VEXAS Syndrome is a recently identified, rare, and serious adult-onset disease characterized by systemic inflammation. The name VEXAS is an acronym describing its core features: Vacuoles (empty spaces in bone marrow cells), E1 enzyme (ineffective due to mutation), X-linked (gene location), Autoinflammatory (immune system attacks tissues), and Somatic (acquired, not inherited, gene change). This complex condition presents as persistent inflammatory symptoms combined with abnormalities in the blood.
The Underlying Genetic Cause
VEXAS Syndrome is caused by an acquired, or somatic, mutation in the UBA1 gene. Since this gene is located on the X chromosome, the disease is considered X-linked and disproportionately affects males, typically presenting in late adulthood. The somatic mutation occurs randomly during a person’s lifetime within hematopoietic stem and progenitor cells, the precursors to all blood and immune cells.
The UBA1 gene encodes the E1 ubiquitin-activating enzyme, an essential component of the ubiquitination pathway. This pathway acts as a cellular tagging system, marking proteins for degradation or activation. The mutation disrupts the E1 enzyme’s normal function, causing a partial loss-of-function within the blood-forming cells.
This disruption leads to a malfunction in protein quality control and subsequent cellular stress. Consequently, the innate immune response is aberrantly activated, and there is a strong bias toward the development of myeloid lineage cells. The resulting uncontrolled inflammation and blood cell abnormalities drive the symptoms of VEXAS Syndrome.
Recognizing the Symptoms
The clinical presentation of VEXAS Syndrome is highly diverse, often mimicking other inflammatory disorders, which contributes to diagnostic difficulty. The condition is characterized by chronic, unexplained systemic inflammation, frequently presenting with recurrent fevers and profound fatigue. Onset typically occurs in the mid-sixties.
Severe skin inflammation is a common feature, manifesting as various dermatoses, including rashes resembling Sweet syndrome (tender, reddish-purple plaques). Inflammation often affects cartilage, particularly in the ears and nose, known as relapsing polychondritis. Joint pain (arthralgia) and arthritis are frequently reported, along with inflammation in the blood vessels (vasculitis).
Inflammation can extend to internal organs, causing pulmonary involvement like lung infiltrates or shortness of breath. A defining component is the presence of hematologic issues, including macrocytic anemia (abnormally large red blood cells) and low platelet count (thrombocytopenia). The syndrome also carries a predisposition for developing hematologic malignancies, such as Myelodysplastic Syndrome (MDS) or multiple myeloma.
Diagnostic Process
VEXAS Syndrome should be suspected in older males presenting with persistent, unexplained systemic inflammation unresponsive to standard treatments, especially when combined with hematologic abnormalities. Initial laboratory work-up reveals significantly raised inflammatory markers, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Blood tests often show cytopenias, including macrocytic anemia and low platelet counts.
The definitive confirmation of VEXAS Syndrome relies on genetic testing. This involves sequencing the UBA1 gene from peripheral blood or bone marrow samples to identify the characteristic somatic mutation. The mutation is typically present at a high variant allele fraction, meaning a large proportion of the blood cells carry the change.
A bone marrow biopsy is often performed to assess the blood-forming tissue. A distinctive finding is the presence of abnormal cytoplasmic vacuoles within the precursor cells of the myeloid and erythroid lineages. This pathological observation, combined with inflammatory and hematologic symptoms, strongly guides the physician toward specific genetic testing.
Current Treatment Approaches
The primary goal of managing VEXAS Syndrome is to control the severe, progressive inflammation and address associated hematologic conditions. Treatment typically begins with high-dose corticosteroids, such as prednisone, which effectively reduce inflammation and provide symptomatic relief. However, patients often become steroid-dependent or relapse when the dose is reduced, necessitating alternative therapies due to the risk of long-term side effects.
Immunosuppressive drugs are frequently used as second-line agents to reduce reliance on corticosteroids. These include conventional disease-modifying anti-rheumatic drugs (DMARDs) and biologic agents that target specific inflammatory pathways. Emerging therapies include Janus kinase (JAK) inhibitors, like ruxolitinib, which modulate the signaling pathways involved in inflammation.
Hematologic and Curative Options
For patients with significant hematologic involvement, such as co-existing MDS, oncology therapies are employed, notably the hypomethylating agent azacitidine. Azacitidine has shown promise for both the blood disorder and in improving inflammatory symptoms for some patients.
The only potential curative treatment option is allogeneic hematopoietic stem cell transplantation (HSCT). This procedure replaces the patient’s mutated cells with a donor’s healthy stem cells. However, HSCT is highly complex and risky, making it suitable only for select patients with severe, refractory disease.