Predicting Rheumatoid Arthritis Flares
Patients with Rheumatoid Arthritis (RA) often have unexpected flares in disease activity characterized by joint pain, swelling, and stiffness. These unpredictable episodes typically have negative consequences to the patient such as loss of income, diminished social participation, and feelings of frustration and depression. Little is known about the underlying mechanisms of RA flares, which present an important obstacle to predicting and ultimately preventing these events. In the July 2020 issue of the New England Journal of Medicine, a team of researchers at HSS and The Rockefeller University reported findings that implicate a newly discovered cell type that could incite a chain of immunological steps leading to RA flares.
These cells, which are virtually undetectable in blood when RA is quiescent, substantially increase one week prior to flares before returning to their usual levels after resolution of the flare. Monitoring patients’ bloodwork for these cells, which the researchers dubbed PRIME cells, could help predict the onset of RA symptoms, making it possible for clinicians and patients to better manage them.
“The possibility of using PRIME cells to predict RA flares, which until now have been very poorly understood and very unpredictable, is very exciting," says HSS rheumatologist and first author Dana Orange, MD.
“This new knowledge may lead to innovative ways to foresee these events and intervene early," adds HSS Physician-in-Chief Lou Bridges, MD, PhD, "thus preventing the detrimental effects of flares on patients.”
This new knowledge may lead to innovative ways to foresee these events and intervene early, thus preventing detrimental effects on patients.
In setting out to better understand RA flares at a molecular level, Dr. Orange and colleagues determined that they needed to sample frequently (sometimes more than once a day) in order to fully capture events leading to the onset and resolution. To solve this challenge, they designed a fingerstick test that would allow participants to collect their own samples at home and mail them in each week, along with a disease activity questionnaire detailing their symptoms.
To analyze the longitudinal samples, the team used RNA sequencing, which can detect differences in gene expression over time. From this data, they could work backward to see when and how different cell types emerged in the bloodstream in relation to the initiation of RA flares.
The analysis revealed the presence of neutrophils, myeloid cells and platelets during flares, which were expected; two weeks prior to flares, B cells were also detected in the blood. It was what the researchers found one week prior to flares that took them by surprise: an influx of a new type of mesenchymal cell, which expressed genes typically found in bone, cartilage, muscle and adipose cells. The team decided to call them PRe-Inflammatory Mesenchymal, or PRIME, cells.
“We were so surprised by this finding that we thought that it must have been some kind of technical artifact, at first,” says Dr. Orange, “but we kept testing and testing and all the results indicated that this represented a mesenchymal cell circulating in the blood prior to flares.”
Further analysis included data previously collected by the NIH-funded Accelerating Medicines Partnership, for which HSS is a clinical research site. The investigators found that PRIME cells share features similar to those of inflammatory synovial fibroblasts, which are known to play a role in the onset of RA flares.
We think that PRIME cells may become activated by B cells in the weeks before a flare and then migrate from the blood into joints during a flare.
Dr. Orange speculates that PRIME cells may act as cellular gatekeepers, providing entryway for B cells to invade joint tissue. “We think that PRIME cells may become activated by B cells in the weeks before a flare and then migrate from the blood into joints during a flare,” adds Dr. Orange.
More research is needed before a causal relationship can be established between B cells and PRIME cells. “If that’s true,” she says, “it opens up a whole new field of research that may one day lead to new treatments that can shut down flares before they happen.”