VEXAS syndrome (vacuoles, E1 ubiquitin-activating enzyme, X chromosome, autoinflammation, somatic) is a rare and severe genetic, autoimmune, and autoinflammatory disease that affects multiple organs throughout the body, including the skin, joints, lungs, vasculature, and cartilaginous structures. It was recently identified in 2020 that it is most common in males over 50 years of age. 

Read on to learn more about the key features and characteristics of VEXAS syndrome, provided in its acronym, as well as its main signs, symptoms, causes, risk factors, treatment options, and much more!

Introduction

VEXAS syndrome¹ is a severe form of autoimmune or autoinflammatory disease that was identified by researchers in 2020. 

Each letter in the VEXAS acronym stands for the following: 

• V: Vacuoles: these ‘storage bubbles’ are often seen in the bone marrow cells of patients with VEXAS syndrome
• E: E1 ubiquitin-activating enzyme: this enzyme (protein) does not function properly in patients with VEXAS syndrome because the gene that produces it (UBA1) contains mutations (changes in its DNA sequence)
• X: X chromosome: the mutated UBA1 gene is located on the X chromosome 
• A: autoinflammation: a key characteristic of VEXAS syndrome is autoinflammation which causes the body’s immune system to attack itself as it ‘mistakes’ healthy tissues and organs for toxic and foreign invaders, e.g. viruses
• S: somatic: the mutations that occur in the UBA1 gene are somatic, meaning that they are not inherited from an affected child’s parents (non-hereditary) and occur randomly 

Prevalence

It is estimated that 1 in every 13,000² people in the United States have VEXAS syndrome, making it a very rare disease.

Causes

As described above, VEXAS syndrome is primarily caused¹ by genetic mutations in the UBA1 gene, which is located on the X chromosome. 

The UBA1 gene is essential for the production of an enzyme called E1 ubiquitin-activating enzyme. The main function of the E1 enzyme³ is to break down damaged or unwanted proteins by helping add ubiquitin ‘tags’ onto them (ubiquitination) so that they can be targeted for degradation (protein breakdown). 

Unfortunately, due to mutations in the UBA1 gene, the E1 enzyme of people with VEXAS syndrome does not function properly (low to no enzyme activity), causing damaged or unwanted proteins to build up in the cell at abnormal and excessive quantities. In response to this threat, the immune system becomes ‘overactive’ and reacts abnormally by attacking healthy tissues and organs^1, including the skin, joints, lungs, vasculature, and cartilaginous structures, leading to severe systemic inflammation. 

Risk factors 

The main risk factors for VEXAS syndrome include:

• Sex: unsurprisingly, since VEXAS syndrome is X-linked, recent research studies have shown that biological males¹ have a higher risk of developing VEXAS syndrome compared to individuals assigned female at birth.
• Age: VEXAS syndrome is more likely to affect people over 50 years of age, with a study published in 2023 showing that 1 in 4,269 individuals assigned male at birth and 1 in 26,238 individuals assigned female at birth  over 50 years of age develop VEXAS syndrome⁴ 

Signs and symptoms

The main symptom of VEXAS syndrome is inflammation, which can lead to a variety of other symptoms and signs^2, including:

• Fever
• Skin rashes (dermatitis)
• Swelling of the ear or nose (chondritis) 
• Joint pain
• Low blood oxygen levels (hypoxemia)
• Headaches
• Shortness of breath (dyspnea)
• A cough
• Red eye
• Swollen testicles (orchitis)

Diagnosis

A healthcare provider will diagnose² a suspected patient with VEXAS syndrome using a series of tests in the following order:

1. Physical examination: the healthcare provider will look for the signs and symptoms of VEXAS syndrome in the patient
2. Genetic testing (or ‘’DNA testing’’): the healthcare provider will check for mutations in the UBA1 gene by taking a DNA sample from the patient’s blood, hair, skin, or other tissue and sending it to the lab for testing. Genetic testing is the only way to confirm VEXAS syndrome, as it is mainly caused by mutations in the UBA1 gene. 

