INTRODUCTION TO VEXAS SYNDROME
Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome, first described in 2020, is a paradigmatic, severe acquired hemato-autoinflammatory disease caused by somatic mutations in the X-linked UBA1 gene of hematopoietic stem and progenitor cells (HSPCs) [ 1 ]. The disease predominantly affects males over the age of 50, with an estimated prevalence of 1 in 4000 [ 2 ]. Female cases are rare and usually associated with Turner syndrome or altered X-chromosome inactivation [ 3 ]. The progression of VEXAS syndrome is driven by clonal dominance of proinflammatory hematopoietic cells harboring pathogenic UBA1 mutations, ultimately leading to bone marrow (BM) failure. UBA1 encodes the ubiquitin-activating enzyme 1 (E1), a key component of the ubiquitylation pathway, which is essential for protein degradation and regulation [ 4 ]. Clinically, VEXAS syndrome presents with steroid-dependent, myeloid-driven systemic inflammation coupled with hematologic abnormalities. Inflammatory features include recurrent high-grade fevers, unprovoked venous thrombosis, and multiorgan inflammation (e.g., pulmonary infiltrates, ear and nose chondritis, neutrophilic dermatosis, ocular inflammation, arthritis, and vasculitis) [ 5 ]. Hematologic manifestations commonly comprise macrocytic anemia, thrombocytopenia, monocytopenia, lymphopenia, and cytoplasmic vacuoles in myeloid and erythroid precursors. Approximately 35% of patients develop myelodysplastic syndrome (MDS) [ 6 ], while 10–20% progress to multiple myeloma or monoclonal gammopathy of unknown significance (MGUS) [ 7 ]. Additional clones bearing classical clonal hematopoiesis of indeterminate potential (CHIP) mutations are often detected [ 8 ], although overt hematologic malignancies remain relatively uncommon.
At the functional level, E1 is responsible for activating ubiquitin during ubiquitylation, a key posttranslational modification that marks proteins for degradation and activity modulation, ultimately regulating multiple cellular processes such as cell survival and differentiation [ 9 – 12 ]. Indeed, protein ubiquitylation may trigger degradation by the ubiquitin-proteasome system (UPS), which governs numerous functions, including cell cycle, metabolism, homeostasis, inflammation, and stress adaptation [ 12 – 15 ]. In humans, two E1 enzymes are expressed, encoded by the UBA1 and UBA6 genes, exhibiting distinct substrate specificities and nonredundant functions [ 16 , 17 ]. Notably, UBA1 is the most highly expressed E1 enzyme and initiates approximately 99% of ubiquitination events [ 18 ]. Two UBA1 isoforms have been characterized, nuclear (UBA1a) and cytoplasmic (UBA1b), which differ in their translation start site [ 4 ]. The most prevalent (94%) pathogenic UBA1 mutations in VEXAS syndrome affect the methionine 41 (Met41) in exon 3, the starting codon of UBA1b. Substitution of Met41 with threonine (Thr), valine (Val), or leucine (Leu) results in reduced translation of UBA1b and expression of a shorter dysfunctional isoform, UBA1c, leading to impaired ubiquitylation, defective protein clearance, and accumulation of misfolded proteins [ 1 , 2 , 19 ]. Distinct UBA1 mutations may selectively affect both the severity and the nature of pathogenic manifestations. Recent studies have linked specific UBA1 variants to different dermatologic phenotypes. Indeed, the p.Met41Leu variant is frequently associated with Sweet syndrome–like neutrophilic eruptions, whereas the p.Met41Val variant has been correlated with vasculitic lesions characterized by mixed inflammatory cell infiltrates [ 20 ]. Moreover, the p.M41Val variant has been connected to kidney involvement, while the p.M41Thr mutation is associated with vein thrombosis and a reduced platelet count [ 21 ]. Overall, disease severity correlates with the extent of UBA1b functional loss: lower residual level of UBA1b drives higher expression of dysfunctional UBA1c and more severe clinical manifestations [ 19 ]. Similarly, mutations affecting the intron 2 splicing acceptor site (5% of VEXAS patients) reduce UBA1b translation and increase UBA1c production, resulting in a severe disease phenotype [ 22 – 24 ]. In contrast, noncanonical mutations occurring downstream of the UBA1b translational start site do not promote UBA1c translation but impair the enzymatic activity of both cytoplasmic and nuclear isoforms. These variants are generally associated with milder autoinflammatory phenotypes [ 25 – 28 ].
