He, Z.; Glass, M. C.; Venkatesan, P.; Feser, M. L.; Lazaro, L.; Okada, L. Y.; Tran, N. T. T.; He, Y. D.; Rachid Zaim, S.; Bennett, C. E.; Ravisankar, P.; Dornisch, E. M.; Arishi, N. A.; Asamoah, A. G.; Barzideh, S.; Becker, L. A.; Bemis, E. A.; Buckner, J. H.; Collora, C. E.; Criley, M. A. L.; Demoruelle, M. K.; Fleischer, C. L.; Garber, J.; Genge, P. C.; Gong, Q.; Graybuck, L. T.; Gustafson, C. E.; Hattel, B. C.; Hernandez, V.; Heubeck, A. T.; Kawelo, E. K.; Krishnan, U.; Kuan, E. L.; Kuhn, K. A.; LaFrance, C. M.; Lee, K. J.; Li, R.; Lord, C.; Mettey, R. R.; Moss, L.; Musgrove, B.; Nguyen, K.

Some autoimmune diseases, including rheumatoid arthritis (RA), are preceded by a critical subclinical phase of disease activity. Proactive clinical management is hampered by a lack of biological understanding of this subclinical \"at-risk\" state and the changes underlying disease development. In a cross-sectional and longitudinal multi-omics study of peripheral immunity in the autoantibody-positive at-risk for RA period, we identified systemic inflammation, proinflammatory-skewed B cells, expanded Tfh17-like cells, epigenetic bias in naive T cells, TNF+IL1B+ monocytes resembling a synovial macrophage population, and CD4 T cell transcriptional features resembling those suppressed by abatacept (CTLA4-Ig) in RA patients. Our findings characterize pathogenesis prior to clinical diagnosis and suggest the at-risk state exhibits substantial immune alterations that could potentially be targeted for early intervention to delay or prevent autoimmunity.