INFLAMMATORY AND IMMUNE-MEDIATED SKIN DISORDERS

Toxic Epidermal Necrolysis (TEN)

Etiology and risk factors

• SJS/TEN most often represents a severe idiosyncratic medication reaction. The highest-yield causal assessment is a complete timeline of prescription, nonprescription, and herbal products used during the preceding four weeks, extending to three months for drugs with long half-lives (Heuer et al., 2024; Pincus & McCalmont, 2019).
• When a single culprit cannot be identified, stop all nonessential medications while balancing the risk of withdrawing indispensable therapy (Heuer et al., 2024; Pincus & McCalmont, 2019).

Pathophysiology

• Extensive necrosis of skin and mucosal epithelium produces vesiculation and desquamation (Gohara et al., 2012; Pincus & McCalmont, 2019).
• Failure of the skin barrier creates a burn-like state with increased susceptibility to infectious and metabolic sequelae (Gohara et al., 2012; Pincus & McCalmont, 2019).

Clinical manifestations

• The eruption can include confluent erythema, dusky or gray-purple skin that signals impending necrosis, vesiculation, and extensive desquamation (Gohara et al., 2012; Pincus & McCalmont, 2019).
• Mucosal necrosis is an important component of the SJS/TEN spectrum. A positive Nikolsky sign may be present in a vesiculobullous eruption (Gohara et al., 2012; Pincus & McCalmont, 2019).

Findings that argue against or redirect

• Classic erythema multiforme is a separate disorder characterized by target-like lesions and often an infectious trigger rather than vast medication-associated skin and mucosal necrosis (Heuer et al., 2024; Pincus & McCalmont, 2019).
• Bullous pemphigoid produces tense subepidermal blisters through an autoimmune reaction against basement-membrane-zone proteins and generally has a more favorable prognosis (Heuer et al., 2024; Pincus & McCalmont, 2019).
• Staphylococcal scalded-skin syndrome, linear IgA bullous dermatosis, pemphigus, acute generalized exanthematous pustulosis, and generalized bullous fixed drug eruption are important alternatives (Heuer et al., 2024; Pincus & McCalmont, 2019).

Diagnostic evaluation

• Recognize the combination of medication exposure, dusky or confluent erythema, epidermal necrosis or desquamation, skin pain, and mucosal involvement. Estimate detached and detachable body-surface area to classify the syndrome (Heuer et al., 2024; Pincus & McCalmont, 2019).
• Obtain a skin biopsy for conventional histology and add direct immunofluorescence when the course is atypical or an autoimmune blistering disorder is possible (Heuer et al., 2024; Pincus & McCalmont, 2019).
• At initial evaluation, obtain CBC with differential, electrolytes, kidney and liver tests, CRP, and cultures or swabs when infection is suspected. Calculate SCORTEN within the first 24 hours and repeat on day 3 to support prognostic assessment (Heuer et al., 2024; Pincus & McCalmont, 2019).
• Arrange dermatology assessment within 24 hours. Obtain urgent ophthalmology evaluation when SJS/TEN is probable and involve gynecology, urology, pulmonology, or other specialties according to mucosal and organ involvement (Heuer et al., 2024; Pincus & McCalmont, 2019).

Expected diagnostic and laboratory findings

• Histology typically shows widespread keratinocyte necrosis that can progress to full-thickness epidermal necrosis and subepidermal separation. Direct immunofluorescence is usually negative and helps exclude autoimmune blistering disease (Heuer et al., 2024; Pincus & McCalmont, 2019).
• Laboratory abnormalities reflect severity and organ involvement rather than providing a single confirmatory test. Electrolyte disturbance, kidney or liver injury, cytopenia, inflammation, and infection may occur (Heuer et al., 2024; Pincus & McCalmont, 2019).

Differential diagnosis

• Erythema multiforme: target-like lesions, commonly associated with HSV, and classified separately from SJS/TEN (Heuer et al., 2024; Pincus & McCalmont, 2019).
• Bullous pemphigoid: tense subepidermal blisters with antibodies directed against basement-membrane-zone proteins (Heuer et al., 2024; Pincus & McCalmont, 2019).
• Staphylococcal scalded-skin syndrome: included among the major alternatives for confluent erythema and widespread superficial skin injury (Heuer et al., 2024; Pincus & McCalmont, 2019).

Treatment and management

• Stop the suspected culprit drug or drugs immediately. Transfer to an intensive-care or specialized burn center when warranted and provide coordinated dermatologic, critical-care, ophthalmologic, and mucosal care (Heuer et al., 2024; Paulmann et al., 2024).
• Supportive care is the cornerstone: manage airway, fluid and electrolytes, temperature, nutrition, pain, wounds, eyes, genitourinary mucosa, respiration, and infection surveillance. Avoid prophylactic systemic antibiotics unless infection is suspected or confirmed (Heuer et al., 2024; Paulmann et al., 2024).
• Systemic corticosteroids, cyclosporine, or etanercept may be considered in specialist-led care, but evidence is heterogeneous and treatment should follow current institutional and specialty guidance. Intravenous immunoglobulin monotherapy has not shown consistent benefit (Heuer et al., 2024; Paulmann et al., 2024).