VEXAS PATHOGENESIS
Although the genetic basis of VEXAS syndrome is well characterized, the pathogenic mechanisms linking somatic UBA1 mutations, inflammation, and clonal dominance of mutant cells remain elusive. Recent advances, however, have begun to unravel key aspects of VEXAS pathogenesis, providing new insights into how UBA1 mutations drive the inflammatory state and clonal advantage (Fig. 1 ).
VEXAS-causing mutations arise in HSPCs, triggering inflammation and promoting progressive clonal dominance of mutant cells. Still, mutant clones are not uniformly distributed across hematopoietic lineages. While HSPCs and myeloid cells are predominantly mutated in individuals with VEXAS syndrome, lymphoid populations are almost exclusively wild-type, suggesting that pathogenic UBA1 mutations are incompatible with lymphoid cell maturation or survival [ 1 , 29 ▪ ]. The natural killer (NK) cell compartment stands out as a remarkable exception, displaying a heterogeneous composition, with mutant clones coexisting alongside wild-type counterparts [ 29 ▪ , 30 , 31 ▪ ]. The erythroid compartment similarly emerges as a mosaic of mutant and wild-type cells. Notably, patients with high variant allele frequencies (VAF) of the VEXAS mutation exhibit defective erythroid maturation, suggesting that the UBA1 mutation impairs terminal erythropoiesis, which potentially contributes to the anemia commonly observed in affected patients [ 32 ]. Single-cell transcriptomic analyses comparing VEXAS patients to age-matched controls confirm these lineage-specific biases, revealing an early shift toward myeloid differentiation of primary mutant HSCs, reduced primitiveness of mutant HSPC, and skewing towards myelopoiesis, along with early arrest in both lymphoid and erythroid differentiation trajectories [ 29 ▪ , 30 , 33 ▪▪ ]. These profound alterations of hematopoiesis are accompanied by activation of inflammatory programs in both mutant HSPCs and their differentiated progeny. Specifically, HSPCs from individuals with VEXAS syndrome display upregulation of gene categories associated with interferon gamma (IFN-γ), interferon alpha (IFN-α), and tumor necrosis factor-alpha (TNF-α) responses, along with a concurrent downregulation of cell cycle-related pathways. Direct comparison of mutant versus wild-type HSPCs within VEXAS patients shows in mutant clones stronger induction of inflammatory signatures, proteotoxic stress, activation of stress-adaptive strategies, including the unfolded protein response (UPR), and a global reduction of protein translation [ 30 , 33 ▪▪ ]. These features reflect the loss of UBA1b function and the resulting dysregulation of protein degradation, demonstrating that the mutant allele intrinsically drives inflammation and disrupts cellular protein homeostasis.
