Residency · Residency · Dermatology
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
Introduction
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent a spectrum of severe, life-threatening mucocutaneous reactions characterized by widespread epidermal necrosis and detachment. With mortality rates reaching 30-50% for TEN, these conditions constitute true dermatologic emergencies requiring immediate recognition, drug withdrawal, and multidisciplinary intensive care.
Classification and Definitions
SJS is defined by epidermal detachment involving less than 10% body surface area (BSA), SJS-TEN overlap involves 10 to 30% BSA, and TEN involves greater than 30% BSA. These are considered a continuum of the same disease process, distinguished solely by the extent of skin involvement. Erythema multiforme (EM) major is a distinct entity (typically HSV-associated, with targetoid lesions and less mucosal involvement) and should not be classified with SJS/TEN.
Epidemiology
The incidence of SJS is 1 to 7 per million per year, and TEN 0.4 to 1.5 per million per year. There is a higher incidence in immunocompromised patients (HIV confers a 100-fold increased risk), patients with active malignancy, and those with slow acetylator phenotype. The female-to-male ratio is approximately 1.5:1, and all ages are affected with incidence increasing with age.
Pathogenesis
Immunologic Mechanisms
Drug-specific cytotoxic CD8+ T cells and NK cells are the primary effectors. Granulysin is the key cytotoxic mediator responsible for keratinocyte death; its concentrations in blister fluid correlate with disease severity, making blister granulysin the most reliable biomarker. The perforin/granzyme B pathway and Fas-FasL interaction also contribute to keratinocyte apoptosis. Annexin A1 has been identified as an autoantigen expressed on keratinocyte surfaces during SJS/TEN.
Pharmacogenomic Associations
Several strong drug-HLA associations have been identified. **HLA-B15:02 with carbamazepine is strongly associated with SJS/TEN in Southeast Asian populations (Han Chinese, Thai, Malaysian), leading to FDA-mandated screening before carbamazepine in at-risk populations. HLA-B58:01 with allopurinol confers SJS/TEN and DRESS risk across multiple ethnicities. HLA-B57:01 with abacavir causes a hypersensitivity reaction (mandatory screening). HLA-A31:01 with carbamazepine** predominantly confers DRESS risk (European and Japanese populations). These associations reflect drug-HLA-TCR interactions where the drug alters the peptide-binding groove or acts as a hapten.
Culprit Drugs
The highest-risk drugs (over 95% drug-induced) include allopurinol (the most common single cause worldwide), aromatic anticonvulsants (carbamazepine, phenytoin, lamotrigine, phenobarbital), sulfonamide antibiotics (TMP-SMX, sulfasalazine), nevirapine, and oxicam NSAIDs (piroxicam, meloxicam). Moderate-risk drugs include quinolones, cephalosporins, and aminopenicillins. The latency period is typically 4 to 28 days after drug initiation (most commonly 1 to 3 weeks), and shorter on re-exposure. Infection-associated SJS is rare, with Mycoplasma pneumoniae being the most common infectious cause, particularly in children, and may occur without drug exposure.
Clinical Features
Prodrome
A prodrome of 1 to 3 days of nonspecific symptoms occurs, including fever, malaise, pharyngitis, myalgia, and arthralgia. Mucous membrane involvement with stinging and burning may precede skin findings.
Cutaneous Findings
Atypical targetoid macules appear as flat, dusky-red or purpuric macules with irregular borders, lacking the three-zone "typical target" pattern of EM. These macules become confluent and develop a dusky, necrotic center with a violaceous or grayish appearance. Epidermal detachment involves full-thickness necrosis with sheetlike denudation revealing a raw, erythematous dermis. The Nikolsky sign is positive, with lateral pressure on uninvolved skin adjacent to a lesion causing epidermal separation. The Asboe-Hansen sign shows extension of a blister with downward pressure. Detached epidermis has a characteristic "wet tissue paper" appearance.
Mucosal Involvement
Mucosal involvement is present in over 90% of SJS/TEN patients, typically involving two or more mucosal sites. Oral mucosa shows painful erosions and hemorrhagic crusting of the lips, causing difficulty eating and drinking. Ocular involvement includes conjunctival inflammation, pseudomembrane formation, and corneal erosions, with risk of cicatricial complications such as symblepharon, corneal opacification, and blindness. Urogenital erosions of the vulva, vagina, and glans carry risk of synechiae and strictures. Respiratory tracheobronchial epithelium may be involved in severe TEN, leading to respiratory failure.
<image>Clinical photographs showing the progression of SJS/TEN: early dusky atypical targetoid macules on the trunk, positive Nikolsky sign with lateral shearing of the epidermis, and full-thickness epidermal detachment revealing an eroded dermis with wrinkled necrotic epidermis sheets</image>
Diagnosis
Clinical Diagnosis
The diagnosis is based on characteristic clinical findings, temporal drug correlation, and mucosal involvement. Skin biopsy for confirmation shows full-thickness epidermal necrosis with a pauci-inflammatory infiltrate (sparse dermal lymphocytes) and a subepidermal cleavage plane. Frozen section of detached skin can provide rapid confirmation, revealing full-thickness necrosis within hours rather than the days required for standard processing.
ALDEN Algorithm (Algorithm of Drug Causality for Epidermal Necrolysis)
The ALDEN algorithm is a systematic scoring system to identify the culprit drug based on temporal relationship (delay between drug initiation and onset), drug notoriety (known association with SJS/TEN), absence of alternative non-drug-related explanations, and de-challenge and re-challenge history.
