Treating a mysterious illness

In 2014, Randy Pherson, an intelligence and homeland security expert from Great Falls, Virginia, began a grueling mission: to get to the bottom of the slew of seemingly random symptoms that, for the next 7 years, would wreak havoc on his body, stump dozens of specialists, and nearly cost him his life.

It all started after Pherson, an avid runner, was diagnosed with severe coronary heart disease. He quickly underwent quadruple bypass surgery, but two weeks into his recovery, he developed a deep rash on his calves and later, red spots the size of half-dollar coins all over his body. The spots seemed to develop from outdoor ant bites, and though “they really hurt for two or three days,” Pherson said, it took a couple weeks for them to disappear. “I looked like a monster from the blue lagoon,” Pherson joked. Sometimes the rashes, which still come and go today, responded to anti-inflammatory medications; often they did not.

Pherson endured the discomfort on and off for months, but grew to expect the unexpected when new symptoms would appear. Over the next six years, while juggling a demanding job, this was the roller-coaster life he lived. He had fevers, sometimes with chills, late in the day. Joint pain followed – first in his left toe and his right wrist for a couple of days, then in his shoulder for a month or more. Anemia came next, accompanied by a white blood cell count that shot up to 10 times above normal levels.

Through it all, Pherson was vigilant. He met with eight different specialists, including cardiologists, pulmonologists, and rheumatologists. Altogether they tested for some 50 conditions, each result proving negative. “They kept trying to eliminate things, but I never received a diagnosis or medication,” said Pherson, now age 73. “They said, ‘we have to find you other doctors. We have to try to find out how to fix this.’”

Yet it was not until 2021 when Pherson was on a trip in Iceland, that a breakthrough occurred. It took a crisis for it to happen, however.

The morning after a day of hiking and seeing waterfalls, Pherson woke up with a fever of nearly 104 degrees, and he felt short of breath when he moved around. He went to a local hospital, where doctors, hearing his story and eager to find answers, discovered blood clots in his lower leg and lungs, and fluid accumulating around his heart and lungs. Pherson, who could barely hold a glass of water, recalled the doctors saying that if “I had not shown up at the hospital and if I had not gotten treatment, that I would have been dead within a month, easily.”

Pherson stayed there for 2½ weeks as doctors performed tests, one of which was a biopsy of his arteries. It showed signs of inflammation.

As luck would have it, the doctors had been working on a research project with Peter Grayson, M.D., M.Sc., a vasculitis investigator at the National Institutes of Health, and they immediately connected him with Pherson, who was then transported to a hospital in the Washington area.

Shortly after his hospital stay, he met with NIH researchers. To further narrow the list of potential conditions creating Pherson’s symptoms, they sequenced his genome to determine the entire genetic makeup of his cells. About five months later, in February 2022, Pherson was diagnosed with VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, an autoimmune condition that results from a mutation in blood cells.

The timing was fortunate. VEXAS had only been discovered in 2020 and since then more than 100 people, mostly men ages 50 and older, have been diagnosed with the condition. “The prevalence of the disease could be in the range of affecting every 1 in 10,000-20,000 people, which is extraordinary for a new rare disease,” Grayson said.

“It’s the first time we have been able to directly link rheumatologic and hematologic disorders by way of a mutation like this,” said Emma M. Groarke, M.B., FRCPath, an attending hematologist and researcher within the Hematopoiesis and Bone Marrow Failure Laboratory at the National Heart, Lung, and Blood Institute (NHLBI). Through a global research effort, scientists and doctors are now working together to help more people with VEXAS receive the right diagnosis and treatment.

Studying UBA1 mutations to guide treatment

When Pherson received news that he had the UBA1 mutation, which causes VEXAS, researchers still weren’t sure if it explained all his symptoms.

He had telltale signs of the condition, such as fevers, rashes, blood clots, anemia, and fluid accumulating around the heart and lungs. However, other symptoms, like eosinophilia, an increase in white blood cells, had not yet been associated with the disease. And even though the cardiovascular disease Pherson had has not yet been tied to VEXAS, researchers have seen it in some people months before or after inflammatory symptoms show up and plan to identify any potential link as they study the disease’s natural course.

