VEXAS Syndrome: Rare Immune Disorder

Imagine your immune system suddenly turning its firepower on you instead of protecting you. You visit one doctor after another, each offering a different diagnosis: maybe lupus, maybe rheumatoid arthritis, or a blood disorder. This is the reality for individuals with VEXAS syndrome, a rare immune disorder discovered only in recent years. A recent study showed that people with VEXAS syndrome often face significant health risks, with many living about 10 years after symptoms first appear. Scientists are now working to better understand what triggers this disorder and how to provide the best care for those affected. 

What exactly is VEXAS syndrome?

The acronym VEXAS stands for:

• Vacuoles: abnormal structures seen in bone marrow cells;
• E1: the enzyme UBA1, where the mutation occurs;
• X: the mutation is on the X chromosome, explaining why most patients are men;
• Autoinflammatory: the immune system is chronically overactive;
• Somatic: Mutations are somatic, meaning that they are not inherited but acquired throughout life. 

VEXAS syndrome is a serious, adult-onset disease. It occurs when a mutation in a gene named UBA1, located on the X chromosome, disrupts how the body controls inflammation. The immune system then remains overactive, leading to generalized, uncontrollable inflammation and abnormalities in blood cells.  Since the mutation affects the X chromosome, the syndrome is more frequent in men over the age of 50. Women can carry the mutation, but they rarely develop symptoms. 

“VEXAS is a groundbreaking discovery because it explains why some older adults develop severe inflammatory disease and blood problems that don’t fit any known diagnosis.”

              –Dr. Wiem Lazzem, an immunology specialist and pharmacist at Habib Thameur Hospital in Tunis, Tunisia

Symptoms you shouldn’t ignore

The most common warning signs include:

• Recurrent and unexplained fever;
• Extreme fatigue;
• Painful skin rashes or nodules;
• Joint pain and swelling;
• Blood abnormalities such as anemia, enlarged red blood cells, or low platelets;
• Lung inflammation (including breath shortness or coughing);
• Inflammation of cartilage in the ears or nose (mimicking relapsing polychondritis);

  “Through its symptoms affecting both the immune system and the bone marrow, VEXAS syndrome can mimic many other diseases. This is one reason why diagnosis is so difficult,” said Dr. Wiem Lazzem to HealthOdysseyHub.   

How does VEXAS syndrome cause immune dysregulation?

  The UBA1 gene is responsible for activating the ubiquitin–proteasome system via the UBA1 enzyme. Once activated, this system removes unwanted proteins from cells and regulates many signaling pathways.  When the UBA1 gene is mutated, blood and immune cells start to malfunction, and protein regulation becomes abnormal. Consequently, the dysregulated blood cells, especially myeloid cells, multiply and become dominant in the blood and bone marrow.

Moreover, abnormal protein recycling stimulates immune cells, leading to the production of excessive inflammatory signals, such as interleukin-6 (IL-6), tumor necrosis factor (TNF), and interferons. The result is chronic generalized inflammation that resembles a combination of autoimmune and autoinflammatory diseases.

Commenting on this topic, Dr. Wiem Lazzem explained, “VEXAS syndrome is ‘immune dysregulation in action’. The immune system, designed to protect us, becomes an engine of constant inflammation.” “This disease has reshaped thinking in immunology, showing that not only inherited mutations but also acquired ones can trigger chronic inflammation,” added Dr. Wiem Lazzem. 

Why is diagnosing VEXAS syndrome so challenging?

VEXAS syndrome is easily mistaken for other diseases for many reasons. First, this disease touches many parts of the body; its symptoms don’t point neatly to a single illness. Second, it develops in patients over 50. At that age, doctors may be more likely to suspect infection, cancer, or common blood disorders first. Moreover, this illness doesn’t follow a single pattern; some individuals mainly have inflammation, others show blood abnormalities, and some have both. This variety makes it even harder to connect the dots.  Since VEXAS syndrome is a recently identified disease, many healthcare providers are still learning about it.

Awareness is improving thanks to new medical guidelines. The more doctors learn about it, the faster patients can get the correct answers and care they need.  Traditional blood tests don’t provide a confirmatory diagnosis. The gold standard is genetic testing by detecting changes (mutations) in the UBA1 gene. This is usually performed through a blood test that analyzes Deoxyribonucleic acid (DNA). Without this, the diagnosis is easily missed, delaying appropriate treatment

“Immunology experts are now searching for immune signatures such as specific cytokine profiles or gene expression patterns that could serve as early biomarkers, so we don’t always have to wait for genetic confirmation.”    -Dr. Wiem Lazzem

Treatment landscape and challenges

Currently, there is no curative treatment for VEXAS syndrome. The available treatment options aim to control inflammation and stabilize the blood system. This includes:

• Corticosteroids: targeting inflammation, but patients may become dependent and experience side effects.
• Targeted therapies: a promising option. It includes drugs that block IL-6 or JAK-STAT signaling (such as tocilizumab or ruxolitinib) and reduce inflammation.
• Azacitidine: a medication used in certain bone marrow disorders, has produced encouraging results in clinical studies.
• Stem cell transplantation: may offer a potential cure for select patients, though it carries significant risks.

Why does awareness matter?

An observational study suggests VEXAS syndrome may be more common than expected, possibly affecting 1 in 4269 men over 50. That means thousands of patients worldwide could be living with this disease without knowing it. Early diagnosis is crucial to avoid complications and reduce the mortality rate. Awareness among both doctors and patients can shorten the diagnostic journey and lead to better outcomes.

Addressing the problem of awareness, Dr. Lazzem asserted, “VEXAS syndrome was discovered in 2020, so many doctors are still not familiar with it. Raising awareness is essential to shorten the long diagnostic journeys patients often face.”

Conclusion

Living with VEXAS syndrome can be overwhelming, especially when symptoms affect nearly every part of daily life and no diagnosis is established. Raising awareness among healthcare professionals and the public is key to ensuring earlier diagnosis and treatment.While there is still no cure, ongoing research and emerging therapies offer hope for better management and, ultimately, improved survival. For patients and their families, knowledge truly becomes power, the first step toward timely care and a chance at better outcomes.   

Disclaimer

The information on HealthOdysseyHub is for educational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment. We strive to keep our content accurate and up-to-date, but healthcare knowledge changes quickly. Always consult a qualified healthcare professional before making decisions based on our content. Some topics may cover alternative or complementary medicine. These may not align with conventional practices. Approach such information with caution and seek multiple opinions before any medical intervention.