Comment on: Efficient detection of somatic UBA1 variants and clinical scoring system predicting patients with variants in VEXAS syndrome: reply

Dear Editor, We would like to respond to the comments made by Rogez et al. [1] about our recent article [2]. Their study using a cohort of patients with suspected VEXAS (vacuoles, E1-enzyme, X-linked, autoinflammatory, somatic) syndrome provides insightful data that support the validity of our scoring system and demonstrate a change in scores over time. In this reply, we describe the concept of using our scoring system for the genetic diagnosis of VEXAS syndrome.

Rogez et al. validated our scoring system using their cohort, and achieved a higher score in the VEXAS group over the entire disease course, including at the first visit, and relatively high scores for the area under the receiver operating characteristic curves (ROC-AUC) in a group of cases with a sufficient observation period (after 12–18 months of follow-up). In such cases achieving high scores with our system, VEXAS syndrome should be strongly considered.

A point to note, they clarified that patients with or without UBA1 variants in the early stages of disease showed lower scores compared with those 18 months after. That is, as we originally anticipated [2], the diagnostic performance of our scoring system was shown by Rogez et al. to be inferior in patients in the early stages of disease. In the 40 UBA1-positive cases in our analysis [2], only a few cases were referred in the early stages of disease [9/40 (22.5%) cases were evaluated within 12 months of disease onset], and the median duration of time from the onset of symptoms to genetic diagnosis was 38.6 months (interquartile range, 17.2–61.7 months), with most cases referred after the development of apparent manifestations. This compares with the median duration of 22.0 months (interquartile range, 14.3–66.7 months) in 49 UBA1-negative cases. Although the study by Rogez et al. included only a small cohort of VEXAS patients at a single facility, we believe that their results, based on serial observations from the early stages of disease, are reliable. Therefore, this suggests that cases in the early post-onset period with a low score may need repeated score assessments during their disease course. In this context, our scoring system only includes elements to be easily assessed in outpatient settings, so that bone marrow examinations and intensive genetic testing can be planned for the definitive diagnosis for VEXAS syndrome.

The clinical presentations of VEXAS syndrome are quite diverse, and the early symptoms are non-specific. Therefore, even if VEXAS syndrome is suspected, differential diagnoses and the assessment of comorbidities are initially very important. Though early diagnosis is desirable, short-term observation of the clinical course may also aid diagnosis in cases progressing over a short period, and we propose that the elements of our scoring system could serve as focal points during follow-up periods. Interestingly, recent reports show that cases with UBA1 variants other than within exon 3 have a slightly different phenotype from those with UBA1 exon 3 variants [3, 4], and the validity of our scoring system in such cases should also be examined. Therefore, in the coming years, the determination of disease onset and diagnostic strategies in patients in the early phase of disease and/or with low scores should be carefully investigated.

Gene panel testing would be a standard method for the diagnosis of autoinflammatory diseases, including those with variants in UBA1 (in exon 3 and other regions) and other genes. As shown in our recent paper [2], targeted sequencing where variant allele frequencies exceed 3% has detection limits, so panel-negative patients with high scores or those whose scores gradually increase during their clinical course should undertake more specific genetic tests, such as peptide nucleic acid-clamping PCR or digital PCR. Our scoring system is intended to help determine whether such intensive genetic examinations should be considered, and we believe that high-specificity examination would be powerful in appropriate cases, even after gene panel testing.

Data availability

The datasets used and analysed during the current study are available from the corresponding author upon reasonable request.

Funding

This work was supported by the Japan Agency for Medical Research and Development (AMED) (grant numbers JP23ek0109674, JP23ek0109549, JP23ek0109617, JP23ek0109648) (to N.M.); the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant-in-Aid for Scientific Research (C) [grant numbers JP23K07229 (to Y.U.), JP23K15353 (to N.T.)]; and the Takeda Science Foundation (to N.M.).

Disclosure statement: The authors have declared no conflicts of interest.

References

Author notes