SJS-TEN

01Pathophysiology

SJS and TEN represent a continuum of the same disease rather than two distinct entities. The underlying mechanism is a drug-induced, immune-mediated cytotoxic reaction targeting keratinocytes. When a susceptible individual is exposed to a culprit drug, the drug or its reactive metabolite is presented by HLA class I molecules on keratinocyte surfaces. This triggers activation of drug-reactive cytotoxic CD8+ T lymphocytes and natural killer (NK) cells in the skin.

The key effector molecule driving keratinocyte death is granulysin, a cytolytic protein secreted by activated cytotoxic T cells and NK cells. Granulysin is the most critical mediator and has been shown to be present in blister fluid at concentrations far exceeding those of other cytotoxic molecules. It induces direct keratinocyte apoptosis in a non-cell-contact-dependent manner, meaning it can spread and cause widespread damage beyond the immediate area of immune cell infiltration. This explains the characteristically disproportionate amount of tissue destruction relative to the sparse inflammatory infiltrate seen on histopathology.

Additional apoptotic pathways contribute to keratinocyte death. The Fas-FasL interaction plays an important role: soluble FasL is upregulated and binds Fas receptors on keratinocytes, activating the caspase cascade and triggering apoptosis. The perforin-granzyme B pathway also participates, with cytotoxic granules directly puncturing keratinocyte membranes. The cumulative effect of these pathways results in confluent epidermal necrosis, where large sheets of epidermis detach from the underlying dermis at the level of the basement membrane zone.

The reason patients develop mucosal involvement is that mucosal epithelium shares the same keratinocyte biology as skin. The oral, ocular, and urogenital mucosae are all susceptible to the same cytotoxic immune attack. This explains why mucosal erosions at two or more sites are a hallmark of the disease and help distinguish SJS/TEN from other blistering disorders.

The genetic susceptibility component is clinically important. Certain HLA alleles dramatically increase the risk of SJS/TEN with particular drugs. HLA-B1502 is strongly associated with carbamazepine-induced SJS/TEN in Southeast Asian and East Asian populations, and HLA-B5801 predisposes to allopurinol-induced SJS/TEN across multiple ethnic groups. These HLA molecules present drug antigens with high efficiency to cytotoxic T cells, lowering the threshold for triggering the immune cascade. This is why pharmacogenomic screening before prescribing these drugs is now recommended in guideline-concordant practice.

02Classification and Clinical Manifestation

The classification is based entirely on the percentage of body surface area (BSA) with epidermal detachment, which determines disease severity and prognosis.

Clinical Manifestation by Phase

Mucosal Involvement

03Diagnostic Workup

The diagnosis of SJS/TEN is fundamentally clinical, made at the bedside by recognizing the triad of recent drug exposure, painful cutaneous eruption with epidermal detachment, and mucosal involvement at two or more sites. The best initial step when you suspect SJS/TEN is a thorough drug history and clinical assessment including evaluation of BSA involvement.

The next step after clinical suspicion is skin biopsy, which serves as the confirmatory test. A punch biopsy taken from the edge of an active lesion (including both affected and unaffected skin) or a frozen section of sloughed epidermis should be sent for both standard histopathology and direct immunofluorescence. The histopathologic hallmark is full-thickness epidermal necrosis with a subepidermal split at the dermal-epidermal junction. The dermis shows only a sparse, predominantly lymphocytic infiltrate. This pattern of extensive epithelial destruction with minimal inflammation is the histologic signature and reflects the apoptosis-driven (rather than inflammation-driven) pathogenesis.

Direct immunofluorescence must be negative in SJS/TEN. This is a key test for ruling out autoimmune blistering diseases that can mimic TEN, such as paraneoplastic pemphigus, linear IgA bullous dermatosis, and bullous pemphigoid. If DIF shows IgG deposits along the basement membrane zone or intercellular deposits, the diagnosis shifts away from SJS/TEN.

The SCORTEN prognostic score should be calculated within 24 hours of admission and recalculated at day 3. It includes seven independent risk factors, each scored as 0 or 1:

04Management and Treatment

Drug withdrawal is the single most important intervention and the answer to "what is the most important first step" on an exam vignette. The mortality benefit of drug withdrawal is time-dependent: drugs with short half-lives (e.g., sulfonamides) that are stopped early carry a better prognosis than drugs with long half-lives (e.g., allopurinol, phenobarbital) stopped late. Every hour of delay in withdrawing the causative agent worsens outcomes. When multiple drugs are suspect, stop all potentially causative agents, not just the most likely one.

