VEXAS syndrome is a rare and recently discovered autoimmune condition that causes widespread inflammation throughout the body, often leading to severe health complications. First identified in 2020, this genetic disorder primarily affects older men and results from a mutation that prevents cells from properly cleaning up damaged proteins, triggering the immune system to attack healthy tissues.

Epidemiology

VEXAS syndrome is a rare condition, though research suggests it may be more common than initially thought. According to studies conducted in the United States, approximately 1 in every 13,000 people are affected by this syndrome^[1]. More detailed research offers a clearer picture of who is most at risk: among Americans over age 50, about 1 in 4,269 men and 1 in 26,238 women have or are likely to develop the syndrome^[18]. This means roughly 13,200 men and 2,300 women over age 50 in the United States currently live with VEXAS syndrome^[5].

The syndrome predominantly affects males, and this gender difference is significant. In fact, males are much more likely to experience VEXAS syndrome than females^[1]. The condition typically appears in late adulthood, with most people developing symptoms in their fifties, sixties, or seventies^[4]. One study found diagnosed patients ranged from 47 to 83 years of age, suggesting either a later onset or challenges in early detection^[10]. Though extremely rare in women, some cases have been documented, possibly related to protective non-mutated genes or acquired abnormalities in the X chromosome^[10].

The prevalence of VEXAS syndrome is actually higher than many other inflammatory conditions, including vasculitis and myelodysplastic syndrome (a condition where immature blood cells fail to develop normally)^[18]. This recent understanding has changed how healthcare professionals view the condition. What was once considered extremely rare is now recognized as affecting thousands of Americans. Because VEXAS syndrome was only identified in 2020, many existing cases may have been misdiagnosed or remain undiagnosed^[3].

Current research has primarily focused on predominantly White populations in the United States, particularly in Pennsylvania. Scientists acknowledge that studying more racially diverse groups, especially those with higher rates of rheumatologic and blood diseases, would provide a more accurate picture of who is most at risk^[18]. This means the true scope and distribution of VEXAS syndrome across different populations worldwide remains to be fully understood.

Causes

VEXAS syndrome is caused by a genetic mutation in the UBA1 gene, which is located on the X chromosome^[1]. Understanding what this gene normally does helps explain why its malfunction causes such widespread problems. The UBA1 gene is responsible for making an enzyme called E1 ubiquitin-activating enzyme, often shortened to E1 enzyme. This enzyme plays a crucial role in keeping your cells healthy and functioning properly^[1].

Think of the E1 enzyme as a cleanup crew inside your cells. Its job is to help your body identify and dispose of waste proteins and heal damage within your cells^[1]. The process it’s involved in is called ubiquitylation, which is a type of modification that marks proteins for breakdown or regulates how cells communicate with each other^[3]. When the UBA1 gene works correctly, cells can maintain proper protein balance, getting rid of old or damaged proteins and making room for new, healthy ones.

However, when someone has VEXAS syndrome, their UBA1 gene has undergone a mutation that makes it produce E1 enzymes that don’t work correctly. This means the cellular cleanup crew is understaffed or ineffective^[1]. The mutation primarily affects an area of the gene at position p.Met41, though several different types of mutations at this location have been identified. The most common variations include p.Met41Thr, p.Met41Val, and p.Met41Leu^[10]. Additional mutations have also been discovered as research continues^[10].

When these malfunctioning enzymes can’t properly clean up damaged proteins, waste begins to accumulate inside cells. This buildup triggers a cascade of problems. Your immune system, designed to protect you from threats, detects this excess waste material. However, because there isn’t actually an infection or foreign invader present, the immune system becomes confused. It sees the protein buildup as a threat and responds by attacking the healthy tissue surrounding these cells, causing inflammation and damage throughout the body^[1].

The mutation that causes VEXAS syndrome is classified as somatic, which is an important distinction. A somatic mutation means it happens randomly during a person’s lifetime and isn’t passed from biological parents to their children—it’s not hereditary^[1]. This type of mutation occurs during cell division when cells make copies of themselves. Sometimes part of the DNA sequence ends up in the wrong place, isn’t complete, or becomes damaged^[1]. In VEXAS syndrome, this mutation occurs specifically in certain immune cells and blood-forming cells in the bone marrow, which is why the condition affects both the immune system and blood production^[4].

