VEXAS syndrome is a disorder involving episodes of fever and abnormal inflammation. VEXAS is an acronym that stands for the technical terms of key descriptors of the condition. Normally, inflammation is an immune system response to injury or foreign invaders (such as bacteria). In people with VEXAS syndrome, part of the immune system called the innate immune response is turned on (activated) abnormally, when there is no injury or foreign invader, which causes fevers and inflammation-related damage to tissues and organs. Based on this process, VEXAS syndrome is classified as an autoinflammatory disease.

VEXAS syndrome typically affects older adults, primarily males, with signs and symptoms of the condition developing in a person's fifties, sixties, or seventies. People with VEXAS syndrome often have inflammation of the joints (arthritis), skin (dermatitis), cartilage in the ear and nose (chondritis), or blood vessels (vasculitis). Inflammation can also develop in other tissues, including in the lungs and eyes. Affected individuals may also have enlarged lymph nodes.

Blood cell abnormalities are common in VEXAS syndrome. Most affected individuals develop a shortage of red blood cells (a condition called anemia), and the red blood cells that are present are abnormally large (macrocytic). People with VEXAS syndrome can also have a shortage of blood cells called platelets (a disorder known as thrombocytopenia); platelets are needed for normal blood clotting. Some affected individuals develop myelodyspastic syndrome, a condition in which immature blood cells fail to develop normally; this condition may progress to a form of blood cancer called leukemia.

VEXAS syndrome is a disease that causes inflammatory and hematologic (blood) manifestations. The syndrome is caused by mutations in the UBA1 gene of blood cells and acquired later in life. Patients do not pass the disease to their children.

What does VEXAS mean?

VEXAS is an acronym defined as follows:

• V - vacuoles are often seen in cells identified in bone marrow biopsies from patients with VEXAS syndrome.

• E - E1 ubiquitin activating enzyme, encoded by the UBA1 gene which is mutated in patients.

• X - the UBA1 gene is located on the X chromosome.

• A - patients have autoinflammation.

• S - the mutations are somatic, meaning they are acquired at some point in life and not inherited.

Research studies indicate that VEXAS is primarily observed in biological males.

Variants (also called mutations) in the UBA1 gene cause VEXAS syndrome. The UBA1 gene provides instructions for making a protein called ubiquitin-activating enzyme E1. This enzyme is necessary for a process that targets damaged or unneeded proteins to be broken down (degraded) within cells. Protein degradation helps maintain the proper balance of protein production and breakdown (protein homeostasis) that cells need to function and survive. The UBA1 gene variants that cause VEXAS syndrome are acquired during a person's lifetime and are present only in certain immune cells and blood-forming cells in the bone marrow. These changes, which are called somatic variants, are not inherited.

UBA1 gene variants that cause VEXAS syndrome result in the production of an enzyme with reduced function. As a result, damaged or unneeded proteins build up inside cells instead of being broken down, which may contribute to abnormal activation of immune cells or cell damage and death. This protein buildup also disrupts protein homeostasis. Old proteins must be removed before cells can make new proteins. If damaged or unneeded proteins are not broken down, they can stop the production of new proteins, which can contribute to the impairment of normal cell functions. When UBA1 gene variants occur in immune cells or blood cells, they lead to abnormal inflammation, impaired blood cell development, and other features of VEXAS syndrome.

Normal Function

The UBA1 gene provides instructions for making the ubiquitin-activating enzyme E1. This enzyme is necessary for the ubiquitin-proteasome system, which targets damaged or unneeded proteins to be broken down (degraded) within cells. Protein degradation helps maintain the proper balance of protein production and breakdown (protein homeostasis). Old proteins need to be removed to make way for new proteins to allow cells to function and survive. The ubiquitin-proteasome system acts as the cell's quality control system by disposing of damaged, misshapen, and excess proteins.

Ubiquitin-activating enzyme E1 is responsible for the first step in the ubiquitin-proteasome system; it turns on (activates) a small protein called ubiquitin. With the assistance of other proteins, the active ubiquitin attaches to a protein that is to be broken down. When a chain of ubiquitin proteins is attached to a protein, the protein is recognized and destroyed by a complex of enzymes called a proteasome.

Health Conditions Related to Genetic Changes

VEXAS syndrome

Variants (also called mutations) in the UBA1 gene have been found to cause VEXAS syndrome. This condition is characterized by episodes of fever and abnormal inflammation affecting many parts of the body, particularly the skin, joints, and blood vessels. The UBA1 gene variants that cause VEXAS syndrome are somatic, which means that they occur after birth during a person's lifetime. These variants occur only in certain immune cells and blood-forming cells in the bone marrow.

Most cases of VEXAS syndrome are caused by genetic variants that change the protein building block (amino acid) methione at position 41 in the ubiquitin-activating enzyme E1 to another amino acid. These variants lead to the production of an abnormally short enzyme with reduced function. As a result, damaged or unneeded proteins build up inside cells instead of being broken down, which may contribute to abnormal activation of immune cells or cell damage and death. This protein buildup also disrupts protein homeostasis. Old proteins must be removed before cells can make new proteins. If these damaged or unneeded proteins are not broken down, they can impair normal cell functions by stopping the production of new proteins. When UBA1 gene variants occur in immune cells or blood cells, they lead to abnormal inflammation, impaired blood cell development, and other features of VEXAS syndrome.

