VEXAS syndrome stands for vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome. It was first described in 2020. VEXAS syndrome is caused by mutations in the UBA1 gene of blood cells and causes inflammatory and hematologic (blood) manifestations. While a genetic condition, it is not hereditary and not passed down to children.
The prevalence of VEXAS syndrome is not yet known, but it is believed to be underestimated. Some research estimates that it affects 1 in 13,000 people, but more research is needed.
VEXAS syndrome affects mostly males and has an age at diagnosis of about 43 to 87 years. Characteristics of VEXAS syndrome include inflammation of the skin, joints, vessels, and cartilage, visual and hearing impairment, and hematological disorders.
There is currently no standard protocol for treating VEXAS syndrome because the condition is novel and still being researched. Some treatments that may be offered include glucocorticoids, conventional disease-modifying antirheumatic drugs (DMARDs), biologically targeted drugs, and allogeneic hematopoietic stem cell transplantation (blood cell-producing stem cells from a donor are given to the recipient).
This article will discuss the knowns and unknowns of VEXAS syndrome, the symptoms and affected organs with VEXAS syndrome, the diagnosis and prognosis of VEXAS syndrome, and treatments to manage VEXAS syndrome.
VEXAS Syndrome: Knowns and Unknowns
The acronym “VEXAS” stands for:
- “V” for “vacuoles”: These membrane-bound subcellular structures are often seen in cells obtained from bone marrow biopsies from people with VEXAS syndrome.
- “E” for “E1“: E1 ubiquitin activating enzyme is encoded by the UBA1 gene, which is mutated in people with VEXAS syndrome.
- “X” for “X-linked”: VEXAS syndrome is X-linked, meaning the UBA1 gene is on the X chromosome.
- “A” for “autoinflammation”: VEXAS syndrome is associated with autoinflammation (in which the immune system mistakenly triggers episodes of inflammation).
- “S” for “somatic”: The mutations involved with VEXAS syndrome are somatic (acquired during a person’s lifetime, not inherited).
A Note on Gendered Language
The research on VEXAS syndrome uses binary language, referring to men or males and women or females, when describing the genetic components of this condition. This article uses binary language to reflect the research terms. Verywell Health recognizes that gender is not binary and is not determined by chromosomal makeup.
VEXAS syndrome is considered an autoinflammatory disease, involving inflammation-related damage to organs and tissues.
VEXAS syndrome is caused by a mutation in the UBA1 gene, which causes it to not produce the E1 enzyme as it should. The E1 enzyme targets damaged or old proteins inside cells to be broken down.
Without the E1 enzyme, damaged proteins and waste build up within the cells. This triggers the immune system to attack healthy tissue because it sees the excess waste as a threat, leading to inflammation, impaired blood cell development, and other characteristics of VEXAS syndrome.
The UBA1 gene variants that cause VEXAS syndrome are found only in certain immune system cells and blood-forming cells in the bone marrow.
Because the UBA1 gene is on the X chromosome, VEXAS syndrome is more common in people with only one X chromosome, such as those with the XY chromosome combination (typical for males) and people with certain genetic conditions.
People with two X chromosomes would need to have a mutation in both copies of the UBA1 gene or a defect in the X chromosome without the mutated gene to develop VEXAS syndrome.
Some estimates suggest about 13,200 men and 2,300 women in the United States have VEXAS syndrome. Prevalence in men over 50 years of age has been estimated to be 1 in 4,269.
Risk factors for VEXAS syndrome include:
- Sex: It primarily occurs in males
- Age: Most cases of VEXAS are identified in mid to late adulthood
- History of autoimmune diseases: It is common for people with VEXAS syndrome to have autoimmune diseases such as systemic lupus erythematosus (SLE), Sweet syndrome, relapsing chondritis, vasculitis, or blood cancers.
