RARE DISEASE
VEXAS syndrome
VEXAS syndrome
VEXAS syndrome
Drug discovery
2
drugs
With orphan designations
Overview
VEXAS syndrome is a severe, adult-onset hemato-inflammatory disorder caused by somatic UBA1 mutations in myeloid cells, leading to systemic inflammation (fever, chondritis, vasculitis) and hematologic manifestations (macrocytic anemia, thrombocytopenia, MDS). Diagnosis requires genetic testing and bone marrow evaluation for myeloid vacuolization. Management is challenging due to treatment refractoriness and high steroid dependence [1][6][10][14].
Burden
Mortality: Up to 50% mortality within 5 years (infections, thromboembolism, MDS progression) [7][9].
Morbidity: Chronic transfusion dependence (100% anemia), recurrent infections (18% pneumonia), osteoporotic fractures [5][12][14].
Healthcare utilization: Requires multidisciplinary care (rheumatology/hematology) and frequent hospitalizations [10][16].
Therapies
First-line: High-dose corticosteroids (temporizing; 66% require chronic use) [1][3][8].
Steroid-sparing agents: JAK inhibitors (ruxolitinib achieves 50% response) [1][7], IL-1/6 inhibitors (66% steroid reduction) [1][3], azacitidine (25% complete response) [1][8].
Curative: Allogeneic stem cell transplant (86% complete remission) [1][8].
Categories: rare circulatory system diseases, rare skin diseases, rare systemic and rheumatological diseases
Research Papers
273 drug discovery papers about VEXAS syndrome, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
273 drug discovery papers about VEXAS syndrome, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2026-09-29 | Endotheliopathy and VWF-ADAMTS13 axis dysfunction in VEXAS thrombogenicity.
Markedly increased risk of thrombosis has been described as a key clinical feature of the recently described VEXAS (vacuoles, E1 enzyme, X linked, autoinflammatory, somatic) syndrome. Critically however, the pathological mechanisms underlying VEXAS-associated hypercoagulability remain poorly understood. We addressed this question in a cohort of 40 VEXAS patients referred to the National Institutes of Health with defined pathological UBA1 sequence variants. In keeping with previous reports, twenty-one (52.5%) VEXAS patients in our cohort experienced thrombotic events. Plasma VWF and FVIII activity levels were both increased in VEXAS compared to age-matched controls. Consistent with endothelial cell (EC) activation and Weibel Palade body exocytosis, plasma VWF propeptide and angiopoietin II levels were also significantly elevated in VEXAS subjects. Furthermore, an accumulation of high molecular weight VWF multimers was seen in VEXAS patients. In keeping with ongoing endotheliopathy, plasma levels of soluble Vascular Cell adhesion Molecule-1 (VCAM-1) and soluble thrombomodulin (sTM) were significantly higher in VEXAS patients compared to controls. Finally, significantly increased thrombin generation and activated protein C resistance (APCR) were also observed in plasma from VEXAS patients. In conclusion, our novel findings demonstrate that VEXAS syndrome is associated with significant EC activation and endotheliopathy. This results in both quantitative and qualitative alterations in plasma VWF levels, increased FVIII levels, enhanced thrombin generation and an APCR phenotype. Further studies will be required to determine whether therapeutic interventions targeted at EC and/or the VWF-ADAMTS13 axis may be useful in VEXAS management.
2026-09-16 | Acute Fulminant Systemic Granulocytic Vasculitis Involving Arteries and Veins in Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic (VEXAS) Syndrome: An Autopsy Case Report.
Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome is a disease concept characterized by UBA1 mutation that was first proposed in 2020. We report an autopsy case of VEXAS syndrome that was retrospectively diagnosed 11 years later through genetic analysis of formalin-fixed, paraffin-embedded (FFPE) bone marrow tissue. The patient was a 65-year-old male with hepatitis C who presented with general fatigue followed by fever 2 weeks later. Shortly before death, phlebitis of the extremities and marked leukocytosis became evident. The patient died within 3 weeks of symptom onset. Autopsy revealed granulocytic vasculitis involving small- to medium-sized arteries and phlebitis in various organs, including the lungs, kidneys, liver, and lymph nodes. Concomitant myelodysplastic syndrome (MDS) was confirmed, leading to a diagnosis of MDS-associated vasculitis. Sanger sequencing of FFPE specimens 11 years later revealed a UBA1 mutation (p. Met41Val), confirming VEXAS syndrome. Although VEXAS syndrome is typically characterized by chronic, treatment-refractory inflammation and poor prognosis, autopsy reports are rare. Herein, we report an autopsy case of VEXAS syndrome associated with MDS and systemic vasculitis that presented with a fulminant clinical course.
2026-09-03 | Clinical and molecular spectrum of VEXAS with multiple UBA1 variants: case study and literature review.
VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a rare adult-onset autoinflammatory disorder, caused by a single somatic UBA1 mutation. We report a novel case with 3 independent UBA1-mutated clones and compare its clinical, hematologic, and laboratory features with those of the only 3 previously reported cases harboring multiple UBA1 mutations. Droplet digital polymerase chain reaction (PCR) and targeted next-generation sequencing of peripheral blood DNA were performed to assess UBA1 variants. Bone marrow specimens were evaluated for morphologic, immunophenotypic, and cytogenetic abnormalities. Clinical and hematologic features included neck swelling, headache, elevated inflammatory markers, leukopenia, macrocytic anemia, and thrombocytopenia. Bone marrow biopsy specimens showed no dysplasia, increased blasts, or cytoplasmic vacuolization. Droplet digital PCR detected atypical positive signals across multiple targets, and next-generation sequencing identified 3 presumed independent UBA1 variants: p.M41V, p.M41L, and c.118-2A > T. Comparison with 3 previously reported VEXAS cases carrying multiple UBA1 variants revealed diverse clinical manifestations, including systemic inflammation, polychondritis, venous thromboembolism, arthritis, and arthralgia, with variable hematologic findings ranging from no neoplasm to myelodysplastic syndrome or multiple myeloma, as well as co-occurring clonal hematopoietic variants. This report describes a novel VEXAS case with multiple UBA1 variants and highlights the clinical and hematologic heterogeneity among patients harboring multiple UBA1 mutations. It also emphasizes the technical challenges in detecting these variants and the importance of sequencing studies for definitive diagnosis in complex or equivocal cases, supporting early identification of UBA1 mutations and closer hematologic surveillance in patients with inflammatory symptoms and cytopenias.
2026-08-17 | VEXAS Syndrome: A Comprehensive Review for Dermatologists Part 2: Work-up, Diagnosis, Treatment, and Prognosis.
VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a recently described, adult-onset inflammatory disorder caused by acquired UBA1 mutations in hematopoietic stem and progenitor cells. Part 2 of this two-part series CME article focuses on practical approaches to diagnosis, treatment, and prognosis, with an emphasis on dermatology-relevant decision-making. Characteristic laboratory findings, the role of bone marrow evaluation, and targeted UBA1 testing are reviewed, along with proposed clinical screening criteria and diagnostic approaches for genetic confirmation. Current management strategies include glucocorticoids, corticosteroid-sparing immunomodulatory agents, hypomethylating agents, and allogeneic hematopoietic stem cell transplantation. Prognostic factors, including UBA1 variant type, clonal burden, progression to myelodysplastic syndromes, and treatment-related complications such as serious infection are reviewed. Multidisciplinary collaboration among dermatology, rheumatology, hematology, and medical genetics is emphasized as essential for optimizing outcomes in this complex and potentially life-threatening syndrome.
2026-07-28 | VEXAS Mimicking Antiphospholipid Syndrome: Diagnostic Challenges of False-Positive Antiphospholipid Antibodies.
Somatic UBA1-mutated VEXAS syndrome is now recognized as a multisystem disorder marked by diffuse systemic inflammation, refractory cytopenia with or without bone marrow dysplasia, and thrombotic events affecting both venous and arterial systems [...].
small molecules
2026-09-24 | Evaluating the Efficacy of Cytokine-Directed Therapies in the Management of VEXAS Syndrome.
To evaluate the efficacy of cytokine-directed therapies in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory somatic) syndrome using previously proposed treatment response criteria. All patients with genetically confirmed VEXAS syndrome who received targeted therapies with JAK inhibitors (JAKi), tumor necrosis factor α inhibitors (TNFαi), or interleukin-1 (IL-1) or IL-6 inhibitors were identified. Clinical and biochemical data were recorded for patients at time of targeted therapy initiation, and at 3-, 6-, and 12-month follow-up time points. Treatment response was labeled as complete response (CR; normalization of C-reactive protein [CRP], prednisone <10 mg/day, and resolution of disease activity), partial response (PR; >50% improvement in CRP, >50% prednisone dose reduction, improvement or resolution of disease features), treatment failure (TF; worsening CRP, increasing prednisone, worsening of disease features), or no response (not meeting criteria for CR, PR, or TF). Overall, 52 patients received an IL-1i, IL-6i, or JAKi therapy. At six-month follow-up, 3 of 19 IL-6i patients experienced CR, 4 of 19 experienced PR, and 7 of 19 experienced TF. 2 of 17 patients receiving JAKi experienced CR, 3 of 17 experienced PR, and 6 of 17 experienced TF. No patients receiving IL-1i or TNFαi experienced CR, and only 1 of 5 IL-1i patients experienced PR. Among those still receiving biologic therapy at 12 months, only 1 of 11 receiving IL-6i and 0 of 7 receiving JAKi experienced CR. IL-6i and JAKi therapies demonstrated limited, unsustained efficacy for management of VEXAS syndrome. IL-1i and TNFαi therapies were not efficacious. Useful application of previously reported treatment response criteria was demonstrated, but future incorporation of hematologic parameters may be beneficial.
