Th150 - Immunophenotypic Abnormalities Similar to Established Rheumatoid Arthritis Are Present in ACPA(+) At-risk Individuals

Samir Zaim – Allen Institute for Immunology; Lauren Okada – Allen Institute for Immunology; Julian Reading – Allen Institute for Immunology; Alexander Heubeck – Allen Institute for Immunology; Charles Roll – Allen Institute for Immunology; Palak Genge – Allen Institute for Immunology; Morgan Weiss – Allen Institute for Immunology; Cole Phalen – Allen Institute for Immunology; Regina Mettey – Allen Institute for Immunology; Cate Speake – Center for Interventional Immunology – Benaroya Research Institute; Jane Buckner – Center for Translational Immunology – Benaroya Research Institute; David Boyle – Division of Rheumatology, Allergy and Immunology – University of California, San Diego; Tom Bumol – Allen Institute for Immunology; Michael Holers – Division of Rheumatology, Department of Medicine – University of Colorado Anschutz Medical Center; Kristen Demoruelle – Division of Rheumatology, Department of Medicine – University of Colorado Anschutz Medical Center; Kristine Kuhn – Division of Rheumatology, Department of Medicine – University of Colorado Anschutz Medical Center; Fan Zhang – Division of Rheumatology, Department of Medicine – University of Colorado Anschutz Medical Center; Peter Skene – Allen Institute for Immunology; Xiaojun Li – Allen Institute for Immunology; Gary Firestein – Division of Rheumatology, Allergy and Immunology – University of California, San Diego; Troy Torgerson – Allen Institute for Immunology; Kevin Deane – Division of Rheumatology, Department of Medicine – University of Colorado Anschutz Medical Center; Mark Gillespie – Allen Institute for Immunology; Adam Savage – Allen Institute for Immunology

Abstract Text: RA-associated autoantibodies (RF, ACPA) are detectable before the onset of clinically-apparent RA (i.e. “Clinical RA”), defining a state known as ‘At-Risk’ for future RA. However, the immunophenotype of this At-Risk state remains incompletely understood. Using a cross-sectional methodology, we analyzed plasma proteomics, PBMC compositions by flow cytometry, and PBMC transcriptomes by scRNA in a cohort of ACPA(+) At-Risk individuals and age, sex and BMI matched ACPA(-) controls. We observed significant differences in 138 plasma proteins between ACPA(+) individuals vs. ACPA(-) controls, including IL-6, IL1B, CCL3, and additional elevated inflammatory chemokines and cytokines. From flow cytometry and scRNA, we observed numerous PBMC phenotypic changes, notably increases in IgD- CD27- B cells and Tregs. A global enrichment of the oxidative phosphorylation pathway, characterized by the upregulation of the ubiquinone oxidoreductase supernumerary subunits (NDUF) genes, was observed across multiple immune cell types including T, B, and monocytes. Furthermore, IgD- CD27- B cells from ACPA(+) individuals expressed significantly lower levels of genes previously shown to be increased in IgD- CD27- B cells or autoimmune processes, including SAMHD1, ARID3A, and ZC3H12D, suggesting dysregulation of this compartment at the preclinical stage. ACPA(+) At-Risk individuals demonstrate numerous immune-related changes that are similar to changes in established Clinical RA, suggesting the “At-Risk” state is on a continuum with Clinical RA. These findings provide insights to potential biomarkers and immunopathologic mechanisms that may impact how we define the ‘At-Risk’ state and its development into RA, and suggest targets for interventions or intermediate endpoints in trials for RA prevention.