VEXAS syndrome is a serious inflammatory and blood disorder caused by acquired mutations in a gene called UBA1, first identified in late 2020 by researchers at the National Institutes of Health. The name is an acronym standing for vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic. Before its discovery, patients with VEXAS were typically bounced between rheumatologists, hematologists, and dermatologists, often carrying several separate diagnoses that never quite fit together. What makes VEXAS unusual is that it was found through a genetics-first strategy rather than bedside observation, and it has turned out to be far more common than anyone initially expected.
How VEXAS Was Found
Most diseases are discovered the traditional way: a doctor notices an unusual pattern in patients and works backward to find a cause. VEXAS was found in reverse. A team at the NIH searched through a large database of blood-sample genetic sequences, looking specifically for damaging mutations in genes involved in ubiquitylation, a fundamental cellular recycling process. They identified 25 men who all carried somatic mutations affecting a specific spot (methionine-41) in UBA1, the gene encoding the body’s main E1 enzyme that kicks off that recycling process. Despite having been diagnosed with a range of seemingly unrelated inflammatory conditions, these men shared a striking cluster of features: blood abnormalities, recurrent fevers, blood clots, lung inflammation, and distinctive vacuoles (tiny bubble-like holes) visible in their bone marrow cells.1PubMed Central. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease
The word “somatic” in the acronym is critical. These mutations are not inherited from a parent; they arise spontaneously in blood-forming stem cells sometime during adulthood. That means genetic testing of a cheek swab or saliva sample could miss the mutation entirely, because it lives only in the blood cell lineage. The mutation then spreads as those stem cells divide, gradually producing a growing population of dysfunctional blood cells that drive inflammation throughout the body.2PubMed Central. VEXAS syndrome: a newly discovered systemic rheumatic disorder
What Goes Wrong Inside the Cell
UBA1 is the enzyme that starts ubiquitylation, a process you can think of as the cell’s quality-control tagging system. When a protein is damaged or no longer needed, it gets tagged with a small molecule called ubiquitin, which marks it for disposal. UBA1 mutations in VEXAS are partial loss-of-function, meaning the enzyme still works but much less effectively. The result is a buildup of misfolded and unwanted proteins inside blood cell precursors, which is likely what produces the characteristic vacuoles visible under a microscope.3PubMed Central. UBA1 dysfunction in VEXAS and cancer Those vacuoles in myeloid and erythroid progenitor cells have become a hallmark of the disease and one of the first clues pathologists look for in a bone marrow biopsy.4The Lancet Haematology. Vacuolated bone marrow progenitors: a guide for clinicians
The downstream consequences of this cellular dysfunction are broad. Research on blood samples from VEXAS patients has found elevated levels of many pro-inflammatory signaling molecules, including IL-1β and IL-18, which point to activation of the inflammasome, a part of the innate immune system that triggers aggressive inflammation when it senses danger. Gene expression analyses also show ramped-up TNF-α and NFκB signaling, pathways involved in both inflammation and cell death.5Nature Communications. VEXAS syndrome is characterized by inflammasome activation and monocyte dysregulation In practical terms, the mutant blood cells are constantly sending out alarm signals that put the entire body into an inflammatory state.
Who Gets VEXAS
Because UBA1 sits on the X chromosome, VEXAS overwhelmingly affects men, who have only one copy. Women have two X chromosomes, so for a woman to develop VEXAS she typically needs both the UBA1 mutation and loss of the other X chromosome in the same blood cells (a phenomenon called mosaic X monosomy). This double requirement makes female cases rare but not impossible.6PubMed. Comparing clinical features between males and females with VEXAS syndrome: data from literature analysis of patient reports When women do develop the syndrome, their clinical features look similar to those seen in men.
Prevalence was initially thought to be vanishingly small, but a study screening a large clinical population found the estimated rate among people over 50 was roughly 1 in 4,269 men and 1 in 26,238 women, or about 1 in 13,591 across the entire cohort regardless of age.7JAMA. Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population Those numbers suggest VEXAS may be more common than many well-known rheumatic diseases. Because the syndrome was only named in 2020, a large number of people are likely still undiagnosed, carrying labels like “unclassified vasculitis” or “treatment-resistant Sweet syndrome” without anyone having tested for a UBA1 mutation.
