Toxic epidermal necrolysis: Part I. Introduction, history, classification, clinical features, systemic manifestations, etiology, and immunopathogenesis
01 Aug 2013-Journal of The American Academy of Dermatology (J Am Acad Dermatol)-Vol. 69, Iss: 2, pp 1-3
TL;DR: Recent studies have implicated granulysin in toxic epidermal necrolysis apoptosis and have suggested that it may be the pivotal mediator of keratinocyte death.
Abstract: Toxic epidermal necrolysis is a life-threatening, typically drug-induced mucocutaneous disease. It is clinically characterized as a widespread sloughing of the skin and mucosa, including both external and internal surfaces. Histologically, the denuded areas show full thickness epidermal necrosis. The pathogenic mechanism involves antigenic moiety/metabolite, peptide-induced T cell activation, leading to keratinocyte apoptosis through soluble Fas ligand, perforin/granzyme B, tumor necrosis factor–alfa, and nitric oxide. Recent studies have implicated granulysin in toxic epidermal necrolysis apoptosis and have suggested that it may be the pivotal mediator of keratinocyte death.
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TL;DR: In this article, the authors present characteristics and subgroup analyses from the first 1257 patients enrolled in the study, and conclude that there are no differences in outcomes of patients with short vs long latency of DILI.
576 citations
TL;DR: Treatment focuses on removal of the causative drug, supportive care, infection prevention, and the often beneficial use of a potent topical steroid.
Abstract: Acute generalized exanthematous pustulosis is a severe cutaneous adverse reaction characterized by the rapid development of nonfollicular, sterile pustules on an erythematous base. It is attributed to drugs in the majority of cases. Antibiotics are the most common cause of acute generalized exanthematous pustulosis; however, a wide variety of drugs has been associated with this condition. Typically, within 48 hours of ingesting the causative medication, there is acute onset of fever and pustulosis with leukocytosis. In severe cases there can be mucous membrane and systemic organ involvement. Histologic findings include intracorneal, subcorneal, and/or intraepidermal pustules with papillary dermal edema containing neutrophils and eosinophils. Treatment focuses on removal of the causative drug, supportive care, infection prevention, and the often beneficial use of a potent topical steroid.
218 citations
TL;DR: A case of SCAR is reported in an 86-year-old patient probably induced by allopurinol and simultaneously fulfilling the diagnostic criteria for DRESS and SJS, thus considered as an overlapping case ofSCARs.
Abstract: Drug-induced severe cutaneous adverse reactions (SCARs) include acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS), and epidermal necrolysis (Ste
200 citations
TL;DR: This review summarizes up-to-date insights on SJS/TEN and describes a protocol for assessment and treatment, and it is hoped these suggested guidelines serve as a practical clinical tool in the management of SJS /TEN.
Abstract: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening mucocutaneous reactions, predominantly drug induced. The mortality rates for SJS and TEN are as high as 30 %, and short- and long-term morbidities are very common. SJS/TEN is one of the few dermatological diseases that constitute a true medical emergency. Early recognition and prompt and appropriate management can be lifesaving. In recent years, our understanding of the pathogenesis, clinical presentation, and management of SJS/TEN has improved. Nevertheless, in 2015, there are still no internationally accepted management guidelines. This review summarizes up-to-date insights on SJS/TEN and describes a protocol for assessment and treatment. We hope these suggested guidelines serve as a practical clinical tool in the management of SJS/TEN. The classic manifestation of SJS/TEN consists of initial "flu-like" symptoms (malaise, fever, anorexia) in the prodromal phase, followed by cutaneous and mucous membrane (ocular, oral, and genital) inflammation and pain, and other systemic involvement. Symptoms usually begin 4-28 days after the onset of drug intake. Treatment is multidisciplinary and includes identification and withdrawal of the culprit drug, transfer to a specialist unit, supportive care, medical treatment, communication, and provision of appropriate information and emotional support.
150 citations
TL;DR: In addition to immune mechanism, metabolism has been found to play a role in the pathogenesis of SCAR, such as recent findings of strong association of CYP2C9*3 with phenytoin‐induced SCAR and impaired renal function with allopurinol SCAR.
Abstract: The clinical manifestations of drug eruptions can range from mild maculopapular exanthema to severe cutaneous adverse drug reactions (SCAR), including drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) which are rare but occasionally fatal. Some pathogens may induce skin reactions mimicking SCAR. There are several models to explain the interaction of human leukocyte antigen (HLA), drug and T-cell receptor (TCR): (i) the "hapten/prohapten" theory; (ii) the "p-i concept"; (iii) the "altered peptide repertoire"; and (iv) the "altered TCR repertoire". The checkpoints of molecular mechanisms of SCAR include specific drug antigens interacting with the specific HLA loci (e.g. HLA-B*15:02 for carbamazepine-induced SJS/TEN and HLA-B*58:01 for allopurinol-induced SCAR), involvement of specific TCR, induction of T-cell-mediated responses (e.g. granulysin, Fas ligand, perforin/granzyme B and T-helper 1/2-associated cytokines) and cell death mechanism (e.g. miR-18a-5p-induced apoptosis; annexin A1 and formyl peptide receptor 1-induced necroptosis in keratinocytes). In addition to immune mechanism, metabolism has been found to play a role in the pathogenesis of SCAR, such as recent findings of strong association of CYP2C9*3 with phenytoin-induced SCAR and impaired renal function with allopurinol SCAR. With a better understanding of the mechanisms, effective therapeutics and prevention for SCAR can be improved.
