VEXAS syndrome is an autoinflammatory disease of older adults caused by acquired mutations in the ubiquitin-activating enzyme UBA1. Standard treatment has not been established, and the prognosis is poor. Therefore, it is important to clarify the clinical characteristics, prognosis, and treatment status of patients in Japan and to develop prognostic factors and biomarkers. Since 2023, we have been conducting a nationwide prospective registry study supported by the Japan Agency for Medical Research and Development (AMED).
To investigate the 1-year outcomes after enrollment in the registry and to clarify the current clinical management of VEXAS syndrome in Japan.
From May 2023 to September 2025, patients suspected of having VEXAS syndrome were enrolled at participating institutions. Peripheral blood samples from all patients were sent to the Kazusa DNA Research Institute, where all exons of UBA1 were analyzed by next-generation sequencing. In patients diagnosed with VEXAS syndrome, clinical manifestations, UBA1 genotypes, treatments, disease activity assessed by the VEXAS Current Activity Form (VEXASCAF), C-reactive protein (CRP) levels, survival, and adverse events were prospectively evaluated every 3 months for 1 year. For patients followed for more than 1 year, the date of final observation was also recorded. In patients without UBA1 mutations, survival status at the final observation date was investigated.
As of September 2025, 130 patients with suspected disease had been enrolled from 36 institutions across Japan, and 66 of them were found to carry UBA1 mutations and were diagnosed with VEXAS syndrome. The median age was 74.0 years (range, 55-89), and all patients were male. The genotypes consisted of 27 Thr, 23 Leu, 11 Val, 4 splice variants, and 1 noncanonical variant. The median variant allele frequency (VAF) was 56.0%. As previously reported, the Leu genotype had a significantly higher VAF than the Val genotype. The median observation period was 343.0 days. By the final observation date, eight patients had died, and five had become transfusion dependent. Although VEXASCAF and CRP levels significantly decreased from baseline, no substantial change was observed from week 12 to week 48. Eleven patients (19%) fulfilled the complete remission criteria proposed by the French National VEXAS study group (FRENVEX) during follow-up. Glucocorticoid dose did not change from baseline to week 48. A total of 59 adverse events of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher were observed, affecting 50% of patients. After adjustment for the observation period from symptom onset, overall survival was better in patients with the Leu genotype than in those with other genotypes, consistent with previous overseas reports. Patients without UBA1 mutations had significantly worse survival than those with VEXAS syndrome.
This study clarified the current clinical characteristics and outcomes of patients with VEXAS syndrome in Japan.
