Comprehensive Survival Analysis of a Cohort of Patients with Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis
01 May 2013-Journal of Investigative Dermatology (ELSEVIER SCIENCE INC)-Vol. 133, Iss: 5, pp 1197-1204
TL;DR: This large-scale population-based follow-up study of Stevens-Johnson syndrome patients confirmed high in-hospital mortality and revealed a remarkable number of deaths after discharge, which could mainly be attributed to severe comorbidities and older age, whereas the impact of severity of reaction on the risk of death was limited to the first few weeks.
About: This article is published in Journal of Investigative Dermatology.The article was published on 2013-05-01 and is currently open access. It has received 306 citations till now. The article focuses on the topics: Mortality rate & Toxic epidermal necrolysis.
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TL;DR: Physicians' knowledge is essential to the improvement of diagnosis and management, and in the limitation and prevention of long-term sequelae.
289 citations
TL;DR: Diagnostics that measure serum granulysin and high-mobility group protein B1 (HMGB1) offer the potential to differentiate early TEN from other, less serious drug reactions, but these tests have not been validated and are not readily available.
Abstract: Toxic epidermal necrolysis (TEN) is a life-threatening, typically drug-induced, mucocutaneous disease. TEN has a high mortality rate, making early diagnosis and treatment of paramount importance. New but experimental diagnostic tools that measure serum granulysin and high-mobility group protein B1 (HMGB1) offer the potential to differentiate early TEN from other, less serious drug reactions, but these tests have not been validated and are not readily available. The mainstay of treatment for TEN involves discontinuation of the offending drug, specialized care in an intensive care unit or burn center, and supportive therapy. Pharmacogenetic studies have clearly established a link between human leukocyte antigen allotype and TEN. Human leukocyte antigen testing should be performed on patients of East Asian descent before the initiation of carbamezapine and on all patients before the initiation of abacavir. The effectiveness of systemic steroids, intravenous immunoglobulins, plasmapheresis, cyclosporine, biologics, and other agents is uncertain.
256 citations
Cites background or methods from "Comprehensive Survival Analysis of ..."
...Dyspigmentation is common after TEN, with both hyperpigmentation and hypopigmentation seen, and may take years to improve.(2,25) Other cutaneous sequelae include scarring, onycholysis and onychodystrophy, which usually resolve within several months, and the loss of fingernails, diffuse thinning of scalp hair, and pruritus....
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...A comprehensive survival analysis of SJS/TEN patients based on data collected in the European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) found that the mortality rate was 23% at 6 weeks and 34% at 1 year.(2) Sepsis leading to multiorgan failure is the most common cause of death, with additional morbidity from gastrointestinal bleeding, pulmonary embolism, myocardial infarction, and pulmonary edema....
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TL;DR: Although all analyses, including the unstratified model, had limitations, glucocorticosteroids and cyclosporine were the most promising systemic immunomodulating therapies for SJS/TEN.
Abstract: Importance Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are rare but severe adverse reactions with high mortality. There is no evidence-based treatment, but various systemic immunomodulating therapies are used. Objectives To provide an overview on possible immunomodulating treatments for SJS/TEN and estimate their effects on mortality compared with supportive care. Data Sources A literature search was performed in December 2012 for articles published in MEDLINE, MEDLINE Daily, MEDLINE Inprocess, Web of Science, EMBASE, Scopus, and the Cochrane Library (Central) from January 1990 through December 2012, and updated in December 2015, in the English, French, Spanish, and German languages looking for treatment proposals for SJS/TEN. Other sources were screened manually. Study Selection Initially, 157 randomized and nonrandomized studies on therapies (systemic immunomodulating therapies or supportive care) for SJS/TEN were selected. Data Extraction and Synthesis Relevant data were extracted from articles. Authors were contacted for further information. Finally, 96 studies with sufficient information regarding eligibility and adequate quality scores were considered in the data synthesis. All steps were performed independently by 2 investigators. Meta-analyses on aggregated study data (random-effects model) and individual patient data (IPD) (logistic regression adjusted for confounders) were performed to assess therapeutic efficacy. In the analysis of IPD, 2 regression models, stratified and unstratified by study, were fitted. Main Outcomes and Measures Therapy effects on mortality were expressed in terms of odds ratios (ORs) with 95% CIs. Results Overall, 96 studies (3248 patients) were included. Applied therapies were supportive care or systemic immunomodulating therapies, including glucocorticosteroids, intravenous immunoglobulins, cyclosporine, plasmapheresis, thalidomide, cyclophosphamide, hemoperfusion, tumor necrosis factor inhibitors, and granulocyte colony-stimulating factors. Glucocorticosteroids were associated with a survival benefit for patients in all 3 analyses but were statistically significant in only one (aggregated data: OR, 0.5; 95%% CI, 0.3-1.01; IPD, unstratified: OR, 0.7; 95% CI, 0.5-0.97; IPD, stratified: OR, 0.8; 95% CI, 0.4-1.3). Despite the low patient size, cyclosporine was associated with a promising significant result in the only feasible analysis of IPD (unstratified model) (OR, 0.1; 95% CI, 0.0-0.4). No beneficial findings were observed for other therapies, including intravenous immunoglobulins. Conclusions and Relevance Although all analyses, including the unstratified model, had limitations, glucocorticosteroids and cyclosporine were the most promising systemic immunomodulating therapies for SJS/TEN. Further evaluation in prospective studies is required. However, this work provides a comprehensive overview on proposed systemic immunomodulating treatments for SJS/TEN, which is of great relevance for treating physicians.
