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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 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) assessment in large-vessel vasculitis (LVV). Methods: Patients 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. Results: Ninety-five patients (GCA=52; TAK=43) contributed 212 FDG-PET studies. The ICC for semi-quantitative 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 significantly associated with physician assessment of clinical disease activity, but the semi-quantitative metric TBRLiver¬ achieved the highest AUC (0.66). Significant but weak correlations with C-reactive protein were observed for SUV metrics (r = 0.19, p

The study rationale was to assess the performance of qualitative and semiquantitative scoring methods for (18)F-FDG PET assessment in large-vessel vasculitis. Methods: Patients with giant cell arteritis or Takayasu arteritis underwent independent clinical and imaging assessments within a prospective observational cohort. (18)F-FDG PET/CT scans were interpreted for active vasculitis by central reader assessment. Arterial (18)F-FDG uptake was scored by qualitative visual assessment using the PET vascular activity score (PETVAS) and by semiquantitative assessment using SUVs and target-to-background ratios (TBRs) relative to liver or blood activity. The performance of each scoring method was assessed by intrarater reliability using the intraclass correlation coefficient (ICC) and areas under the receiver-operating-characteristic curve, applying physician assessment of clinical disease activity and reader interpretation of vascular PET activity as independent reference standards. The Wilcoxon signed-rank test was used to analyze change in arterial (18)F-FDG uptake over time. Results: Ninety-five patients (giant cell arteritis, 52; Takayasu arteritis, 43) contributed 212 (18)F-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 target-to-background ratio metrics were more strongly associated with reader interpretation of PET activity than SUV metrics. All assessment methods were significantly associated with physician assessment of clinical disease activity, but the semiquantitative metric liver tissue-to-background ratio (TBR(Liver)) achieved the highest area under the receiver-operating-characteristic curve (0.66). Significant but weak correlations with C-reactive protein were observed for SUV metrics (r = 0.19, P < 0.01) and TBR(Liver) (r = 0.20, P < 0.01) but not for PETVAS. In response to increased treatment in 56 patients, arterial (18)F-FDG uptake was significantly reduced when measured by semiquantitative (TBR(Liver), 1.31–1.23; 6.1% change; P < 0.0001) or qualitative (PETVAS, 22–18; P < 0.0001) methods. Semiquantitative metrics provided information complementary to qualitative evaluation in cases of severe vascular inflammation. Conclusion: Both qualitative and semiquantitative methods of measuring arterial (18)F-FDG uptake are useful in assessing and monitoring vascular inflammation in large-vessel vasculitis. Compared with qualitative metrics, semiquantitative methods have superior reliability and better discriminate treatment response in cases of severe inflammation.