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Review
. 2024 May 31.
doi: 10.1007/s12185-024-03799-9. Online ahead of print.

VEXAS syndrome

Hideaki Nakajima  1 , Hiroyoshi Kunimoto  2
Affiliations
Review

VEXAS syndrome

Hideaki Nakajima et al. Int J Hematol. .

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.

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References

    1. Beck DB, Ferrada MA, Sikora KA, et al. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. N Engl J Med. 2020;383(27):2628–38. - PubMed - PMC - DOI
    1. Finley D, Ciechanover A, Varshavsky A. Thermolability of ubiquitin-activating enzyme from the mammalian cell cycle mutant ts85. Cell. 1984;37(1):43–55. - PubMed - DOI
    1. Schulman BA, Harper JW. Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways. Nat Rev Mol Cell Biol. 2009;10(5):319–31. - PubMed - PMC - DOI
    1. Lenk SE, Dunn WA Jr, Trausch JS, et al. Ubiquitin-activating enzyme, E1, is associated with maturation of autophagic vacuoles. J Cell Biol. 1992;118(2):301–8. - PubMed - DOI
    1. Stephen AG, Trausch-Azar JS, Handley-Gearhart PM, et al. Identification of a region within the ubiquitin-activating enzyme required for nuclear targeting and phosphorylation. J Biol Chem. 1997;272(16):10895–903. - PubMed - DOI

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