ObjectiveTo investigate immune dysregulation in the peripheral blood that contributes to the pre‐rheumatoid arthritis (RA) stage of RA development in anticitrullinated protein antibody (ACPA)+ individuals.MethodsUsing 37 markers by mass cytometry, we investigated peripheral blood mononuclear cells (PBMCs) from ACPA+ at‐risk individuals, ACPA+ early untreated patients with RA, and ACPA− controls in the Tokyo Women's Medical University cohort (n = 17 in each group). Computational algorithms, FlowSOM and Optimized t‐Distributed Stochastic Neighbor Embedding, were employed to explore specific immunologic differences between study groups. These findings were further evaluated, and longitudinal changes were explored, using flow cytometry and PBMCs from the US‐based Targeting Immune Responses for Prevention of RA cohort that included 11 ACPA+ individuals who later developed RA (pre‐RA), of which 9 had post‐RA diagnosis PBMCs (post‐RA), and 11 ACPA− controls.ResultsHLA‐DR⁺ peripheral helper T (Tph) cells, activated regulatory T cells, PD‐1^hi CD8⁺ T cells, and CXCR5⁻CD11c⁻CD38⁺ naive B cells were significantly expanded in PBMCs from at‐risk individuals and patients with early RA from the Tokyo Women's Medical University cohort. Expansion of HLA‐DR⁺ Tph cells and CXCR5⁻CD11c⁻CD38⁺ naive B cells was likewise found in both pre‐RA and post‐RA time points in the Targeting Immune Responses for Prevention of RA cohort.ConclusionThe expansion of HLA‐DR⁺ Tph cells and CXCR5⁻CD11c⁻CD38⁺ naive B cells in ACPA+ individuals, including those who developed inflammatory arthritis and classified RA, supports a key role of these cells in transition from pre‐RA to classified RA. These findings may identify a new mechanistic target for treatment and prevention in RA.image