HLA-A*32:01 and Lamotrigine-Induced Drug Reaction With Eosinophilia and Systemic Symptoms

HLA-A

Class I allelic association, HLA-A 32:01, with delayed hypersensitivity to lamotrigine

Matched case-control study conducted at two US academic medical centres (Vanderbilt and Mass General Brigham), including 29 patients with RegiSCAR-confirmed lamotrigine-induced DRESS (score ≥ 4) and 290 lamotrigine-tolerant controls matched on sex, self-reported race and age. Class I and class II HLA typing identified a single significant association after Bonferroni correction: HLA-A 32:01, carried by 41.4% of cases (12 patients) versus 4.1% of controls (odds ratio 16.4; 95% CI 6.4-42.5; corrected P < .001). The haplotype combining HLA-A 32:01 and HLA-B 44:02 was also enriched (OR 18.4; 95% CI 4.6-83.8). No class II locus reached significance after correction. The authors stress that this marker is absent from commercial pharmacogenomic panels, which test HLA-B 15:02 and HLA-A 31:01, neither validated for lamotrigine-induced DRESS.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

An odds ratio of 16 for an adverse event carrying 3-10% mortality is enough to question what preprescription HLA panels actually contain: testing HLA-B 15:02 before lamotrigine may provide false reassurance, since that allele was never validated for this drug. The limitations are the sample size, 29 cases, and the fact that control typing was imputed from array data while cases were typed at high resolution: independent replication is needed before any formal recommendation. The practical relevance is nonetheless immediate for prescribers of lamotrigine, a first-line agent in bipolar disorder and epilepsy, and one of the top five causes of DRESS.

Analysis by Dr Thibaut Benquey