Recent advances in the genetics and immunology of Stevens-Johnson syndrome and toxic epidermal necrosis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are rare but life-threatening severe cutaneous adverse reactions (SCARs), which are majorly (65-75%) induced by a variety of drugs. SJS/TEN could be recognized as SCARs or drug immune reactions, if the reactions are elicited by drugs. The recent studies suggested that SJS/TEN is a specific immune reaction initiated by the cytotoxic T lymphocytes (CTLs) via human leukocyte antigens (HLAs)-restricted pathway. The patho-mechanism involving HLA-restricted presentation of a drug or its metabolites for T-cell activation is supported by the findings of strong genetic associations with HLA alleles (e.g. HLA-B*15:02 and carbamazepine-SJS/TEN, and HLA-B*58:01 and allopurinol-SJS/TEN). However, the genetic associations of SJS/TEN or drug induced cutaneous immune reactions are complex, which are drug specific and ethnicity specific. The genetic polymorphisms and diversity of HLA alleles may provide different binding affinities for drug antigens to launch the activation of specific CTLs responses, further leading to the unique clinical manifestations in SJS/TEN. Fas-FasL and perforin/granzyme B have been advocated mediating the epidermal necrosis in SJS/TEN. Our recent study showed that granulysin, a cytotoxic protein produced by CTLs or natural killer (NK) cells, is the key mediator for disseminated keratinocyte death in SJS/TEN. From the point of view of a physician, the profounder understanding of the genetic predisposition and patho-mechanism we discover, the better strategies for prevention, clinical management, and therapeutic methods of SJS/TEN we can develop in the near future.     

Endothelial cell apoptosis in severe drug‐induced bullous eruptions

Background Toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS) are characterized by extensive keratinocyte apoptosis mediated by cytotoxic proteins. Similar features have been found in another severe dysimmune syndrome, allogeneic acute graft‐versus‐host disease, where endothelial cell apoptosis has been recently characterized. Objectives To determine whether endothelial cell apoptosis occurs in dermal vessels of TEN and SJS, and whether it is linked to expression of cytotoxic proteins. Methods Skin biopsies of eight patients with severe drug‐induced bullous eruptions (four TEN, four SJS), eight with drug‐induced urticaria and eight healthy controls were compared. Blood vessel damage was studied by electron microscopy and quantified by CD31 immunostaining. Apoptotic cells, characterized by electron microscopy, were quantified on terminal deoxyribonucleotidyl transferase‐mediated deoxyuridine triphosphate nick end labelling assay. Immunohistochemistry was also used to characterize and quantify inflammatory cells and granzyme B, tumour necrosis factor (TNF)‐α and Fas ligand (FasL) expression. Results Endothelial cell apoptosis was observed in all TEN and SJS cases: it occurred in 85% of the vessel sections. It occurred in one case of drug‐induced urticaria, in 5% of vessel sections, but not in healthy controls. Numbers of CD68+ macrophages and CD8+ T lymphocytes were significantly higher in TEN and SJS compared with both other groups; granzyme B and TNF‐α but not FasL were expressed. Conclusions Characterization of endothelial cell apoptosis in TEN and SJS is important to assess a factor worsening skin damage, with possible extension to other organs. It may also be useful for the development of novel therapeutic strategies.     

Sparfloxacin induced toxic epidermal necrolysis

Toxic epidermal necrolysis (TEN) is a life-threatening cutaneous adverse drug reaction. TEN is known to occur with the fluoroquinolone class of antibiotics, but only four cases of sparfloxacin induced TEN have been reported to the WHO database. This is another case report of sparfloxacin induced TEN.     

Toxic Epidermal Necrolysis Possibly Linked to Hyperacute Graft-versus-Host Disease after Allogeneic Bone Marrow Transplantation

Toxic epidermal necrolysis (TEN) is a severe blistering skin disease of high mortality. TEN may occur after bone marrow transplantation (BMT). In such cases, TEN have been attributed to graft-versus-host disease (GVHD) or an adverse drug reaction. It is very difficult to distinguish the causes of TEN after BMT. We report a 21-year-old Japanese man who developed TEN eight days after BMT, evaluate the differential diagnosis of hyperacute GVHD and an adverse drug reaction, and deduce that hyperacute GVHD was the more likely pathogenesis of TEN in this patient.     

