VEXAS Syndrome: Causes, Symptoms, and Treatment

VEXAS syndrome is a severe inflammatory disease caused by acquired mutations in a gene called UBA1, which plays a central role in the body’s protein-recycling machinery. First described in 2020, the condition primarily strikes men over 50 and can masquerade as a range of seemingly unrelated disorders, from blood cancers to autoimmune conditions, before the true diagnosis emerges. The name itself is an acronym: Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic. Despite being identified only recently, prevalence estimates suggest VEXAS may be far more common than anyone initially suspected.

What Causes VEXAS Syndrome

VEXAS arises from somatic mutations in the UBA1 gene, located on the X chromosome. “Somatic” means these mutations are not inherited from a parent; instead, they develop spontaneously in blood-forming stem cells during a person’s lifetime. The UBA1 gene encodes the major E1 enzyme that initiates a process called ubiquitylation, which is essentially how cells tag damaged or unneeded proteins for disposal. When UBA1 is mutated, this tagging system malfunctions, and the downstream effects cascade into widespread inflammation and bone marrow failure.¹

The original discovery identified mutations at a specific spot on the UBA1 protein, methionine-41 (often written as p.Met41). These mutations alter how the cytoplasmic version of the enzyme is produced, effectively knocking out its function in the cell’s main compartment. Researchers have since found additional mutations at other sites on UBA1 that reduce catalytic activity through different mechanisms, including abnormal chemical bonding within the enzyme itself.² Regardless of the specific mutation, the result is the same broad outcome: global ubiquitylation levels drop, and the cell’s ability to manage its protein quality control falls apart.³

Because UBA1 sits on the X chromosome, men (who carry only one copy) are far more vulnerable. If a somatic mutation arises in their single UBA1 copy, there is no backup. Women have two X chromosomes, so the second copy usually compensates, which is why VEXAS overwhelmingly affects men. Cases in women have been documented, but they are rare and tend to involve unusual chromosomal situations.

At the cellular level, the broken ubiquitylation system triggers inflammasome activation, a kind of intracellular alarm that drives the release of powerful inflammatory molecules. Patients with VEXAS show significantly elevated levels of IL-1β and IL-18, two cytokines central to inflammation, along with high circulating levels of IL-1RA, the body’s own attempt to dampen the fire.⁴ This unrelenting inflammatory signaling is what drives the disease’s wide-ranging symptoms.

Bone Marrow Failure and Blood Abnormalities

The bone marrow is ground zero for VEXAS. Because the UBA1 mutation arises in blood-forming stem cells, the marrow itself becomes progressively dysfunctional. One of the hallmark findings on a bone marrow biopsy is the presence of vacuoles, small bubble-like cavities inside myeloid and erythroid precursor cells. These vacuoles are so characteristic that they earned the “V” in the syndrome’s name.⁵ They appear prominently in the earliest stages of red blood cell and white blood cell development, particularly in proerythroblasts, promyelocytes, and myeloblasts.⁶

Progressive bone marrow failure leads to low blood counts, a condition broadly termed cytopenia. Many patients develop anemia severe enough to require regular red blood cell transfusions. Roughly 30 to 50 percent of people with VEXAS receive a diagnosis of myelodysplastic syndrome (MDS), a group of blood cancers where the marrow fails to produce healthy blood cells. Interestingly, the relationship runs mostly in one direction: while MDS is common in VEXAS, only about 1 percent of unselected MDS patients actually carry UBA1 mutations.⁷ This overlap means VEXAS can hide behind an MDS label for years before anyone thinks to test for UBA1.

Blood Clots

Thrombosis is one of the more dangerous features of VEXAS and one that often appears early. In a study of 119 patients, clots occurred in roughly half, with venous blood clots far outnumbering arterial ones. Deep vein thrombosis and pulmonary embolism accounted for most events. The cumulative risk of venous thromboembolism reached about 40 percent within five years of symptom onset, while arterial clots reached about 11 percent over the same period.⁸ An earlier literature review found similar patterns, with venous clots reported in over a third of cases and arterial clots in under 2 percent.⁹

What makes these clots especially concerning is that many are unprovoked, meaning they arise without the usual triggers like surgery, immobilization, or cancer. About two-thirds of venous clots in VEXAS patients had no identifiable provocation, and roughly 40 percent were recurrent. Perhaps most striking, about one in five venous clots occurred in patients already on blood thinners.⁸ This has led researchers to recommend preventive anticoagulation during high-risk situations for all VEXAS patients.

Skin, Cartilage, and Lung Symptoms

VEXAS does not confine itself to the blood and marrow. The inflammatory signaling spills into multiple organ systems, and the pattern of involvement often mimics conditions that rheumatologists, dermatologists, and pulmonologists see regularly.

