What Is VEXAS Syndrome? Newly Discovered Disease May Be More Common Than Once Thought

VEXAS syndrome—an autoimmune condition that primarily affects the bone marrow and blood—may be more common than previously thought, particularly among men over the age of 50, new research shows.

First identified in late 2020, VEXAS syndrome is linked to a somatic mutation in the UBA1 gene in the bone marrow, which means it’s acquired over the course of a person’s lifetime, not inherited. The syndrome can cause inflammation in multiple organs, including the skin, lungs, joints, and blood vessels.

Because VEXAS syndrome is a very new condition, researchers of the new study, published this week in the Journal of the American Medical Association (JAMA), sought to identify its prevalence in the U.S. population.

Though still generally rare, researchers concluded that it may affect as many as one in 4,269 men and one in 26,238 women, both over the age of 50, in the U.S.—far more than expected for a newly discovered condition.

“Most newly discovered diseases at the National Institutes of Health are very, very rare diseases that a doctor may never see in their lifetime,” Peter Grayson, MD, principal investigator of the National Institute of Arthritis, Musculoskeletal, and Skin Diseases vasculitis translational research program, told Health. “This one’s a bit different. This one is actually turning out [that]—even though it’s a rare disease—it’s more common than anticipated.”

Here’s what we know about VEXAS syndrome so far, how researchers discovered the condition, and how additional studies and trials are working to help people with VEXAS. 

A New Disease With a Higher Prevalence Than Expected

For the new study, researchers analyzed genetic data from more than 163,000 participants within the Geisinger health system in Pennsylvania, looking for the UBA1 gene variant associated with VEXAS syndrome.

"We took the approach of looking at every individual in their database, in their health system, that had mutations in UBA1, and looked at how common they were, what symptoms patients had, and what diagnoses they had,” said David Beck, MD, PhD, assistant professor at New York University's Grossman School of Medicine, who has co-authored multiple studies on VEXAS syndrome, along with Dr. Grayson.

Out of those participants, 11 had the UBA1 gene variant—two women and nine men—and all 11 also had symptoms consistent with VEXAS syndrome. Overall, it was concluded that one in 13,591 people may have VEXAS syndrome, with the disease mainly affecting men over the age of 50.

Although the new study helped researchers determine the prevalence of VEXAS syndrome, the disease was actually identified about three years ago in 2020, when a team of researchers discovered the UBA1 gene mutation in a group of patients who were unable to get a clear diagnosis or effective treatment for a variety of symptoms they were experiencing.

“At first pass, it wasn’t totally clear that these patients [had] the same symptoms, because with rheumatologic diseases, symptoms can change over time,” Dr. Beck told Health. “But when we found enough patients [...] we were able to find a lot of similarities in their symptoms and clinical presentations.”

That research, published in December 2020 in the New England Journal of Medicine, gave both the 25 patients seeking answers a definitive diagnosis, and the previously unknown disease the name VEXAS syndrome, which is an acronym for: vacuoles [in the bone marrow cells], E1 enzyme, X-linked, autoinflammatory, and somatic—all key characteristics of the disease.

Nonspecific Symptoms That Affect a Specific Population

One key reason why VEXAS syndrome was difficult to pin down is because the disease has a wide range of symptoms that frequently mimic other diseases, according to Dr. Grayson.

“VEXAS has been around well before our identification of it, it’s just that patients were classified as having other diagnoses. But they didn’t quite fit those diagnoses,” Dr. Beck said. “It was hiding within well-established clinical diagnoses.”

Patients with VEXAS syndrome often have fever and extreme fatigue—two symptoms that can be attributed to many different diseases. The condition can also show up in various ways on the skin, in the lungs and joints, and within a person’s vasculature, or blood vessels.

“[Patients] get inflammation in their skin, which is in the form of many different types of rashes,” said Dr. Grayson. “They get inflammation in their cartilage, which can lead to swelling of the ears or the nose; they can get inflammation in their joints, and in their lungs, and even in their blood vessels.”

People with VEXAS syndrome may also see their blood counts fall over time, which can be dangerous if left untreated, Dr. Grayson added.

Because of those different manifestations, patients may have initially sought the help of rheumatologists, hematologists, dermatologists, or other doctors, which led to a greater likelihood of being misdiagnosed with a number of different conditions.

Now, however, physicians are more aware of VEXAS syndrome, and thus know what to look for in diagnosing it, Ifeyinwa Obiorah, MD, PhD, assistant professor of pathology at the University of Virginia Health System, told Health. 

If a healthcare provider sees symptoms that may be indicative of VEXAS syndrome, they can suggest a bone marrow biopsy, which can give a hematologist a closer look at a person’s blood. If someone has VEXAS syndrome, they’ll usually have bubbles or vacuoles—the “V” in VEXAS—in their blood that are visible. Further genetic testing may also identify a mutation in the UBA1 gene, said Dr. Obiorah.

Seeing a male patient over the age of 50 with VEXAS-like symptoms may also push a physician to consider the disease as a diagnosis. Men are primarily affected by VEXAS syndrome, likely due to UBA1 mutation being on the X chromosome. Men have one “X” and one “Y” chromosome, so they’re more likely to have VEXAS, though it is still possible for women to have the disease, too.

Treatment Options Still Left to Be Discovered

As a newly identified disease, there are still many questions left unanswered about VEXAS, especially how to treat it.

Many VEXAS patients will take anti-inflammatory medications called glucocorticoids to help manage symptoms, but those can often have unwanted steroid side effects.

“It’s a really wonderful thing to be able to give these patients that diagnosis of VEXAS syndrome, some of whom have been struggling with these symptoms for years and years,” Dr. Grayson said. “But then the next question immediately is always, ‘Okay, so what do we do about it?’ And that’s the part that’s been very difficult—it’s a disease that, to date, has been very difficult to treat.”

Treating VEXAS is important, however, as the disease is oftentimes quite severe. It can cause blood clots, anemia, fatigue, and low platelets, and some people with VEXAS will have blood cancers, Dr. Obiorah said. The disease is associated with high morbidity and mortality.

One potentially promising treatment is a bone marrow transplant, Dr. Beck explained.

“For really severe cases or cases where there’s a lot of blood problems, there have been over 20 patients with VEXAS already transplanted—having a bone marrow transplant,” Dr. Beck said. “This can be curative because you’re replacing the mutation in the blood. But it comes with considerable risks associated with the procedure.”

Drs. Beck and Grayson are continuing to do research on VEXAS, and are focusing on figuring out ways to help treat or cure the condition.

In the meantime, however, the recent strides made in identifying and gathering more information about VEXAS is a place to start. It’s important that physicians especially are on the lookout for VEXAS and know to test for it if need be, Drs. Grayson and Obiorah said.

“With more patients being diagnosed with [VEXAS], we’ll learn more about what can happen and how best to treat it,” Dr. Beck said. “Increased recognition will be an important point towards getting better control over treatment.”