In vivo dynamics of intraepidermal CD8+ T cells and CD4+ T cells during the evolution of fixed drug eruption

Background Although a severe form of fixed drug eruption (FDE) clinically and histologically mimics toxic epidermal necrolysis (TEN), subsequent evolution of the two conditions is quite different. It remains unknown, however, which factors determine whether these lesions resolve spontaneously or subsequently progress to TEN. Objectives Because epidermal injury in TEN can be locally reproduced in the evolving FDE lesions, we sought to investigate how epidermal damage can be induced in the evolving FDE lesions and how disease progression to TEN can be prevented, by analysing the FDE lesions induced by clinical challenge with the causative drug. Methods We immunohistochemically investigated in vivo dynamics of T‐cell trafficking and activation that occur in the evolving FDE lesions using sequential biopsy specimens obtained at multiple time points from the FDE lesions. Results Intraepidermal CD8+ T cells, which are resident in the lesional epidermis as a stable homogeneous population of memory T cells, transiently acquire a natural killer‐like phenotype and express cytotoxic granules upon activation. The influx into the epidermis of CD4+ T cells including Foxp3+ regulatory T cells (Tregs) during the evolution serves to ameliorate epidermal damage induced by activation of the intraepidermal CD8+ T cells. Interleukin‐15 derived from the lesional epidermis could maintain the survival of the intraepidermal CD8+ T cells even in the absence of antigenic stimulus over a prolonged period of time (> 4 years). Conclusions Whether Tregs could migrate to the lesions upon activation of intraepidermal CD8+ T cells would determine whether the inflammation becomes resolved spontaneously or progresses to TEN.     

Toxic epidermal necrolysis; 15 years'' experience in a Dutch burns centre

BACKGROUND: Toxic epidermal necrolysis (TEN) is a severe and potentially fatal drug reaction characterized by an extensive skin rash with blisters and exfoliation, frequently accompanied by mucositis. The wounds caused by TEN are similar to second-degree burns and severe cases may involve large areas of skin loss. OBJECTIVES: Analysis of our results in patients with TEN and evaluation of the variety of therapeutic interventions that has been studied and suggested in TEN. PATIENTS/METHODS: Retrospective analysis of 19 consecutive patients with TEN treated in our burns centre between 1989 and 2004. RESULTS: Immediate withdrawal of any potentially fatal drug, maximum supportive care, and a restricted and tailored antibiotic, medical and surgical treatment regimen confined mortality to 21%, whereas prognosis scores like APACHE II and SCORTEN predicted mortality of 22 and 30%, respectively. A positive contribution of selective digestive decontamination is suggested but has yet to be established. CONCLUSIONS: Because of a potentially fatal outcome, fast referral of a patient suspected of TEN to a specialized centre (mostly a burns unit or specialized dermatology centre) for expert wound management and tailored comprehensive care is strongly advised and contributes to survival.     

Cutaneous adverse drug reactions seen in a tertiary hospital in Johor,Malaysia

Background Adverse drug reactions are most commonly cutaneous in nature. Patterns of cutaneous adverse drug reactions (ADRs) and their causative drugs vary among the different populations previously studied. Objective Our aim is to determine the clinical pattern of drug eruptions and the common drugs implicated, particularly in severe cutaneous ADRs in our population. Materials and Methods This study was done by analyzing the database established for all adverse cutaneous drug reactions seen from January 2001 until December 2008. Results A total of 281 cutaneous ADRs were seen in 280 patients. The most common reaction pattern was maculopapular eruption (111 cases, 39.5%) followed by Stevens‐Johnson Syndrome (SJS: 79 cases, 28.1%), drug reaction with eosinophilia and systemic symptoms (DRESS: 19 cases, 6.8%), toxic epidermal necrolysis (TEN: 16 cases, 5.7 %), urticaria/angioedema (15 cases, 5.3%) and fixed drug eruptions (15 cases, 5.3%). Antibiotics (38.8%) and anticonvulsants (23.8%) accounted for 62.6% of the 281 cutaneous ADRs seen. Allopurinol was implicated in 39 (13.9%), carbamazepine in 29 (10.3%), phenytoin in 27 (9.6%) and cotrimoxazole in 26 (9.3%) cases. Carbamazepine, allopurinol and cotrimoxazole were the three main causative drugs of SJS/TEN accounting for 24.0%, 18.8% and 12.5% respectively of the 96 cases seen whereas DRESS was mainly caused by allopurinol (10 cases, 52.6%) and phenytoin (3 cases, 15.8%). Discussion The reaction patterns and drugs causing cutaneous ADRs in our population are similar to those seen in other countries although we have a much higher proportion of severe cutaneous ADRs probably due to referral bias, different prescribing habit and a higher prevalence of HLA‐B*1502 and HLA‐B*5801 which are genetic markers for carbamazepine‐induced SJS/TEN and allopurinol‐induced SJS/TEN/DRESS respectively. Conclusion The most common reaction pattern seen in our study population was maculopapular eruptions. Antibiotics, anticonvulsants and NSAIDs were the most frequently implicated drug groups. Carbamazepine and allopurinol were the two main causative drugs of severe ADRs in our population.     

