RNA Identification of PRIME Cells Predicting Rheumatoid Arthritis Flares.

TitleRNA Identification of PRIME Cells Predicting Rheumatoid Arthritis Flares.
Publication TypeJournal Article
Year of Publication2020
AuthorsOrange, DE, Yao, V, Sawicka, K, Fak, J, Frank, MO, Parveen, S, Blachere, NE, Hale, C, Zhang, F, Raychaudhuri, S, Troyanskaya, OG, Darnell, RB
JournalN Engl J Med
Volume383
Issue3
Pagination218-228
Date Published2020 07 16
ISSN1533-4406
KeywordsAdult, Arthritis, Rheumatoid, B-Lymphocytes, Female, Fibroblasts, Flow Cytometry, Gene Expression, Humans, Male, Mesenchymal Stem Cells, Middle Aged, Patient Acuity, Sequence Analysis, RNA, Surveys and Questionnaires, Symptom Flare Up, Synovial Fluid
Abstract

<p><b>BACKGROUND: </b>Rheumatoid arthritis, like many inflammatory diseases, is characterized by episodes of quiescence and exacerbation (flares). The molecular events leading to flares are unknown.</p><p><b>METHODS: </b>We established a clinical and technical protocol for repeated home collection of blood in patients with rheumatoid arthritis to allow for longitudinal RNA sequencing (RNA-seq). Specimens were obtained from 364 time points during eight flares over a period of 4 years in our index patient, as well as from 235 time points during flares in three additional patients. We identified transcripts that were differentially expressed before flares and compared these with data from synovial single-cell RNA-seq. Flow cytometry and sorted-blood-cell RNA-seq in additional patients were used to validate the findings.</p><p><b>RESULTS: </b>Consistent changes were observed in blood transcriptional profiles 1 to 2 weeks before a rheumatoid arthritis flare. B-cell activation was followed by expansion of circulating CD45-CD31-PDPN+ preinflammatory mesenchymal, or PRIME, cells in the blood from patients with rheumatoid arthritis; these cells shared features of inflammatory synovial fibroblasts. Levels of circulating PRIME cells decreased during flares in all 4 patients, and flow cytometry and sorted-cell RNA-seq confirmed the presence of PRIME cells in 19 additional patients with rheumatoid arthritis.</p><p><b>CONCLUSIONS: </b>Longitudinal genomic analysis of rheumatoid arthritis flares revealed PRIME cells in the blood during the period before a flare and suggested a model in which these cells become activated by B cells in the weeks before a flare and subsequently migrate out of the blood into the synovium. (Funded by the National Institutes of Health and others.).</p>

DOI10.1056/NEJMoa2004114
Alternate JournalN. Engl. J. Med.
PubMed ID32668112
Grant ListUL1 TR000043 / TR / NCATS NIH HHS / United States
Bridge Funding Award / / American College of Rheumatology Research and Education Foundation / International
1UM1HG008901 / NH / NIH HHS / United States
NS034389 / NH / NIH HHS / United States
NS081706 / NH / NIH HHS / United States
NS097404 / NH / NIH HHS / United States
U01 HG009379 / NH / NIH HHS / United States
UH2AR067677 / NH / NIH HHS / United States
SFARI 240432 / / Simons Foundation / International
Robertson Therapeutic Development Fund / / Robertson Foundation / International
T32 HG003284 / HG / NHGRI NIH HHS / United States
R01 GM071966 / GM / NIGMS NIH HHS / United States
UL1 TR001866 / TR / NCATS NIH HHS / United States