Genetic predictors of carbamazepine and lamotrigine induced Stevens-Johnson syndrome and toxic epidermal necrolysis_Journal of Epilepsy

Authors：

 WANGWei , HUFayun , WUXintong , ANDongmei , YANBo ,  ZHOUDong

Department of Neurology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China;

Corresponding author：

ZHOUDong, Email: zhoudong66@yahoo.de

Keywords：

Antiepileptic drugs; Stevens-Johnson syndrome; Toxic epidermal necrolysis; HLA alleles

DOI：

10.7507/2096-0247.20150005

Video：

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Objective The aim of this study was to investigate the pathogenesis of AED-induced SJS/TEN across the spectrum of HLA-A, -B and -DRB1 alleles, and to explore the different clinical characteristics of patients with and without the HLA-B*15:02 allele in the SJS/TEN group. Methods A total of twenty-three patients exhibiting AED-induced SJS/TEN (16 CBZ-SJS/TEN, seven LTG-SJS/TEN) and fifty-two patients who exhibited tolerance to AEDs were recruited. High-resolution HLA genotyping was performed to estimate the prevalence of the HLA-A, -B and -DRB1 alleles for each subject. Patients in the SJS/TEN group were further divided to positive HLA-B*15:02 allele group and negative HLA-B*15:02 allele group depending on whether carrying the HLA-B*15:02 allele, and the clinical feathers were compared between the two groups. Results Nine of twenty-three patients (39%) in the SJS/TEN group were male, and the mean age of this group was 32 (8-68) years old. Twenty-eight of fifty-four (54%) patients in the tolerant group were male, and the mean age of the tolerant group was 28 (9-64) years old.Fourteen subjects in the SJS/TEN group carried the HLA-B*15:02 allele, whereas only four subjects (7.7%) in the AED-tolerant group carried this allele; the carrier rate of HLA-B*15:02 was significantly different between the groups (P<0.001). Among the fourteen patients who carried the HLA-B*15:02 allele in the SJS/TEN group, composing the positive HLA-B*15:02 allele group, eight patients (57.1%) were female, whereas six of nine patients in the negative HLA-B*15:02 allele group were female. The difference of the gender didn't have statistical significance between the two groups, nor did the other clinical characteristics, including mean age, the dosage of the AEDs, the interval from the drug administration to the onset of the SJS/TEN, fever, allergic history, abnormal MRI and abnormal EEG results. Conclusions The pathogenesis of AED-induced SJS/TEN is a complex process, which may involve one or more alleles. The HLA-B*15:02 allele may be a genetic susceptibility factor of the AED-induced SJS/TEN. However, we didn't find significant difference of the clinical characteristics of SJS/TEN between the patients with and without the HLA-B*15:02 allele. Notably, further studies using larger samples are required to confirm these conclusions.

Citation： WANGWei, HUFayun, WUXintong, ANDongmei, YANBo, ZHOUDong. Genetic predictors of carbamazepine and lamotrigine induced Stevens-Johnson syndrome and toxic epidermal necrolysis. Journal of Epilepsy, 2015, 1(1): 32-36. doi: 10.7507/2096-0247.20150005 Copy

