfer to burn unit or intensive care unit is mandatory
• Patients with >30% BSA who clinically deteriorate may require surgical intervention

Children and young people should be managed in age-appropriate specialist units with pediatric intensive care capabilities. 1

Supportive Care

Fluid management: 2

• Establish IV access and initiate fluid resuscitation guided by urine output
• Critical pitfall: Avoid overaggressive fluids that cause pulmonary, cutaneous, and intestinal edema
• Monitor vital signs, urine output, and electrolytes regularly

Wound care: 2

• Specialized skin failure management
• Critical pitfall: Indiscriminate prophylactic antibiotics increase resistant organism colonization 2

Ophthalmologic Management

Failure to involve ophthalmology within 24 hours leads to permanent visual impairment. 2

Every case requires ophthalmology consultation. 2, 6

• Apply preservative-free lubricant eye drops every 2 hours throughout acute illness 2
• Daily ophthalmologist examination to remove inflammatory debris and break down conjunctival adhesions 2
• Consider amniotic membrane transplantation for better visual outcomes 2

Immunomodulatory Therapy

There is no reliable evidence on benefits or lack of benefit of any systemic treatments including prednisolone, IVIg, anti-TNF biologics, or ciclosporin. 1

If immunomodulatory therapy is instituted, administer under specialist skin failure multidisciplinary team supervision in the context of clinical research and/or case registry. 1

Options when used: 2

• IV methylprednisolone 0.5-1 mg/kg if started within 72 hours of onset, then convert to oral with tapering over at least 4 weeks
• OR Cyclosporine 3 mg/kg daily for 10 days, tapered over 1 month (has shown reduced mortality compared to predicted rates)

Genital and Mucosal Care

For vaginal involvement: 1

• Consider clobetasol propionate 0.05% ointment applied to tampon or vaginal applicator
• Alternative for younger children: hydrocortisone foam pessaries
• Note developmental differences in prepubertal girls and relevant child protection issues

Multidisciplinary Team Coordination

Team should be led by dermatologist or plastic surgeon with skin failure expertise and include intensive care physicians, ophthalmologists, and specialist skincare nurses. 2

Special Considerations for Pediatric Patients

Test for infective triggers (HSV, Mycoplasma pneumoniae) and consult infectious disease team in all pediatric cases. 1, 5

Mortality in pediatric TEN appears lower than in adults (0% for SJS, 2.5-8.5% for overlap, 8.5-14.7% for TEN vs. 0-3.1%, ~14.3%, and 17-25% respectively in adults). 6

Recurrence is more common in children (up to 18% of cases), likely because infections—which may recur—are more common triggers than drugs, which can be avoided. 5

Discharge Planning and Long-Term Follow-Up

Provide written documentation that patient must permanently avoid the culprit drug and all potentially cross-reactive medications. 2

Encourage MedicAlert bracelet listing the culprit drug. 2

Document drug allergy in all medical records and inform all healthcare providers. 2

Discuss potential long-term sequelae: 1

• Skin pigmentation changes and scarring
• Nail abnormalities
• Ocular complications
• Oral and dental problems
• Respiratory complications (particularly bronchiolitis obliterans)
• Urogenital problems

If multiple potential causes exist, give balanced advice on likely risk/benefit regarding re-exposure—for example, if exposed to analgesia prior to the episode but infection is likely the cause, it is unnecessary to advise avoidance of all commonly used analgesia. 1

Discuss risk of recurrence if infection is likely to have been the cause. 1

Prognosis and Mortality

Overall SJS/TEN mortality is approximately 22%, with SJS <10% and TEN up to 30%. 1

More than 50% of survivors develop significant long-term sequelae. 3