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Abstract Background The relationship between the HLA-B*1502 gene and maculopapular exanthema (MPE) induced by antiepileptic drugs (AEDs) has not yet been elucidated. In this study, we investigated the association between AED-induced MPE (AED-MPE) and the HLA-B*1502 gene in patients in Northwest China. Methods We enrolled 165 subjects including nine patients with AED-MPE and 156 AED-tolerant patients as controls. HLA-B*1502 gene polymorphism was detected using digital fluorescence molecular hybridization (DFMH). The results of HLA genotyping were expressed as positive or negative for the HLA-B*1502 allele. An analysis of AED-MPE risk factors was performed using binary logistic regression, and differences in genotype frequencies between groups were assessed with the continuity correction chi-square test. Results We found that the HLA-B*1502 gene was a risk factor for AED-MPE (P = 0.028). The incidence of MPE induced by the two types of AEDs was different, and the incidence of aromatic AEDs use was higher that of non-aromatic AEDs use (P = 0.025). The comparison of the gene frequencies of the HLA-B*1502 allele between the two groups taking aromatic AEDs was also statistically significant (P = 0.045). However, there were no significant differences in terms of age, gender, ethnicity, or region in patients with MPE induced by AEDs. In addition, no association between the HLA-B1502 allele and CBZ- or OXC-induced MPE was found. Conclusions In northwestern China, the HLA-B*1502 allele was associated with aromatic AED-MPE. Since MPE can develop into Stevens–Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), the HLA-B*1502 gene should be evaluated before administering AEDs.

Background: Stevens-Johnson Syndrome (SJS) is an infrequent yet severe mucocutaneous reaction that involves less than 10% of the Body Surface Area (BSA). It is predominantly induced by certain medications, including anticonvulsants (e.g., Lamotrigine, Carbamazepine, Phenytoin, Phenobarbitone), Allopurinol at doses above 100 mg per day, and sulphonamides (e.g., Cotrimoxazole, Sulfasalazine). Genetic predispositions, particularly the presence of the HLA-B*1502 allele, significantly increase the risk of developing SJS. This case report discusses a unique presentation of SJS in a young female patient, emphasizing the critical need for genetic screening and careful monitoring when prescribing Carbamazepine, especially in populations at higher genetic risk., Case Presentation: A 19-year-old female patient, who had been on Phenytoin and Sodium Valproate for epilepsy management over the past year, was newly prescribed Carbamazepine. Within a week of initiating Carbamazepine, the patient experienced a seizure, followed by the sudden onset of fever, painful sores, and blisters covering the upper body, along with mucous discharge from both eyes. These symptoms rapidly worsened. Based on clinical presentations and the extent of epidermal detachment, the patient was diagnosed with SJS. The severity and mortality risks were assessed using the SCORTEN score. Therapeutic interventions included intravenous Ranitidine, Ondansetron, Paracetamol, Midazolam, Levetiracetam, and Dexamethasone, along with oral Fluconazole, Chlorpheniramine tablets, and Ciprofloxacin eye drops. The patient showed significant improvement and was discharged after fourteen days with followup advice., Conclusion: This case underscores the critical importance of performing genetic testing for the HLA-B*1502 allele and conducting baseline blood tests before initiating Carbamazepine therapy. Such precautionary measures can significantly mitigate the risk of severe adverse reactions like SJS. This report adds to the scientific literature by highlighting the potential dangers associated with anticonvulsant therapies and the necessity for personalized medicine approaches in preventing life-threatening conditions. The main takeaway is the pivotal role of genetic screening and vigilant monitoring in the management of patients requiring anticonvulsant medications to prevent serious adverse reactions., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The relationship between the HLA-B*1502 gene and maculopapular exanthema (MPE) induced by antiepileptic drugs (AEDs) has not yet been elucidated. In this study, we investigated the association between AED-induced MPE (AED-MPE) and the HLA-B*1502 gene in patients in Northwest China.Methods: We enrolled 165 subjects including nine patients with AED-MPE and 156 AED-tolerant patients as controls. HLA-B*1502 gene polymorphism was detected using digital fluorescence molecular hybridization (DFMH). The results of HLA genotyping were expressed as positive or negative for the HLA-B*1502 allele. An analysis of AED-MPE risk factors was performed using binary logistic regression, and differences in genotype frequencies between groups were assessed with the continuity correction chi-square test.Results: We found that the HLA-B*1502 gene was a risk factor for AED-MPE (P = 0.028). The incidence of MPE induced by the two types of AEDs was different, and the incidence of aromatic AEDs use was higher that of non-aromatic AEDs use (P = 0.025). The comparison of the gene frequencies of the HLA-B*1502 allele between the two groups taking aromatic AEDs was also statistically significant (P = 0.045). However, there were no significant differences in terms of age, gender, ethnicity, or region in patients with MPE induced by AEDs. In addition, no association between the HLA-B1502 allele and CBZ- or OXC-induced MPE was found.Conclusions: In northwestern China, the HLA-B*1502 allele was associated with aromatic AED-MPE. Since MPE can develop into Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), the HLA-B*1502 gene should be evaluated before administering AEDs. [ABSTRACT FROM AUTHOR]

