Patient Hector Campos presented to the emergency department with shortness of breath, an irregular fever, and swollen, itchy ears. His wife stated 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 similarly confused by the man’s symptoms.
Creepy, right? But it’s not real — Campos and Choi are both characters on the NBC medical series Chicago Med. During the episode, which aired in March 2021, Choi initially misdiagnosed Campos’ symptoms as pneumonia and a bacterial infection, but got a test comes back to widespread inflammation. Campos’ condition is rapidly deteriorating, and the medical team is upset until fellow emergency room physician Dean Archer suggests it could be VEXAS, a rare autoinflammatory syndrome. Genetic sequencing eventually finds a mutation that confirms the diagnosis, and Choi begins treating the patient.
The episode is fictional, but depictions like this match surprisingly closely with real-life 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 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 the portrayals in popular media because [it shows] they read the newspaper.”
Despite this, these presentations of VEXAS syndrome tend to emphasize severe cases, in part because this was also the case in the NEJM study. Of the 25 cases studied by the researchers, 10 of the patients died from VEXAS-related causes.
But recent research has added a milder side to the case definition of VEXAS. In an article published Jan. 24 in JAMA, Beck and his colleagues scanned genetic sequence data from more than 160,000 people to determine 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.
As a result, the researchers estimated 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 disease is found in tens of thousands of people,” Beck said. “Not just because we know there are many patients out there who are suffering, who don’t get a diagnosis, or who don’t get the treatment that can help them, and just take a step in that direction; It is also very surprising that despite all the biomedical research, one can still make such discoveries.”
VEXAS is an acronym that stands for several key features of the syndrome. In each case of the syndrome, a patient has a genetic mutation that codes for the E1 enzyme. The mutation occurs on a gene on the X chromosome, which you might remember from biology class is a sex chromosome – males only have one, making them more susceptible to VEXAS. And the mutation is somatic, meaning it’s acquired during life rather than inherited from a parent. The final feature that gives VEXAS its “S” is crucial: Because VEXAS is caused by a somatic mutation, the syndrome is not passed on and only occurs in older patients, typically over the age of 50, Beck said.
This type of research, Beck pointed out, has been made possible by recent advances in genetic sequencing, making it readily available and affordable for patients. All study participants attended care at a Geisinger Health Facility in central and northeastern Pennsylvania between 1996 and 2022. Regions of their genome that code for proteins – have been sequenced.
“Actually, I was struck by the popular media portrayals because [it shows] they read the newspaper.”
— David Beck, New York University Grossman School of Medicine
All 11 participants found to have mutations in the gene for the E1 enzyme were anemic, and the vast majority had abnormally large red blood cells and low platelet counts — all symptoms consistent with VEXAS syndrome. Importantly, however, some of the more serious symptoms associated with VEXAS, such as B. inflammation of the cartilage (which caused Campos’s swollen ears) were not present in these patients. This suggests that there may be a wider spectrum of severity in VEXAS syndrome cases.
Another confounding aspect of the study was the fact that the two women retrospectively identified as having VEXAS syndrome only had the VEXAS-related mutation on one of their X chromosomes, not both. “It’s confusing to us,” since researchers initially thought VEXAS only affected males, Beck said. “We’ve slowly been recognizing more women who have the disease, and we don’t understand why that is.” One phenomenon at play may be X-inactivation, a process by which one of the two X chromosomes changes of a woman being silenced in her cells.
The researchers wrote in the study that future analyzes will be crucial to understanding the prevalence of the syndrome in different populations because 94 percent of the participants in the Geisinger cohort were white.
There are currently no Food and Drug Administration-approved treatments for VEXAS, but a Phase II clinical trial is underway to investigate 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 a procedure is not without its risks.
On the research side, Beck said scientists are still trying to figure out how a mutation in the gene that encodes E1 leads to the widespread inflammation seen in cases of VEXAS. This enzyme starts a process for a cell to eliminate proteins it no longer needs, and research is ongoing to determine how a dysfunctional E1 enzyme affects this process.
“If you are an elderly person with systemic inflammation, have low blood counts, do not have a definite diagnosis and need steroids, but have no definite diagnosis,” you should contact your doctor about genetic testing for VEXAS syndrome. said Beck.
“It may lead to better treatments for you — and at least a clear diagnosis,” he said.