Progression to rheumatoid arthritis in at-risk individuals is defined by systemic inflammation and by T and B cell dysregulation

Rheumatoid arthritis (RA) is frequently preceded by an at-risk phase of disease marked by presence of anti-citrullinated protein antibodies (ACPA) but absence of clinically detectable synovitis. Preemptive treatment of at-risk individuals (ARI) could prevent or delay future tissue damage but immunobiology of this state is unclear. Using integrative multiomics, we longitudinally profiled ARI, where one-third of participants developed clinical RA on study, and found evidence of systemic inflammation, broad activation of naïve T and B cell subsets, proinflammatory-skewing of effector B cells, expansion of memory T cells with an activated Tfh-like signature despite no appreciable elevation in circulating ACPA levels. CD4 T-cell gene signatures from ARI who went on to develop clinical RA reflected those of RA patients that responded to Abatacept, implicating these cell states in RA pathogenesis.