According to a new study, approximately 13,200 men and 2,300 other women in the United States over the age of 50 have VEXAS syndrome. Long considered a mysterious disease until its genetic basis was identified in 2020, the latest findings, led by researchers at NYU Grossman School of Medicine, offer the first indication of the disease’s prevalence nationwide.
Although a rare disease, the syndrome has a high mortality rate, with up to half of people, mostly men, dying within five years of diagnosis. The syndrome most often involves unexplained fevers and low blood oxygen levels in people diagnosed with other illnesses, such as rheumatoid arthritis, lupus, and blood cancer. Some of the symptoms have been linked to an overactive immune system, which can cause inflammation and classify the syndrome as an autoimmune disease.
The researchers say they hope their findings will raise doctors’ awareness of the disorder, particularly because high-dose steroids, JANUS kinase inhibitors and bone marrow transplantation have been shown to be effective in controlling some symptoms.
“Now that we know that VEXAS syndrome is more common than many other types of rheumatologic conditions, physicians should add this condition to their list of potential diagnoses when faced with patients with persistent, unexplained inflammation and a low blood cell count, or anemia,” says study geneticist and principal investigator David Beck, MD, PhD. Beck, an assistant professor in the Department of Medicine and the Department of Biochemistry and Molecular Pharmacology at NYU Langone Health, also led the federal research team that initially identified the shared UBA1 mutation in VEXAS patients.
In the new study, published in the Journal of the American Medical Association (JAMA) online Jan. 24, researchers analyzed the electronic health records of 163,096 mostly white men and women in Pennsylvania who agreed to have their blood DNA tested for signs of genetic disease. Twelve were found to carry the UBA1 mutation, all showing symptoms of VEXAS.
Statistically, this corresponded to one in 4,269 American men over the age of 50 and one in 26,238 women over the age of 50 with or at risk of developing the syndrome. According to the researchers, this is a higher prevalence figure than many other inflammatory conditions, including vasculitis and myeloid dysplasia syndrome.
“Our study offers the first insight into the frequency of VEXAS syndrome in the United States, particularly in men, who also have the highest number of deaths from it,” says Beck, who leads several clinical research efforts on VEXAS syndrome at NYU Langone Center for Human Genetics and Genomics.
Previous research, led by Beck, traced the origins of the syndrome to a mutation or change in the alphabetic code that makes up DNA, in the UBA1 gene (short for Ubiquitin-like Modifying Activating Enzyme 1.) L enzyme generally helps in protein breakdown.
VEXAS represents several of its biological characteristics: vacuoles in blood cells, the E1 enzyme, X-linked, auto-inflammatory and somatic.
For the study, researchers analyzed the electronic medical records of adult patients who volunteered to participate in the Geisinger MyCode community health initiative. The program has been collecting data for more than 25 years from patients at Geisinger’s more than 10 hospitals in central and northeastern Pennsylvania. Almost all of the study participants who agreed to have their blood DNA tested were white; half were over 60 years old.
Beck says the team next plans to analyze patient records in more racially diverse groups, particularly among those with higher rates of rheumatology and blood diseases, to get a more accurate picture of who is. most at risk for VEXAS syndrome. They also plan to search for additional genetic causes, test new therapies for the syndrome, and develop a simple blood test for UBA1 to help with diagnosis.
Funding for the study was provided by National Institute of Health grants R00AR078205 and T32GM136542.
Besides Beck, other NYU Langone researchers involved in this study are Samuel Magaziner, MPhil; and Ann Cantor, MS. Other co-investigators on the study are Dale Bodian, PhD, at Geisinger Research in North Bethesda, Md.; Vandan Shah, MD; Uyenlinh Mirshahi, PhD; Natasha Strande PhD; Jeremy Haley, MS; Adam Cook, MS; Wesley Hill; Yi Ding, MD, PhD; and David Carey, PhD, at Geisinger Health in Danville, Pennsylvania; Jung Kim, PhD, and Douglas Stewart, at the National Cancer Institute in Rockville, Md.; Alan Schwartz, MD, PhD, at Washington University in St. Louis, Mo.; Peter Grayson, MD, and Marcela Ferrada, MD, at the National Institute of Arthritis, Musculoskeletal and Skin Diseases at Bethesda; and Daniel Kastner, MD, at the National Human Genome Research Institute, also at Bethesda.