What Is VEXAS Syndrome?

Autoimmune or Genetic? How Does VEXAS Syndrome Cause MDS?

VEXAS syndrome is a genetic disease that appears in adulthood, in which patients develop inflammatory and hematologic symptoms that can lead to bone marrow failure. It can be a precursor of myelodysplastic syndrome (MDS) and other bone marrow cancers. 

What Does VEXAS Mean? 

VEXAS is an acronym that describes a group of disorders that, together, form a syndrome. Each initial stands for one symptom or finding that is required for the diagnosis: 

• Vacuoles inside immature blood cells: red blood cells, platelets, and white blood cells present abnormal vacuoles (small bubbles filled with liquid) when analyzed in the microscope.
• E1 enzyme is abnormal due to mutations in the UBA1 gene. This affects the process that targets damaged or unneeded proteins to be broken down within cells.
• X-linked: The UBA1 gene is located on the X chromosome.
• Autoinflammatory refers to problems with the immune system's reactions, resulting in immune cells targeting the body's own healthy tissues by mistake. This can cause intense episodes of inflammation that result in such symptoms as fever, rash, or joint swelling, and it depends on steroid therapy to be controlled.  
• Somatic mutations in UBA1 happen specifically in cells originating in the bone marrow, so although this condition is hereditary, patients don’t show symptoms until adulthood. 
  
  

VEXAS syndrome can cause MDS due to inflammation and the production of abnormal blood cells in the bone marrow. However, due to its genetic nature, it's a rare condition present in approximately 15,000 people in the US.  

In this image, there are different blood cells with white "dots" inside. The white dots are vacuoles filled with liquid that interfere with normal cell functions.

What are the Symptoms of VEXAS Syndrome? 

Many symptoms are attributed to generalized inflammation due to the alteration of the E1 enzyme that controls which proteins are degraded by the immune system. As a consequence, the immune system may get "confused" and attack healthy tissues in the body. 

The most common symptoms are: 

• Skin rashes 
• Joint pain 
• Inflammation of blood vessels (vasculitis) that can show up as circulation issues and rashes that don't react to pressure or rash cream
• Eye swelling
• Flu-like symptoms

How is VEXAS Syndrome Diagnosed?

To confirm the diagnosis of VEXAS syndrome, a pathologist needs to analyze a bone marrow biopsy, and genetic testing of the bone marrow cells needs to look for UBA1 gene alterations and chromosome X alterations. Also, a physical examination and questioning about inflammation symptoms, including rashes, fever, or flu-like symptoms will indicate the diagnosis. 

VEXAS syndrome is characterized by vacuoles inside the immature blood cells in the marrow. When seen under the microscope, doctors look for several diseases, including MDS, sideroblastic anemia, copper deficiency, zinc excess, and acute alcohol exposure. Based on the big picture that considers genetics, physical examination, patient history and symptoms, doctors will be able to establish an accurate diagnosis.

What are the Treatments for VEXAS Syndrome? 

Treating VEXAS syndrome is challenging because it’s a genetic disorder and needs to be tackled by therapies used in high-risk patients, for example, allogeneic bone marrow transplantation (ASCT).

Conventional treatments that suppress the immune system or hypomethylating agents have a small impact on patients with this condition. So, the main goals for VEXAS syndrome patients are to reduce the symptoms, control the inflammation, and improve the quality of life. 

Besides ASCT, other treatments have been reported in VEXAS syndrome; 

• Corticosteroids; like prednisone, dexamethasone and cortisone, help reduce inflammation and improve patient's quality of life, however they can make the body more prone to infections because of their numbing effect on the immune system. 
• Immunosuppressants: are drugs like tacrolimus, cyclosporine, mycophenolate mofetil, and azathioprine. Their main function is to stop immune system cells from reacting against healthy body tissues (like skin, joints, gastrointestinal system).  The risk of infection increases because of their effect, but they are also successful in aggressive episodes where a site of the body is affected.
• Monoclonal antibodies like tocilizumab (Actemra) is effective against systemic inflammation symptoms like joint pain, eye swelling, and blood vessel inflammation (vasculitis).
• Janus kinase inhibitors (JAKi) like ruxolitinib can effectively control systemic inflammation. They work by targeting specific "messengers" inside the immune system and can help regulate the immune system and potentially treat certain conditions that relate to the systemic inflammation of the body. 
• Azacitidine (Vidaza) is a chemotherapy used in blood cancers, such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). It works by inducing cell death, getting rid of abnormal cells.
• Alternative therapies, including participation in clinical trials.  

When diagnosing VEXAS syndrome, the healthcare team will create a personalized treatment plan based on the symptoms, lifestyle, and health status. If you have questions regarding your treatment or want to know if you are eligible for one of the treatments mentioned, it's important that you contact your doctor. 

What clinical trials are currently recruiting? 

Currently, a phase II study NCT05027945 with ASCT for patients with VEXAS syndrome is recruiting. You can create a free account and stay up to date with more clinical trial information, connect your records to track your labs, and more!  

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Sources:

1. VEXAS syndrome in myelodysplastic syndrome with autoimmune disorder  
2. VEXAS syndrome 
3. Benign and malignant hematologic manifestations in patients with VEXAS syndrome due to somatic mutations in UBA1 
4. Image from: Tosato, F., Pelloso, M., Zuin, J., & Basso, D. (2023). Peripheral blood cells vacuoles in VEXAS syndrome. American Journal of Hematology, 98(10), 1663–1664. https://doi.org/10.1002/ajh.26931 
5. VEXAS syndrome: Current clinical, diagnostic and treatment approaches.