Association analysis between HLA-A/B alleles and maculopapular exanthema induced by carbamazepine or oxcarbazepine_Journal of Epilepsy

Authors：

 HE Na , SONG Wang , LIU Xiaorong , LI Bingmei , SHI Yiwu

Department of Neurology, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China;

Corresponding author：

HE Na, Email: henachilli@163.com

Keywords：

Carbamazepine; Oxcarbazepine; Maculopapular exanthema; Genetic risk factors

DOI：

10.7507/2096-0247.202112010

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Objective To analyze the correlation between HLA-A and B genotypes and maculopapular exanthema (MPE) caused by Carbamazepine (CBZ) and Oxcarbazepine (OXC), and to explore the genetic risk factors of MPE. Methods Patients with MPE (rash group) and patients without MPE (non-rash group) after taking CBZ or OXC were retrospectively collected from January 2016 to October 2021 in the Second Affiliated Hospital of Guangzhou Medical University. DNA was extracted from peripheral blood. HLA-A and HLA-B alleles were sequenced by high resolution sequencing, and a case-control study was conducted to analysis the correlations between MPE and HLA genotypes. Results A total of 100 patients with CBZ-MPE, 100 patients with CBZ-tolerant, 50 patients with OXC-MPE, and 50 patients with OXC-tolerant were collected. There was no significant difference in age and sex between CBZ, OXC rash groups and non-rash groups The average latency of CBZ-rash group was (11.31±11.00) days and their average dosage was (348.46±174.10) mg; the average latency of OXC-rash group was (11.67±10.34) days and their average dosage was (433.52±209.22) mg [equivalent to CBZ (289.01±139.48 mg)], showing no significant difference in latency and dosage between CBZ and OXC (P>0.05). The positive rates of HLA-A*24:02 and A*30:01 in CBZ-rash group were 28% and 6%, respectively, which were significantly higher than those in CBZ-non rash group (16% and 0%, both P=0.04). The positive rate of HLA-B*40:01 in CBZ-rash group was 18%, which was significantly lower than that in CBZ-non rash group (40%, P<0.001). No association between HLA-A or B genotype and OXC-rash was found yet. When pooled, it was still found that the positive rates of HLA-A*24:02 and A*30:01 in the rash group were higher than those in the non-rash group, while the positive rate of HLA-B*40:01 in the rash group was lower than that in the non-rash group, and the difference was statistically significant (P<0.05). Conclusions HLA-A*24:02 and A*30:01 were associated with MPE caused by CBZ, and may be common risk factors for aromatic antiepileptic drugs.

Citation： HE Na, SONG Wang, LIU Xiaorong, LI Bingmei, SHI Yiwu. Association analysis between HLA-A/B alleles and maculopapular exanthema induced by carbamazepine or oxcarbazepine. Journal of Epilepsy, 2022, 8(2): 108-115. doi: 10.7507/2096-0247.202112010 Copy

