Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

• Drug-Hapten Formation and Antigen Presentation: Offending medications (particularly NSAIDs, sulfonamides, anticonvulsants) undergo hepatic metabolism via cytochrome P450 enzymes to form reactive intermediates that bind to cutaneous proteins, creating neoantigens. These drug-protein conjugates are processed and presented to T cells via major histocompatibility complex (MHC) Class I molecules on keratinocytes and dendritic cells. Individuals with specific HLA alleles (HLA-B*5801 for allopurinol, HLA-B*1502 for carbamazepine in Han Chinese populations) have structural similarities to the drug-hapten complex, enhancing T cell receptor (TCR) recognition through molecular mimicry and cross-reactivity. This explains the strong genetic predisposition observed in certain populations and the marked association between specific drugs and HLA types in different ethnic groups.

• Cytotoxic T Cell Expansion and Keratinocyte Targeting: CD8+ cytotoxic T lymphocytes (CTLs) become activated upon recognizing the drug-hapten-MHC complex, undergoing massive clonal expansion and trafficking to affected skin. Activated CTLs recognize MHC Class I-peptide complexes presented by keratinocytes themselves, which express constitutive MHC Class I molecules. The infiltrating T cell population is predominantly composed of CD8+ cells with a helper T cell (CD4+) component; notably, studies show these cells produce excessive amounts of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and granulysin. Granulysin, a 15-kDa protein released by CTLs and natural killer T cells, is a particularly critical mediator in SJS/TEN pathophysiology—it directly permeabilizes cell membranes of keratinocytes, leading to loss of cellular integrity independent of classical apoptotic pathways.

• Keratinocyte Apoptosis and Death Receptor Pathways: Multiple death pathways are simultaneously activated in keratinocytes. The Fas-FasL (CD95-CD95L) system is upregulated, with increased Fas expression on keratinocytes and FasL expression on infiltrating lymphocytes. Cross-linking of Fas by FasL triggers the extrinsic apoptotic pathway, recruiting the adaptor protein FADD and initiating pro-caspase 8 activation. The TNF-α pathway similarly activates TNF receptor 1 signaling, recruiting TRADD and TRAF2, further amplifying caspase cascades. Simultaneously, mitochondrial-mediated apoptosis is triggered through caspase 8-dependent cleavage of Bid (a BH3-only protein), creating truncated Bid (tBid) that translocates to mitochondria and promotes outer mitochondrial membrane permeabilization through BAX/BAK activation. This results in cytochrome c release, apoptosome formation, and activation of the executioner caspases (3 and 7), ultimately leading to DNA fragmentation and programmed cell death. The combination of granulysin-mediated direct cytotoxicity and apoptotic pathways results in rapid, massive keratinocyte death.

• Epidermal-Dermal Separation and Barrier Dysfunction: The anatomic site of separation in SJS/TEN occurs at the dermo-epidermal junction rather than within the epidermis, a critical distinguishing feature. Keratinocyte apoptosis and death within the basal layer, combined with the direct cytotoxic effects of granulysin on keratinocyte-basement membrane interactions, disrupt hemidesmosomes (which normally anchor the epidermis to the dermis). Loss of these anchoring structures, along with degradation of extracellular matrix proteins by activated dermal inflammatory cells, results in subepidermal blister formation. The entire epidermis essentially becomes necrotic and separates as a consequence of basement membrane zone disruption. This differs fundamentally from bullous pemphigoid (where autoantibodies target hemidesmosomal antigens) and from the intraepidermal blistering of pemphigus, making the clinical appearance and histopathology distinct.

• Systemic Effects and Multi-Organ Involvement: While skin manifestations are most visible, SJS/TEN is fundamentally a systemic disease. The same pathophysiologic mechanisms operative in skin also affect mucous membranes (oral, conjunctival, urogenital), respiratory epithelium, and gastrointestinal tract. Respiratory epithelial involvement can progress to acute respiratory distress syndrome (ARDS) through similar mechanisms of epithelial necrosis and inflammation. Hepatic injury reflects direct drug toxicity combined with T cell infiltration of hepatic sinusoids. The inflammatory cascade—involving TNF-α, IL-6, and other cytokines—contributes to systemic complications including sepsis, disseminated intravascular coagulation (DIC), and multi-organ failure, particularly in extensive TEN cases.