2026-09-22 | UBA1 as a proteostasis-innate immunity checkpoint: lessons from vexas syndrome and therapeutic implications
Ubiquitin-like modifier activating enzyme 1 (UBA1) occupies the apex of the canonical ubiquitination cascade and supplies activated ubiquitin to a broad network of E2 conjugating enzymes and E3 ligases. Although traditionally regarded as an essential housekeeping enzyme, human genetics has revealed a more instructive function for UBA1: it determines whether proteostatic stress is buffered, converted into inflammatory adaptation, or progresses to cell death. Somatic UBA1 mutations causing VEXAS syndrome provide a natural experiment in this threshold biology. Partial and compartment-selective loss of UBA1 activity permits hematopoietic cells to survive while reducing ubiquitination capacity, activating stress-response pathways, altering cell-death thresholds, and promoting innate immune dysregulation. Single-cell and functional studies further demonstrate early inflammatory activation in UBA1-mutant hematopoietic progenitors, myeloid-biased differentiation, monocyte dysfunction, and inflammasome-associated signaling. Conversely, profound pharmacological UBA1 inhibition with agents such as TAK-243 drives proteotoxic collapse and is being explored as an anticancer strategy. Here, we propose that UBA1 functions as a proteostasis-innate immunity checkpoint whose biological output is determined by residual enzymatic activity, subcellular distribution, lineage context, and clone size. This framework reconciles inflammatory disease caused by partial UBA1 dysfunction with the antitumor effects of UBA1 inhibition and suggests a mechanism-based approach to therapeutic intervention in VEXAS syndrome and malignancy.
2026-09-07 | Human Monocytic Models Reveal Genotype-Dependent Inflammatory Programs in VEXAS Syndrome.
VEXAS syndrome is a severe X-linked autoinflammatory disorder caused by somatic mutations in ubiquitin-like modifier activating enzyme 1 (UBA1), with clinical outcomes that vary by UBA1 genotype. We aimed to elucidate genotype-specific inflammatory programs and identify potential therapeutic targets. We conducted longitudinal deep phenotyping, including whole blood RNA sequencing (RNA-seq) and clinical activity assessment. Peripheral blood samples were analyzed by single-cell RNA-seq. Human monocytic cell lines harboring each major UBA1 mutation (p.Met41Val, p.Met41Thr, or p.Met41Leu) were generated and subjected to transcriptomic and functional analyses. Thirteen patients with VEXAS syndrome contributed a total of 79 RNA-seq samples. Among genes up-regulated in VEXAS syndrome, RNASE1 showed the strongest correlation with longitudinal disease activity (r = 0.70, false discovery rate < 0.05) and was up-regulated in patients' monocytes. In UBA1-mutant monocytic cell lines, genotype-dependent ubiquitination defects were observed in a graded manner (p.Met41Val > p.Met41Thr > p.Met41Leu), even in the absence of exogenous stimuli. These defects were accompanied by unfolded protein response activation, increased pro-inflammatory cytokine production, progressive cell death, and RNASE1 up-regulation, all following the same graded pattern of recapitulating patient genotype-phenotype associations. Transcriptomic analyses demonstrated enrichment of pro-inflammatory, interferon, and necroptosis signatures in more severe genotypes. Notably, inhibition of receptor-interacting protein kinase 3 (RIPK3) markedly attenuated all pathologic features, including RNASE1 up-regulation. Our UBA1-mutant monocytic cell-line models, representing three distinct genotypes, recapitulate genotype-dependent inflammatory phenotypes that can be modulated by RIPK3 inhibition, providing a translational platform for mechanistic investigation and precision therapy development in VEXAS syndrome.
2026-08-18 | An Italian cartography of VEXAS-related thrombosis.
Thrombotic events (TEs) occur in up to 40% of patients with vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic (VEXAS) syndrome, but data on its clinical-genomics features and anticoagulation strategies are limited. To gain more insight into this, we conducted a two-step study evaluating the prevalence and outcome of TE in VEXAS. First, among 1086 patients followed for TEs, 198 were men aged >40 years with unprovoked thrombosis and no known thrombophilia; 21 also had at least one VEXAS-compatible feature and underwent UBA1 exon 3 testing. No UBA1 mutation was detected in these 21 patients. Next, we leveraged our Italian VEXAS network, and we accrued 87 molecularly confirmed Italian VEXAS cases (median age 70 years). Any history of TE was documented in 43/87 patients (49%), deep vein thrombosis being the most common (71%). Because follow-up varied, incident thrombosis was analyzed using a time-to-first-event framework from molecular VEXAS diagnosis, with death without prior TE treated as a competing event. Among 49 patients without prior/concomitant TE, five developed incident post-diagnosis TE; the 24-month cumulative incidence was 18.3%. Thrombophilia testing revealed a 15% co-occurrence, including heterozygous Factor V Leiden, Factor II G20210A, and anti-cardiolipin antibodies. Treatments comprised direct oral anticoagulants (DOACs) (51%), low molecular weight heparin (LMWH) (28%), Fondaparinux (14%), and vitamin K antagonists (AVKs) (7%). Notably, 27% experienced multiple TEs, of which 22% occurring despite anticoagulation during disease flares. Our findings provide an updated cartography of VEXAS-related TE, suggesting early screening for thrombophilia in these patients to inform both personalized anticoagulation and disease-control strategies.
2026-08-01 | Recurrent Lymphocytic Pleural Effusions as an Atypical Presentation of VEXAS Syndrome: A Case Report
Background VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a recently described adult-onset autoinflammatory disorder caused by somatic mutations in the UBA1 gene. The condition predominantly affects men over 50 years of age and manifests with heterogeneous rheumatologic, dermatologic, hematologic, and systemic inflammatory features. Pulmonary manifestations occur in over half of patients, but pleural effusions are relatively uncommon.[1] Given its clinical heterogeneity and overlap with autoimmune, infectious, and hematologic diseases, diagnosis remains challenging and relies on genetic confirmation of UBA1 mutations. Case Report A 60-year-old man presented with a 1-year history of non-productive cough, dyspnea, pleuritic chest pain, fatigue, night sweats, and 10 kg unintentional weight loss. He reported intermittent left ankle swelling, bilateral stiffness, and 2 episodes of unilateral periorbital edema responsive to short prednisone courses. Laboratory investigations revealed mild macrocytic anemia (hemoglobin 121 g/L, MCV 97.6 fL) and elevated C-reactive protein (38.7 mg/L). Autoimmune and infectious workup, including ANA, ANCA, rheumatoid factor, and extensive infectious serologies, were negative. Imaging demonstrated recurrent right-sided pleural effusions without evidence of malignancy. Thoracentesis yielded a lymphocyte-predominant exudative effusion (80% lymphocytes), with negative cultures and cytology. A subsequent contralateral pleural effusion showed similar findings. Flow cytometry identified a minor B-cell population without definitive lymphoproliferative disorder. Bone marrow biopsy revealed hypercellular marrow with trilineage hematopoiesis, megakaryocytic dysplasia, and mild fibrosis, but no lymphoma. Next-generation sequencing identified a somatic UBA1 p.Met41Thr (c.122T>C) mutation (variant allele fraction 76.6%), confirming VEXAS syndrome, along with a concurrent DNMT3A frameshift mutation (VAF 39.7%) consistent with clonal hematopoiesis. The patient was treated with oral prednisone 30-40 mg daily, resulting in complete resolution of inflammatory arthritis, improvement of constitutional symptoms, and normalization of inflammatory markers after 4 weeks. He was subsequently referred for initiation of ruxolitinib as a steroid-sparing agent.[2] Conclusion This case highlights VEXAS syndrome as a diagnostic consideration in older men with persistent systemic inflammation, recurrent lymphocytic pleural effusions, episodic arthritis, and periorbital edema in the absence of infection, malignancy, or autoimmune disease. Pleural effusions, although uncommon, may be the primary pulmonary manifestation. Comprehensive evaluation, including next-generation sequencing for UBA1 mutations, is essential for accurate diagnosis and facilitates targeted management with glucocorticoids and steroid-sparing agents. Early recognition improves outcomes and underscores the need for multidisciplinary care. References [1.] Al-Hakim A. Rheumatology (Oxford) 2025;64:5217-29. [2.] Heiblig M. Blood 2022;140:927-31.
cell therapies
2026-09-18 | Diagnostic and Therapeutic Challenge: VEXAS Syndrome with Multisystem Inflammation and Myelodysplasia: A Case Report.
VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is an adult-onset autoinflammatory disorder caused by somatic UBA1 mutations linking systemic inflammation with haematologic dysfunction. We report a 59-year-old man presenting with fatigue, fevers, and severe macrocytic anaemia (haemoglobin 8.1 g/dL, MCV >120 fL), mild thrombocytopenia, and markedly elevated inflammatory markers. Autoimmune and malignancy workup was negative. Bone marrow biopsy showed hypercellularity with multilineage dysplasia and cytoplasmic vacuolisation, and genetic testing confirmed a somatic UBA1 mutation. High-dose glucocorticoids led to rapid resolution of inflammatory manifestations and normalisation of inflammatory markers; however, cytopenias progressed despite erythropoiesis-stimulating agents and ruxolitinib, with haemoglobin declining to <7 g/dL, resulting in transfusion dependence. The patient is undergoing evaluation for allogeneic haematopoietic stem cell transplantation (HSCT). This case highlights VEXAS syndrome as an aggressive haematoinflammatory disorder with limited responsiveness to conventional and targeted therapies and emphasises early consideration of advanced strategies, including HSCT, in selected patients.
