Adult-onset autoinflammation caused by somatic mutations in UBA1: A Dutch case series of patients with VEXAS.

BACKGROUND: A novel autoinflammatory syndrome was recently described in male patients who harbored somatic mutations in the X-chromosomal UBA1 gene. These patients were characterized by adult-onset, treatment-refractory inflammation with fever, cytopenia, dysplastic bone marrow, vacuoles in myeloid and erythroid progenitor cells, cutaneous and pulmonary inflammation, chondritis, and vasculitis, which is abbreviated as VEXAS. OBJECTIVE: This study aimed to (retrospectively) diagnose VEXAS in patients who had previously been registered as having unclassified autoinflammation. We furthermore aimed to describe clinical experiences with this multifaceted, complex disease. METHODS: A systematic reanalysis of whole-exome sequencing data from a cohort of undiagnosed patients with autoinflammation from academic hospitals in The Netherlands was performed. When no sequencing data were available, targeted Sanger sequencing was applied in cases with high clinical suspicion of VEXAS. RESULTS: A total of 12 male patients who carried mutations in UBA1 were identified. These patients presented with adult-onset (mean age 67 years, range 47-79 years) autoinflammation with systemic symptoms, elevated inflammatory parameters, and multiorgan involvement, most typically involving the skin and bone marrow. Novel features of VEXAS included interstitial nephritis, cardiac involvement, stroke, and intestinal perforation related to treatment with tocilizumab. Although many types of treatment were initiated, most patients became treatment-refractory, with a high mortality rate of 50%. CONCLUSION: VEXAS should be considered in the differential diagnosis of males with adult-onset autoinflammation characterized by systemic symptoms and multiorgan involvement. Early diagnosis can prevent unnecessary diagnostic procedures and provide better prognostic information and more suitable treatment options, including stem cell transplantation.

Impaired fasting glucose is associated with increased arterial stiffness in elderly people without diabetes mellitus: the Rotterdam Study.

OBJECTIVES: To study the association between impaired fasting glucose (IFG) and arterial stiffness in older adults. DESIGN: Cross-sectional population-based study. SETTING: The Rotterdam Study, a Dutch population-based cohort study. PARTICIPANTS: Two thousand nine hundred eighty-seven subjects aged 60 and older. MEASUREMENTS: Arterial stiffness assessed by measuring common carotid arterial distensibility and glucose status classified into three categories: normal fasting glucose (NFG) (fasting glucose <6.1 mmol/L), IFG (fasting glucose 6.1-6.9 mmol/L), and diabetes mellitus (DM). RESULTS: In the total cohort, common carotid distensibility decreased with increasing impairment of glucose metabolism. Subjects younger than 75 with IFG were comparable with subjects with NFG with respect to arterial stiffness. Subjects aged 75 and older with IFG had stiffer arteries than subjects with NFG, reaching the same arterial stiffness as subjects with DM. For subjects younger than 75, mean difference in distensibility coefficient between subjects with NFG and with IFG was 0.1 (95% confidence interval (CI)=-0.04-0.05, P=.88) and between subjects with NFG and with DM was 1.2 (95% CI=0.7-1.7, P<.001). For subjects aged 75 and older, the mean difference between these groups was 0.7 (95% CI=0.2-1.2, P=.007) and 0.8 (0.3-1.4; P=.002), respectively. In the total cohort, fasting glucose was strongly associated with carotid distensibility (beta-coefficient=-0.29, P<.001). CONCLUSION: IFG is related to arterial stiffness in elderly subjects. An advanced stage of arterial stiffness, comparable with that of subjects with DM, is only reached at the age of 75.