Novel Treatments for Drug-Induced Toxic Epidermal Necrolysis (Lyell’s Syndrome)

Abstract

Drug-induced toxic epidermal necrolysis (TEN) is a life-threatening disease characterized by extensive destruction of the epidermis. It apparently results from the formation of specific toxic drug metabolites by the keratinocytes. The mortality rate which averages 25–30% is mainly due to secondary septicemia, and to ionic and metabolic disturbances following loss of epidermal integrity. Apoptosis is the likely mechanism leading to massive keratinocyte death in TEN. Dysregulations in the tumor necrosis factor-α (TNF-α) pathway, CD95 system (Fas ligand, CD95L; Fas receptor, CD95R) and calcium homeostasis in the epidermis are involved in this apoptotic process. An active role has also been ascribed to T lymphocytes, macrophages and factor XIIIa-positive dermal dendrocytes. Despite progress, treatment of TEN remains controversial. In the past, systemic glucocorticoids were used in order to target the inflammatory reaction in TEN. However, there was no evidence for improvement of the healing process, while corticosteroids worsened the prognosis by increasing the risk of septicemia. Only a few cases have been treated with other drugs including cyclophosphamide, pentoxyfilline, thalidomide, anti-TNF-α antibodies and cyclosporin A. In the recent past, some TEN patients were treated with intravenous human immunoglobulins (IVIG). The rationale for such a treatment was to block the CD95 system on keratinocytes. The early promising clinical results of IVIG treatment in TEN were subsequently challenged. This review compares the effectiveness and drawbacks of the major drugs presently used in TEN treatment. Some future prospects in TEN management are also discussed.

Toxic epidermal necrolysis: Revisiting the tentative link between early apoptosis and late necrosis (Review)

“…Conversely, treatments that only block the activities of the proinflammatory cytokines and receptors produced in TEN, without acting on the deregulation of the electron transport chain in mitochondriae will probably have a limited effect on the course of TEN. This may be the case for intravenous immunoglobulins, systemic corticosteroids, cyclosporine and anti-TNF-· agents (47). Until effective chemical treatments are developed that are able to neutralize the reactive electrophilic metabolites and to restore the electron transfer chain in TEN keratinocytes, we suggest that several blocking agents (e.g.…”

Analytical quantification of the inflammatory cell infiltrate and CD95R expression during treatment of drug-induced toxic epidermal necrolysis

“…To date, no cause other than drugs has been found in TEN although 5% of the cases remain ''idiopathic' ' [22]. The mortality rate, which is higher than 40% in patients with more than 30% skin detachment is mainly due to septicemia and metabolic disturbances following the loss of epidermal integrity [11].The mechanism leading to massive keratinocyte death in TEN is thought to be apoptosis [18]. Disregulations in the tumor necrosis factor-a (TNF-a) pathway, CD95 system (Fas ligand-CD95L, Fas receptor-CD95R) and calcium homeostasis in the epidermis are likely involved [18].…”

“…Indeed, TEN keratinocytes express large amounts of active CD95L able to induce apoptosis of CD95R-positive cells. CD95R, which belongs to the TNF/NGF receptor family is over-expressed in TEN epidermis.The TEN initiation phase leading to keratinocyte apoptosis is followed by an amplification phase involving inflammatory cells [18]. An active role has been ascribed to T lymphocytes, particularly CD4+ cells in the dermis and CD8+ cells in the epidermis.…”

“…Disregulations in the tumor necrosis factor-a (TNF-a) pathway, CD95 system (Fas ligand-CD95L, Fas receptor-CD95R) and calcium homeostasis in the epidermis are likely involved [18]. Indeed, TEN keratinocytes express large amounts of active CD95L able to induce apoptosis of CD95R-positive cells.…”

“…The TEN initiation phase leading to keratinocyte apoptosis is followed by an amplification phase involving inflammatory cells [18]. An active role has been ascribed to T lymphocytes, particularly CD4+ cells in the dermis and CD8+ cells in the epidermis.…”