Progression to rheumatoid arthritis in at-risk individuals is defined by systemic inflammation and by T and B cell dysregulation
Ziyuan He, Marla C. Glass, Pravina Venkatesan, Marie L. Feser, Leander Lazaro, Lauren Okada, Nhung T. T. Tran, Yudong D. He, Samir Rachid Zaim, CE Bennett, Padmapriyadarshini Ravisankar, Elisabeth M. Dornisch, Alexandra C. Ferrannini, Najeeb A. Arishi, Ashley G. Asamoah, Saman Barzideh, Lynne A. Becker, Elizabeth A. Bemis, Jane H. Buckner, Christopher E. Collora, Megan A. L. Criley, M. Kristen Demoruelle, Chelsie Fleischer, Jessica Garber, Palak C. Genge, Qiuyu Gong, Lucas T. Graybuck, Claire E. Gustafson, Brian C. Hattel, Veronica Hernandez, Alexander T. Heubeck, Erin K. Kawelo, Upaasana Krishnan, Emma L. Kuan, Kristine A. Kuhn, Christian M. LaFrance, Kevin J. Lee, Ruoxin Li, Cara Lord, R Mettey, Laura Moss, Blessing Musgrove, Katherine Nguyen, Andrea Ochoa, Vaishnavi Parthasarathy, Mark-Phillip Pebworth, Chong Pedrick, Tao Peng, Cole Phalen, Julian Reading, Charles R. Roll, Jennifer Seifert, Marguerite D. Siedschlag, Cate Speake, Christopher C. Striebich, Tyanna Stuckey, Elliott Swanson, Hideto Takada, Tylor Thai, Zachary Thomson, Nguyen Trieu, Vlad Tsaltskan, Wei Wang, Morgan Weiss, Amy Westermann, Fan Zhang, David L. Boyle, Ananda W. Goldrath, Thomas F. Bumol, Xiaojun Li, V. Michael Holers, Peter J. Skene, Adam K. Savage, Gary S. Firestein, Kevin D. Deane, Troy R. Torgerson, Mark A. Gillespie
Abstract
Rheumatoid arthritis (RA) is preceded by an at-risk stage of disease that can be marked by the presence of anticitrullinated protein antibodies (ACPAs) but the absence of clinically apparent synovitis (clinical RA). Preemptive intervention in at-risk individuals could prevent or delay future tissue damage; however, the immunobiology of this stage is unclear. Using integrative multiomics, we longitudinally profiled at-risk individuals, where one-third of participants developed clinical RA on study. We found evidence of systemic inflammation and signatures of activation in naïve T and B cells of at-risk individuals. During progression to clinical RA, proinflammatory skewing of atypical B cells and expansion of memory CD4 T cells with signatures of activation and B cell help were present without elevations in circulating ACPA titers. Epigenetic changes in naïve CD4 T cells suggested a predisposition to differentiate into effector cells capable of B cell help. These findings characterize pathogenesis of the ACPA + at-risk stage and support the concept that the disease begins much earlier than clinical RA. Additionally, an extensive immune resource of the at-risk stage and progression to clinical RA with interactive tools was developed to enable further investigation.