Risk Factors

Certain characteristics and circumstances significantly increase a person’s likelihood of developing VEXAS syndrome. The most prominent risk factor is biological sex. Being male dramatically increases risk because the UBA1 gene is located on the X chromosome^[1]. Males have only one X chromosome (paired with a Y chromosome), so if a mutation occurs in the only copy of the UBA1 gene they have, it’s sufficient to cause the condition. Females have two X chromosomes, which means they would typically need mutations in both copies of the gene or loss of one X chromosome for the disorder to develop^[4]. This chromosomal difference explains why the vast majority of VEXAS cases occur in men.

Age is another critical risk factor. VEXAS syndrome is considered an adult-onset condition, meaning symptoms don’t appear until later in life^[4]. The syndrome typically affects older adults, with signs and symptoms developing when people are in their fifties, sixties, or seventies^[4]. This late appearance might be because the somatic mutation takes time to develop, accumulate in enough cells to cause symptoms, or because the effects of the mutation become more pronounced as people age. The condition is primarily seen in males over age 50^[5], making older age combined with male sex the highest risk profile.

Beyond these primary factors, having certain pre-existing conditions may indicate increased risk, though these conditions might also represent misdiagnoses of unrecognized VEXAS syndrome. People with VEXAS often have clinical diagnoses of other inflammatory or blood-related conditions before their correct diagnosis. These include relapsing polychondritis (inflammation of cartilage), polyarteritis nodosa (inflammation of blood vessels), Sweet syndrome (a skin condition), and myelodysplastic syndrome^[11]. Studies have found that about 40 percent of patients with VEXAS syndrome also have concomitant myelodysplastic syndrome^[12].

It’s important to understand that unlike many diseases, VEXAS syndrome doesn’t have lifestyle-related risk factors. You cannot increase or decrease your risk through diet, exercise, smoking habits, or other behavioral choices. The mutation happens spontaneously in bone marrow cells, and researchers don’t yet understand why it occurs in some people and not others. Because the condition was only discovered in 2020, scientists are still working to identify whether any environmental factors, exposures, or other health conditions might trigger or contribute to the development of these genetic mutations.

Symptoms

The main symptom of VEXAS syndrome is inflammation, which occurs when your immune system mistakenly attacks healthy tissue throughout your body^[1]. This inflammation isn’t limited to one area—it can affect multiple organs and systems simultaneously, leading to a complex array of symptoms that often confuse healthcare providers and delay proper diagnosis. Understanding where inflammation occurs helps explain the diverse symptoms people experience.

Many people with VEXAS syndrome experience constitutional symptoms, meaning symptoms that affect the whole body. Fever that keeps coming back is extremely common^[2]. These fevers often appear late in the day, sometimes accompanied by chills^[15]. Profound tiredness or fatigue affects most patients, making even simple daily activities exhausting^[2]. Some people experience weight loss without trying, and headaches may occur^[1].

Skin problems are prevalent and often striking in appearance. Painful skin rashes develop in many patients^[2]. These rashes can take various forms and may appear as tender nodules, red spots, or more extensive skin changes. One patient described developing red spots “the size of half-dollar coins” all over his body that “really hurt for two or three days” and took weeks to disappear^[15]. The skin manifestations can be so severe that patients say they “looked like a monster”^[15].

Joint involvement causes significant discomfort and disability. Joint pain and swelling are common symptoms^[2], with the pain sometimes moving from one joint to another. One person experienced pain “first in his left toe and his right wrist for a couple of days, then in his shoulder for a month or more”^[15]. This type of inflammatory joint pain is called arthritis, and it can make movement difficult and painful.