• High-Risk Medications (Strongly Associated): Sulfonamide antibiotics (trimethoprim-sulfamethoxazole, sulfadiazine) represent the most consistently implicated drug class historically, with relative risks 100-200 fold above baseline. Nonsteroidal anti-inflammatory drugs (NSAIDs), particularly oxicams (meloxicam, piroxicam) and older NSAIDs, carry substantial risk; newer NSAIDs like celecoxib appear to have lower risk profiles. Anticonvulsants, especially phenytoin, carbamazepine, and phenobarbital, are classic culprits; carbamazepine shows particularly strong HLA associations (HLA-B*1502 in Han Chinese populations confers 26.1% risk vs. 3% in carriers without this allele). Allopurinol carries relative risk of 80-110 fold in the first 8 weeks of therapy, with HLA-B*5801 conferring substantially elevated risk. Acetaminophen causes SJS/TEN in overdose settings or with prolonged use. Antibiotics beyond sulfonamides implicated include fluoroquinolones, macrolides, and beta-lactams. Antiretrovirals, particularly nevirapine in HIV-positive patients with CD4 counts >250 cells/μL (where immune reconstitution-like reactions occur), carry elevated risk. Sulfonylureas and thiazide diuretics represent older associations with lower contemporary incidence due to reduced use.

• Infection-Associated Cases (10-20% of Cases): Certain infections trigger SJS/TEN through similar immunologic mechanisms without drug exposure. Mycoplasma pneumoniae represents the most common infectious trigger in pediatric SJS, accounting for up to 50% of SJS cases in children compared to <5% in adults. Herpes simplex virus (HSV), particularly HSV-1, causes recurrent or persistent SJS in a subset of patients (termed HSV-associated SJS or HAEM—herpes-associated erythema multiforme), characterized by recurrent episodes coinciding with viral reactivation. Other implicated pathogens include Histoplasma capsulatum, Coccidioides immitis, and rarely hepatitis A and B, suggesting cross-reactive immune responses to viral or fungal antigens presented on epithelial surfaces.

• Host Genetic Factors and HLA Associations: Genetic predisposition profoundly influences SJS/TEN risk. **HLA-B*5801 shows strong association with allopurinol-induced SJS/TEN, with odds ratios >1000 in some populations. HLA-B*1502, found predominantly in Han Chinese, Thai, and other East Asian populations, confers massive increased risk for carbamazepine-induced SJS/TEN (relative risk 26-80 fold); screening for this allele before carbamazepine initiation is now standard in endemic regions. HLA-A*3101** is associated with carbamazepine reactions in European and other populations. Other HLA associations include HLA-B*1511 with oxicams and HLA-B*5701 with abacavir in HIV-positive patients. These associations underscore the critical role of antigen presentation in disease pathogenesis and support pharmacogenetic screening where feasible.

• Drug Dosing and Duration: While SJS/TEN can theoretically occur at any point during drug exposure, most reactions develop within 2-6 weeks of drug initiation, corresponding to the time required for priming of drug-specific T cell responses. Drugs with long elimination half-lives (phenytoin, carbamazepine, allopurinol) may trigger delayed reactions weeks after discontinued use. High-dose therapy increases risk, likely due to increased hapten formation and antigen load. Polypharmacy is a risk factor, though it remains debated whether drug-drug interactions increase risk or whether temporal clustering of multiple drugs increases statistical likelihood of identifying a culprit.

• Patient Factors Modulating Risk: Age extremes (very young children and elderly patients) carry somewhat elevated risk, possibly reflecting immune response characteristics. Immunosuppression including HIV infection with low CD4 counts increases SJS/TEN risk, particularly with certain medications (nevirapine). Prior reaction to a related drug significantly increases risk of cross-reactivity, particularly within anticonvulsant and antibiotic classes. Systemic lupus erythematosus and other autoimmune conditions may increase susceptibility through altered immune tolerance. Renal and hepatic impairment increase risk by reducing drug clearance and increasing metabolite accumulation.

