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Kim, Ji, Kim, Jung, Cha, and Shin: HLA-A∗24:02/B∗51:01 haplotype and lamotrigine-induced cutaneous adverse drug reactions in Koreans
Original Article

Translational and Clinical Pharmacology 2016;24(3):143-146.

Published online: 19 January 2016

DOI: https://doi.org/10.12793/tcp.2016.24.3.143

HLA-A∗24:02/B∗51:01 haplotype and lamotrigine-induced cutaneous adverse drug reactions in Koreans

Eun-Young Kim1, Ki-Hwan Ji2, Hye-Jin Kim1, Hye-Eun Jung3, Eun-Young Cha3, Jae-Gook Shin∗, 1, 3

1Department of Clinical Pharmacology, Inje University College of Medicine, Busan Paik Hospital, Busan 47392, Republic of Korea

2Department of Neurology, Inje University College of Medicine, Busan Paik Hospital, Busan 47392, Republic of Korea

3Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 47392, Republic of Korea

∗Correspondence: J. G. Shin; Tel: +82-51-890-6709, Fax: +82-51-893-1232, E-mail: phshinjg@gmail.com

Received 27 July 2016       Revised 1 September 2016       Accepted 1 September 2016

Copyright © 2016 Korean Society for Clinical Pharmacology and Therapeutics

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Antiepileptic drugs (AEDs) have been known to induce cutaneous adverse drug reaction (cADR), ranging from a mild maculopapular eruption (MPE) to potentially life-threatening cADRs such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Despite studies examining mechanisms associated with human leukocyte antigen (HLA), the association between lamotrigine (LTG)-induced cADR and HLA alleles still has room to investigate. We investigated HLA-A, -B, and -C alleles in LTG-induced cADR. The medical records of four patients with LTG-induced cADR were retrospectively reviewed. All patients were treated with LTG for epilepsy. All recovered from cADR after stopping LTG treatment and receiving intensive care. HLA-A, -B, and -C genotyping was performed in all four patients using a PCR-sequence-based typing (SBT) method. Two patients had SJS, and the other two had MPE due to LTG. The range of latency to cADR after the initial LTG dose was 19–42 days. Two patients experienced cross-reactivity with other aromatic or new AEDs. Expression of the HLA-A∗24:02/B∗51:01 haplotype was detected in three (75%) patients with LTG-induced cADR. The other patient carried homozygous HLA-B∗58:01 alleles. The results suggest that Korean individuals with the HLA-A∗24:02/B∗51:01 haplotype may be susceptible to LTG-induced cADR. Further investigations are necessary to confirm these findings.

Keywords: Lamotrigine, cutaneous adverse drug reactions, Stevens–Johnson syndrome, maculopapular eruption, HLA class I genotype

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Table 1.
Clinical characteristics of the patients, including previous history of AED-induced MPE
ID Sex Age Comorbidity Previous AED-induced MPE
Drug Dose (mg/day) Latency (days) Timea
1 M 58 Ischemic stroke PHT 400 2 7 yrs
        LTG 50 18 7 yrs
        TPM 100 36 7 yrs
2 F 26 None CBZ 200 4 20 days
3 M 69 Rheumatic mitral valve disease None      
4 F 39 None None      

AED: antiepileptic drug, MPE: maculopapular eruption, PHT: phenytoin, LTG: lamotrigine, TPM: topiramate, CBZ: carbamazepine.

a Time period between previous AED-induced MPE and current LTG-induced cADR.

Table 2.
Clinical characteristics of patients with LTG-induced cADRs
ID Phenotype Dose (mg/day) Latency to cADRa (days) Current drugs
Initial Maximum Initial Maximum
1 MPE 25 25 35 35 VPA, PB
2 MPE 50 100 19 5 LEV
3 SJS 100 150 42 14 LEV, TPM
4 SJS 25 100 30 1 LEV

LTG: lamotrigine, cADR: cutaneous adverse drug reaction, MPE: maculopapular eruption, SJS: Stevens-Johnson syndrome, VPA: valproate, PB: phenobarbital, LEV: levitriacetam, TPM: topiramate.

a Latency to cADR after initial and maximum dose.

Table 3.
HLA-A, -B, and -C genotypes of the patients
ID HLA-A∗ HLA-B∗ HLA-C∗
1 24:02/31:01 51:01/55:04 03:03/03:04
2 33:03/33:03 58:01/58:01 03:03/03:04
3 24:02/31:01 48:01/51:01 08:03/14:02
4 24:02/24:02 48:01/51:01 07:02/14:02
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