Spanish cohort of VEXAS syndrome: clinical manifestations, outcome of treatments and novel evidences about UBA1 mosaicism.

BACKGROUND: The vacuoles, E1-enzyme, X linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease (AID) due to postzygotic UBA1 variants. OBJECTIVES: To investigate the presence of VEXAS syndrome among patients with adult-onset undiagnosed AID. Additional studies evaluated the mosaicism distribution and the circulating cytokines. METHODS: Gene analyses were performed by both Sanger and amplicon-based deep sequencing. Patients' data were collected from their medical charts. Cytokines were quantified by Luminex. RESULTS: Genetic analyses of enrolled patients (n=42) identified 30 patients carrying UBA1 pathogenic variants, with frequencies compatible for postzygotic variants. All patients were male individuals who presented with a late-onset disease (mean 67.5 years; median 67.0 years) characterised by cutaneous lesions (90%), fever (66.7%), pulmonary manifestations (66.7%) and arthritis (53.3%). Macrocytic anaemia and increased erythrocyte sedimentation rate and ferritin were the most relevant analytical abnormalities. Glucocorticoids ameliorated the inflammatory manifestations, but most patients became glucocorticoid-dependent. Positive responses were obtained when targeting the haematopoietic component of the disease with either decitabine or allogeneic haematopoietic stem cell transplantation. Additional analyses detected the UBA1 variants in both haematopoietic and non-haematopoietic tissues. Finally, analysis of circulating cytokines did not identify inflammatory mediators of the disease. CONCLUSION: Thirty patients with adult-onset AID were definitively diagnosed with VEXAS syndrome through genetic analyses. Despite minor interindividual differences, their main characteristics were in concordance with previous reports. We detected for the first time the UBA1 mosaicism in non-haematopoietic tissue, which questions the previous concept of myeloid-restricted mosaicism and may have conceptual consequences for the disease mechanisms.

Prevalence of gout in the adult general population in Spain: Estimating the proportion of undiagnosed cases.

OBJECTIVE: To estimate the prevalence of gout in Spain. METHODS: Cross-sectional, population-based study of people aged 20 years or older. First, randomly selected individuals were contacted by telephone and rheumatic disease screening questionnaires were conducted. If the first screening was positive, medical records were then reviewed and/or a phone questionnaire was conducted by a rheumatologist, followed by an appointment if necessary. Newly diagnosed cases had to fulfil the ACR/EULAR 2015 criteria. To calculate the prevalence and its 95% CI, the sample design was taken into account and weighing was calculated according to age, sex and geographic origin. RESULTS: In all, 4916 individuals were included, 1361 had a positive screening result for gout (59 of them reported a prior diagnosis). Of these, 51 were classified as missing and 95 were classified as gout cases. An additional case was detected through a positive screening for fibromyalgia and Sjögren's syndrome, although a previous gout diagnosis was confirmed by a review of the medical records. Of the 96 gout cases, 31 (32%) were de novo diagnoses. The estimated weighted prevalence of gout was 2.4% (95% CI 1.95-2.95), with a higher prevalence in men (4.55% [95%CI 3.65-5.65]) than women (0.38% [95%CI 0.19-0.76]). CONCLUSION: EPISER2016 is the first population-based study to estimate the prevalence of gout in Spain. Undiagnosed patients accounted for a substantial proportion of cases, highlighting the need for population-approaches when estimating the prevalence of infra-diagnosed diseases. Reliable national approaches are key to obtaining accurate estimates of diseases to better aid healthcare and workforce planning.