VEXAS Syndrome

VEXAS syndrome is a rare and serious condition that causes the immune system to attack the body by mistake, leading to widespread inflammation and blood problems. Discovered only in 2020, this condition primarily affects men over 50 and is caused by a genetic mutation that happens during life, not one inherited from parents.

Table of contents

• What is VEXAS syndrome?
• What does the name VEXAS mean?
• How common is VEXAS syndrome?
• What causes VEXAS syndrome?
• Who is at risk?
• What are the symptoms?
• How is VEXAS syndrome diagnosed?
• How is VEXAS syndrome treated?
• What is the outlook?

What is VEXAS syndrome?

VEXAS syndrome is a rare condition in which the immune system attacks the body by mistake. This is called an autoinflammatory condition. The disorder causes swelling and irritation, called inflammation, throughout the body^[1][2].

The condition was first described in December 2020 by a group of researchers in the United States^[3][15]. Using a new approach to identify diseases, researchers discovered that seemingly unrelated adult-onset inflammatory conditions were actually connected by the same genetic mutation.

VEXAS syndrome can affect many parts of the body, including blood, bone marrow, blood vessels, skin, cartilage (especially in the ears and nose), joints, lungs, eyes, and testicles^[1]. The condition can be fatal if it’s not treated^[1].

What does the name VEXAS mean?

The letters in VEXAS syndrome’s name are an acronym that describes key features of the condition^[1][4]:

• Vacuoles: Rounded, empty spaces that form in abnormal cells. People with VEXAS syndrome usually have vacuoles in their bone marrow cells.
• E1 enzyme: The ineffective E1 enzyme that cells make when the UBA1 gene is mutated. This enzyme normally helps the body clean up waste proteins and heal damage inside cells.
• X-linked: The mutated UBA1 gene that causes VEXAS syndrome is located on the X chromosome. Two chromosomes determine biological sex. Females have XX chromosomes and males have XY chromosomes.
• Autoinflammation: The medical term for inflammation that occurs when the immune system attacks the body.
• Somatic: The mutation that causes VEXAS syndrome is somatic. That means it happens randomly during life and isn’t passed from biological parents to their children (it’s not hereditary).

How common is VEXAS syndrome?

VEXAS syndrome is very rare. Research suggests the condition affects an estimated 1 in every 13,000 people in the United States^[1][4]. More specifically, about 13,200 men and another 2,300 women in the United States over age 50 are estimated to have VEXAS syndrome^[5][18].

The condition is more common than many other inflammatory conditions, including vasculitis and myeloid dysplasia syndrome^[5][18].

What causes VEXAS syndrome?

A genetic mutation to the UBA1 gene causes VEXAS syndrome^[1][4]. Genetic mutations are changes to DNA sequence that happen during cell division when cells make copies of themselves. If part of the DNA sequence is in the wrong place, isn’t complete or is damaged, symptoms of a genetic condition might occur.

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 within cells. Protein breakdown helps maintain the proper balance that cells need to function and survive^[4].

When someone has VEXAS syndrome, their UBA1 gene malfunctions and doesn’t produce E1 enzyme correctly. The enzyme usually acts like a janitor that cleans up damaged or old proteins inside cells. When VEXAS syndrome is present, the E1 enzyme cleaning crew is understaffed. Eventually, damaged proteins and waste build up inside cells. This backup triggers the immune system, which sees the excess waste as a threat. But because there isn’t actually an infection in that area, the immune system attacks and damages healthy tissue, which causes inflammation^[1].

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^[4].

Who is at risk?

VEXAS syndrome predominantly affects males over the age of 50^[3][5]. Studies have found that males are much more likely to experience VEXAS syndrome^[1][2].

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^[4].

The condition typically affects older adults, with signs and symptoms developing in a person’s fifties, sixties, or seventies^[4].

What are the symptoms?

The main symptom of VEXAS syndrome is inflammation. Where inflammation occurs causes other symptoms^[1]. Symptoms of VEXAS syndrome can affect organs throughout the body and may differ from person to person^[2].