2026-08-01 | VEXAS Syndrome: A Clinical Case Series from Calgary
Background VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome was first described in November 2020.[1] It is typically an adult-onset, treatment-refractory autoinflammatory disorder caused by somatic mutations in the UBA1 gene.[1] Canadian data remain limited.[2] We describe a case series of 5 patients with VEXAS syndrome from Calgary, 2 of whom underwent allogenic hematopoietic stem cell transplant (alloHSCT) with excellent response. Case Report This case series features 5 male patients (Table 1). The median age at disease onset was 65 (range 50-77) years. The median delay in diagnosis was 18 (range 1-46) months. The median disease duration was 44 (range 20-79) months. All patients had somatic UBA1 variants: p.Met41Val (n=2), p.Met41Thr, p.Met41Leu, and 1 uncharacterized p.? variant (Table 1). All patients reported constitutional symptoms. Initial working diagnoses included unspecified inflammatory condition, adult-onset Still’s disease, relapsing polychondritis (n=2), and atypical polyarteritis nodosa vs undifferentiated connective tissue disease (Table 1). Elevated inflammatory markers were observed in all patients (CRP frequently >100 mg/L). Vacuoles were confirmed on bone marrow biopsy in 4 patients. Three patients presented with, and 1 later developed, macrocytic anemia, whereas 1 patient had intermittent normocytic anemia. Thrombocytopenia and lymphopenia were each observed in 3 patients. Two patients developed myelodysplastic syndrome following diagnosis of VEXAS. Patients trialed several different therapies including hydroxychloroquine, methotrexate, azathioprine, mycophenolate, rituximab, anakinra, tocilizumab, tofacitinib, ruxolitinib, colchicine and dapsone with limited or no sustained benefit. Corticosteroids were required at moderate-to-high doses in most patients. At present, patient A is maintained on prednisone 35 mg daily. Patient B is taking prednisone 15 mg daily and ruxolitinib 20 mg twice daily. Patient C underwent alloHSCT in April 2025 with resolution of symptoms and discontinuation of prior medications (prednisone and ruxolitinib). Repeat bone marrow biopsy showed <0.5% UBA1. Patient D continues with prednisone 5-6 mg daily and azacitidine. Patient E underwent alloHSCT in August 2023. He developed chronic graft-versus-host disease requiring treatment with prednisone 7 mg daily and belumosudil. There was no evidence of UBA1 mutation on repeat bone marrow biopsy. Conclusion In conclusion, this case series highlights the multisystem nature of VEXAS syndrome and the substantial diagnostic delay often encountered in clinical practice. We recommend considering VEXAS syndrome in patients with treatment-resistant autoinflammatory syndrome and cytopenias, especially macrocytic anemia. While conventional immunosuppressive medications have provided limited benefit, allogeneic hematopoietic stem cell transplant may be promising for select patients. References [1.] Beck D. N Engl J Med 2020;383:2628-38. [2.] Williams S. J Rheumatol 2024;51:734-7.
2026-07-06 | VEXAS syndrome unmasked from relapsing polychondritis and infection mimicry: a case-based review.
VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a UBA1-driven hemato-inflammatory disorder that mimics relapsing polychondritis, vasculitis, and myelodysplastic syndromes, often causing diagnostic delay. We describe a case presenting with relapsing polychondritis-like features and summarize, through a focused literature review, its diagnostic pathway and therapeutic implications. A 74-year-old man presented with three weeks of fever, auricular and nasal chondritis, iritis, and pulmonary infiltrates. Inflammatory markers were elevated with macrocytic anaemia. Antimicrobial therapy failed, whereas glucocorticoids produced rapid defervescence and clinical improvement. Bone-marrow examination revealed cytoplasmic vacuoles in myeloid precursors with dysplastic features. Sanger sequencing of UBA1 exon 3 on peripheral-blood DNA identified the canonical variant c.122T > C, p.(Met41Thr) as a mixed C/T chromatogram peak at codon 41. At structured 6-month follow-up the patient remained relapse-free on glucocorticoids. The genetic finding nevertheless supported the diagnosis. Diagnostic difficulty arises from clinical heterogeneity. A practical pathway emerges: recognition of relapsing polychondritis and infection presentations, evaluation of macrocytosis and cytopenias, bone-marrow examination for precursor vacuoles, UBA1 sequencing with adequate analytic sensitivity, and exclusion of mimics. Glucocorticoids are first-line; steroid-sparing options-interleukin-1 and interleukin-6 inhibitors, Janus kinase inhibitors, and allogeneic hematopoietic stem cell transplantation-are selected by phenotype, severity, and transplant eligibility. VEXAS syndrome should be suspected in older adults with refractory inflammation and unexplained cytopenias. Early recognition of marrow vacuolization and UBA1 sequencing with adequate analytic sensitivity may shorten diagnostic delay and facilitate risk-adapted treatment.
2026-06-27 | Variable vessel vasculitis of arteries and veins in VEXAS syndrome.
A man in his 50s receiving immunomodulatory therapy for presumed Behçet's disease presented with odynophagia and jaw pain. Three months earlier, he had developed deep vein thrombosis and extensive superficial phlebitis with transmural inflammation on histopathology. Imaging revealed carotid artery vasculitis and unilateral inflammation around the temporal vessels. Ultrasound demonstrated wall thickening of the right temporal vein with normal temporal arteries. Persistent systemic inflammation and bicytopenia prompted bone marrow examination revealing myelodysplastic syndrome. Detection of a somatic UBA1 mutation confirmed VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). Glucocorticoids and interleukin-1 blockade were initiated. Due to severe cytopenia, the patient underwent allogeneic haematopoietic stem cell transplantation, resulting in clinical remission. VEXAS causes variable vessel vasculitis, affecting arteries and veins alike even without thrombosis. In older men with myelodysplasia or cytopenia, VEXAS should be considered in the differential of both venous and arterial vasculitis. Ultrasound may distinguish temporal phlebitis from giant cell arteritis.
2026-06-26 | Trisomy 8 clonal expansion during disease progression and azacitidine resistance in VEXAS syndrome: a case report.
Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an adult-onset autoinflammatory disorder driven by clonal hematopoiesis with somatic UBA1 mutations. Azacitidine can reduce the mutant clonal burden and improve inflammatory manifestations. However, the clonal basis of treatment resistance remains poorly understood. A 61-year-old man presented with predominant gastrointestinal symptoms, macrocytic anemia, thrombocytopenia, and systemic inflammation. A bone marrow examination revealed cytoplasmic vacuoles in myeloid precursors and trisomy 8. Retrospective genetic testing identified a somatic UBA1 p.Met41Val variant, thus establishing the diagnosis of VEXAS syndrome in this patient. At the time of referral and during immunosuppressive therapy with prednisolone and cyclosporine, the UBA1 variant allele frequency was consistently higher than the trisomy 8 burden, although relapse coincided with an expansion of trisomy 8. Azacitidine reduced the clonal burdens of both the UBA1 mutation and trisomy 8. However, both persisted at similar levels, and after 21 cycles, the disease progressed to myelodysplastic syndrome with increased blasts-2, accompanied by concordant re-expansion of UBA1-mutated and trisomy 8 clones. These findings suggest that a trisomy 8 subclone likely emerged within a UBA1-mutated founder clone and expanded during treatment, whereas the disomy 8 fraction of the UBA1-mutated clone was preferentially eliminated by azacitidine. Urgent cord blood transplantation resulted in sustained clinical and molecular remission. This case suggests that trisomy 8 may contribute to disease progression and azacitidine resistance in VEXAS syndrome.
proteins
2025-09-22 | Comparative Efficacy and Safety of Anakinra and Canakinumab in Patients With VEXAS Syndrome: An International Multicenter Study.
The aim of this study was to compare differences in clinical response, drug survival, and adverse event rates between anakinra and canakinumab in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. This multicenter international study includes patients with VEXAS from France, Israel, and Italy treated with interleukin-1 inhibition. Global response (GR) was defined as the absence of inflammatory symptoms and ≥50% decrease in steroid dose and C-reactive protein. Multiple regression analysis was performed to identify associated variables. Drug survival was analyzed using Kaplan-Meier plots and log-rank test, with Cox regression models for associated factors. We included 47 male patients with VEXAS; 44 received anakinra and 9 received canakinumab, with 6 patients using both at different time points. GR at 1 month was 34% for anakinra and 100% for canakinumab (P < 0.001) and 22% and 78% at 3 months, respectively (P = 0.001). Treatment with canakinumab was associated with a higher odds ratio (OR) of achieving GR at 3 months (OR 28.8, 95% confidence interval 3.0-273.9; P = 0.004) in a multivariable analysis. Median drug survival was 54 (interquartile range [IQR] 30-56) months for canakinumab at 300 mg/month compared with 7 (IQR 4-8) months for canakinumab 150 mg/month and 1 (IQR 1-2.5) months for anakinra (P = 0.01). Injection-site reactions were only recorded for the anakinra group (47 vs 0%; P = 0.006), whereas infections were more frequent in the anakinra group (31% and 11%; P = 0.3). Canakinumab demonstrated superior clinical response and drug survival with fewer adverse events compared with anakinra. Monthly canakinumab 300 mg may be considered as an effective steroid-sparing therapeutic option for patients with VEXAS.
2025-09-19 | VEXAS anemia is a mosaic erythroblastopenia
VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently discovered autoinflammatory disorder linked to somatic mutations in the UBA1 gene, resulting in a profound cytoplasm-restricted defect in ubiquitylation. The disease is characterized by a macrocytic anemia that remains poorly understood. To investigate the erythroid lineage in VEXAS, we conducted a comprehensive study combining in vivo assessments of patients' mature red cells and marrow erythroblasts, alongside in vitro base-editing models of erythropoiesis. Here we show that mature red cells do not exhibit ubiquitylation defects, and patient-derived bone marrow erythroblasts lack UBA1 mutations beyond the basophilic stage of erythroid differentiation. In vitro base editing of UBA1 variants in CD34+ primary cells resulted in high mortality during early erythroid differentiation, but not during monocytic differentiation. Edited erythroid precursors displayed TP53 overexpression linked to defective ubiquitylation and anomalies in ribosome biogenesis, reminiscent of Diamond-Blackfan anemia. We propose that VEXAS-associated anemia should be considered as a mosaic erythroblastopenia, where the severity of anemia is influenced by the quality and quantity of the UBA1-WT compartment. Our findings offer new insights into the physiopathology of VEXAS and may suggest new potential therapeutic options.
