Synovial inflammation in knee osteoarthritis (OA) causes disorganized synovial angiogenesis and complement activation in synovial fluid, but links between complement and synovial microvascular ...pathology have not been established. Since complement causes vascular pathology in other diseases and since sex-differences exist in complement activation and in OA, we investigated sex differences in synovial fluid complement factors, synovial tissue vascular pathology, and associations between complement and synovial vascular pathology in patients with late-stage knee OA.
Patients with symptomatic, late-stage radiographic knee OA undergoing total knee arthroplasty or high tibial osteotomy provided matched synovial fluid and tissue biopsies during surgery. Complement factors (C2, C5, adipsin, MBL, and CFI) and terminal complement complex (sC5b-C9) were measured in synovial fluid by multiplex or enzyme-linked immunosorbent assay, respectively. Features of synovial vascular pathology (vascularization, perivascular edema, and vasculopathy) were assessed by histopathology. Multivariate linear regression models were used to assess associations between synovial fluid complement factors and histopathological features of vascular pathology, with adjustment for age, sex, body mass index, and sex interaction. Sex-disaggregated comparisons were completed.
Synovial fluid biomarker and histopathology data were included from 97 patients. Most synovial fluid complement factors and synovial tissue histopathological features were similar between sexes. Synovial fluid C5 trended to lower levels in males (-20.93 ng/mL 95%CI -42.08, 0.23
0.05). Median vasculopathy scores (0.42 95%CI 0.07, 0.77
0.02) were higher in males. In the full cohort, C5 concentration was associated with lower vascularization scores (-0.005 95%CI -0.010, -0.0001
0.04) while accounting for sex*C5 interaction. In sex-disaggregated analyses, increased C5 concentration was associated with lower vascularization scores (-0.005 95%CI -0.009, -0.0001
0.04) in male patients, but not in female patients. Males had higher sC5b-C9 compared to females. Additionally, males with high C5 had a higher synovial fluid concentration of sC5b-C9 compared to males with low C5. No differences were found in females.
Higher synovial fluid C5 levels were associated with increased complement activation and decreased synovial vascularization in males but not in females with OA. Future studies should test whether synovial fluid complement activation suppresses synovial angiogenesis and identify mechanisms accounting for C5-related sex-differences in synovial fluid complement activation in patients with knee OA.
To examine the association between ultrasound (US)-detected knee inflammation and intermittent and constant pain experiences in patients with knee osteoarthritis (OA).
Participants with ...radiographically early-stage (Kellgren-Lawrence arthritis grading scale KL ≤ 2) and late-stage (KL ≥ 3) disease and frequent symptoms underwent musculoskeletal US measures of inflammation using the Outcome Measures in Rheumatology (OMERACT) knee US scoring system. Pain experiences were captured using the Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP) tool. We assessed the association between US-synovitis and ICOAP pain experiences using a series of linear, logistic, or multinomial logistic regression models (as appropriate for each variable), while adjusting for age, sex, BMI, and radiographic stage. Secondary analyses were performed similarly by radiographic stage.
Pain and synovitis measures from 248 patients (453 knees) were included. Worse synovitis was associated with higher ICOAP constant pain scores (β 8.05, 95% CI 0.67-15.43), but not intermittent pain scores. Moderate-to-severe synovitis was associated with a 4.73-fold increased relative risk (95% CI 1.06-17.00) of a constant pain pattern. In secondary analyses, moderate-to-severe synovitis in early radiographic OA was associated with 2.70-higher odds (95% CI 1.04-7.02) of any constant pain, 3.28-higher odds (95% CI 1.43-7.52) of any intermittent pain, and with higher intermittent (β 10.47, 95% CI 1.03-19.91) and constant (β 12.62, 95% CI 3.02-22.23) pain scores. No associations were identified for synovitis in those with late radiographic OA.
In patients with knee OA, moderate-to-severe synovitis is most strongly associated with constant pain. Inflammation may play context-specific roles across pain experiences, especially in earlier radiographic stages of knee OA.
