Faculty Bibliography
Searched for:
in-biosketch:true
person:db1510
Total Results:
93
American College of Rheumatology Guidance Statement for Diagnosis and Management of VEXAS Developed by the International VEXAS Working Group Expert Panel
OBJECTIVE:Vacuoles E1 enzyme X-linked autoinflammatory somatic syndrome (VEXAS) is a recently identified rare genetic disorder associated with somatic mutations in the UBA1 gene. VEXAS presents with a combination of inflammatory and hematologic manifestations, leading to increased morbidity and mortality. METHODS:Given the variability in disease presentation and the limited number of studies to date, no clinical documents currently exist to provide guidance to health care providers about the management of VEXAS. To address this gap, we formed an international multidisciplinary panel of VEXAS experts. RESULTS:Through formalized meetings and a voting process, the group developed consensus clinical guidance considerations for the management of VEXAS. These considerations offer practical advice on several key topics: (1) clinical features of VEXAS, (2) UBA1 screening methods, (3) the diagnosis of myelodysplastic syndromes (MDSs) in patients with VEXAS, and (4) prognosis and management. The aim is to provide expert guidance on which patients to test, how to test for VEXAS, how to approach MDS in the context of VEXAS, and considerations for management. CONCLUSION/CONCLUSIONS:This work marks the first formal international consensus guidance for VEXAS and is intended to be used as a resource for clinicians seeking to understand the disease and its management.
PMID: 40787890
ISSN: 2326-5205
CID: 5906872
Clinical features in VEXAS syndrome: a systematic review
OBJECTIVE:To systematically characterize the complete phenotypic spectrum of VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome through comprehensive analysis of all published cases since its discovery in 2020. METHODS:We conducted a systematic review following PRISMA guidelines across five databases. Studies reporting genetically confirmed VEXAS cases were included. To minimize duplicate counting while maximizing data utility, we applied stringent inclusion criteria. Prevalence estimates were calculated using Wilson score intervals. Results were discussed, with secondary analysis focusing on rare manifestations of the disease, and clinical recommendations as appropriate. RESULTS:Analysis of 720 patients from 33 case reports and 21 case series across 32 countries revealed cutaneous involvement as the predominant manifestation (81.8%, 95% CI: 78.8-84.5%), followed by constitutional symptoms (69.4%, 95% CI: 66.0-72.7%) and respiratory disease (61.3%, 95% CI: 57.6-64.7%). Joint involvement (47.3%, 95% CI: 43.5-51.2%), ocular disease (44.3%, 95% CI: 40.5-48.2%) and venous thromboembolism (41.8%, 95% CI: 38.3-45.4%) were also common. Myelodysplastic syndrome occurred in 35.8% (95% CI: 32.3-39.4%) of patients. Previously under-recognized manifestations included significant respiratory involvement and a broad spectrum of vascular complications. Rare but clinically significant features included cardiac involvement (7.6%), renal disease (7.0%) and CNS manifestations (7.8%). CONCLUSION:This systematic review provides the most comprehensive characterization of VEXAS syndrome to date, establishing robust prevalence estimates across all organ systems and identifying rare manifestations with important clinical implications. These findings will facilitate earlier diagnosis, inform monitoring strategies and guide future research priorities.
PMCID:12494223
PMID: 40570089
ISSN: 1462-0332
CID: 6072047
Type I interferon-mediated autoinflammation in two unrelated patients due to a proximal intronic splice site variant in DNASE2
PURPOSE/UNASSIGNED:splice site variant in two unrelated patients. METHODS/UNASSIGNED:We performed exome and RNA sequencing to identify and validate variants. A minigene assay assessed splicing effects. DNase II activity was tested in cell lysates. Structural modeling, cytokine profiling, and immune stimulation assays were conducted to evaluate pathway activation and therapeutic response. RESULTS/UNASSIGNED:variant that reduced USP43 expression and enhanced IFN signaling. Both patients showed increased JAK-STAT activation and responded clinically to JAK1/2 inhibition with ruxolitinib. CONCLUSION/UNASSIGNED:associated with DNase II deficiency and type I interferon-mediated autoinflammation. Our findings expand the genotypic and phenotypic spectrum of this disorder, highlight the role of intronic variants in rare immune diseases, and support JAK inhibition as a targeted treatment approach.