• Prodromal Phase (1-3 Days Before Rash): Patients frequently experience nonspecific constitutional symptoms including high fever (often ≥38.5°C), severe malaise, myalgias, and arthralgias. These symptoms reflect the massive inflammatory cytokine surge triggered by T cell activation and are often misattributed to viral illness. Oropharyngeal pain and difficulty swallowing frequently herald the reaction, reflecting early mucosal involvement. Upper respiratory symptoms including cough and dyspnea may occur as airway epithelium becomes involved. Patients may report ocular irritation and lacrimation. This prodromal phase is critical diagnostically, as recognition that mucosal pain precedes rash—rather than occurring concurrently—should heighten suspicion for SJS/TEN rather than drug eruptions or infectious exanthems.

• Cutaneous Eruption - Morphology and Distribution: The characteristic lesion of SJS/TEN is a flat, atypical target or iris lesion, morphologically distinct from the raised papular targets of erythema multiforme minor (EM). These lesions consist of a central zone of epidermal necrosis (appearing dusky purple or gray), surrounded by an erythematous halo with an outer macular ring, all in the same plane (hence "flat" targets). Lesions typically begin symmetrically on the face, trunk, and proximal extremities, with rapid centripetal spread over 24-72 hours. The palms and soles are frequently affected, a feature helping distinguish SJS/TEN from other exanthems. Unlike EM minor, which typically spares mucous membranes, SJS/TEN almost invariably involves oral mucosa (95-100% of cases), often severely. Patients develop oral erosions, hemorrhagic crusting, and pseudomembrane formation, making eating and swallowing intensely painful. Conjunctival involvement occurs in 50-80% of cases, manifesting as conjunctivitis with exudate, pseudomembrane formation, and corneal involvement in severe cases. Genital mucosal involvement occurs in ~30% of cases, causing severe dysuria and potential urinary retention. Anal and rectal erosions may occur, causing severe pain with defecation. The presence of mucosal involvement in >2 sites is highly characteristic and distinguishes SJS/TEN from exanthematous drug reactions.

• Lesion Evolution: Individual lesions evolve over 7-10 days from initial erythema through blister formation to crusting and eventual healing with potential post-inflammatory hyperpigmentation. However, the overall eruption is characterized by continued new lesion formation during the acute phase, such that the skin shows a polymorphic appearance with lesions at different stages of evolution. The confluence of lesions in SJS/TEN (particularly with BSA >20%) creates large denuded areas, functionally equivalent to second-degree burns, with weeping, painful erosions.

• Physical Examination Findings Beyond Rash: Nikolsky sign (lateral pressure on uninvolved skin causing epidermal sloughing) is typically positive in SJS/TEN, reflecting the subepidermal plane of cleavage and basal keratinocyte death. This finding is relatively specific for diseases with suprabasal or subepidermal necrosis but is not pathognomonic. Flaccid bullae and erosions on mucosal surfaces are prominent, with severe mucositis limiting oral intake. Conjunctival chemosis, pseudomembranes, and progressive corneal involvement may occur. Systemic findings reflecting multi-organ involvement include fever persisting despite antimicrobial therapy (reflecting the immunologic rather than infectious etiology), tachycardia and hemodynamic instability from massive fluid losses and systemic inflammation, hepatosplenomegaly from hepatic involvement and T cell infiltration, and lymphadenopathy.

