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The syndrome, although rare, has a high mortality rate, with approximately half of patients dying within 5 years of diagnosis.
VEXAS syndrome, which stands for vacuoles in blood cells, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, and somatic, presents with rheumatologic and hematologic features caused by somatic variants in UBA1 and pathogenic variants, which are linked to a variety of clinical manifestations. According to research published in Journal of the American Medical Association (JAMA),1 the condition is much more common than previous estimates, affecting approximately 13,200 men and 2,300 women over the age of 50 in the United States. This prevalence is higher than other rheumatologic conditions, such as myeloid dysplasia syndrome and vasculitis.
“Now that we know VEXAS syndrome is more common than many other types of rheumatologic conditions, physicians need to add this condition to their list of potential diagnoses when confronted by patients with persistent and unexplained inflammation and low blood cell counts, or anemia,” geneticist and study lead investigator David Beck, MD, PhD, stated. Beck, assistant professor in the Department of Medicine and the Department of Biochemistry and Molecular Pharmacology at NYU Langone Health, led the research team that originally identified the UBA1 mutation among patients with VEXAS.
Symptoms of the autoimmune condition include unexplained fevers and low blood oxygen levels in patients with other diseases, such as rheumatoid arthritis (RA), blood cancer, and lupus. The syndrome, although rare, has a high mortality rate, with approximately half of patients dying within 5 years of diagnosis.
Using a genomic ascertainment method, the retrospective observational study analyzed UBA1 variants in exome data taken from 163,096 patients (mean age 52.8 years; 61% female; 94% White) within a single regional health system in the United States to evaluate the prevalence of pathogenic variants and clinical manifestations. Clinical phenotypes were determined based on Geisinger electronic health record (EHR) data from January 1996 to January 2022. Outcome measures included the presence of rheumatologic, pulmonary, dermatologic, and hematologic symptoms in patients with somatic UBA1 variant using bone marrow biopsy pathology analysis, in vitro enzymatic assays, laboratory data, and EHR data.
In total, 11 patients had somatic variants at known pathogenic UBA1 positions, all of which reported clinical manifestations that were consistent with VEXAS syndrome. The syndrome affected men significantly more than women (9 vs 2, respectively). Seven (64%) patients had arthritis and 36% (n = 4) had rheumatologic diseases, such as dermatomyositis, sarcoidosis, psoriasis, and polymyalgia rheumatica. Although 45% (n = 5/11) did not have rheumatologic and/or hematologic diagnoses that were previously linked with VEXAS syndrome, all patients had anemia, which was predominantly macrocytic (91%, n = 10/11) and concomitant thrombocytopenia (91%, n = 10/11).
1 male patient had a pathogenic variant prior to VEXAS symptom onset and 2 female patients had disease with heterozygous variants. Further, a previously unreported UBA1 variant was found in 1 of the symptomatic patients. Ultimately, disease-causing UBA1 variants were found in 1 in 13,591 unrelated participants, 1 in 4269 male participants older than 50 years, and 1 in 26,238 women older than 50 years.
As data was taken from a single-center regional cohort of predominantly European descent, results may not be generalizable to other geographic locations and ethnicities. Additionally, investigators could not account for missing data of treatment, testing, or findings from external clinicians that was not captured in the Geisinger EHR.
Future research in unselected and genetically diverse patients will aid in better defining the prevalence of the disease in the general population as well as the phenotypic spectrum. Investigators aimed to raise awareness of VEXAS syndrome among clinicians, as Janus kinase (JAK) inhibitors, bone marrow transplantation, and high-dose steroids have been shown to effectively control certain symptoms.
“Our study offers the first glimpse of just how common VEXAS syndrome is in the United States, particularly among men, who also happen to be the most to die from it,” Beck concluded.
Beck DB, Bodian DL, Shah V, et al. Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population. JAMA. 2023;329(4):318-324. doi:10.1001/jama.2022.24836