PRIME Cells in RA Scouting Report

Written By: University of Colorado Rheumatology Fellows

Based on: Orange DE, et. al. RNA Identification of PRIME Cells Predicting Rheumatoid Arthritis Flares. NEJM. 2020;383:218-28

Topic Overview

Rheumatoid arthritis (RA), like many systemic autoimmune disorders, is characterized by periods of disease exacerbation and quiescence. Despite advances in our understanding of disease pathophysiology, little is known about the immunologic drivers of disease flares in RA. Previous studies have utilized cross-sectional analyses of RA patients with varying disease duration and clinical disease activity. This study offers unique insight into the immunologic changes, including in so-called PRIME (preinflammatory mesenchymal) cells, that occur directly preceding, during, and following disease flares, by utilizing a longitudinal design of four patients over years of intensive monitoring with frequent acquisition of transcriptional profiles and patient reported clinical data. A major strength of this paper lies in its unique methodology, as it generates detailed immunologic data that can be tightly correlated with concurrent clinical disease findings. 

Implications for Patients, Providers, & Researchers

Current implications: This paper describes immunologic changes in a small number of RA patients (n = 4). As such, applicability to wider populations (e.g., seropositive versus seronegative RA patients, early RA versus established RA, on csDMARD versus bDMARD therapy) is uncertain. The paper generates data that contributes to our understanding of immunologic underpinnings of RA flares, which can be helpful in patient education and counseling. Most importantly, this paper describes a methodology (proof of concept for the use of longitudinal transcriptomics) that can be utilized in the investigation of other autoimmune illnesses characterized by disease flares (SLE, vasculitis, etc…), and in studies investigating pre-clinical disease periods and the transition to overt clinical findings (e.g. pre-RA or incomplete lupus).

Future implications: Most immediately, this paper describes a clinical measurement tool that could provide educational benefit for patients and providers through explanation of how a flare may be happening (though not necessarily yet why). It holds potential in terms of personalized and precision medicine in the assessment and treatment of RA, and can be utilized in different stages of disease and perhaps even provide indication of transition between phases of disease (e.g. pre-clinical autoimmunity to clinical RA). Additionally, by understanding how flares may be occurring, this can further inform the process of identifying targets for novel therapies—a development that impacts both researchers and clinicians. This paper may highlight a new therapeutic target for treatment of RA (PRIME cells as the target).

Will PRIME Win its First Round Match-up?

PRIME certainly measures up against its competitor, R4RA. The latter is less ‘adaptable’ in future practice compared to PRIME as it relies on synovial biopsy. While the methodology described in both papers can be considered invasive, blood draws are certainly cheaper, less labor intensive, much more tolerable for patients when considering personalized medicine as opposed to acquiring tissue samples.

Could PRIME Win it All?

PRIME will have a very steep hill to climb to win it all. On one hand, the paper demonstrates the power of words (authors coining the term ‘PRIME’ cells) and a novel methodological approach. Anointing these cells as PRIME cells provides a better hook for readers than something along the lines of “A unique transcription profile found in CD45-CD31-PDPN+ synovial fibroblasts immediately precedes RA flares”. On the other hand, several competitors in the field offer immediate changes to clinical practice, and hence are likely to win out over the ‘delayed gratification’ of PRIME.


  1. Orange DE, et. al. RNA Identification of PRIME Cells Predicting Rheumatoid Arthritis Flares. NEJM. 2020;383:218-28
  2. Gravallese EM, Robinson WH. PRIME Time in Rheumatoid Arthritis. NEJM. 2020;383:278-279

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