A medical mystery that remained hidden in plain sight for decades has finally been solved, rewriting textbooks and offering hope to patients worldwide.
VEXAS is an adult-onset autoinflammatory disease that bridges the worlds of rheumatology and hematology. The name itself is an acronym that reveals the core characteristics of this condition:
in bone marrow precursor cells
ubiquitin-activating enzyme (from the UBA1 gene) that is mutated
location of the UBA1 gene
characteristics
Unlike many genetic conditions, VEXAS syndrome is not inherited but rather caused by somatic mutations that occur later in life. These mutations specifically affect the UBA1 gene in hematopoietic stem and progenitor cells, primarily impacting biological males over 50 3 6 . The disease is surprisingly common, affecting approximately 1 in 4,000 men over age 50 4 6 .
At the molecular level, VEXAS syndrome is driven by mutations in the UBA1 gene, which provides instructions for making the ubiquitin-activating enzyme E1. This enzyme plays a crucial role in the ubiquitin-proteasome system, the cellular machinery responsible for tagging and removing damaged or unnecessary proteins 1 .
Under normal conditions, the UBA1 gene produces two main protein isoforms:
The most common VEXAS mutations affect codon 41 (p.Met41) of the UBA1 gene, preventing production of the cytoplasmic UBA1b isoform. This forces cells to use an alternative starting point at methionine 67, generating a novel, functionally impaired isoform called UBA1c 1 4 .
| Mutation | Prevalence | Clinical Characteristics | 5-Year Survival |
|---|---|---|---|
| p.Met41Thr | 60% | Higher rates of inflammatory eye disease | 83% |
| p.Met41Val | 20% | More severe disease, increased undifferentiated inflammatory syndromes | 76.7% |
| p.Met41Leu | 20% | Skin involvement, Sweet syndrome | 100% |
The loss of functional UBA1b disrupts protein ubiquitination, leading to accumulation of misfolded proteins that trigger endoplasmic reticulum stress and activate inflammatory pathways 1 . This cellular stress activates the unfolded protein response and promotes release of pro-inflammatory cytokines, ultimately driving the systemic inflammation characteristic of VEXAS 1 .
VEXAS syndrome presents with a diverse array of symptoms that often mimic other conditions, leading to frequent misdiagnosis. The clinical manifestations can be broadly categorized into inflammatory and hematologic features.
Present in 81-84% of patients, with skin lesions being the initial sign in up to 63% of cases 4
Affecting ears and nose in approximately 60% of patients 4
Including cough and shortness of breath, affecting 49-61% of patients 4
Occurring in 39-44% of patients as episcleritis, scleritis, uveitis, or conjunctivitis 4
Present in 90-100% of patients, not attributable to vitamin deficiencies 4
Including low platelet counts (45-83%), low lymphocytes (80%), and decreased monocytes (50%) 4
The severity of VEXAS cannot be overstated. Studies indicate that 28-33% of patients require ICU admission, with mortality rates ranging between 18-40% 2 4 . Sepsis represents the leading cause of death, followed by organ failure, cardiovascular events, and intestinal perforation 2 .
Traditionally, diagnosing VEXAS required bone marrow biopsy to identify characteristic vacuoles in precursor cells. However, recent research has revealed that peripheral blood cytological analysis may offer a less invasive screening approach 8 .
Male >50 years with unexplained inflammatory symptoms + macrocytic anemia
Increased vacuoles in leukocytes, immature neutrophils, micronuclei
Vacuoles in myeloid and erythroid precursor cells
Identification of somatic UBA1 mutations (gold standard)
| Diagnostic Method | Key Findings | Utility |
|---|---|---|
| Genetic Testing | Somatic mutations in UBA1 gene (primarily at codon 41) | Gold standard for diagnosis |
| Bone Marrow Biopsy | Vacuoles in myeloid and erythroid precursor cells | Supportive diagnostic evidence |
| Peripheral Blood Smear | Immature neutrophils, increased vacuoles, micronuclei | Less invasive screening tool |
| Blood Counts | Macrocytic anemia, thrombocytopenia, lymphopenia | Initial clinical suspicion |
A 2024 study demonstrated that cytological examination of blood smears can identify distinctive features in VEXAS patients, including:
These cytological findings correlate with increased levels of proinflammatory cytokines like IL-1β and IL-8, providing both diagnostic clues and insights into disease mechanisms 8 .
