VEXAS syndrome

Abstract

VEXAS syndrome is a recently identified, adult-onset autoinflammatory disease caused by somatic mutations in UBA1. UBA1 is an X-linked gene encoding E1 ubiquitin activating enzyme and its mutation in hematopoietic stem and progenitor cells leads to their clonal expansion and myeloid-skewed differentiation. UBA1 mutations in VEXAS are clustered at the second methionine (p.Met41), eliminating UBA1b isoform translated from p.Met41. Loss of UBA1b impairs ubiquitination and activates innate immune pathways, leading to systemic autoinflammation manifested as recurrent fever, chondritis, pulmonary involvement, vasculitis, or neutrophilic dermatitis. VEXAS syndrome is frequently associated with hematological disorders such as myelodysplastic syndrome (MDS), plasma cell dyscrasia and venous thromboembolism. Macrocytic anemia/macrocytosis and vacuoles in myeloid/erythroid precursors are prominent features of VEXAS syndrome, and their presence in patients with autoinflammatory symptoms prompts physicians to screen for UBA1 variant. Treatment of VEXAS syndrome is challenging and no consistently effective therapies have been established. Anti-inflammation therapies including glucocorticoids and anti-interleukin-6 have shown limited efficacy, while azacytidine and JAK inhibitors such as ruxolitinib were found to induce favorable, mid-term responses. Hematopoietic stem cell transplantation is the only curative option for VEXAS and should be considered for younger, fit patients with poor prognostic factors or recalcitrant symptoms.

Keywords: Inflammation; Myelodysplastic syndrome; UBA1; VEXAS syndrome.

Fig. 1

Structure and variants of UBA1 gene. A Structure of UBA1 and its three isoforms. UBA1 consists of five functional domains: inactive adenylation domain [IAD], first catalytic cysteine half domain [FCCH], active adenylation domain [AAD], second catalytic cysteine half domain [SCCH], and ubiquitin fold domain [UFD]. IAD and AAD adenylate the first ubiquitin, and transfer ubiquitin to the catalytic cysteine domains to form a thioester bond. UBA1a preferentially localizes in nucleus due to the nuclear localization signal (NLS) at the N-terminus, while UBA1b and UBA1c are cytoplasmic. B Reported variants of UBA1 in VEXAS syndrome. Orange or green stars show co-existence of two missense variants in the same patient.

Fig. 2

Morphology of hematopoietic cells in VEXAS patients. Representative images of PB and BM smears (adopted from Kunimoto, et al. Int J Hematol 118:494–502, 2023 [41]). A Macrocytic anemia in PB. B Megakaryocytic dysplasia. Upper panel; micromegakaryocyte. Lower panel; multinucleation of megakaryocytes. C Myeloid and erythroid dysplasias. Upper left; Pseudo-Pelger-Huët anomaly. Upper right; decreased granulation of myeloid cells. Lower left; megaloblastic changes and multinuclearity in erythroid cells. Lower right; karyorrhexis. D Ring sideroblast. E Cytoplasmic vacuoles in myeloid and erythroid precursors.

Fig. 3

Proposed management for VEXAS syndrome based on current understandings. Screening of UBA1 variant should be performed based on typical auto-inflammatory symptoms and laboratory findings. Scoring system for UBA1 variant screening may be helpful for identifying VEXAS patients, although its sensitivity may not be sufficient at early stage of the disease [13]. JAKi, especially ruxolitinib and AZA are promising agents for controlling auto-inflammatory symptoms and cytopenia. Agents and managements considered to be critical in current practice are shown in bold type. Patients with risk factors (poor prognostic factors) or treatment refractory cases should be directed to allo-HSCT at an early stage. This tentative algorithm must be updated by incorporating new data from future clinical trials. DMARD Disease-modifying anti-rheumatic drugs; JAKi Janus kinase inhibitor; AZA azacytidine; ESA erythropoiesis-stimulating agents; TPO-RA thrombopoietin receptor agonists; allo-HSCT allogeneic hematopoietic stem cell transplantation