Newly discovered VEXAS syndrome may affect thousands more Americans than previously thought

Newly discovered VEXAS syndrome may affect thousands more Americans than previously thought

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The patient, Hector Campos, came to the emergency department with shortness of breath, intermittent fever, and swollen, itchy ears. His wife explained that Campos had tested negative for COVID-19. “What do you think this could be?” Campos asked Chief of Emergency Medicine Ethan Choi, who was also confused by the man’s symptoms.

Scary, right? But it’s not real — Campos and Choi are characters on the NBC medical drama Chicago Med. In the course of the episode, which aired in March 2021, Choi initially misdiagnosed Campos’ symptoms as pneumonia and a bacterial infection, but a test came back for widespread inflammation. Campos’ condition rapidly worsens and the medical team is baffled, until fellow emergency room surgeon Dean Archer suggests it may be VEXAS, a rare autoinflammatory syndrome. Genetic sequencing eventually found a mutation confirming the diagnosis, and Choi began treating the patient.

The episode is fictional, but images like this are surprisingly accurate for real cases of VEXAS, said David Beck, a clinical genetics researcher at New York University’s Grossman School of Medicine. “In terms of the clinical manifestations,” he told The Daily Beast, “they were spot on.” Beck should know: He and his colleagues first named the syndrome in a study published in The New England Journal of Medicine in 2020. “I was actually impressed by images in popular media because [it shows] they have read the newspaper.

However, these presentations of VEXAS syndrome tend to emphasize severe cases, in part because the NEJM paper did as well. Of the 25 cases studied by the researchers, 10 of the patients died of VEXAS-related causes.

But more recent research has expanded the VEXAS case definition to include a softer side. IN document published in JAMA is Jan. 24, Beck and colleagues scanned genetic sequencing reads from more than 160,000 people to determine how common VEXAS syndrome is and how its symptoms manifest in patients. The research team found that nine male patients and two female patients in their study had mutations that cause VEXAS.

And as a result, researchers estimate that the syndrome affects about 13,200 men and 2,300 women over the age of 50 in the US alone.

“It’s exciting to go from trying to understand a few patients to finding that the same genetic cause and the same disease occurs in tens of thousands of individuals,” Beck said. “Not only because we know that there are many patients who are suffering, who are not getting a diagnosis or who are not getting the treatment that can help them, but just taking a step in that direction; it’s also very surprising that you can still make discoveries like this despite all the biomedical research that’s going on.”

VEXAS is an acronym that stands for several key features of the syndrome. In each case of the syndrome, the patient has a genetic mutation encoding the E1 enzyme. The mutation occurs on a gene on the X chromosome, which, as you may remember from biology class, is the sex chromosome – males only have one, making them more likely to get VEXAS. And the mutation is somatic, meaning it is acquired during life, not inherited from a parent. That last feature, which gives VEXAS its “S,” is crucial: Because VEXAS is caused by a somatic mutation, the syndrome is not passed on and occurs only in older patients, usually over the age of 50, Beck said .

This type of research, Beck emphasized, has been made possible by recent advances in genetic sequencing, making it readily available and accessible to patients. All study participants sought care at a Geisinger health facility in central and northeastern Pennsylvania between 1996 and 2022. As part of a collaboration between Geisinger and the Regeneron Genetics Center to map genetic variation in the human genome, participants’ exomes—regions of their genomes that code for proteins—were sequenced.

I was actually impressed by images in popular media because [it shows] they read the newspaper.

David Beck, NYU Grossman School of Medicine

All 11 participants found to have mutations in the gene for the E1 enzyme were anemic, and the majority had abnormally large red blood cells and low platelet counts, all symptoms consistent with VEXAS syndrome. Importantly, however, some of the more severe symptoms associated with VEXAS, such as cartilage inflammation (which causes Campos’ swollen ears), are not present in these patients. This suggests that there may be a wider spectrum of severity when it comes to cases of VEXAS syndrome.

Another puzzling aspect of the study is the fact that the two women who were retrospectively found to have VEXAS syndrome only suffered from the VEXAS-associated mutation of one on their X chromosomes, not both. “It’s confusing to us” because researchers originally thought VEXAS only affected men, Beck said. “We’re slowly recognizing more females who have the disease, and we don’t understand why.” One phenomenon at play could be X-inactivation, a process where one of a female’s two X chromosomes is silenced in their cells.

The researchers wrote in the study that future analyzes will be critical to understanding the prevalence of the syndrome in different populations because 94 percent of the participants in the Geisinger cohort were white.

At the moment there is there is no treatment for VEXAS approved by the Food and Drug Administration, but a phase II clinical trial is underway to study whether blood stem cell transplants can treat or cure the syndrome. In 2022, a team of French researchers published a study suggests that such a transplant can lead to complete remission, but such a procedure is not without risks.

On the research side, Beck said scientists are still trying to understand how a mutation in the gene that codes for E1 leads to the widespread inflammation seen in VEXAS cases. This enzyme starts a process for the cell to eliminate proteins it no longer needs, and further research is ongoing to determine how a malfunctioning E1 enzyme affects this process.

“If you’re an older person with systemic inflammation, low blood cell counts, no clear diagnosis, and you need steroids but no clear diagnosis,” you should contact your doctor about genetic testing for VEXAS syndrome, Beck said.

“It could help get better treatment for you — and at least a clear diagnosis,” he said.

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