X-linked infantile spinal muscular atrophy

Variants in the UBA1 gene have been reported to cause X-linked infantile spinal muscular atrophy. This condition is characterized by severe muscle weakness that begins at birth or in early infancy. Weakness in the chest muscles that control breathing often causes death from respiratory failure in early childhood.

UBA1 gene variants that cause X-linked infantile spinal muscular atrophy are inherited and present in all cells in the body. They all change one DNA building block (nucleotide) in an area of the gene known as exon 15. These variants reduce the activity, function, or production of the enzyme. This shortage of functional enzyme allows damaged or unneeded proteins to build up inside cells instead of being broken down, which may damage cells and contribute to cell death. This buildup also disrupts protein homeostasis. If damaged or unneeded proteins are not broken down, they can impair normal cell functions by stopping the production of new proteins. An imbalance in protein production and breakdown can ultimately lead to cell death. Specialized nerve cells that control muscle movement (motor neurons) are particularly susceptible to disruptions in cell function, likely due to their large size. Loss of these cells causes many of the signs and symptoms of X-linked infantile spinal muscular atrophy.

Other Names for This Gene

• GXP1
• SMAX2
• UBA1, ubiquitin-activating enzyme E1 homolog A
• UBA1_HUMAN
• UBA1A
• UBE1
• UBE1X
• ubiquitin-activating enzyme E1
• ubiquitin-like modifier activating enzyme 1

Genomic Location

VEXAS syndrome is acquired, rather than inherited. Most cases result from new variants in the UBA1 gene, and occur in people with no previous history of the disorder in their family. The condition is not passed down to children of affected individuals.

The UBA1 gene is located on the X chromosome, which is one of the two sex chromosomes. Males have only one X chromosome, and a variant in the only copy of the UBA1 gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene, or there would have to be a loss of one of the X chromosomes, to cause the disorder.

Patients with VEXAS can have a wide range of inflammatory symptoms affecting multiple organs including:

• skin (rashes that can be painful).
• cartilaginous structures (pain and swelling of the ear and nose).
• lungs (cough and shortness of breath).
• joints (swelling and pain).
• vasculature (inflammation of vessels).

Patients often have fever and extreme fatigue. The hematologic features can include anemia, low platelets, and blood clots. On many occasions patients with VEXAS have associated clinical diagnoses, including relapsing polychondritis, polyarteritis nodosa, sweet syndrome and myelodysplastic syndrome.

A VEXAS diagnosis uses genetic testing, which looks for mutations in the UBA1 gene located in the X chromosome.

There is no standardized treatment for VEXAS currently, however the inflammatory features can be treated with steroids and other immunosuppressants. Some patients may be candidates for bone marrow transplantation. Since VEXAS can affect multiple organs, patients will need a team of doctors—including a rheumatologist and hematologist—to manage their disease.

In 2020, a team of NIH researchers reported the discovery of a rare and often-deadly inflammatory disorder, which they named VEXAS. Affected people have varying symptoms that can include anemia, recurrent fevers, painful rashes, blood clots, and shortness of breath. Because these symptoms overlap with other autoimmune and inflammatory diseases, VEXAS can be hard to recognize. But having an accurate diagnosis is important for effective treatment.

VEXAS was discovered by searching for genetic variants that were shared among more than 2,500 patients with body-wide inflammation or other unusual and undiagnosed conditions. The identified gene, UBA1, is on the X chromosome, and all 25 people initially diagnosed with VEXAS were male. Since men have only one X chromosome, they only have one copy of the gene. Women typically have two X chromosomes and therefore two copies of UBA1. In women, a mutation in only one copy is likely to cause less severe or no disease. The genetic mutations that cause this disease occur after birth and so aren’t transmitted from parents to children.

A research team set out to assess the symptoms and prevalence of VEXAS-related variants in a larger population. The group was led by Dr. David Beck of New York University, in collaboration with Drs. Jung Kim and Douglas Stewart of NIH’s National Cancer Institute. The scientists combed through data from more than 160,000 patients in a regional health care system in Pennsylvania. All had agreed to have their DNA screened. Participants were predominantly white (94%, which roughly matches regional demographics), and more than half were women (61%). The mean age of participants was 53. Results appeared online in JAMA on January 24, 2023.

Genetic analysis revealed that 12 of the participants (or 1 in 13,591 people) appeared to have disease-related variants in UBA1. Ten were men and two were women. Health records showed that all 12 had symptoms consistent with VEXAS, including a range of autoimmune, lung, or skin abnormalities. 

By closely examining the 12 participants’ medical records, the researchers found that UBA1 variants led to a broader range of symptoms than originally thought. “Classic” symptoms of VEXAS were also sometimes absent. The researchers note that a diagnosis based on symptoms alone could easily miss cases of VEXAS that would be caught by UBA1 testing.

“Our study offers the first glimpse of just how common VEXAS syndrome is in the United States, particularly among men, who also happen to be the most likely to die from it,” Beck says. “Now that we know VEXAS syndrome is more common than many other types of rheumatologic conditions, physicians need to add this condition to their list of potential diagnoses when confronted by patients with persistent and unexplained inflammation and low blood cell counts, or anemia.”

The team now aims to conduct similar studies among more racially diverse groups to gain a clearer picture of who’s most at-risk for developing VEXAS. “In addition, there are other genes that may be associated with inflammatory disorders like VEXAS,” Stewart says. “The team is investigating if mutations in those genes are linked to VEXAS-like medical problems for the people who harbor those variants.”

—by Vicki Contie

VEXAS syndrome is a rare condition. Research suggests the condition affects an estimated 1 in 13,000 people.