Management and treatment options

At present, there is no specific or standardised treatment¹ for VEXAS syndrome as it is newly identified, and a lot remains unknown about the disease.  

However, the main current treatment² options for VEXAS syndrome include:

• Corticosteroids: these are hormone-based drugs used to relieve inflammation
• Immunosuppressants: to suppress or inhibit the ‘overactive’ immune system so that it does not attack the body’s own organs and result in autoinflammation 
• Bone marrow transplant: these might be offered to some patients with bone marrow failure

Prevention strategies 

Unfortunately, since VEXAS syndrome has a strong genetic basis and mutations in the UBA1 gene occur randomly without a known cause (at least not to date), it cannot be prevented.²

Complications 

If left untreated, VEXAS syndrome can lead to a wide range of severe complications² including:

• Bone marrow failure: which can lead to death 
• Myocarditis (inflammation of the heart muscle)
• Arthritis
• Leukaemia (cancer of white blood cells)
• Anaemia: This is characterised by low red blood cells or haemoglobin
• Dermatitis 
• Chondritis (swollen cartilage)
• Vasculitis (inflammation of blood vessels)
• Deep vein thrombosis (DVT): this occurs when a blood clot develops in a vein deep within the body, e.g. legs
• Colitis (inflammation of the colon or large intestine)

When to see a doctor 

See a doctor² immediately if you experience any of the above-mentioned signs and symptoms of VEXAS syndrome. 

Visit the emergency room or call 911² immediately if you develop: 

• Breathlessness 
• Fever that remains above 39.5°C (103°F) even after a two-hour home treatment  

Summary 

VEXAS syndrome is a newly identified, rare, unpreventable, and severe form of autoimmune, autoinflammatory, and genetic disease that mainly affects individuals assigned to males at birth over 50 years of age. It was given the acronym VEXAS, as each letter provides a key characteristic or feature seen in patients with the disease. These include: 

• Vacuoles (V), which are commonly seen in bone marrow cells of patients 
• E1 ubiquitin-activating enzyme (E) which has low to no enzyme activity due to mutations in the UBA1 gene 
• The mutated UBA1 gene is located on the X chromosome (X)
• The disease causes autoinflammation (A), resulting in the body’s immune system attacking itself 
• Mutations in the UBA1 gene are somatic (S), meaning that they are non-hereditary and occur randomly 

VEXAS syndrome is mainly caused by mutations in the UBA1 gene which decreases the enzyme activity and the function of E1 ubiquitin-activating enzymes. In turn, damaged or unwanted proteins build up at abnormal levels within the cell, causing the immune system to ‘overreact’ and mistake healthy organs such as the skin, joints, lungs, vasculature, and cartilaginous structures for toxic foreign invaders, e.g. viruses.  

VEXAS syndrome causes a wide range of inflammatory signs and symptoms, including:

• Skin rashes (dermatitis) 
• Joint pain
• Breathlessness (dyspnea) and a cough 
• Inflammation in the blood vessels (vasculitis) 
• Swelling in the ear or nose (chondritis)

At present, VEXAS syndrome is mainly diagnosed via a physical examination and genetic testing. A diagnosis of VEXAS syndrome is confirmed when mutations in the UBA1 gene are found in patients using genetic testing. 

Corticosteroids, immunosuppressants, and in some cases, bone marrow transplants are the main current management and treatment options for VEXAS syndrome. 

If left untreated, VEXAS syndrome can lead to severe complications, which can be fatal, including bone marrow failure, leukaemia, and myocarditis. 

See a doctor immediately if you develop any signs or symptoms of VEXAS syndrome. 

Visit the emergency room  or call 911(or equivalent in your country)  immediately if you develop a fever above 39.5°C (103°F) and/or breathlessness.