VEXAS syndrome is a newly identified, complex autoinflammatory disease, first described in 2020. It represents a fusion of inflammatory and hematologic disorders previously treated separately. The condition is defined by a specific genetic mutation that drives chronic, systemic inflammation throughout the body. Understanding VEXAS requires recognizing its genetic foundation, dual clinical presentation, and the specialized approach necessary for diagnosis and management.
Defining the Syndrome and Its Genetic Cause
The name VEXAS is an acronym derived from the core features of the condition: Vacuoles, E1 enzyme, X-linked, Autoinflammatory, and Somatic. Vacuoles refers to the abnormal, empty spaces observed in the precursor cells of the myeloid and erythroid lineages within the bone marrow. The final letter, Somatic, indicates the genetic change is acquired during a person’s lifetime and is not inherited.
The E1 enzyme, specifically the E1 ubiquitin-activating enzyme, is the protein affected by this mutation. This enzyme is encoded by the UBA1 gene and plays a fundamental role in ubiquitination, which tags damaged or unneeded proteins for breakdown and recycling. When the UBA1 gene is mutated, the dysfunctional E1 enzyme disrupts this pathway, causing waste products to accumulate inside the cell. This accumulation activates the innate immune system, resulting in the chronic Autoinflammatory response seen in patients.
The X-linked nature refers to the location of the UBA1 gene on the X chromosome. Since males typically possess only one X chromosome, a single acquired mutation is sufficient to cause the disease. Consequently, VEXAS syndrome predominantly affects adult males, with symptom onset generally occurring after age 50 or 60. The mutation occurs within hematopoietic progenitor cells, driving both the inflammatory and hematologic components of the disease.
Recognizing the Clinical Signs
VEXAS syndrome is characterized by severe, treatment-resistant inflammatory symptoms combined with underlying blood cell abnormalities. Common signs of systemic inflammation include persistent, recurrent, and unexplained fever. Patients frequently experience profound fatigue and unexplained weight loss, reflecting the body’s chronic inflammatory state.
The autoinflammatory process often manifests in the skin and cartilage, leading to distinct dermatological and rheumatologic features. Skin rashes may resemble Sweet syndrome (painful, raised lesions) or manifest as vasculitis (inflammation of blood vessel walls). Inflammation affecting cartilage, known as chondritis, is a notable feature, often presenting as painful swelling of the ears or nose, similar to relapsing polychondritis.
The underlying hematologic issues are defining features of VEXAS syndrome. Patients frequently develop macrocytic anemia (abnormally large red blood cells) and may exhibit low platelet counts (thrombocytopenia). A significant concern is the strong association with myelodysplastic syndrome (MDS), a bone marrow failure disorder that can progress to acute myeloid leukemia. The presence of vacuoles in the myeloid and erythroid precursors observed during a bone marrow examination links the clinical picture to the genetic cause.
Diagnosis and Differential Considerations
Diagnosing VEXAS syndrome requires integrating clinical, laboratory, and genetic evidence due to its overlap with many other disorders. Diagnosis is typically established when an adult male, usually over 50, presents with chronic inflammatory symptoms alongside unexplained cytopenias, particularly macrocytic anemia. Laboratory tests consistently show evidence of systemic inflammation, such as elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels.
The definitive diagnosis relies on detecting the somatic UBA1 gene mutation. This is typically accomplished using specialized genetic testing, often next-generation sequencing (NGS), performed on peripheral blood or bone marrow samples. Because the mutation is somatic and restricted to blood-forming cells, testing must specifically look for this acquired change in the hematopoietic lineage.
A bone marrow biopsy is an important step in the diagnostic workup, serving two purposes. It allows pathologists to visualize the characteristic vacuoles within the precursor cells, which is the “V” component of the acronym. The biopsy also assesses for features of an associated hematologic malignancy, such as myelodysplastic syndrome. VEXAS syndrome can mimic conditions like polyarteritis nodosa, giant cell arteritis, and classic autoinflammatory syndromes, making the UBA1 genetic test essential for accurate identification.
Current Management and Treatment Approaches
Treatment for VEXAS syndrome is complex, focusing on controlling aggressive systemic inflammation and managing hematologic dysfunction. High-dose glucocorticoids, such as prednisone, are typically used as first-line therapy because they effectively suppress inflammatory symptoms. However, patients often require sustained, high doses to maintain control, leading to significant side effects associated with long-term steroid use.
To mitigate reliance on steroids, various immunosuppressive and immunomodulatory agents are often introduced. These second-line therapies may include conventional disease-modifying antirheumatic drugs (DMARDs) like methotrexate, or biologic agents targeting specific inflammatory pathways. Janus kinase (JAK) inhibitors represent a class of targeted therapy that has shown promise by blocking signals that drive the autoinflammatory response.
For patients with severe disease or those who fail to respond to standard immunosuppression, more intensive treatments are considered. Hypomethylating agents, such as azacitidine (typically used for MDS), have been explored due to the hematologic component of VEXAS. Hematopoietic stem cell transplantation (HSCT) is currently the only potentially curative treatment option, as it replaces the diseased stem cells carrying the UBA1 mutation with healthy donor cells. This procedure carries significant risks and is limited by the advanced age and comorbidities common in VEXAS patients.