Newly identified preinflammatory mesencyhmal cells, or PRIME cells, are potential predictors of rheumatoid arthritis (RA) flares, according to study results published in the New England Journal of Medicine.

While symptoms of RA are dynamic, with episodes of quiescence and flares, the factors leading to the autoimmune flares are not clearly understood. Several genes were previously associated with RA activity, and the aim of the current study was to identify transcriptional signatures that preceded clinical symptoms.

The study included 4 RA patients who were seropositive for anti-cyclic citrullinated peptide antibodies, including an index patient and 3 additional patients. All study participants were followed for up to 4 years and documented disease activity during the follow-up.


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Home blood collection strategy that allows high-quality RNA in large quantities for sequencing was developed and the participants completed home finger stick blood collection and mailed the samples overnight each week, where RNA was sequenced.  Specimens were obtained from 364 time points during eight flares over a period of 4 years in the index patient, and from 235 time points during flares in the 3 additional patients.

Analysis of finger stick blood specimens identified 2613 genes that were differentially expressed during a flare, compared with baseline, including 1437 genes with increased expression during a flare, and 1176 genes that were decreased during flares.

One cluster of gene transcripts increased 2 weeks before a flare and were enriched with developmental pathways for naïve B cells and leukocytes.

A second cluster of transcripts increased during the week before a flare and decreased over the duration of the flare. This cluster was enriched for pathways that were not typical of blood specimens, including cartilage morphogenesis, endochondral bone growth, and extracellular matrix organization. This gene activity suggested the presence of a mesenchymal cell.

The changes in transcriptional profiles in blood weeks before the onset of symptoms showed gene expression profiles of classical mesenchymal surface markers and genes, thus the researchers referred to these cells as preinflammatory mesenchymal cells, or PRIME cells.

According to the researchers, the data support a model in which PRIME cells in the blood become activated by B cells in the weeks before a flare and then migrate from blood to the synovium and contribute to the inflammatory process.

“We present longitudinal genomics as a strategy to study the antecedents to rheumatoid arthritis flares that may be generalizable to autoimmune diseases associated with waxing and waning clinical courses,” wrote the researchers.

Reference

Orange DE, Yao V, Sawicka K, et al. RNA Identification of PRIME cells predicting rheumatoid arthritis flares. N Engl J Med. 2020;383(3):218-228. doi:10.1056/NEJMoa2004114