Definitive diagnosis requires genetic testing to identify somatic UBA1 mutations. The NIH recommends genetic testing for men over 50 with unexplained inflammatory symptoms plus macrocytic anemia or specific conditions like relapsing polychondritis, Sweet syndrome, or polyarteritis nodosa that respond poorly to conventional treatments 3 .
Understanding disease mechanisms often requires accurate models. A landmark April 2025 study published in Nature Medicine unveiled a novel humanized model of VEXAS syndrome that replicates the human condition with remarkable fidelity .
Researchers used an innovative base editing approach to introduce the most common VEXAS mutation (p.Met41Thr) into healthy human hematopoietic stem and progenitor cells (HSPCs). This technique involved:
HSPCs from healthy male donors
Using ABE8.20-m56 and guide RNA targeting Met41
Measuring successful mutation introduction
Confirming molecular and cellular changes
This approach achieved approximately 90% editing efficiency, creating UBA1-mutant HSPCs that mirrored the molecular features of patient-derived cells without affecting cell growth, cycle, or viability .
| Parameter | UBA1-mutant cells | Control Cells | Significance |
|---|---|---|---|
| UBA1b expression | Lost | Normal | Confirmed molecular defect |
| Ubiquitylated proteins | Reduced | Normal | Validated disrupted protein degradation |
| Organelle structure | Vacuoles present | Normal | Recapitulated cellular hallmark |
| Engraftment capacity | Enhanced | Standard | Explained clonal dominance |
| Inflammatory signatures | Activated | Normal | Mimicked human disease state |
The engineered UBA1-mutant cells exhibited hallmark features of VEXAS syndrome:
When transplanted into immunodeficient mice, these engineered human cells demonstrated competitive advantage over wild-type cells, progressively dominating the hematopoietic system and mirroring the clonal dominance observed in VEXAS patients .
This humanized model represents a crucial advancement, providing researchers with a powerful tool for drug screening and therapeutic development while offering insights into the mechanisms driving clonal dominance in VEXAS syndrome .
Currently, no standardized treatment guidelines exist for VEXAS syndrome. Management typically involves a combination of approaches targeting both inflammatory manifestations and hematologic abnormalities.
Often required at high doses (≥20 mg prednisolone daily) but with significant long-term toxicity 4
Including JAK inhibitors and IL-6 inhibitors, though responses are often partial 1
Exploring hypomethylating agents and other clone-directed therapies 1
Preclinical/Phase 1The future of VEXAS management lies in developing therapies that target both the inflammatory manifestations and the underlying clonal hematopoiesis. The recent creation of accurate disease models accelerates this process, offering hope for more effective treatments .
The discovery of VEXAS syndrome represents a triumph of molecular medicine, demonstrating how genotype-driven approaches can unravel medical mysteries that defy traditional diagnostic categories. In just a few years, VEXAS has transformed from an unrecognized collection of symptoms to a well-defined disease with known genetic cause, diagnostic criteria, and ongoing therapeutic development.
This journey highlights the power of scientific collaboration across disciplines—genetics, rheumatology, hematology—and the importance of considering somatic mutations in adult-onset inflammatory diseases. As research continues to unravel the complexities of VEXAS, each discovery brings us closer to effective treatments for this challenging condition, offering hope to patients who have long sought answers to their suffering.
For individuals and physicians facing unexplained inflammatory conditions, the VEXAS story serves as a powerful reminder: some medical mysteries remain hidden in plain sight, waiting for the right tools and perspectives to reveal them.
For more information on ongoing VEXAS research and clinical trials, visit the NIH Clinical Center website (clinicaltrials.gov) or contact the National Institute of Arthritis and Musculoskeletal and Skin Diseases.