Progression to rheumatoid arthritis in at-risk individuals is defined by systemic inflammation and by T and B cell dysregulation
Science Translational Medicine, 2025
He Z., Glass M., Venkatesan P., Feser M., Lazaro L., Okada L., Tran N., He Y., Zaim S., Bennett C., Ravisankar P., Dornisch E., Ferrannini A., Arishi N., Asamoah A., Barzideh S., Becker L., Bemis E., Buckner J., Collora C., Criley M., Demoruelle M., Fleischer C., Garber J., Genge P., Gong Q., Graybuck L., Gustafson C., Hattel B., Hernandez V., Heubeck A., Kawelo E., Krishnan U., Kuan E., Kuhn K., LaFrance C., Lee K., Li R., Lord C., Mettey R., Moss L., Musgrove B., Nguyen K., Ochoa A., Parthasarathy V., Pebworth M., Pedrick C., Peng T., Phalen C., Reading J., Roll C., Seifert J., Siedschlag M., Speake C., Striebich C., Stuckey T., Swanson E., Takada H., Thai T., Thomson Z., Trieu N., Tsaltskan V., Wang W., Weiss M., Westermann A., Zhang F., Boyle D., Goldrath A., Bumol T., Li X., Holers V., Skene P., Savage A., Firestein G., Deane K., Torgerson T., Gillespie M.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Immunological & Inflammatory Diseases | Patient Stratification | Plasma |  Olink Explore 3072/384 |
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.