Revisiting osteoarthritis as an inflammatory disease: characterization of synovitis grading and synovial pathotypes in surgical specimens

ABSTRACT Background: Synovial inflammation is increasingly recognized as a relevant component of osteoarthritis (OA), yet its histopathological and immunological features in advanced disease remain incompletely characterized. Whether distinct synovial pathotypes are associated with specific clinical, laboratory, radiographic characteristics, or postoperative outcomes is still unclear. Methods: In this cross-sectional study, synovial tissue samples from OA patients undergoing hip or knee arthroplasty, or other joint surgery, were analyzed through standardized histology (Krenn score) and semi- quantitative immunohistochemistry (CD3, CD20, CD68, CD138). Pathotypes were categorized as lympho- myeloid, diffuse-myeloid, or pauci-immune. Preoperative demographics, Kellgren–Lawrence radiographic grade, systemic inflammatory markers, and postoperative outcomes were retrieved from clinical records. Comparisons were performed using Kruskal–Wallis and Fisher’s exact tests. A multivariable logistic regression identified predictors of the lympho-myeloid pathotype. Results: 244 samples were analyzed. High-grade synovitis was present in 64.3% of specimens. Pathotype distribution was: 55.3% lympho-myeloid, 11.9% diffuse-myeloid, and 32.8% pauci-immune. Lympho- myeloid tissues displayed the highest inflammatory burden, including elevated Krenn scores and higher systemic inflammatory indices. Pathotype distribution varied across joints, whereas the proportion of high- grade synovitis did not. In multivariable modeling, higher BMI increased the odds of lympho-myeloid pathotype (OR 1.11, 95%CI 1.01–1.22). No associations emerged for inflammatory markers, Kellgren– Lawrence grade or preoperative pain. Postoperative complications were not different across pathotypes. Conclusions: Advanced OA displays marked synovial heterogeneity, with immune infiltration patterns that parallel systemic inflammatory signatures. Our findings support the concept that synovial pathotypes ARTICLE IN PRESS capture relevant biological variation within OA and may contribute to a more refined framework for disease stratification in future studies.