Spectrum of cutaneous adverse reactions to aromatic antiepileptic drugs and human leukocyte antigen genotypes in Thai patients and meta-analysis

Chonlaphat Sukasem,Sadeep Medhasi,Kanoot Jaruthamsophon,Napatrupron Koomdee,Leena Chularojanamontri,Patompong Satapornpong,Thanyada Rungrotmongkol,Thawinee Jantararoungtong,Napatra Tovanabutra,Chonlawat Chaichan,Sarawut Oo-Puthinan,Papapit Tuchinda,Suthida Sririttha,Pawinee Rerknimitr,Thapanat Nakkrut,Wichai Aekplakorn,Jettanong Klaewsongkram,Naravut Suvannang,Surasak Saokaew,Ticha Rerkpattanapipat,Apichaya Puangpetch

doi:10.1038/s41397-021-00247-3

Abstract

Aromatic antiepileptic drugs (AEDs)-induced cutaneous adverse drug reactions (cADRs) add up to the limited use of the AEDs in the treatment and prevention of seizures. Human leukocyte antigen-B (HLA-B) alleles have been linked to AEDs-induced cADRs. We investigated the association between cADRs (including Stevens–Johnson syndrome; SJS/toxic epidermal necrolysis; TEN, drug reaction with eosinophilia and systemic symptoms; DRESS, and Maculopapular eruption; MPE) caused by AEDs (phenytoin, carbamazepine, lamotrigine, phenobarbital and oxcarbazepine) and HLA-B alleles in Thai population. Through the case-control study, 166 patients with AEDs-induced cADRs, 426 AEDs-tolerant patients (AEDs-tolerant controls), and 470 healthy subjects (Thai population) were collected. The HLA genotypes were detected using the polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) method. We also performed a meta-analysis with these data and other populations. The carrier rate of HLA-B*15:02 was significantly different between AEDs-induced cADRs group and AEDs-tolerant group (Odds ratio; OR 4.28, 95% Confidence interval; CI 2.64–6.95, p < 0.001), AEDs-induced cADRs group and Thai population (OR 2.15, 95%CI 1.41–3.29, p < 0.001). In meta-analysis showed the strong association HLA-B*15:02 with AEDs-induced cADRs (OR 4.77, 95%CI 1.79–12.73, p < 0.001). Furthermore, HLA-B*15:02 was associated with SJS/TEN induced by AEDs (OR 10.28, 95%CI 6.50–16.28, p < 0.001) Phenytoin (OR 4.12, 95%CI 1.77–9.59, p = 0.001) and carbamazepine (OR 137.69, 95%CI 50.97–371.98, p < 0.001). This study demonstrated that genetic association for AEDs-induced cADRs was phenotype-specific. A strong association between HLA-B*15:02 and AEDs-induced SJS/TEN was demonstrated with an OR of 10.79 (95%CI 5.50–21.16, p < 0.001) when compared with AEDs-tolerant group. On the other hand, the carrier rates of HLA-B*08:01, HLA-B*13:01, and HLA-B*56:02 were significantly higher in the DRESS group compared with the AEDs-tolerant group (p = 0.029, 0.007, and 0.017, respectively). The HLA-B*15:02 allele may represent a risk factor for AEDs-induced cADRs.

Highlights

Aromatic antiepileptic drugs (AEDs), such as phenytoin (PHT), carbamazepine (CBZ), lamotrigine (LTG), phenobarbital (PB), and oxcarbazepine (OXC), commonly prescribed to prevent or treat seizure, are frequently associated with cutaneous adverse drug reactions [1]
We investigated the association between cutaneous adverse drug reactions (cADRs) caused by AEDs and human leukocyte antigen (HLA)-B alleles in Thai population
The overall incidence of cADRs induced by AEDs is ~10% [2]. cADRs can be classified into two types, immediate and delayed type. cADRs associated with AEDs are usually delayed type, and clinical manifestations include from mild maculopapular eruption (MPE) to severe and life-threatening severe cutaneous adverse reactions (SCARs); Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and hypersensitivity syndrome (HSS)/drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) [3]

Summary

Introduction

Aromatic antiepileptic drugs (AEDs), such as phenytoin (PHT), carbamazepine (CBZ), lamotrigine (LTG), phenobarbital (PB), and oxcarbazepine (OXC), commonly prescribed to prevent or treat seizure, are frequently associated with cutaneous adverse drug reactions (cADRs) [1]. CADRs associated with AEDs are usually delayed type, and clinical manifestations include from mild maculopapular eruption (MPE) to severe and life-threatening severe cutaneous adverse reactions (SCARs); Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and hypersensitivity syndrome (HSS)/drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) [3]. MPE, the mild delayed type cADRs, presents as a widespread, symmetrically distributed rash composed of pink-to-red macules and papules that may coalesce to form plaques. SJS and TEN are severe life-threatening delayed type cADRs characterized by febrile illness in acute phases followed by the predominant involvement of skin and mucous membrane necrosis and systemic symptoms. Alleles of the human leukocyte antigen (HLA) genes have been associated with cADRs, and the screening of HLA alleles prior to the administration of AEDs can prevent the occurrence of cADRs

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Methods

Conclusion