Background: Carbamazepine (CBZ) is often implicated in drug-induced Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). CBZ-induced SJS/TEN is strongly associated with the HLA-B*1502 allele in Southeast Asia. Objectives: The objective was to determine the prevalence of HLA-B*1502 allele in patients with CBZ-induced SJS/TEN and in their first-degree relatives. Materials and Methods: Ten cases of CBZ-induced SJS/TEN from a single center were contacted and offered HLA-B*1502 genotyping for themselves and their first-degree relatives. Eight patients and 12 relatives consented for genotyping. Results: HLA-B *1502 was positive in all patients who were tested, of whom 50% of them were Malay and 50% were Chinese. The frequency of the HLA-B*1502 allele in the first-degree relatives was 58%. Conclusion: HLA-B*1502 is common in first-degree relatives of patients with CBZ-induced SJS/TEN.

Objective: Carbamazepine, widely used in the treatment of partial and generalized tonic–clonic seizures, has been associated with life‐threatening Stevens‐Johnson syndrome/toxic epidermal necrolysis among some Asians. The HLA‐B*1502 genotype that occurs with varying frequency among Asians is recommended for screening prior to starting carbamazepine. Our goal is to explore the cost‐effectiveness of screening for the presence of this genetic allele. Methods: We constructed a Markov model in a hypothetical cohort of adult Asian patients with epilepsy in the United States being considered for carbamazepine to investigate the cost‐effectiveness of two alternative strategies: (1) no HLA‐B*1502 gene allele screening and using carbamazepine and (2) HLA‐B*1502 gene allele screening and starting levetiracetam in the case of a positive screen. Results: For the lifetime horizon, HLA‐B*1502 gene screening was the cost‐effective choice compared to no gene screening, with an incremental cost‐effectiveness ratio of $27 058 per quality‐adjusted life‐year (QALY), below the $50 000/QALY threshold in 99.69% of probabilistic sensitivity analyses. Although gene screening strategy was more expensive than a no screening strategy, it was more effective, yielding more QALYs, across all Asian ethnic groups. Significance: Our analysis confirms the 2007 US Food and Drug Administration recommendation to screen for HLA‐B*1502 allele before starting treatment with carbamazepine in patients of Asian ancestry in the United States. [ABSTRACT FROM AUTHOR]

Background & Objective: Association between HLA-B*1502 and carbamazepine-induced Steven- Johnson syndrome/toxic epidermal necrolysis (CBZ-SJS/TEN) was reported in many Southeast Asian populations but not in Indonesian. The purpose of this study was to evaluate the association between HLA-B*1502 andCBZ-SJS/TEN in an Indonesian population. Methods: Patients with history of CBZ-SJS/TEN are recruited as cases and those who tolerated CBZ as controls. HLA-B typing was performed. Results: We recruited 14 cases with CBZ-SJS/TEN and 53 controls. Positive HLA-B*1502 was found in 8 (57.1%) cases and 14 (26.4%) controls (OR 3.7, 95% CI 1.09-12.61, p=0.035). Conclusion: HLA-B*1502 is associated with CBZ-SJS/TEN patients in Indonesian. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated a strong association between carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS) and HLA-B*1502 in Han Chinese. Here, we extended the study of HLA-B*1502 susceptibility to two different antiepileptic drugs, oxcarbazepine (OXC) and phenobabital (PB). In addition, we genotyped HLA-B*1511 in a case of CBZ-induced SJS with genotype negative for HLA-B*1502. The presence of HLA-B*1502 was determined using polymerase chain reaction with sequence-specific primers (PCR-SSP). Moreover, we genotyped HLA-B*1502 in 17 cases of antiepileptic drugs (AEDs)-induced cutaneous adverse drug reactions (cADRs), in comparison with AEDs-tolerant ( n=32) and normal controls ( n=38) in the central region of China. The data showed that HLA-B*1502 was positive in 5 of 6 cases of AEDs-induced SJS (4 CBZ, 1 OXC and 1 PB), which was significantly more frequent than AEDs-tolerant (2/32, 18 CBZ, 6 PB and 8 OXC) and normal controls (3/38). Compared with AEDs-tolerant and normal controls, the OR for patients carrying the HLA-B*1502 with AEDs-induced SJS was 6.25 (95% CI: 1.06-36.74) and 4.86 (95% CI: 1.01-23.47). The sensitivity and specificity of HLA-B*1502 for prediction of AEDs-induced SJS were 71.4%. The sensitivity and specificity of HLA-B*1502 for prediction of CBZ-induced SJS were 60% and 94%. HLA-B*1502 was not found in 11 children with maculopapular exanthema (MPE) ( n=9) and hypersensitivity syndrome (HSS) ( n=2). However, we also found one case of CBZ-induced SJS who was negative for HLA-B*1502 but carried HLA-B*1511. It was suggested that the association between the CBZ-induced SJS and HLA-B*1502 allele in Han Chinese children can extend to other aromatic AEDs including OXC and PB related SJS. HLA-B*1511 may be a risk factor for some patients with CBZ-induced SJS negative for HLA-B*1502. [ABSTRACT FROM AUTHOR]

