Toxic Epidermal Necrolysis(TEN)

is a rare, potentially fatal, adverse drug reaction characterized by tenderness and erythema of the skin and mucosa, and extensive mucocutaneous exfoliation.

• This exfoliation is due to extensive death of keratinocytes via apoptosis.

Incidence: 0.4 to 1.2 cases per million per year.

Spectrum of Drug Reactions: SJS to TEN

• Spectrum of adverse cutaneous drug reactions with increasing severity and extent of epidermal detachment associated with increased mortality.

• SJS: < 10% BSA; 1-5% mortality• SJS-TEN overlap: 10-30% BSA• TEN: > 30% skin detachment; 25-35%

mortality.

Causative Agents

• More than 100 different drugs have been associated with TEN.

• Most frequently incriminated drugs:

• Antibiotics (quinolones, aminopenicillins, tetracyclines, cephalosporins, imidazole antifungal agents)

• NSAIDS

• Anticonvulsants

• Allopurinol

Clinical Features

Figure 22.4 Cutaneous features of toxic epidermal necrolysis (TEN). A Characteristic dusky-red color of the early macular eruption in TEN. Lesions with this color often progress to full-blown necrolytic lesions with dermo-

epidermal detachment. B Positive Nikolsky sign: epidermal detachment reproduced by mechanical pressure on an area of erythematous skin.

Clinical Features

Figure 22.5 Clinical features of toxic epidermal necrolysis (TEN). A Detachment of large sheets of necrolytic epidermis (&gt;30% body surface area), leading to extensive areas of denuded skin. B Hemorrhagic crusts with

mucosal involvement. C Epidermal detachment of palmar skin.

Treatment• Optimal medical management requires early diagnosis,

immediate discontinuation of the causative drug(s), and supportive care.

• Careful daily wound care, hydration, and nutritional support are essential, and preferably, done in an ICU.

• No specific treatments for TEN have met evidence-based medicine standards of acceptance.

• The use of corticosteroids is controversial and they may even increase mortality.

Pathophysiology• Exfoliation in TEN is due to extensive keratinocyte cell

death via apotosis.

• Apotosis is mediated by interaction of the death receptor Fas and its ligand, FasL (CD95L).

• Increased FasL expression in TEN.

• The molecular mechanism by which culprit drugs up-regulate keratinocyte FasL expression in TEN is currently unknown.

• FasL activity can be blocked with monoclonal Abs that interfere with the interaction of Fas and FasL rationale for molecular strategies to treat TEN.

Fas-mediated Keratinocyte Apoptosis in TEN and Potential Mechanism of Inhibition by IVIG

In 1998, it was reported that IVIG contains Abs that are able to block the binding of FasL to Fas, thus inhibiting Fas-mediated keratinocyte apoptosis in vitro.

(French et al., 2006)

Histology

Figure 22.1 Histology of toxic epidermal necrolysis (TEN). A Histology of an early-stage lesion of TEN. Arrows: apoptotic keratinocytes. B Histology of a late-stage lesion of TEN featuring separation of the epidermis from the dermis, and full-thickness necrosis of the epidermis.