Written By: the RheumMadness Leadership Team

Topic Overview

VEXAS is a newly described adult-onset autoinflammatory syndrome caused by a mutation in the UBA1 gene on the X-chromosome that encodes the E1 enzyme, a key component of the ubiquitylation system. To date, VEXAS has exclusively been described in older patients, unlike other known autoinflammatory syndromes caused by a genetic mutation. This is because VEXAS is due to a somatic (a.k.a., acquired) mutation in blood cells that occurs later in life, rather than an inherited mutation that affects all cells from the beginning of fetal development. In this way, VEXAS is somewhat akin to an acquired mutation that leads to cancer, only instead of cancer this mutation leads to severe inflammation. VEXAS was discovered when researchers found three men with what appeared to be two different copies of the UBA1 gene on the X-chromosome. This was unexpected finding as men only have one X-chromosome and thus should only have one copy of each gene. Instead of attributing their findings to a sequencing error, the researchers evaluated the clinical phenotypes of these men and discovered that all three had cytopenias, strange vacuoles in the myeloid cells of the bone marrow, and intense inflammatory syndromes. Ultimately, they found 25 cases of this new syndrome and performed a variety of incredible experiments to describe it further. All patients had cytopenias and inflammatory syndromes including chondritis, vasculitis, and neutrophilic infiltrates of the lungs and skin. The syndrome was subsequently named for its major features: V for Vacuoles seen on bone marrow biopsy, E for E1 gene, X for X-chromosome, A for Autoinflammatory, and S for Somatic mutation.

Implications for Patients, Providers, & Researchers

Current implications: To date, VEXAS has only been described in 25 patients, so the current implications are somewhat small. However, the association between relapsing polychondritis and myelodysplasia in older men is already well recognized and VEXAS may explain this connection. Furthermore, the true incidence of VEXAS remains unknown. Perhaps additional clinical manifestations beyond those currently described will appear as more cases are reported. It is even possible that women with somatic UBA1 mutations could be affected, just to a lesser degree than men given their two X-chromosomes. Awareness of VEXAS is critical for practicing adult rheumatologists who are not used to looking for genetic causes of adult-onset inflammatory diseases.

Future implications: This team’s strength lies primarily in its future implications, as it is the first adult-onset inflammatory syndrome known to be caused by a somatic mutation. There are likely many more of these kinds of syndromes that have yet to be described. The methodology used by the VEXAS research team may prove foundational for future work in this area. Many rheumatologists have been dumbfounded by adult patients with severe inflammatory syndromes that are refractory to treatment; perhaps thanks to VEXAS over the next several decades we will start to learn the names (and targeted treatment options) for these conditions.

Will VEXAS Win its First Round Match-up?

VEXAS stands a very good chance against its first-round opponent, anti-CD38 in refractory systemic lupus erythematosus, largely due to the groundbreaking scientific work of the VEXAS team. However, they do need to be on alert for anti-CD38’s ability to steal the ball and shoot three-pointers, as anti-CD38 is an actual treatment that could be considered for very sick patients with systemic lupus erythematosus, whereas targeted treatment options for VEXAS (bone marrow transplant? Gene therapy?) remain theoretical at best.

Could VEXAS Win it All?

It’s far-fetched but not impossible for this small but mighty Cinderella team to win the tournament, as the future implications truly are something special. Assuming VEXAS makes it through the first round, it might have to watch out for RP subtypes in the second round as that’s another excellent study from the same senior author (Peter Grayson), and who knows if it could make it through the juggernauts coming out of the ANCA and SLE regions. But the science of VEXAS alone could help it go all the way!

Reference(s)

1. Beck et al. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. NEJM. 2020;383:2628-38
2. Check out the RheumMadness Podcast Episode on this topic!

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