VEXAS syndrome is a serious inflammatory disease caused by a genetic mutation that develops spontaneously in blood stem cells, triggering widespread inflammation throughout the body. First identified in December 2020 by researchers at the National Institutes of Health, it primarily affects men over 50 and can mimic a wide range of autoimmune and blood disorders, often going undiagnosed for years.
What the Name Means
VEXAS is an acronym that captures the disease’s core features. The V stands for vacuoles, which are tiny bubble-like spaces that appear inside bone marrow cells in more than 80% of patients. E1 refers to the type of enzyme disrupted by the disease. X marks the chromosome where the affected gene sits. A stands for autoinflammatory, reflecting the runaway inflammation the mutation triggers. S stands for somatic, meaning the mutation isn’t inherited from a parent but instead arises on its own during a person’s lifetime.
How the Mutation Causes Disease
The root of VEXAS is a mutation in a gene called UBA1, which sits on the X chromosome. This gene produces an enzyme that plays a critical role in tagging damaged or unwanted proteins inside cells so they can be recycled and cleared away. When UBA1 is mutated, that cleanup process breaks down. Damaged proteins accumulate, and the immune system responds with persistent, uncontrolled inflammation.
Because the mutation is somatic, it isn’t present at birth. Instead, it appears in a blood stem cell at some point during adulthood, then spreads as that stem cell divides and produces new blood cells. This means the mutation shows up in blood and bone marrow samples but not in other tissues like skin. It also explains why the disease develops later in life rather than in childhood.
Since UBA1 is on the X chromosome, men are far more vulnerable. Men have only one X chromosome, so a single mutation can knock out the gene’s function entirely. Women have two copies, which gives them a backup. This is why VEXAS overwhelmingly affects men, though rare cases in women do occur.
Who Gets VEXAS
A 2023 population study published in JAMA estimated that roughly 1 in 4,269 men over age 50 carry a UBA1 variant associated with VEXAS. Among women over 50, the rate drops to about 1 in 26,238. Across all adults over 50, the overall prevalence is approximately 1 in 7,931. Those numbers make VEXAS far more common than researchers initially expected for a disease that was only discovered a few years ago. The average age at onset is around 67.
Symptoms and What It Looks Like
VEXAS produces a bewildering mix of symptoms because the inflammation it generates can affect nearly any organ system. Fevers, fatigue, and weight loss are common early signs. Skin problems, including painful rashes and nodules, appear frequently. The eyes, lungs, and cartilage (particularly in the ears and nose) are often involved. Joint pain and swelling can look identical to rheumatoid arthritis.
Blood abnormalities are a hallmark. Nearly all patients develop some combination of low red blood cell counts (often with unusually large red blood cells), low platelet counts, and drops in white blood cell subtypes like lymphocytes, monocytes, or neutrophils. Many patients are also found to have myelodysplastic syndrome, a condition where the bone marrow fails to produce healthy blood cells efficiently. Blood clots, including dangerous clots in the lungs or deep veins, are another recognized complication.
This wide-ranging symptom profile is exactly what makes VEXAS so tricky. Before its discovery, many of these patients were diagnosed with conditions like Sweet syndrome (a type of inflammatory skin disease), relapsing polychondritis (inflammation of cartilage), polyarteritis nodosa, Behçet’s disease, or various forms of vasculitis. Some carried multiple diagnoses simultaneously, none of which fully explained the full picture. VEXAS often turns out to be the unifying explanation behind what appeared to be several separate conditions.
How VEXAS Is Diagnosed
Diagnosis requires genetic testing. Specifically, doctors look for a UBA1 mutation in blood or bone marrow samples. The mutation will not appear in skin tissue, so a skin biopsy cannot confirm or rule out the disease.
A bone marrow aspirate often provides the first major clue. When pathologists examine the sample under a microscope, they typically see characteristic vacuoles (small empty-looking holes) inside developing blood cells. This finding appears in more than 80% of VEXAS patients and is striking enough to prompt genetic testing. However, a small number of patients have few or no visible vacuoles, so their absence alone doesn’t rule out VEXAS. If the clinical picture is suspicious, genetic testing should still be pursued.
In practice, VEXAS should be considered in any man over 50 who has unexplained inflammation affecting multiple organ systems alongside blood count abnormalities, particularly macrocytic anemia (large red blood cells) and low platelets. When those features appear together with conditions like relapsing polychondritis or Sweet syndrome, the combination is especially suggestive.
Treatment Options
There is no single standard treatment for VEXAS, and management depends heavily on which symptoms are most prominent. Most patients need some form of immune suppression to control the inflammation.
Corticosteroids like prednisone are often the first line of defense. They reduce inflammation and pain effectively, but long-term steroid use carries well-known side effects, so doctors work to find alternatives that can lower the steroid dose over time. Immune-suppressing medications are commonly used for this purpose. These include drugs that block specific inflammatory signals, such as tocilizumab, and a class of medications called JAK inhibitors (ruxolitinib, tofacitinib, and baricitinib among them). These medications help prevent the immune system from attacking healthy tissue.
For patients with more severe blood involvement, chemotherapy may be used to target the abnormal bone marrow cells carrying the mutation.
Stem Cell Transplant as a Potential Cure
The only treatment with curative potential is an allogeneic stem cell transplant, where a patient’s bone marrow is replaced with healthy donor marrow. Because the UBA1 mutation lives in blood stem cells, replacing those stem cells can eliminate the source of the disease entirely.
A systematic review pooling data from 39 transplanted patients found an overall survival rate of 86% and an event-free survival rate (meaning alive without disease relapse or major complications) of 56%, with follow-up periods ranging from 8 to 18.5 months. The transplant-related mortality rate was 14%, and a significant proportion of patients experienced graft-versus-host disease, a complication where the donor cells attack the recipient’s body. These numbers reflect a procedure that works but carries real risks, particularly for older patients who may already be in poor health.
Prognosis
VEXAS is a serious diagnosis. Current estimates place the five-year mortality rate between 18% and 40%, a range that reflects differences in disease severity, mutation type, and access to treatment. The patients who fare worst tend to be those with severe blood count problems, frequent blood clots, or progression to full myelodysplastic syndrome. Patients who respond well to immune-suppressing therapy or who are healthy enough to undergo a stem cell transplant generally have better outcomes, though the disease requires ongoing monitoring and management regardless.