VEXAS inflammatory syndrome

VEXAS stands for vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic syndrome.

• Vacuoles are hollow, cavity-like structures that develop in the myeloid cells. Myeloid cells are blood cells that arise from progenitor cells (which become blood cells).
• E1 enzyme refers to an enzyme made by the UBA1 gene that normally activates ubiquitin protein (ubiquitin-activating enzyme).
• X-linked is a reference to the fact that the gene mutation occurs on the X chromosome in men who show “mosaicism”: a condition in which the genetic mutation is limited to some cells while the other cells have the normal gene.
• Auto-inflammatory talks to the main symptom of the disease: systemic inflammation that doesn’t have an obvious cause.
• Somatic syndrome here means the condition develops later in life rather than being present at birth.

The symptoms of VEXAS include:

• Problems related to the blood, blood cells and blood cell production:
  • Blood clots in veins
  • Dysplastic bone marrow—problems with bone marrow that affect blood cell production
  • Cytopenias, or reduction in the number of mature blood cells
  • Unusual hollows or cavity-like structures or vacuoles in the myeloid cells and erythroid precursor cells
• Fever that keeps coming back
• Abnormalities in the lungs, including pulmonary inflammation
• Problems linked to inflammation:
  • Inflammation that is resistant to many treatments (treatment-refractory), develops later in life and can be fatal
  • Neutrophilic cutaneous inflammation (skin lesions caused by the infiltration of neutrophils, a type of immune cells)
  • Chondritis, or inflammation in the cartilage
  • Vasculitis, or inflammation in the blood vessels

VEXAS is caused by a mutation in the UBA1 gene which results in problems with a regulatory protein called ubiquitin. Ubiquitin is present in almost all tissues of the human body. When ubiquitin combines with another substrate protein (ubiquitylation), it can change that protein’s location, activity, and even mark it for degradation (destruction). Ubiquitin also has a role in regulating the immune system. In this condition, the enzyme that activates ubiquitylation is affected.

Researchers at the US National Institutes of Health’s National Human Genome Research Institute looked at the genome sequences of 2,560 people who had an inflammatory disease but its cause was unknown. The scientists studied about 800 genes involved in ubiquitylation—which affects how proteins act within the cells and the immune system—in these people and found the specific change that causes VEXAS in three adult men. Later investigations showed 47 more people with this mutation.

There’s another nuance to what the scientists discovered about this rare genetic disease: Most men have only one X chromosome (as they have XY sex chromosomes). But the scientists found both normal X chromosomes and X chromosomes with the UBA1 gene mutation that causes VEXAS in the men who were positive for VEXAS. So the scientists looked for further explanation for how it affects these men. The answer was mosaicism or the occurrence of groups of cells with the mutations and others with the normal form of the gene in the same body.

The scientists confirmed this using DNA-sequencing methodologies.

Scientists believe that women may be protected against this disease because they have two copies of the X chromosome in each cell, which may have a protective effect in this case.

Currently, testing patients for this genetic mutation in the UBA1 gene is the way to diagnose the condition. Risk factors include being male and middle-aged—these factors could help with the diagnosis to a small extent.

Treatment options are yet to be developed. Scientists already know that many of these patients don’t respond to many treatments like steroids and chemotherapy.