Understanding VEXAS Syndrome: Why this often-missed condition affects men over 50

VEXAS syndrome is a clonal blood disorder that can trigger widespread inflammation throughout the body and mostly affects men over age 50. It is a systemic inflammatory autoimmune disease that can involve multiple organs and mimic more common conditions, making it hard to correctly diagnose.

The name VEXAS stands for Vacuoles, E1 enzyme, X-linked, Autoinflammatory and Somatic, reflecting key features of the disease.

Experts are now recognizing that VEXAS may be more common than previously thought, with 1 in 4,000 men over age 50 carrying the associated mutation in the blood. Early detection is critical for managing this potentially life-threatening condition.

To better understand VEXAS syndrome and its treatment options, including clinical trials, we spoke with leukemia specialist Danielle Hammond, M.D. Here is what she shared.

Risk factors for VEXAS syndrome and how it is diagnosed

First identified in 2020, VEXAS syndrome is caused by acquired mutations in the UBA1 gene that arise in blood-forming cells. It is not something you inherit from your family. The gene mutation happens later in life. It occurs most often in older men because the UBA1 gene sits on the X chromosome. Men have only one X chromosome, so a mutation in that gene can directly lead to the condition.

The symptoms of VEXAS can look like several other blood or inflammatory conditions, so it’s often missed. On average, getting the correct diagnosis can take about three years because patients often see multiple specialists before the condition is identified. However, a genetic test for the UBA1 mutation can confirm the diagnosis and help doctors choose the best treatment.

Hammond stresses that awareness is key: “VEXAS syndrome is often overlooked because its symptoms mimic more common diseases. Especially for men over 50 with unexplained inflammation and low blood counts, genetic testing for VEXAS-associated UBA1 mutations should be part of the diagnostic workup.”

Symptoms of VEXAS syndrome

VEXAS syndrome can affect multiple organ systems, making it difficult to diagnose. Common symptoms include:

• Unexplained recurrent fevers
• Large red blood cells (Macrocytosis)
• Low platelet counts (Thrombocytopenia)
• Skin inflammation and rash
• Inflammation of cartilage, especially in the ears (Relapsing polychondritis)
• Lung inflammation (Pneumonitis)
• Involvement of other organs like the kidneys, eyes, and epididymis
• Increased risk of blood clots (Venous thrombosis)

Patients with VEXAS syndrome are often initially misdiagnosed as having myelodysplastic syndrome (MDS), an age-related disorder in which the bone marrow produces faulty blood cells, leading to low blood counts and, in some cases, progression to acute myeloid leukemia (AML). Although VEXAS syndrome can be associated with MDS and cause the abnormal appearance of vacuoles in bone marrow cells, it is a distinct condition with both hematological and inflammatory autoimmune components.

“Patients can get incorrectly or incompletely labeled with a diagnosis of MDS. But when we run the usual genetic testing of their blood and bone marrow, we often don’t find the mutations or chromosomal changes that typically accompany a diagnosis of MDS.”

Treatment options for VEXAS syndrome

Currently, steroids are the first line of treatment for managing inflammation in VEXAS syndrome. While they can be effective, long-term use is associated with significant side effects, such as weight gain, bone loss and an increased risk of infections. As a result, there’s a growing need for alternative therapies that reduce reliance on chronic steroids.

For some patients, an allogeneic hematopoietic stem cell transplant offers the potential for a cure, though it is still being studied for this disease and is not suitable for all patients.

There are no therapies approved by the Food and Drug Administration (FDA) for VEXAS syndrome yet, but some treatments used for other diseases have shown promise. One is a class of immunosuppressant medications called JAK inhibitors, such as ruxolitinib. These drugs may help reduce inflammation and lower the dose of steroids patients need. Another therapy is azacitidine, a drug commonly used for MDS. Early studies suggest it may help with both inflammation and low blood counts, which are key features of VEXAS.

The first clinical trial designed specifically for VEXAS syndrome also recently opened. The PAXIS trial is studying pacritinib, a drug already approved for use in a blood cancer called myelofibrosis. The main treatment goal is to improve inflammatory disease control and help patients taper off steroids.

As awareness of this disease continues to grow, Hammond expects more clinical trials for VEXAS to open.

“We’re finally seeing the first drug trial specifically for VEXAS syndrome, and that’s a big step forward for patients,” she says. “It’s an exciting time because these early advances are likely just the beginning. We expect more trials to follow, and that momentum gives us hope for the future.”

VEXAS syndrome prognosis and what it means for life expectancy

VEXAS syndrome affects each person differently. It can range from manageable to severe, depending on factors such as time from symptom onset to diagnosis, levels of inflammation, which organs are involved and whether you develop other blood disorders like MDS. Without appropriate treatment, VEXAS can be life-threatening.

Early studies suggested that about 30-50% of men with VEXAS syndrome die within five years of diagnosis. Median survival is estimated to be around 10 years from the time symptoms begin, though it can be shorter in people with more aggressive disease or significant complications.

These numbers can be frightening, but it is important to remember that they reflect what is known so far about a newly identified condition. As awareness grows, doctors are diagnosing VEXAS earlier and learning which treatments work best for different patients. Ongoing research and clinical trials are focused on improving disease control, reducing complications and helping patients live longer and better with VEXAS syndrome.

Multidisciplinary care for VEXAS syndrome

Because VEXAS syndrome affects multiple organ systems, it’s important to seek care at a center that provides coordinated care from a team of specialists. At MD Anderson, experts from leukemia, rheumatology, dermatology, pulmonology, cardiology and pathology work together to manage every part of the disease.

Because VEXAS is a newly discovered condition, research continues to advance. This makes it especially important to seek care from clinicians who understand its complexity and can offer personalized treatment plans as well as access to the newest therapies and clinical trials.

Request an appointment at MD Anderson online or call 1-877-632-6789.