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.     

3 Severe cutaneous adverse reactions time latency between beginning of drug use and onset of reaction

Background Toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS) are acute life‐threatening severe cutaneous adverse reactions (SCAR) with an unclear pathogenesis mainly caused by drugs. Allopurinol and trimethoprim/sulphamethoxazole (TMS) are both well known to be associated with these conditions. In addition, TMS is known to induce generalized bullous fixed drug eruption (GBFDE), a less severe condition with a very short induction period that is clinically often confused with SJS or TEN. Aim We want to further investigate the risk profile of allopurinol and TMS for inducing SCAR, as the hazard functions of these substances are different. Furthermore, the re‐review of cases using more specific criteria to differentiate between SCAR and GBFDE should allow us to detect misclassification of cases. Methods 984 cases of SJS, SJS/TEN overlap and TEN were ascertained by a population‐based registry between 1990 and 1999. The following analysis is based on a random sample of 115 cases earlier accepted as SJS or TEN, which were exposed to either allopurinol or TMS, and 38 cases excluded in the previous review. An independent expert committee blinded for possible causes re‐reviewed these cases in clinical terms, as the original review process took place over a period of 10 years. In this analysis special emphasis is given to the time latency between beginning of drug use and onset of SCAR. Results Before re‐review 162/984 patients with SCAR reported the use of allopurinol and 131/984 the use of TMS within 2 weeks prior to the onset of the adverse reaction. After the re‐review the percentage of doubtful cases was higher for TMS (28/57) than for allopurinol (30/83). For definite cases of SJS or TEN the range between the lower and upper quartile of the time latency between beginning of drug use and onset of SCAR was 14–34 days for allopurinol, in contrast to 5–15 days for TMS. The time latency for doubtful and excluded cases after the use of TMS was much shorter (2.5 and 2 days, respectively). Conclusions The high numberof doubtful cases after the re‐review reveals the difficulty of applying approved detailed definitions to the variety of clinical patterns of cutaneous adverse reactions. We could confirm a high correlation of time latency between beginning of drug use and onset of SCAR and GBFDE for allopurinol and TMS, which may have an important impact on the risk profile of these and other suspected drugs, as well as on pathogenetic and therapeutic considerations of severe adverse events. When drug exposure occurs outside the relevant interval of time latency for SJS and TEN, other risk factors and/or differential diagnoses such as GBFDE should be considered.     

Association between HLA-B*58:01 allele and severe cutaneous adverse reactions with allopurinol in Han Chinese in Hong Kong

Background Allopurinol has been reported as a common cause of severe cutaneous adverse reactions (SCARs). Recent studies in various populations suggest that HLA‐B*58:01 is a strong genetic marker for allopurinol‐induced SCAR, especially in populations with a high frequency of HLA‐B*58:01. Objectives To confirm the association link between HLA‐B*58:01 and hypersensitivity reactions attributed to allopurinol use in Han Chinese patients in Hong Kong. Methods We performed a case–control study to investigate whether the HLA‐B*58:01 allele predisposes to allopurinol‐induced SCAR in Han Chinese patients in Hong Kong. The HLA‐B*58:01 genotyping was performed in 20 patients with allopurinol‐induced SCAR or erythema multiforme major (EMM; n = 1) and in 30 patients tolerant to allopurinol. Results All of the 19 patients with allopurinol‐induced SCAR examined but not the patient with EMM carried HLA‐B*58:01 whereas only four (13%) of the control patients had this allele. The positive rate of the HLA‐B*58:01 was significantly higher in the cases than in the allopurinol‐tolerant control group [odds ratio (OR) 123·5, 95% confidence interval (CI) 12·8–1195·1; P < 1 × 10^?4] and was even higher after removal of the patient with EMM (OR 229·7, 95% CI 11·7–4520·4). The sensitivity and specificity of the HLA‐B*58:01 allele for prediction of allopurinol‐induced SCAR were 100% and 86·7%, respectively. Conclusions This study confirmed the strong association between the HLA‐B*58:01 and allopurinol‐induced SCAR in Hong Kong Han Chinese patients. A screening test for the HLA‐B*58:01 allele should effectively reduce the risk for allopurinol‐induced SCAR in Chinese populations.     

