Predicting Flares of Rheumatoid Arthritis Disease Activity

A longitudinal genomic analysis of rheumatoid arthritis (RA) flares identified a new type of cell, preinflammatory mesenchymal (PRIME) cells, are in the blood during the period before a flare. The research, published in New England Journal of Medicine Thursday, suggested that these cells become activated in the weeks before a flare.¹

Flares of RA disease activity can be unpredictable and follow periods of clinical stability.

“Such waxing and waning clinical courses are characteristic of many autoimmune diseases, including multiple sclerosis, systemic lupus erythematosus, and inflammatory bowel disease, underscoring a need to develop approaches to understand the factors that trigger transitions from quiescence to autoimmune flare,” the authors explained.

The researchers followed 4 patients with RA who were seropositive for cyclized citrullinated protein antibody (CCP). Their disease activity was assessed at home each week and up to 4 times daily during escalation of flares using the Routine Assessment of Patient Index Data 3 (RAPID3) questionnaire. RAPID3 was also used, along with the Disease Activity Score 28 (DAS28) to assess disease activity at clinic visits each month and during flares.

The researchers also used home blood collection strategies in order to get high-quality RNA for sequencing. The patients were followed for 1 to 4 years with weekly home collection of fingerstick blood specimens. As a result, the authors were able to “capture data before the onset of flares and identify different RNA signatures (AC2 and AC3) evidence in peripheral blood 1 to 2 weeks before a flare.”

According to the results, levels of circulating PRIME cells decreased during flares. “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,” the authors concluded.

In an accompanying editorial,² Ellen M. Gravallese, MD, of Brigham and Women’s Hospital, and William H. Robinson, MD, PhD, of Stanford University School of Medicine and VA Palo Alto Health Care System, noted that the research “sheds light on the kinectics of immune activtation leading to flares.”

They added that further studies are needed to define PRIME cells’ contribution to cytokine production, antigen presentation, and other functions that augment inflammation. However, they did note that since there is a lack of consensus about how to best define RA flare and only a small number of patients were studied, these findings might not be generalizable.

“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,” Garavallese and Robinson concluded.

References

1. 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

2. Gravallese EM, Robinson WH. PRIME time in rheumatoid arthritis. N Engl J Med. 2020;383(3):278-279. doi:10.1056/NEJMe2018218