• Important Clinical Variants: Recurrent HSV-associated SJS (HAEM-recurrent SJS): A distinctive subset of SJS patients, predominantly female, experience recurrent episodes triggered by HSV reactivation, sometimes without identified drug trigger. Each recurrence correlates with PCR-documented HSV reactivation and may respond to chronic suppressive acyclovir therapy, suggesting different pathophysiologic mechanisms than drug-induced disease. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome may present similarly with fever, mucosal involvement, and systemic symptoms but is distinguished by profound eosinophilia (>1500/μL) and atypical lymphocytes, normal to modestly elevated eosinophils in SJS/TEN, hepatomegaly with hepatitis, and association with anticonvulsants and allopurinol. Severe cutaneous adverse reactions (SCARs) is an umbrella term encompassing SJS/TEN, DRESS, and drug reaction with eosinophilia and systemic symptoms (DRESS), reflecting their overlapping clinical features and pathophysiology.

• Clinical Diagnostic Criteria - RegiSCAR Scoring System: The Revised Registry for Severe Cutaneous Adverse Reactions (RegiSCAR) scoring system provides the most validated approach to diagnosis, incorporating clinical, histopathologic, and laboratory findings. The scoring system assigns points for: (1) Atypical target lesions (typical targets=0 points, atypical targets=1, no targets but raised/flat lesions=0); (2) **Muc

Immediate priorities (first hour)

• Withdraw the culprit drug: the only intervention with reproducible mortality benefit. Earlier withdrawal — particularly of agents with short half-lives — correlates with improved survival, so stop every non-essential medication started in the preceding 4–8 weeks rather than waiting to identify a single agent.
• Triage and transfer: calculate detached/detachable BSA and SCORTEN (age, malignancy, tachycardia, BSA, urea, glucose, bicarbonate) on day 1 and again on day 3. American Burn Association referral criteria include exfoliative skin disorders such as TEN; transfer to a burn center or ICU with dermatology support is standard US practice and is endorsed by the Society of Dermatology Hospitalists consensus guidance on SJS/TEN.

Supportive care is the definitive therapy

• Fluids and electrolytes: transepidermal water loss drives hypovolemia, but requirements are lower than for thermal burns of equal BSA; titrate crystalloid to urine output rather than applying a burn formula.
• Wound care: anti-shear handling, non-adherent or biologic dressings, warm ambient room to prevent hypothermia; aggressive debridement of all detached epidermis is not required. Avoid silver sulfadiazine when a sulfonamide is the suspected trigger.
• Nutrition and analgesia: early enteral feeding via nasogastric tube for hypercatabolism and painful mucositis; opioid analgesia.
• Mucosal care: urgent ophthalmology consultation (within 24 hours) — ophthalmology consensus reviews and expert practice support lubrication, topical corticosteroid/antibiotic drops, lysis of symblephara, and early amniotic membrane transplantation for moderate-to-severe acute ocular involvement. Genitourinary involvement warrants topical corticosteroids and barrier/dilator strategies to prevent synechiae.

Immunomodulation (adjunctive, not proven)

• Calcineurin inhibitors: cyclosporine, the most commonly used adjunct in US centers, based on observational data only.
• TNF-α inhibitors: etanercept, supported by limited randomized data suggesting faster re-epithelialization.
• Systemic corticosteroids and IVIG: widely used historically; meta-analyses have not shown consistent mortality benefit, and no agent is FDA-approved.

Avoid

• Prophylactic systemic antibiotics (select for resistant organisms without reducing sepsis), rechallenge or structurally related drugs (aromatic anticonvulsants cross-react), and NSAIDs. Per FDA labeling, screen for **HLA-B*1502** before carbamazepine in patients of Asian ancestry.

Acute and life-threatening

• Sepsis: loss of the epidermal barrier permits colonization by Staphylococcus aureus and Pseudomonas aeruginosa; this is the leading cause of death. Because fever is intrinsic to the disease, the signals are hypothermia, new hypotension, worsening hyperglycemia, oliguria, or altered mental status — an emergency requiring cultures and empiric antibiotics.
• Hypovolemic shock and acute kidney injury: massive transepidermal water and protein loss plus poor oral intake from mucositis. Serum urea (BUN >28 mg/dL) is one of the seven SCORTEN variables; a rising creatinine, while not scored, likewise signals worsening prognosis.
• Respiratory failure: sloughing of bronchial epithelium produces bronchial casts, hypoxemia, and ARDS. Early dyspnea, hypoxemia, or increased secretions out of proportion to chest radiograph should prompt ICU escalation and consideration of bronchoscopy — an emergency, as it independently predicts death.
• Gastrointestinal involvement: esophageal and intestinal epithelial necrosis causing hemorrhage, protein-losing enteropathy, and later strictures.
• DIC and multiorgan failure in extensive TEN.

