Toxic epidermal necrolysis associated with severe hypocalcaemia, and treated with cyclosporin

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.

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“…Only rare TEN cases have been treated with CSA in uncontrolled studies [84,85,86,87,88,89,90]. Beneficial effects were generally reported.…”

Section: Ten Treatmentsmentioning

confidence: 99%

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

Paquet

Pierard

Quatresooz³

2005

Int Arch Allergy Immunol

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“…Only a very limited number of cases have been treated with other drugs, such as cyclophosphamide [10, 11], pentoxifylline [12], thalidomide [13]and cyclosporin A (CsA) [14, 15, 16, 17]. The present paper reviews the background suggesting that CsA could be a good candidate to abate the evolving TEN process.…”

Section: Introductionmentioning

confidence: 99%

Would Cyclosporin A Be Beneficial to Mitigate Drug-Induced Toxic Epidermal Necrolysis?

Paquet¹,

Pierard²

1999

Dermatology

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Drug-induced toxic epidermal necrolysis (TEN) is a rare life-threatening disease whose mortality remains high. The treatment of the disease is badly settled. Several kinds of drugs have been tested, including systemic corticosteroids, cyclophosphamide, pentoxifylline and thalidomide, but without any clear-cut outcome. Cyclosporin A (CsA) has many inhibitory effects on the main cell populations involved in TEN (T lymphocytes, macrophages and keratinocytes). CsA could also act on tumor necrosis factor α metabolism, a cytokine which is important in TEN epidermal destruction. Moreover, apoptosis is the mechanism leading to keratinocyte death and CsA has antiapoptotic properties. CsA has already been used successfully on a limited series of TEN patients. We have reviewed the potential theoretical useful effects of CsA in TEN. We conclude that CsA could be a good candidate to reverse TEN progression.

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“…In vitro, CsA inhibits the drug-induced expression of CD95R and CD95L-mRNA and blocks drug-mediated apoptosis of some cell types [7]. Only few TEN cases have been treated with CsA in uncontrolled studies [1,9,12,21,25,26,32]. Clinical beneficial effects were generally reported, but not supported by specific biological evaluations.…”

mentioning

confidence: 99%

“…Cyclosporin A was also proposed for reversing TEN progression [1,9,12,15,21,25,26,32]. The suppressive action of CsA primarily targets T-cell functions, and it inhibits the macrophage activation [15].…”

mentioning

confidence: 99%

“…However, there was no evidence for a benefit in the healing process, while they worsened the prognosis by increasing the risk of septicemia [8]. Only a few case reports have reported other treatment modalities including cyclophosphamide [6], pentoxyfilline [23], thalidomide [31] and cyclosporin A (CsA) [1,9,12,15,18,21,25,26,32]. Although T lymphocytes are the main target of CsA, the drug could also somewhat prevent keratinocyte apoptosis in TEN [15].…”

mentioning

confidence: 99%

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

et al. 2005

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The treatment of drug-induced toxic epidermal necrolysis (TEN) remains unsatisfactory. Intravenous immunoglobulins (IVIg) and intravenous cyclosporin A (CsA) have shown some efficacy in short series of patients. We assessed the effects of IVIg and CsA on TEN lesional and apparently uninvolved skin using standard histology and immunohistochemistry. Cutaneous biopsies were taken from necrotic and clinically uninvolved TEN skin at admission (D1) before any treatment, and after a 5-day treatment (D5). Two IVIg-treated patients (0.75 g/kg/day), two CsA-treated patients (5 mg/kg/day) and two control patients only receiving supportive care were compared. Biopsies were examined by standard histology and immunohistochemistry using antibodies directed to CD68 antigen (macrophages), CD45R0 antigen (activated T lymphocytes), Factor XIIIa (dermal dendrocytes) and the CD95 receptor (apoptosis marker). The different cell densities were evaluated by computerized image analysis. The clinical outcomes with the different treatments were also recorded. There was no obvious difference in the duration of hospitalization in intensive care unit between the three groups but one patient passed away in each of the IVIg-and CsAgroups. At D5, no differences were found between the three groups in the histological and clinical rate of reepithelialization, and in the evolution of T lymphocyte, macrophage and dendrocyte densities in the epidermis and dermis. However, the expression of the CD95 receptor was similarly and strongly abated at D5 in the epidermis of IVIg-and CsA-treated patients, while it was conversely increased in the two patients under supportive care only. Such a difference was found both in necrotic and uninvolved sites. IVIg and CsA treatments thus appeared to exert no obvious effect on the inflammatory infiltrate, but both abated the expression of the CD95 receptor in the skin of TEN patients. This effect did not seem sufficient to fully reverse the clinical evolution of the disease. It is inferred that IVIg and CsA do not completely abate the TEN process.Keywords Toxic epidermal necrolysis AE Cyclosporin A AE Immunoglobulin Drug-induced toxic epidermal necrolysis (TEN) is a lifethreatening disease characterized by extensive destruction of the epidermis [5]. 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 epid...

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Toxic epidermal necrolysis associated with severe hypocalcaemia, and treated with cyclosporin

Cited by 33 publications

References 9 publications

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

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

Would Cyclosporin A Be Beneficial to Mitigate Drug-Induced Toxic Epidermal Necrolysis?

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

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