Background: We investigated the association between oxcarbazepine (OXC)-induced maculopapular eruption (MPE) and HLA-B alleles in a northern Han Chinese population, and conducted an analysis of clinical risk factors for OXC-MPE. Methods: Forty-two northern Han Chinese patients who had been treated with OXC in Changchun, China were genotyped. Among them were 14 cases with OXC-induced MPE; the remaining 28 were OXC-tolerant. The HLA-B allele frequencies of the normal control group were found in the Allele Frequency Net Database. Polymerase chain reaction-sequence specific primer( PCR-SSP )was used for HLA-B"1502 testing and direct sequencing for four-digit genotype determination. Results: Four-digit allele sequencing showed that there was no statistically significant difference in the frequency of the HLA-B"1502 allele between the OXC-MPE and OXC-tolerant controls (3.6% versus 7.5%, OR = 0.38, 95% CI = 0.04-3.40, P = 0.65), as well as between OXC-MPE and normal controls (3.6% versus 2.4%, OR = 1.54, 95% CI = 0.20-11.73, P = 0.49). However, a significant difference in the frequency of HLA-B"3802 alleles was found between the MPE group and normal controls (10.7% versus 1.9%, OR = 6.329, 95% CI = 1.783-22.460, P = 0.018). There was no significant difference in terms of age, gender, or final OXC dose between the OXC-MPE and OXC-tolerant groups. Conclusions: There was no significant association between OXC-MPE and HLA-B"1502 in the northern Han Chinese population in our study. Instead, HLA-B"3802 was found to be a potential risk factor for OXC-MPE. [ABSTRACT FROM AUTHOR]

Background Carbamazepine (CBZ) is broadly used for the treatment of epilepsy, neuropathic pain and other neurological diseases, owing to its effectiveness and low price. CBZ can induce Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). There are several studies that found an association between HLA-B*1502 and CBZ-induced SJS/TEN, especially in people of Thai origin. In Thailand the prevalence of HLA-B*1502 was found to be in the range 8.1-14 %. Objective This study aimed to determine if screening for HLA-B*1502 in Thai patients who were to receive CBZ is cost effective. Setting Srinagarind Hospital, Khon Kaen University, Thailand. Method A comparison between treatment cost of CBZ induced SJS/TEN and the HLAB*1502 screening costs in the Thai population. Main outcome measure Comparison of the costs of treatment of CBZ induced SJS/TEN and costs of HLA-B*1502 screening test. Results When persons having the HLA-B*1502 allele receive CBZ, the chance of developing SJS/TEN is as high as 88.1 %, while persons without the HLA-B*1502 allele do not develop SJS/TEN. Therefore, a model was calculated to compare the cost of treatment between HLA-B*1502 testing before giving CBZ and if the patients were not tested for HLAB*1502. It was found that screening 100 patients before giving CBZ would save an amount of 98,549.94 baht per 100 cases of CBZ-prescribed patients. Conclusion The screening for HLA-B*1502 allele before giving carbamazepine is cost effective. The results of the present study may also apply to other populations if the HLA-B*1502 frequency is high enough. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Oxcarbazepine (OXC) is a promising alternative for patients who cannot tolerate carbamazepine. Recently, however, it has been reported that OXC-induced cutaneous adverse drug reactions (cADRs) are prevalent and may lead to drug discontinuation. Additionally, these reactions are thought to be associated with HLA-B*1502. This study aims to investigate the incidence, features and risk factors of OXC-cADRs, and to explore their relation to HLA-B alleles in Southern Han Chinese. Methods: A prospective study was performed to investigate the incidence, features and risk factors of OXC-cADRs, in which 252 new users were recruited. To examine the association between OXC-cADRs and HLA-B alleles, 14 maculopapular eruption (MPE) cases, including 9 additional cases beyond this prospective observation, were genotyped by PCR-SSP and sequencing. Thirty-five OXC-tolerant patients served as controls. Results: Five patients (2.0%) developed an OXC-cADR, and all were mild MPE. History of other AED allergy (p =0.005, OR=121.23) and non-AED allergy (p =0.006, OR=59.92) were significant risk factors for OXC-cADRs in multivariate logistic regression analysis. Only one patient with OXC-MPE was positive for HLA-B*1502; and the frequency of HLA-B*1502 in OXC-MPE did not differ significantly from that in OXC-tolerant controls. Four HLA-B*1302 alleles were detected in OXC-MPE cases, which was significantly different from that in general population of southern Han Chinese (p =0.001, OR=7.83). Conclusions: The incidence of OXC-induced cADRs was low, and no severe reactions occurred. Patients with a history of allergy are more susceptible to OXC-cADRs. No significant association between HLA-B*1502 and OXC-MPE was found. The associations between OXC-MPE and HLA alleles warrant further studies. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: Recent studies associated the HLA-B∗1502 allele with carbamazepine (CBZ)-induced Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) in patients from China, Thailand and Malaysia. No association has been found in patients from Europe or Japan. Linkage summary reports from East and South-east Asia predict a highly significant odds ratio (OR) of 84.75 (95% confidence interval [CI]=42.53–168.91; p =8.96×10[–15]) with sensitivity and negative predictive values of 92% and 98%, respectively. The higher prevalence of HLA-B∗1502 allele among certain Asian populations (10–15%) compared to Caucasians (1–2%) may explain a 10-fold to 25-fold higher incidence of CBZ-SJS/TEN in patients from Asia. Screening for HLA-B∗1502 before using CBZ can prevent SJS/TEN in certain populations, but screening may be less beneficial in populations with low HLA-B∗1502 allele frequency and in patients exposed to CBZ for more than 2 months. A retrospective study demonstrated that the costs of HLA-B∗1502 screening were less than those of SJS treatment. This article reviews possible benefits and concerns of HLA-B∗1502 screening in clinical practice. [Copyright &y& Elsevier]

