Scientists at the National Institutes of Health have discovered a rare and deadly inflammatory disease affecting men called the VEXAS syndrome.
The revelation, published Tuesday in the New England Journal of Medicine, may lead to effective therapies for the disease, which has killed 40 percent of known patients.
Those afflicted have an autoinflammatory condition, with symptoms including unexplained fevers, blood clots and inflammation of the cartilage, lung tissue and blood vessels. When blood vessels are inflamed, it can affect the body's vital organs.
"These patients are really sick. They don't respond to any treatments, from high doses of steroids to various chemotherapies," Dr. Dan Kastner, a senior author of the article and scientific director of the Intramural Research Program at the NIH's National Human Genome Research Institute, said.
Many have spent years going from doctor to doctor in search of answers, Kastner added. "It's incredibly frustrating for those patients, and frightening for their families."
What is the VEXAS syndrome?
Historically, scientists have identified new diseases by looking at symptoms. More recently, they've been able to go a step further, taking a group of people who have similar symptoms and analyzing their genomes to look for any similarities that could point to a genetic cause.
This time, the scientists flipped the script: The team started with a list of more than 800 genes linked to inflammation, then compared those genes with about 2,500 patients in an NIH database with undiagnosed illnesses.
"Instead of starting with symptoms, start with a list of genes," Dr. David Beck, a clinical fellow at the National Human Genome Research Institute, and lead author of the new report, said in a statement. "Then, study the genomes of undiagnosed individuals and see where it takes us."
The journey led them to three patients — all men — who were found to have the same mutation in a gene called UBA1.
A previously unknown genetic disease had revealed itself.
"This was like trying to find a needle inside of a needle in a haystack," Kastner said. The research team further identified 22 more men with the same defect. They called the finding the VEXAS syndrome, after an acronym based on a complex set of genomic factors: "vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic."
Vacuoles are cavity-like structures that look like bubbles. In men with the VEXAS syndrome, they are found in a type of blood cell called a myeloid cell. "Somatic" means the disease occurs at some point during a person's life, rather than being born with it.
The syndrome doesn't appear to occur until adulthood, and has been found only in men. One reason for that could be that the mutation is linked to the X chromosome. Men have only one X chromosome, while women have two. The researchers hypothesize that the additional X chromosome could somehow override the mutation and provide a protective effect. (Indeed, other genetic disorders, such as certain types of hemophilia, are also X-linked, and are therefore much more likely to occur in men than women.)
The VEXAS syndrome patients had no other obvious clinical connection. "It's using a gene mutation to link people together that otherwise would not have thought were connected to one another," Kastner said. "It's the beauty of genetics."
An additional 25 patients have since been found to have the syndrome since the study was completed, bringing the known total to 50. But since nearly 125 million people in the U.S. live with some form of chronic inflammatory disease, according to the NIH researchers, the real number with the syndrome is suspected to be much higher.
"I would guess that in the United States that there are at least hundreds of patients with this disease and maybe even a lot more than that," Kastner said.
Dr. Kenneth Warrington, a rheumatologist at the Mayo Clinic in Rochester, Minnesota, said the importance of providing a name to a disease cannot be overemphasized. "It is tremendously encouraging and wonderful to see that we can start to reach an understanding of these rare, serious and difficult-to-treat illnesses."
Warrington, who was not involved in the new study, said he and his colleagues often have no way of diagnosing specific inflammatory conditions and must often rely on basic clinical features, such as inflammatory rashes on the skin.
Now that scientists have found a marker for this particular syndrome, it "absolutely advances the field," he said.
Other outside experts agreed. "We don't always have a diagnosis, so we say, 'Well, let's throw the kitchen sink at the patient,'" said Dr. Natalie Azar, an assistant clinical professor of medicine and rheumatology at NYU Langone and a medical contributor for NBC News. "This opens up a whole world of potential therapeutics down the line."
Future treatments for VEXAS syndrome could include bone marrow transplants or, potentially, gene-editing therapy.
"Science touches lives," said Dr. S. Louis Bridges, physician-in-chief and chair of the department of medicine at the Hospital for Special Surgery in New York City. Bridges was not involved with the new research.
"This is one of those things where, if we didn't have this extremely highly specialized group of people in genetic defects, we never would have found it," Bridges said.