Severe drug‐induced skin reactions: clinical pattern,diagnostics and therapy

The spectrum of severe drug‐induced skin reactions includes not only Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) but also generalized bullous fixed drug eruption (GBFDE), acute generalized exanthematous pustulosis (AGEP) and hypersensitivity syndrome (HSS), also called drug reaction with eosinophilia and systemic symptoms (DRESS). These reactions differ in clinical presentation as well as prognosis, causative agents and therapy. Therefore, the appropriate diagnostic measures should be undertaken rapidly, in order to prove the diagnosis. In addition to a thorough clinical examination, a skin biopsy should be taken and specific laboratory investigations should be done if AGEP or HSS/DRESS is suspected. Since these reactions are drug‐induced, the causative agent should be rapidly identified and withdrawn. Besides adequate supportive therapy, systemic immunomodulatory treatments may be considered. Despite intensive care management, the prognosis in SJS and TEN is often poor and influenced by the amount of skin detachment as well as the age of the patients and the pre‐existing underlying conditions. Severe sequelae may develop in survivors and affect especially mucosal sites. The prognosis of GBFDE is better but recurrent events may lead to more severe involvement. In HSS/DRESS sequelae have been also described as well as long lasting and recurrent courses, whereas AGEP usually heals without problems.     

Fatal toxic epidermal necrolysis due to lansoprazole

Toxic epidermal necrolysis (TEN) is a serious cutaneous reaction and is most commonly drug induced. It is associated with significant morbidity and mortality. We describe a patient who developed fatal TEN after re-exposure to lansoprazole. Three years previously he presented with erythema multiforme due to the same drug. To our knowledge this is the first published report of TEN occurring with lansoprazole.     

Severe flucloxacillin‐induced acute generalized exanthematous pustulosis (AGEP), with toxic epidermal necrolysis (TEN)‐like features: does overlap between AGEP and TEN exist? Clinical report and review of the literature

Acute generalized exanthematous pustulosis (AGEP) and Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) are rare but severe cutaneous adverse drug reactions. Especially in TEN, large areas of the skin and mucosae may become detached. Although AGEP and SJS/TEN are distinct entities with a different clinical picture, pathogenesis, prognosis and treatment, they may share some features, raising the hypothesis of overlap between both entities. We present a severe case of AGEP, caused by flucloxacillin, clinically presenting with TEN‐like features and pronounced systemic symptoms with haemodynamic and respiratory instability. Furthermore, we present a review of the literature on cases of AGEP with features resembling SJS/TEN or a supposed overlap with SJS/TEN.     

Granulocyte colony‐stimulating factor in toxic epidermal necrolysis (TEN) and Chelsea & Westminster TEN protocol

Background: Toxic epidermal necrolysis (TEN) is a rare but life‐threatening, allergic drug reaction. Skin blistering with epidermal and mucosal necrolysis with subsequent detachment from an inflamed underlying dermis is a hallmark of the condition. The pathogenesis of TEN is not well understood, accounting for controversies about its management and significant delay in initiating potentially beneficial therapy. There are no management protocols based on a robust evidence base. Objectives: Prompt recognition of the diagnosis and consensus on early management initiatives are necessary in order to improve outcomes and survival in TEN. To date, TEN management has been directed at arresting the allergic reaction and treating the complications. We have identified a need for specific medical interventions to accelerate wound regeneration. This approach has not previously been adopted in the management of TEN. Methods: We observed that in two cases of severe TEN, dramatic re‐epithelialization and recovery coincided with the introduction of granulocyte colony‐stimulating factor (G‐CSF) for neutropenia. We explain how addition of the G‐CSF promotes recovery from TEN by enhanced bioregeneration of the damaged tissues through accelerated re‐epithelialization. Conclusion: G‐CSF has been used for severe neutropenia in TEN, but we recommend and explain why, as in our Chelsea and Westminster protocol, G‐CSF should be considered in treating severe TEN irrespective of the severity of neutropenia.     