Novel insights into the mechanisms underlying inflammation and dominance of mutant clones in VEXAS syndrome have emerged from recent in vitro and in vivo disease models [ 29 ▪ , 34 ▪ , 35 ]. Genome engineering of wild-type HSPCs through base editing successfully installs the p.Met41Thr mutation in the UBA1 gene, creating an in vitro model that faithfully recapitulates genotypic and phenotypic features observed in mutant HSPCs of VEXAS patients [ 29 ▪ ]. Xenograft mouse models, established by transplanting base-edited human HSPCs carrying the UBA1 mutation, allow in vivo investigation of the hematopoietic abnormalities and clonal dynamics characteristic of VEXAS disease [ 29 ▪ ]. These disease models unveil the mechanisms of clonal dominance in VEXAS syndrome, providing evidence that healthy hematopoiesis is compromised by a detrimental inflammatory milieu, leading to dominance of inflammation-resilient UBA1 mutant clones and BM failure. UBA1 mutant HSPCs do not exhibit increased proliferative capacity compared to wild-type cells but display greater resilience to the inflammatory milieu, attributing their clonal dominance to an inflammation-driven survival advantage rather than a cell-intrinsic proliferative benefit. The absence of proliferative advantage and the somatic origin of the disease may suggest that the UBA1 mutant clone emerged early in life and gradually expanded over time until achieving clonal dominance. A slowdown in the cell cycle, accompanied by the adoption of a senescence-like state, may account for the persistence and pro-survival benefit of mutant HSPCs despite proteotoxic stress and dysfunctional differentiation properties [ 29 ▪ ]. In addition, activation of the PERK-mediated cytoprotective UPR may confer further survival advantage within the inflamed BM niche, thus sustaining clonal dominance [ 30 ]. Finally, a recent human cell line model of VEXAS syndrome suggests that partial functional compensation of UBA1 deficiency by UBA6 may also contribute to mutant cell fitness [ 36 ]. Collectively, these mechanisms identify potential therapeutic vulnerabilities that could be exploited to selectively target UBA1 mutant clones.
Clonal dominance of UBA1 mutant cells is sustained by an inflammatory milieu that they help to establish and maintain. Recent murine models, including conditional UBA1 knockout in neutrophils and a patient-derived xenograft, recapitulate the autoinflammatory manifestations characteristic of VEXAS syndrome [ 34 ▪ , 35 ]. Across hematopoietic differentiation, all mature subsets exhibit activation of IFN-γ, IFN-α, and TNF-α signatures, associated with downregulation of cell cycle-related genes [ 29 ▪ , 31 ▪ ]. Notably, these inflammatory responses are not limited to the myeloid lineages, which are predominantly mutated, but also occur in lymphoid populations, almost exclusively wild-type, indicating that the inflammatory signals extend beyond mutant clones and act in trans on the wild-type hematopoiesis [ 29 ▪ ]. The activation of such transcriptional responses is mirrored by the detection of interleukin (IL)-6, IL-18, IFN-γ, IL-1β, and TNF in the plasma of individuals with VEXAS syndrome, reflecting inflammasome activation and myeloid cell dysregulation [ 31 ▪ , 37 ▪▪ ]. A key underlying pathogenic mechanism may involve the loss of cytoplasmic ubiquitylation in mutant myeloid cells, which impairs the endoplasmic reticulum–associated degradation (ERAD) pathway and drives chronic UPR activation, leading to inflammation [ 38 ]. The combined effect of proteotoxic stress-triggered responses, cytokine release, and lack of negative selection of mutant myeloid cells fosters an inflammatory BM environment that progressively impairs normal hematopoiesis. Accordingly, recent evidence suggests that autoinflammatory symptoms precede hematologic abnormalities [ 39 ]. Moreover, at high VAF of mutant clones, monocytes appear functionally impaired, exhibiting exhaustion, defective efferocytosis, and dysfunction of the endo-lysosomal pathway [ 31 ▪ , 37 ▪▪ , 40 ]. I n vitro analyses further demonstrate increased apoptosis and pyroptosis in monocytes and neutrophils collected from the blood of VEXAS patients [ 41 ]. Granular analysis of the NK compartment reveals that in VEXAS patients NK cells are reduced in terms of absolute number, have a lower cytotoxic potential compared to controls, and display markers of chronic activation and exhaustion [ 42 ]. Hence, the reduced number of NK cells correlates with the risk of severe infections. In addition, lymphoid cells, predominantly wild-type, exhibit clonal expansion and activation of effector memory T cells as well as skewed B cell differentiation [ 31 ▪ ]. Finally, anemia, one of the hallmarks of VEXAS, results from massive cell death of erythroid cells during differentiation. Accordingly, patient-derived and gene-edited HSPCs fail to generate erythroid colonies in vitro [ 29 ▪ ]. Mechanistically, impaired regulation in p53 ubiquitylation during erythropoiesis has been recently implicated in this massive cell death [ 43 ]. Transcriptomic analyses from BM-derived samples further show robust enrichment of heme-metabolism in VEXAS patients compared to controls, suggesting a compensatory response to ineffective erythropoiesis [ 29 ▪ ]. Notably, these abnormalities were more pronounced in patients carrying the p.Met41Val mutation, highlighting a correlation between the genotype and the extent of the phenotype.
