VEXAS syndrome ‘more common than expected’
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VEXAS syndrome is “more common than expected” in both men and women, with one in 13,591 individuals demonstrating a UBA1 disease-causing variant, according to data published in JAMA.
“In our JAMA paper, to understand how common VEXAS is, and the full spectrum of medical problems associated with it, we inverted this approach and used the ‘genome first’ ascertainment strategy,” Douglas R. Stewart, MD, of the division of cancer epidemiology and genetics at the National Cancer Institute, in Maryland, told Healio. “This means we identified patients based on genetic sequence rather than phenotypic consequence.
“From our collaboration with Geisinger Health, in Danville, PA, we searched for VEXAS-associated UBA1 variants in over 175,000 people who had undergone exome sequencing and then reviewed their charts for documenting the medical problems associated with those variants,” he added.
To examine the prevalence of pathogenic variants in UBA1 variations, as well as the connected clinical manifestations, Stewart and colleagues conducted a retrospective, observational study of individuals with blood, serum and DNA samples present in the Geisinger MyCode Community Health Initiative. Included participants had received care within the Geisinger health systemic and agreed to be part of the cohort. For the purposes of this analysis, phenotype data of relevance included clinical diagnoses, procedures, medications received and laboratory results.
Data obtained between Jan. 1, 1996, through Jan. 1, 2022, were included. Genetic analyses were conducted with ancestry data included to highlight potential study limitations. There were no inclusion or exclusion criteria based on race or ethnicity.
All available medical data were reviewed in any participants with genetic variations of interest. Data on blood cell count, erythrocyte sedimentation rate and C-reactive protein were included. In participants who did not receive a clinical diagnosis of VEXAS syndrome, a UBA1 variation-carrier was considered to have the syndrome if there were concomitant clinical features in two different organ systems known to be linked with the disease. The researchers also considered the prevalence of VEXAS as a study outcome.
The analysis included a total of 163,096 participants, of whom 11 had “likely” pathogenic UBA1 variations, according to the researchers. Of those individuals, all 11 demonstrated clinical manifestations consistent with VEXAS. Although five of the 11 did not meet hematological or rheumatologic disease criteria for VEXAS, all had anemia, with 10 demonstrating macrocytic disease and concomitant thrombocytopenia.
Also among the 11 patients, the researchers reported a pathogenic variant in one male participant prior to the onset of VEXAS-related signs or symptoms, while two female individuals demonstrated disease with heterozygous variants. The researchers additionally found a previously unreported UBA1 variant (c.1861A > T; p.Ser621Cys) in a symptomatic patient, with in vitro data pointing to a catalytic defect and pathogenicity.
In all, disease-causing UBA1 variants were discovered in one out of 13,591 unrelated participants (95% CI, 1:7,775 to 1:23,758), as well as in 1 out of 4,269 men older than 50 years (95% CI, 1:2,319 to 1:7,859), and in 1 out of 26,238 women older than 50 years (95% CI, 1:7,196 to 1:147,669).
“VEXAS is more common than expected,” Stewart said. “In this retrospective observational study of 163,096 participants, one in 13,591 individuals harbored a UBA1 disease-causing variant, and all participants had hematologic features, along with a broad spectrum of autoimmune, pulmonary, and dermatologic clinical manifestations.
“Importantly, since UBA1 is on the X chromosome, most patients identified to date have been men,” he added. “Since VEXAS is more common than expected in both men and women, we hope this paper changes clinical practice by encouraging more broad testing of UBA1 variants in people with non-specific rheumatologic disorders and anemia.”
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