Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation that leads to pain, joint damage, and disability, which affects approximately 18 million people worldwide. While RA therapies targeted to specific inflammatory pathways have emerged, only some patients’ symptoms improve with treatment, emphasizing the need for multiple treatment approaches tailored to different disease subtypes. To more precisely define cellular drivers 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 healthcare system, analyzed tissues from RA donors at the single-cell level, integrating multiple forms of analysis to stratify RA by six subtypes of inflammation. Findings, published in Nature, shed new light on the variety of cellular causes of RA, which may inform more targeted, effective and patient-tailored therapeutic approaches.
“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 findings from the study 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 molecular- and cellular-level understandings of autoimmune diseases and identify promising drug targets. Through collaboration with researchers and clinicians across the U.S. and U.K., the investigators analyzed 79 donor samples of synovial tissue, the inflamed tissue in RA that normally helps cushion and sustain joints. In particular, the researchers examined tissue from patients with new-onset disease and from patients unresponsive to treatment to better identify both the initial drivers of RA as well as those of refractory disease.
To “deconstruct” RA pathology on a cellular level, the researchers combined surface protein data and histologic analysis with multiple forms of single-cell RNA-sequencing and bulk RNA sequencing. Despite the variety of methods used to analyze over 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). While some CTAPS, such as those enriched with T and B cells, were expected finding for an autoimmune disease like RA, the researchers were surprised to see CTAPs 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.
Going forward, the researchers aim to expand upon their knowledge of the cell types involved in RA by studying how interconnections between cells promote disease states. Furthermore, they hope this work will encourage increased synovial tissue analysis in RA patients, which is currently not standard practice. While 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 the tissue matters,” said co-senior author Michael Brenner, MD, of the Brigham’s Division of Rheumatology, Inflammation and Immunity. “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. 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.”
Disclosures: Raychaudhuri is a founder for Mestag Therapeutics, a scientific advisor for Janssen and Pfizer, and a consultant for Gilead and Rheos Medicines. Brenner is a founder for Mestag Therapeutics and a consultant for GlaxoSmithKline, 4FO Ventures and Scailyte AG. A complete list of disclosures is available in the article.
Funding: This work was supported by the Accelerating Medicines Partnership (AMP) in Rheumatoid Arthritis and Lupus Network, a public- private partnership (AbbVie, Arthritis Foundation, Bristol-Myers Squibb Company, Foundation for the National Institutes of Health, GlaxoSmithKline, Janssen Research and Development, Lupus Foundation of America, Lupus Research Alliance, Merck Sharp and Dohme, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Pfizer, Rheumatology Research Foundation, Sanofi and Takeda Pharmaceuticals International). Funding was provided through grants from the National Institutes of Health (UH2-AR067676, UH2-AR067677, UH2-AR067679, UH2-AR067681, UH2-AR067685, UH2- AR067688, UH2- AR067689, UH2-AR067690, UH2-AR067691, UH2-AR067694 and UM2- AR067678), as well as NIH grants to Raychaudhuri (NHGRI U01HG009379 and NIAMS R01AR063759) and Brenner (NIAMS R01AR073833 and R01AR073290). A complete list of funding is available in the article.
Paper cited: Zhang, F et al. “Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes” Nature DOI: 10.1038/s41586-023-06708-y
Authorship: Co-first authors are Fan Zhang (University of Colorado Anschutz Medical Campus), Anna Helena Jonsson (BWH), Aparna Nathan (Harvard University), and Nghia Millard (BWH). Co-senior authors alongside Raychaudhuri and Brenner are Kevin Wei (BWH), Deepak Rao (BWH), Laura Donlin (Hospital for Special Surgery) and Jennifer Anolik (University of Rochester Medical Center).
BWH co-authors include Qian Xiao, Maria Gutierrez-Arcelus, Gerald Watts, Dana Weisenfeld, Joyce Kang, Laurie Rumker, Joseph Mears, Kathryn Weinand, Ellen Gravallese, Katherine P Liao, Michelle Curtis, Kathryne Marks, Michelle Curtis, Qian Xiao, Maria Gutierrez-Arcelus, Gerald F. M. Watts, Dana Weisenfeld, Kathryne E. Marks, Joyce B. Kang, Laurie Rumker, Joseph Mears, Kathryn Weinand, Ellen Gravallese, Adam Chicoine, Kazyoshi Ishigaki, Gregory Keras, Ilya Korsunksy, James A. Lederer, Zhihan Li, Yhong Li, Yakir Reshef, Saori Sakaue, Zhu Zhu, Katherine Liao.
Additional authors include William Apruzzese, Kamil Slowikowski, Dana Orange, Javier Rangel-Moreno, Laura Geraldino-Pardilla, Kevin Deane, Darren Tabechian, Arnoldas Ceponis, Gary Firestein, Mark Maybury, Ilfita Sahbudin, Ami Ben-Artzi, Arthur Mandelin II, Alessandra Nerviani, Felice Rivellese, Costantino Pitzalis, Laura Hughes, Diane Horowitz, Edward DiCarlo, Brendan Boyce, Larry Moreland, Susan Goodman, Harris Perlman, Michael Holers, Andrew Filer, Vivian Bykerk, Saba Nayar, Nida Meednu, Ian Mantel, Myles Lewis