Long-term sequelae

• Ocular: the most common chronic morbidity. Conjunctival scarring produces symblepharon, trichiasis, limbal stem cell deficiency, chronic dry eye, corneal neovascularization, and blindness. Lifelong ophthalmologic follow-up is required even if acute eye disease seemed mild.
• Mucosal strictures: vaginal adhesions and stenosis, urethral stricture, phimosis, esophageal stenosis, and oral synechiae.
• Cutaneous/adnexal: dyspigmentation, hypertrophic scarring, nail dystrophy or anonychia, scarring alopecia, eruptive melanocytic nevi.
• Pulmonary: bronchiolitis obliterans, described particularly after Mycoplasma-associated disease in children.
• Psychiatric: post-traumatic stress and depression are common and underdiagnosed.

Treatment-related

• IVIG: thrombosis, aseptic meningitis, hemolysis, volume overload, and renal injury with sucrose-containing preparations; anaphylaxis in IgA deficiency.
• Cyclosporine: nephrotoxicity, hypertension, tremor, and added infection risk.
• TNF-α inhibitors: reactivation of latent tuberculosis and infection.
• Corticosteroids: hyperglycemia, impaired re-epithelialization, and masking of sepsis.
• Silver sulfadiazine: re-exposure to a sulfonamide in sulfa-triggered cases.

• The stem you must recognize: fever and mucosal pain 1–4 weeks after starting a sulfonamide, allopurinol, an aromatic anticonvulsant, or nevirapine, followed by dusky flat atypical targets, painful skin, a positive Nikolsky sign, and erosions at two or more mucosal sites.
• Single best next step: stop the offending drug and transfer to a burn center/ICU. Everything else — fluids, wound care, immunomodulation — comes after drug withdrawal. Do not delay for biopsy; diagnosis is clinical.
• The consult examiners want: urgent ophthalmology within 24 hours. Ocular scarring is the leading cause of long-term disability, and acute eye findings can look deceptively mild.
• The association tested: **HLA-B*5801 with allopurinol and HLA-B*1502 with carbamazepine** in patients of Asian ancestry — the FDA advises screening for HLA-B*1502 before starting carbamazepine in that population.
• Pediatric twist: Mycoplasma pneumoniae is the classic non-drug trigger in children, presenting with prominent mucositis and sparse skin disease (Mycoplasma-induced rash and mucositis). Look for cold agglutinins or a reticulonodular infiltrate.
• Prognosis: SCORTEN — age, malignancy, heart rate, BSA detached, urea, glucose, bicarbonate — calculated on days 1 and 3.
• Common distractor #1 — staphylococcal scalded skin syndrome: young child, exfoliative toxin cleaving desmoglein-1, split in the granular layer (superficial, intraepidermal), mucosa spared, no drug history. SJS/TEN splits at the dermo-epidermal junction and virtually always hits mucosa.
• Common distractor #2 — treatment: corticosteroids, IVIG, cyclosporine, and etanercept are adjuncts with unproven mortality benefit; none is the "best next step." Also avoid choosing prophylactic systemic antibiotics — treat infection when it appears, don't prophylax.
• Do not confuse with erythema multiforme major: EM major does involve mucosa, so mucositis alone is not the discriminator. The distinguishing features are **raised, typical three-zone targets in an acral/extensor distribution with little or no widespread epidermal detachment**, usually HSV-driven and often recurrent, and generally self-limited — though severe mucosal disease can still require admission. Lesion morphology, distribution, and extent of detachment separate it from SJS/TEN; EM major is a distinct disease, not the mild end of the SJS spectrum.