What are the other Names for this Condition? (Also known as/Synonyms)

• Vacuoles, E1 enzyme, X- linked, Autoinflammatory Somatic Syndrome
• VEXAS Autoinflammatory Disease (VEXAS-AID)
• VEXAS-AID (VEXAS Autoinflammatory Disease)

What is VEXAS Syndrome? (Definition/Background Information)

• VEXAS Syndrome is an acronym for Vacuoles, E1 enzyme, X- linked, Autoinflammatory Somatic Syndrome. The syndrome is a rare and recently reported genetic disorder typically affecting males
  • V for vacuoles refers to open spaces found in cells of bone marrow biopsies from patients with VEXAS Syndrome
  • E refers to the E1 ubiquitin-activating enzyme, encoded in the UBA1 gene, which shows late-in-age mutations (not inherited) in VEXAS Syndrome patients, who are usually over 45 years old
  • X refers to the UBA1 gene being located on the X chromosome. Since men have only one X chromosome, when they have the mutation, they develop the disease. Since women have two X chromosomes, a mutation on one is of trivial consequence since their normal X prevents disease expression
  • A refers to the autoinflammatory process triggered in the first-responder complex of the inflammatory/immune system
  • S refers to somatic genetic mutation causing the disorder. The mutation occurs after birth, not in the ‘germline’ portions of the X chromosome contributed by the mother and father determining gender
• The disorder occurs in an X-linked somatic pattern. However, a positive family history of VEXAS Syndrome is not yet observed. It may be diagnosed through a combination of physical exams, blood tests, bone marrow aspiration and biopsy, imaging studies, and genetic testing
• Currently, there is no specific treatment for VEXAS Syndrome. Typically, treatment is provided to manage the symptoms and prevent complications. High-dose corticosteroids are observed to be somewhat effective. Bone marrow transplantation has also been attempted
• The prognosis for individuals with VEXAS Syndrome is typically unfavorable, with many succumbing to the condition despite treatment. Severe cases result in complications such as progressive anemia, multiorgan failure (heart, kidney, brain, and intestines), and stroke

Who gets VEXAS Syndrome? (Age and Sex Distribution)

• VEXAS Syndrome is a rare disorder, first reported in 2020. Currently, it is proposed that about 1 in 4,000 men over the age of 50 might have the syndrome
• VEXAS Syndrome is reported in males over age 45 in a vast majority of cases
• Cases have been reported mainly in France, the Netherlands, and the United States. It is likely that with better awareness, many more cases will be reported worldwide

One female case has been reported in a woman who only had one X chromosome. This is termed Turner syndrome. The second X chromosome normally present in women would presumably have protected her from developing VEXAS Syndrome. For that reason, all but one reported VEXAS syndrome patients are males.

What are the Risk Factors for VEXAS Syndrome? (Predisposing Factors)

The greatest risk factor for VEXAS Syndrome is being male.

• Adult men over 45 or older constitute the majority of cases
• The risk of family members of VEXAS Syndrome patients being affected has not yet been determined
• Extremely rarely, having only one X chromosome in a female (Turner syndrome) also carries a risk for VEXAS syndrome

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of VEXAS Syndrome? (Etiology)

VEXAS Syndrome is caused by mutations in the UBA1 gene, which provides instructions for making an enzyme E1, which normally activates the ubiquitin protein. The low enzyme activity results in cellular replication disruption and inflammation.

• The mutation of the UBA1 gene is caused by DNA damage through poor transcription brought on by processes related to aging
• One of the main aspects of VEXAS involves the low renewal of blood cells - white, red, and platelets in the bone marrow. This leads to the symptoms of anemia, thrombocytopenia (low platelets), and myelodysplastic syndrome
• The other result of VEXAS Syndrome is increased inflammation in the skin and other organs

What are the Signs and Symptoms of VEXAS Syndrome?

The signs and symptoms of VEXAS Syndrome can vary widely depending on the severity of the disorder. 

• Systemic inflammatory processes include recurring (non-infectious) fevers and fatigue
• Arthritis of many joints, usually symmetric
• Respiratory disease, shortness of breath from inflammatory lung disease
• Cutaneous findings are common and include vasculitis of superficial and deep vessels and pustular and inflammatory rashes with a Sweet syndrome pattern
• Inflammation of the cartilage of the nose and ears (polychondritis)
• Blood abnormalities are prominently noted. These include:
  • Macrocytic anemia, in the setting of normal B12 and folate levels
  • Thrombocytopenia (low platelets)

How is VEXAS Syndrome Diagnosed?

VEXAS Syndrome is diagnosed through a combination of the following:

• Clinical examination and assessment of presenting signs and symptoms
• Evaluation of family history of the condition
• Blood testing for inflammatory markers and formed blood elements such as red blood cells, white blood cells, and platelets
• Testing for immunoglobulin levels and the presence of monoclonal spikes
• Bone marrow aspiration and biopsy 
• Imaging studies
• Genetic testing can confirm the presence of mutations in the UBA1 gene

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of VEXAS Syndrome?

The complications of VEXAS Syndrome can include the following:

• Myelodysplastic syndrome (generalized bone marrow failure)
• Multiple myeloma (a form of blood cell cancer)
• Monoclonal gammopathy of undetermined significance (MGUS)
• Respiratory failure
• Progressive anemia
• Blood clots and stroke

Severe cases of VEXAS Syndrome can result in death.

How is VEXAS Syndrome Treated?

Currently, there is no specific treatment for VEXAS Syndrome. Hence, treatment is primarily focused on managing the symptoms and preventing complications.

• Corticosteroids at high doses can have some effect on the condition
• Management of hematologic abnormalities and other organ-based deficiencies
• Tocilizumab is theoretically a treatment option
• A stem cell transplant research study is underway (at the NIH, United States)

How can VEXAS Syndrome be Prevented?

• Presently, it is not possible to prevent VEXAS Syndrome as the cause is a genetic mutation. 
• However, early diagnosis and appropriate treatment can help prevent or delay the onset of some complications

What is the Prognosis of VEXAS Syndrome? (Outcomes/Resolutions)

• The prognosis for individuals with VEXAS Syndrome is generally poor. The current reported death rate is 50%
• Some affected individuals with more extensive UBA1 mutations are at a higher risk for multiple myeloma and other hematologic malignancies

Additional and Relevant Useful Information for VEXAS Syndrome:

The following link is a useful resource for information on other rare conditions on DoveMed:

https://www.dovemed.com/diseases-conditions/rare-disorders/