About 13,200 men and another 2,300 women in the United States over age 50 are estimated to have VEXAS syndrome, according to a new study led by researchers at NYU Grossman School of Medicine. VEXAS was long considered a mystery illness until its genetic basis was identified in 2020, and the latest findings offer the first indication of how common the illness is domestically.
The rare syndrome carries 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 diseases, such as rheumatoid arthritis, lupus, and blood cancer such as leukemia. Some of the symptoms have been linked to an overactive immune system—which can cause inflammation—making the syndrome an autoimmune condition.
Researchers hope their findings will raise awareness of the disorder among physicians, particularly because high-dose steroids, JANUS kinase inhibitors, and bone marrow transplants have proven effective in controlling some symptoms.
"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 levels, or anemia," says geneticist and study lead investigator David B. Beck, MD, PhD. Dr. Beck, an assistant professor in the Department of Medicine and the Department of Biochemistry and Molecular Pharmacology at NYU Langone Health and director of NYU Langone's clinical Inflammatory Disease Genetics Program, also led the federal research team that initially identified the shared UBA1 mutation among VEXAS patients.
In the new study, published online in the Journal of the American Medical Association (JAMA) January 24, researchers analyzed the electronic health records of 163,096 mostly White men and women in Pennsylvania who agreed to have their blood DNA screened for signs of genetic disease. Twelve were found to have the UBA1 mutation, with all experiencing VEXAS symptoms.
Statistically, this corresponds to 1 in 4,269 American men over age 50 and 1 in 26,238 women over age 50 having or being likely to develop the syndrome. This, researchers say, is a higher prevalence rate than many other inflammatory conditions, including vasculitis and myeloid dysplasia syndrome.
"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," says Dr. Beck, who is leading several clinical research efforts into VEXAS syndrome at NYU Langone's Center for Human Genetics and Genomics.
Previous research, led by Dr. Beck, traced the origins of the syndrome to a mutation, or change in the letter code that makes up DNA, in the gene UBA1 (short for ubiquitin-like modifier activating enzyme 1). The enzyme usually assists in protein breakdown.
VEXAS is an acronym formed from many of its biological characteristics: vacuoles in blood cells; the E1 enzyme; X-linked, meaning the gene is on the X chromosome; autoinflammatory; 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 in Geisinger's 10-plus hospitals in Central and Northeastern Pennsylvania. Almost all study participants who agreed to have their blood DNA tested were White, and half were over the age of 60.
Dr. Beck says the team next plans to analyze patient records in more racially diverse groups, especially among those with higher rates of rheumatologic and blood disease, to gain a more precise picture of who is most at risk of VEXAS syndrome. They also plan to look for additional genetic causes, test new therapies for the syndrome, and develop a simple blood test for UBA1 to make it easier to diagnose.
Beck, D.B., et al. (2023) Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population. JAMA. doi.org/10.1001/jama.2022.24836.