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

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.