231 citations
TL;DR: The understanding of the pathogenesis of SJS/TEN has improved: drug-specific T cell-mediated cytotoxicity, genetic linkage with HLA- and non-HLA-genes, TCR restriction, and cytot toxicity mechanisms were clarified.
Abstract: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are considered a delayed-type hypersensitivity reaction to drugs. They represent true medical emergencies and an early recognition and appropriate management is decisive for the survival. SJS/TEN manifest with an “influenza-like” prodromal phase (malaise, fever), followed by painful cutaneous and mucous membrane (ocular, oral, and genital) lesions, and other systemic symptoms. The difference between SJS, SJS/TEN overlap, and TEN is defined by the degree of skin detachment: SJS is defined as skin involvement of 30%, and SJS/TEN overlap as 10–30% skin involvement. The diagnosis of different degrees of epidermal necrolysis is based on the clinical assessment in conjunction with the corresponding histopathology. The mortality rates for SJS and TEN have decreased in the last decades. Today, the severity-of-illness score for toxic epidermal necrolysis (SCORTEN) is available for SJS/TEN severity assessment. Drugs with a high risk of causing SJS/TEN are anti-infective sulfonamides, anti-epileptic drugs, non-steroidal anti-inflammatory drugs of the oxicam type, allopurinol, nevirapine, and chlormezanone. Besides conventional drugs, herbal remedies and new biologicals should be considered as causative agents. The increased risk of hypersensitivity reactions to certain drugs may be linked to specific HLA antigens. Our understanding of the pathogenesis of SJS/TEN has improved: drug-specific T cell-mediated cytotoxicity, genetic linkage with HLA- and non-HLA-genes, TCR restriction, and cytotoxicity mechanisms were clarified. However, many factors contributing to epidermal necrolysis still have to be identified, especially in virus-induced and autoimmune forms of epidermal necrolysis not related to drugs. In SJS/TEN, the most common complications are ocular, cutaneous, or renal. Nasopharyngeal, esophageal, and genital mucosal involvement with blisters, erosions as well as secondary development of strictures also play a role. However, in the acute phase, septicemia is a leading cause of morbidity and fatality. Pulmonary and hepatic involvement is frequent. The acute management of SJS/TEN requires a multidisciplinary approach. Immediate withdrawal of potentially causative drugs is mandatory. Prompt referral to an appropriate medical center for specific supportive treatment is of utmost importance. The most frequently used treatments for SJS/TEN are systemic corticosteroids, immunoglobulins, and cyclosporine A.
207 citations
Cites background from "Comprehensive Survival Analysis of ..."
...correlation to comorbidities, but not to the disease severity [161]....
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TL;DR: Predictors of mortality included increasing age, increasing number of chronic conditions, infection, hematological malignancy (non-Hodgkin's lymphoma, leukemia), and renal failure, and further studies are needed to confirm mortality findings to improve prognostication of SJS/TEN.
200 citations
Cites background or result from "Comprehensive Survival Analysis of ..."
...Mortality for SJS/TEN is considerable and has been reported to be between 10-34% (Kim et al., 2012; Sekula et al., 2013); controversy exists as to whether newer treatments, such as intravenous immunoglobulin, actually decrease mortality (Schneck et al., 2008)....
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...Other predictors included female sex, which is consistent with previous studies (Sekula et al., 2013), and younger age in adults....
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...An international registry study of 460 patients with SJS, SJS/TEN and TEN found that mortality rates increased over time to 1-year mortality rates of 24%, 43% and 49%, respectively (Sekula et al., 2013)....
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...However, they are components of the APACHE II (part: chronic health classification), which is a validated severity scoring system applied to severely ill patients, and that was found as a risk factor for in-hospital death in patients with TEN (Knaus et al., 1985; Palmieri et al., 2002)....
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