February 14, 2023

VEXAS syndrome more common than realized

At a Glance

  • A severe inflammatory disease called VEXAS is more prevalent and has a broader range of symptoms than expected.
  • Additional studies of racially diverse populations are needed to better understand the scope and symptoms of this hard-to-recognize disease.
Older man talking to a doctor The study suggests that VEXAS disease, which was only recently discovered, may be more common than previously thought. Lucky Business / Shutterstock

In 2020, a team of NIH researchers reported the discovery of a rare and often-deadly inflammatory disorder, which they named VEXAS. Affected people have varying symptoms that can include anemia, recurrent fevers, painful rashes, blood clots, and shortness of breath. Because these symptoms overlap with other autoimmune and inflammatory diseases, VEXAS can be hard to recognize. But having an accurate diagnosis is important for effective treatment.

VEXAS was discovered by searching for genetic variants that were shared among more than 2,500 patients with body-wide inflammation or other unusual and undiagnosed conditions. The identified gene, UBA1, is on the X chromosome, and all 25 people initially diagnosed with VEXAS were male. Since men have only one X chromosome, they only have one copy of the gene. Women typically have two X chromosomes and therefore two copies of UBA1. In women, a mutation in only one copy is likely to cause less severe or no disease. The genetic mutations that cause this disease occur after birth and so aren’t transmitted from parents to children.

A research team set out to assess the symptoms and prevalence of VEXAS-related variants in a larger population. The group was led by Dr. David Beck of New York University, in collaboration with Drs. Jung Kim and Douglas Stewart of NIH’s National Cancer Institute. The scientists combed through data from more than 160,000 patients in a regional health care system in Pennsylvania. All had agreed to have their DNA screened. Participants were predominantly white (94%, which roughly matches regional demographics), and more than half were women (61%). The mean age of participants was 53. Results appeared online in JAMA on January 24, 2023.

Genetic analysis revealed that 12 of the participants (or 1 in 13,591 people) appeared to have disease-related variants in UBA1. Ten were men and two were women. Health records showed that all 12 had symptoms consistent with VEXAS, including a range of autoimmune, lung, or skin abnormalities. 

By closely examining the 12 participants’ medical records, the researchers found that UBA1 variants led to a broader range of symptoms than originally thought. “Classic” symptoms of VEXAS were also sometimes absent. The researchers note that a diagnosis based on symptoms alone could easily miss cases of VEXAS that would be caught by UBA1 testing.

“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 likely to die from it,” Beck says. “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.”

The team now aims to conduct similar studies among more racially diverse groups to gain a clearer picture of who’s most at-risk for developing VEXAS. “In addition, there are other genes that may be associated with inflammatory disorders like VEXAS,” Stewart says. “The team is investigating if mutations in those genes are linked to VEXAS-like medical problems for the people who harbor those variants.”

—by Vicki Contie

Related Links

References: Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population. Beck DB, Bodian DL, Shah V, Mirshahi UL, Kim J, Ding Y, Magaziner SJ, Strande NT, Cantor A, Haley JS, Cook A, Hill W, Schwartz AL, Grayson PC, Ferrada MA, Kastner DL, Carey DJ, Stewart DR. JAMA. 2023 Jan 24;329(4):318-324. doi: 10.1001/jama.2022.24836. PMID: 36692560.

Funding: NIH’s National Cancer Institute (NCI), National Human Genome Research Institute (NHGRI), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and National Institute of General Medical Sciences (NIGMS); Relapsing Polychondritis Foundation.