U.S. researchers have identified a strong association between a variant of the human leukocyte antigen gene (HLA-A*32:01) and a severe adverse reaction that is induced by the antiseizure drug lamotrigine but note that this variant is not included in current commercial pharmacogenomic tests that screen new users for such events.
Writing in JAMA Network Open, Matthew Krantz, MD, from Vanderbilt University Medical Center, and co-authors explain that drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, potentially fatal drug hypersensitivity reaction characterized by extensive skin eruption, fever, lymphadenopathy, and internal organ involvement. It carries a mortality rate of three percent to 10%.
Lamotrigine, which is widely prescribed in seizure and bipolar disorders, has emerged as one of the most common causes of DRESS in the United States and Europe, with an estimated incidence of one in 1,000 to one in 10,000 exposed patients, making it a significant pharmacovigilance concern.
Although there are HLA-based markers for adverse reactions to other antiseizure-drugs, including HLA-A*31:01 and HLA-B*15:02 for carbamazepine-induced severe cutaneous adverse reactions, no HLA associations with lamotrigine-induced DRESS have been established in U.S. populations, highlighting a critical gap in precision drug safety.
To address this, Krantz and team carried out HLA class I (HLA-A, HLA-B, and HLA-C) and class II (HLA-DPB1, HLA-DQA1, HLA-DQB1, and HLA-DRB1) typing among 29 patients with lamotrigine-induced DRESS (median age 33 years, 86% women, 79% White) and 290 lamotrigine-tolerant control participants matched by age, sex, and race.
They found that patients with lamotrigine-induced DRESS were a significant 16.4 times more likely to carry HLA-A*32:01 than controls, at rates of 41.4% and 4.1%, respectively, making HLA-A*32:01 the strongest genetic signal reported for lamotrigine-induced DRESS in any population to date.
By contrast, no other alleles, including HLA-A*31:01 and HLA-B*15:02, or class II loci showed significant associations with lamotrigine-induced DRESS.
Krantz et al. note that HLA-A*31:01 and HLA-B*15:02 “are routinely included in pharmacogenomic panels ordered by psychiatrists and neurologists prior to initiating aromatic antiepileptic drugs for mood stabilization or seizure prophylaxis.
“However, the absence of enrichment of these alleles among lamotrigine DRESS case participants in our study indicates they lack clinical utility for this indication and with current reporting structure may falsely reassure prescribing health care professionals and their patients when these markers provide no meaningful risk stratification for lamotrigine-induced DRESS in U.S. populations,” they caution.
The researchers also acknowledge that HLA-A*32:01 was present in fewer than half of case participants, indicating that—like other class I HLA risk alleles for DRESS—it is neither necessary nor sufficient for the reaction. They estimate that roughly 2,400 patients would need testing to prevent one case but point out that this is similar to the figures for HLA-A*31:01 and carbamazepine-induced DRESS.
“That performance is in the same range as a test already in routine use for carbamazepine, so it’s not a hypothetical standard—it’s the one the field has accepted,” said Krantz.
The authors conclude: “Given that HLA-A*32:01 is not included in existing commercial pharmacogenomic panels, adding this marker could improve preprescription DRESS risk identification for lamotrigine.”
With a rapid PCR assay for HLA-A*32:01 already developed for vancomycin-induced DRESS, the marker is inexpensive and immediately testable.