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening severe cutaneous adverse reactions. Recently, strong associations of HLA-B*1502 with carbamazepine-induced SJS/TEN have been found in Han Chinese patients. These associations have been confirmed in several Asian populations, excluding Japanese. SJS patients carrying HLA-B*1508, HLA-B*1511, or HLA-B*1521, which are members of the HLA-B75 type along with HLA-B*1502, were detected in studies in India and Thailand. In the current study, we genotyped the HLA-B locus from 14 Japanese typical and atypical SJS/TEN patients in whom carbamazepine was considered to be involved in the onset of adverse reactions. Although there were no HLA-B*1502 carriers, four patients had HLA-B*1511. Our data suggest that HLA-B*1511, a member of HLA-B75, is a risk factor for carbamazepine-induced SJS/TEN in Japanese. [ABSTRACT FROM AUTHOR]

Summary: Antiepileptic drugs including lamotrigine (LTG) and carbamazepine (CBZ) are among the most common causes of cutaneous adverse reactions (cADRs). Human leukocyte antigen (HLA)-B*1502 has been strongly associated with CBZ-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). To investigate this relationship, we performed high-resolution HLA genotyping on LTG-tolerant controls, healthy volunteers, and patients affected by LTG-induced cADRs, ranging from maculopapular exanthema (MPE) to SJS/TEN. Patients with LTG-induced cADRs (n =25, including three with SJS/TEN and 22 with MPE), 21 LTG-tolerant controls, and 71 healthy volunteers were enrolled. The differences in the starting dosage of LTG among the SJS/TEN, MPE, and LTG-tolerant control groups were not statistically significant. HLA-B*1502 frequency was 33.3% (1/3; LTG-induced SJS/TEN group), 9.1% (2/22; LTG-induced MPE group), 4.8% (1/21; LTG-tolerant group), and 8.5% (6/71; healthy volunteers). There was no significant difference in the frequency of subjects with the HLA-B*1502 allele between the SJS/TEN group and LTG-tolerant group (p =0.239, OR=10.0, 95% CI 0.44–228.7), and healthy volunteers (p =0.26, OR=5.42, 95% CI 0.43–68.8), MPE and LTG-tolerant groups (p =1.0, OR=1.08, 95% CI 0.20–5.8), and healthy volunteers (p =1.0, OR=2.0, 95% CI 0.17–23.9). None of the HLA alleles detected were associated with LTG-induced cADRs. In conclusion, HLA-B*1502 and other HLA alleles are not directly associated with LTG-induced MPE. The possibility that HLA-B*1502 is associated with an increased risk of LTG-induced SJS/TEN could not be excluded. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to investigate the association between carbamazepine (CBZ)-induced cutaneous adverse drug reactions (cADRs) and the HLA-B*1502 allele among patients from central China. Eight patients with Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), 28 with mild maculopapular eruptions (MPEs), 50 CBZ-tolerant controls, and 71 healthy volunteers were recruited. HLA genotyping was performed using the polymerase chain reaction sequence-based typing (SBT) method. As a result, the HLA-B*1502 allele was observed at the following rates: (1) 100% (8/8) among those with CBZ-induced SJS/TEN, (2) 10.7% (3/28) among those with CBZ-induced MPEs; (3) 8.0% (4/50) among CBZ-tolerant controls; (4) 8.5% (6/71) among healthy volunteers. The eight patients with SJS/TEN positive for the HLA-B*1502 allele had an odds ratio (OR) of 184 compared with CBZ-tolerant controls. There was no significant difference in frequency between patients with MPEs and CBZ-tolerant controls (P >0.05). Thus, CBZ-induced SJS/TEN, but not MPEs, is strongly associated with HLA-B*1502. Testing for HLA-B*1502 should be recommended for patients from central China prior to initial CBZ treatment. [ABSTRACT FROM AUTHOR]

