VEXAS: A Novel Rheumatologic, Hematologic Syndrome That's Making Waves
6 min read
Older men with a novel adult-onset, severe autoinflammatory syndrome known by the acronym VEXAS are likely hiding in plain sight in many adult rheumatology, hematology, and dermatology practices.
New clinical features are being described to fill out the clinical profile of such patients who may be currently misdiagnosed with other conditions, according to researchers who first described the syndrome in the last quarter of 2020.

VEXAS is often misdiagnosed as treatment-refractory relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, or giant cell arteritis. These seemingly unrelated disorders are actually tied together by a single thread recently unraveled by David B. Beck, MD, PhD, a clinical fellow at the National Human Genome Research Institute, and colleagues, including rheumatologist Marcela Ferrada, MD, and others at institutes of the National Institute of Health, Bethesda, Md.

The connection between these disparate clinical presentations lies in somatic mutations in UBA1, a gene that initiates cytoplasmic ubiquitylation, a process by which misfolded proteins are tagged for degradation. VEXAS appears primarily limited to men because the UBA1 gene lies on the X chromosome, although it may be possible for women to have it because of an acquired loss of X chromosome.

Leukocytoclastic vasculitis seen in the legs and feet of a man with VEXAS.

VEXAS is an acronym for:

V acuoles in bone marrow cells

E -1 activating enzyme, which is what UBA1 encodes for

X -linked

A utoinflammatory

Somatic mutation featuring hematologic mosaicism

Beck said that VEXAS is "probably affecting thousands of Americans," but it is tough to say this early in the understanding of the disease. He estimated that the prevalence of VEXAS could be 1 per 20,000-30,000 individuals.

A New Way of Looking for Disease

VEXAS has caused a major stir among geneticists because of the novel manner in which Beck and his coinvestigators made their discovery. Instead of starting out in the traditional path to discovery of a new genetic disease — that is, by looking for clinical similarities among patients with undiagnosed diseases and then conducting a search for a gene or genes…
Jeff Evans and Bruce Jancin
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