VEXAS syndrome is a severe, adult-onset autoinflammatory disorder first identified in 2020 that causes a wide range of inflammatory symptoms. The name is an acronym for its features: Vacuoles, E1 enzyme, X-linked, Autoinflammatory, and Somatic. The discovery of VEXAS provided a unified diagnosis for symptoms that previously seemed unrelated, bridging medical specialties like rheumatology and hematology. This condition primarily affects men over the age of 50.
The Genetic Cause of VEXAS
VEXAS syndrome is caused by a specific genetic mutation in the UBA1 gene. This is not an inherited condition but results from a “somatic” mutation, a genetic change acquired during a person’s lifetime. These mutations occur after conception and are not present in every cell, being found in myeloid cells, a type of white blood cell involved in the immune response.
The “X-linked” aspect of the name refers to the UBA1 gene’s location on the X chromosome, which is why the disorder almost exclusively affects men. Men have one X chromosome (XY), so a single mutation is enough to cause the disease. Women have two X chromosomes (XX), and a healthy copy of the gene on the second X chromosome can compensate for a mutated one.
The UBA1 gene provides instructions for making the ubiquitin-activating enzyme E1. This enzyme is part of the cellular waste disposal system, tagging old or damaged proteins for removal. When the UBA1 mutation impairs this enzyme’s function, unwanted proteins build up inside the cell. This accumulation triggers an abnormal activation of the immune system, resulting in widespread inflammation.
Associated Symptoms and Conditions
VEXAS syndrome presents with diverse symptoms affecting multiple organ systems due to systemic inflammation. Patients often experience constitutional symptoms like recurrent fevers without a clear infectious cause, fatigue, and unexplained weight loss.
Rheumatologic issues are common, manifesting as painful joint inflammation (arthritis) affecting various parts of the body. A distinctive feature is chondritis, the inflammation of cartilage. This targets the cartilage in the ears and nose, causing pain, swelling, and redness.
Dermatologic manifestations are a component of the syndrome. Patients can develop skin problems, including rashes and painful, red or purplish skin lesions known as neutrophilic dermatosis. Vasculitis, or inflammation of the blood vessels, can also occur, leading to skin symptoms and affecting blood flow.
Inflammation can extend to the pulmonary system, causing issues within the lungs. Symptoms include a persistent cough and shortness of breath (dyspnea). The risk of blood clots, known as venous thromboembolism, is also elevated in individuals with VEXAS syndrome.
The syndrome has a connection to hematologic, or blood-related, disorders. Many patients develop macrocytic anemia, where red blood cells are too few and larger than normal. A low platelet count (thrombocytopenia) is also common. A number of individuals with VEXAS are also diagnosed with myelodysplastic syndrome (MDS), a cancer where immature blood cells in the bone marrow do not mature.
The Diagnostic Process
Diagnosing VEXAS syndrome is complex because its symptoms overlap with many other rheumatologic and hematologic diseases. A diagnosis is often considered when a specialist recognizes a pattern of disconnected inflammatory and blood-related symptoms in an adult male patient that do not respond to standard treatments.
A diagnostic procedure is a bone marrow biopsy, where a small sample of bone marrow is examined under a microscope. A characteristic finding in VEXAS patients is the presence of vacuoles—small, clear, bubble-like structures—inside myeloid and erythroid precursor cells. These vacuoles are an indicator of the syndrome and are the origin of the “V” in the VEXAS acronym.
While bone marrow findings are suggestive, a conclusive diagnosis is achieved through genetic testing. This involves analyzing a patient’s blood or bone marrow for the specific somatic mutation in the UBA1 gene. Confirming this genetic mutation provides a conclusive diagnosis and distinguishes VEXAS from other inflammatory conditions.
Current Treatment Approaches
Managing VEXAS syndrome focuses on controlling widespread inflammation and alleviating its symptoms. There is no standard treatment protocol, and therapies are tailored to the individual’s specific manifestations and disease severity.
High-dose corticosteroids are the first-line treatment used to quickly reduce severe inflammation. Symptoms often return when the steroid dose is lowered, and long-term use of high-dose corticosteroids carries a risk of side effects.
Other medications that suppress the immune system may be used, including various immunosuppressants and biologic drugs that target specific inflammatory components. Targeted therapies like Janus kinase (JAK) inhibitors are also being investigated. These have shown promise in controlling both the inflammatory and hematologic aspects of the disease in some patients.
The only known curative option for VEXAS syndrome is an allogeneic hematopoietic stem cell transplant (HSCT). This procedure replaces the patient’s defective hematopoietic stem cells with healthy ones from a donor, which can eliminate the mutated cells causing the disease. However, HSCT is a high-risk procedure with potential complications and is reserved for younger, healthier patients with severe disease.