“There are many different facets of the disease,” said Bhavisha A. Patel, M.D., a hematologist and researcher in NHLBI’s Hematopoiesis and Bone Marrow Failure Laboratory. “I believe that is what is challenging when we think about treatment, because it’s so heterogeneous.”

Patel explained that VEXAS results in widespread inflammation but shares features of other blood disorders. As a result, physicians currently use treatments, like steroids and immune-modulating therapies, to reduce and regulate inflammation. Other times they use medication to break up inflammatory clots, which affect about half of people with VEXAS. However, these are all temporary solutions as researchers study the durability of these treatments.

Since being diagnosed with VEXAS, Pherson has started taking a low-dose steroid and an immune-modulating therapy that’s often prescribed for arthritis. He also takes other treatments to curtail the side effects of these therapies. And while he has resumed all his normal activities – but at a slightly slower pace – he knows the symptoms can change and vary dramatically over time. This is why he works with six specialists. “You need to have them all talking to each other,” he said. “You have to try to keep everyone educated as part of a team.” He is also participating in studies at NIH to help researchers better understand the condition and identify future treatments.

In working to create tailored therapies for VEXAS, investigators are studying the UBA1 mutation. For example, is the location of the UBA1 mutation causing severe clotting in blood vessels, or is the clotting a result of the mutation creating a hyperinflammatory environment? They are exploring similar links between VEXAS and blood-related cancers, while studying shared features between VEXAS and clonal hematopoiesis, a condition that results from a mutation in blood cells and is associated with increased risks for atherosclerosis.

For now, “the VEXAS treatment strategy is twofold,” Groarke said. “One is controlling the inflammation. The other is to try to eradicate the underlying clone. You know, get rid of the UBA1 mutation.”

To expand on the latter, researchers started the first allogenic hematopoietic stem cell bone marrow transplant trial at the NIH Clinical Center in November.

Testing a cure for VEXAS

“There have been a handful of patients from around the world who have had transplants, but this is the first-ever trial for this disease using a transplant,” Groarke said.

The concept for the bone marrow transplant is similar to transplants used for conditions like sickle cell disease and leukemia. Researchers have started by working with a small group of adults with VEXAS who are eligible for the trial and have a full or partially-matched bone marrow donor. As part of this process, study participants will undergo light chemotherapy to help their body receive the new bone marrow, where blood cells are produced.

The goal is to create an immunological “reset” to help the body eliminate the UBA1 mutation or at least deactivate it so that VEXAS symptoms are no longer present. Then, with the help of new stem cells from the donor, the recipient’s body would ideally produce normal blood cells.

“It basically wipes out the bone marrow and stem cells in hopes of having the new marrow make home and produce normal cells,” Patel said. “Because it’s a new disease and new treatment, safety is the highest priority in our treatment protocol.”

Current study participants include adults with life-threatening forms of VEXAS who haven’t responded to or wouldn’t be able to take other treatment, such as steroids or immune-modulating therapies. Pherson, for example, is part of the study, but his symptoms don’t justify having a bone marrow transplant. After participants receive the transplant, they will stay in touch with researchers for the first 100 days and check in throughout the first year. After that, they will check in annually for two years and provide updates about their progress.

The concept for the trial grew from earlier research in France involving six adults with VEXAS who had bone marrow transplants. Five participants remained in remission. One passed away due to complications from an infection. In a paper in Blood Advances, the researchers explained the goal of this type of research is to not only test the safety and efficacy of bone marrow transplants for VEXAS, but to identify adults who respond best to the curative treatment.

So far, the NIH trial is limited to adults who are expected to do best with the transplant. This includes adults ages 18-75, who don’t have underlying health conditions or infections, and who aren’t allergic to certain medications. However, Patel noted that the transplant is just one treatment option.

“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.”

Resources:

To learn more about VEXAS, visit https://www.niams.nih.gov/labs/grayson-lab/vexas.

To learn more about the clinical research trial, visit https://clinicaltrials.gov/ct2/show/NCT05027945.