VEXAS Syndrome and Affected Organs
Several organs and systems can be affected by VEXAS syndrome, including:
- Skin
- Lungs
- Structures containing cartilage, like the ears and nose
- Joints
- Vasculature and blood cells
- Eyes
- Cardiovascular system
- Gastrointestinal (GI) system
- Neurological system
- Reproductive and urinary systems (genitourinary)
- Lymphatic system
The main symptoms of VEXAS syndrome include:
- Recurrent fever
- Polychondritis: A condition that causes inflamed cartilage
- Neutrophilic dermatosis: Autoinflammatory skin conditions involving infiltration of neutrophils (inflammatory cells) in the affected tissue
- Vasculitis: An autoimmune disorder that causes inflammation in the blood vessels
- Ophthalmic: Manifestations relating to the eye
- Hematological manifestations with myelodysplastic syndrome (MDS): A group of disorders in which the bone marrow doesn’t make enough healthy blood cells
Other symptoms of VEXAS syndrome are:
- Painful skin rashes
- Fatigue
- Night sweats
- Muscle aches
- Gastrointestinal symptoms, such as abdominal pain and diarrhea
- Kidney involvement, such as proteinuria (elevated protein in the urine), erythrocyturia (blood in the urine) with dysmorphic erythrocytes (abnormal red blood cells), and progressive renal disease
- Epididymitis (inflammation of the epididymis, the coiled tube at the back of the testicle)
- Prostatitis (inflammation of the prostate)
- Orchitis (testicle inflammation)
- Headache
- Nervous system involvement
- Joint stiffness
- Enlarged spleen
- Anemia (a low number of healthy red blood cells), low platelets, and blood clots
- Arthritis
- Muscle inflammation
- Abnormally large red blood cells
- Inflammation/redness of the eyes
- Low blood oxygen levels
- Shortness of breath
- Persistent cough
- Swollen testicles
VEXAS Syndrome Phenotypes
Three basic phenotypes (patterns of observable characteristics) for VEXAS syndrome have been suggested.
Phenotype 1 includes mild to moderately severe symptoms, including:
- Recurrent fever
- Weight loss
- Less frequent pulmonary (lung) involvement
- Lymphadenomegaly (enlargement of one or more lymph nodes)
- Lower risk of thrombotic (blood clot) complications
- Lower C-reactive protein (CRP) (a protein made by the liver that is a marker for inflammation) levels
- Lower leukocytosis (high white blood cell count) levels
Phenotype 2Â characteristics related to MDS include:
- Relapsing chondritis (inflammation of cartilage)
- Frequent cardiac and gastrointestinal involvement
- Pulmonary infiltrates (substance denser than air in the lungs)
- Frequent infections
- Hematological manifestations
- Thrombocytopenia (low platelet count)
Phenotype 3’s inflammatory characteristics occur in older adults and include:
- Frequent weight loss
- Vasculitis
- Less frequently relapsing chondritis
- High CRP levels
VEXAS Syndrome Rash
VEXAS syndrome often (more than 85% of the time) causes skin symptoms, such as:
- Neutrophilic dermatoses (resembling Sweet syndrome): Tender, firm, pigmented or purpuric (red or purple spots on lighter skin tones, brown to black on darker skin tones, that don’t change color when pressed) nodules, and plaques that may have a small depression in the middle (resembling a navel)
- Vasculitis: Resembling livedo racemosa (mottling of the skin in an irregular, netlike pattern), polyarteritis nodosa (produces painful, discolored nodules), or giant cell arteritis (causes inflammation of blood vessels)
- Erythema nodosum: Tender, red or darker-colored bumps, commonly presents symmetrically on the shins)
- Urticaria (hives): Sometimes itchy welts or bumps, red on lighter skin tones, skin-colored or darker-colored on darker skin tones
- Skin blisters: Fluid filling a space between layers of the skin, causing a “bubble”
- Maculopapular rash: Mix of macules (flat, discolored areas of skin), and papules (small, raised bumps)
Skin symptoms are often the first sign of VEXAS syndrome.
Who Diagnoses VEXAS Syndrome?
The only definitive way to confirm VEXAS syndrome is by genetic testing, looking for alterations in the UBA1 gene. This is typically done by using genomic DNA from bone marrow tissue or peripheral blood leukocytes (white blood cells).
VEXAS syndrome may be recognized by clinical manifestations or the results of testing by a variety of healthcare providers, including:
- Rheumatologists (specialists in inflammatory joint diseases and many autoimmune diseases)
- Immunologists (immune system condition specialists)
- Hematologists (blood condition specialists)
- Geneticists (specialists in genetic conditions)
- Pathologists (specialists in lab and anatomic medicine)
- Ophthalmologists (eye specialists)
- Dermatologists (skin specialists)
- Internal medicine specialists
- Geriatricians
- Radiologists
Steps to Diagnosis
Guidelines for the diagnosis of VEXAS syndrome have not yet been established. Often, a diagnosis is made retrospectively for research purposes.