Carbamazepine (CBZ) has been reported as the most common culprit drug for Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in several Asian countries including Thailand. A strong association between HLA-B*1502 and CBZ-induced SJS/TEN has been reported in Han Chinese but not in Caucasian and Japanese populations. A case–control study was conducted to determine whether HLA-B*1502 is a valid pharmacogenetic test for SJS/TEN caused by CBZ in a Thai population. Among 42 CBZ-induced patients with SJS/TEN, 37 (88.10%) patients carried the HLA-B*1502 while only 5 (11.90%) of the CBZ-tolerant controls had this allele. The risk of CBZ-induced SJS/TEN was significantly higher in the patients with HLA-B*1502, with an odds ratio (OR) of 54.76 [95% confidence interval (CI) 14.62–205.13, p = 2.89 × 10−12]. The sensitivity and specificity of HLA-B*1502 for prediction of CBZ-induced SJS/TEN were 88.10%. By assuming a 0.27% as a prevalence rate of CBZ-induced SJS/TEN in a Thai population, the positive predictive value (PPV) and negative predictive value (NPV) of the HLA-B*1502 were 1.92% and 99.96%. Results from this study suggest that HLA-B*1502 may be a useful pharmacogenetic test for screening Thai individuals who may be at risk for CBZ-induced SJS and TEN. [ABSTRACT FROM AUTHOR]

Background: Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis are severe cutaneous reactions caused by certain drugs, including antiepileptic carbamazepine. A strong association has been reported between human leucocyte antigen (HLA)-B*1502 and carbamazepine-induced SJS in Han Chinese patients. European studies suggested that HLA-B*1502 is not a universal marker but is ethnicity-specific for Asians. Aim: To study the association between HLA-B*1502 and carbamazepine-induced SJS in Indian patients. Methods: Eight individuals who fulfilled the diagnostic criteria of SJS induced by carbamazepine were identified and HLA-B molecular typing was performed. HLA-B genotyping was carried out by polymerase chain reaction using sequence-specific primers. Results: Out of eight patients studied for genotype, six patients were found to have the HLA-B*1502 allele. Conclusion: This study suggests an association between HLA-B*1502 and carbamazepineinduced SJS in Indian patients. [ABSTRACT FROM AUTHOR]

Severe cutaneous adverse reactions (SCARs) are associated with over 200 medicines including lamotrigine, an antiepileptic drug. Previous studies have suggested the involvement of immune mechanisms in the development of drug-induced SCARs.High-resolution HLA genotyping was performed for 65 patients of European ancestry treated with lamotrigine (22 cases with lamotrigine-induced SCARs and 43 controls on lamotrigine without SCAR-related symptoms). Association of HLA genetic variants with SCARs in these patients were evaluated by contrasting allele frequencies between the cases and the controls for each of 112 HLA four-digit alleles.Five alleles were observed with higher frequencies in the cases compared with the treated controls with exact P values less than 0.05. These include B∗5801 (P = 0.037), previously reported to be associated with allopurinol-induced SCARs. Marginal association evidence was also observed for alleles Cw∗0718 and DQB1∗0609, both of which were strongly correlated with B∗5801. Other alleles identified were A∗6801 (P = 0.012) and DRB1∗1301 (P = 0.045). In contrast to the study of carbamazepine-induced Stevens-Johnson syndrome in Han Chinese patients, none of the cases carried B∗1502. Accounting for the large number of hypothesis tests conducted, none of the associations identified were statistically significant.No single major HLA-related genetic risk factor was identified for lamotrigine-induced SCARs in patients of European origin. Only suggestive evidence was obtained for B∗5801, A∗6801, Cw∗0718, DQB1∗0609, and DRB1∗1301. Confirmation of these results in a larger, independent sample is needed to determine whether any of the HLA alleles identified are truly associated with the development of lamotrigine-induced SCARs. [ABSTRACT FROM AUTHOR]

