How Is VEXAS Syndrome Different From MDS? When to Test

VEXAS syndrome is a rare genetic condition that causes severe, widespread inflammation and abnormal blood counts, whereas Myelodysplastic Syndrome (MDS) is a group of blood cancers caused by faulty blood-forming cells in the bone marrow. While they are distinct conditions, they can look very similar under a microscope and frequently coexist ^[1][2].

Your doctor may consider genetic testing for a mutation in the UBA1 gene (the cause of VEXAS) if you have unexplained fevers, treatment-resistant inflammation, skin rashes, or cartilage pain alongside your cytopenias (low blood counts) ^[3]. VEXAS is most common in men over the age of 50, but it can also affect women and younger adults ^[3][2].

Important Safety Warning: Do not wait for genetic testing if you experience a fever, especially if your white blood cell count is low. In MDS, a fever can be a sign of a life-threatening infection rather than a VEXAS flare. Seek urgent emergency care if you have a fever (follow your doctor’s temperature threshold), chills, sudden chest pain, shortness of breath, coughing up blood, one-sided leg swelling, sudden vision changes, or severe eye pain.

Understanding the Difference

MDS primarily affects how your bone marrow produces blood cells. In contrast, VEXAS is an autoinflammatory syndrome ^[2]. This means the innate immune system becomes hyperactive and attacks the body’s own tissues. Unlike inherited genetic diseases passed down in families, VEXAS is caused by a somatic (acquired during your lifetime) mutation in the UBA1 gene ^[1]. This mutation occurs in the blood stem cells but triggers severe inflammation throughout the body.

MDS and VEXAS can be difficult to tell apart because they share many features:

• Both cause cytopenias, particularly macrocytic anemia (a condition where you don’t have enough red blood cells, and the ones you do have are larger than normal) ^[4].
• Both feature abnormal, poorly formed blood cells in the bone marrow ^[5].
• They frequently coexist. In one major VEXAS registry, about half of the patients also had an overlapping hematologic (blood) disease, most commonly MDS ^[2].

When MDS coexists with VEXAS, studies of certain patient groups have shown the MDS component sometimes has a lower blast count (the number of immature, cancerous cells) and fewer high-risk genetic mutations ^[5][4]. However, having VEXAS does not guarantee a low-risk MDS prognosis. Your hematologist must still calculate your formal MDS risk score (using systems like IPSS-R or IPSS-M) based on your blood counts, marrow blasts, and cytogenetic findings ^[5].

Clinical Clues It Might Be VEXAS

Because VEXAS drives systemic inflammation, it causes symptoms that are unusual for standard MDS. Your doctor may suspect VEXAS if your blood abnormalities are accompanied by:

• Unexplained fevers or extreme fatigue that doesn’t resolve ^[2].
• Skin inflammation, such as painful red nodules, rashes, or neutrophilic dermatoses (conditions like Sweet syndrome, where inflammatory white blood cells accumulate in the skin) ^[2][6].
• Relapsing polychondritis (painful, repeated inflammation of the cartilage, especially in the ears or nose) ^[2][7].
• Lung or eye inflammation, such as pulmonary infiltrates (substances like fluid or inflammatory cells in the lungs) or redness and severe pain in the eyes ^[6][7].
• Blood clots (venous thrombosis), which have been reported in over a third of patients in some VEXAS cohorts ^[2][7].

Bone Marrow Clues: The Role of Vacuoles

When a pathologist examines a bone marrow biopsy, one major clue can point toward VEXAS: the presence of vacuoles (empty, bubble-like spaces) inside the precursor cells (the early, immature cells that grow into red and white blood cells) ^[8][9].

However, vacuoles are not a perfect diagnostic tool. While prominent vacuolization strongly suggests VEXAS, it can also be seen in MDS alone, as well as in nutritional deficiencies, toxic exposures, or heavy alcohol use ^[8][10]. Similarly, the absence of vacuoles does not completely rule out VEXAS ^[9]. Because of this, a marrow biopsy alone cannot confirm the diagnosis—clinicopathologic correlation and UBA1 genetic testing are required ^[8][11].

When is UBA1 Genetic Testing Needed?

Standard MDS genetic tests, often done using Next-Generation Sequencing (NGS), check for common MDS-related mutations like TET2, DNMT3A, or SF3B1 ^[5][1]. However, many of these standard panels do not include the UBA1 gene.

Testing for the UBA1 mutation may be considered by your doctor if you:

• Have refractory (treatment-resistant) multisystem inflammation and blood abnormalities ^[3][2].
• Have a bone marrow biopsy showing prominent vacuoles in your blood precursor cells ^[12][13].
• Have macrocytic anemia accompanied by skin lesions, lung involvement, or ear/nose cartilage inflammation ^[3].

Testing is usually done on blood or bone marrow samples ^[12]. Because the mutation might only be present in a small fraction of cells, the laboratory must use highly sensitive methods ^[3]. The assay should ideally check for “p.Met41 variants” (the most common specific location for VEXAS mutations) as well as other rare parts of the UBA1 gene ^[2][14]. Keep in mind that no test is perfect; a negative result does not completely rule out VEXAS if clinical suspicion remains very high, and your doctor may recommend testing a different tissue sample ^[15][3].

Why Team-Based Care Matters

If you are diagnosed with VEXAS—with or without MDS—your care will require a team approach. Because the disease affects multiple systems, you will likely need a hematologist (blood cancer specialist) to manage your blood counts and any MDS features, and a rheumatologist (a specialist in inflammatory and autoinflammatory diseases) to manage the severe inflammation ^[6][2]. Depending on your symptoms, dermatologists, pulmonologists, or ophthalmologists may also be involved ^[6][2].

Treatment for VEXAS is highly individualized, and many therapies are used off-label based on specialist experience rather than large clinical trials. Options may include:

• Corticosteroids, which help control inflammation but often require continuous use and carry long-term risks ^[16].
• Targeted immune therapies like JAK inhibitors or IL-6 inhibitors, which can calm the immune system but may lower blood counts and increase the risk of infections or blood clots ^[16][17].
• MDS therapies like azacitidine, which may be used if VEXAS coexists with MDS or if the inflammation is heavily linked to the mutated blood cells ^[18][16].

All of these medications carry significant side effects and require careful monitoring. Your medical team will weigh the risks of infection, blood count drops, and blood clots when designing your treatment plan ^[19][20].