VEXAS CLINICAL MANAGEMENT
Therapeutic approaches for VEXAS syndrome are still largely empirical and rely on retrospective studies. Patients’ prognosis and quality of life are unfortunately poor, with a five-year mortality rate of approximately 50% [ 1 ]. However, the recent publication of international treatment guidelines has marked a significant step toward the first standardization of VEXAS management [ 44 ▪▪ ]. These guidelines provide expert-based recommendations aiming at optimizing therapeutic strategies, improving clinical outcomes, and guiding treatment decisions for both inflammatory and hematologic manifestations of the disease.
First-line treatments for VEXAS syndrome focus on controlling inflammation and typically involve mid- to high-dose corticosteroids (prednisone 10–50 mg/day or higher). However, complete remission is rarely achieved, and the long-term toxicity associated with corticosteroids has prompted the use of corticosteroid-sparing agents, such as anticytokine therapies. Among them, anti-IL-1, anti-IL-6 agents, and anti-TNF show different degrees of efficacy. In detail, a retrospective study from the FRENVEX, with a median follow-up of 12 months, reports an overall response rate at 6 months of 26% for anti-IL-6, while anti-IL-1 and TNF inhibitors show lower efficacy [ 45 ]. Similarly, a retrospective study conducted across 126 Spanish hospitals demonstrates improvements with anti-IL-1 and anti-IL-6 treatments, while no benefit is observed with TNF inhibitor therapy [ 21 ]. Data from the AIDA Network VEXAS registry, with a median follow-up of 3 months for anti-IL-1 or 4.5 months for anti-IL-6, demonstrated that 23% of patients on IL-1 and 15% of patients on anti-IL-6 achieved complete efficacy, while partial efficacy was seen in 46% and 77%, respectively [ 46 ]. The concomitant use of cyclosporine was also found to be effective in our experience when combined with anti-IL-1 agents [ 47 ]. In contrast, 55.5% of patients treated with TNF inhibitors failed to respond, indicating that this class is the least effective. A retrospective study from the UK VEXAS cohort shows similar efficacy at 6 months with both anti-IL-1 and anti-IL-6 [ 48 ]. Notably high discontinuation rates due to severe injection site reactions were registered for anti-IL-1 treatment, in particular for anakinra. More recently, an Italian–French multicenter study has evaluated the effectiveness and safety of anti-IL-1 agents in VEXAS syndrome and found that canakinumab was superior to anakinra [ 49 ].
