HLA‐B*15:02 association with carbamazepine‐induced Stevens‐Johnson syndrome and toxic epidermal necrolysis in an Indian population: a pooled‐data analysis and meta‐analysis

This study aimed to investigate the prevalence and association of HLA‐B*15:02 with carbamazepine‐induced Stevens‐Johnson syndrome and toxic epidermal necrolysis (CBZ‐SJS/TEN) in the Indian population in Malaysia, which mostly originated from Southern India. HLA‐B alleles in five Indian case patients with CBZ‐SJS/TEN and 52 CBZ‐tolerant controls, and followed by a pooled sample of seven cases from two centers in Malaysia were analyzed. Positive association for HLA‐B*15:02 with CBZ‐SJS/TEN was detected in Indians (40% [2/5] vs. 3.8% [2/52], odds ratio [OR] 16.7, p = 0.0349), of which 80% (4/5) of the Indian patients originated from Southern India. A pooled sample of seven cases showed stronger association between HLA‐B*15:02 and CBZ‐SJS/TEN (57.1% [4/7] vs. 3.8% [2/52], OR 33.3, 95% confidence interval [CI] 4.25–162.21, p = 1.05 × 10^?3). Subsequent meta‐analysis on Indians from Malaysia and India further demonstrated a significant and strong association between HLA‐B*15:02 and CBZ‐SJS/TEN (OR 38.54; 95% CI 6.83–217.34, p < 1.0 × 10^?4). Our study is the first on Indians predominantly from Southern India that demonstrated HLA‐B*15:02 as a strong risk factor for CBZ‐SJS/TEN despite a low population allele frequency. This stressed the importance of testing for HLA‐B*15:02, irrespective of the ancestral background, including populations with low allele frequency.     

HLA Class I markers in Japanese patients with carbamazepine‐induced cutaneous adverse reactions

Carbamazepine (CBZ) is frequently used for treating epilepsy, but this drug causes cutaneous adverse drug reactions (cADRs) that may range from mild to severe. It is reported recently that the human leukocyte antigen HLA‐B*1502 is associated with Stevens‐Johnson syndrome (SJS) induced by CBZ in Han Chinese. We examined HLA class I in 15 Japanese patients who fulfilled the diagnostic criteria for CBZ‐induced cADRs (mild in 10 and severe = SJS in 5). HLA‐B*1518, HLA‐B*5901 and HLA‐C*0704 alleles showed higher relative risks (above 10.0) for severe cADRs. The haplotype (HLA‐A*2402‐B*5901‐C*0102) had high relative risk (16.09) for severe cADRs. In patients with severe cADRs, frequencies of HLA‐A*1101, HLA‐A*3303, HLA‐B*1501, HLA‐B*4403, HLA‐B*5101, HLA‐B*5201, HLA‐C*0702, and HLA‐C*1202 alleles are relatively lower than in the Japanese population. These data may suggest that HLA‐B*5901 is one of the candidate markers for CBZ‐induced SJS in Japanese.     

Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B*1502 allele in Thai population

Purpose: 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. Methods: 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. Results: 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. Conclusions: CBZ‐ and PHT‐induced SJS, but not MPE, is associated with HLA‐B*1502 allele in Thai population.     

Association between HLA‐B*1502 and carbamazepine‐induced severe cutaneous adverse drug reactions in a Thai population

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.     

The HLA-B*15:02 polymorphism and Tegretol®-induced serious cutaneous reactions in epilepsy: An updated systematic review and meta-analysis

Tegretol^® [carbamazepine (CBZ)], an aromatic drug approved for epilepsy treatment, can induce adverse drug reactions (ADRs) after its administration. Several genetic studies of epilepsy have shown that genetic polymorphisms increase the risk of ADRs, and some interactions between CBZ and other treatments can also induce adverse effects. Thus, to avoid such interactions and to provide an overview of the genetic profiles involved in ADRs with CBZ, for the first time, a systematic review and meta-analysis focusing on epilepsy was performed, using Cochrane Library, Embase and PubMed databases to find studies published between January 1980 and October 2016. Of the eligible studies, those selected were related to the impact of genetic polymorphisms on ADRs in patients receiving antiepileptic treatment. The results of these selected studies are expressed as pooled odds ratios (ORs) with 95% confidence intervals (CIs), based on data from individual patients. Out of 807 articles, nine were included in the present meta-analysis to assess the association between human leukocyte antigen (HLA)-B*15:02 polymorphisms and CBZ-induced serious cutaneous reactions (SCRs), such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), in epilepsy. It was found that HLA-B*15:02 polymorphisms were significantly associated with CBZ SCR risk (OR: 27.325, 95% CI: 9.933–51.166), while subgroup analyses by ethnicity showed that the association was significant in Han Chinese (OR: 42.059, 95% CI: 9.587–184.514). The HLA-B*15:02 polymorphism was also strongly associated with the CBZ-SJS subgroup (OR: 152.089, 95% CI: 34.737–665.901) and significantly associated with the CBZ-SJS/TEN subgroup (OR: 13.993, 95% CI: 7.291–26.856). Also, the allele was overrepresented in the Han Chinese population (OR: 17.886, 95% CI: 8.411–38.034) within the CBZ-SJS/TEN subgroup. Although the number of studies available in other Asian ethnicities was insufficient for determining publication bias, it nevertheless showed a relationship between the HLA-B*15:02 polymorphism and SCRs. In addition, despite the small number of included studies, the results reveal strong evidence that the HLA-B*15:02 polymorphism can induce SCRs among Asian CBZ users. These findings should prompt physicians to individualize CBZ therapy for patients with epilepsy.