When Dana Orange’s patients experience flare-ups of rheumatoid arthritis (RA), they can be devastating. One woman’s pain is so great that she can’t bend her elbow to brush her teeth. Another is unable to support the weight of her purse. Still another takes 30 minutes to roll out of bed and 90 minutes more bath and dress.
But the worst part, says Orange, a rheumatologist at the Rockefeller University, is that these attacks are wholly unpredictable. A new study may change that. Orange and her colleagues found that in the weeks before an RA attack, a newly identified cell type builds up in the blood, possibly triggering inflammation in the joints. If researchers can target those cells for diagnosis or therapy, they could predict or even prevent the flares.
The new findings are “intriguing,” because they may help clinicians and patients more effectively manage the ebbs and flows of the disease, says Dirk Elewaut, a rheumatologist at Ghent University who was not involved in the study.
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RA is an autoimmune disease that causes debilitating pain and irreversible joint damage, among other symptoms. It affects an estimated 1.3 million people in the United States, with women more than twice as likely as men to develop the disease. Anti-inflammatory and immunosuppressant medications can help keep the disease in check, but the drugs’ effectiveness can wane over time, and up to one-third of patients on these drugs can experience flare-ups.
To better understand how the condition changes from day to day, Orange and colleagues decided to track fragments of messenger RNA in the blood of five patients with uncontrolled RA. They wanted to see whether—prior to a flare-up—there were any consistent changes in the kinds of RNA circulating in the bloodstream.
But ideal tracking would require patients to come to the lab at least weekly for blood draws, the team thought. That was unrealistic to ask of patients, so they had the five volunteers collect their own blood at home once per week (or multiple times if they were experiencing flare-ups) via pinprick—similar to the method some people with diabetes use to monitor their disease. The researchers also developed a new buffering solution which, when mixed with blood samples, would preserve RNA for at least 24 hours, allowing patients to mail their blood samples to the team’s lab.
Collectively, the blood draws continued for more than 200 weeks—a time of “blood, sweat, and tears,” says Robert Darnell, a neuro-oncologist at the Rockefeller University and senior author on the study. When the team finally reviewed the samples, researchers analyzed which types of RNA were abundant in each patient before, during, and after reported flares. They then matched those data to known signatures associated with cells causing inflammation to re-create patterns of immune activity.
That’s when they found a “major unexpected [RNA] signature,” Darnell says. Its source: mesenchymal cells, which develop into the body’s connective tissues and fill spaces between joints. This mesenchymal RNA consistently appeared in the weeks before flares in each patient, in tandem with RNA associated with inflammation. This led the team to dub these distinctive cells preinflammatory mesenchymal (PRIME) cells.
To validate their findings, the researchers then took samples from 19 additional patients with active RA and found that PRIME cells were present at much higher levels than in healthy controls, the team reports this week in The New England Journal of Medicine. Although this finding doesn’t mean PRIME cells cause the attacks, Darnell says, the patterns suggest they are integral to flare-ups of joint inflammation.
The researchers also found RNA signatures associated with immature white blood cells that peaked in the days prior to PRIME cell activity. White blood cells are responsible for initiating cascades of immune activity—recruiting other inflammatory cells in order to do so—and dysfunctional white blood cells have been implicated in multiple autoimmune diseases. Taken together, the finding suggests PRIME cells could be mobilized by abnormal immune system activity, Darnell says.
Prior research has found that similar inflammation-causing connective tissue cells cause the disease in the joints of mice, but this is the first time such cells have been found in the human bloodstream. That makes this study “important,” as it could direct researchers’ attention to ways in which these cells could be manipulated to rein in the disease, says Robert Winchester, a rheumatologic pathologist at Columbia University. However, the study is just a first step, Elewaut cautions. Knowing for certain how PRIME cells influence flare-ups will require “a much larger set” of experiments.
Other experts are excited by the new buffering solution. Stanley Cohen, a rheumatologist at the University of Texas Southwestern Medical Center who was not involved in the study, says it could help researchers monitor disease activity in patients with other autoimmune conditions that wax and wane, including lupus and ankylosing spondylitis. “One could easily imagine cut-and-pasting this entire protocol” to other diseases, Darnell says. Those include COVID-19—because severe cases feature a storm of immune cells, clotting factors, and other inflammatory signals in the blood. Darnell has already begun to adapt the method for monitoring COVID-19 in patients quarantining at home.
Darnell says the findings could help researchers “take the Benjamin Franklin approach to preventing fires: an ounce of prevention, rather than a pound of cure.” Orange sees a more concrete benefit for her patients. If the PRIME cells help diagnosis and treatment, “you could, at the bare minimum, plan your life, and perhaps even stop the flares from coming.”
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sciencemag.org, 17 July 2020
; https://www.sciencemag.org/news/2020/07/newly-identified-cell-type-may-help-predict-treat-rheumatoid-arthritis-flares?utm_campaign=news_daily_2020-07-17&et_rid=101614567&et_cid=3411797 ”>https://www.sciencemag.org