1.	He N, Min FL, Shi YW, et al. Cutaneous reactions induced by oxcarbazepine in Southern Han Chinese: Incidence, features, risk factors and relation to HLA-B alleles. Seizure, 2012, 21(8): 614-618.
2.	中华医学会神经病学分会脑电图与癫痫学组. 抗癫痫药物应用专家共识. 中华神经科杂志, 2011, 44(1): 56-65.
3.	Toledano R, Gil-Nagel A. Adverse effects of antiepileptic drugs. Semin Neurol, 2008, 28(3): 317-327.
4.	Shi YW, Min FL, Zhou D, et al. HLA-A*24: 02 as a common risk factor for antiepileptic drug-induced cutaneous adverse reactions. Neurology, 2017, 88(23): 2183-2191.
5.	Roujeau JC. Clinical heterogeneity of drug hypersensitivity. Toxicology, 2005, 209(2): 123-129.
6.	柴长凤, 胡瑞宏, 毕晓莹. 奥卡西平药物基因组学研究进展. 世界临床药物, 2018, 39(12): 850-855.
7.	盛琳琳. 奥卡西平与卡马西平治疗成人部分性癫痫的效果比较. 中国当代医药, 2021, 28(3): 102-105.
8.	雷婧, 谢婷, 南庆玲, 等. 新型与传统抗癫痫药物对新诊断癫痫患儿的疗效及安全性分析. 中国医药, 2020, 15(7): 1106-1110.
9.	吴思凡, 谭长宇, 樊红彬, 等. 奥卡西平和卡马西平治疗脑卒中后继发性癫痫疗效与安全性的Meta分析. 药学实践杂志, 2018, 36(4): 373-378.
10.	民福利, 王晓, 范翠霞, 等. 奥卡西平导致的皮肤不良反应与HLA-B~1502、HLA-B~1301基因的关系. 实用医学杂志, 2021, 37(16): 2080-2083+2088.
11.	Shi YW, Wang J, Min FL, et al. HLA risk alleles in aromatic antiepileptic drug-induced maculopapular exanthema. Front Pharmacol, 2021, 12: 671572.
12.	Arif H, Buchsbaum R, Weintraub D, et al. Comparison and predictors of rash associated with 15 antiepileptic drugs. Neurology, 2007, 68(20): 1701-1709.
13.	Alvestad S, Lydersen S, Brodtkorb E. Rash from antiepileptic drugs: influence by gender, age, and learning disability. Epilepsia, 2007, 48(7): 1360-1365.
14.	Wang XQ, Lang SY, Shi XB, et al. Antiepileptic drug-induced skin reactions: a retrospective study and analysis in 3793 Chinese patients with epilepsy. Clin Neurol Neurosurg, 2012, 114(7): 862-865.
15.	何娜, 民福利, 石奕武, 等. 卡马西平和拉莫三嗪所致皮疹的临床特征及危险因素分析. 实用医学杂志, 2016, 32(22): 3760-3764.
16.	黄亚莉, 任惠. 芳香族抗癫痫药物所致严重皮肤不良反应的研究进展. 癫痫杂志, 2017, 3(04): 325-328.
17.	石奕武. 芳香族抗癫痫药物导致皮肤型药物不良反应与HLA基因的关系进展. 实用医学杂志, 2012, (13): 2119-2121.
18.	Mehta TY, Prajapati LM, Mittal B, et al. Association of HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome among Indians. Indian journal of dermatology, venereology and leprology, 2009, 75(6): 579-582.
19.	Tassaneeyakul W, Tiamkao S, Jantararoungtong T, et al. Association between HLA-B*1502 and carbamazepine-induced severe cutaneous adverse drug reactions in a Thai population. Epilepsia, 2010, 51(5): 926-930.
20.	Chang CC, Too CL, Murad S, et al. Association of HLA-B*1502 allele with carbamazepine-induced toxic epidermal necrolysis and Stevens-Johnson syndrome in the multi-ethnic Malaysian population. International journal of dermatology, 2011, 50(2): 221-224.
21.	Man CB, Kwan P, Baum L, et al. Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese. Epilepsia, 2007, 48(5): 1015-1018.
22.	Shi YW, Min FL, Qin B, et al. Association between HLA and Stevens-Johnson syndrome induced by carbamazepine in Southern Han Chinese: genetic markers besides B*1502? Basic Clin Pharmacol Toxicol, 2012, 111(1): 58-64.
23.	Chen P, Lin JJ, Lu CS, et al. Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. N Engl J Med, 2011, 364(12): 1126-1133.
24.	Hung SI, Chung WH, Jee SH, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics, 2006, 16(4): 297-306.
25.	Li LJ, Hu FY, Wu XT, et al. Predictive markers for carbamazepine and lamotrigine-induced maculopapular exanthema in Han Chinese. Epilepsy Res, 2013, 106(1-2): 296-300.
26.	Shirzadi M, Thorstensen K, Helde G, et al. Do HLA-A markers predict skin-reactions from aromatic antiepileptic drugs in a Norwegian population? A case control study. Epilepsy research, 2015, 118: 5-9.
27.	Shi YW, Min FL, Liu XR, et al. HLA-B alleles and Lamotrigine-induced cutaneous adverse drug reactions in the Han Chinese population. Basic Clin Pharmacol Toxicol, 2011, 109: 42-46.
28.	Alfirevic A, Jorgensen AL, Williamson PR, et al. HLA-B locus in Caucasian patients with carbamazepine hypersensitivity. Pharmacogenomics, 2006, 7(6): 813-818.