Differential diagnosis of severe cutaneous drug eruptions

Adverse cutaneous reactions to drugs are frequent, mostly secondary to antibacterials, however, serious adverse cutaneous reactions are infrequent. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are a spectrum of the same disease. They are the more severe drug eruptions, with a mortality around 30% for TEN. The confusion between erythema multiforme major and SJS means that erythema multiforme major is the main differential diagnosis. Skin disorders involving desquamation, in particular after pustulosis, are also common differential diagnoses. Mechanical or autoimmune blistering are also potential misdiagnoses of TEN/SJS. Hypersensitivity Syndrome (HSS) or Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) is a severe cutaneous drug reaction with often a long duration of eruption and serious other organ involvement. Exfoliative dermatitis, whether caused by psoriasis, dermatitis or lymphoma, can be thought of as a differential diagnosis of DRESS/HSS. Angio-immunoblastic lymphadenopathy, viral eruption and vasculitis are other differential diagnoses of DRESS/HSS. Prompt recognition of a severe drug reaction and withdrawal of the culprit drug is often the most important therapeutic action. Alternatively, a delay in starting a specific treatment for a disease misdiagnosed as a drug eruption could be deleterious.     

药物所致重症多形红斑和中毒性表皮坏死松解症的临床研究

对药物所致征症多形红斑（ＳＪＳ）和中毒性表皮松解症（ＴＥＮ）进行了对比研究。两者最常见的致敏解药物是解镇痛药，其次是抗生素类和镇静抗癫痫药。ＳＪＳ和ＴＥＮ的发病年龄、性别和潜伏期无差异，但ＴＥＮＲ 发热时间、急性期和恢复期时间明显长于ＳＪＳ，发热程度、粘膜损害程度和合并症发生率明显高于ＳＪＳ。ＳＪＳ预后良好，无１例死亡，ＴＥＮ的死亡率高达３９％。关于皮质类固醇激素在治疗ＴＥＮ中的应用，我们认为早期     

Toxic epidermal necrolysis: review of pathogenesis and management

Toxic epidermal necrolysis (TEN) is a severe cutaneous drug reaction with a mortality rate of approximately 30%. The hallmark of TEN is widespread epidermal sloughing due to keratinocyte apoptosis. Multiple genetic associations between TEN and specific ethnic populations have been determined. The pathophysiology of TEN has yet to be fully elucidated; however, current pathogenic models implicate Fas ligand, granulysin, and reactive oxygen species. The value of current therapies, such as intravenous immunoglobulin and corticosteroids, remains under evaluation.     

Fatal toxic epidermal necrolysis and severe granulocytopenia following therapy with cefuroxime

Toxic epidermal necrolysis (TEN) is one of the most threatening adverse reactions to various drugs. No case of concomitant occurrence TEN and severe granulocytopenia following the treatment with cefuroxime has been reported to date. Herein we present a case of TEN that developed eighteen days of the initiation of cefuroxime axetil therapy for urinary tract infection in a 73-year-old woman with chronic renal failure and no previous history of allergic diathesis. The condition was associated with severe granulocytopenia and followed by gastrointestinal hemorrhage, severe sepsis and multiple organ failure syndrome development. Despite intensive medical treatment the patient died. The present report underlines the potential of cefuroxime to simultaneously induce life threatening adverse effects such as TEN and severe granulocytopenia. Further on, because the patient was also taking furosemide for chronic renal failure, the possible unfavorable interactions between the two drugs could be hypothesized. Therefore, awareness of the possible drug interaction is necessary, especially when given in conditions of their altered pharmacokinetics as in case of chronic renal failure.     

Widespread Bullous Fixed Drug Eruption Mimicking Toxic Epidermal Necrolysis

This paper is written to heighten awareness of the presence of the most severe form of fixed drug eruption. Two patients with a widespread bullous form of fixed drug eruption (FDE) were initially given the diagnosis of toxic epidermal necrolysis (TEN). Both gave a history of a previous widespread eruption from the responsible drug, each had biopsies consistent with fixed drug eruption, and most importantly, both had an uncomplicated course, with complete cutaneous reepithelialization within 10 days. These observations suggest that widespread bullous fixed drug eruption may portend a more favorable prognosis than TEN, thus stressing the potential importance of distinguishing the two diseases. A review of fixed drug eruption and possible means of differentiating the widespread bullous form from TEN are discussed.     

