Somatic mutations in UBA1 cause VEXAS (Vacuoles, E1 ubiquitin activating enzyme, X-linked, Autoinflammatory Somatic) syndrome, an adult-onset inflammatory disease with an overlap of hematologic manifestations. VEXAS syndrome is characterized by a high mortality rate and significant clinical heterogeneity. We sought to determine independent predictors of survival in VEXAS and to understand the mechanistic basis for these factors. We analyzed 83 patients with somatic pathogenic variants in UBA1 at p.Met41 (p.Met41Leu/Thr/Val), the start codon for translation of the cytoplasmic isoform of UBA1 (UBA1b). Patients with the p.Met41Val genotype were most likely to have an undifferentiated inflammatory syndrome. Multivariate analysis showed ear chondritis was associated with increased survival, while transfusion dependence and the p.Met41Val variant were independently associated with decreased survival. Using in vitro models and patient-derived cells, we demonstrate that p.Met41Val variant supports less UBA1b translation than either p.Met41Leu or p.Met41Thr, providing a molecular rationale for decreased survival. In addition, we show that these three canonical VEXAS variants produce more UBA1b than any of the six other possible single nucleotide variants within this codon. Finally, we report a patient, clinically diagnosed with VEXAS syndrome, with two novel mutations in UBA1 occurring in cis on the same allele. One mutation (c.121 A>T; p.Met41Leu) caused severely reduced translation of UBA1b in a reporter assay, but co-expression with the second mutation (c.119 G>C; p.Gly40Ala) rescued UBA1b levels to those of canonical mutations. We conclude that regulation of residual UBA1b translation is fundamental to the pathogenesis of VEXAS syndrome and contributes to disease prognosis.

VEXAS is caused by somatic mutations in UBA1 (UBA1mut) and characterized by heterogenous systemic auto-inflammation and progressive hematologic manifestations, meeting criteria for myelodysplastic syndrome (MDS) and plasma cell dyscrasias. The landscape of myeloid-related gene mutations leading to typical clonal hematopoiesis (CH) in these patients is unknown. Retrospectively, we screened 80 VEXAS patients for CH in their peripheral blood (PB) and correlated findings with clinical outcomes in 77. UBA1mutwere most common at hotspot p.M41 (median variant allele frequency/VAF = 75%). Typical CH mutations co-occurred with UBA1mut in 60% of patients, mostly in DNMT3A and TET2, and were not associated with inflammatory or hematologic manifestations. In prospective single-cell proteogenomic sequencing (scDNA), UBA1mutwas the dominant clone, present mostly in branched clonal trajectories. Based on integrated bulk and scDNA analyses, clonality in VEXAS followed two major patterns: with either typical CH preceding UBA1mutselection in a clone (Pattern 1), or occurring as an UBA1mutsubclone or in independent clones (Pattern 2). VAF in PB differed markedly between DNMT3A and TET2 clones (median VAF of 25% vs 1%). DNMT3A and TET2 clones associated with hierarchies representing patterns 1 and 2, respectively. Overall survival for all patients was 60% at 10 years. Transfusion-dependent anemia, moderate thrombocytopenia, and typical CH mutations, each correlated with poor outcome. In VEXAS, UBA1mut cells are the primary cause of systemic inflammation and marrow failure, being a new molecularly defined somatic entity associated with MDS. VEXAS-associated MDS is distinct from classical MDS in its presentation and clinical course.

The study rationale was to assess the performance of qualitative and semi-quantitative scoring methods for 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) assessment in large-vessel vasculitis (LVV). MethodsPatients with giant cell arteritis (GCA) or Takayasu's arteritis (TAK) underwent clinical and imaging assessment, blinded to each other, within a prospective observational cohort. FDG-PET-CT scans were interpreted for active vasculitis by central reader assessment. Arterial FDG uptake was scored by qualitative visual assessment using the PET vascular activity score (PETVAS) and by semi-quantitative assessment using standardized uptake values (SUV) and target-to-background ratios (TBR) relative to liver/blood activity. Performance of each scoring method was assessed by intra-rater reliability using the intra-class coefficient (ICC) and area under receiver-operator characteristic curves (AUC), using physician assessment of clinical disease activity and reader interpretation of vascular PET activity as independent reference standards. Wilcoxon signed-rank test was used to analyze change in arterial FDG uptake over time. ResultsNinety-five patients (GCA=52; TAK=43) contributed 212 FDG-PET studies. The ICC for semiquantitative evaluation [0.99 (range 0.98-1.00)] was greater than the ICC for qualitative evaluation [0.82 (range 0.56-0.93)]. PETVAS and TBR metrics were more strongly associated with reader interpretation of PET activity than SUV metrics. All assessment methods were

Objectives To assess whether data from FDG-PET should be incorporated into eligibility criteria for clinical trials in Takayasu’s arteritis (TAK). Methods The study was conducted in two parts. Part One was an international online survey among physicians with experience managing TAK to determine, using clinical vignettes, whether FDG-PET data influences decisions about enrolment in trials. Part Two used patient data from an observational cohort study in TAK to assess agreement regarding decisions about enrolment into trials, based on clinical assessment with and without incorporation of FDG-PET data. Results In Part One, 68 physicians responded to the survey. Most physicians had used FDG-PET to diagnose TAK (82%) or monitor disease activity (66%). In vignettes representing active clinical disease, FDG-PET findings increased physician confidence in disease assessment and reduced outlier assessments. The greatest variability in decisions regarding enrolment into trials was observed in vignettes representing constitutional symptoms alone and elevated acute phase reactants. In these cases, FDG-PET findings influenced decisions about enrolment and improved physician confidence. In multivariable models, FDG-PET findings were 1.29x more strongly associated with enrolment decisions compared with levels of acute phase reactants. In Part Two, incorporation of FDG-PET data significantly improved agreement about enrolment decisions between raters, (IRR = 0.68 [95%CI (0.67–0.69)] to IRR = 0.88 [95%CI 0.87–0.89]; p< 0.01). Conclusions Incorporation of FDG-PET data into assessment of TAK influences decisions about enrolment of patients into trials, improves physician confidence about clinical assessment, and could help reduce variability in study populations. Future trials in TAK should consider incorporating FDG-PET data into eligibility criteria.