Elderly woman suffering from pain in knee. Tendon problems and Joint inflammation on dark background.
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Researchers from the Broad Institute of MIT and Harvard and Brigham and Women’s Hospital have made significant strides in understanding rheumatoid arthritis (RA) through new research that provides a cellular atlas of RA defining six subtypes of inflammation. The study, published in Nature, examined the cellular drivers of RA by analyzing tissues from RA donors at the single-cell level.

RA affects around 18 million people worldwide and while therapies that target specific pathways of the disease are now available, these medications only improve the symptoms of some patients. The new study provided a detailed, single-cell analysis of the condition and in the process identified new targets for therapeutic development

“In the treatment of individuals with rheumatoid arthritis, we struggle to find the right treatment for the right patient,” said corresponding author Soumya Raychaudhuri, MD, PhD, of the Brigham’s division of rheumatology, inflammation, and immunity and the Broad Institute, where he is an institute member. “We aimed to determine why some subsets of patients don’t respond to conventional treatments by looking at the subtypes of inflammation. We did so from many different angles, using multiple cutting-edge, single-cell techniques, and integrating results in a way that hasn’t been done before for an inflammatory disease.”

The new research is a major advance in the understanding of RA and is the result of a nine-year-old public-private partnership called Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus. The goal of the program is to develop molecular and cellular level knowledge of autoimmune diseases and to identify new potential drug targets.

For this study, a collaboration among U.S. and U.K. researchers, the team analyzed 79 samples of synovial tissue from donors with RA. Synovial tissue helps cushion and sustain joint health and is the tissue that become inflamed in RA. The researchers focused on patients with new onset of the disease and patients who were unresponsive to treatment as a method to get a better understanding of the early drivers of RA development as well as patients with refractory disease.

According to the paper, the researchers noted that they “deconstructed” RA pathology on a cellular level using surface protein data, histologic analysis, single-cell RNA-sequencing, and bulk RNA sequencing. After using a range of methods to analyze more than 314,000 cells in the study, the investigators found six distinct major forms of inflammation which they stratified by cell type, which they refer to as cell-type adundance phenotypes (CTAPs). Some CTAPs identified were not surprising including those enriched with T and B cells, but the team also found CTAPs there were associated with structural cells such as fibroblasts and endothelial cells, with relatively few inflammatory leukocyctes.

The hope is that these findings can change the paradigm for how RA is diagnosed by providing more information on the different cell types involve in RA and how their interconnections lead to its development. One change would be for a more comprehensive testing strategy that includes not only blood tests, as are currently used, but also testing of synovial tissues which significantly differ from blood.

“What this study shows is that the tissue matters. Our findings point to the value of getting synovial tissue biopsies to evaluate the nature of the pathological process, which can be so different across patients, said co-senior author Michael Brenner, MD, of the Brigham’s division of rheumatology, inflammation, and immunity. “Clinical trials going forward will benefit greatly from assessing tissue characteristics alongside responses to a therapy. By providing this atlas of cell types and pathways involved in RA, we are better able to pursue our precision medicine goal of being able to select the right drug for the right patient and achieve a high response rate.”

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