Unraveling VEXAS: An Autoimmune Condition Impacting Men Over 50

Our understanding of autoimmune diseases is advancing, including the recent discovery of VEXAS, a severe inflammatory condition that affects mainly middle-aged men.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic) is a collection of diverse symptoms that were previously considered separate conditions and diseases. “There is one specific gene mutation that causes VEXAS, but this syndrome doesn’t cause the same symptoms for every patient,” says Jose Pablo Garcia, M.D., a rheumatologist with the University of Miami Health System.

One study estimates that one in every 13,591 people (men and women) with some symptoms of VEXAS has the gene mutation. According to the U.S. National Institutes of Health, medical records show that one out of every 4,269 men older than age 50 has been diagnosed with VEXAS. 

What are the symptoms of VEXAS?

The inflammation caused by VEXAS syndrome can trigger one or more of the following symptoms:

• anemia
• fever
• headaches
• joint pain
• low blood oxygen levels
• night sweats
• persistent cough
• red eye
• shortness of breath
• skin rash
• swelling
• swollen testicles

“Usually, the patient’s experience starts with a constellation of odd inflammatory symptoms,” Dr. Garcia says. “It’s not uncommon that we see a VEXAS patient — typically a male older than 50 — with recurrent fevers with no known cause. These patients find it very hard to taper off of the steroids that we’re using to control their inflammatory symptoms (such as fever, rash, or joint swelling/joint pain). Patients with VEXAS usually require high doses of prednisone (above 20 mg). This is a unique feature.”

Complications of VEXAS

If the inflammation triggered by VEXAS syndrome advances, some patients become more likely to develop other health conditions, including:

• anemia
• arthritis
• bone marrow failure
• chondritis (swollen cartilage)
• colitis
• deep vein thrombosis
• dermatitis
• leukemia
• myocarditis
• vasculitis

“As VEXAS advances, some patients develop chondritis (specifically, relapsing polychondritis, which is inflammation of the cartilage of the nose, outer ear, and/or trachea),” says Dr. Garcia. “We now know that relapsing chondritis and stridorous breathing (high-pitched sounds caused by a partially blocked airway) with sore throat are often key indicators of VEXAS.”

What causes VEXAS?

Since VEXAS was officially recognized as an autoimmune condition in 2020, “we have found that it is a somatic mutation that happens randomly in the bone marrow,” Dr. Garcia says. “We know it’s a mutation of the UBA1 gene on the X chromosome.” That’s why VEXAS primarily affects males. “It’s very rare for a woman to get it because it would require two random mutations in the X chromosomes, which would be remarkably rare.

“Unfortunately, we don’t know why these myeloid cells undergo a mutation. We don’t know yet if this gene mutation is inherited or if it’s triggered by, say, environmental or lifestyle conditions. That is still being investigated,” he says.

How is VEXAS diagnosed?

The only way to confirm that a patient has VEXAS is through genetic testing for the UBA1 gene mutation. The sample for genetic testing can come from the patient’s blood or bone marrow.

“One feature that is unique to VEXAS is its association with a group of blood disorders called myelodysplastic syndrome (MDS), including macrocytosis (enlarged red blood cells),” Dr. Garcia says. If a patient has severe macrocytosis (an MCV greater than 100), without any clear cause, and they need consistently high doses of prednisone, they should be tested for the VEXAS gene mutation.

“For patients with MDS, the gold standard for genetic testing is a bone marrow biopsy,” he says. “If we don’t suspect the patient has MDS, then we can conduct the genetic testing with a blood sample.”

Most VEXAS patients are diagnosed and treated by a rheumatologist, hematologist, or dermatologist — depending on their primary symptoms.

How is VEXAS treated?

Because VEXAS is an inflammatory condition, the first line of therapy is steroids.

“It usually requires a very high dose of steroids to control the symptoms,” Dr. Garcia says. “All of the other immunosuppressants that we usually use in rheumatology haven’t proved to be successful in treating VEXAS, unfortunately.”

Some immunosuppressants may offer marginal benefit (per available case reports). However, she says, these studies have not been able to induce remission for patients, meaning they have not been able to completely get off of steroids or manage their symptoms at low doses of steroids.

Additional treatments for VEXAS are based on each patient’s symptoms.

For patients with MDS, treatments like JAK inhibitors (like Ruxolitinib) can help.

“The other treatments that are being explored are biologics, specifically IL-6 inhibitors (which block the activity of an inflammation-triggering protein). This class of drugs has had some good results,” he says.

“There are also case reports of doctors and their patients with VEXAS trying different treatments to control inflammatory arthritis symptoms and those that mimic rheumatoid arthritis. Patients with these symptoms may try the drug methotrexate.” This drug is currently used to treat a variety of conditions, from cancers to inflammatory bowel diseases.

Research on VEXAS is ongoing with hopes of better understanding the mechanisms that trigger the gene mutation that causes this syndrome. Clinicians are working to improve diagnostics and identify the types of medications and anti-inflammatory therapies that can best help patients with VEXAS.

Written by Dana Kantrowitz.

Tags: chronic inflammation, Dr. Jose Pablo Garcia, inflammation in men, rheumatology