2025-04-15 | Disturbing immune homeostasis by neutrophil loss of Uba1 induces VEXAS-like autoinflammatory disease in mice
ABSTRACT Objective VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is an identified haemato-rheumatoid disease caused by somatic UBA1 mutations in hematopoietic stem cells. We report Uba1 loss in various mouse hematopoietic cell types leads to diverse effects, with approximately 70% Uba1 depletion in neutrophils inducing non-lethal VEXAS-like symptoms. Methods Using nine different Cre/flox-mediated conditional-knockout (CKO) models, we interrogated the phenotypes caused by hematopoietic loss of Uba1 . Neutrophil-specific depletion of Uba1 were validated and VEXAS-like phenotypes were examined. Results Uba1 loss in HSCs induces extensive hematopoietic cell death while in B or T cells, or megakaryocytes induces corresponsive cell death but these mutants appear normal. Uba1 loss in monocytes and neutrophils failed to induce cell death and the mutants are viable. Among the models, only Uba1 loss in neutrophils manifests autoinflammatory symptoms including increased counts and percentage of neutrophils, increased proinflammatory cytokines, vacuoles in myeloid cells and dermatitis. Residual Uba1 is about 30% in the mutant neutrophils, which manifest disturbed cellular hemostasis. Genetic loss of Morrbid partially mitigated the VEXAS-like symptoms. Conclusion Our study reveals diverse effects of Uba1 loss in hematopoietic cells and establishes a VEXAS-like murine model, facilitating understanding and potential treatments for this syndrome prevalent in aged men. HIGHLIGHTS WHAT IS ALREADY KNOWN ON THIS TOPIC VEXAS syndrome is a recently identified hematological and immunological disease prevalent in adult man but rarely in adult woman. Somatic mutations in the E1-enzyme encoding gene UBA1 in hematopoietic stem cells is the driver on the top of the genetic etiology of the disease. However, the major pathogenic cell type(s) for VEXAS syndrome has not been experimentally examined and mouse models recapitulating the disease are lacking. WHAT THIS STUDY ADDS Using nine different conditional-knockout (CKO) murine models, we interrogated the pleiotropic phenotypes caused by loss of the ubiquitin activation enzyme Uba1 in different hematopoietic cell types; Our results demonstrated that among the nine tested CKO mutants, only neutrophil loss of Uba1 results in VEXAS-like autoinflammatory disease; The VEXAS-like symptoms in the S100a8Cre-CKO mutant mice include: increased counts of white blood cells and neutrophils, increased percentage of neutrophils, increased serum level of proinflammatory cytokines (IL-1β, IL-6 and TNFα), observation of vacuoles, increased survival, and increased phagocytosis in mutant neutrophils; Pharmacological treatments with IL-1 inflammatory pathway inhibitors Anakinra or Canakinumab or genetic loss of the myeloid pro-survival regulator Morrbid partially mitigated the VEXAS-like symptoms in the S100a8Cre-CKO mutants; HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY The study reports a technical strategy of developing the murine models for VEXAS syndrome. In addition, the study dissects cellular and molecular mechanisms, especially the cell-type-dependent tolerance and pathogenicity of loss of function of Uba1 , for the occurrence of the autoinflammation diseases in mice. The study provides translational implications in etiology and potential treatment choices for the newly-identified haemato-rheumatoid syndrome in clinical management.
other
2025-11-03 | Bone marrow microenvironment overlap between vexas and myelodysplastic syndrome demonstrated by targeted transcriptomic and artificial intelligence
Abstract Introduction: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is an inflammatory process that involves bone marrow (BM). Active inflammation is also a major feature of the microenvironment in the BM of patients with myelodysplastic syndrome (MDS). To explore the overlap between VEXAS and MDS, we used an artificial intelligence (AI) approach and compared the transcriptomic profile of the BM from VEXAS patients (N=59) with the BM from MDS patients (N=1021) and the BM of individuals without specific diagnostic abnormality or with CHIP (clonal hematopoiesis of indeterminate potential) (N=1030) (Normal). Methods: RNA was extracted from the bone marrow samples from patients with VEXAS (N=59), MDS (N=1030), and Normal (1030). The RNA was sequenced by next generation sequencing (NGS) using a targeted RNA panel of 1600 genes. Hybrid capture sequencing library preparation was used, and RNA was quantified using transcript per million (TPM). To compare between the three groups, we used the RNA expression levels in an AI model based on Bayesian statistics and random forest. Bayesian statistics were used to rank the genes that distinguish between groups, then random forest was used to establish the signatures that distinguish between the groups. Two thirds of the samples were used for training and one third was used for testing the models. Results: Using the AI model described above, the BM of patients with VEXAS was significantly different from normal. Only 8 genes (SF3A1, SMAD5, PRPF8, MCM3AP, NFYC, FGFR1OP, PPM1D, THRA) were adequate to distinguish VEXAS from normal with AUC of 0.910 (95% CI: 0.0867-0.953)(A). Except for PPM1D, all genes were at significantly higher levels in VEXAS while PPM1D expression was significantly lower in VEXAS. Three of the 8 genes are involved in RNA splicing and 3 in DNA damage repair. Of the tested 1600 genes, 453 genes showed significant (LogFDR <-3) difference in the level of expression between VEXAS and normal. In contrast, only 152 genes were significantly different (LogFDR <-3) between MDS and VEXAS. Using the same AI model, 40 genes were needed to distinguish VEXAS from MDS (AUC : 0.905, 95% CI: 0.0861-0.950)(B). All genes that were significantly abnormal in VEXAS as compared with normal were also significantly abnormal in MDS as compared with normal. The difference was in the same direction in that those with high expression in VEXAS vs. normal were also high in MDS vs. normal and vice versa. Conclusions: These findings suggest that while the presenting symptoms in VEXAS are systemic inflammatory processes involving lungs, skin, blood vessels, and joints, there are significant abnormalities in bone marrow microenvironment mimicking the abnormalities seen in MDS. The demonstration that changes in splicing and DNA repair gene are the major molecular abnormalities that distinguish VEXAS BM as compared to normal suggests that therapeutic approaches targeting these abnormalities may help in ameliorating the clinical manifestation of this disease.
2025-11-01 | 51 A Comprehensive Analysis of Clinical, Pathological, and Genetic Profiles of Indian Cohort of Patients with VEXAS Syndrome
Abstract The VEXAS syndrome is a recently recognized, acquired monogenic adult onset haemato-inflammatory syndrome defined by somatic mutations within the UBA1 gene. It is an acronym that stands for vacuoles, E1 enzyme, X-linked inheritance, autoinflammatory tendencies, and somatic mutations. It presents as a severe progressive disease displaying varied characteristics that bridge hematologic and rheumatologic domains. In this series, we describe nine cases of VEXAS syndrome diagnosed at our institute, marking the first report from the Indian Subcontinent. A comprehensive analysis was conducted on patients diagnosed over the past 4 years (2020–2024), documenting clinical presentations, pathological findings, genetic characteristics, and outcomes. The UBA1 gene region(Exons 2-3 and intervening intron) was amplified by PCR and sequenced bidirectionally using Big Dye terminator v1.1 kit (Applied Biosystems); sequencing was performed on the Spectrum Compact Capillary Electrophoresis System (Promega). Results A total of nine cases were identified from 53 patient blood samples sent to our institute for UBA1 gene mutation testing with clinical suspicion of VEXAS (9/53,16.9%). All the patients were males with an age range from 42-77 years. Prominent clinical characteristics noted were a history of fever (9), arthritis/ arthralgia (8), inflammatory skin lesions (5), vasculitis (4), ocular inflammatory conditions (5), relapsing polychondritis (5), unprovoked venous thrombosis (3) and ear chondritis (3). Persistent unexplained cytopenia was present in all the patients, manifesting as anemia (8, 6 of which were macrocytic), thrombocytopenia (3), and neutropenia (2). We documented three cases of VEXAS coexisting with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and monoclonal gammopathy (MGUS), with the SLE-associated case being the first reported in the literature. Bone marrow examination was performed on seven patients, all exhibiting dyshematopoietic features(100%). Further, all seven cases also showed cytoplasmic vacuolations in the hematopoietic precursors. UBA1 somatic mutations included p.Met41Thr (c. 122 T>C Exon 2) (67%), p.Met41Val (c.121 A>G Exon 2) (22%) and a rare variant of UBA1 mutation in acceptor splice site of Exon 3 (c. 118 G>C) (11%). Follow-up ranged from 12 to 120 months, with a mean overall survival (OS) of 35.6 months and 4 cases succumbed to the disease. On Kaplan–Meier analysis, p.Met41Val cases have significantly inferior OS, with the mean OS of 17 (95% CI 7.2–27.8) months; in p.Met41Thr cases, the OS was 100.8 (95% CI 53.2–148.4) months (p = 0.006). The clinicopathological features of our cohort align closely with the available literature. However, our study is unique in highlighting the need to consider VEXAS syndrome even in patients with SLE and RA. Additionally, we have reported a rare variant of UBA1 mutation, further contributing to the expanding genetic spectrum of the disease and emphasizing the necessity of aggressive treatment for cases with p.Met41Val mutation, given their poor prognosis.
2025-09-04 | UBA1-depleted neutrophils disrupt immune homeostasis and induce VEXAS-like autoinflammatory disease in mice
VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a haemato-rheumatoid disease caused by somatic UBA1 mutations in hematopoietic stem cells (HSCs). The pathogenic cell type(s) responsible for the syndrome are unknown and murine models recapitulating the disease are lacking. We report that loss of Uba1 in various mouse hematopoietic cell types resulted in pleiotropic consequences and demonstrate that murine mutants with about 70% loss of Uba1 in neutrophils induced non-lethal VEXAS-like symptoms. Depletion of Uba1 in HSCs induced extensive hematopoietic cell loss while depletion of Uba1 in B or T cells, or in megakaryocytes induced corresponsive cell death but these mutants appeared normal. Depletion of Uba1 in monocytes and neutrophils failed to induce cell death and the mutants were viable. Among the tested models, only depletion of Uba1 in neutrophils induced autoinflammatory symptoms including increased counts and percentage of neutrophils, increased proinflammatory cytokines, occurrence of vacuoles in myeloid cells, splenomegaly and dermatitis. Residual Uba1 was about 30% in the mutant neutrophils, which disrupted cellular hemostasis. Finally, genetic loss of the myeloid pro-survival regulator Morrbid partially mitigated the VEXAS-like symptoms. The established VEXAS-like murine model will assist understanding and treatment of the newly identified autoinflammatory syndrome prevalent among aged men.
antibodies
2026-09-29 | Endotheliopathy and VWF-ADAMTS13 axis dysfunction in VEXAS thrombogenicity.
