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15-07-2020 | Rheumatology | News | Article

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PRIME cells may be a biomarker of imminent rheumatoid arthritis flares

Claire Barnard

medwireNews: Blood transcriptional profile changes and the presence of a novel cell type – termed PRIME cells – may be indicative of an impending flare in patients with rheumatoid arthritis (RA), suggest findings from a longitudinal genomic analysis published in The New England Journal of Medicine.

For the study, Dana Orange (Rockefeller University, New York, USA) and co-researchers recruited four RA patients who supplied weekly home-collected fingerstick blood samples and completed Routine Assessment of Patient Index Data 3 (RAPID3) questionnaires for 1–4 years. They obtained samples from 364 timepoints during eight flares over 4 years in the index patient, and from 235 timepoints during flares in the three additional patients, and carried out RNA sequencing to evaluate blood transcriptional profiles.

The investigators say that RAPID3 scores positively correlated with DAS28 scores at monthly clinic visits, and white blood cell counts estimated from RNA sequences positively correlated with laboratory-measured counts. This suggests “that patient reports of disease activity paired with analysis of fingerstick blood specimens may provide a high-quality and robust means by which patients can participate in longitudinal clinical research studies,” they note.

In all, there were 2791 genes with significant differential expression before and during an RA flare, which Orange and team categorized into five clusters. Two of the clusters, termed antecedent cluster 2 (AC2) and AC3, classified genes with differential expression before a flare. AC2 transcripts increased 2 weeks before and bore “RNA hallmarks of naive B cells,” while AC3 transcripts increased in the week leading up to a flare and then decreased after symptom onset.

“AC3 was enriched for pathways that were not typical of blood specimens, including cartilage morphogenesis, endochondral bone growth, and extracellular matrix organization, suggesting the presence of a mesenchymal cell,” report the researchers.

They add: “Given their expression of classical mesenchymal surface markers and genes, we refer to these cells as preinflammatory mesenchymal cells, or PRIME cells.”

And using flow cytometry, Orange et al demonstrated that PRIME cells occurred more frequently in blood samples taken from an additional 19 patients with RA compared with healthy controls.

“We suggest that before a clinical flare, B-cell immune activation (detected as AC2) acts on PRIME cells, which traffic to the blood (detected as AC3) and subsequently to the synovial sublining during flares of disease activity,” summarize the study authors.

The authors of an accompanying editorial say that if Orange and team’s results are validated in a broad population of RA patients, “it may become possible to intervene to prevent clinical flares when the telltale precursor changes associated with flare immunopathogenesis are detected and before clinical symptoms emerge.”

However, Ellen Gravallese (Brigham and Women’s Hospital, Boston, Massachusetts, USA) and William Robinson (Stanford University School of Medicine, Palo Alto, California, USA) caution that it is not yet known whether the findings are generalizable “since a small number of patients were studied and medications were not considered, and it remains likely that distinct cellular and molecular mechanisms are at play in different subpopulations of patients with rheumatoid arthritis.”

The editorialists conclude: “This study illustrates the exciting potential of longitudinal genomics to identify key antecedents of disease flares in an approach that may be applicable to the investigation of pathogenic and protective immune responses in a wide range of human diseases.”

medwireNews is an independent medical news service provided by Springer Healthcare. © 2020 Springer Healthcare part of the Springer Nature Group

N Engl J Med 2020; 383: 218–228
N Engl J Med 2020; 383: 278–279

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