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We characterized cellular and chromatin accessibility profiles in knee OA and radiographic progressors (RPs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed multimodal immunophenotyping using cytometry by time\u2010of\u2010flight mass spectrometry (CyTOF) on peripheral blood samples from 21 patients with knee OA and 11 healthy controls (HCs). To confirm findings, we developed DNA methylation\u2010based imputation models and applied them to two independent validation cohorts (n = 723). Finally, single\u2010cell Assay for Transposase\u2010Accessible Chromatin sequencing (scATAC\u2010seq) was performed to interrogate chromatin accessibility landscapes in a patient subset.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CyTOF identified significant expansions of CD8\n                      <jats:sup>+<\/jats:sup>\n                      central memory T cells, CD4\n                      <jats:sup>+<\/jats:sup>\n                      Treg cells, and nonclassical monocytes in patients with OA versus HCs (all\n                      <jats:italic>P<\/jats:italic>\n                      \u2264 0.05). These expansions were robustly confirmed in the large\u2010scale validation cohorts (all\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.0001). Conversely, RPs displayed validated reductions in circulating CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      central memory pools. scATAC\u2010seq revealed extensive epigenetic remodeling, particularly within monocytes and Treg cells. Paradoxically, unsupervised clustering indicated that epigenetically defined proinflammatory clusters were depleted in OA blood. Pathway analysis revealed that these depleted clusters possessed activated, migratory phenotypes, whereas the expanded circulating cells among patients with OA displayed quiescent, nonmigratory epigenetic signatures.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Knee OA is characterized by validated systemic expansions of specific Treg cell and monocyte subsets. Single\u2010cell epigenetic profiling suggests epigenetically distinct subpopulations driven by age, OA, comorbid conditions, or migration from circulation to the periphery.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.70240","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T11:47:53Z","timestamp":1780573673000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Multimodal Peripheral Blood Immunophenotyping and Single\u2010Cell Epigenetic Analysis of Knee Osteoarthritis Reveals Expansion and Epigenetic Dysregulation of Treg Cell and Nonclassical Monocyte Populations"],"prefix":"10.1002","author":[{"given":"Aleksander","family":"Szymczak","sequence":"first","affiliation":[{"name":"Arthritis and Clinical Immunology Program Oklahoma Medical Research Foundation  Oklahoma City"},{"name":"Oklahoma City Veterans Affairs Medical Center  Oklahoma City 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