VEXAS is a serious inflammatory disease caused by an acquired genetic mutation in blood stem cells. First identified in 2020, it primarily affects men over 50 and triggers widespread inflammation across multiple organ systems, including the skin, lungs, joints, and blood. The name itself is an acronym: Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic. It is more common than initially thought, affecting roughly 1 in every 4,269 men older than 50.
What Causes VEXAS
VEXAS starts with a mutation that develops spontaneously in blood-forming stem cells in the bone marrow. It is not inherited from your parents. The mutation occurs in a gene called UBA1, located on the X chromosome, which produces an enzyme responsible for tagging damaged or unwanted proteins in your cells so they can be recycled. This protein-recycling process, called ubiquitylation, is essential for keeping cells functioning properly.
The specific mutation hits a single spot on the gene (a position known as methionine-41), which knocks out the normal version of the enzyme that works in the main body of the cell. In its place, the cell produces a stunted, poorly functioning version. Without proper protein recycling, immune cells become hyperactivated and trigger inflammation throughout the body. Over time, these mutant blood cells multiply and outnumber healthy ones, making the inflammation progressively worse and harder to control.
Because UBA1 sits on the X chromosome, men are far more vulnerable. Men have only one X chromosome, so a single mutation is enough to cause disease. Women have two copies and can typically rely on the backup, though rare cases in women have been reported.
Symptoms and How It Affects the Body
VEXAS is a multisystem disease, meaning it can show up in many different parts of the body at once or over time. The most common features are recurrent fevers, skin lesions, lung problems, joint pain, blood clots, and various forms of blood vessel inflammation (vasculitis). In a large case series, skin involvement appeared in about 83% of patients, lung problems in 50%, and joint pain in 27%.
On the blood side, VEXAS causes progressive abnormalities that often bring patients to a hematologist before anyone suspects the underlying condition. Macrocytic anemia (unusually large red blood cells combined with low red blood cell counts) is common, along with low platelet counts. Many patients develop myelodysplastic syndrome, a condition where the bone marrow fails to produce healthy blood cells efficiently. Some patients become dependent on regular blood transfusions.
Blood clots are another hallmark. Deep vein thrombosis and pulmonary embolism occur at rates far higher than in the general population, adding to the disease’s danger. The combination of inflammation, blood abnormalities, and clotting risk makes VEXAS particularly difficult to manage.
Why It’s Often Misdiagnosed
Before VEXAS was identified, many patients spent years being treated for other conditions. The disease mimics several well-known inflammatory disorders, including relapsing polychondritis (which causes cartilage inflammation, especially in the ears and nose), Sweet syndrome (painful skin lesions with fever), and various forms of vasculitis.
A French study comparing VEXAS-related polychondritis with the standard form of the disease found striking differences. VEXAS patients were overwhelmingly male (96% vs. 30%), older at diagnosis (average age 66 vs. 44), and far more likely to have fever, skin lesions, lung infiltrates, and eye involvement. Their inflammatory markers were roughly seven times higher. Perhaps most telling, 75% of VEXAS patients had myelodysplastic syndrome, compared to none in the standard polychondritis group. Only 27% of VEXAS patients achieved remission with treatment, compared to 90% of those with the standard form. If you’re an older man with an inflammatory condition that stubbornly resists treatment and comes with blood count abnormalities, VEXAS should be on the radar.
How VEXAS Is Diagnosed
Diagnosis requires genetic testing to confirm a mutation in the UBA1 gene. This is typically done through sequencing of blood or bone marrow samples, specifically looking for mutations at the methionine-41 position. Standard genetic panels for inherited conditions won’t catch it because VEXAS is a somatic mutation, meaning it arises in the body’s cells after birth rather than being passed down through families.
A bone marrow biopsy often provides the first major clue. The hallmark finding is prominent vacuoles (small fluid-filled bubbles) inside early-stage blood cells called myeloid and erythroid precursors. This vacuolization pattern is not unique to VEXAS and can appear with certain medications, nutritional deficiencies, or other blood disorders. But when it shows up alongside unexplained inflammation and blood count problems, it strongly points toward VEXAS and should prompt genetic testing.
Treatment Options
There is currently no FDA-approved treatment specifically for VEXAS. Most patients rely on high-dose corticosteroids to control inflammation, and while steroids often work initially, the disease tends to flare whenever the dose is reduced. Long-term steroid use brings its own serious problems: bone thinning, weight gain, high blood sugar, cataracts, and increased infection risk.
To reduce steroid dependence, doctors use immune-suppressing medications. JAK inhibitors (a class of drugs that block specific inflammatory signaling pathways) have shown promise in dampening the overactive immune response. Other immune-modulating therapies that target inflammatory signaling molecules are also used. These medications help control swelling and reduce the need for steroids, though responses vary significantly between patients.
The only treatment with the potential to cure VEXAS is a bone marrow transplant from a donor. Because the mutation lives in blood stem cells, replacing those stem cells with healthy ones from a matched donor can eliminate the source of disease. In a review of 33 patients who received transplants, about 82% were alive at a median follow-up of nine months. However, the procedure carries substantial risks, particularly infections, which were the leading cause of death among transplant recipients. Candidates are generally 75 or younger and must have either steroid-resistant inflammation, persistent blood count problems requiring transfusions, or evidence of progression toward blood cancer. Given that VEXAS patients tend to be older with multiple health issues, the decision involves careful assessment of organ function, infection risk, and overall fitness.
Prognosis and Outlook
VEXAS is a serious diagnosis. The five-year mortality rate ranges from 18% to 40%, with infections being the leading cause of death. This reflects both the disease itself and the toll of immunosuppressive treatments that leave patients vulnerable. Progressive bone marrow failure and transformation to blood cancer are additional long-term risks.
The disease was only defined in 2020 by researchers at the National Institutes of Health, and awareness is still growing. Prevalence studies suggest roughly 1 in 13,591 adults overall carry the mutation, a figure much higher than expected for a condition considered “rare.” Many patients likely remain undiagnosed, particularly those currently being treated for conditions like myelodysplastic syndrome, relapsing polychondritis, or unexplained vasculitis who haven’t been tested for UBA1 mutations. Increasing recognition among rheumatologists, hematologists, and dermatologists is steadily improving the speed of diagnosis.