Common symptoms include^[1][2][3]:

• Fever that keeps coming back
• Tiredness and fatigue
• Painful skin rashes
• Swelling
• Joint pain and swelling
• Eye redness and irritation
• Cough
• Shortness of breath
• Low blood oxygen levels
• Headaches
• Swelling and irritation of one or both testicles
• Swelling and irritation of the cartilage in the nose and ears

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^[4].

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. 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^[4].

Some affected individuals develop myelodysplastic syndrome, a condition in which immature blood cells fail to develop normally; this condition may progress to a form of blood cancer called leukemia. Blood clots may also occur^[2][4].

How is VEXAS syndrome diagnosed?

Diagnosing VEXAS syndrome can be challenging due to its rarity and the overlap of symptoms with other inflammatory conditions^[3]. VEXAS syndrome may be hard to diagnose because of the range of possible symptoms and because the symptoms can be like those of other conditions that cause inflammation^[8].

The only way to confirm a diagnosis of VEXAS syndrome is through genetic testing. To do genetic testing, a healthcare professional takes a sample of blood or bone marrow and sends it to a lab to look for the changed gene that causes the condition^[8][14]. Genetic testing to identify the UBA1 gene mutation is essential for definitive diagnosis^[3].

Healthcare providers may also do a bone marrow biopsy, imaging tests like a chest CT scan, or lung function tests to rule out other conditions^[5]. Bone marrow evaluation is important to identify cytoplasmic vacuoles in bone marrow cells, which are characteristic of VEXAS syndrome^[11].

How is VEXAS syndrome treated?

Currently, there is no known cure for VEXAS syndrome, and treatment mainly focuses on managing the symptoms^[3]. Treatment for VEXAS syndrome depends on the symptoms and most often involves medicines for inflammation and medicines that lessen the immune system response^[8][14].

Medicines

Corticosteroids. Corticosteroid medicines, such as prednisone, ease swelling and irritation, called inflammation, and pain. Patients tend to respond most profoundly to glucocorticoids, though their use is associated with significant adverse effects. There can be serious side effects, and the risk of side effects rises when taken at high doses over a long time. Side effects may include bone thinning, easy bruising from skin thinning, weight gain, high blood sugar, cataracts and glaucoma, among others^[8][12].

Medicines that suppress the immune system. These include medicines such as tocilizumab. They also include a class of medicines called Janus kinase inhibitors (JAKi), such as ruxolitinib, tofacitinib and baricitinib. These medicines help keep the immune system from attacking healthy cells. This helps with swelling and irritation while lowering the need for steroid medicines^[8][14].

Research has shown that azacitidine, a DNA hypomethylating agent, demonstrates significant efficacy particularly in patients with myelodysplastic syndrome. JAK inhibitors and IL-6 inhibitors may also be viable treatment options^[7][12].

Chemotherapy medicines. For some people, treatment may involve chemotherapy, which uses strong medicines to kill cells^[8][14].

Bone marrow transplant

Also called a stem cell transplant, this procedure replaces bone marrow that isn’t working well with new stem cells. Bone marrow transplants may be an option in some cases^[5][8][14].

Because different organs can be affected, patients may need to see specialists. Supportive therapies tailored to the individual patient’s needs are also important^[3][5].

What is the outlook?

VEXAS syndrome can be fatal if it’s not treated^[1]. Without treatment, the condition can lead to death^[2]. The syndrome carries a high mortality rate, with up to half of people dying within 5 years of diagnosis^[5][18].

The condition is associated with significant mortality and morbidity. Healthcare providers will suggest treatments to manage symptoms, but ongoing research is being conducted to better understand its pathogenesis, clinical features, and potential treatment options^[3][12].

Researchers hope that raising awareness of the disorder among physicians will lead to earlier diagnosis and treatment. High-dose steroids, JANUS kinase inhibitors, and bone marrow transplants have proven effective in controlling some symptoms^[18].