1.	Tartarone A, Lerose R. Stevens-Johnson syndrome and toxic epidermal necrolysis:what do we know? Therapeutic Drug Monitoring, 2010, 32(16):669-672.
2.	Chan HL, Stern RS, Arndt KA, et al. The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. A population-based study with particular reference to reactions caused by drugs among outpatients. Archives of Dermatology, 1990, 126(22):43-47.
3.	Chang YS, Huang FC, Tseng SH,et al. Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis:acute ocular manifestations, causes, and management. Cornea, 2007, 26(2):123-129.
4.	Khoo AK, Foo CL. Toxic epidermal necrolysis in a burns centre:a 6-year review. Burns:Journal of the International Society For Burn Injuries, 1996, 22(4):275-278.
5.	Knowles SR, Shapiro LE, Shear NH. Anticonvulsant hypersensitivity syndrome:incidence, prevention and management. Drug Safety, 1999, 21(7):489-501.
6.	Mockenhaupt M, Messenheimer J, Tennis P,et al. Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology, 2005, 64(7):1134-1138.
7.	Hung SI, Chung WH, Jee SH, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenetics Genomics, 2006, 16(4):297-306.
8.	Chung WH, Hung SI, Hong HS, et al. Medical genetics:a marker for Stevens johnson syndrome. Nature, 2004, 428(6982):486.
9.	McCormack M, Alfirevic A, Bourgeois S, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. The New England Journal of Medicine, 2011, 364(12):1134-1143.
10.	Ikeda H, Takahashi Y, Yamazaki E, et al. HLA class I markers in Japanese patients with carbamazepine-induced cutaneous adverse reactions. Epilepsia, 2010, 51(14):297-300.
11.	Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. The New Engl and Journal of Medicine, 1994, 331(6):1272-1285.
12.	Haldane JB. The estimation and significance of the logarithm of a ratio of frequencies. Annals of Human Genetics, 1956, 20(3):309-311.
13.	Locharernkul C, Loplumlert J, Limotai C, et al. Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B*1502 allele in Thai population. Epilepsia, 2008, 49(12):2087-2091.
14.	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 Clinical Pharmacology Toxicology, 2012, 111(20):58-64.
15.	Kim SH, Lee KW, Song WJ, et al. Carbamazepine-induced severe cutaneous adverse reactions and HLA genotypes in Koreans. Epilepsy Research, 2011, 97(16):190-197.
16.	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(3):579-582.
17.	Cheung YK, Cheng SH, Chan EJ,et al. HLA-B alleles associated with severe cutaneous reactions to antiepileptic drugs in Han Chinese. Epilepsia, 2013, 54(7):1307-1314.
18.	Middleton D, Hawkins BR, Williams F, et al. HLA class I allele distribution of a Hong Kong Chinese population based on high-resolution PCR-SSOP typing. Tissue Antigens, 2004, 63(6):555-561.

1. Tartarone A, Lerose R. Stevens-Johnson syndrome and toxic epidermal necrolysis:what do we know? Therapeutic Drug Monitoring, 2010, 32(16):669-672.
2. Chan HL, Stern RS, Arndt KA, et al. The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. A population-based study with particular reference to reactions caused by drugs among outpatients. Archives of Dermatology, 1990, 126(22):43-47.
3. Chang YS, Huang FC, Tseng SH,et al. Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis:acute ocular manifestations, causes, and management. Cornea, 2007, 26(2):123-129.
4. Khoo AK, Foo CL. Toxic epidermal necrolysis in a burns centre:a 6-year review. Burns:Journal of the International Society For Burn Injuries, 1996, 22(4):275-278.
5. Knowles SR, Shapiro LE, Shear NH. Anticonvulsant hypersensitivity syndrome:incidence, prevention and management. Drug Safety, 1999, 21(7):489-501.
6. Mockenhaupt M, Messenheimer J, Tennis P,et al. Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology, 2005, 64(7):1134-1138.
7. Hung SI, Chung WH, Jee SH, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenetics Genomics, 2006, 16(4):297-306.
8. Chung WH, Hung SI, Hong HS, et al. Medical genetics:a marker for Stevens johnson syndrome. Nature, 2004, 428(6982):486.
9. McCormack M, Alfirevic A, Bourgeois S, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. The New England Journal of Medicine, 2011, 364(12):1134-1143.
10. Ikeda H, Takahashi Y, Yamazaki E, et al. HLA class I markers in Japanese patients with carbamazepine-induced cutaneous adverse reactions. Epilepsia, 2010, 51(14):297-300.
11. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. The New Engl and Journal of Medicine, 1994, 331(6):1272-1285.
12. Haldane JB. The estimation and significance of the logarithm of a ratio of frequencies. Annals of Human Genetics, 1956, 20(3):309-311.
13. Locharernkul C, Loplumlert J, Limotai C, et al. Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B*1502 allele in Thai population. Epilepsia, 2008, 49(12):2087-2091.
14. 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 Clinical Pharmacology Toxicology, 2012, 111(20):58-64.
15. Kim SH, Lee KW, Song WJ, et al. Carbamazepine-induced severe cutaneous adverse reactions and HLA genotypes in Koreans. Epilepsy Research, 2011, 97(16):190-197.
16. 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(3):579-582.
17. Cheung YK, Cheng SH, Chan EJ,et al. HLA-B alleles associated with severe cutaneous reactions to antiepileptic drugs in Han Chinese. Epilepsia, 2013, 54(7):1307-1314.
18. Middleton D, Hawkins BR, Williams F, et al. HLA class I allele distribution of a Hong Kong Chinese population based on high-resolution PCR-SSOP typing. Tissue Antigens, 2004, 63(6):555-561.

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