biostudies-literatureHe ZNIAMS NIH HHSeadt7214https://www.ebi.ac.uk/biostudies/studies/S-EPMC12767604biostudies-literatureUnknown17(817)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 withScience translational medicineProgression to rheumatoid arthritis in at-risk individuals is defined by systemic inflammation and by T and B cell dysregulation.PMC12767604P30 AR079369Zhang FAsamoah AGMettey RRZaim SRPeng TGraybuck LTReading JLi XJSwanson EGParthasarathy VGarber JOchoa ACollora CEGenge PCKuan ELFeser MLBoyle DLWang WVenkatesan PFirestein GSGillespie MARoll CROkada LYKrishnan UHeubeck ATFleischer CLLi RGoldrath AWWestermann ALaFrance CMTsaltskan VSavage AKTakada HHe ZHattel BCHolers VMBecker LABuckner JHGong QStuckey TJRavisankar PHe YDSpeake CThai TStriebich CCTorgerson TRPedrick CDemoruelle MKPebworth MPBarzideh SGustafson CEHernandez VKuhn KATrieu NSeifert JASkene PJDeane KDSiedschlag MDMusgrove BThomson ZJArishi NAWeiss MDABennett CEBumol TFDornisch EMLazaro LTran NTTBemis EAGlass MCLord CMoss LFerrannini ACKawelo EKLee KJCriley MALPhalen CGNguyen KHfalseProgression to rheumatoid arthritis in at-risk individuals is defined by systemic inflammation and by T and B cell dysregulation.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 with2025-01-01T00:00:00Z2025 Sep2026-06-06T11:15:18.442Z2026-05-29T03:12:30.704ZS-EPMC127676044099172610.1126/scitranslmed.adt7214