Previous studies found a strong association between HLA-B*1502 and carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS) in Han Chinese, but not in Caucasian populations. Even in Han Chinese, the HLA-B*1502 was not associated with CBZ-induced maculopapular eruptions (MPE). This study seeks to identify whether HLA-B*1502 is associated with CBZ- or phenytoin (PHT)-induced SJS or MPE in a Thai population. Eighty-one Thai epileptic patients between 1994 and 2007 from the Chulalongkorn Comprehensive Epilepsy Program were recruited. Thirty-one subjects had antiepileptic drug (AED)-induced SJS or MPE (6 CBZ-SJS, 4 PHT-SJS, 9 CBZ-MPE, 12 PHT-MPE), and 50 were AED-tolerant controls. For the first time, a strong association between HLA-B*1502 and PHT-induced SJS was found (p = 0.005). A strong association was also found between the HLA-B*1502 and CBZ-induced SJS (p = 0.0005), making Thai the first non-Chinese population demonstrating such an association. Some patients, who were HLA-B*1502 and suffered from CBZ-induced SJS, could be tolerant to PHT and vice versa. This suggests that HLA-B*1502 may be a common attribute required for a Thai patient to develop SJS from these two AEDs; other different elements, however, are also needed for each AED. In addition, no association between HLA-B alleles and CBZ- or PHT-induced MPE was found. CBZ- and PHT-induced SJS, but not MPE, is associated with HLA-B*1502 allele in Thai population. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study is to examine the association of HLA-B*1502 allele with CBZ-induced SJS/TEN in the mainland Han Chinese population. Methods: HLA-B*1502 genotyping with sequence-specific primer polymerase chain reaction (PCR-SSP) and PCR-sequencing based typing (PCR-SBT) was performed on 17 CBZ-induced SJS/TEN patients, 21 CBZ-tolerant controls, and 185 healthy controls recruited during 2008-2010. Results: HLA-B*1502 allele was present in 94.1% (16/17) of CBZ-SJS/TEN patients, 9.5% (2/21) of CBZ-tolerant patients, and 9.2% (17/185) of healthy controls. The risk of CBZ-induced SJS/TEN was significantly higher ( P < 0.01) in the patients with HLA-B*1502. One CBZ-induced SJS patient tested negative for HLA-B*1502, and the test result showed HLA-B*3503/B*4601. Conclusions: We found a strong association between HLA-B*1502 and CBZ-induced SJS/TEN in the Han Chinese population from central and northern China. Combined with previous studies of the southern Han Chinese subpopulation, our results suggest that HLA-B*1502 is strongly associated with CBZ-induced SJS/TEN in the whole Han Chinese population. [ABSTRACT FROM AUTHOR]

Abstract: Previous studies have found a strong association between HLA-B*1502 and carbamazepine-induced Stevens–Johnson syndrome in Asian areas including Taiwan, Hongkong and Thailand. This study explores the association between HLA-B*1502 allele and carbamazepine-induced cutaneous adverse reactions in Han Chinese of southern China mainland, and find the genetic marker that can predict carbamazepine-induced cutaneous adverse reactions. HLA-B*1502 allele genotyping was performed by a polymerase chain reaction–sequence specific primers (PCR–SSP) method in 48 Han Chinese subjects who had carbamazepine-induced cutaneous adverse reactions, including 9 severe cutaneous adverse reaction patients with Stevens–Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) and 39 cutaneous adverse reaction patients with maculopapular eruption (MPE). Meanwhile 80 carbamazepine-tolerant controls and 62 healthy individuals were also tested. The frequency of HLA-B*1502 allele among SJS/TEN patients (100%) is significantly higher than carbamazepine-tolerant controls (13.75%, P <0.001) and healthy individuals (17.74%, P <0.001). But the frequency between MPE patients and carbamazepine-tolerant controls (25.64% vs.13.75%, P =0.110) did not have any significant difference. The data showed that HLA-B*1502 allele is strongly associated with carbamazepine-induced SJS/TEN but not MPE in Han Chinese of southern China mainland. [Copyright &y& Elsevier]

Abstract: Background: Recent study demonstrated that HLA-B*1502 was a common risk allele in aromatic antiepileptic drugs (AEDs) induced Stevens–Johnson syndrome and toxic epidermal necrolysis in Han Chinese. However, the association of AEDs-induced mild maculopapular eruption (MPE) with HLA-B*1502 remains unclear until recently. In the present study, we conducted a pilot study to detect a possible association of oxcarbazepine (OXC)-induced MPE with HLA-B*1502 allele in Chinese Han population. Methods: We enrolled 90 subjects involving 9 patients with OXC-induced MPE and two groups of controls, 9 OXC-tolerant and 72 normal controls. High-resolution HLA genotyping was performed by specific kit. The results of HLA genotyping are expressed as positive or negative for HLA-B*1502 allele. Differences in genotype frequencies between groups were assessed by the Fisher''s exact test. Results: Four cases were detected as positive for HLA-B*1502 amongst 9 patients. However, only 1 subject was positive amongst 9 tolerant controls, and 6 subjects were positive amongst 72 normal controls. The difference in HLA-B*1502 allele frequencies between the MPE group and normal controls was statistically significant (OR: 8.8; 95% CI: 1.853–41.790; P =0.011). In addition, we also observed an increased frequency of HLA-B*1502 allele in patients (44.44%) compared with tolerant controls (11.11%), although it failed to reach statistical significance (P =0.294). Conclusions: Our findings indicate that HLA-B*1502 allele may contribute to the genetic susceptibility to OXC-induced MPE in Chinese Han population. In order to safer AEDs use, we recommend that HLA-B*1502 allele should be tested for patients with OXC-induced MPE before changing to other AEDs, and AEDs with similar chemical structure should be avoided in individuals who test positive for HLA-B*1502 allele. It should be pointed out that, however, our results may well be just by chance owing to the small sample size and should be further confirmed in future studies. [Copyright &y& Elsevier]

