The patient, Hector Campos, came to the emergency department with shortness of breath, irregular 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 the head of emergency medicine, Ethan Choi, who was similarly stunned by the man’s symptoms.
Scary, right? But it’s not real – Campos and Choi are the heroes of the NBC medical drama Chicago Med. Over the course of the episode, which aired in March 2021, Choi initially misdiagnoses Campos’ symptoms as pneumonia and a bacterial infection, but the test returns for extensive inflammation. Campos’s condition deteriorates rapidly and the medical team is annoyed until fellow ER surgeon Dean Archer suggests it may 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 to real VEXAS cases, said David Beck, a clinical genetics researcher at New York University Grossman School of Medicine. “In terms of clinical signs,” 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’ve been impressed with popular media portrayals because [it shows] they read the newspaper.
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Still, these representations of the VEXAS team tend to highlight severe cases, in part because the NEJM article did as well. Of the 25 cases the researchers examined, 10 patients died from VEXAS-related causes.
But more recent research has extended the VEXAS case definition to a softer side. In an article published in CAVITY On January 24, Beck and colleagues scanned the genetic sequencing reads of 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 and two female patients in their study had the mutations that caused VEXAS.
As a result, the researchers estimated that in the United States alone, about 13,200 men and 2,300 women over the age of 50 are affected by the syndrome.
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“Going from trying to understand a few patients to finding that the same genetic cause and the same disease occurs in tens of thousands of people is exciting,” said Beck. “It’s not just because we know there are many patients who suffer, who don’t get a diagnosis or treatment that can help them, and they just don’t take a step in that direction; it is also very surprising that these kinds of discoveries can still be made, despite all the biomedical research that is going on.”
VEXAS is an acronym that stands for several of the band’s key features. In each case of the syndrome, the patient has a genetic mutation that encodes the E1 enzyme. The mutation is in a gene on the X chromosome, which you remember from biology class is a sex chromosome – men only have one, making them more susceptible to VEXAS. And the mutation is somatic, meaning it is acquired over the course of life, rather than inherited from a parent. This last characteristic, which gives VEXAS its “S”, is key: Because VEXAS is caused by a somatic mutation, the syndrome is not passed on and only occurs in older patients, usually over the age of 50, Beck said.
Beck emphasized that this type of research has been made possible by recent advances in genetic sequencing, which make it readily available and inexpensive for patients. All study participants sought care at a Geisinger healthcare 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: the regions of their genomes that code for proteins, were sequenced.
All of the 11 participants found to have mutations in the E1 enzyme gene 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 more serious symptoms associated with VEXAS, such as cartilage inflammation (which caused Campos’s ears to swell), did not occur 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 that the two women retrospectively identified as having VEXAS syndrome only had a VEXAS-associated mutation on one their X chromosomes, not both. “It’s confusing for us,” because originally scientists thought VEXAS was only for men, Beck said. “We are slowly recognizing more women with the disease and we don’t understand why that is.” One phenomenon may be X-inactivation, a process where one of a woman’s two X chromosomes becomes silenced in cells.
The researchers wrote in the study that future analyzes will be critical to understanding the prevalence of this syndrome across populations, as 94 percent of participants in the Geisinger cohort were Caucasian.
There is currently no Food and Drug Administration-approved treatment for VEXAS, but Phase II clinical trials are underway to investigate whether blood stem cell transplants can treat or cure the syndrome. In 2022, a team of French scientists published a study suggesting that such a transplant can lead to complete remission, but such a procedure is not without risks.
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As for research, Beck said scientists are still trying to figure out how the mutation in the E1 gene leads to the widespread inflammation seen in VEXAS cases. This enzyme starts the process of eliminating proteins in the cell that it no longer needs. Further research is underway to determine how the dysfunctional E1 enzyme affects this process.
“If you’re an elderly person with systemic inflammation, low blood count, don’t have a clear diagnosis, and need steroids but don’t have a clear diagnosis,” Beck said, you should see your doctor about genetic testing for VEXAS.
“This could help to develop better treatments – and at least a clear diagnosis,” he said.
Read more in The Daily Beast.
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