CO:10:1 | High-grade synovitis and histological pathotype distribution in patients with advanced osteoarthritis undergoing joint replacement: a more inflammatory disease than we thought?

Jacopo Ciaffi¹, Lorenzo Bianchi¹, Luana Mancarella², Federica Pignatti², Veronica Brusi², Lucia Lisi², Simona Neri², Elisa Assirelli², Alberto Righi³, Marco Gambarotti³, Francesco Ursini¹. | ¹SSD Medicina e Reumatologia, IRCCS Istituto Ortopedico Rizzoli, Alma Mater Studiorum Università di Bologna; ²SSD Medicina e Reumatologia, IRCCS Istituto Ortopedico Rizzoli, Bologna; ³SSD di Anatomia e Istologia Patologica, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy

Background. Osteoarthritis (OA) has traditionally been regarded as a degenerative disease, with inflammation playing only a marginal role. However, recent evidence suggests that synovitis may significantly contribute to OA pathophysiology. This study aimed to describe the grade of synovitis and the distribution of synovial histological pathotypes in patients with advanced OA undergoing joint replacement, and to explore associations with clinical, laboratory, and radiographic variables.

Materials and Methods. A retrospective observational study was conducted on patients with OA who underwent primary total hip or knee arthroplasty between 2000 and 2024. Synovial membrane samples collected during surgery were analyzed histologically using hematoxylin-eosin staining and immunohistochemistry. The Krenn synovitis score was applied to assess inflammation severity. Based on cellular composition, samples were classified into three main synovial pathotypes: lympho-myeloid, diffuse myeloid, and pauci-immune. Clinical and laboratory data (including ESR, CRP, BMI, Kellgren-Lawrence grade, and rheumatologic history) were retrieved from medical records. Associations between histological features and clinical parameters were evaluated through univariate and multivariate logistic regression.

Resulus. Ninety-nine patients were included (mean age 74 ± 11 years; 51.5% female). High-grade synovitis (Krenn score above 4) was observed in 62.6% of cases. The most frequent synovial pathotype was lympho-myeloid (57.6%), followed by pauci-immune (30.3%) and diffuse myeloid (12.1%). No significant differences in synovitis grade or pathotype distribution were found between hips and knees (Figure 1). The Krenn score was significantly higher in lympho-myeloid samples (mean 5.8 ± 1.0 vs. 4.3 ± 1.1; p < 0.001). Histology revealed greater cellularity, organized lymphoid aggregates, and abundant CD20+, CD3+ infiltrates in this pathotype, along with increased synovial hyperplasia and neoangiogenesis. At multivariate analysis, Kellgren-Lawrence grade was independently associated with the lympho-myeloid pathotype (OR 1.763; 95% CI 1.041–2.984; p = 0.035; figure 2). Elevated ESR (>20 mm/h) showed a non-significant trend toward association (OR 1.622; p = 0.091), while age, sex, BMI, and CRP were not predictive. Lympho-myeloid pathotype was associated with higher VAS pain scores (mean 7.2 vs. 6.0; p = 0.048) and longer disease duration (mean 9.6 vs. 6.4 years; p = 0.031).

Conclusions. This study reveals a high prevalence of both high-grade synovitis and the lympho-myeloid pathotype in patients with advanced OA undergoing joint replacement. These findings challenge the traditional view of OA as a purely degenerative disease and support the concept that distinct inflammatory phenotypes may exist within OA. The presence of structured immune infiltrates and their association with structural damage, pain severity, and disease chronicity suggest a pathogenic and prognostic role of synovial inflammation. Further studies are warranted to define the clinical implications of synovial pathotypes and their relevance for therapeutic strategies.