Janus kinase inhibitors (JAKis) offer a promising approach by targeting multiple disease-relevant cytokines, including type I and type II interferons, as well as IL-6. Several retrospective and prospective studies suggest a superior benefit of the JAKi compared to individual anticytokine inhibitors [ 46 , 48 ]. Notably, the efficacy of JAKis varies depending on the specific type of JAKi used, with Ruxolitinib demonstrating a higher response rate compared to other JAKis [ 21 , 45 , 48 , 50 , 51 ]. Furthermore, a recent report highlights that JAK2 is highly expressed in VEXAS patients’ cells, marking it as a key target in the management of inflammatory symptoms [ 52 ]. However, JAKi's are associated with side effects such as worsening cytopenia and increased risk of serious infections, often leading to treatment discontinuation [ 53 , 54 ]. Although anticytokine therapies may control autoinflammatory symptoms, they are less effective in addressing the hematologic manifestations of the disease, which often progress to BM failure [ 48 , 55 , 56 ]. As such, cytotoxic treatments targeting pathogenic clones, including the hypomethylating agent 5-azacitidine, are required to manage clonal dominance. Multiple studies have demonstrated partial or complete molecular remission of UBA1 mutant clones following repeated cycles of 5-azacitidine, alongside control of both inflammatory and hematological symptoms [ 45 , 57 – 59 ], with a reduction in steroid usage [ 60 ]. Interestingly, despite 5-azacitidine being routinely used to treat MDS patients, its efficacy also extends to patients without concomitant MDS [ 61 ]. While one retrospective study reported long-term clinical and molecular remission in a VEXAS patient after decades of 5-azacitidine treatment [ 62 ], follow-up after discontinuation in prospective studies remains limited due to the recent discovery of the disease. Some studies have reported genetic and clinical remission lasting up to 84 months following drug discontinuation [ 63 ], while others documented a high relapse rate [ 64 ], suggesting the need for further monitoring. Notably, 5-azacitidine treatment was also used as a bridge therapy before allogeneic hematopoietic stem cell transplantation (allo-HSCT) [ 65 ]. Despite its widespread use, the mechanism of action of 5-azacitidine remains unclear. Moreover, its potential damage to wild-type clones, as the drug predominantly targets VEXAS mutant clones, though not exclusively, is unknown. Furthermore, the need for repeated administration significantly impacts the patient's quality of life.
Another emerging approach in the management of hematological symptoms is the use of erythropoiesis-stimulating agents (ESAs) to treat moderate to severe anemia. A retrospective study involving 32 patients demonstrated the efficacy and safety of ESAs, highlighting the need for further investigation in prospective studies [ 66 ].
Currently, the only curative option for VEXAS patients is allo-HSCT, although it is burdened by substantial morbidity and mortality [ 67 ]. To date, 33 patients have undergone allo-HSCT, with 27 surviving, and 11 showing full eradication of VEXAS clones [ 68 ]. Occasionally, the VEXAS clinical phenotype remains controlled despite the presence of mixed chimerism. A phase II trial sponsored by the U.S. National Cancer Institute is ongoing to assess allogeneic HSCT in VEXAS syndrome and will help define which patients are most appropriate candidates for this approach ( https://www.clinicaltrials.gov/study/NCT05027945 ).
The complexity of the disease necessitates a multidisciplinary approach, including continuous evaluation of treatment efficacy and proactive management of secondary complications.
CONCLUSION
Despite substantial progress has been made in understanding and managing VEXAS syndrome, further investigation is needed to identify key targetable mechanisms that sustain inflammatory circuits and afford pro-survival benefits to UBA1 mutant cells. Uncovering these pathways will be critical to instruct novel therapeutic strategies against VEXAS progression, enabling early intervention and ultimately improving prognosis and life expectancy. Notably, VEXAS syndrome may exemplify an extreme paradigm of acquired disorders in which mutant proinflammatory clones gain the capacity to partially shield themselves from the very hostile microenvironment they induce. Consequently, the mechanisms of clonal dominance underlying VEXAS syndrome may offer broader insights into disease evolution and resistance in clonal hematopoiesis, MDS, and other inflammation-associated hematologic malignancies.
Acknowledgements
We thank Samuele Ferrari, Elisa Diral, Alessandro Tomelleri, Simone Cenci, Luigi Naldini, Lorenzo Dagna, Marco Matucci Cerinic and Fabio Ciceri for helpful discussion.
Financial support and sponsorship
Research on VEXAS syndrome was supported by grants from the Italian Ministry of University and Research (grant no. 2022 PRIN: 2022APWTE3 to Giacomo De Luca and Giulio Cavalli), from the American Society of Hematology (2024 Global Research Award to Samuele Ferrari) and from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (Grant agreement No. 101165007 to Samuele Ferrari).
Conflicts of interest
There are no conflicts of interest.
Footnotes
These authors share first authorship.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
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