HLA Screening in Reducing the Risk of Antiepileptic Drug-induced Cutaneous Adverse Reactions

Cutaneous adverse drug reactions (cADRs) include mild maculopapular exanthema (MPE) and severe cutaneous reactions such as hypersensitivity syndrome, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). cADRs are considered as a major public health issue because of their potentially life-threatening morbidity, especially severe cutaneous reactions. The incidence of SJS/TEN is estimated to vary from 1 in 1,000 to 10,000 drug exposures, and its mortality is as high as 35%. Antiepileptic drugs (AEDs), particularly those with aromatic ring structures such as carbamazepine (CBZ), oxcarbazepine (OXC), lamotrigine (LTG), phenobarbital (PB), and phenytoin (PHT), are among the most common causes of severe cutaneous reactions. The incidence of AED-induced SJS was estimated as 0.2% and all cases occurred in individuals receiving aromatic AEDs. Previous studies have validated that the human leukocyte antigen (HLA) allele HLA-B\*15:02 is strongly associated with CBZ-induced SJS/TEN in southern Han Chinese and populations in southeast Asia. Our recent studies indicated that HLA-A\*24:02 is a common genetic risk factor for CBZ-, LTG-, and PHT-induced SJS/TEN. It is also associated with MPE. Additionally, another four alleles, including HLA-B\*15:01, HLA-B\*15:11, HLA-A\*02:01,and HLA-DRB1\*01:01, were showed to be potential risk factors for aromatic AEDs-induced SJS/TEN. In 2007, the US Food and Drug Administration issued the safety alert that recommended HLA-B\*15:02 screening for people with Asian ancestry before starting CBZ, and avoidance of the drug if the test is positive. Subsequent studies from Taiwan, Hong Kong and Thailand demonstrated that HLA-B\*15:02 screening before commencing CBZ can significantly reduce the incidence of CBZ-induced SJS/TEN. However, the overall incidence of AEDs-induced SJS/TEN remained unchanged in Hong Kong, as PHT-induced SJS/TEN increased when CBZ-SJS/TEN decreased. Moreover, no study focuses on the incidences of AEDs-induced