Markedly increased risk of thrombosis has been described as a key clinical feature of the recently described VEXAS (vacuoles, E1 enzyme, X linked, autoinflammatory, somatic) syndrome. Critically however, the pathological mechanisms underlying VEXAS-associated hypercoagulability remain poorly understood. We addressed this question in a cohort of 40 VEXAS patients referred to the National Institutes of Health with defined pathological UBA1 sequence variants. In keeping with previous reports, twenty-one (52.5%) VEXAS patients in our cohort experienced thrombotic events. Plasma VWF and FVIII activity levels were both increased in VEXAS compared to age-matched controls. Consistent with endothelial cell (EC) activation and Weibel Palade body exocytosis, plasma VWF propeptide and angiopoietin II levels were also significantly elevated in VEXAS subjects. Furthermore, an accumulation of high molecular weight VWF multimers was seen in VEXAS patients. In keeping with ongoing endotheliopathy, plasma levels of soluble Vascular Cell adhesion Molecule-1 (VCAM-1) and soluble thrombomodulin (sTM) were significantly higher in VEXAS patients compared to controls. Finally, significantly increased thrombin generation and activated protein C resistance (APCR) were also observed in plasma from VEXAS patients. In conclusion, our novel findings demonstrate that VEXAS syndrome is associated with significant EC activation and endotheliopathy. This results in both quantitative and qualitative alterations in plasma VWF levels, increased FVIII levels, enhanced thrombin generation and an APCR phenotype. Further studies will be required to determine whether therapeutic interventions targeted at EC and/or the VWF-ADAMTS13 axis may be useful in VEXAS management.
2026-09-16 | Acute Fulminant Systemic Granulocytic Vasculitis Involving Arteries and Veins in Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic (VEXAS) Syndrome: An Autopsy Case Report.
Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome is a disease concept characterized by UBA1 mutation that was first proposed in 2020. We report an autopsy case of VEXAS syndrome that was retrospectively diagnosed 11 years later through genetic analysis of formalin-fixed, paraffin-embedded (FFPE) bone marrow tissue. The patient was a 65-year-old male with hepatitis C who presented with general fatigue followed by fever 2 weeks later. Shortly before death, phlebitis of the extremities and marked leukocytosis became evident. The patient died within 3 weeks of symptom onset. Autopsy revealed granulocytic vasculitis involving small- to medium-sized arteries and phlebitis in various organs, including the lungs, kidneys, liver, and lymph nodes. Concomitant myelodysplastic syndrome (MDS) was confirmed, leading to a diagnosis of MDS-associated vasculitis. Sanger sequencing of FFPE specimens 11 years later revealed a UBA1 mutation (p. Met41Val), confirming VEXAS syndrome. Although VEXAS syndrome is typically characterized by chronic, treatment-refractory inflammation and poor prognosis, autopsy reports are rare. Herein, we report an autopsy case of VEXAS syndrome associated with MDS and systemic vasculitis that presented with a fulminant clinical course.
2026-09-03 | Clinical and molecular spectrum of VEXAS with multiple UBA1 variants: case study and literature review.
VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a rare adult-onset autoinflammatory disorder, caused by a single somatic UBA1 mutation. We report a novel case with 3 independent UBA1-mutated clones and compare its clinical, hematologic, and laboratory features with those of the only 3 previously reported cases harboring multiple UBA1 mutations. Droplet digital polymerase chain reaction (PCR) and targeted next-generation sequencing of peripheral blood DNA were performed to assess UBA1 variants. Bone marrow specimens were evaluated for morphologic, immunophenotypic, and cytogenetic abnormalities. Clinical and hematologic features included neck swelling, headache, elevated inflammatory markers, leukopenia, macrocytic anemia, and thrombocytopenia. Bone marrow biopsy specimens showed no dysplasia, increased blasts, or cytoplasmic vacuolization. Droplet digital PCR detected atypical positive signals across multiple targets, and next-generation sequencing identified 3 presumed independent UBA1 variants: p.M41V, p.M41L, and c.118-2A > T. Comparison with 3 previously reported VEXAS cases carrying multiple UBA1 variants revealed diverse clinical manifestations, including systemic inflammation, polychondritis, venous thromboembolism, arthritis, and arthralgia, with variable hematologic findings ranging from no neoplasm to myelodysplastic syndrome or multiple myeloma, as well as co-occurring clonal hematopoietic variants. This report describes a novel VEXAS case with multiple UBA1 variants and highlights the clinical and hematologic heterogeneity among patients harboring multiple UBA1 mutations. It also emphasizes the technical challenges in detecting these variants and the importance of sequencing studies for definitive diagnosis in complex or equivocal cases, supporting early identification of UBA1 mutations and closer hematologic surveillance in patients with inflammatory symptoms and cytopenias.
2026-08-17 | VEXAS Syndrome: A Comprehensive Review for Dermatologists Part 2: Work-up, Diagnosis, Treatment, and Prognosis.
VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a recently described, adult-onset inflammatory disorder caused by acquired UBA1 mutations in hematopoietic stem and progenitor cells. Part 2 of this two-part series CME article focuses on practical approaches to diagnosis, treatment, and prognosis, with an emphasis on dermatology-relevant decision-making. Characteristic laboratory findings, the role of bone marrow evaluation, and targeted UBA1 testing are reviewed, along with proposed clinical screening criteria and diagnostic approaches for genetic confirmation. Current management strategies include glucocorticoids, corticosteroid-sparing immunomodulatory agents, hypomethylating agents, and allogeneic hematopoietic stem cell transplantation. Prognostic factors, including UBA1 variant type, clonal burden, progression to myelodysplastic syndromes, and treatment-related complications such as serious infection are reviewed. Multidisciplinary collaboration among dermatology, rheumatology, hematology, and medical genetics is emphasized as essential for optimizing outcomes in this complex and potentially life-threatening syndrome.
2026-07-28 | VEXAS Mimicking Antiphospholipid Syndrome: Diagnostic Challenges of False-Positive Antiphospholipid Antibodies.
Somatic UBA1-mutated VEXAS syndrome is now recognized as a multisystem disorder marked by diffuse systemic inflammation, refractory cytopenia with or without bone marrow dysplasia, and thrombotic events affecting both venous and arterial systems [...].
small molecules
2026-09-24 | Evaluating the Efficacy of Cytokine-Directed Therapies in the Management of VEXAS Syndrome.
To evaluate the efficacy of cytokine-directed therapies in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory somatic) syndrome using previously proposed treatment response criteria. All patients with genetically confirmed VEXAS syndrome who received targeted therapies with JAK inhibitors (JAKi), tumor necrosis factor α inhibitors (TNFαi), or interleukin-1 (IL-1) or IL-6 inhibitors were identified. Clinical and biochemical data were recorded for patients at time of targeted therapy initiation, and at 3-, 6-, and 12-month follow-up time points. Treatment response was labeled as complete response (CR; normalization of C-reactive protein [CRP], prednisone <10 mg/day, and resolution of disease activity), partial response (PR; >50% improvement in CRP, >50% prednisone dose reduction, improvement or resolution of disease features), treatment failure (TF; worsening CRP, increasing prednisone, worsening of disease features), or no response (not meeting criteria for CR, PR, or TF). Overall, 52 patients received an IL-1i, IL-6i, or JAKi therapy. At six-month follow-up, 3 of 19 IL-6i patients experienced CR, 4 of 19 experienced PR, and 7 of 19 experienced TF. 2 of 17 patients receiving JAKi experienced CR, 3 of 17 experienced PR, and 6 of 17 experienced TF. No patients receiving IL-1i or TNFαi experienced CR, and only 1 of 5 IL-1i patients experienced PR. Among those still receiving biologic therapy at 12 months, only 1 of 11 receiving IL-6i and 0 of 7 receiving JAKi experienced CR. IL-6i and JAKi therapies demonstrated limited, unsustained efficacy for management of VEXAS syndrome. IL-1i and TNFαi therapies were not efficacious. Useful application of previously reported treatment response criteria was demonstrated, but future incorporation of hematologic parameters may be beneficial.
2026-09-22 | UBA1 as a proteostasis-innate immunity checkpoint: lessons from vexas syndrome and therapeutic implications
Ubiquitin-like modifier activating enzyme 1 (UBA1) occupies the apex of the canonical ubiquitination cascade and supplies activated ubiquitin to a broad network of E2 conjugating enzymes and E3 ligases. Although traditionally regarded as an essential housekeeping enzyme, human genetics has revealed a more instructive function for UBA1: it determines whether proteostatic stress is buffered, converted into inflammatory adaptation, or progresses to cell death. Somatic UBA1 mutations causing VEXAS syndrome provide a natural experiment in this threshold biology. Partial and compartment-selective loss of UBA1 activity permits hematopoietic cells to survive while reducing ubiquitination capacity, activating stress-response pathways, altering cell-death thresholds, and promoting innate immune dysregulation. Single-cell and functional studies further demonstrate early inflammatory activation in UBA1-mutant hematopoietic progenitors, myeloid-biased differentiation, monocyte dysfunction, and inflammasome-associated signaling. Conversely, profound pharmacological UBA1 inhibition with agents such as TAK-243 drives proteotoxic collapse and is being explored as an anticancer strategy. Here, we propose that UBA1 functions as a proteostasis-innate immunity checkpoint whose biological output is determined by residual enzymatic activity, subcellular distribution, lineage context, and clone size. This framework reconciles inflammatory disease caused by partial UBA1 dysfunction with the antitumor effects of UBA1 inhibition and suggests a mechanism-based approach to therapeutic intervention in VEXAS syndrome and malignancy.
