Numbers of a new type of cell discovered in the blood of rheumatoid arthritis patients increase dramatically immediately before a flare.
Raised levels of a new type of cell, named PRIME cells, have been found circulating in the blood of patients with rheumatoid arthritis immediately before they experience a flare.
It is hoped that the research published, in the New England Journal of Medicine, will lead to a greater understanding of how flares evolve, so that they can be better predicted, prevented and treated.
Like many autoimmune diseases, rheumatoid arthritis is characterized by periods of stability interrupted by unpredictable flares, and such unpredictable “waxing and waning” of pain and inflammation can make life difficult for patients.
Dana Orange, assistant professor of clinical investigation at Rockefeller University in New York, and colleagues, used RNA sequencing techniques to test the blood of a rheumatoid arthritis patient over time to identify molecular changes corresponding to increased rheumatoid arthritis activity.
“We were interested in understanding the molecular events that lead to flares of rheumatoid arthritis,” explained Dr. Orange. “While the risks for developing rheumatoid arthritis, such as genetic risk factors like HLA-DR and environmental risk factors like smoking, have been well documented, it was not clear what is happening when patients transition from baseline to flare. We reasoned that a longitudinal study would be an ideal way to study this change over time.”
A single index patient was taught how to collect fingerstick blood specimens, which were sent to the lab for analysis, and the patient also kept a record of symptoms to identify when flares occurred. A total of 364 blood specimens were obtained over a four-year period, during which the patient experienced eight flares.
The results of the analyses were then validated using 235 samples were collected from another three patients.
The analyses revealed that around two weeks before a flare, there was an increase in the activity of B cells, which create antibodies. This was not unexpected as it is a common trait of autoimmune disorders
However, a week before the flare, there was an increase in expression of an RNA signature which did not accord with any known cell type. The cells, which have been named PRIME cells, which stands for PRe-Inflammatory Mesenchymal cells, disappeared during the flare.
“During the flare, we saw signatures of innate immune cells such as neutrophils, platelets and myeloid cells,” reported Orange, who is also an assistant attending physician at the Hospital for Special Surgery, New York.
Normally there are very low levels of these PRIME cells circulating in blood of patients with rheumatoid arthritis, about one in every 10,000 live peripheral blood mononuclear cells is a PRIME cell, she explained. “We don’t know their normal function but they do share some gene expression signatures of mesenchymal stem cells in addition to synovial fibroblasts. We are very interested to study their role in other clinical scenarios.”
She added: “The discovery of PRIME cells in blood prior to RA flares was of particular interest because others had shown that RA synovial fibroblasts can spread arthritis, and function as critical gatekeepers of synovial inflammatory infiltrates in animal models.”[i],[ii]
The researchers believe that PRIME cells may be precursors to these synovial fibroblasts, which are known to play a role in causing rheumatoid arthritis symptoms.
The researchers have extended their study to test the blood of the blood of a greater number of rheumatoid arthritis patients to confirm the generalizability of their findings. They are also testing factors that might activate B cells and investigating whether B cells might produce a signal that activates PRIME cells.
“We hope that this approach could be used to predict impending flare and hopefully prevent flares,” Orange said.
Orange DE, Yao V, Sawicka K, Fak J, Frank MO, Parveen S, Blachere NE, Hale C, Zhang F, Raychaudhuri S, Troyanskaya OG, Darnell RB. RNA Identification of PRIME Cells Predicting Rheumatoid Arthritis Flares. N Engl J Med. 2020 Jul 16;383(3):218-228. doi: 10.1056/NEJMoa2004114. PMID: 32668112.
[i] Lefèvre S, Knedla A, Tennie C, et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat Med 2009; 15: 1414-20.
[ii] Croft AP, Campos J, Jansen K, et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature 2019; 570: 246-51.