Common Risk Allele in Aromatic Antiepileptic-Drug Induced Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis in Han Chinese

Abstract

Aims: Compared with other categories of drugs, such as antibiotics and NSAIDs, antiepileptic therapies are associated with a high incidence of Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We previously reported that carbamazepine (CBZ)–SJS/TEN is strongly associated with the HLA-B*1502 in Han Chinese, which has been confirmed in other Southeast Asian countries where the allele is prevalent. Here, we extend the study of HLA susceptibility to three different antiepileptic drugs, phenytoin (PHT), lamotrigine (LTG) and oxcarbazepine (OXC), which have structure similarity to CBZ. Materials & methods: We carried out a case–control association study. We enrolled 26 PHT-, six LTG- and three OXC-induced SJS/TEN patients, 113 PHT-tolerant and 67 LTG-tolerant subjects who were on the drug, respectively, for more than 3 months without the adverse reactions, and 93 normal subjects from the general population. The HLA-A, B, C and DRB1 genotypes were determined. Results: We found that HLA-B*1502 was present in eight out of 26 (30.8%) PHT–SJS/TEN (OR: 5.1; 95% CI: 1.8–15.1; p = 0.0041), two out of six (33%) LTG–SJS (odds ratio [OR]: 5.1; 95% CI: 0.8–33.8; p = 0.1266) and three out of three (100%) OXC–SJS (OR: 80.7; 95% CI: 3.8–1714.4; p = 8.4 × 10^-4) patients. In addition, HLA-B*1301, Cw*0801 and DRB1*1602 also showed an association with PHT–SJS/TEN (p = 0.0128–0.0281; OR: 3.0–4.3). Conclusion: Our results indicate that OXC, PHT and LTG, which possess an aromatic ring just as CBZ does, when causing SJS/TEN, share a common risk allele. Aromatic antiepileptic drugs causing SJS/TEN in HLA-B*1502 carriers may act on a similar pathogenetic mechanism, although other genetic/nongenetic factor(s) may also contribute to the pathomechanism of the disease. We suggest that aromatic antiepileptic drugs, including CBZ, OXC and PHT, should be avoided in the B*1502 carrier and caution should also be exercised for LTG.

KEYWORDS::

• antiepileptic drugs
• cutaneous adverse drug reaction
• HLA susceptibility
• lamotrigine
• oxcarbazepine
• phenytoin
• Stevens–Johnson syndrome
• toxic epidermal necrolysis

Financial & competing interests disclosure

This research was supported by grants from the National Science Council, Taiwan (NSC 98-2320-B-010-002-MY3, 98-2314-B-182A-027-MY3), Chang-Gung Memorial Hospital, National Yang-Ming University (Aim for the top university plan), National Research Program for Genomic Medicine, and National Genotyping Core, Taiwan. The authors have filed a patent for ‘Risk assessment for adverse drug reactions‘. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This research was supported by grants from the National Science Council, Taiwan (NSC 98-2320-B-010-002-MY3, 98-2314-B-182A-027-MY3), Chang-Gung Memorial Hospital, National Yang-Ming University (Aim for the top university plan), National Research Program for Genomic Medicine, and National Genotyping Core, Taiwan. The authors have filed a patent for ‘Risk assessment for adverse drug reactions‘. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.