2026-09-07 | Human Monocytic Models Reveal Genotype-Dependent Inflammatory Programs in VEXAS Syndrome.
VEXAS syndrome is a severe X-linked autoinflammatory disorder caused by somatic mutations in ubiquitin-like modifier activating enzyme 1 (UBA1), with clinical outcomes that vary by UBA1 genotype. We aimed to elucidate genotype-specific inflammatory programs and identify potential therapeutic targets. We conducted longitudinal deep phenotyping, including whole blood RNA sequencing (RNA-seq) and clinical activity assessment. Peripheral blood samples were analyzed by single-cell RNA-seq. Human monocytic cell lines harboring each major UBA1 mutation (p.Met41Val, p.Met41Thr, or p.Met41Leu) were generated and subjected to transcriptomic and functional analyses. Thirteen patients with VEXAS syndrome contributed a total of 79 RNA-seq samples. Among genes up-regulated in VEXAS syndrome, RNASE1 showed the strongest correlation with longitudinal disease activity (r = 0.70, false discovery rate < 0.05) and was up-regulated in patients' monocytes. In UBA1-mutant monocytic cell lines, genotype-dependent ubiquitination defects were observed in a graded manner (p.Met41Val > p.Met41Thr > p.Met41Leu), even in the absence of exogenous stimuli. These defects were accompanied by unfolded protein response activation, increased pro-inflammatory cytokine production, progressive cell death, and RNASE1 up-regulation, all following the same graded pattern of recapitulating patient genotype-phenotype associations. Transcriptomic analyses demonstrated enrichment of pro-inflammatory, interferon, and necroptosis signatures in more severe genotypes. Notably, inhibition of receptor-interacting protein kinase 3 (RIPK3) markedly attenuated all pathologic features, including RNASE1 up-regulation. Our UBA1-mutant monocytic cell-line models, representing three distinct genotypes, recapitulate genotype-dependent inflammatory phenotypes that can be modulated by RIPK3 inhibition, providing a translational platform for mechanistic investigation and precision therapy development in VEXAS syndrome.
2026-08-18 | An Italian cartography of VEXAS-related thrombosis.
Thrombotic events (TEs) occur in up to 40% of patients with vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic (VEXAS) syndrome, but data on its clinical-genomics features and anticoagulation strategies are limited. To gain more insight into this, we conducted a two-step study evaluating the prevalence and outcome of TE in VEXAS. First, among 1086 patients followed for TEs, 198 were men aged >40 years with unprovoked thrombosis and no known thrombophilia; 21 also had at least one VEXAS-compatible feature and underwent UBA1 exon 3 testing. No UBA1 mutation was detected in these 21 patients. Next, we leveraged our Italian VEXAS network, and we accrued 87 molecularly confirmed Italian VEXAS cases (median age 70 years). Any history of TE was documented in 43/87 patients (49%), deep vein thrombosis being the most common (71%). Because follow-up varied, incident thrombosis was analyzed using a time-to-first-event framework from molecular VEXAS diagnosis, with death without prior TE treated as a competing event. Among 49 patients without prior/concomitant TE, five developed incident post-diagnosis TE; the 24-month cumulative incidence was 18.3%. Thrombophilia testing revealed a 15% co-occurrence, including heterozygous Factor V Leiden, Factor II G20210A, and anti-cardiolipin antibodies. Treatments comprised direct oral anticoagulants (DOACs) (51%), low molecular weight heparin (LMWH) (28%), Fondaparinux (14%), and vitamin K antagonists (AVKs) (7%). Notably, 27% experienced multiple TEs, of which 22% occurring despite anticoagulation during disease flares. Our findings provide an updated cartography of VEXAS-related TE, suggesting early screening for thrombophilia in these patients to inform both personalized anticoagulation and disease-control strategies.
2026-08-01 | Recurrent Lymphocytic Pleural Effusions as an Atypical Presentation of VEXAS Syndrome: A Case Report
Background VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a recently described adult-onset autoinflammatory disorder caused by somatic mutations in the UBA1 gene. The condition predominantly affects men over 50 years of age and manifests with heterogeneous rheumatologic, dermatologic, hematologic, and systemic inflammatory features. Pulmonary manifestations occur in over half of patients, but pleural effusions are relatively uncommon.[1] Given its clinical heterogeneity and overlap with autoimmune, infectious, and hematologic diseases, diagnosis remains challenging and relies on genetic confirmation of UBA1 mutations. Case Report A 60-year-old man presented with a 1-year history of non-productive cough, dyspnea, pleuritic chest pain, fatigue, night sweats, and 10 kg unintentional weight loss. He reported intermittent left ankle swelling, bilateral stiffness, and 2 episodes of unilateral periorbital edema responsive to short prednisone courses. Laboratory investigations revealed mild macrocytic anemia (hemoglobin 121 g/L, MCV 97.6 fL) and elevated C-reactive protein (38.7 mg/L). Autoimmune and infectious workup, including ANA, ANCA, rheumatoid factor, and extensive infectious serologies, were negative. Imaging demonstrated recurrent right-sided pleural effusions without evidence of malignancy. Thoracentesis yielded a lymphocyte-predominant exudative effusion (80% lymphocytes), with negative cultures and cytology. A subsequent contralateral pleural effusion showed similar findings. Flow cytometry identified a minor B-cell population without definitive lymphoproliferative disorder. Bone marrow biopsy revealed hypercellular marrow with trilineage hematopoiesis, megakaryocytic dysplasia, and mild fibrosis, but no lymphoma. Next-generation sequencing identified a somatic UBA1 p.Met41Thr (c.122T>C) mutation (variant allele fraction 76.6%), confirming VEXAS syndrome, along with a concurrent DNMT3A frameshift mutation (VAF 39.7%) consistent with clonal hematopoiesis. The patient was treated with oral prednisone 30-40 mg daily, resulting in complete resolution of inflammatory arthritis, improvement of constitutional symptoms, and normalization of inflammatory markers after 4 weeks. He was subsequently referred for initiation of ruxolitinib as a steroid-sparing agent.[2] Conclusion This case highlights VEXAS syndrome as a diagnostic consideration in older men with persistent systemic inflammation, recurrent lymphocytic pleural effusions, episodic arthritis, and periorbital edema in the absence of infection, malignancy, or autoimmune disease. Pleural effusions, although uncommon, may be the primary pulmonary manifestation. Comprehensive evaluation, including next-generation sequencing for UBA1 mutations, is essential for accurate diagnosis and facilitates targeted management with glucocorticoids and steroid-sparing agents. Early recognition improves outcomes and underscores the need for multidisciplinary care. References [1.] Al-Hakim A. Rheumatology (Oxford) 2025;64:5217-29. [2.] Heiblig M. Blood 2022;140:927-31.
cell therapies
2026-09-18 | Diagnostic and Therapeutic Challenge: VEXAS Syndrome with Multisystem Inflammation and Myelodysplasia: A Case Report.
VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is an adult-onset autoinflammatory disorder caused by somatic UBA1 mutations linking systemic inflammation with haematologic dysfunction. We report a 59-year-old man presenting with fatigue, fevers, and severe macrocytic anaemia (haemoglobin 8.1 g/dL, MCV >120 fL), mild thrombocytopenia, and markedly elevated inflammatory markers. Autoimmune and malignancy workup was negative. Bone marrow biopsy showed hypercellularity with multilineage dysplasia and cytoplasmic vacuolisation, and genetic testing confirmed a somatic UBA1 mutation. High-dose glucocorticoids led to rapid resolution of inflammatory manifestations and normalisation of inflammatory markers; however, cytopenias progressed despite erythropoiesis-stimulating agents and ruxolitinib, with haemoglobin declining to <7 g/dL, resulting in transfusion dependence. The patient is undergoing evaluation for allogeneic haematopoietic stem cell transplantation (HSCT). This case highlights VEXAS syndrome as an aggressive haematoinflammatory disorder with limited responsiveness to conventional and targeted therapies and emphasises early consideration of advanced strategies, including HSCT, in selected patients.
2026-08-01 | VEXAS Syndrome: A Clinical Case Series from Calgary
Background VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome was first described in November 2020.[1] It is typically an adult-onset, treatment-refractory autoinflammatory disorder caused by somatic mutations in the UBA1 gene.[1] Canadian data remain limited.[2] We describe a case series of 5 patients with VEXAS syndrome from Calgary, 2 of whom underwent allogenic hematopoietic stem cell transplant (alloHSCT) with excellent response. Case Report This case series features 5 male patients (Table 1). The median age at disease onset was 65 (range 50-77) years. The median delay in diagnosis was 18 (range 1-46) months. The median disease duration was 44 (range 20-79) months. All patients had somatic UBA1 variants: p.Met41Val (n=2), p.Met41Thr, p.Met41Leu, and 1 uncharacterized p.? variant (Table 1). All patients reported constitutional symptoms. Initial working diagnoses included unspecified inflammatory condition, adult-onset Still’s disease, relapsing polychondritis (n=2), and atypical polyarteritis nodosa vs undifferentiated connective tissue disease (Table 1). Elevated inflammatory markers were observed in all patients (CRP frequently >100 mg/L). Vacuoles were confirmed on bone marrow biopsy in 4 patients. Three patients presented with, and 1 later developed, macrocytic anemia, whereas 1 patient had intermittent normocytic anemia. Thrombocytopenia and lymphopenia were each observed in 3 patients. Two patients developed myelodysplastic syndrome following diagnosis of VEXAS. Patients trialed several different therapies including hydroxychloroquine, methotrexate, azathioprine, mycophenolate, rituximab, anakinra, tocilizumab, tofacitinib, ruxolitinib, colchicine and dapsone with limited or no sustained benefit. Corticosteroids were required at moderate-to-high doses in most patients. At present, patient A is maintained on prednisone 35 mg daily. Patient B is taking prednisone 15 mg daily and ruxolitinib 20 mg twice daily. Patient C underwent alloHSCT in April 2025 with resolution of symptoms and discontinuation of prior medications (prednisone and ruxolitinib). Repeat bone marrow biopsy showed <0.5% UBA1. Patient D continues with prednisone 5-6 mg daily and azacitidine. Patient E underwent alloHSCT in August 2023. He developed chronic graft-versus-host disease requiring treatment with prednisone 7 mg daily and belumosudil. There was no evidence of UBA1 mutation on repeat bone marrow biopsy. Conclusion In conclusion, this case series highlights the multisystem nature of VEXAS syndrome and the substantial diagnostic delay often encountered in clinical practice. We recommend considering VEXAS syndrome in patients with treatment-resistant autoinflammatory syndrome and cytopenias, especially macrocytic anemia. While conventional immunosuppressive medications have provided limited benefit, allogeneic hematopoietic stem cell transplant may be promising for select patients. References [1.] Beck D. N Engl J Med 2020;383:2628-38. [2.] Williams S. J Rheumatol 2024;51:734-7.