The association of HLA B*15:02 allele and Stevens–Johnson syndrome/toxic epidermal necrolysis induced by aromatic anticonvulsant drugs in a South Indian population

Background

The presence of HLA‐B*15:02 allele is considered a risk factor for development of Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in patients taking aromatic anticonvulsant drugs like carbamazepine and phenytoin. The genetic association is ethnicity specific. Testing for HLA‐B*15:02 allele is suggested as a prerequisite before starting carbamazepine in certain ethnic groups. There are only a few/no studies from south India on HLA association of SJS/TEN.

Aims

To identify any association between HLA‐B*15:02 allele and SJS/TEN induced by carbamazepine/phenytoin among native population.

Methods (including settings, design, and statistical analysis used)

A case–control study done in a tertiary care center at Kottayam in Kerala state of south India. Cases were 12 native patients who developed SJS/TEN owing to aromatic anticonvulsant drugs (phenytoin – 8; carbamazepine – 4), and controls were 11 persons tolerant to these drugs from unrelated families of the same ethnic group. HLA‐B typing was done by PCR SSP method.

Results

There was only one HLA‐B*15:02 carrier among cases and controls. He/she had SJS/TEN induced by carbamazepine.

Conclusions

Association of HLA‐B*15:02 with phenytoin‐induced SJS/TEN is rare in the population studied. The one limitation of the study was the small sample size.     

A patch testing and cross‐sensitivity study of carbamazepine‐induced severe cutaneous adverse drug reactions

Background The usefulness of the drug patch testing for Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) is still controversial. Recent studies have shown that HLA‐B*1502 is strongly associated with CBZ‐SJS/TEN in Chinese and Southeast Asian populations. Objective To evaluate the usefulness of patch tests for patients with carbamazepine (CBZ)‐induced SJS, TEN and drug reaction with eosinophilia and systemic symptoms (DRESS) and the cross‐reactivity in patch tests among the aromatic antiepileptic drugs. Methods We measure the frequency of positive patch test reactions and cross‐sensitivity to structure‐related aromatic anti‐epileptic drugs (AEDs) for patients after SJS/TEN or DRESS episodes caused by CBZ. CBZ and other structure‐related AEDs used for patch testing were prepared in 10% and 30% petrolatum. Secondary measures included the association of HLA‐B*1502 genotype and frequency of possible side effects from the patch tests. Results Positive patch test reactions to 30% CBZ in the CBZ‐SJS/TEN were 62.5% (10/16), and 70% (7/10) in the CBZ‐DRESS. None of the 10 healthy controls displayed a positive reaction to tested agents. Cross‐sensitivity to other aromatic AEDs was observed in both the CBZ‐SJS/TEN and the CBZ‐DRESS. Only the HLA‐B*1502 genotype was present and strongly associated with the CBZ‐SJS/TEN, but not with the CBZ‐DRESS. Conclusion Drug patch testing is a safe and useful method for the identification of CBZ as the culprit drug of SJS/TEN as well as DRESS. Testing of chemically or pharmacologically related AEDs may provide information on cross‐reactivity for these patients.     

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.     

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.     

Update on pathobiology in Stevens-Johnson syndrome and toxic epidermal necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are rare but life-threatening severe cutaneous adverse reactions (SCARs), which are mainly induced by a variety of drugs. Once considered to be unpredictable, significant progress has been achieved in understanding the pathological mechanisms underlying such reactions. Recent studies suggested that SJS/TEN is a specific immune reaction where human leukocyte antigen (HLA) alleles specific for certain drugs in defined populations are involved in the activation of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Upon the activation, various cytotoxic and immunological signals, including but not limited to Fas/Fas ligand, perforin/granzyme B, and granulysin are launched to mediate the disseminated keratinocyte death in SJS/TEN. This review provides an update on the pathobiology of SJS/TEN in both the genomic and immunologic perspectives. The knowledge gained from these cutting-edge studies will form the basis for better prevention and management of SJS/TEN.     

