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Objective: Rheumatoid arthritis (RA) has a "pre‐RA" period in which multiple autoantibodies, including antibodies to citrullinated (cit) proteins (ACPA), rheumatoid factor (RF), anti–peptidyl arginine deiminase (anti‐PAD), among others, have been described; however, few studies have tested all autoantibodies in a single pre‐RA cohort. This study aims to evaluate the prevalence of multiple autoantibodies in pre‐RA and potentially identify an autoantibody profile in pre‐RA that indicates imminent onset of clinical RA. Methods: We evaluated 148 individuals with two pre‐ and one post‐RA diagnosis samples available from the Department of Defense Serum Repository and matched controls. Samples were tested for immuglobulin (Ig) G anti–cyclic cit peptide‐3 (anti‐CCP3), five ACPA fine specificities, five anti‐PAD isoforms, as well as RF IgA and RF IgM using commercial platforms; cutoffs were determined using levels present in <1% of controls. Results: Positivity of anti‐CCP3, RF IgA and RF IgM, anti‐PAD1, anti–cit‐vimentin 2, anti–cit‐fibrinogen, and anti–cit‐histone 1 increased over time in pre‐RA, although anti‐PAD and ACPA fine specificities were predominately present within anti‐CCP3–positive individuals. Within anti‐CCP3–positive samples from the pre‐RA period, positivity for RFs as well as anti‐PAD and ACPA fine specificities classified samples as being closer to the time of RA diagnosis. Conclusion: Multiple autoantibodies are present in pre‐RA and increase in positivity as the time of RA diagnosis approaches. These results confirm previous findings predicting imminent RA and provide a pathway using commercial‐grade assays to assess the risk for and timing of development of clinical RA. [ABSTRACT FROM AUTHOR]

Objective: To 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. Methods: Using 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. Results: HLA‐DR+ peripheral helper T (Tph) cells, activated regulatory T cells, PD‐1hi 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. Conclusion: The 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. [ABSTRACT FROM AUTHOR]

Some autoimmune diseases, including rheumatoid arthritis (RA), are preceded by a critical subclinical phase of disease activity. Proactive clinical management is hampered by a lack of biological understanding of this subclinical 'at-risk' state and the changes underlying disease development. In a cross-sectional and longitudinal multi-omics study of peripheral immunity in the autoantibody-positive at-risk for RA period, we identified systemic inflammation, proinflammatory-skewed B cells, expanded Tfh17-like cells, epigenetic bias in naive T cells, TNF+IL1B+ monocytes resembling a synovial macrophage population, and CD4 T cell transcriptional features resembling those suppressed by abatacept (CTLA4-Ig) in RA patients. Our findings characterize pathogenesis prior to clinical diagnosis and suggest the at-risk state exhibits substantial immune alterations that could potentially be targeted for early intervention to delay or prevent autoimmunity. We provide a suite of tools at https://apps.allenimmunology.org/aifi/insights/ra-progression/ to facilitate exploration and enhance accessibility of this extensive dataset.