Study sheds new light on the variety of cellular causes of rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation leading to pain, joint damage and disability, affecting approximately 18 million people worldwide. Although RA therapies targeting specific inflammatory pathways have emerged, only some patients’ symptoms improve with treatment, highlighting the need for multiple treatment approaches tailored to different disease subtypes. To more precisely define the cellular causes of RA, an international research consortium, co-led by researchers from the Broad Institute of MIT and Harvard and Brigham and Women’s Hospital, a founding member of the Mass General Brigham health care system, analyzed tissues from RA donors to the at the single-cell level, integrating multiple forms of analysis to stratify RA based on six subtypes of inflammation. Findings, published in Natureshed new light on the variety of cellular causes of RA, which may lead to more targeted, effective and patient-tailored therapeutic approaches.

“In treating people with rheumatoid arthritis, we struggle to find the right treatment for the right patient,” says 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 wanted to determine why some subgroups of patients do not respond to conventional treatments by looking at the subtypes of inflammation. We did this from many different angles, using multiple advanced, single-cell techniques and by integrating the results in a way that is has not been done before for an inflammatory disease.”

The study findings represent a major milestone in the Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus program, a public-private partnership launched in 2014 to advance the understanding of autoimmune diseases at the molecular and cellular levels and identify promising drug targets to identify. Working with researchers and physicians in the US and Britain, the researchers analyzed 79 donor samples of synovial tissue, the inflamed tissue in RA that normally helps soften and support joints. In particular, the researchers examined tissue from patients with new disease and from patients who did not respond to treatment to better identify both the initial causes of RA and those of refractory diseases.

To ‘deconstruct’ RA pathology at the cellular level, the researchers combined surface protein data and histological analysis with multiple forms of single-cell RNA sequencing and bulk RNA sequencing. Despite the variety of methods used to analyze more than 314,000 cells, the researchers consistently found evidence of six major types of inflammation, which they stratified by associated cell type, called cell type abundance phenotypes (CTAPs). Although some CTAPS, such as those enriched in T and B cells, would be expected to be used for an autoimmune disease like RA, the researchers were surprised to see that CTAPs were associated with structural cells such as fibroblasts and endothelial cells, with relatively few inflammatory leukocytes. They also found that patients’ CTAPs were dynamic and could change over time in response to treatment.

In the future, the researchers want to expand their knowledge of the cell types involved in RA by studying how interconnections between cells promote disease states. Furthermore, they hope that this work will advance the analysis of synovial tissues in RA patients, which is not currently standard practice. Although blood tests are more common in RA patients, findings from this study and others emphasize that the cellular profile of synovial tissue differs substantially from that of blood.

 

What this study shows is that tissue matters. Our findings point to the value of obtaining synovial tissue biopsies to evaluate the nature of the pathological process, which can be so different among patients. Future clinical trials will benefit greatly from assessing tissue characteristics in addition to responses to therapy. By providing this atlas of cell types and pathways involved in RA, we are better able to pursue our goal of precision medicine: being able to select the right drug for the right patient and achieve a high response rate.

 

Michael Brenner, MD, co-senior author, Brigham’s Division of Rheumatology, Inflammation and Immunity