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Rheumatoid Arthritis Flare-Up Clues Found in Blood Transcriptomes Tested Over Time

NEW YORK – A prospective, longitudinal RNA sequencing study on blood samples from individuals with rheumatoid arthritis has uncovered a cell type that seems to become more prominent in samples from individuals about to experience exacerbated disease, known as a flare up.

"[P]RIME cells, which bear hallmarks of synovial fibroblasts, are more common in patients with rheumatoid arthritis than in healthy controls, and increase in blood just before flares," the authors reported in the New England Journal of Medicine on Thursday, noting that "this study of rheumatoid arthritis activity provides an example of an approach to the study of waxing and waning inflammatory diseases."

For their analysis, the researchers did RNA sequencing on 364 blood samples collected from one individual with rheumatoid arthritis over four years, along with more than 200 samples from three more rheumatoid arthritis patients experiencing flare-ups based on disease activity data gleaned from "Routine Assessment of Patient Index Data 3" (RAPID3) questionnaires.

Based on differential expression profiles from samples collected before RAPID3-documented flare-ups, along with available single-cell RNA-seq data previously generated for synovial samples, the team narrowed in on synovial fibroblast-like cells dubbed "pre-inflammation mesenchymal," or PRIME, cells that appeared to undergo expansion in the blood in the week or two leading up to bouts of inflammation.

"We were so surprised to see that the genes expressed right before a flare are normally active in the bone, muscle, and extracellular matrix — strange pathways to find in blood cells," co-first author Dana Orange, a molecular neuro-oncology researcher affiliated with Rockefeller, said in a statement.

The investigators went on to validate those findings with flow cytometry-based cell sorting and RNA sequencing on blood samples for another 19 individuals with rheumatoid arthritis, generating additional data to suggest PRIME cell features might eventually lead to better strategies for predicting or treating rheumatoid arthritis flare-ups.

"If we can reliably identify these new cells in patients, we may be able to tell them 'You're about to have a flare,' so they can prepare themselves. This would make flares less disruptive and easier to manage," senior author Robert Darnell, a molecular neuro-oncology researcher at Rockefeller, said in a statement, adding that "[i]f these cells are antecedents to joint sickness, they become a potential target for new drugs."

After bringing in data on a naïve B cell-related transcriptome signature in the blood samples considered, Darnell and his colleagues proposed a model in which activated immune B cells interact with newly recruited PRIME cells, which in turn move into the blood in the lead up to inflammatory events and, eventually, to the inflamed synovium space near damaged bone and cartilage at rheumatoid arthritis-affected joints.

"This finding is reminiscent of those in recent studies showing that autoreactive naïve B cells are activated in patients with rheumatoid arthritis," the authors proposed. "Although the triggers of this B-cell activation are unknown, infectious factors (e.g., bacterial or viral antigens), environmental factors, or endogenous toxins could either provide a source of specific antigens or activate pattern-recognition receptors."