Toxic Epidermal Necrolysis Kristine Scruggs, MD AM Report July 28, 2009

Definition SJS/TEN:  Lesions: Small blisters on dusky purpuric macules or atypical targets  Mucosal involvement common  Prodrome of fever and malaise common Stevens-Johnson Syndrome:  Rare areas of confluence.  Detachment </= 10% BSA Toxic Epidermal Necrolysis:  Confluent erythema is common.  Outer layer of epidermis separates easily from basal layer with lateral pressure.  Large sheet of necrotic epidermis often present.  >30% BSA involved.

Presentation Fever (often >39) and flu-like illness 1-3 days before mucocutaneous lesions appear Confluent erythema Facial edema or central facial involvement Lesions are painful Palpable purpura Skin necrosis, blisters and/or epidermal detachment Mucous membrane erosions/crusting, sore throat Visual Impairment (secondary to ocular involvement) Rash 1-3 weeks after exposure, or days after 2 nd exposure

Epidemiology 2-7/million people/year SJS: age 25-47, TEN: age Women: >60% Poor prognosis:  Intestinal/Pulmonary involvement  Greater extent of detachment  Older age Mortality:  SJS: 5%  TEN: 30% Risk Factors:  HIV infection  Genetic factors Certain HLA types “Slow acetylators” Polymorphisms in IL4 receptor gene  Concomitant viral infections  Underlying immunologic diseases  Physical factors UV light, radiation therapy  Malignancy  Higher doses of known offenders

Pathogenesis Secondary to cytotoxicity and delayed hypersensitivity reaction to the offending agent. Antigen is either the implicated drug or a metabolite. Histopathology:  Granulysin (cytolytic protein produced by cytotoxic T cells and NK cells)  Expression of HLA-DR and intracellular adhesion molecule (ICAM)-1 by Keratinocytes CD4 cells (in dermis) CD8 T cells (in epidermis)  Apoptosis of keratinocytes facilitated by TNF-alpha, perforin and granzyme secretion fas-ligand expression (cell death receptor) Subepidermal split with cell-poor bullous. Epidermis shows full thickness necrosis.

Etiologies Medications (Odds Ratio for exposure in hospitalized pts):  Sulfonamide antibiotics (172)  Allopurinol (52)  Amine antiepileptics Phenytoin (53) Carbamazepine (90)  Lamotrigine  NSAIDs (72) Infections (e.g. Mycoplasma pneumonia) Other: Vaccinations, Systemic diseases, Chemical exposure, Herbal medicines, Foods

Differential Diagnosis for Vesicular or Bullous Rash Bullous Pemphigoid Often affects the elderly Dermatitis Herpetiformis Associated with gluten intolerance Cicatricial Pemphigoid Mucosal involvement, sometimes cutaneous Pemphigus Affects middle-aged or elderly

Differential Diagnosis, cont. Linear IgA Disease Itchy, ring-shaped, no internal disease Contact Dermatitis Varicella/Zoster Virus Herpes Simplex Virus Hand-Foot-Mouth Disease (Enteroviruses)

Differential Diagnosis, cont. Erythema Multiforme Staphylococcal Scalded Skin Syndrome Bullous Impetigo Toxic Shock Syndrome Paraneoplastic Pemphigus Cutaneous emboli Diabetic Bullae Porphyria Cutanea Tarda Porphyria Variegata Pseudoporphyria Bullous dermatosis of Hemodialysis Coma Bulloae Epidermolysis Bullosa Acquisita

Treatment Early diagnosis - biopsy Immediate discontinuation of offending agent Supportive care – pay close attention to ocular complications  IV hydration (e.g. Parkland formula)  Antihistamines  Analgesics  Local v. systemic corticosteroids  Think about nursing requirements! Possible treatment in burn unit, wound care IVIg?

Prognosis Independent Prognosis FactorsWeight Age>/= 40 years1 MalignancyYes1 BSA Detached>/= 10%1 Tachycardia>/= 120/min1 Serum urea>10 mmol/l1 Serum glucose>14 mmol/l1 Serum bicarbonate<20 mmol/l1 SCORTEN #7

Resources: Cooper, et al. The Washington Manual of Medical Therapeutics, 32 nd Edition High, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae. Up To Date Kasper, et al. Harrison’s Principles of Internal Medicine, 16 th Edition Nirken, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: Clinical manifestations, pathogenesis, and diagnosis. Up To Date