Tens of thousands of Americans could be sick with this lethal disease and be completely unaware of it as genetic sequencing eventually reveals a mutation that confirms it.
Hector Campos presented to the emergency room with shortness of breath, fluctuating fever, and swollen, itching ears. Campos had tested negative for COVID-19, according to his wife. “What do you suppose it could be?” Campos enlisted the help of Ethan Choi, the chief of emergency medicine, who was equally perplexed by the man’s symptoms.
Ten of the 25 patients studied by the researchers died as a result of VEXAS. Recent research, however, has broadened the case definition of VEXAS to include a milder side. Beck and his colleagues reviewed DNA sequencing findings from more than 160,000 people in an article published in JAMA on Jan. 24 to discover how frequent VEXAS syndrome is and how its symptoms present in patients. The researchers discovered that nine male patients and two female patients in their study had VEXAS-causing mutations.
As a result, the researchers estimated that the disease affects around 13,200 men and 2,300 women over the age of 50 in the United States alone.
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“It’s thrilling to go from trying to understand a few patients to find that the same genetic cause and the same disease is found in tens of thousands of individuals,” Beck said. That last feature, which gives VEXAS its “S,” is crucial: Because VEXAS is caused by a somatic mutation, the syndrome isn’t passed down and only occurs in older patients, typically over the age of 50, Beck said.
Beck underlined that recent improvements in genetic sequencing have made this type of study possible by making it easily accessible and inexpensive to patients. The participants’ exomes—regions of their genomes that encode proteins—were sequenced as part of a collaboration between Geisinger and the Regeneron Genetics Center to map genetic diversity across the human genome.
All 11 subjects with mutations in the E1 enzyme gene were anemic, with unusually big red blood cells and a low platelet count—all symptoms associated with VEXAS syndrome. This shows that there may be a greater range of severity in VEXAS syndrome cases.
There are currently no FDA-approved therapies for VEXAS
Another perplexing element of the study was that the two women identified as having VEXAS syndrome only had the VEXAS-related mutation on one of their X chromosomes, not both. “We’ve been slowly recognizing more females that have the disease, and we don’t understand why that is.” One such mechanism is X-inactivation, which occurs when one of a female’s two X chromosomes is silenced throughout her cells.
Because 94 percent of the participants in the Geisinger cohort were white, the researchers said in the report that further analyses will be crucial to determining the prevalence of the condition in other communities.
There are currently no FDA-approved therapies for VEXAS, however, a phase II clinical trial is underway to see whether blood stem cell transplantation can treat or cure the illness. A group of French experts published a paper in 2022 claiming that such a transplant could result in complete remission, however, such a surgery is not without hazards.
Scientists are still trying to figure out how a mutation in the gene that encodes E1 causes the extensive inflammation found in VEXAS patients
According to Beck, scientists are still trying to figure out how a mutation in the gene that encodes E1 causes the extensive inflammation found in VEXAS patients. This enzyme initiates a process in which a cell eliminates proteins it no longer requires, and more research is being conducted to identify how a defective E1 enzyme affects this process.
“If you’re an older individual with systemic inflammation, low blood counts, don’t have any clear diagnosis, and you require steroids but don’t have any clear diagnosis,” you should contact your doctor about genetic testing for VEXAS syndrome, Beck said.
“It may help lead to better treatments for you—and at least a clear diagnosis,” he said.