149 citations
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TL;DR: This work was supported in part by Grants-in-Aid from the Ministry of Education, Science, and Culture of Japan and by a Research Grant from the Princess Takamatsu Cancer Research Fund, and performed in part through Special Coordination Funds of the Science and Technology Agency of the Japanese Government.
5,054 citations
TL;DR: This paper showed that there is a strong association in Han Chinese between the human leukocyte antigen HLA-B*1502 and Stevens-Johnson syndrome induced by carbamazepine, a drug commonly prescribed for the treatment of seizures.
Abstract: Stevens-Johnson syndrome and the related disease toxic epidermal necrolysis are life-threatening reactions of the skin to particular types of medication. Here we show that there is a strong association in Han Chinese between a genetic marker, the human leukocyte antigen HLA-B*1502, and Stevens-Johnson syndrome induced by carbamazepine, a drug commonly prescribed for the treatment of seizures. It should be possible to exploit this association in a highly reliable test to predict severe adverse reaction, as well as for investigation of the pathogenesis of Stevens-Johnson syndrome.
1,557 citations
TL;DR: This study suggests that an illustrated atlas is a useful tool for standardizing the diagnosis of acute severe bullous disorders that are attributed to drugs or infectious agents.
Abstract: • Background and Design.— To conduct a prospective case-control study about causative factors of severe bullous erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, we needed to define criteria for classifying the cases and standardize the collection of data so that cases could be reliably diagnosed according to this classification. Based on review of case histories and photographs of patients, a group of experts proposed a classification based on the pattern of erythema multiforme—like lesions (categorized as typical targets, raised or flat atypical targets, and purpuric macules) and on the extent of epidermal detachment. An atlas illustrating this classification that included photographs and schematic drawings was developed. We compared the evaluations of 28 cases by four nonphysicians relying on the atlas with the evaluations of the same cases by five experts not using the atlas to determine the usefulness of this atlas for classifying cases according to our nosologic schema. Results.— The following consensus classification in five categories was proposed: bullous erythema multiforme , detachment below 10% of the body surface area plus localized "typical targets" or "raised atypical targets"; Stevens-Johnson syndrome , detachment below 10% of the body surface area plus widespread erythematous or purpuric macules or flat atypical targets; overlap Stevens-Johnson syndrome— toxic epidermal necrolysis , detachment between 10% and 30% of the body surface area plus widespread purpuric macules or flat atypical targets; toxic epidermal necrolysis with spots , detachment above 30% of the body surface area plus widespread purpuric macules or flat atypical targets; and toxic epidermal necrolysis without spots , detachment above 10% of the body surface area with large epidermal sheets and without any purpuric macule or target. Using the atlas, the nonexperts showed excellent agreement with the experts. Conclusion.— This study suggests that an illustrated atlas is a useful tool for standardizing the diagnosis of acute severe bullous disorders that are attibuted to drugs or infectious agents. Whether the five categories proposed represent distinct etiopathologic entities will require further epidemiologic and laboratory investigations. ( Arch Dermatol. 1993;129:92-96)
1,449 citations
TL;DR: In this population of HIV-1-positive individuals, withholding abacavir in those with HLA-B*5701, H LA-DR7, and Hla-DQ3 should reduce the prevalence of hypersensitivity from 9% to 2.5% without inappropriately denying abacvir to any patient.
1,366 citations
TL;DR: Risks were increased for trimethoprim–sulfamethoxazole and other sulfonamide antibiotics, chlormezanone, quinolones, and aminopenicillins among drugs usually used for short periods.
Abstract: Background Toxic epidermal necrolysis and Stevens–Johnson syndrome are rare, life-threatening, drug-induced cutaneous reactions. We conducted a case–control study to quantify the risks associated with the use of specific drugs. Methods Data were obtained through surveillance networks in France, Germany, Italy, and Portugal. Drug use before the onset of disease was compared in 245 people who were hospitalized because of toxic epidermal necrolysis or Stevens–Johnson syndrome and 1147 patients hospitalized for other reasons (controls). Crude relative risks were calculated and adjusted for confounding by multivariate methods when numbers were large enough. Results Among drugs usually used for short periods, the risks were increased for trimethoprim–sulfamethoxazole and other sulfonamide antibiotics (crude relative risk, 172; 95 percent confidence interval, 75 to 396), chlormezanone (crude relative risk, 62; 21 to 188), aminopenicillins (multivariate relative risk, 6.7; 2.5 to 18), quinolones (multivariate rel...
1,219 citations