Toxic epidermal necrolysis and Stevens-Johnson syndrome: soluble Fas ligand involvement in the pathomechanisms of these diseases

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are considered part of a spectrum of adverse cutaneous drug reactions showing severe and extensive skin detachment. TEN and SJS are morphologically characterized by active apoptotic keratinocyte cell death that results in the separation of the epidermis from the dermis. TEN is a life-threatening disease with a high mortality rate (20-30%). Although several therapies have been tried, there is no specific outstanding of generally accepted treatment for TEN at present. The pathogeneses of TEN and SJS have not yet been fully elucidated. We have demonstrated that high concentrations of soluble FasL (sFasL) are detected in TEN/SJS patients' serum samples and sFasL secreted by peripheral blood mononuclear cells interacts with the Fas expressed on diseased keratinocytes in TEN/SJS. Our data suggested sFasL is a prime candidate for therapeutic intervention, whereas a few recent papers have reported sFasL levels were not elevated in some TEN patients. An urgent review of the pathophysiology in TEN/SJS is needed to resolve this issue and to determine more effective treatment regimes.     

Schwere Arzneimittelreaktionen der Haut

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are severe drug-induced bullous skin reactions. They are rare, but often life-threatening and have a high mortality rate. Acute generalized exanthematous pustulosis (AGEP) is a severe cutaneous adverse reaction, but after the suspected drug is withdrawn, the skin heals rapidly and mortality is low. The clinical pattern, histology and inducing drugs differ substantially between AGEP and the SJS/TEN group.     

Association of HLA-B*1502 allele with carbamazepine-induced toxic epidermal necrolysis and Stevens-Johnson syndrome in the multi-ethnic Malaysian population

Background Carbamazepine (CBZ), a frequently used anticonvulsant drug, is one of the most common causes of life‐threatening cutaneous adverse drug reactions such as toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS). Recent studies have revealed a strong association between HLA‐B*1502 and CBZ‐induced TEN/SJS in the Taiwan Han Chinese population. Objectives This study is aimed to investigate the association between human leucocyte antigens (HLA) and CBZ‐induced TEN/SJS in the multi‐ethnic Malaysian population. Methods A sample of 21 unrelated patients with CBZ‐induced TEN/SJS and 300 race‐matched, healthy controls were genotyped for HLA‐A, ‐B and ‐DR using polymerase chain reaction (PCR). Allele frequencies were compared. Results HLA‐B*1502 was present in 75.0% (12/16) of Malay patients with CBZ‐induced TEN/SJS but in only 15.7% (47/300) of normal controls (odds ratio 16.15, 95% confidence interval 4.57–62.4; corrected P‐value = 7.87 × 10^?6), which suggests a strong association between HLA and CBZ‐induced TEN/SJS. Additionally, HLA‐B*1502 was found in all three Chinese and two Indian patients. Existing data show that frequencies of the HLA‐B*1502 allele are generally much higher in Asian populations than in White European populations, which explains the higher incidences of SJS and TEN in Asian countries. Conclusions HLA‐B*1502 is strongly associated with CBZ‐induced TEN/SJS in the Malay population in Malaysia, as has been seen in Han Chinese in Taiwan. This indicates that the genetic association apparent in the incidence of CBZ‐induced TEN/SJS is linked with the presence of HLA‐B*1502, irrespective of racial origin. Screening of patients for this genetic marker can help to prevent the occurrence of TEN/SJS.     

Differences in immunological alterations and underlying viral infections in two well-defined severe drug eruptions

Background. Similar drugs (e.g. anticonvulsants) have been implicated in the development of two distinct forms of severe cutaneous drug reactions, Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and drug–induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS). Aim. To investigate immunological alterations and underlying viral infections that could contribute to the variability in the clinical presentations of these diseases. Methods. We retrospectively analysed clinical variables, serum immunoglobulin levels, numbers of circulating white blood cells, lymphocytes and their subsets, serum levels of several cytokines, and underlying viral infections in both drug reactions, using samples obtained at onset from 9 patients with SJS/TEN and 19 patients with DIHS/DRESS. Results. There were significant differences between the two drug eruptions in the duration of drug intake before onset, the levels of IgG, IgA and IgM, the numbers of circulating white blood cell, lymphocyte, CD3+ T cell and CD8+ T cells, the serum levels of interferon-γ, and the titres of anti-herpes simplex virus IgG at onset. Conclusions. The difference in the pattern of immune responses shaped in part by previous and underlying viral infections at the time of drug exposure could cause a marked deviation in the pathological phenotype of severe drug eruptions. Elucidating these host factors may provide a basis for therapeutic approaches in patients with severe drug reactions.