VEXAS Syndrome is a recently identified, severe adult-onset autoinflammatory disorder that connects previously disparate chronic inflammatory conditions into a single disease entity. Discovered in 2020, this complex syndrome predominantly affects older men and is characterized by systemic inflammation and hematologic abnormalities. The condition presents a diagnostic challenge because its symptoms often overlap with other rheumatologic and blood disorders, delaying accurate identification. It represents an important finding in the study of inflammatory diseases, highlighting how an acquired genetic change can drive widespread immune system dysfunction.
Defining VEXAS Syndrome
The name VEXAS is an acronym summarizing the disorder’s five defining features. The “V” stands for Vacuoles, small, fluid-filled spaces observed within precursor blood cells during bone marrow examination. The “E” refers to the E1 ubiquitin-activating enzyme, which is functionally impaired.
The “X” indicates the X-linked nature of the disease, meaning the causative gene is on the X chromosome, explaining why the syndrome is seen almost exclusively in males. “A” denotes Autoinflammatory, classifying VEXAS as a disease where the innate immune system activates without an external trigger. The “S” represents Somatic, signifying that the genetic change is acquired during a person’s lifetime rather than being inherited.
The underlying genetic change is a somatic mutation in the UBA1 gene, located on the X chromosome. This mutation occurs in hematopoietic stem cells, the bone marrow cells responsible for producing all mature blood cells. Affecting the blood-forming lineage, this acquired mutation results in mosaicism, where only a subset of the body’s cells carries the defect.
Recognizing the Clinical Signs
Patients with VEXAS syndrome typically experience chronic, recurring inflammation that resists conventional treatments. Common symptoms include persistent fevers, unexplained fatigue, and significant weight loss. These systemic manifestations can last for years before diagnosis, often leading to misdiagnosis as other inflammatory diseases.
More specific findings often involve inflammation of the cartilage (chondritis), particularly affecting the ears and nose, which can mimic relapsing polychondritis. Skin inflammation is also common, presenting as painful, red rashes that may resemble Sweet syndrome or various forms of vasculitis. Inflammation can also affect the lungs, causing pulmonary infiltrates, and the joints, resulting in inflammatory arthritis.
Because the mutation affects blood cell production, hematologic issues are nearly always present, including low blood cell counts, such as macrocytic anemia and thrombocytopenia. The combination of systemic inflammation and blood abnormalities is a hallmark of VEXAS syndrome. The disease often arises in mid to late adulthood, with the median age of symptom onset occurring in the late 50s or 60s.
The Biological Basis of Autoinflammation
The mechanism of VEXAS syndrome centers on the UBA1 gene, which provides instructions for making the E1 ubiquitin-activating enzyme. This enzyme initiates the ubiquitylation pathway, a process that tags proteins with ubiquitin, marking them for recycling, degradation, or signaling. The somatic mutation typically affects the methionine-41 codon (p.Met41) of the UBA1 gene, leading to a dysfunctional E1 enzyme.
This impairment results in decreased ubiquitylation, particularly in the hematopoietic stem cells where the mutation originates. The disrupted protein tagging and recycling process causes a buildup of misfolded or damaged proteins inside affected myeloid lineage cells, such as monocytes and macrophages. This cellular stress and accumulation of abnormal components trigger an uncontrolled response from the innate immune system.
The resulting state is systemic autoinflammation, where the body’s first line of defense is constantly activated without an infection. This activation leads to the persistent release of inflammatory signaling molecules, which drive the symptoms observed throughout the body. This chronic dysfunction in protein handling within the myeloid cells links the blood abnormalities to the widespread inflammatory symptoms.
Diagnosis and Management Strategies
The definitive diagnosis of VEXAS syndrome requires genetic sequencing to identify the characteristic somatic mutation in the UBA1 gene. Testing is performed on peripheral blood or bone marrow samples, looking for the specific acquired genetic change in the blood-forming cells. A bone marrow biopsy often reveals the presence of vacuoles within the myeloid and erythroid precursor cells.
Diagnosis is often challenging because the clinical presentation mimics other conditions, requiring a high degree of suspicion, especially in older male patients with unexplained systemic inflammation and blood count abnormalities. The presence of both autoinflammatory features and a hematologic disorder, such as myelodysplastic syndrome (MDS) or macrocytic anemia, should prompt consideration of VEXAS syndrome.
Management strategies focus on controlling the severe inflammation, as there is currently no known cure for the underlying genetic defect. High-dose corticosteroids are typically the first-line treatment because they effectively reduce inflammation, but patients often require chronic therapy, leading to potential side effects. Traditional immunosuppressive drugs or standard anti-inflammatory treatments often show poor or inconsistent results.
For those whose inflammation is difficult to control, various targeted biologics and immunosuppressants are used, including JAK inhibitors, which target specific inflammatory pathways. The only potentially curative approach is allogeneic hematopoietic stem cell transplantation (HSCT), which replaces the patient’s mutated blood-forming cells with healthy donor cells. However, this procedure is complex and carries significant risks, making it an option reserved for patients with more aggressive disease progression or associated blood cancers.