VEXAS syndrome: is it more a matter of inflammation or hematopoietic clonality? A case series approach to diagnosis, therapeutic strategies and transplant management

Abstract

VEXAS syndrome is a complex hemato-inflammatory disorder, driven by somatic mutations in the UBA1 gene within hematopoietic precursor cells. It is characterized by systemic inflammation, rheumatological manifestations, and frequent association with myelodysplastic syndrome (MDS). We present a series of four VEXAS cases, all of which include concomitant MDS, each displaying distinct genetic signatures and clinical features at diagnosis, with a focus on their diagnostic and therapeutic implications. Our findings underscore the importance of extending UBA1 sequencing beyond exon 3 in cases with strong clinical suspicion. Given the rarity of non-canonical variants and the limited gene annotation, germline tissue control should be considered to differentiate somatic from germline mutations. Hematological management, including considerations for transplantation, was primarily guided by the Revised International Prognostic Scoring System (IPSS-R) for MDS due to the absence of a specific risk stratification system for VEXAS or therapy guidelines. A critical point of our discussion is the role of inflammation in the peri-transplant period; in one patient, the combination of disease-modifying antirheumatic drugs (DMARDs) and high-dose corticosteroids before transplant was crucial in controlling inflammation, resulting in a successful hematopoietic stem cell transplantation (HSCT). In contrast, uncontrolled inflammation contributed to the peri-transplant death of another patient. These cases highlight the importance of effective inflammation management in optimizing HSCT outcomes. Additionally, our study emphasizes the urgent need for specific management guidelines for VEXAS syndrome, including a comprehensive risk stratification system and optimal timing for transplantation.

Keywords: Exon 14; Hematopoietic cell transplant; Inflammation; UBA1; VEXAS syndrome.

Fig. 1

Bone marrow smear of Patient 1. The smear, examined at 10x magnification, showed hypercellularity (a). At 40x magnification, multilineage dysplasia was evident with a reduced erythroid series (b), mainly comprising dysplastic maturing erythroblasts. The granulocytic series was hyperplastic (b), with a left-shifted maturation curve. Cytoplasmic vacuoles were observed in erythroid and myeloid precursors (c, d, e). The blast count was estimated at 10–15%. Megakaryocytes exhibited significant dysplasia (d), with hypolobated and irregular nuclei (b)

Fig. 2

¹⁸FDG PET/CT imaging for the characterization of a pulmonary nodule in VEXAS syndrome. The examination demonstrated heterogeneous radiotracer uptake, characterized by a central area of hypometabolism within the irregular lesion located in the apical segment of the left lower lobe. Concurrently, diffuse hypermetabolic activity was observed in the bone marrow, accompanied by widespread and heterogeneous hepatosplenic uptake, without any distinct focal lesions identified

Fig. 3

Diagnostic flow-chart for VEXAS syndrome. Abbreviations: CRP, C-Reactive Protein; CS, corticosteroids; ddPCR, digital droplet PCR; DMARDs, disease-modifying antirheumatic drugs; ESR, erythrocyte sedimentation rate; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasms; MGUS, monoclonal gammopathy of unterminated significance; NGS, next-generation sequencing; WES, whole exome sequencing; WGS, whole genome sequencing

Fig. 4

Proposed management for VEXAS syndrome. Abbreviations: CS, corticosteroids; ESA, erythropoiesis-stimulating agent; EPO, erythropoietin; HMA, hypomethylating agent; IPSS-R, revised international; RBCs, red blood cells; prognostic score system; MDS, myelodysplastic syndrome