Unravelling the Genetic Link: An Umbrella Review on HLA-B∗15:02 and Anti-Epileptic Drug-induced Stevens–Johnson Syndrome / Toxic Epidermal Necrolysis

Abstract

Abstract Purpose This umbrella review was conducted to summarize the evidence between association between HLA*1502 allele with various antiepileptic induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Methods Pubmed, Scopus and EMBASE were searched for eligible reviews in May 2023. Study was registered in PROSPERO. Two authors independently screened titles and abstracts and assessed full-text reviews for eligibility. The quality of meta-analyses was appraised with AMSTAR-2 and the quality of case control studies were appraised with Newcastle- Ottawa Scale (NOS). Narrative summaries of each anti-epileptic drug were analysed. Pre-established protocol was registered on the International Prospective Register of Systematic Reviews database (ID: CRD42023403957). Results Included studies are meta-analyses and case control studies evaluating the association of HLA-B*1502 allele with the following antiepileptics: 7 meta-analyses for Carbamazepine (CBZ), 3 meta-analyses for Lamotrigine (LTG), 3 case-control studies for Oxcarbazepine (OXC), 9 case-control studies Phenytoin (PHT) and 4 case-control studies study for Phenobarbitone. The findings of this umbrella review suggest that there is strong association between HLA B-1502 with SJS/TEN for Carbamazepine and Oxcarbazepine and a milder association for Lamotrigine and Phenytoin. Conclusions In summary, although HLA-B*1502 is less likely to be associated with Phenytoin or Lamotrigine -induced SJS/TEN compared to Carbamazepine-induced SJS/TEN, it is a significant risk factor which if carefully screened could potentially reduce development of SJS/TEN. In view of potential morbidity and mortality, HLA-B*1502 testing may be beneficial in patients who are initiating Lamotrigine / Phenytoin therapy. However, further studies are required to examine the association of other alleles with development of SJS/TEN and to explore the possibility of genome-wide association studies prior to initiation of treatment.