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.	中華醫學會神經病學分會腦電圖與癲癇學組. 抗癲癇藥物應用專家共識. 中華神經科雜志, 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.	柴長鳳, 胡瑞宏, 畢曉瑩. 奧卡西平藥物基因組學研究進展. 世界臨床藥物, 2018, 39(12): 850-855.
7.	盛琳琳. 奧卡西平與卡馬西平治療成人部分性癲癇的效果比較. 中國當代醫藥, 2021, 28(3): 102-105.
8.	雷婧, 謝婷, 南慶玲, 等. 新型與傳統抗癲癇藥物對新診斷癲癇患兒的療效及安全性分析. 中國醫藥, 2020, 15(7): 1106-1110.
9.	吳思凡, 譚長宇, 樊紅彬, 等. 奧卡西平和卡馬西平治療腦卒中后繼發性癲癇療效與安全性的Meta分析. 藥學實踐雜志, 2018, 36(4): 373-378.
10.	民福利, 王曉, 范翠霞, 等. 奧卡西平導致的皮膚不良反應與HLA-B~1502、HLA-B~1301基因的關系. 實用醫學雜志, 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. 卡馬西平和拉莫三嗪所致皮疹的臨床特征及危險因素分析. 實用醫學雜志, 2016, 32(22): 3760-3764.
16.	黃亞莉, 任惠. 芳香族抗癲癇藥物所致嚴重皮膚不良反應的研究進展. 癲癇雜志, 2017, 3(04): 325-328.
17.	石奕武. 芳香族抗癲癇藥物導致皮膚型藥物不良反應與HLA基因的關系進展. 實用醫學雜志, 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. 中華醫學會神經病學分會腦電圖與癲癇學組. 抗癲癇藥物應用專家共識. 中華神經科雜志, 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. 柴長鳳, 胡瑞宏, 畢曉瑩. 奧卡西平藥物基因組學研究進展. 世界臨床藥物, 2018, 39(12): 850-855.
7. 盛琳琳. 奧卡西平與卡馬西平治療成人部分性癲癇的效果比較. 中國當代醫藥, 2021, 28(3): 102-105.
8. 雷婧, 謝婷, 南慶玲, 等. 新型與傳統抗癲癇藥物對新診斷癲癇患兒的療效及安全性分析. 中國醫藥, 2020, 15(7): 1106-1110.
9. 吳思凡, 譚長宇, 樊紅彬, 等. 奧卡西平和卡馬西平治療腦卒中后繼發性癲癇療效與安全性的Meta分析. 藥學實踐雜志, 2018, 36(4): 373-378.
10. 民福利, 王曉, 范翠霞, 等. 奧卡西平導致的皮膚不良反應與HLA-B~*1502、HLA-B~*1301基因的關系. 實用醫學雜志, 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. 卡馬西平和拉莫三嗪所致皮疹的臨床特征及危險因素分析. 實用醫學雜志, 2016, 32(22): 3760-3764.
16. 黃亞莉, 任惠. 芳香族抗癲癇藥物所致嚴重皮膚不良反應的研究進展. 癲癇雜志, 2017, 3(04): 325-328.
17. 石奕武. 芳香族抗癲癇藥物導致皮膚型藥物不良反應與HLA基因的關系進展. 實用醫學雜志, 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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