Symptoms and Clinical Features
VEXAS is a multi-system disease, and its symptoms tend to overlap with several other conditions, which is exactly why it went unrecognized for so long. The most common threads are systemic inflammation (fevers, elevated inflammatory markers, fatigue), blood abnormalities, skin problems, cartilage inflammation, lung involvement, blood clots, and eye disease. Nearly all patients show macrocytic anemia, meaning their red blood cells are abnormally large and often insufficient in number.8PubMed Central. Macrocytic anemia and polychondritis: VEXAS syndrome
Skin
Skin manifestations develop in the vast majority of patients. In one cohort, 88% of patients developed skin involvement, and in nearly half of those, the skin findings appeared before or at the same time as other symptoms of the disease.9PubMed. Cutaneous involvement in VEXAS syndrome: clinical and histopathologic findings The rashes and lesions take several forms, including tender red or purplish bumps, swollen papules (sometimes on the neck and trunk), and firm plaques or nodules.10JAMA Dermatology. UBA1 Variations in Neutrophilic Dermatosis Skin Lesions of Patients With VEXAS Syndrome Under a microscope, the patterns typically fall into categories such as neutrophilic dermatosis, leukocytoclastic vasculitis, and perivascular dermatitis. Interestingly, the specific genetic variant a patient carries influences which pattern predominates. The Met41Leu variant tends to produce neutrophilic infiltrates that resemble a condition called histiocytoid Sweet syndrome, while the Met41Val variant is more often associated with vasculitic lesions.11PubMed Central. Skin Manifestations of VEXAS Syndrome and Associated Genotypes
Cartilage and Joints
More than half of patients identified with VEXAS meet diagnostic criteria for relapsing polychondritis, a condition in which the immune system attacks cartilage, most often in the ears, nose, and airways.12PubMed Central. Somatic Mutations in UBA1 Define a Distinct Subset of Relapsing Polychondritis Patients With VEXAS This overlap has made some researchers wonder how many people diagnosed with relapsing polychondritis actually have VEXAS as the underlying cause. The clinical picture is similar enough that VEXAS should be on the differential for any older man presenting with polychondritis alongside blood count abnormalities.13PubMed Central. Autoimmunity and Autoinflammation: Relapsing Polychondritis and VEXAS Syndrome Challenge
Lungs
Lung involvement is common. A systematic review found pulmonary infiltrates in over 40% of patients, with pleural effusion (fluid around the lungs) and interstitial pneumonia also reported.14PubMed Central. Pulmonary manifestations in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome: a systematic review In one detailed study of 45 patients with chest CT scans, 87% had ground-glass opacities, roughly half had consolidations, and 53% had pleural effusions. About 44% reported shortness of breath and 40% reported cough.15PubMed. Pleuropulmonary Manifestations of Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic (VEXAS) Syndrome Lung disease in VEXAS can mimic infections or other inflammatory lung conditions, adding yet another layer of diagnostic confusion.
Eyes
Somewhere between 16% and 46% of patients develop eye problems. The most common finding is periorbital edema (puffy swelling around the eyes), followed by episcleritis and scleritis (inflammation of the white of the eye). Uveitis, conjunctivitis, blepharitis, and orbital inflammatory disease round out the list of reported ocular manifestations.16Clinical Insights in Eyecare. Case Report: VEXAS Syndrome Expands the List of Systemic Diseases Underlying Episcleritis
Blood Clots
Thrombosis is one of the most dangerous features of VEXAS and a major driver of its morbidity. In one large study, clots occurred in about 49% of patients, with venous clots accounting for the lion’s share. Nearly two-thirds of the venous clots were unprovoked (no clear trigger like surgery or immobility), 41% recurred, and one in five occurred even while the patient was already on blood thinners. The cumulative risk of venous thrombosis reached roughly 40% by five years from symptom onset.17PubMed Central. Venous and arterial thrombosis in patients with VEXAS syndrome Arterial clots, while less common, carried a cumulative incidence of about 11% by five years. These numbers are high enough that clinicians now recommend clot-prevention strategies during high-risk periods for essentially all VEXAS patients.
An earlier literature review placed the venous clot rate at about 36% and arterial thrombosis at under 2%, with deep vein thrombosis being more common than pulmonary embolism.18PubMed Central. Thrombosis in VEXAS syndrome The underlying mechanism likely involves the chronic inflammation itself promoting a pro-clotting state, though the exact pathways are still being studied.
Diagnosis
Confirming VEXAS requires detecting the UBA1 mutation in blood or bone marrow cells. In practice, Sanger sequencing of the relevant portion of the UBA1 gene is the standard approach. In one cohort of 104 patients referred for testing, Sanger sequencing identified VEXAS variants in 12%, and next-generation sequencing (a more expensive, broader technique) did not catch any additional cases, suggesting that targeted Sanger sequencing is sufficient for diagnosis.19PubMed Central. Diagnostic and Monitoring Strategies for VEXAS Syndrome: Evaluating Sanger Sequencing, NGS, and the SWIM-Score A bone marrow biopsy showing the characteristic vacuoles in blood cell precursors adds strong supporting evidence but is not diagnostic on its own, since vacuolation also occurs in other conditions like certain drug toxicities and nutritional deficiencies.20PubMed. VEXAS syndrome: A review of bone marrow aspirate and biopsies reporting myeloid and erythroid precursor vacuolation
The tricky part is thinking of VEXAS in the first place. If you are a man over 50 with unexplained fevers, macrocytic anemia, recurrent blood clots, skin rashes, and inflammation that bounces around different organ systems, the diagnosis should be on the radar. But because most practicing doctors trained before 2020, awareness is still catching up. Many patients go years before the right test is ordered.
Treatment Options
Treating VEXAS is a two-pronged problem: controlling the runaway inflammation and, ideally, eliminating the mutant blood cells that cause it. Neither goal is easy, and there is no consensus treatment protocol yet.
