David Adams spent half a decade fighting an illness he couldn’t name. He was in and out of the hospital several times per year. His inflamed joints made his hands feel like they had been squeezed into gloves – and he could no longer play his beloved classical and jazz guitars.
He had constant fevers and fatigue. He even developed pain and swelling in his genitalia, which was his first sign that something was really wrong.
“At the turn of the year 2016, I started with some really painful effects in the male anatomy,” said Adams, now 70. “After that, again, a lot of fatigue – my primary care physician at that point had blood tests done, and my white blood cell count was very, very low.”
Next, Adams, who lives in Alexandria, Virginia, saw a hematologist, a pulmonologist, a urologist, a rheumatologist and then a dermatologist. Some of them thought he might have cancer.
Adams’ symptoms continued, with even more fatigue, pneumonia and a large rash below his waist. He tried at least a dozen medications, saw about two dozen doctors, and nothing helped.
In 2019, worsening symptoms forced him to retire early from his decades-long career in clinical data systems. But he remained in the dark about what was causing the problems.
Finally, in 2020, scientists at the National Institutes of Health discovered and named a rare genetic disorder: VEXAS syndrome, which wreaks havoc on the body through inflammation and blood problems.
Adams had an appointment with his rheumatologist at the time, and when he walked into the office, he saw that his physician “was giddy like a little kid.”
In his doctor’s hands was a copy of a paper in the New England Journal of Medicine detailing the discovery of VEXAS syndrome.
Adams had his answer.
“For the first time, there was a one-to-one correlation of symptoms,” he said. “It was quite a shock.”
An estimated 1 in about 13,500 people in the United States may have VEXAS syndrome, a new study suggests, which means the mysterious and sometimes deadly inflammatory disorder may be more common than previously thought.
In comparison, the genetic disorder spinal muscular atrophy affects about 1 in 10,000 people and Huntington’s disease occurs in about 1 in every 10,000 to 20,000 people.
Since its discovery, occasional VEXAS cases have been reported in medical research, but the study reveals new estimates of its prevalence.
The research, published Tuesday in the journal JAMA, suggests that about 1 in 13,591 people in the US have mutations in the UBA1 gene, which develop later in life and cause VEXAS syndrome.
“This study is demonstrating that there’s likely tens of thousands of patients in the US that have this disease, and the vast majority of them are probably not being recognized because physicians aren’t really considering this as a diagnosis more broadly,” said Dr. David Beck, an assistant professor in the Department of Medicine at NYU Langone Health and a lead author of the study.
VEXAS syndrome is not inherited, so people who have it don’t pass the disease to their children. But the UBA1 gene is on the X chromosome, so the syndrome is an X-linked disease. It predominantly affects men, who carry only one X chromosome. Women have two X chromosomes, so if they have a mutation in a gene on one X chromosome but not the other, they are generally unaffected.
“It’s present in 1 in 4,000 men over the age of 50. So we think it’s a disease that should be thought about in terms of testing for individuals that have the symptoms,” said Beck, who also led the federal research team that identified the shared UBA1 mutation among VEXAS patients in 2020.
“The benefit of VEXAS syndrome is that we have a test. We have a genetic test that can help directly provide the diagnosis,” he said. “It’s just a question of patients who meet the criteria – who are older individuals with systemic inflammation, low blood counts, who really aren’t responding to anything but steroids – then advocating to their doctors to get genetic testing to get a diagnosis.”
Adams, who became a patient of Beck’s, said that finally getting a diagnosis – and understanding the cause of his symptoms – was life-changing.
“It really was incredibly freeing to have the diagnosis,” he said.
“You can’t fight your enemy unless your enemy has a name,” he added. “We finally had something where we could point to and say, ‘OK, we understand what’s going on. This is VEXAS.’ “
For the new study, Beck and his colleagues at the NIH, New York University, Geisinger Research and other institutions analyzed data on 163,096 patients in a health system in central and northeastern Pennsylvania, from January 1996 to January 2022, including electronic health records and blood samples.
Eleven of the patients had a disease-causing UBA1 variant, and a 12th person had a “highly suspicious” variant.
Only three of the 12 are still alive. A five-year survival rate of 63% has been previously reported with VEXAS.
Among the 11 patients in the new study who had pathogenic variants in UBA1, only two were women. Seven had arthritis as a symptom, and four had been diagnosed with rheumatologic diseases, such as psoriasis of the skin or sarcoidosis, which causes swollen lumps in the body. All had anemia or low blood cell counts.
“None had been previously clinically diagnosed with VEXAS syndrome,” Beck said.
The finding “is emphasizing how it’s important to be able to pick these patients out, give them the diagnosis and start the aggressive therapies or aggressive treatments to keep their inflammation in check,” he said.
VEXAS – an acronym for five clinical characteristics of the disease – has no standardized treatment or cure, but Beck said symptoms can be managed with medications like the steroid prednisone or other immunosuppressants.
“But the toxicities of prednisone over years is challenging. There are other anti-inflammatory medications that we use, but they’re only partially effective at the moment,” he said. “One treatment for individuals that we’ve seen that’s very effective is bone marrow transplantation. That comes with its own risks, but that’s just underscoring the severe nature of the disease.”
Although the new study helps provide estimates of the prevalence and symptoms of VEXAS syndrome, the data is not representative of the entire United States, and Beck said that more research needs to be done on a larger, more diverse group of people.
Some men might be hesitant to seek medical care for VEXAS symptoms, but Adams said that doing so could save their life.
“Eventually, it’s going to get so bad that you’ll end up like my first hospitalization, where you’re on death’s door,” Adams said. “You don’t want to be in that situation.”
Adams has been taking prednisone to ease his symptoms, and it’s helped. But because steroid use can have side effects such as cataracts and weight gain, he has been working with his doctors to find other therapies so he can reduce his intake of the medication.
Beck and his colleagues are studying targeted therapies for VEXAS syndrome, as well as conducting stem cell bone marrow transplant trials at the NIH.
“There are many different facets of the disease,” Dr. Bhavisha Patel, a hematologist and researcher in the National Heart, Lung and Blood Institute’s Hematopoiesis and Bone Marrow Failure Laboratory, said in an NIH news release last month.
“I believe that is what is challenging when we think about treatment, because it’s so heterogeneous,” said Patel, who was not involved in the new study.
“Both at NIH and worldwide, the groups that have dedicated themselves to VEXAS are looking for medical therapies to offer to other patients who don’t qualify for a bone marrow transplant,” she said. “We continue to collaborate on many projects in order to categorize this disease further and ultimately come up with the best treatment options.”