Tens of Thousands of Americans Could Have Deadly Disease Without Even Knowing It

The patient, Hector Campos, arrived at the emergency room with shortness of breath, a erratic fever and swollen, itchy ears. His wife explained that Campos had tested negative for COVID-19. “What do you think it could be?” Campos asked emergency medicine chief Ethan Choi, who was also confused by the man’s symptoms.

Scary, right? But it’s not real – Campos and Choi are both characters in the NBC medical drama Chicago Mediterranean. During the episode, which aired in March 2021, Choi initially misdiagnoses Campos’ symptoms as pneumonia and a bacterial infection, but a test comes back for widespread inflammation. Campos’ condition deteriorates rapidly and the team of doctors are miffed until fellow emergency surgeon Dean Archer suggests it could be VEXAS, a rare autoinflammatory syndrome. Genetic sequencing eventually finds a mutation confirming the diagnosis, and Choi begins treating the patient.

The episode is fictional, but depictions like this are surprisingly accurate compared to real cases of VEXAS, said David Beck, a clinical genetics researcher at New York University’s Grossman School of Medicine. “In terms of clinical manifestations,” he told The Daily Beast, “they’ve been perfect.” 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 impressed, actually, with the portrayals in popular media, because [it shows] they read the newspaper.

Even so, these portrayals of VEXAS syndrome tend to highlight severe cases, in part because the NEJM article did too. Of the 25 cases studied by the researchers, 10 of the patients died of VEXAS-related causes.

But more recent research has expanded the case definition of VEXAS to include a softer side. In an article published in JAMA on Jan. 24, Beck and his colleagues scanned gene sequencing reads from more than 160,000 people to determine just how common VEXAS syndrome really 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 caused VEXAS.

And as a result, researchers have estimated that the syndrome affects around 13,200 men and 2,300 women over the age of 50 in the United States alone.

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

VEXAS is an acronym that stands for several key features of the syndrome. In all cases of the syndrome, a patient has a genetic mutation coding for the E1 enzyme. The mutation occurs on a gene on the X chromosome, which as you may recall from biology class is a sex chromosome – men only have one, making them more prone to falling out with VEXAS. And the mutation is somatic, which means that it is acquired during life and not inherited from a parent. This last characteristic, which gives VEXAS its “S”, is crucial: as VEXAS is caused by a somatic mutation, the syndrome is not transmitted and only occurs in older patients, usually over the age of 50. , Beck said.

This type of research, Beck pointed out, has been made possible by recent advances in genetic sequencing that make it easily accessible and affordable for patients. Study participants all 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 across the human genome, the participants’ exomes—regions of their genomes that code for proteins—were sequenced.

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

Another puzzling aspect of the study was the fact that the two women retrospectively identified as having VEXAS syndrome only had the VEXAS-linked mutation a of their X chromosomes, not both. “It’s confusing for us,” because researchers originally thought VEXAS only affected men, Beck said. “We are slowly recognizing more women with the disease, and we don’t understand why.” One phenomenon at play could be X-inactivation, a process in which one of a woman’s two X chromosomes is silenced in all of her cells.

The researchers wrote in the study that future analyzes will be key to understanding the prevalence of the syndrome in various populations, since 94% of participants in the Geisinger cohort were white.

Currently, there is no Food and Drug Administration-approved treatment for VEXAS, 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 suggesting that such a transplant can lead to complete remission, but such an intervention is not without risks.

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

“If you are an elderly person with systemic inflammation, low blood count, no clear diagnosis, and need steroids but no clear diagnosis” you should Contact your doctor about genetic testing for VEXAS syndrome, Beck says.

“It can help you get better treatments and at least a clear diagnosis,” he said.