Supportive care in a burn unit is the backbone of treatment. Fluid resuscitation follows principles similar to burn care but at reduced volumes (roughly two-thirds of standard Parkland formula estimates) because the dermal vasculature is less damaged in SJS/TEN than in thermal burns. Electrolytes, renal function, and serum albumin must be monitored frequently. Albumin replacement may be needed for significant hypoalbuminemia.

Regarding immunomodulatory therapy, the evidence landscape has shifted considerably. Cyclosporine A at a dose of 3-5 mg/kg/day divided into two doses for 10-14 days followed by a taper is now considered the most evidence-supported systemic agent based on multiple observational studies and a randomized trial showing improved re-epithelialization time and reduced mortality. Cyclosporine works by inhibiting T-cell activation and reducing the cytotoxic immune response driving keratinocyte death. It is contraindicated in patients with uncontrolled infections, severe renal impairment, or uncontrolled hypertension. Monitor renal function and blood pressure closely during treatment.

Systemic corticosteroids remain controversial. Short-course, high-dose pulse corticosteroids (dexamethasone 1.5 mg/kg IV over 3 days) have shown benefit in some studies when given very early. However, prolonged corticosteroid use is associated with increased infection risk, delayed wound healing, and higher mortality, and most current guidelines advise against prolonged courses.

IVIG was historically used but has not shown consistent survival benefit in well-designed studies and is no longer considered first-line. If used, the theoretical mechanism is blockade of Fas-FasL interaction by anti-Fas antibodies present in pooled immunoglobulin. The dose studied is typically 0.2-0.5 g/kg/day for 3-4 consecutive days (total dose ~1-2 g/kg).

Ocular management deserves emphasis because ocular complications are the leading cause of long-term morbidity. Daily slit-lamp examinations during the acute phase, aggressive lubrication with preservative-free tears, topical corticosteroids (e.g., prednisolone acetate 1% every 2-4 hours), and mechanical lysis of forming synechiae are essential. In severe cases, amniotic membrane transplantation within the first 1-2 weeks can prevent cicatricial complications including symblepharon, trichiasis, and corneal opacification.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common way students lose points on SJS/TEN questions is failing to distinguish SJS from Erythema Multiforme Major. Test writers exploit this by presenting a patient with targetoid lesions and oral erosions. The critical discriminator is the morphology of the targets and the distribution: EM has raised, typical three-zone targets on the extremities (acral distribution), whereas SJS has flat, atypical targets concentrated on the trunk. Additionally, EM is most commonly triggered by HSV infection, while SJS is almost always a drug reaction. If the vignette mentions a recent herpes outbreak and acral targets, think EM. If it mentions a new medication started 1-3 weeks ago and truncal involvement with mucosal erosions, think SJS.

A second common trap involves SSSS vs. TEN in a pediatric patient. Both present with widespread skin sloughing and a positive Nikolsky sign. The discriminator tested is mucosal involvement: SSSS spares the mucosa, while SJS/TEN always involves it. Additionally, the biopsy cleavage plane differs fundamentally: SSSS splits superficially within the granular layer (intraepidermal), while TEN shows full-thickness epidermal necrosis with subepidermal detachment.

Students also frequently miss the "Next Best Step" logic in management questions. When a vignette presents an acute SJS/TEN case, the answer to "what is the most important first step" is always immediate withdrawal of the offending drug, not starting IVIG, not transferring to a burn unit, and not ordering a biopsy. Drug withdrawal is both the first and highest-yield intervention.

Finally, be alert for pharmacogenomic screening questions. If a vignette describes a Southeast Asian patient about to start carbamazepine, the next step before prescribing is HLA-B1502 testing. If the vignette describes any patient about to start allopurinol (particularly in Southeast Asian or African American populations), the next step is HLA-B5801 testing. This represents the tested competency of preventing SJS/TEN through pre-prescription genetic screening, which is increasingly emphasized as a testable concept.