VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is an adult-onset systemic inflammatory disease caused by somatic pathogenic variants in the UBA1 gene, which encodes ubiquitin-like modifier-activating enzyme 1, the principal E1 enzyme initiating ubiquitin-mediated protein degradation. Unlike inherited genetic disorders, VEXAS arises from postzygotic (somatic) mutations that develop during an individual's lifetime within hematopoietic stem cells rather than being present from conception. The condition predominantly affects males older than 50 years; affected females account for approximately 4% of described cases and typically carry specific chromosomal conditions affecting X-chromosome dosage, such as Turner syndrome or acquired X-chromosome monosomy. Per expert clinical review, VEXAS syndrome is recognized as likely underdiagnosed and underrecognized. A large population-based study identified a prevalence of approximately one in 4,000 among males older than 50 years, substantially higher than initially estimated when the syndrome was first described in 2020. The overall general population prevalence, which the packet classifies as very rare, does not capture this age- and sex-stratified burden.

The clinical presentation of VEXAS syndrome spans both inflammatory and hematologic domains. Recurrent fever is among the most characteristic and consistently observed features across the affected population. Macrocytic anemia is a hallmark hematologic finding, present in the majority of affected individuals, and often presents before the inflammatory manifestations are fully recognized. Chondritis—inflammatory destruction of cartilaginous structures—affects the ears (chondritis of the pinna) and nose (nasal chondritis) in many patients, and in some can lead to saddle-nose deformity. Pulmonary infiltrates reflecting systemic alveolar or interstitial inflammation are a frequent finding on imaging. Thromboembolism, including venous thrombosis and pulmonary embolism, represents a significant and life-threatening complication. Per expert clinical review, additional manifestations include skin lesions (neutrophilic dermatosis, leukocytoclastic vasculitis), myelodysplastic syndrome features, lymphopenia, and systemic inflammation that may be classified as relapsing polychondritis, Sweet syndrome, or undifferentiated inflammatory syndrome before VEXAS is recognized. Genotype-phenotype analyses have identified that specific pathogenic variants at the recurrent UBA1 p.Met41 site produce distinct inflammatory profiles: the p.Met41Val variant is associated with less ear chondritis and more undifferentiated inflammatory presentations, whereas other substitutions at the same site confer different clinical patterns.

VEXAS syndrome is caused by somatic pathogenic variants in the UBA1 gene located on the X chromosome at Xp11.3. UBA1 encodes the principal E1 ubiquitin-activating enzyme, which initiates the ubiquitin-proteasome system by activating ubiquitin for transfer to target proteins destined for degradation. Somatic UBA1 mutations—acquired de novo in hematopoietic stem cells during an individual's lifetime—impair this function in immune cell lineages, resulting in accumulation of misfolded proteins, unfolded protein response activation, and aberrant inflammatory signaling. The predominantly male presentation reflects X-chromosome biology: males possess a single X chromosome, so a somatic UBA1 mutation affects the only functional UBA1 allele in affected hematopoietic clones. Females are largely protected because a second X chromosome provides an intact UBA1 copy in most cells. VEXAS is not transmitted from parent to child through Mendelian inheritance; it is an acquired somatic condition. The UBA1-mutated hematopoietic clone expands over time, which correlates with the adult-onset and progressive nature of the syndrome.

Per expert clinical guidelines, formal diagnostic criteria for VEXAS syndrome have not been established. The condition is recognized in males over 50 years presenting with systemic autoinflammatory features—including recurrent fever, chondritis, skin lesions, and pulmonary infiltrates—combined with hematologic abnormalities such as macrocytic anemia, cytopenia, or morphologic features consistent with myelodysplastic syndrome. Diagnosis is confirmed by molecular identification of a somatic UBA1 pathogenic variant in peripheral blood or bone marrow. Next-generation sequencing with sensitivity adequate for detecting somatic variants at low variant allele frequencies, or targeted UBA1 sequencing panels, constitute the primary molecular diagnostic approaches. Bone marrow biopsy characteristically reveals cytoplasmic vacuolation in erythroid and myeloid precursors—the morphologic finding that contributed to the syndrome's acronym. The diagnostic evaluation following identification of VEXAS includes assessment of hematologic disease extent, organ system involvement, and thrombotic risk per published expert guidance.

No FDA-approved pharmacological therapies are specifically indicated for VEXAS syndrome. Per expert clinical review, the therapeutic management of individuals with VEXAS syndrome is currently based on retrospective cohort data and expert opinion in the absence of large prospective randomized trials, reflecting the recency of the syndrome's identification. Two primary treatment strategies have been employed: targeting the inflammatory process and targeting the UBA1-mutated hematopoietic stem cell population. Anti-inflammatory approaches have historically centered on corticosteroids, which effectively suppress systemic inflammation but frequently require sustained high doses and are associated with cumulative adverse effects including infection risk and metabolic complications. Conventional immunosuppressive agents, Janus kinase (JAK) inhibitors, interleukin-1 and interleukin-6 pathway inhibitors, and azacitidine (a hypomethylating agent used in myelodysplastic syndrome) have been explored in case series with variable responses reported. Allogeneic hematopoietic stem cell transplantation (HSCT)—which replaces the UBA1-mutated hematopoietic stem cell population with donor cells—is under active investigation as a potentially curative intervention. Expert review notes that a Phase II clinical study of allogeneic HSCT for VEXAS syndrome is ongoing. Per expert review, cigarette smoking is identified by expert review as a circumstance associated with worsening of peripheral arterial disease in the context of VEXAS-related vascular inflammation.

VEXAS syndrome is associated with significant morbidity and mortality, reflecting its chronic relapsing inflammatory course and progressive hematologic complications. Thromboembolic events are a leading cause of acute morbidity. Hematologic complications—including worsening cytopenia, progressive macrocytic anemia, and evolution to frank myelodysplastic syndrome or acute myeloid leukemia—are recognized long-term risks. Corticosteroid dependence, the predominant current treatment approach, introduces cumulative treatment-related morbidity. Per expert review, the overall prognosis of VEXAS syndrome varies according to the predominant clinical phenotype (inflammatory versus hematologic burden), the specific UBA1 pathogenic variant, and the response to treatment. Longitudinal outcome data are still accumulating given that the syndrome was first described in 2020; long-term survival statistics remain limited. Genotype-phenotype correlations are an active area of investigation and may refine prognostic stratification.

Active clinical trial records are present for VEXAS syndrome, including a large observational registry study of autoinflammatory diseases incorporating VEXAS and a study focused on clonal hematopoiesis of immunological significance. Per expert clinical review, a Phase II study of allogeneic hematopoietic stem cell transplantation for individuals with VEXAS syndrome is ongoing, representing the most advanced interventional investigation with curative intent. Clinical trial registries in the United States and Europe are maintained as primary resources for identifying current study opportunities in this condition.