Pharmacogenetics of cutaneous adverse drug reactions

Drug-induced hypersensitivity reactions are of major medical concern because they are associated with high morbidity and high mortality. In addition, individual patients' reactions are impossible to predict in each patient. In the field of severe cutaneous adverse drug reactions (cutaneous ADR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug-induced hypersensitivity syndrome (DHIS) or drug rash with eosinophilia and systemic symptoms (DRESS), major advances have recently been gained through studies of an association between HLA alleles and drug hypersensitivity induced by specific drugs. The results of these pharmacogenomic studies allow prediction of the risk of adverse reactions in patients treated with certain drugs, including carbamazepine and other aromatic antiepileptic drugs, allopurinol and abacavir. However, different ethnic populations show variations in the genetic associations. A strong association between carbamazepine-induced SJS/TEN and HLA-B*1502 has been found in Southeast Asian patients but not in Caucasian and Japanese patients. Moderate associations between aromatic amine anticonvulsants and other HLA alleles have been proposed in Japanese patients. In contrast, HLA-B*5801 was found to be associated with allopurinol-induced cutaneous ADR, including SJS/TEN and DIHS/DRESS, in Caucasian and Asian patients, including the Japanese. These differences may, at least in part, be due to the differences in allele frequency in different ethnic populations. This article reviews the progress in pharmacogenomics, associated mainly with carbamazepine and allopurinol in different ethnic populations. Pharmacogenetic screening based on associations between adverse reactions and specific HLA alleles helps to avoid serious conditions associated with drug hypersensitivity.     

A multicentre study to determine the value and safety of drug patch tests for the three main classes of severe cutaneous adverse drug reactions

Background Drug patch tests (PTs) can reproduce delayed hypersensitivity to drugs and entail a moderate re‐exposure of patients to offending drugs. Objectives To determine the value of PTs for identifying the responsible drug in severe cutaneous adverse drug reactions (SCARs) such as acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Methods In a multicentre study, PTs were conducted on patients referred for DRESS, AGEP or SJS/TEN within 1 year of their SCAR. All drugs administered in the 2 months prior to and the week following the onset of the SCAR were tested. Results Among the 134 patients included (48 male, 86 female; mean age 51·7 years), positive drug PTs were obtained for 24 different drugs. These included positive tests for 64% (46/72) of patients with DRESS, 58% (26/45) of those with AGEP and 24% (4/17) of those with SJS/TEN, with only one relapse of AGEP. The value of PTs depended on the type of drug and the type of SCAR (e.g. carbamazepine was positive in 11/13 DRESS cases but none of the five SJS/TEN cases). PTs were frequently positive for beta lactams (22 cases), pristinamycin (11 cases) and in DRESS with pump proton inhibitors (five cases), but were usually negative for allopurinol and salazopyrin. Of 18 patients with DRESS, eight had virus reactivation and positive PTs. In DRESS, multiple drug reactivity was frequent (18% of cases), with patients remaining sensitized many years later. Conclusions PTs are useful and safe for identifying agents inducing SCAR.     

Epidermal necrolysis: 60 years of errors and advances

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare conditions characterized by extensive epidermal detachment and mucositis. Both are associated with a high mortality rate and significant long‐term morbidity. Since the initial report introducing the term TEN in 1956, diagnosis of the condition has been fraught with difficulties that continue to exist today. The terms ‘erythema multiforme major’ (EMM) and SJS, and their relationship to TEN have also been confusing to clinicians. It is now recognized that EMM is a different entity from SJS and TEN in terms of demographics, causality and severity. SJS and TEN represent a continuum of disease, and differ only by the extent of epidermal detachment and therefore severity. The term ‘epidermal necrolysis’ (EN) is used in this article to describe the spectrum of disease that includes SJS and TEN. Important advances in understanding the pathomechanism and treatment of EN have been made over the years. These include the recognition of human leucocyte antigen (HLA) associations (e.g. HLA‐B*1502 with carbamazepine‐induced TEN) and understanding of the pathogenic roles of drug‐specific cytotoxic T cells and granulysin. It was previously believed that widespread keratinocyte death in EN is predominantly mediated by soluble Fas‐ligand and that intravenous immunoglobulin therapy is useful in blocking this mechanism with resultant survival benefits. Further studies have since proven these theories to be incorrect. This short review describes the key advances in the terminology, classification, causality and treatment of EN, and identifies future priorities and challenges in the understanding and management of this condition.     