2026-07-06 | VEXAS syndrome unmasked from relapsing polychondritis and infection mimicry: a case-based review.
VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a UBA1-driven hemato-inflammatory disorder that mimics relapsing polychondritis, vasculitis, and myelodysplastic syndromes, often causing diagnostic delay. We describe a case presenting with relapsing polychondritis-like features and summarize, through a focused literature review, its diagnostic pathway and therapeutic implications. A 74-year-old man presented with three weeks of fever, auricular and nasal chondritis, iritis, and pulmonary infiltrates. Inflammatory markers were elevated with macrocytic anaemia. Antimicrobial therapy failed, whereas glucocorticoids produced rapid defervescence and clinical improvement. Bone-marrow examination revealed cytoplasmic vacuoles in myeloid precursors with dysplastic features. Sanger sequencing of UBA1 exon 3 on peripheral-blood DNA identified the canonical variant c.122T > C, p.(Met41Thr) as a mixed C/T chromatogram peak at codon 41. At structured 6-month follow-up the patient remained relapse-free on glucocorticoids. The genetic finding nevertheless supported the diagnosis. Diagnostic difficulty arises from clinical heterogeneity. A practical pathway emerges: recognition of relapsing polychondritis and infection presentations, evaluation of macrocytosis and cytopenias, bone-marrow examination for precursor vacuoles, UBA1 sequencing with adequate analytic sensitivity, and exclusion of mimics. Glucocorticoids are first-line; steroid-sparing options-interleukin-1 and interleukin-6 inhibitors, Janus kinase inhibitors, and allogeneic hematopoietic stem cell transplantation-are selected by phenotype, severity, and transplant eligibility. VEXAS syndrome should be suspected in older adults with refractory inflammation and unexplained cytopenias. Early recognition of marrow vacuolization and UBA1 sequencing with adequate analytic sensitivity may shorten diagnostic delay and facilitate risk-adapted treatment.
2026-06-27 | Variable vessel vasculitis of arteries and veins in VEXAS syndrome.
A man in his 50s receiving immunomodulatory therapy for presumed Behçet's disease presented with odynophagia and jaw pain. Three months earlier, he had developed deep vein thrombosis and extensive superficial phlebitis with transmural inflammation on histopathology. Imaging revealed carotid artery vasculitis and unilateral inflammation around the temporal vessels. Ultrasound demonstrated wall thickening of the right temporal vein with normal temporal arteries. Persistent systemic inflammation and bicytopenia prompted bone marrow examination revealing myelodysplastic syndrome. Detection of a somatic UBA1 mutation confirmed VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). Glucocorticoids and interleukin-1 blockade were initiated. Due to severe cytopenia, the patient underwent allogeneic haematopoietic stem cell transplantation, resulting in clinical remission. VEXAS causes variable vessel vasculitis, affecting arteries and veins alike even without thrombosis. In older men with myelodysplasia or cytopenia, VEXAS should be considered in the differential of both venous and arterial vasculitis. Ultrasound may distinguish temporal phlebitis from giant cell arteritis.
2026-06-26 | Trisomy 8 clonal expansion during disease progression and azacitidine resistance in VEXAS syndrome: a case report.
Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an adult-onset autoinflammatory disorder driven by clonal hematopoiesis with somatic UBA1 mutations. Azacitidine can reduce the mutant clonal burden and improve inflammatory manifestations. However, the clonal basis of treatment resistance remains poorly understood. A 61-year-old man presented with predominant gastrointestinal symptoms, macrocytic anemia, thrombocytopenia, and systemic inflammation. A bone marrow examination revealed cytoplasmic vacuoles in myeloid precursors and trisomy 8. Retrospective genetic testing identified a somatic UBA1 p.Met41Val variant, thus establishing the diagnosis of VEXAS syndrome in this patient. At the time of referral and during immunosuppressive therapy with prednisolone and cyclosporine, the UBA1 variant allele frequency was consistently higher than the trisomy 8 burden, although relapse coincided with an expansion of trisomy 8. Azacitidine reduced the clonal burdens of both the UBA1 mutation and trisomy 8. However, both persisted at similar levels, and after 21 cycles, the disease progressed to myelodysplastic syndrome with increased blasts-2, accompanied by concordant re-expansion of UBA1-mutated and trisomy 8 clones. These findings suggest that a trisomy 8 subclone likely emerged within a UBA1-mutated founder clone and expanded during treatment, whereas the disomy 8 fraction of the UBA1-mutated clone was preferentially eliminated by azacitidine. Urgent cord blood transplantation resulted in sustained clinical and molecular remission. This case suggests that trisomy 8 may contribute to disease progression and azacitidine resistance in VEXAS syndrome.
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2025-09-22 | Comparative Efficacy and Safety of Anakinra and Canakinumab in Patients With VEXAS Syndrome: An International Multicenter Study.
The aim of this study was to compare differences in clinical response, drug survival, and adverse event rates between anakinra and canakinumab in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. This multicenter international study includes patients with VEXAS from France, Israel, and Italy treated with interleukin-1 inhibition. Global response (GR) was defined as the absence of inflammatory symptoms and ≥50% decrease in steroid dose and C-reactive protein. Multiple regression analysis was performed to identify associated variables. Drug survival was analyzed using Kaplan-Meier plots and log-rank test, with Cox regression models for associated factors. We included 47 male patients with VEXAS; 44 received anakinra and 9 received canakinumab, with 6 patients using both at different time points. GR at 1 month was 34% for anakinra and 100% for canakinumab (P < 0.001) and 22% and 78% at 3 months, respectively (P = 0.001). Treatment with canakinumab was associated with a higher odds ratio (OR) of achieving GR at 3 months (OR 28.8, 95% confidence interval 3.0-273.9; P = 0.004) in a multivariable analysis. Median drug survival was 54 (interquartile range [IQR] 30-56) months for canakinumab at 300 mg/month compared with 7 (IQR 4-8) months for canakinumab 150 mg/month and 1 (IQR 1-2.5) months for anakinra (P = 0.01). Injection-site reactions were only recorded for the anakinra group (47 vs 0%; P = 0.006), whereas infections were more frequent in the anakinra group (31% and 11%; P = 0.3). Canakinumab demonstrated superior clinical response and drug survival with fewer adverse events compared with anakinra. Monthly canakinumab 300 mg may be considered as an effective steroid-sparing therapeutic option for patients with VEXAS.
2025-09-19 | VEXAS anemia is a mosaic erythroblastopenia
VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently discovered autoinflammatory disorder linked to somatic mutations in the UBA1 gene, resulting in a profound cytoplasm-restricted defect in ubiquitylation. The disease is characterized by a macrocytic anemia that remains poorly understood. To investigate the erythroid lineage in VEXAS, we conducted a comprehensive study combining in vivo assessments of patients' mature red cells and marrow erythroblasts, alongside in vitro base-editing models of erythropoiesis. Here we show that mature red cells do not exhibit ubiquitylation defects, and patient-derived bone marrow erythroblasts lack UBA1 mutations beyond the basophilic stage of erythroid differentiation. In vitro base editing of UBA1 variants in CD34+ primary cells resulted in high mortality during early erythroid differentiation, but not during monocytic differentiation. Edited erythroid precursors displayed TP53 overexpression linked to defective ubiquitylation and anomalies in ribosome biogenesis, reminiscent of Diamond-Blackfan anemia. We propose that VEXAS-associated anemia should be considered as a mosaic erythroblastopenia, where the severity of anemia is influenced by the quality and quantity of the UBA1-WT compartment. Our findings offer new insights into the physiopathology of VEXAS and may suggest new potential therapeutic options.