Additional complications and red flags

• Sepsis, shock, acute kidney injury, respiratory epithelial involvement, multiorgan failure, and extensive barrier loss drive early mortality (Heuer et al., 2024; Paulmann et al., 2024).
• Ocular scarring and vision loss, oral and esophageal injury, genital and urinary adhesions or stenosis, chronic pain, pigment change, and psychological trauma can persist after recovery (Heuer et al., 2024; Paulmann et al., 2024).
• Document the culprit drug permanently and counsel against related re-exposure (Heuer et al., 2024; Paulmann et al., 2024).

Clinical Reasoning Priorities

• Recognize first: A painful, rapidly progressive dusky or targetoid eruption with mucosal erosions, epidermal blistering or detachment, fever, and recent medication exposure should be treated as possible Stevens-Johnson syndrome or toxic epidermal necrolysis until evaluated urgently (Gohara et al., 2012; Heuer et al., 2024).
• Reassess probability: Recent initiation or dose escalation of a high-risk medication, skin pain, prominent mucosal involvement, and epidermal detachment increase probability. A predominantly pruritic eruption without mucosal disease, tenderness, blistering, or systemic illness should redirect consideration toward another drug eruption or dermatosis (Heuer et al., 2024).
• Do not miss: Staphylococcal scalded skin syndrome, generalized bullous fixed drug eruption, DRESS, acute generalized exanthematous pustulosis, erythema multiforme major, autoimmune blistering disease, and thermal injury can resemble epidermal necrolysis and require different management (Heuer et al., 2024).
• Use decisive testing: Diagnosis is clinical and is supported by skin biopsy when morphology or the differential remains uncertain. Estimate detached and detachable body-surface area to classify SJS, overlap disease, or TEN, and use a validated severity assessment to inform prognosis and level of care (Heuer et al., 2024).
• Act on time-sensitive decisions: Stop all suspected culprit medications immediately and transfer the patient to an experienced intensive, burn, or dermatologic care setting when indicated. Begin meticulous fluid, temperature, wound, pain, nutritional, infection-surveillance, ocular, oral, and genitourinary supportive care while specialists determine whether systemic immunomodulating therapy is appropriate (Heuer et al., 2024; Paulmann et al., 2024).

Differentiate this condition from erythema multiforme when assessing mucocutaneous lesions. Review urgent dermatologic distinctions in the Infection, Immunodeficiency, and Inflammatory Skin Disorders Quiz.

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References

Gohara, M. A., Schaffer, J. V., Abbasi, N. R., Kingsley, M. M., Sheehan, J. M., & Arndt, K. A. (2012). Inflammatory dermatoses (rashes). In M. C. Henderson, L. M. Tierney, Jr., & G. W. Smetana (Eds.), The patient history: An evidence-based approach to differential diagnosis (2nd ed., pp. 239–255). McGraw-Hill Medical.

Heuer, R., Paulmann, M., Annecke, T., Behr, B., Boch, K., Boos, A. M., Brockow, K., French, L. E., Gille, J., Gundlach, V., Hartmann, B., Höger, P., Hofmann, S. C., Klein, T., Lehnhardt, M., Liß, Y., Maier, P., Mandel, P., Marathovouniotis, N., . . . Nast, A. (2024). S3 guideline: Diagnosis and treatment of epidermal necrolysis (Stevens-Johnson syndrome and toxic epidermal necrolysis) – Part 1: Diagnosis, initial management, and immunomodulating systemic therapy. JDDG: Journal der Deutschen Dermatologischen Gesellschaft, 22(10), 1448–1466. https://doi.org/10.1111/ddg.15515

Paulmann, M., Heuer, R., Annecke, T., Behr, B., Boch, K., Boos, A. M., Brockow, K., French, L. E., Gille, J., Gundlach, V., Hartmann, B., Höger, P., Hofmann, S. C., Klein, T., Lehnhardt, M., Liß, Y., Maier, P., Mandel, P., Marathovouniotis, N., . . . Nast, A. (2024). S3 guideline: Diagnosis and treatment of epidermal necrolysis (Stevens-Johnson syndrome and toxic epidermal necrolysis) – Part 2: Supportive therapy of EN in the acute and post-acute stages. JDDG: Journal der Deutschen Dermatologischen Gesellschaft, 22(11), 1576–1593. https://doi.org/10.1111/ddg.15516

Pincus, L. B., & McCalmont, T. H. (2019). Diseases of the skin. In G. D. Hammer & S. J. McPhee (Eds.), Pathophysiology of disease: An introduction to clinical medicine (8th ed.). McGraw-Hill Education.