Breathing difficulties affect many patients. Coughing and shortness of breath are frequent complaints^[2]. These respiratory symptoms occur because inflammation can affect the lungs, causing problems like lung infiltrates, pleural effusion (fluid around the lungs), inflammation of the airways, or inflammation of the air sacs in the lungs^[10]. Some people develop low blood oxygen levels, a condition called hypoxemia, which makes them feel breathless even at rest^[1].

Cartilage inflammation is a distinctive feature of VEXAS syndrome. Swelling and irritation of the cartilage in the nose and ears, called chondritis, can cause pain, redness, and changes in the shape of these structures^[2]. When this happens repeatedly over time, it’s called relapsing polychondritis, and it’s one of the conditions often diagnosed before VEXAS syndrome is properly identified.

Eye symptoms can be alarming and uncomfortable. Red eye and eye irritation occur in some patients^[2]. The inflammation can affect various parts of the eye, potentially threatening vision if not properly managed.

For men, inflammation can affect the testicles, causing swelling and irritation called orchitis^[1]. This can be painful and concerning, adding to the already burdensome symptom list.

Blood-related problems are particularly serious in VEXAS syndrome. Most affected individuals develop anemia, a shortage of red blood cells that makes people feel tired and weak^[4]. The red blood cells that are present are often abnormally large, a condition called macrocytic anemia^[4]. Many patients also develop thrombocytopenia, a shortage of platelets—the blood cells needed for normal clotting^[4]. Paradoxically, despite low platelet counts, some people develop blood clots^[2], which can be dangerous if they travel to the lungs, brain, or heart.

One patient’s white blood cell count shot up to 10 times above normal levels^[15], illustrating how dramatically VEXAS can affect blood cell production. The bone marrow, where blood cells are made, often doesn’t work properly, and some people develop progressive bone marrow failure or myelodysplastic syndrome^[4].

The overlap of symptoms with many other conditions makes diagnosis difficult. Before receiving a correct diagnosis, patients are often tested for 50 or more different conditions, meeting with numerous specialists without finding answers^[15]. This diagnostic odyssey can last for years, during which symptoms may worsen or new symptoms may appear.

Prevention

Unfortunately, there is no known way to prevent VEXAS syndrome. Because the condition results from a somatic mutation—a random genetic change that happens in certain cells during a person’s lifetime—it cannot be predicted or prevented through lifestyle modifications, vaccinations, supplements, or any currently available medical interventions^[1].

The spontaneous nature of the UBA1 gene mutation means it occurs unpredictably in bone marrow cells sometime during adulthood. Unlike hereditary genetic conditions that can sometimes be anticipated through family history or genetic counseling, VEXAS syndrome doesn’t run in families. Parents don’t pass it to children, and having the condition doesn’t mean your children will develop it^[4]. This also means there are no screening tests that can identify who will develop VEXAS before symptoms appear.

Since behavioral and environmental risk factors haven’t been identified, there are no lifestyle changes known to reduce risk. Healthy habits like maintaining a balanced diet, exercising regularly, avoiding smoking, and managing stress are always beneficial for overall health, but researchers have found no evidence that these practices specifically prevent VEXAS syndrome. The condition appears to develop regardless of a person’s health behaviors or environmental exposures.

However, what can be done is improving early detection and diagnosis. Now that VEXAS syndrome has been identified and genetic testing is available, healthcare providers are becoming more aware of the condition. If you’re an older male experiencing unexplained recurring fevers, inflammation, and blood abnormalities—especially if you’ve been tested for many conditions without receiving a clear diagnosis—discussing VEXAS syndrome testing with your doctor might lead to earlier identification. While this isn’t prevention, earlier diagnosis can lead to earlier treatment, which may improve outcomes and quality of life.

Researchers are actively studying VEXAS syndrome to better understand why the UBA1 mutation occurs in some people. As they learn more about the molecular mechanisms and potential triggers, future prevention strategies might become possible. For now, the focus remains on improving awareness among healthcare providers, developing better diagnostic tools, and creating more effective treatments for those who develop the condition.

