The patient, Hector Campos, came to the emergency department with shortness of breath, irregular fever, and swollen, itchy ears. Campos has tested negative for COVID-19, his wife explained. “What do you think this could be?” Campos asked Ethan Choi, chief of emergency medicine, who was similarly confused by the man’s symptoms.
Scary, isn’t it? But it’s not real — Campos and Choi are both characters on the NBC medical drama Chicago Med. During the episode that 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 worsens rapidly, and the team of doctors is mystified until fellow ER surgeon Dean Archer suggests it might be VEXAS, a rare autoimmune inflammatory syndrome. Genetic sequencing eventually finds a mutation that confirms the diagnosis, and Choi begins treating the patient.
The episode is fictional, but such depictions are surprisingly accurate for 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 are localized.” Beck should know: The syndrome was named after a study he and his colleagues first published. The New England Journal of Medicine In 2020. “Of course, I am impressed by the portrayals in the popular media [it shows] They have read the paper.
Nevertheless, these depictions of VEXAS syndrome tend to highlight severe cases, as the NEJM paper did in part. Of the 25 cases studied by the researchers, 10 patients died of VEXAS-related causes.
But more recent research has expanded the case definition of VEXAS to include a milder side. In a paper published in Jama On January 24, Beck and his colleagues scanned genome sequence reads from more than 160,000 people to determine how common VEXAS syndrome really is and how its symptoms manifest in patients. In their study, the research team found that nine male patients and two female patients had mutations that caused VEXAS.
As a result, researchers estimated that the syndrome affects about 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 that the same genetic cause and the same disease is found in tens of thousands of people,” Beck said. “Not just because we know there are so many patients out there who are suffering, undiagnosed or undertreated that could help them, but just taking a step in that direction. It’s amazing that you can still make discoveries like this with all the biomedical research going on.
VEXAS is an acronym 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 remember from biology class, is the sex chromosome—males only have one, making them more prone to come down with VEXAS. The mutation is somatic, meaning it is acquired during life as opposed to being inherited from parents. That last feature, which gives VEXAS its “S,” is critical: Because VEXAS is caused by a genetic mutation, the syndrome is not transmitted and usually occurs only in older patients over the age of 50, Beck said.
As Beck emphasizes, recent advances in genomic sequencing have made it readily available and affordable for patients. All study participants sought care at a Geisinger Health Care Center in central and northeastern Pennsylvania between 1996 and 2022. Mapping genetic variation across the human genome as part of a collaboration between Geysinger and the Regeneron Genomics Center, participants’ exomes—regions of their genomes that encode proteins—were sequenced.
“In fact, I am impressed by the portrayals in the popular media [it shows] They have read the paper.“
– 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, these patients did not have the more severe symptoms associated with VEXAS, such as cartilage inflammation (which caused Campos’ ear swelling). This suggests that there may be a wide spectrum of severity when it comes to VEXAS syndrome.
Another puzzling aspect of the study is that the two women later diagnosed with VEXAS syndrome only suffered from the VEXAS-associated mutation. one On their X chromosomes, neither. “It was confusing to us,” Beck said, adding that researchers initially thought VEXAS only affected men. “We’re slowly diagnosing more women with this disease, and we don’t understand why.” One phenomenon at play may be X-inactivation, the process in which one of a woman’s two X chromosomes is silenced throughout their cells.
Because 94 percent of the participants in the Geisinger cohort were white, future analyzes will be critical to understanding the prevalence of the syndrome in different populations, the researchers wrote in the study.
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 group of French researchers published a study showing 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 encoding E1 leads to the widespread inflammation seen in VEXAS cases. This enzyme initiates a process to remove proteins that a cell no longer needs, and further research is underway to determine how an inactive E1 enzyme affects this process.
“If you’re an older person with systemic inflammation, low blood counts, no clear diagnosis, if you need steroids but no clear diagnosis,” you should talk to your doctor about genetic testing for VEXAS syndrome. Beck said.
“It will help you get better treatment and at least a clearer diagnosis,” he said.