ObjectiveStructural changes of osteoarthritis (OA) may occur in the absence of pain. In this study, we aimed to identify histopathologic features that are associated with symptomatic knee OA.MethodsMedial tibial plateaus and synovium samples were obtained at the time of total knee replacement (TKR) surgery for OA (advanced OA group) or were obtained postmortem from subjects who had not sought medical attention for knee pain during the last year of life (non-OA control group). To identify features of OA, we compared the patients with advanced OA with the age-matched non-OA controls (n = 26 per group). To identify OA features associated with symptoms, we compared two additional groups of subjects who were matched for severity of chondropathy (n = 29 per group): patients undergoing TKR for symptomatic OA (symptomatic chondropathy group) and postmortem subjects with similar severity of chondropathy who were asymptomatic during the last year of life (asymptomatic chondropathy group). The histologic features of the samples were graded, and immunoreactivities for macrophages (CD68) and nerve growth factor (NGF) in the synovium were quantified. The cellular localization of synovial NGF was determined by double immunofluorescence analysis.ResultsAdvanced OA cases displayed more severe changes in the synovium (synovitis, increased synovial NGF, and CD68-immunoreactive macrophages) and cartilage (loss of cartilage surface integrity, loss of proteoglycan, tidemark breaching, and alterations in chondrocyte morphology) than did the non-OA controls. Synovial NGF was localized predominantly to fibroblasts and to some macrophages. The symptomatic chondropathy group displayed greater levels of synovitis, synovial NGF, and loss of cartilage integrity, in addition to alterations in chondrocyte morphology, than did the asymptomatic chondropathy group (P < 0.05 for each comparison).ConclusionSynovitis, increased synovial NGF, alterations in chondrocyte morphology, and loss of cartilage integrity are features of knee OA that may be associated with symptoms.

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Background Pain is the major symptom of knee osteoarthritis (OA) and is usually the reason sufferers first seek clinical assistance; however the precise relationship between tibiofemoral pathology and OA pain is not entirely clear. Although magnetic resonance imaging (MRI) studies have linked pain to synovitis, subchondral changes and meniscal abnormalities, the histopathological features specific to symptoms in OA are not well understood. Objectives To identify which histological features are associated with symptomatic human knee OA. Better understanding of pain-associated structural and biochemical modifications is crucial for the development of more targeted and effective analgesic treatments. Methods Medial tibial plateaux and synovia were obtained from post-mortem (PM) cases who had not sought help for knee pain and from patients undergoing total knee replacement (TKR) surgery for symptomatic OA. The Academic Rheumatology joint tissue repository (n >2000) was screened to select TKR and PM cases displaying similar macroscopic joint chondropathy (n = 29/group). Tissues were compared to identify which histological features were associated with painful OA, assuming TKR cases experienced greater levels of knee pain than PM. OA changes (Mankin score) and synovitis were histologically graded and CD68-positive macrophages and nerve growth factor (NGF) quantified using immunohistochemistry and computer-assisted image analysis. Results Synovitis, loss of cartilage surface integrity, proteoglycan loss, tidemark breaching and subchondral changes were all characteristic features of end-stage OA. In the current study, TKR and PM cases were matched for similar macroscopic chondropathy scores (207 v. 196, respectively, P > 0.05). Total knee replacement cases (median age 68 years, 55% male) were slightly younger (P < 0.05) than post-mortem cases (median age 71 years, 55% male). Synovial fractional area positive for NGF was increased in TKR compared with PM cases (13.9% vs. 9.3%, P = 0.021). Synovitis score and loss of cartilage surface integrity were also greater in the surgical group (P = 0.001 and 0.014, respectively), although CD68 fractional areas did not differ significantly between groups (P = 0.21). Adjusting for age differences did not affect the results. Conclusions Symptomatic OA is associated with increased synovial NGF expression, synovitis and loss of cartilage surface integrity compared to PM cases with similar macroscopic joint surface appearances who did not seek TKR. Synovial NGF may be a key inflammatory mediator associated with OA knee pain. Identifying structural, cellular and molecular signatures of symptomatic OA may lead to targeted treatment strategies in the future. Disclosure of Interest None Declared

4 group]) as covariates. Each covariate was divided into two groups according to the median value. Results: The ninety-three of 250 patients showed the K/L grade 2 group, while the remaining 157 patients showed the K/L grades 3 or 4. The mean SDS score of the patients in the present study was 39.6 points, and 50.8% (127 patients) of the patients were identified to be in a depressive state. No significant differences of the SDS scores of the patients with K/ L grade 2 were observed in comparison to those of the patients with K/L grade 3 or 4. In logistic regression analyses using SDS as a dependent variable, the independent variables those had achieved a statistically significant regression coefficient were the following two factors: JKOMcondition in daily life scores [b¼1.264, p¼0.002, odds ratio (OR); 3.54 (95% CI; 1.57 to 7.99)] and JKOM-health condition scores [b¼0.917, p¼0.005, OR; 2.50 (95% CI; 1.32 to 4.76)]. Conclusions: Among the patients with knee OA, approximately half of the patients were defined as a depressive state. The radiographic OA severities of the patients were not associated with the depressive state, but the daily life conditions and the health conditions evaluated by the patient-oriented outcome measure were the independent significant influential factors for the severity of depressive state in patients with knee OA.