2025-04-15 | Disturbing immune homeostasis by neutrophil loss of Uba1 induces VEXAS-like autoinflammatory disease in mice
ABSTRACT Objective VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is an identified haemato-rheumatoid disease caused by somatic UBA1 mutations in hematopoietic stem cells. We report Uba1 loss in various mouse hematopoietic cell types leads to diverse effects, with approximately 70% Uba1 depletion in neutrophils inducing non-lethal VEXAS-like symptoms. Methods Using nine different Cre/flox-mediated conditional-knockout (CKO) models, we interrogated the phenotypes caused by hematopoietic loss of Uba1 . Neutrophil-specific depletion of Uba1 were validated and VEXAS-like phenotypes were examined. Results Uba1 loss in HSCs induces extensive hematopoietic cell death while in B or T cells, or megakaryocytes induces corresponsive cell death but these mutants appear normal. Uba1 loss in monocytes and neutrophils failed to induce cell death and the mutants are viable. Among the models, only Uba1 loss in neutrophils manifests autoinflammatory symptoms including increased counts and percentage of neutrophils, increased proinflammatory cytokines, vacuoles in myeloid cells and dermatitis. Residual Uba1 is about 30% in the mutant neutrophils, which manifest disturbed cellular hemostasis. Genetic loss of Morrbid partially mitigated the VEXAS-like symptoms. Conclusion Our study reveals diverse effects of Uba1 loss in hematopoietic cells and establishes a VEXAS-like murine model, facilitating understanding and potential treatments for this syndrome prevalent in aged men. HIGHLIGHTS WHAT IS ALREADY KNOWN ON THIS TOPIC VEXAS syndrome is a recently identified hematological and immunological disease prevalent in adult man but rarely in adult woman. Somatic mutations in the E1-enzyme encoding gene UBA1 in hematopoietic stem cells is the driver on the top of the genetic etiology of the disease. However, the major pathogenic cell type(s) for VEXAS syndrome has not been experimentally examined and mouse models recapitulating the disease are lacking. WHAT THIS STUDY ADDS Using nine different conditional-knockout (CKO) murine models, we interrogated the pleiotropic phenotypes caused by loss of the ubiquitin activation enzyme Uba1 in different hematopoietic cell types; Our results demonstrated that among the nine tested CKO mutants, only neutrophil loss of Uba1 results in VEXAS-like autoinflammatory disease; The VEXAS-like symptoms in the S100a8Cre-CKO mutant mice include: increased counts of white blood cells and neutrophils, increased percentage of neutrophils, increased serum level of proinflammatory cytokines (IL-1β, IL-6 and TNFα), observation of vacuoles, increased survival, and increased phagocytosis in mutant neutrophils; Pharmacological treatments with IL-1 inflammatory pathway inhibitors Anakinra or Canakinumab or genetic loss of the myeloid pro-survival regulator Morrbid partially mitigated the VEXAS-like symptoms in the S100a8Cre-CKO mutants; HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY The study reports a technical strategy of developing the murine models for VEXAS syndrome. In addition, the study dissects cellular and molecular mechanisms, especially the cell-type-dependent tolerance and pathogenicity of loss of function of Uba1 , for the occurrence of the autoinflammation diseases in mice. The study provides translational implications in etiology and potential treatment choices for the newly-identified haemato-rheumatoid syndrome in clinical management.
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2025-11-03 | Bone marrow microenvironment overlap between vexas and myelodysplastic syndrome demonstrated by targeted transcriptomic and artificial intelligence
Abstract Introduction: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is an inflammatory process that involves bone marrow (BM). Active inflammation is also a major feature of the microenvironment in the BM of patients with myelodysplastic syndrome (MDS). To explore the overlap between VEXAS and MDS, we used an artificial intelligence (AI) approach and compared the transcriptomic profile of the BM from VEXAS patients (N=59) with the BM from MDS patients (N=1021) and the BM of individuals without specific diagnostic abnormality or with CHIP (clonal hematopoiesis of indeterminate potential) (N=1030) (Normal). Methods: RNA was extracted from the bone marrow samples from patients with VEXAS (N=59), MDS (N=1030), and Normal (1030). The RNA was sequenced by next generation sequencing (NGS) using a targeted RNA panel of 1600 genes. Hybrid capture sequencing library preparation was used, and RNA was quantified using transcript per million (TPM). To compare between the three groups, we used the RNA expression levels in an AI model based on Bayesian statistics and random forest. Bayesian statistics were used to rank the genes that distinguish between groups, then random forest was used to establish the signatures that distinguish between the groups. Two thirds of the samples were used for training and one third was used for testing the models. Results: Using the AI model described above, the BM of patients with VEXAS was significantly different from normal. Only 8 genes (SF3A1, SMAD5, PRPF8, MCM3AP, NFYC, FGFR1OP, PPM1D, THRA) were adequate to distinguish VEXAS from normal with AUC of 0.910 (95% CI: 0.0867-0.953)(A). Except for PPM1D, all genes were at significantly higher levels in VEXAS while PPM1D expression was significantly lower in VEXAS. Three of the 8 genes are involved in RNA splicing and 3 in DNA damage repair. Of the tested 1600 genes, 453 genes showed significant (LogFDR <-3) difference in the level of expression between VEXAS and normal. In contrast, only 152 genes were significantly different (LogFDR <-3) between MDS and VEXAS. Using the same AI model, 40 genes were needed to distinguish VEXAS from MDS (AUC : 0.905, 95% CI: 0.0861-0.950)(B). All genes that were significantly abnormal in VEXAS as compared with normal were also significantly abnormal in MDS as compared with normal. The difference was in the same direction in that those with high expression in VEXAS vs. normal were also high in MDS vs. normal and vice versa. Conclusions: These findings suggest that while the presenting symptoms in VEXAS are systemic inflammatory processes involving lungs, skin, blood vessels, and joints, there are significant abnormalities in bone marrow microenvironment mimicking the abnormalities seen in MDS. The demonstration that changes in splicing and DNA repair gene are the major molecular abnormalities that distinguish VEXAS BM as compared to normal suggests that therapeutic approaches targeting these abnormalities may help in ameliorating the clinical manifestation of this disease.
2025-11-01 | 51 A Comprehensive Analysis of Clinical, Pathological, and Genetic Profiles of Indian Cohort of Patients with VEXAS Syndrome
Abstract The VEXAS syndrome is a recently recognized, acquired monogenic adult onset haemato-inflammatory syndrome defined by somatic mutations within the UBA1 gene. It is an acronym that stands for vacuoles, E1 enzyme, X-linked inheritance, autoinflammatory tendencies, and somatic mutations. It presents as a severe progressive disease displaying varied characteristics that bridge hematologic and rheumatologic domains. In this series, we describe nine cases of VEXAS syndrome diagnosed at our institute, marking the first report from the Indian Subcontinent. A comprehensive analysis was conducted on patients diagnosed over the past 4 years (2020–2024), documenting clinical presentations, pathological findings, genetic characteristics, and outcomes. The UBA1 gene region(Exons 2-3 and intervening intron) was amplified by PCR and sequenced bidirectionally using Big Dye terminator v1.1 kit (Applied Biosystems); sequencing was performed on the Spectrum Compact Capillary Electrophoresis System (Promega). Results A total of nine cases were identified from 53 patient blood samples sent to our institute for UBA1 gene mutation testing with clinical suspicion of VEXAS (9/53,16.9%). All the patients were males with an age range from 42-77 years. Prominent clinical characteristics noted were a history of fever (9), arthritis/ arthralgia (8), inflammatory skin lesions (5), vasculitis (4), ocular inflammatory conditions (5), relapsing polychondritis (5), unprovoked venous thrombosis (3) and ear chondritis (3). Persistent unexplained cytopenia was present in all the patients, manifesting as anemia (8, 6 of which were macrocytic), thrombocytopenia (3), and neutropenia (2). We documented three cases of VEXAS coexisting with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and monoclonal gammopathy (MGUS), with the SLE-associated case being the first reported in the literature. Bone marrow examination was performed on seven patients, all exhibiting dyshematopoietic features(100%). Further, all seven cases also showed cytoplasmic vacuolations in the hematopoietic precursors. UBA1 somatic mutations included p.Met41Thr (c. 122 T>C Exon 2) (67%), p.Met41Val (c.121 A>G Exon 2) (22%) and a rare variant of UBA1 mutation in acceptor splice site of Exon 3 (c. 118 G>C) (11%). Follow-up ranged from 12 to 120 months, with a mean overall survival (OS) of 35.6 months and 4 cases succumbed to the disease. On Kaplan–Meier analysis, p.Met41Val cases have significantly inferior OS, with the mean OS of 17 (95% CI 7.2–27.8) months; in p.Met41Thr cases, the OS was 100.8 (95% CI 53.2–148.4) months (p = 0.006). The clinicopathological features of our cohort align closely with the available literature. However, our study is unique in highlighting the need to consider VEXAS syndrome even in patients with SLE and RA. Additionally, we have reported a rare variant of UBA1 mutation, further contributing to the expanding genetic spectrum of the disease and emphasizing the necessity of aggressive treatment for cases with p.Met41Val mutation, given their poor prognosis.
2025-09-04 | UBA1-depleted neutrophils disrupt immune homeostasis and induce VEXAS-like autoinflammatory disease in mice
VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a haemato-rheumatoid disease caused by somatic UBA1 mutations in hematopoietic stem cells (HSCs). The pathogenic cell type(s) responsible for the syndrome are unknown and murine models recapitulating the disease are lacking. We report that loss of Uba1 in various mouse hematopoietic cell types resulted in pleiotropic consequences and demonstrate that murine mutants with about 70% loss of Uba1 in neutrophils induced non-lethal VEXAS-like symptoms. Depletion of Uba1 in HSCs induced extensive hematopoietic cell loss while depletion of Uba1 in B or T cells, or in megakaryocytes induced corresponsive cell death but these mutants appeared normal. Depletion of Uba1 in monocytes and neutrophils failed to induce cell death and the mutants were viable. Among the tested models, only depletion of Uba1 in neutrophils induced autoinflammatory symptoms including increased counts and percentage of neutrophils, increased proinflammatory cytokines, occurrence of vacuoles in myeloid cells, splenomegaly and dermatitis. Residual Uba1 was about 30% in the mutant neutrophils, which disrupted cellular hemostasis. Finally, genetic loss of the myeloid pro-survival regulator Morrbid partially mitigated the VEXAS-like symptoms. The established VEXAS-like murine model will assist understanding and treatment of the newly identified autoinflammatory syndrome prevalent among aged men.
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Drug Discovery Landscape
2 orphan drug designations for VEXAS syndrome.
2 orphan drug designations for VEXAS syndrome.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Momelotinib dihydrochloride | small molecules | EMA | GlaxoSmithKline Trading Services Limited | |
momelotinib | small molecules | FDA | GlaxoSmithKline |
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