Eslicarbazepine acetate (ESL) is an anticonvulsant drug approved for the treatment of focal epilepsies, and related to oxcarbazepine and carbamazepine (CBZ), which are also derivatives of the dibenzazepine family. ESL is contraindicated in patients with hypersensitivity reactions to CBZ.We report a patient with frontal lobe epilepsy responding to treatment with ESL without any serious adverse effects after developing a severe skin rash following treatment with CBZ. HLA testing revealed an HLA-A*31:01 haplotype, that increases the risk of CBZ-induced cutaneous reactions.This case study shows that, in clinical practice, ESL may be considered in a patient with the HLA-A*31:01 haplotype and a hypersensitivity reaction to CBZ. [ABSTRACT FROM AUTHOR]

We describe a 28-year-old Malaysian Australian man of Han Chinese descent with toxic epidermal necrolysis (TEN), occurring 2 weeks after commencing carbamazepine. He was subsequently found to be positive for human leukocyte antigen (HLA)-B*1502. Carbamazepine-induced Stevens–Johnson syndrome/TEN is strongly associated with the HLA-B*1502 allele, which is highly prevalent in Han Chinese, Malay, Thai and Indian populations. Prospective screening for the allele may prevent this cutaneous adverse drug reaction from occurring, but many neurologists and other medical practitioners are still unaware of the medico-legal risks of prescribing carbamazepine in susceptible populations and the availability of HLA-B*1502 testing. Performing HLA-B*1502 genotyping and avoiding carbamazepine in at-risk individuals has been proven to decrease incidences of drug-induced TEN. This test is widely available at most large pathology services in Australia, with results available within 2 weeks. The recommendation by regulatory bodies should be strengthened to ensure that the broad medical community is made more aware of this pertinent issue. [ABSTRACT FROM AUTHOR]

Abstract: Antiepileptic drugs-induced Stevens–Johnson syndrome (SJS) is a life-threatening severe cutaneous adverse reaction. Recent studies in Thailand and Taiwan showed a significant association between phenytoin (PHT)-induced SJS and human leucocyte antigen HLA-B*1502 allele. Although the US FDA had issued an alert to clinicians, insufficient information is available to recommend testing for HLA-B*1502 in Asian patients in line for PHT treatment. Therefore, extended studies are necessary to further evaluate the potential association between PHT-induced SJS and HLA-B*1502 allele in various populations. To date, no similar data exist in mainland China. Here, we describe two Chinese Han cases of PHT-induced SJS with negative HLA-B*1502 allele, in which HLA high-resolution genotyping showed two heterozygous HLA-B*4601/B*5102 and HLA-B*3701/B*4601 allele, respectively. Our findings provide evidence to support that other genetic markers or nongenetic factors could contribute to the susceptibility of PHT-induced SJS, except for HLA-B*1502 allele. Further studies are encouraged to investigate the genetic link with PHT-induced serious skin reactions in future. [Copyright &y& Elsevier]

Abstract: Previous studies have reported that patients with phenytoin-induced Stevens–Johnson syndrome and toxic epidermal necrolysis (PHT-induced SJS/TEN) were positive for HLA-B*1502. We genotyped two patients with PHT-induced SJS using both polymerase chain reaction with sequence-specific primers and sequencing. The results revealed that one patient from Henan Province had HLA-B*1501/B*5401, and the other patient from Guangdong Province had HLA-B*1502/B*4601. When this information was combined with the results from Taiwan and Hong Kong, a significant difference was observed in the presence of HLA-B*1502 between PHT-SJS and PHT-tolerant populations (35% vs 8%, P =0.001, OR=6.08, 95% CI=2.183–16.946). Additional studies in large samples are required to confirm the association between HLA-B*1502 and PHT-induced SJS/TEN. [Copyright &y& Elsevier]