Incidence of Stevens–Johnson syndrome following combination drug use of allopurinol,carbamazepine and phenytoin in Taiwan: A case–control study

The goal of our study was to investigate the incidence of Stevens–Johnson syndrome (SJS), the frequency of SJS diagnosis, and the association between SJS and prior use of allopurinol, carbamazepine or phenytoin. This case–control study utilized data from the National Health Insurance Research Database (NHIRD) of Taiwan. Controls visited the emergency department of the same hospital for trauma or fractures (excluding burns) and used allopurinol, carbamazepine or phenytoin during the past 3 months. We determined whether patients were prescribed a combination of drugs in addition to allopurinol, carbamazepine or phenytoin within the last 3 months. We identified 1 853 985 controls and 7327 SJS‐diagnosed patients using the Taiwan NHIRD records for 2000–2008. Higher use of allopurinol (49.8%), carbamazepine (39.1%) or phenytoin (21.3%) was observed among patients (n = 3131) than among controls (n = 2858). The overall SJS incidence rate was 3.6/1 000 000. Drug combinations were uncommon (<10%) in patients or controls taking allopurinol. However, combination drug use exceeded 10% in patients taking carbamazepine or phenytoin. Logistic regression analysis of recent combination drug use revealed that phenobarbital, valproate, non‐steroidal anti‐inflammatory drugs (NSAIDs) including piroxicam and tenoxicam, and antibiotics including amoxicillin and cephalexin were strongly associated with SJS. Patients with gout or epilepsy taking allopurinol, carbamazepine or phenytoin should be evaluated carefully by physicians. Concurrent use of piroxicam, tenoxicam, phenobarbital, valproate, amoxicillin or cephalexin, in addition to carbamazepine or phenytoin, may increase the incidence of SJS.     

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.     

内蒙古汉族Stevens-Johnson综合征/中毒性表皮坏死松解症患者致敏药物及HLA基因筛查

【摘要】 目的 总结内蒙古汉族Stevens-Johnson综合征/中毒性表皮坏死松解症（SJS/TEN）患者致敏药物及筛查易感基因。方法 内蒙古医科大学附属医院皮肤科2015—2019年确诊的68例汉族SJS/TEN患者,抽取外周血提取DNA,采用PCR筛查HLA-B*5801、HLA-B*1502、HLA-A*3101等位基因。收集患者的临床资料,参照基因分型,分析致敏药物。结果 68例SJS/TEN患者,男36例,女32例,年龄46.06 ± 19.97（3 ~ 84）岁。检出HLA-B*5801阳性5例,4例为别嘌醇致敏;HLA-B*1502阳性14例,5例为卡马西平、4例为拉莫三嗪致敏,5例致敏/可疑致敏药物为抗菌药物、解热镇痛药等;HLA-A*3101阳性1例,可疑致敏药物为中药活血针剂,成分不清。结论 HLA-B*5801对别嘌醇、HLA-B*1502对卡马西平和拉莫三嗪的预测性良好,建议用药前筛查,而HLA-A*3101在本地区人群阳性率不高。     

HLA-A31 strongly associates with carbamazepine-induced adverse drug reactions but not with carbamazepine-induced lymphocyte proliferation in a Japanese population