Genetic testing is diagnostic for VEXAS syndrome. VEXAS syndrome may be tested for if a healthcare provider suspects it after observing symptoms. Healthcare providers are recommended to consider VEXAS syndrome in men older than 50 who present with:
- Systemic inflammation
- Multiorgan involvement
- Cytopenia (lower than normal red blood cells, white blood cells, or platelets)
VEXAS syndrome can resemble and/or occur alongside other systemic inflammatory conditions and may be missed initially. People with VEXAS syndrome have often had symptoms for four to five years before receiving a diagnosis.
Diagnostic tests and procedures that may be performed if VEXAS syndrome is suspected include:
Prognosis With Diagnosed VEXAS Syndrome
VEXAS syndrome is chronic and progressive. It can have complications such as:
- Progressive anemia
- Respiratory failure
- Multiorgan involvement, such as kidney, heart, bowel, and brain
- Blood clots that can block veins or arteries
- Arterial stroke (blockage of a blood vessel in the brain)
Survival rates are still being researched. Survival rates may depend on how the condition manifests. A study of 116 people with VEXAS syndrome grouped participants into three clusters.
- Cluster 1 (47% of the participants): Mild to moderate disease
- Cluster 2 (16% of the participants): MDS association
- Cluster 3 (37% of the participants): Constitutional manifestations, higher C-reactive protein levels, less frequent chondritis
The five-year survival rates (number of participants still alive five years after diagnosis or beginning treatment) for each of the clusters in the study were:
- Cluster 1: 84%
- Cluster 2: 51%
- Cluster 3: 90%
Other research shows an overall five-year survival rate of about 50%.
Research on VEXAS syndrome is still relatively new, and more is needed to determine survival rates, and ways to improve them.
Treatments to Manage VEXAS Syndrome
VEXAS syndrome can be challenging to treat, and often requires the cooperation of different specialist teams.
There is no standardized treatment protocol for VEXAS syndrome, and more research is needed to help find the best courses of treatment.
The two main approaches to treatment are:
- Target and eradicate the UBA1-mutated hematopoietic (cells that develop into types of blood cells) population
- Inhibit the inflammatory features of the condition
Treatments that may be used in treating VEXAS syndrome include:
- High-dose corticosteroids
- Glucocorticosteroids (GCSs)
- Synthetic DMARDs
- Interleukin (IL)-1Â antagonists
- IL-6Â antagonists
- IL-17A antagonists
- Janus kinase (JAK) inhibitors
- DNA methyltransferase (DNMT) inhibitors
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a procedure that may be suggested for people with VEXAS syndrome that is not responding to medication. In this procedure, blood cell–producing stem cells from a donor are given to the recipient, usually after treatment to eradicate the recipient’s blood-producing cells.
Allo-HSCT may be particularly beneficial for people who are in the early stages of VEXAS syndrome, who are high risk, and who have poor clinical response.
Clinics and Interdisciplinary CareÂ
Clinical trials, such as one sponsored by the National Cancer Institute (NCI), and other studies are underway to explore treatments for VEXAS syndrome further.
VEXAS syndrome typically requires a treatment plan that involves healthcare providers from several specialties. If you aren’t sure where to start, ask your primary care provider or the healthcare provider who diagnosed your VEXAS syndrome for a referral to specialists for treatment.
Summary
VEXAS syndrome is an autoinflammatory condition caused by mutations in the UBA1 gene. It primarily affects men in middle age to late adulthood.
VEXAS syndrome can affect several organs and systems and cause symptoms, including inflammation of the skin, joints, vessels, eyes, and cartilage. Genetic testis is diagnostic for VEXAS syndrome.
There is currently no standard protocol for treating VEXAS syndrome. Some treatments that may be suggested include glucocorticoids, conventional disease-modifying antirheumatic drugs (DMARDs), biologically targeted drugs, and allogeneic hematopoietic stem cell transplantation.