1. He N, Min FL, Shi YW, et al. Cutaneous reactions induced by oxcarbazepine in Southern Han Chinese: Incidence, features, risk factors and relation to HLA-B alleles. Seizure, 2012, 21(8): 614-618.
2. 中华医学会神经病学分会脑电图与癫痫学组. 抗癫痫药物应用专家共识. 中华神经科杂志, 2011, 44(1): 56-65.
3. Toledano R, Gil-Nagel A. Adverse effects of antiepileptic drugs. Semin Neurol, 2008, 28(3): 317-327.
4. Shi YW, Min FL, Zhou D, et al. HLA-A*24: 02 as a common risk factor for antiepileptic drug-induced cutaneous adverse reactions. Neurology, 2017, 88(23): 2183-2191.
5. Roujeau JC. Clinical heterogeneity of drug hypersensitivity. Toxicology, 2005, 209(2): 123-129.
6. 柴长凤, 胡瑞宏, 毕晓莹. 奥卡西平药物基因组学研究进展. 世界临床药物, 2018, 39(12): 850-855.
7. 盛琳琳. 奥卡西平与卡马西平治疗成人部分性癫痫的效果比较. 中国当代医药, 2021, 28(3): 102-105.
8. 雷婧, 谢婷, 南庆玲, 等. 新型与传统抗癫痫药物对新诊断癫痫患儿的疗效及安全性分析. 中国医药, 2020, 15(7): 1106-1110.
9. 吴思凡, 谭长宇, 樊红彬, 等. 奥卡西平和卡马西平治疗脑卒中后继发性癫痫疗效与安全性的Meta分析. 药学实践杂志, 2018, 36(4): 373-378.
10. 民福利, 王晓, 范翠霞, 等. 奥卡西平导致的皮肤不良反应与HLA-B~*1502、HLA-B~*1301基因的关系. 实用医学杂志, 2021, 37(16): 2080-2083+2088.
11. Shi YW, Wang J, Min FL, et al. HLA risk alleles in aromatic antiepileptic drug-induced maculopapular exanthema. Front Pharmacol, 2021, 12: 671572.
12. Arif H, Buchsbaum R, Weintraub D, et al. Comparison and predictors of rash associated with 15 antiepileptic drugs. Neurology, 2007, 68(20): 1701-1709.
13. Alvestad S, Lydersen S, Brodtkorb E. Rash from antiepileptic drugs: influence by gender, age, and learning disability. Epilepsia, 2007, 48(7): 1360-1365.
14. Wang XQ, Lang SY, Shi XB, et al. Antiepileptic drug-induced skin reactions: a retrospective study and analysis in 3793 Chinese patients with epilepsy. Clin Neurol Neurosurg, 2012, 114(7): 862-865.
15. 何娜, 民福利, 石奕武, 等. 卡马西平和拉莫三嗪所致皮疹的临床特征及危险因素分析. 实用医学杂志, 2016, 32(22): 3760-3764.
16. 黄亚莉, 任惠. 芳香族抗癫痫药物所致严重皮肤不良反应的研究进展. 癫痫杂志, 2017, 3(04): 325-328.
17. 石奕武. 芳香族抗癫痫药物导致皮肤型药物不良反应与HLA基因的关系进展. 实用医学杂志, 2012, (13): 2119-2121.
18. Mehta TY, Prajapati LM, Mittal B, et al. Association of HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome among Indians. Indian journal of dermatology, venereology and leprology, 2009, 75(6): 579-582.
19. Tassaneeyakul W, Tiamkao S, Jantararoungtong T, et al. Association between HLA-B*1502 and carbamazepine-induced severe cutaneous adverse drug reactions in a Thai population. Epilepsia, 2010, 51(5): 926-930.
20. Chang CC, Too CL, Murad S, et al. Association of HLA-B*1502 allele with carbamazepine-induced toxic epidermal necrolysis and Stevens-Johnson syndrome in the multi-ethnic Malaysian population. International journal of dermatology, 2011, 50(2): 221-224.
21. Man CB, Kwan P, Baum L, et al. Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese. Epilepsia, 2007, 48(5): 1015-1018.
22. Shi YW, Min FL, Qin B, et al. Association between HLA and Stevens-Johnson syndrome induced by carbamazepine in Southern Han Chinese: genetic markers besides B*1502? Basic Clin Pharmacol Toxicol, 2012, 111(1): 58-64.
23. Chen P, Lin JJ, Lu CS, et al. Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. N Engl J Med, 2011, 364(12): 1126-1133.
24. Hung SI, Chung WH, Jee SH, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics, 2006, 16(4): 297-306.
25. Li LJ, Hu FY, Wu XT, et al. Predictive markers for carbamazepine and lamotrigine-induced maculopapular exanthema in Han Chinese. Epilepsy Res, 2013, 106(1-2): 296-300.
26. Shirzadi M, Thorstensen K, Helde G, et al. Do HLA-A markers predict skin-reactions from aromatic antiepileptic drugs in a Norwegian population? A case control study. Epilepsy research, 2015, 118: 5-9.
27. Shi YW, Min FL, Liu XR, et al. HLA-B alleles and Lamotrigine-induced cutaneous adverse drug reactions in the Han Chinese population. Basic Clin Pharmacol Toxicol, 2011, 109: 42-46.
28. Alfirevic A, Jorgensen AL, Williamson PR, et al. HLA-B locus in Caucasian patients with carbamazepine hypersensitivity. Pharmacogenomics, 2006, 7(6): 813-818.

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Association analysis between HLA-A/B alleles and maculopapular exanthema induced by carbamazepine or oxcarbazepine

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