PMCID:12747285
PMID: 41472683
ISSN: 2693-5015
CID: 6072049
Rapid clinical deployment of UBA1 testing in patients with VEXAS syndrome
OBJECTIVE:VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a recently described autoinflammatory syndrome caused by pathogenic variants in UBA1. However, there is a dearth of widely available UBA1 testing aside from large, expensive sequencing studies. Thus, we sought to rapidly develop, validate, and clinically deploy a cost-effective assay for detecting the most common UBA1 variants. METHODS:We developed, validated, and implemented a single base extension mass spectrometry assay for detecting pathogenic UBA1 variants at the c.121, c.122, and c.118-1 positions in patients with suspected VEXAS syndrome. Assay performance characteristics were assessed using peripheral blood and bone marrow samples from patients with (n = 8) and without (n = 36) VEXAS. RESULTS:The assay demonstrated a lower limit of detection (LOD) of 10% variant allele fraction for each mutation. The analytical accuracy, sensitivity, and specificity were each demonstrated to be 100% at the LOD, with excellent intra- and interrun reproducibility. Based on literature review of reported UBA1 variants associated with VEXAS, to date, this assay detects the most prevalent variants, with a clinical sensitivity of 97% or more. CONCLUSIONS:A cost-effective, mass spectrometry-based assay with high analytical and clinical performance can feasibly be implemented in hospital laboratories for diagnosis of VEXAS syndrome.
PMCID:13016694
PMID: 40418703
ISSN: 1943-7722
CID: 6072063
Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies
Neurodevelopmental proteasomopathies are a group of disorders caused by variants in proteasome subunit genes, that disrupt protein homeostasis and brain development through poorly characterized mechanisms. Here, we report 26 distinct variants in PSMC5, encoding the AAA⁺ ATPase subunit PSMC5/RPT6, in individuals with syndromic neurodevelopmental conditions. Combining genetic, multi-omics and biochemical approaches across cellular models and Drosophila, we unveil the essential role of proteasomes in sustaining key cellular processes. Loss of PSMC5/RPT6 function impairs proteasome activity, leading to protein aggregation, disruption of mitochondrial homeostasis, and dysregulation of lipid metabolism and immune signaling. It also compromises synaptic balance, neuritogenesis, and neural progenitor cell stemness, causing deficits in higher-order functions, including learning and locomotion. Pharmacological targeting of integrated stress response kinases reveals a mechanistic link between proteotoxic stress and spontaneous type I interferon activation. These findings expand our understanding of proteasome-dependent quality control in neurodevelopment and suggest potential therapeutic strategies for neurodevelopmental proteasomopathies.
PMCID:12658096
PMID: 41298377
ISSN: 2041-1723
CID: 5968482
Characterizing VEXAS syndrome in women: Findings from an international multicenter study
BACKGROUND:VEXAS syndrome is an autoinflammatory disease caused by somatic UBA1 mutations on the X chromosome, predominantly affecting men. OBJECTIVE:To characterize VEXAS syndrome in women and to compare the features of VEXAS syndrome between sexes. METHODS:We conducted an international, multicenter study, including 12 women and 301 men with genetically confirmed VEXAS syndrome. Data were collected using a standardized case report form. Bone marrow analyses and molecular investigations were performed locally. RESULTS:Clinical features, age at onset, UBA1 mutation type, variant allele frequency, and mortality were comparable between sexes. Acquired X monosomy was found in 6/8 tested women. Additional clonal mutations were present in 3/5 tested women. Three additional UBA1-mutated women without typical inflammation are described separately. CONCLUSION/CONCLUSIONS:VEXAS syndrome affects women with clinical features similar to men, supporting the need for UBA1 testing in women with compatible presentations. X monosomy is common but not universal, suggesting alternative pathogenic mechanisms.