Pathophysiology

Pathophysiology refers to the changes in normal bodily functions that occur when someone has a disease. Understanding what goes wrong inside the body in VEXAS syndrome helps explain why people experience such varied and severe symptoms. The chain of events begins at the molecular level, inside individual cells, and eventually affects entire organ systems.

The story starts with the UBA1 gene, which normally provides instructions for making the E1 ubiquitin-activating enzyme. This enzyme is expressed in two forms: a nuclear form called UBA1a that starts at position p.Met1, and a cytoplasmic form called UBA1b that starts at position p.Met41^[3]. The cytoplasmic form, which exists in the main body of the cell rather than the nucleus, is particularly important for the process of ubiquitylation.

Ubiquitylation is a sophisticated cellular process that regulates intracellular signaling and protein breakdown. Proteins are marked with small molecules called ubiquitin, which signals that they should be degraded through either the proteasome (a cellular protein-shredding machine) or the autophagy-lysosome system (the cell’s recycling center)^[3]. This process is essential for maintaining protein homeostasis—the proper balance between making new proteins and breaking down old or damaged ones that cells need to function and survive^[4].

When the UBA1 mutation occurs at position p.Met41, it causes loss of the normal cytoplasmic UBA1b form and creates a new, catalytically impaired form called UBA1c^[10]. This mutant enzyme has reduced function. As a result, the process of marking damaged or unneeded proteins for breakdown is disrupted. Proteins that should be eliminated instead accumulate inside cells^[4].

This protein buildup has several consequences. First, old proteins must be removed before cells can make new proteins. When damaged proteins aren’t broken down, they physically block the production of new proteins, impairing normal cell functions^[4]. Second, the accumulation of damaged proteins can directly damage cells or interfere with their normal activities. Third, and perhaps most importantly, this backup of cellular waste triggers alarm signals.

The immune system, particularly the innate immune response (the body’s first line of defense), detects these abnormal conditions inside cells. The innate immune pathways become activated^[3]. Normally, inflammation is a helpful immune response to injury or infection. But in VEXAS syndrome, inflammation is activated abnormally when there is no actual injury or foreign invader^[4]. This makes VEXAS an autoinflammatory disease—a condition where part of the immune system called the innate immune response is turned on inappropriately, causing inflammation-related damage to tissues and organs^[4].

The inflammation in VEXAS syndrome is systemic, meaning it affects the entire body rather than being localized to one area. Different tissues and organs respond to this inappropriate immune activation in various ways. In the skin, inflammation causes rashes, nodules, and painful lesions. In joints, it produces arthritis with swelling and pain. In blood vessels, it causes vasculitis—inflammation of the vessel walls that can restrict blood flow. In the lungs, it leads to inflammation of airways and air sacs, interfering with breathing. In cartilage, particularly in the ears and nose, it causes painful swelling and potentially permanent damage.

The bone marrow is especially affected because the UBA1 mutation occurs primarily in myeloid cells—white blood cells that affect immune response and inflammation—and in blood-forming cells in the bone marrow^[5]. These mutated cells activate needlessly and cause inflammatory symptoms^[5]. The mutation also impairs the normal development of blood cells, leading to the blood abnormalities seen in VEXAS. Microscopic examination of bone marrow cells from people with VEXAS reveals characteristic vacuoles—rounded, empty spaces within cells that form because of the abnormal protein processing^[1].

The blood cell production problems manifest in multiple ways. Red blood cell production is impaired, causing anemia. The red blood cells that are produced are abnormally large because the cell division process is disrupted. Platelet production may be reduced, causing thrombocytopenia. Some people develop myelodysplastic syndrome, where immature blood cells fail to mature properly. In some cases, this can progress to leukemia, a form of blood cancer^[4].

The interplay between impaired protein degradation, activated immune pathways, disrupted blood cell development, and systemic inflammation creates a self-perpetuating cycle. Inflammation can further damage cells, creating more protein waste that can’t be properly cleared. The compromised bone marrow produces defective immune cells that continue the inflammatory process. This is why VEXAS syndrome tends to be progressive and severe without treatment, and why managing the condition requires addressing both the inflammatory and hematologic components of the disease.