2025/09/24 by Ziyuan He, Marla C. Glass, Pravina Venkatesan +74 · 1 voice · 1 citation
Immunology and Microbiology · Medicine · #T-cell and B-cell Immunology #Systemic Lupus Erythematosus Research #Rheumatoid Arthritis Research and Therapies
paper · doi:10.1126/scitranslmed.adt7214
openalex publication_date 2025/09/24 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/29
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.