PMID: 40985189
ISSN: 1365-2796
CID: 5954262
Distinct characteristics of VEXAS-causative UBA1 M41 and recurrent functional non-M41 mutations
VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a severe inflammatory and hematologic disease caused by somatic mutations in UBA1. Canonical pathogenic mutations at UBA1 p.Met41 (M41) lead to the loss of the cytoplasmic isoform (UBA1b), while non-canonical mutations outside of M41 (non-M41) result in reduced activity of both nuclear and cytoplasmic isoforms. Studies have reported clinical differences between canonical and non-canonical mutations, but these findings are constrained by small sample sizes and scarcity of genetic studies. In our study, we screened 29,000 individuals for UBA1 variants, referred for a broad range of hematologic diseases, and subjected to 62-gene panel sequencing, identifying 232 patients carrying likely disease-causing mutations. We identified decreased polyubiquitylation in all of the 18 UBA1 variants tested and found differences in H2A/B monoubiquitylation alteration between M41 and non-M41 mutations. Our findings confirm that patients harboring M41 mutations present at most with myelodysplastic neoplasms (MDS) and suggest that M41 mutations generally do not tolerate multiple co-mutations. In contrast, non-M41 mutations are more likely to appear with co-mutations and are detected in patients with hematologic neoplasms other than MDS. Our study establishes that M41 and non-M41 mutations exhibit distinct clinical and biological phenotypes, significantly enhancing UBA1 variant interpretation.
PMID: 41068485
ISSN: 1476-5551
CID: 5952272
Mapping the infectious burden in VEXAS syndrome: a systematic review and rationale for prevention
Infections are increasingly recognised as a major cause of morbidity and mortality in patients with vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. We conducted a systematic review to characterise the infectious burden of VEXAS syndrome and propose preventive strategies. We included 57 studies (813 patients) showing that infections in patients with VEXAS syndrome were frequent, severe in 40-60% of cases, and fatal in 6-15% of cases. Pulmonary infections were most common, followed by cutaneous infections and bacteraemia. Opportunistic pathogens, such as Pneumocystis jirovecii, Legionella pneumophila, non-tuberculous mycobacteria, and varicella zoster virus, were frequently reported, even in patients not receiving immunosuppressive therapy, which suggests intrinsic immune dysfunction. Prophylaxis with co-trimoxazole (or other Pneumocystis prophylaxis, such as atovaquone or pentamidine) and valaciclovir should particularly be considered for patients at high risk of infection, including those receiving immunosuppressive therapy and those with lymphopenia, pMet41Val mutation, or previous severe or recurrent infections. Posaconazole might be appropriate in patients with neutropenia who are taking azacitidine. Vaccination against Streptococcus pneumoniae, varicella zoster virus, influenza, and SARS-CoV-2 is recommended. These data highlight the need to integrate infectious risk into VEXAS syndrome management and to evaluate preventive strategies in prospective studies.
PMID: 40915301
ISSN: 2665-9913
CID: 5937582
Clonal dominance: mutations in VEXAS syndrome take advantage of inflammation
PMID: 40481273
ISSN: 1759-4804
CID: 5862962
Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome: A comprehensive review of cases across different ethnicities
OBJECTIVES/OBJECTIVE:Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) is an autoinflammatory disease associated with somatic mutations in the UBA1 gene. Although the disease has been described in many different countries, no studies have investigated the origin of patients to determine if the disease is universal across ancestries. The aim of this study is to investigate the distribution of VEXAS syndrome across continents and ethnicities. METHODS:A literature review of all reported cases of VEXAS syndrome was conducted between October 2020 and April 2025 using the term 'VEXAS' with the all-field filter in the Pubmed and Web of Science databases. Epidemiological and clinical data were collected for included patients. If the country of origin was not described, it was assumed to be the same as the country of clinical evaluation. A subgroup analysis was performed for patients whose country of origin or ethnicity was documented by the authors. RESULTS:674 cases of VEXAS syndrome were collected, with patients described from four continents and 32 countries. Considering the subgroup of patients with documented country of origin, 451 patients were from four continents and 19 countries. Of these, ethnicity was recorded for 372 patients with the presence of Caucasian, Central or East Asian, South Asian, Middle Eastern, Central American and South American ethnicities. CONCLUSION/CONCLUSIONS:The results support a broad global distribution of the disease and highlight the importance of investigating the disease regardless of the patient's origin and ethnicity in cases of compatible symptoms.
PMID: 40441957
ISSN: 1879-0828
CID: 5854412
