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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.

ObjectiveRelapsing polychondritis (RP) is a systemic inflammatory disease of unknown etiology. The study objective was to examine the contribution of rare genetic variations in RP.MethodsWe performed a case-control exome-wide rare variant association analysis including 66 unrelated European American RP cases and 2923 healthy controls. Gene-level collapsing analysis was performed using Firth’s logistics regression. Pathway analysis was performed on an exploratory basis with three different methods: Gene Set Enrichment Analysis (GSEA), sequence kernel association test (SKAT) and higher criticism test. Plasma DCBLD2 levels were measured in patients with RP and healthy controls using enzyme-linked immunosorbent assay (ELISA).ResultsIn the collapsing analysis, RP was associated with higher burden of ultra-rare damaging variants in theDCBLD2gene (7.6% vs 0.1%, unadjusted odds ratio = 79.8, p = 2.93 x 10-7). Patients with RP and ultra-rare damaging variants inDCBLD2had a higher prevalence of cardiovascular manifestations. Plasma DCBLD2 protein levels were significantly higher in RP than healthy controls (5.9 vs 2.3, p < 0.001). Pathway analysis showed statistically significant enrichment of genes in the tumor necrosis factor (TNF) signaling pathway driven by rare damaging variants inRELB,RELAandRELusing higher criticism test weighted by degree and eigenvector centrality.ConclusionsThis study identified specific rare variants inDCBLD2as putative genetic risk factors for RP. Genetic variation within the TNF pathway is also potentially associated with development of RP. These findings should be validated in additional patients with RP and supported by future functional experiments.

Somatic mutations in UBA1 cause vacuoles, E1 ubiquitin-activating enzyme, X-linked, autoinflammatory somatic (VEXAS) 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, whereas 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 3 canonical VEXAS variants produce more UBA1b than any of the 6 other possible single-nucleotide variants within this codon. Finally, we report a patient, clinically diagnosed with VEXAS syndrome, with 2 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 coexpression 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.

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.