#2-06E. The VEXAS Spectrum: Unpacking Clinical Heterogeneity by UBA1 Variant Allele Frequency (Arthritis Rheum, 2025)

How does the somatic mutation burden in the UBA1 gene influence the clinical presentation of VEXAS syndrome, a progressive autoinflammatory disorder? This study addresses this question by analyzing whole exome sequencing data from 192,584 individuals, examining the link between UBA1 variant allele frequency (VAF) and disease manifestations. The authors identified 23 participants with pathogenic variants and found that higher VAF was associated with increased disease severity and penetrance. The most critical clinical point is that cases with a high VAF (>20%) developed macrocytic anemia significantly more often than those with a low VAF (≤20%), suggesting VAF could serve as a prognostic marker. However, a key limitation is the lack of longitudinal VAF measurements, which makes it unclear how a rising mutation level directly impacts symptom development over time. For clinicians, this research is crucial as it highlights that individuals with low VAF may initially be asymptomatic or present with milder symptoms, yet can develop clinically relevant disease years later, underscoring the need for careful long-term monitoring in these patients.

Citation: Anderson, M, et al. Clinical Manifestations of VEXAS Syndrome Across a Broad Spectrum of UBA1 Mutation Burden. Arthritis & Rheumatology. 2025. DOI: 10.1002/art.43327.

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