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

Abstract

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.

Keywords: immune system diseases; inflammation; polymorphism, genetic.

Figure 1

Cutaneous lesions and cytosolic vacuoles in patients (Pt) with vacuoles, E1-enzyme, X linked, autoinflammatory and somatic syndrome. (A) Multiple erythematous papules on the chest and neck (Pt 10). (B) Erythematous and edematous plaques, and a few papules on the chest and neck (Pt 10). (C) Urticaria-like lesions on the abdomen (Pt 22). (D) Livedo racemosa (Pt 22). (E) Ear chondritis (Pt 22). (F, G, H) Cytosolic vacuoles in myeloid precursor cells in bone marrow aspirate from Pt 3.

Figure 2

Amplicon-based deep sequencing (ADS) of UBA1 gene in patients (Pt) with vacuoles, E1-enzyme, X linked, autoinflammatory and somatic syndrome. (A) ADS results obtained using DNA samples extracted from haematopoietic tissues. (B) Comparative results of ADS analyses using DNA samples extracted from haematopoietic tissues and non-haematopoietic tissues (nails). Columns represent the mean value of three independent experiments, and the error bars, the SD. MAF, mutant allele frequency.

Figure 3

Analytical results during treatment with the hypomethylating drug decitabine in patient 9. Evolution of mutant allele frequency of UBA1 gene (A), erythrocyte sedimentation rate (ESR) (B), haemoglobin concentration (C), mean corpuscular volume (MCV) (D) and leucocytes (E) and platelet (F) counts before and after treatment. Blue and red arrows indicate the different cycles of treatment with azacytidine and decitabine, respectively. The horizontal dotted red lines indicate the normal reference range for each parameter, and the blue rectangle indicates treatment with decitabine.

Figure 4

Reversal of analytical abnormalities after HLA-matched related allogeneic haematopoietic stem cell transplantation (allo-HSCT) in patient 10. Evolution of mutant allele frequency of UBA1 gene (A), erythrocyte sedimentation rate (ESR) (B), haemoglobin concentration (C), mean corpuscular volume (MCV) (D) and leucocytes (E) and platelet (F) counts before and after allo-HSCT. The horizontal dotted red lines indicate the normal reference range for each parameter, and the blue rectangle indicates the post-allo-HSCT period. WBC, white blood cell.