SCORTEN Prognostic Score
SCORTEN is a validated severity-of-illness score calculated within the first 24 hours that predicts mortality. One point is assigned for each of the following: age above 40 years, malignancy, heart rate above 120 bpm, initial BSA of epidermal detachment above 10%, serum urea above 28 mg/dL (BUN above 10 mmol/L), serum glucose above 252 mg/dL (above 14 mmol/L), and bicarbonate below 20 mEq/L. Predicted mortality corresponds to: 0 to 1 points, 3%; 2 points, 12%; 3 points, 35%; 4 points, 58%; 5 or more points, above 90%.
| SCORTEN Parameter | Criterion (1 point each) |
|---|---|
| Age | > 40 years |
| Malignancy | Present |
| Heart rate | > 120 bpm |
| Epidermal detachment | > 10% BSA |
| Serum urea (BUN) | > 28 mg/dL (>10 mmol/L) |
| Serum glucose | > 252 mg/dL (>14 mmol/L) |
| Bicarbonate | < 20 mEq/L |
| SCORTEN Score | Predicted Mortality |
|---|---|
| 0–1 | 3% |
| 2 | 12% |
| 3 | 35% |
| 4 | 58% |
| ≥5 | >90% |
Management
Immediate Actions
The culprit drug must be identified and withdrawn immediately, as mortality increases for every day of continued exposure after onset. The ALDEN algorithm should be used when multiple drugs are suspects. Transfer to a burn unit or ICU is indicated for TEN and extensive SJS-TEN overlap, as improved outcomes are seen in specialized units.
Supportive Care (The Foundation of Management)
Fluid and electrolyte management is less aggressive than traditional burn resuscitation (two-thirds of the standard Parkland formula) due to less third-spacing. Temperature management maintains ambient temperature at 30 to 32 C to prevent hypothermia. Wound care uses non-adherent, silicone-based dressings with gentle handling of skin; silver sulfadiazine should be avoided because it is a sulfonamide and may be the culprit. Nutritional support with early enteral nutrition via nasogastric tube addresses high caloric and protein requirements. Pain management often requires opioid analgesia, and gabapentin may be helpful. Infection prevention involves sterile handling and monitoring for sepsis (the leading cause of death), while prophylactic antibiotics should be avoided. Ophthalmology consultation is urgent, with daily eye examination and amniotic membrane transplantation for severe ocular involvement. Urogenital care includes Foley catheter placement if urethral involvement is present and gynecology consultation for vaginal synechiae prevention.
Specific Therapies (Controversial)
Cyclosporine (3 to 5 mg/kg/day) is the most promising adjunctive therapy based on retrospective and prospective studies showing reduced mortality and shorter time to re-epithelialization. Its mechanism includes inhibition of T-cell activation and granulysin production. Systemic corticosteroids remain controversial; early short courses (pulse IV dexamethasone or methylprednisolone) may be beneficial if given within 48 hours of onset, but prolonged use increases infection risk and is generally discouraged. IVIg, based on the rationale of blocking Fas-FasL interaction, has shown inconsistent results in meta-analyses and is not recommended as monotherapy, though it may have a role in combination. Anti-TNF-alpha agents (etanercept) showed reduced mortality with a single 50 mg dose versus corticosteroids in a single RCT, promising but requiring further validation. Plasmapheresis has limited evidence but may remove circulating granulysin and cytokines.
<image>SCORTEN prognostic scoring table with the seven clinical parameters, point values, and corresponding predicted mortality rates, alongside a clinical management algorithm for SJS/TEN showing drug withdrawal, transfer to burn unit/ICU, supportive care components, and specific therapy options with cyclosporine highlighted as the most evidence-supported adjunct</image>
Long-Term Sequelae
Ocular sequelae are the most disabling, affecting up to 75% of survivors and including chronic dry eye, symblepharon, trichiasis, corneal scarring, and visual impairment, requiring long-term ophthalmologic follow-up. Cutaneous sequelae include dyspigmentation, scarring, persistent photosensitivity, nail dystrophy, and eruptive melanocytic nevi. Mucosal sequelae encompass oral synechiae, esophageal strictures, vaginal stenosis, and phimosis. Psychological impact is significant, with PTSD, anxiety, and depression common in survivors, warranting proactive screening and treatment. Pulmonary bronchiolitis obliterans is rare but serious.
Key Clinical Pearls
SJS/TEN is a dermatologic emergency, and every hour of continued culprit drug exposure increases mortality. Nikolsky sign positivity with confluent dusky macules and mucosal erosions is the clinical triad demanding immediate action. SCORTEN should be calculated within the first 24 hours to guide prognosis and level of care. Cyclosporine has the strongest evidence base among specific therapies and should be considered early in the course. HLA screening before prescribing high-risk drugs (carbamazepine in Southeast Asians, allopurinol in at-risk populations) is a proven prevention strategy. Ophthalmology consultation is mandatory because ocular sequelae are the most common cause of long-term morbidity.
References
- Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004;428(6982):486.
- Chung WH, Hung SI, Yang JY, et al. Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. Nat Med. 2008;14(12):1343-1350.
- Sekula P, Dunant A, Mockenhaupt M, et al. Comprehensive survival analysis of a cohort of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. J Invest Dermatol. 2013;133(5):1197-1204.
- Gonzalez-Herrada C, Rodriguez-Martin S, Cachafeiro L, et al. Cyclosporine use in epidermal necrolysis is associated with an important mortality reduction. J Allergy Clin Immunol. 2017;139(2):607-615.