Skin problems are among the most visible features. In a study of 83 patients, the predominant findings on skin biopsy were leukocytoclastic vasculitis (inflammation that damages small blood vessels), neutrophilic dermatosis (infiltration of white blood cells into the skin), and perivascular dermatitis, each accounting for roughly a third of cases.¹⁰ In clinical terms, this translates to tender red or purplish bumps, sometimes with swelling, firm plaques, nodules, and occasionally a mottled, net-like discoloration of the skin called livedo racemosa.¹¹ These skin findings frequently lead to an initial diagnosis of Sweet syndrome or cutaneous vasculitis before VEXAS is recognized.

Cartilage inflammation, especially of the ears and nose, overlaps heavily with a condition called relapsing polychondritis. In a French comparison of 95 patients, those with VEXAS-associated polychondritis showed ear cartilage inflammation at rates above 90 percent and nose cartilage involvement in nearly half.¹² VEXAS-related polychondritis patients tend to be male, over 45 at onset, and more likely to have fever, deep vein thrombosis, and pulmonary infiltrates than patients with classic relapsing polychondritis.¹³

Lung involvement adds another layer of complexity. A systematic review catalogued a range of pulmonary complications in VEXAS patients, including pulmonary vasculitis, bronchiolitis obliterans (scarring of the small airways), alveolar hemorrhage, bronchiectasis, and interstitial pneumonia.¹⁴ Pulmonary infiltrates can wax and wane with flares, and steroid-resistant lung involvement has been reported.¹⁵

Why VEXAS Is So Often Misdiagnosed

Given that VEXAS touches the blood, skin, joints, cartilage, lungs, and vascular system, it is perhaps unsurprising that most patients accumulate several wrong diagnoses before the true condition is identified. Depending on which symptom appears first, patients may be told they have MDS, Sweet syndrome, relapsing polychondritis, giant cell arteritis, polyarteritis nodosa, or undifferentiated connective tissue disease. Because VEXAS was only described in 2020, many clinicians still do not think to test for it, and patients diagnosed with these conditions before 2020 may never have been re-evaluated.

Definitive diagnosis requires genetic testing of the UBA1 gene. Standard Sanger sequencing can reliably detect UBA1 mutations across a wide range of variant allele frequencies, and next-generation sequencing (NGS) confirms these findings without adding much additional diagnostic yield in most cases.¹⁶ Some centers use a specialized technique called PNA-PCR, which can preferentially amplify the mutant allele, followed by Sanger sequencing to pinpoint the exact variant. Among 40 patients identified with this approach, the most common mutation was Met41Thr, followed by Met41Leu and Met41Val.¹⁷

The practical challenge is knowing when to order the test. A bone marrow biopsy showing vacuolization in precursor cells should raise a red flag, but vacuoles are not exclusive to VEXAS and can appear in other settings, such as copper deficiency or drug toxicity.⁵ In at least one reported case, the diagnosis was made only after retrospective re-examination of archived bone marrow slides that had originally been read as unremarkable.¹⁸ The overall message from the diagnostic literature is that clinicians should consider VEXAS testing in any man over 50 presenting with unexplained inflammation, cytopenias, and blood clots, especially when multiple organ systems are involved.

Treatment Approaches

There is no cure for VEXAS outside of stem cell transplantation, and treatment for most patients centers on controlling inflammation, supporting blood counts, and preventing complications. The therapeutic landscape is evolving rapidly, but a few strategies have emerged as the main pillars.

Corticosteroids

High-dose corticosteroids are usually the first line of defense and can dramatically tamp down flares. The problem is that most patients cannot taper off steroids without relapsing, and long-term steroid use carries serious side effects including infections, bone loss, and metabolic problems. In some cases, steroid-resistant disease develops. One reported case involved a patient whose pulmonary involvement initially improved with methylprednisolone pulse therapy but who relapsed on tapering; the patient’s macrocytic anemia progressed to pancytopenia, and he ultimately died of sepsis from severe neutropenia.¹⁵ This kind of trajectory underscores the need for steroid-sparing agents.

JAK Inhibitors

Janus kinase (JAK) inhibitors have generated considerable interest as a steroid-sparing option. These drugs block inflammatory signaling pathways downstream of cytokine receptors, and early reports suggested they could control several VEXAS manifestations.¹⁹ A systematic review covering 186 patients treated with various JAK inhibitors found that about a third achieved complete response and another 30 percent had partial response. Ruxolitinib was the most commonly used agent, with roughly 29 percent of 117 patients reaching complete or partial remission. Upadacitinib showed the highest complete remission rate at around 38 percent, though in a much smaller group of 13 patients.²⁰ These are encouraging numbers, but most of the evidence comes from case series rather than controlled trials, so the picture remains incomplete.

