HLA-B*1502 Allele is Associated with a Cross-Reactivity Pattern of Cutaneous Adverse Reactions to Antiepileptic Drugs
Department of Neurology, Institute of Neurology, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.The Journal of international medical research (Impact Factor: 1.44). 02/2012; 40(1):377-82. DOI: 10.1177/147323001204000140
The US Food and Drug Administration has recommended genetic screening for the human leucocyte antigen-B (HLA-B)*1502 allele in patients of Asian ethnicity before starting carbamazepine therapy, to avoid the fatal adverse treatment-related events associated with this drug. The association between cross-reactivity to antiepileptic drugs (AEDs) and the HLA-B*1502 allele has been only rarely reported. Here, two cases of cross-reactivity to AEDs, where cutaneous adverse drug reactions (cADRs) developed in female Han Chinese patients with epilepsy who tested positive for the HLA-B*1502 allele, are described. If the genetic association could be confirmed in larger studies, the HLA-B*1502 allele should be tested for in any patient experiencing cADRs, to avoid crossreactivity to AEDs.
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ABSTRACT: Purpose: HLA-B*15:02 screening is recommended before starting carbamazepine in Han Chinese and Southeast Asians because the allele is strongly predictive of Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) induced by the drug. We examined whether other HLA-B alleles are also involved and whether the association extends to other antiepileptic drugs (AEDs). Methods: Cases of SJS/TEN induced by any AEDs were recruited and matched (1:5) with AED-tolerant controls. Carrier rates of HLA-B alleles, determined by direct sequencing, were compared between cases and controls. Results were meta-analyzed with previous studies to examine the associations between HLA-B*15:02 and SJS/TEN induced by phenytoin and lamotrigine. Key findings: A total of 55 cases (27 carbamazepine, 15 phenytoin, 6 lamotrigine, 7 other AEDs) and 275 controls were recruited. In drug-specific analysis, the carrier rate of HLA-B*15:02 was significantly higher in carbamazepine-SJS/TEN cases compared with carbamazepine-tolerant controls (92.3% vs. 11.9%; p = 3.51 × 10(-18) ; odds ratio (OR) 89.25; 95% confidence interval (CI) 19.25-413.83), and also in phenytoin-SJS/TEN cases compared with phenytoin-tolerant controls (46.7% vs. 20.0%; p = 0.045; OR 3.50; 95% CI 1.10-11.18). Meta-analyses showed a strong association of HLA-B*15:02 with phenytoin-SJS/TEN (p < 3 × 10(-4) ; OR 4.26; 95% CI 1.93-9.39) and, to a lesser extent, lamotrigine-SJS/TEN (p = 0.03; OR 3.59; 95% CI 1.15-11.22). Compared with drug-tolerant controls, the carrier rates of HLA-B*40:01 and HLA-B*58:01 were lower in cases of SJS/TEN induced by carbamazepine (p = 0.004) and other AEDs (p = 0.009), respectively. Significance: SJS/TEN induced by carbamazepine and phenytoin is strongly and moderately associated with HLA-B*15:02 in Han Chinese, respectively. Possible protective associations with HLA-B*40:01 and HLA-B*58:01 warrant further investigation.
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ABSTRACT: A considerable heterogeneity exists in the literature on the role of different HLA alleles in carbamazepine (CBZ)-induced cutaneous adverse drug reactions (cADRs) of varying severity among diverse ethnic groups. The aim of the present study was to understand and summarize this heterogeneity and evaluate the contribution of common HLA alleles to susceptibility to cADRs in patients treated with CBZ through a meta-analysis. A literature search of Embase, Medline, Web of Knowledge, and Cochrane database of systematic reviews was performed up to 28 September 2013. A total of 20 reports were identified as eligible studies, which included 720 CBZ-intolerant [Stevens-Johnson syndrome and toxic epidermal necrolysis (bullous lesions): n=277; hypersensitivity syndrome/maculopapular exanthema (nonbullous lesions): n=359; others: n=84], 1512 CBZ-tolerant, and 1113 normal controls. We observed HLA-A*3101 and HLA-B*1502 as risk markers and HLA-B*4001 as a protective marker for susceptibility to cADRs when comparing intolerant with tolerant patients. Stratification by clinical outcome showed HLA-B*1502 and HLA-B*1511 as risk and HLA-A*2402 as protective markers for bullous lesions in the Asians [HLA-B*1502: odds ratio (OR)=80.70; 95% confidence interval (CI)=45.62-142.77; P=1.8×10; I=33%, HLA-B*1511: OR=17.43; 95% CI=3.12-97.40; P=1.1×10; I=0%, HLA-A*2402: OR=0.27; 95% CI=0.11-0.64; P=2.7×10; I=0%]. Furthermore, HLA-A*3101 was observed to be a universal risk marker, irrespective of cADR type [OR (bullous lesions)=5.65; 95% CI =2.70-11.78; P=4.03×10; I=49%, OR (nonbullous lesions)=8.58; 95% CI=5.55-13.28; P=4.46×10; I=0%]. Sensitivity analysis showed HLA-B*4001 as a protective marker in Chinese population for showing bullous lesions (OR=0.14; 95% CI=0.06-0.32; P=3.2×10; I=0%). In summary, our meta-analysis showed the presence of HLA alleles contributing toward risk of as well as protection against various CBZ-induced cADRs.
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ABSTRACT: Antiepileptic drugs can induce potentially life-threatening hypersensitivity reactions such as Stevens-Johnson syndrome at a frequency of one in 10,000 to one in 1000 treated patients. There is a considerable cross-reactivity among different antiepileptic drugs but the mechanisms are not known. In this review we have summarized current evidence on antiepileptic drug-induced hypersensitivity reactions and performed meta-analyses of published case-control studies that investigated associations between HLA alleles and several antiepileptic drugs in diverse populations. As the heterogeneity between studies was high, we conducted subsequent subgroup analyses and showed that HLA-B*15:02 was associated with carbamazepine, lamotrigine and phenytoin-induced Stevens-Johnson syndrome in Asian populations indicating that pretreatment testing may prevent cross-reactivity. Additionally, we explored the potential of new, high-throughput technologies that may help to understand the mechanisms and predict the risk of adverse drug reactions in the future.