The association between levetiracetam-induced maculopapular exanthemaand <i>HLA</i> alleles in patients with epilepsy_Journal of Epilepsy

Authors：

WANG Wei , HU Fayun , REN Jiechuan ,  ZHOU Dong

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

Corresponding author：

ZHOU Dong, Email: zhoudong66@yahoo.de

Keywords：

Epilepsy; Levetiracetam; Cutaneous adverse drug reactions; Rash; HLA-DRB1*04:05 allele

DOI：

10.7507/2096-0247.20170017

Video：

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Objective It has been reported that many different kinds of antiepileptic drugs (AEDs) induced cutaneous adverse drug reactions (cADRs) are associated with human leukocyte antigen (HLA) genes. However, previous studies mainly focused on the traditional AEDs. There are very few research focused on the new AEDs, especially levetiracetam (LEV). This study aimed to evaluate the clinical characteristics of LEV-induced cADRs and to explore its possible genetic association with the HLA alleles. Methods Nine cases with LEV-induced cADRsfrom September 2011 to December 2014 were recruited. Demographic and clinical information of these cases was summarized. Additionally, cases were matched with LEV-tolerant controls (1 : 4).High-resolution HLA-A, -B, -DRB1 genotyping were performed for each subject. The allele frequencies between the cases and controls were compared. Results Nine cases with LEV-induced cADRs formed the LEV-cADRs group. And 36 epilepsy patients who had received or have been receiving LEV treatment for at least 3 months without any adverse drug reactions formed the LEV-tolerant controls group. All LEV-induced cADRs were mild skin rashes whichoccurred within 30 days of LEV exposure. The mean latency from LEV exposure to skin rash was (15.67±5.41) days (ranging 6~27). Two patients in the LEV-cADRs group carried the HLA-DRB1*0405allele, while none subjects in the control group carried this allele. The carrier rate of HLA-DRB1*0405 allele between the LEV-cADRs group and control group was statistical significant [P=0.036, OR=13.875, 95%CI(1.273, 151.230)]. Conclusions Safety monitoring was necessary within four weeks after the initiation of LEV treatment, although it has been regarded as a safe AED.Our study suggested thatHLA-DRB1*0405 allele may be a risk factor for LEV-induced cADRs. However, the Further studies with large samples are needed to clarify this hypothesis and the genetic and immunological mechanisms of LEV-induced cADRs should also be further explored in the future.

Citation： WANG Wei, HU Fayun, REN Jiechuan, ZHOU Dong. The association between levetiracetam-induced maculopapular exanthemaand HLA alleles in patients with epilepsy. Journal of Epilepsy, 2017, 3(2): 121-125. doi: 10.7507/2096-0247.20170017 Copy

1.	Berkovic SF, Knowlton RC, Leroy RF, et al. Levetiracetam N01057 Study Group. Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Neurology, 2007, 69(8): 1751-1760.
2.	French JA, Pedley TA. Clinical practice. Initial management of epilepsy. N Engl JMed, 2008, 359(7): 166-176.
3.	Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature, 2004, 428(11): 486.
4.	McCormack M, Alfirevic A, Bourgeois S, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med, 2001, 364(1): 1134-1143.
5.	Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med, 1994, 331(5): 1272-1285.
6.	Haldane JB. The estimation and significance of the logarithm of a ratio of frequencies. Ann Hum Genet, 1956, 20(6): 309-311.
7.	Hovinga CA. Levetiracetam: a novel antiepileptic drug. Pharmacotherapy, 2001, 21(10): 1375-1388.
8.	Lo BW, Kyu HH, Jichici D, et al.Meta-analysis of randomized trials on first line and adjunctive levetiracetam.Can J NeurolSci, 2001, 38(4): 475-486.
9.	Lyseng-Williamson KA. Levetiracetam: a review of its use in epilepsy.Drugs, 2011, 71(4): 489-514.
10.	Mbizvo GK, Dixon P, Hutton JL, et al. The adverse effects profile of levetiracetam in epilepsy: a more detailed look. Int J Neurol Sci, 2014, 124(5): 627-634.
11.	Arif H, Buchsbaum R, Weintraub D, et al. Comparison and predictors of rash associated with 15 antiepileptic drugs. Neurology, 2007, 68(8): 1701-1709.
12.	Wang XQ, Lang SY, ShiXB, et al. Antiepileptic drug-induced skinreactions: a retrospective study and analysis in 3793 Chinese patients with epilepsy. Clin Neurol Neurosurg, 2012, 114(7): 862-865.
13.	Gómez-Zorrilla S, FerrazAV, Pedrós C, et al. Levetiracetam-induced drug reaction with eosinophilia and systemic symptoms syndrome. Ann Pharmacother, 2012, 46(5): e20.
14.	Hall DJ, Fromm JS. Drug reaction with eosinophilia and systemic symptoms syndrome in a patient taking phenytoin and levetiracetam: a case report. J Med Case Rep, 2013, 7(2): 2.
15.	Eleni K. Dress syndrome induced by levetiracetam. J Eur Acad Dermatol Venereol, 2015, 29(4): 377-378.
16.	US Food and Drug Administration.Potential signals of serious risks/new safety information identified by the Adverse Event Reporting System (AERS) between July-September2010.http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm237585.htm. 2012, Accessed April 17.
17.	Zou LP, Ding CH, Song ZJ, et al. Stevens-Johnson syndrome induced by levetiracetam.Seizure, 2012, 21(7): 823-825.
18.	Duong TA, Haddad C, Valeyrie-Allanore L, et al. Levetiracetam: a possible new inducer of toxic epidermal necrolysis and Stevens-Johnson syndrome in 2 cases. Dermatol, 2013, 149(7): 113-115.

