VEXAS syndrome 

Autoinflammatory disease as an MDS precursor

What is VEXAS Syndrome?

VEXAS syndrome (Vacuolated myeloid and erythroid precursors, E1 enzyme; mutations in UBA1 lead to lack of cytoplasmic E1 enzyme, X-linked;UBA1 gene located on X chromosome, Autoinflammatory; severe inflammation, steroid dependent, Somatic; mutations in UBA1 restricted to myeloid origin cells) is a monogenic disease of adulthood, where patients develop inflammatory and hematologic symptoms. Myeloid-driven autoinflammation and progressive bone marrow failure can lead to poor prognosis.

Vexas syndrome is considered an autoinflammatory disease and inflammation, as well as the bone marrow cell production anomalies, are precursors of MDS and other bone marrow dysplasias. 

VEXAS Syndrome and MDS

UBA1 is an X-linked gene that escapes X inactivation. To date, VEXAS has been reported exclusively in men, and women likely are protected by the unmutated allele. These mutations were seen in hematopoietic progenitor cells in bone marrow and lineage restricted to myeloid cells in circulation.

Vacuoles are rare in marrow myeloid and erythroid precursor cells. When seen, it indicates a non-specific abnormality in several diseases including MDS, sideroblastic anaemia, copper deficiency, zinc excess and acute alcohol exposure. Different mechanisms of formation result in vacuoles with diverse histological features and distributions.  In patients with MDS are often of irregular shape with indistinct outlines and a tendency to coalesce suggesting the presence of glycogen, in VEXAS syndrome, numerous round vacuoles consisting of lipid droplets and disordered cellular organelles occur in myeloid and erythroid precursors.

VEXAS Syndrome treatment 

High-risk therapies such as allogeneic bone marrow transplantation should be considered in select patients with VEXAS syndrome given the clonal nature of the disease, persistent and progressive hyperinflammation from complex activation of multiple innate immune pathways, and predisposition to hematologic malignancies.
Treating VEXAS syndrome is challenging because it is unlikely to improve with immunosuppressive drugs or hypo-methylating drugs, Janus kinase inhibitors were effective for some features of systemic inflammatory disease, particularly skin involvement. When diagnosed, it should be considered for alternative therapies including participation in clinical trials. 

Currently recruiting 

A Phase II Study of Allogeneic Hematopoietic Stem Cell Transplant for Subjects With VEXAS (Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic) Syndrome. NCT05027945 

References:

1. https://pubmed.ncbi.nlm.nih.gov/33971000/
2. https://ehoonline.biomedcentral.com/articles/10.1186/s40164-021-00217-2 
3. https://ashpublications.org/blood/article/137/26/3591/475940/VEXAS-syndrome