Introduction: SJS and TEN are two rare self-limited but serious cutaneous drug reactions with significant morbidity and mortality. There are many drugs associated with the condition. We report a case of early TEN syndrome post Carbamazepine use, review the current literature and discuss the management challenges., Case Report: A 51-year-old female was admitted to hospital for investigation and management of complex partial seizures secondary to a meningioma. She was commenced on 100mg BD of Carbamazepine for seizure control and discharged home. Surgical resection of the meningioma was performed electively 2 weeks later. A localized erythematous macular rash mainly in the left shoulder was noted on postoperative day 3. Two days later, the patient had sloughing of the mucosa of the lips in addition to progression of the rash. Early Toxic Epidermal Necrolysis (TEN) syndrome was diagnosed by the Burns and Dermatology teams and the culprit drug was discontinued. Skin biopsy confirmed the diagnosis. The patient was commenced on intravenous immunoglobulins with excellent improvement in skin integrity and resolution of excoriations noted on discharge., Discussion: Stevens - Johnson syndrome (SJS) and TEN are two rare self-limited but serious cutaneous drug reactions with significant morbidity and mortality. The current treatment of TENS/SJS is divided into early management and symptom control. The immediate cessation of the culprit drug is quintessential. There is vast documented evidence of carbamazepine- induced SJS/TEN in patients of Asian ethnicity due to the presence of the HLA allele B*1502. HLA-B*1502 screening should be performed when using aromatic anticonvulsants such as carbamazepine in high-risk patients., (© The Author(s) 2015.)

Drug-induced adverse reactions are a significant problem in healthcare worldwide and are estimated to cost billions of dollars annually in the United States. A portion of such reactions is observed to strongly associate with certain human leukocyte antigen (HLA) alleles; one of the strongest associations is the HLA-B*1502 protein with carbamazepine (CBZ)-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) - the odds ratio value can even be higher than one thousand. The particularly strong association in CBZ-induced SJS/TEN suggests that the HLA-B*1502 is not only a genetic marker but also a participant in the pathogenesis of the disease. In the current study, we attempt to computationally model the atomic-level structure of the complete HLA-B*1502/peptide/CBZ/T-cell receptor (TCR) complex architecture based on prior knowledge obtained from epidemiological investigations as well as in vitro and in vivo assays. The model tells a different story about the molecular mechanism of CBZ-induced SJS/TEN from that previously reported for abacavir (ABC)-induced hypersensitivity (HSR); the CBZ molecule is located at the interface between HLA-B*1502/peptide and TCR, directly contacts the P3-P6 residues of antigen peptide, and bound within a pocket region encompassed by two TCR CDR3 fingers. Molecular dynamics simulation and binding energy analysis further reveal that the CBZ shows considerably high affinity to TCR over HLA-B*1502/peptide, which can tightly interact with the former rather than the latter. From the model, two hypotheses are proposed that can well explain most previous observations and are expected to guide next wet-lab experiments. This study could help to promote our understanding of the molecular mechanism and pathological implication underlying CBZ-induced SJS/TEN.

Objectives: To determine the association between severe cutaneous drug reactions (SCDR), HLA-B*1502 allelism, carbamazepine dose and treatment duration in a Singapore paediatric population., Method: Case-control study of SCDR with carbamazepine and HLA-B*1502. We recruited 32 cases, 5 with Steven Johnson Syndrome/Toxic Epidermolytic Necrolysis (SJS/TEN) (2 Chinese, 3 Malay), 6 with hypersensitivity syndrome (HSS) (5 Chinese, 1 Indian), 11 with minor drug reactions (9 Chinese, 2 Malay) and 10 controls (7 Chinese, 2 Malay, 1 Indian). HLA-B*1502 allelism was assayed. HLA-B*1502 status and the type of drug reaction were compared using univariate analysis. The time-span from treatment onset to reaction and the dose-time to reaction association in the 3 groups were analysed., Results: HLA-B*1502 was positive in: 5/5 (SJS/TEN), 0/6 (HSS), 1/11 (minor drug reactions) and 1/10 controls. OR for SJS/TEN in HLA-B*1502-positive patients relative to that in HLA-B*1502-negative patients was estimated by exact logistic regression to be 27.20 (95% CI 2.67 to ∞). Median treatment duration (days) until allergic reactions was 12 (range 11-13), 16 (range 10-37) and 11 (range 0-63) for SJS/TEN, HSS and minor drug reactions, respectively. Median dose at onset of reactions was 6.2 mg/kg/day (range 4.6-7.4), 9.8 mg/kg/day (range 7.7-12.2) and 6.7 mg/kg/day (range 3.6-20.0) for the 3 groups, respectively., Conclusions: HLA-B*1502 positivity increases the odds of carbamazepine-induced SCDR in Singapore children of Chinese and Malay ethnicity. Adverse drug reactions to carbamazepine occurred within 2 weeks and at low doses., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)