1. Berkovic SF, Knowlton RC, Leroy RF, et al. Levetiracetam N01057 Study Group. Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Neurology, 2007, 69(8): 1751-1760.
2. French JA, Pedley TA. Clinical practice. Initial management of epilepsy. N Engl JMed, 2008, 359(7): 166-176.
3. Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature, 2004, 428(11): 486.
4. McCormack M, Alfirevic A, Bourgeois S, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med, 2001, 364(1): 1134-1143.
5. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med, 1994, 331(5): 1272-1285.
6. Haldane JB. The estimation and significance of the logarithm of a ratio of frequencies. Ann Hum Genet, 1956, 20(6): 309-311.
7. Hovinga CA. Levetiracetam: a novel antiepileptic drug. Pharmacotherapy, 2001, 21(10): 1375-1388.
8. Lo BW, Kyu HH, Jichici D, et al.Meta-analysis of randomized trials on first line and adjunctive levetiracetam.Can J NeurolSci, 2001, 38(4): 475-486.
9. Lyseng-Williamson KA. Levetiracetam: a review of its use in epilepsy.Drugs, 2011, 71(4): 489-514.
10. Mbizvo GK, Dixon P, Hutton JL, et al. The adverse effects profile of levetiracetam in epilepsy: a more detailed look. Int J Neurol Sci, 2014, 124(5): 627-634.
11. Arif H, Buchsbaum R, Weintraub D, et al. Comparison and predictors of rash associated with 15 antiepileptic drugs. Neurology, 2007, 68(8): 1701-1709.
12. Wang XQ, Lang SY, ShiXB, et al. Antiepileptic drug-induced skinreactions: a retrospective study and analysis in 3793 Chinese patients with epilepsy. Clin Neurol Neurosurg, 2012, 114(7): 862-865.
13. Gómez-Zorrilla S, FerrazAV, Pedrós C, et al. Levetiracetam-induced drug reaction with eosinophilia and systemic symptoms syndrome. Ann Pharmacother, 2012, 46(5): e20.
14. Hall DJ, Fromm JS. Drug reaction with eosinophilia and systemic symptoms syndrome in a patient taking phenytoin and levetiracetam: a case report. J Med Case Rep, 2013, 7(2): 2.
15. Eleni K. Dress syndrome induced by levetiracetam. J Eur Acad Dermatol Venereol, 2015, 29(4): 377-378.
16. US Food and Drug Administration.Potential signals of serious risks/new safety information identified by the Adverse Event Reporting System (AERS) between July-September2010.http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm237585.htm. 2012, Accessed April 17.
17. Zou LP, Ding CH, Song ZJ, et al. Stevens-Johnson syndrome induced by levetiracetam.Seizure, 2012, 21(7): 823-825.
18. Duong TA, Haddad C, Valeyrie-Allanore L, et al. Levetiracetam: a possible new inducer of toxic epidermal necrolysis and Stevens-Johnson syndrome in 2 cases. Dermatol, 2013, 149(7): 113-115.

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The association between levetiracetam-induced maculopapular exanthemaand HLA alleles in patients with epilepsy

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