Carbamazepine (CBZ) is the most frequent culprit drug for severe cutaneous adverse drug reactions (ADR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS). A strong association between human leukocyte antigen (HLA)-B*1502 and CBZ-induced SJS/TEN has been reported in Han Chinese, Thai, Malaysian and Indian populations, but not in Caucasian or Japanese populations. Recent studies showed an association between HLA-A*3101 and CBZ-induced ADR in Caucasian and Japanese populations. We conducted a case-control study to determine HLA genotyping of patients with CBZ-induced ADR in a Japanese population. Fifteen patients with CBZ-induced ADR and 33 subjects who had taken CBZ for more than 3 months without evidence of any ADR as a control were enrolled. In addition, the results of a CBZ-induced lymphocyte stimulation test were compared between the groups. A strong association was found between HLA-A31 and CBZ-induced ADR (P < 0.001), and a weak association was found between HLA-A11 and HLA-B51 with CBZ-induced ADR. No HLA-B*1502 was found in either patients or control subjects. The mean CBZ-induced lymphocyte stimulation index was significantly high in patients with CBZ-induced ADR compared with CBZ-tolerant patients (P < 0.001); however, no significant difference was seen between HLA-A31-positive subjects and HLA-A31-negative subjects in either group. These findings suggest that HLA-A31 is strongly associated with CBZ-induced ADR in the Japanese, but does not determine CBZ-induced lymphocyte proliferation.     

Severe Cutaneous Adverse Reactions: A Single-Center Retrospective Study of 173 Patients in China

BackgroundSevere cutaneous adverse reactions (SCAR) to drugs are a crucial public health issue and the use of systemic corticosteroids in SCAR has been controversial.ObjectiveTo analyze clinical features, causative drugs, treatment, outcomes, and prognostic factors of SCAR in the case-series of 173 patients, and add more information to the debate of using systemic corticosteroids in SCAR management.MethodsA retrospective study of 173 SCAR patients diagnosed with drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) or acute generalized exanthematous pustulosis (AGEP) at a tertiary care institution in China between January 2014 and December 2017 was conducted.ResultsOf 173 patients, allopurinol, carbamazepine, and antibiotics are the most frequently implicated drugs for DRESS (40.4%), SJS/TEN (26.0%), and AGEP (40.0%) respectively. Moreover, there is a strongly negative correlation between early corticosteroids use and the progression (p=0.000) and severity (p=0.01) of skin lesions. However, there is no association between early corticosteroids use and the mortality of SCAR (odds ratio: 1.01, 95% confidence interval: 0.95~1.08). In addition, lymphadenopathy, eosinophilia, and interval from onset to corticosteroids treatment were correlated with SCAR prognosis.ConclusionPrompt short-course systemic corticosteroids use is associated with early-stage skin lesions remission without influencing the disease mortality. Lymphadenopathy and eosinophilia were the independent poor prognostic factors of SCAR.     

Stevens–Johnson syndrome and toxic epidermal necrolysis due to anticonvulsants share certain clinical and laboratory features with drug‐induced hypersensitivity syndrome,despite differences in cutaneous presentations

Background. Drug‐induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is characterized by late disease onset, fever, rash, hepatic dysfunction, haematological abnormalities, lymphadenopathy and often, human herpesvirus (HHV) reactivation. The diagnosis of DIHS is based on the combined presence of these findings. Anticonvulsants are a major cause of DIHS and may also cause Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We examined whether SJS/TEN due to anticonvulsants display similar clinical and laboratory features seen in DIHS. Methods. Patients diagnosed with SJS or TEN due to anticonvulsants (n = 8) were examined and their clinical features and laboratory findings were compared with patients with anticonvulsant‐related DIHS (n = 6). Results. Seven of the eight patients with SJS/TEN developed symptoms > 3 weeks after starting anticonvulsants. Hepatic dysfunction was present in six patients with SJS/TEN and five patients with DIHS. Leucocytosis and/or eosinophilia was noted in seven patients with SJS/TEN and four patients with DIHS. Only one patient in the SJS/TEN group had atypical lymphocytosis; this was present in four patients with DIHS. Reactivation of HHV‐6 was detected in one of the four patients tested in the SJS/TEN group, although it was seen in five of the six patients with DIHS. Conclusions. TSJS/TEN due to anticonvulsants may exhibit some clinical and laboratory features of DIHS. The nature of the cutaneous involvement should be emphasized in the diagnosis of DIHS.     