Azacitidine

Azacitidine, a drug approved for MDS, has emerged as one of the most promising treatments for VEXAS because it can target the mutant clone itself rather than just suppressing downstream inflammation. A large retrospective study from the French VEXAS registry found that azacitidine improved both inflammation and blood counts. About 65 percent of transfusion-dependent patients became transfusion-independent, and 77 percent showed platelet improvement. On the molecular level, 65 percent of patients achieved a meaningful reduction in the mutant clone’s burden, and in 43 percent the clone dropped to very low levels.²¹ A smaller case report documented complete molecular remission in two patients, meaning the UBA1-mutant clone became undetectable by ultra-deep sequencing.²² The catch is that infections and cytopenias are common side effects, particularly in the first few treatment cycles.²¹

Other Biologics

Given the role of IL-1β and IL-6 in VEXAS inflammation, researchers have tried blocking these cytokines directly. Tocilizumab, an IL-6 inhibitor, showed some ability to achieve partial responses in patients with high inflammatory activity, but its effectiveness for complete remission was limited, likely because it does not address the hematologic component. Anti-IL-1 and anti-TNF agents performed poorly overall and are generally not recommended as first-choice options.²³ The disconnect here makes sense: drugs that block a single inflammatory molecule downstream may quiet some symptoms without touching the dysfunctional clone that keeps producing them.

Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation, where the patient’s bone marrow is replaced with a donor’s, is the only treatment with the potential to cure VEXAS by eliminating the mutant clone entirely. A review of 33 transplanted patients found that complete eradication of the UBA1 mutation was documented in 11 cases with post-transplant molecular data.²⁴ However, transplant carries substantial risks: graft-versus-host disease, infections, organ damage, and treatment-related mortality, all amplified by the fact that most VEXAS patients are older men often already weakened by months or years of active disease and steroid exposure. Transplant is generally reserved for patients with severe disease, particularly those who are transfusion-dependent or progressing toward marrow failure.

How Common VEXAS Actually Is

When VEXAS was first described, many assumed it was exceedingly rare. That assumption has not held up. A study using a large US clinical database estimated the prevalence of UBA1 variants associated with VEXAS at roughly 1 in 4,269 men over 50 and 1 in 26,238 women over 50, giving an overall estimate of about 1 in 13,591 for the entire cohort studied.²⁵ For context, that prevalence for men over 50 would make VEXAS roughly as common as some better-known blood disorders.

UK data suggests somewhat lower numbers than the US estimates, but still found that canonical UBA1 mutations appear in about 1 percent of individuals with autoinflammatory disorders who had not been referred to hematology. Among those investigated for myeloid malignancies, the estimated incidence was about 1.5 per 100,000, translating to roughly 171 new UK cases per year.²⁶ The gap between US and UK figures likely reflects differences in the populations screened and how broadly genetic testing was applied, rather than a true biological difference between countries.

Prognosis and Predictors of Outcome

VEXAS carries a significant mortality risk. Infections, particularly sepsis, are the leading cause of death, followed by organ failure and cardiovascular events.²⁷ The infection risk is compounded by both the disease itself, which disrupts normal immune cell production, and the immunosuppressive treatments used to control it.

Not all VEXAS patients face the same trajectory. Two factors have emerged as the strongest independent predictors of death: the specific UBA1 mutation type and whether a patient becomes dependent on blood transfusions. Patients carrying the valine variant (Met41Val) had nearly four times the risk of death compared to those with other variants, and patients who became transfusion-dependent also had about a 3.5-fold increased mortality risk.²⁸ No other clinical features showed an independent association with survival in that analysis. This has practical implications for clinical decision-making: patients with the valine variant or worsening transfusion needs may be candidates for more aggressive interventions, including earlier consideration of transplant.

Living with a Disease That Did Not Have a Name Until 2020

One of the more unusual aspects of VEXAS is that thousands of people likely had the condition before it was recognized as a distinct entity. Many were managed under diagnoses like MDS, relapsing polychondritis, Sweet syndrome, or unexplained vasculitis. Some received treatments that addressed individual symptoms without ever touching the underlying problem. The 2020 discovery reframed all of these cases: what looked like unrelated conditions in the same patient turned out to be one disease with one genetic cause.¹

For patients today, awareness remains the biggest hurdle. Many hematologists and rheumatologists are now familiar with VEXAS, but clinicians in other specialties, such as dermatology or pulmonology, who may see a VEXAS patient presenting with skin lesions or lung infiltrates, may not immediately connect the dots. The diagnostic overlap with other conditions means that patients who have been told they have MDS with an inflammatory component, polychondritis that does not behave like typical polychondritis, or recurrent unprovoked blood clots alongside unexplained anemia should ask about UBA1 testing. Genetic testing is straightforward and increasingly available, and a positive result fundamentally changes the treatment approach.

Research is moving quickly. Clinical trials are exploring targeted therapies, and the molecular understanding of UBA1 dysfunction is deepening. Azacitidine and transplant represent the two ends of the therapeutic spectrum: disease modification versus potential cure, with JAK inhibitors occupying a middle ground. As larger prospective studies mature, the treatment algorithm will inevitably become more refined. For a disease that did not exist in the medical vocabulary five years ago, the pace of progress has been striking.