Corticosteroids
Steroids remain the most reliably effective anti-inflammatory therapy. Most clinicians start with prednisone at roughly 1 mg per kilogram of body weight. Steroids typically bring symptoms under control quickly, but the effect is dose-dependent and often temporary. Many patients find it nearly impossible to taper below moderate doses without their symptoms flaring back, which creates long-term problems like bone loss, diabetes, and infection risk.21ReumatologÃa ClÃnica. VEXAS syndrome: Clinical manifestations, diagnosis, and treatment Traditional steroid-sparing immunosuppressants like methotrexate, azathioprine, and mycophenolate have shown little evidence of working well on their own in VEXAS, making the steroid dependency especially frustrating.
JAK Inhibitors
Drugs that block Janus kinase (JAK) signaling pathways have emerged as one of the more promising options. A systematic review covering 186 patients treated with various JAK inhibitors found that about a third achieved a complete response and roughly another 30% had a partial response.22PubMed Central. JAK Inhibitors for Treatment of VEXAS Syndrome: A Systematic Review of 186 Cases Among the JAK inhibitors used, ruxolitinib has received the most attention. A retrospective multicenter analysis found encouraging evidence supporting ruxolitinib specifically, with clinical remissions and reduced steroid use in most patients treated with it.23PubMed Central. Ruxolitinib is more effective than other JAK inhibitors to treat VEXAS syndrome: a retrospective multicenter study Other JAK inhibitors such as tofacitinib, baricitinib, and upadacitinib have also been used with varying response rates. About 37% of patients on JAK inhibitors experienced adverse effects, so these drugs are not without downsides, but for many VEXAS patients they represent the best available route to getting off high-dose steroids.
Azacitidine
Azacitidine, a drug more commonly used in blood cancers like myelodysplastic syndrome (MDS), has also shown activity in VEXAS. A large retrospective study found inflammatory response rates of 41% at six months and 54% at twelve months, regardless of whether the patient also had MDS. Responses tended to be delayed, with the median response taking around six months to appear.24PubMed. Efficacy and safety of azacitidine for VEXAS syndrome: a large-scale retrospective study from FRENVEX This slow onset means patients typically need ongoing steroid support while waiting for azacitidine to take effect, which demands patience and careful management.
Stem Cell Transplant
Allogeneic stem cell transplant (using donor cells) is the only treatment with curative potential, because it replaces the patient’s mutant blood-forming cells entirely. A review of 33 transplanted patients found that about 82% were alive at follow-up, and in cases where post-transplant genetic testing was done, complete clearance of the UBA1 mutation was confirmed. However, transplant carries substantial risks: graft-versus-host disease developed in over half the patients, and infections were common and implicated in four of the six deaths.25PubMed Central. Allogenic haematopoietic stem cell transplantation in VEXAS: A review of 33 patients The median age at transplant was 59, and many VEXAS patients are older with comorbidities that make transplant risky. It remains a curative option in principle, but choosing the right candidates is a delicate balancing act.26PubMed Central. Role of allogeneic hematopoietic cell transplantation in VEXAS syndrome
Prognosis and What Drives It
VEXAS is a serious disease. Overall survival has been estimated at roughly 50% at ten years.27PubMed Central. Role of allogeneic hematopoietic cell transplantation in VEXAS syndrome Two factors have emerged as the strongest independent predictors of worse outcomes. The first is genotype: patients carrying the valine variant (p.Met41Val) had a median survival of nine years and a death rate of 50%, compared to 18% and 22% for the leucine and threonine variants, respectively. The second is transfusion dependence. Patients who became reliant on blood transfusions had roughly 3.5 times the risk of death compared to those who did not, and the valine variant carried a similar hazard.28Arthritis & Rheumatology. Genotype and Transfusion Dependence Predicts Mortality in VEXAS Syndrome, a Newly Described Disease with Overlap Inflammatory and Hematologic Features No other clinical features reached statistical significance as mortality predictors in that analysis, which makes genotyping useful not just for confirming the diagnosis but for gauging how aggressively to treat.
Progression to a hematologic malignancy, particularly myelodysplastic syndrome, is another serious concern. The link between VEXAS and blood cancers is not incidental; the same mutant stem cells that drive inflammation can also acquire additional mutations that push toward malignancy over time. This relationship between chronic inflammation and cancer risk is part of why some clinicians argue for considering transplant earlier rather than later in younger patients, even though the procedure’s risks are high.
New Variants and Expanding Boundaries
When VEXAS was first described, only mutations at the methionine-41 position in UBA1 were known to cause it. Since then, novel variants elsewhere in the gene have been reported in patients with clinical pictures indistinguishable from classic VEXAS.29PubMed Central. Novel Somatic UBA1 Variant in a Patient With VEXAS Syndrome This means standard genetic testing that only looks at the canonical hotspot could miss atypical cases. As more variants are identified, the true prevalence of the syndrome is likely to climb, and the clinical spectrum may broaden to include milder presentations that currently fly under the radar. For a disease that has only been known for five years, the pace of discovery around VEXAS has been remarkably fast, and the boundaries of what counts as VEXAS are still being drawn.