Distinguishing between erythema multiforme major and Stevens-Johnson syndrome/toxic epidermal necrolysis immunopathologically

The early clinical presentations of Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are similar to that of erythema multiforme major (EMM). Cytotoxic molecules, especially granulysin, are expressed in the skin lesions of SJS/TEN and cause extensive keratinocyte death. It is postulated that the function of regulatory T cells (Treg) in SJS/TEN is inadequate. This study examined whether an immunohistological examination of cytotoxic molecules and the immunophenotype of Treg is useful for discriminating SJS from EMM in the early period. Over the past 9 years, the lesional skin of 14 patients with SJS/TEN and 16 patients with EMM was biopsied. Double immunofluorescence labeling of CD8 and granulysin, perforin, or granzyme B was performed, and immunohistochemical analyses of granulysin, perforin, granzyme B, CD1a, CD3, CD4, CD8, CD68 and Foxp3 were conducted using a highly sensitive indirect immunoperoxidase technique. The number of cells positive for each antibody per five high‐power fields was counted. The proportions of granulysin⁺ cells/CD8⁺ cells (P = 0.012) and perforin⁺ cells/CD8⁺ cells (P = 0.037) in SJS/TEN were significantly higher than in EMM. The number of Foxp3⁺ cells/five high‐power fields in SJS/TEN was significantly lower than in EMM (P = 0.004). Similarly, the number of CD4⁺ cells/five high‐power fields in SJS/TEN was significantly lower than in EMM (P = 0.0017). These data suggest that these panels of antibodies for labeling cytotoxic molecules, CD4 and Treg are useful for discriminating early SJS/TEN and EMM with a skin biopsy.     

Detection of HLA‐B*58:01, the susceptible allele for allopurinol‐induced hypersensitivity,by loop‐mediated isothermal amplification

Background Allopurinol, a common medication for gout treatment, can cause rare but life‐threatening severe cutaneous adverse reactions. A strong pharmacogenetic association of human leucocyte antigen (HLA)‐B*58:01 with allopurinol‐induced drug hypersensitivity has been reported, especially in the Han Chinese population. Objectives To develop a rapid and simple loop‐mediated isothermal amplification (LAMP) assay of HLA‐B*58:01 and evaluate its feasibility in predicting allopurinol‐induced drug hypersensitivity. Methods Two sets of LAMP primers targeting exons 2 and 3 of HLA‐B*58:01 were designed. DNA extracted from 20 clinical blood samples of patients with gout was used to evaluate the effectiveness of the two LAMP primer sets for the detection of HLA‐B*58:01. Results The results were compared with routine clinical genotyping methods. All extracted DNA samples tested with the HLA‐B*58:01 LAMP assay showed agreement with the routine genotyping results. No amplifications were observed when unextracted blood samples were tested. Conclusions The HLA‐B*58:01 LAMP assay was confirmed to be simple, rapid and specific for the detection of HLA‐B*58:01, and therefore of potential value in the diagnosis of allopurinol‐induced hypersensitivity.     

Role of nanocrystalline silver dressings in the management of toxic epidermal necrolysis (TEN) and TEN/Stevens–Johnson syndrome overlap

Toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS) are severe mucocutaneous eruptions. There is currently no defined optimal approach to wound care. The objective of this study was to evaluate silver dressings in the wound‐care management of TEN and SJS/TEN syndrome overlap with a retrospective case review of nine patients with TEN and SJS/TEN overlap presenting to our institution. Nanocrystalline silver dressings appear to be useful in the rapid commencement of healing in these patients. TEN and SJS/TEN overlap are rare conditions. This contributed to a relatively small number of cases included in the study. The ease of application, antimicrobial properties and low frequency of change make nanocrystalline silver dressings ideal in TEN/SJS.