To identify the presence and distribution of histopathological features of synovial inflammation and tissue damage, and to test their associations with US imaging measures of synovitis and ...patient-reported measures of pain in knee osteoarthritis (OA).
In the cross-sectional study of 122 patients undergoing surgery for painful late-stage (Kellgren-Lawrence Grade 3 or 4) knee OA, we compared ultrasound (US) measures of synovitis (n=118) and pain (Knee Injury and Osteoarthritis Outcome Score) to histopathological measures of inflammation vs. synovial tissue damage in synovial tissue biopsies. Associations of histopathological features with US measures of inflammation or pain were assessed using linear or logistic regression, while controlling for covariates.
Histopathological features of inflammation were associated with higher odds of moderate/severe US synovitis (OR=1.34 95%CI 1.04, 1.74), whereas features of synovial tissue damage were associated with lower odds of moderate/severe US synovitis (OR = 0.77 95%CI 0.57, 1.03). Worse histopathological scores for synovial tissue damage were associated with more pain (-1.47 95%CI -2.88, -0.05), even while adjusting for synovial inflammation (-1.61 95%CI -3.12, -0.10).
Synovial tissue damage is associated with pain in late-stage knee OA, independent from inflammation and radiographic damage. These novel findings suggest that preventing synovial tissue damage may be an important goal of disease-modifying OA therapy.
Pain experiences in patients with knee osteoarthritis (OA) may be influenced differently by OA risk factors, reducing the translatability of preclinical research into the clinic. Our objective was to ...contrast evoked pain patterns after exposure to different OA risk factors including acute joint trauma, chronic instability, or obesity/metabolic syndrome using rat models of experimental knee OA. We tested longitudinal patterns of evoked pain behaviors (knee pressure pain threshold and hindpaw withdrawal threshold) in young male rats exposed to different OA-inducing risk factors including (1) nonsurgical joint trauma (impact-induced anterior cruciate ligament (ACL) rupture); (2) surgical joint destabilization (ACL + medial meniscotibial ligament transection); and (3) high fat/sucrose (HFS) diet-induced obesity. Histopathology for synovitis, cartilage damage, and subchondral bone morphology was performed. Pressure pain threshold was reduced (more pain) most, and earlier by joint trauma (Week 4-12) and HFS (Week 8-28) than by joint destabilization (Week 12). Hindpaw withdrawal threshold was reduced transiently after joint trauma (Week 4), with smaller and later reductions after joint destabilization (Week 12), but not with HFS. Synovial inflammation occurred at Week 4 after joint trauma and instability but only coincided with pain behaviors after joint trauma. Cartilage and bone histopathology were most severe after joint destabilization and least severe with HFS. The pattern, intensity, and timing of evoked pain behaviors varied due to OA risk factor exposure and were inconsistently associated with histopathological OA features. These findings may help to explain the challenges with translating preclinical OA pain research to multimorbid clinical OA contexts.
Osteoarthritis (OA) is the most prevalent musculoskeletal disease worldwide. Chronic pain remains the foremost concern of OA patients and is poorly controlled by available pharmacotherapies. Current ...preclinical research, which aims to develop analgesics better suited for OA, is largely dependent on animal models and laboratory pain testing. This review summarises commonly used small animal models for studying experimental OA, including their benefits and limitations. Also discussed are a variety of validated methods for studying pain within these models.
Various surgical approaches exist for Total Hip Arthroplasty (THA), but approach specific complication rates remain unknown. The purpose of this systematic review and meta-analysis was to compare ...rates of common complications between surgical approaches.
Four electronic databases (Medline, Embase, AMED, Ovid Healthstar) were searched from inception to June 2019. Three pairs of reviewers were involved in determining eligibility, rating internal and external validity, and data extraction. Pooled estimates were generated using a random-effects model and relative risk (RR) was calculated for dislocation, intraoperative and early postoperative fracture, early infection, deep vein thrombosis (DVT), wound complication, and failure of implant ingrowth between four approaches (posterior, anterior, direct lateral, and anterolateral).
Sixty-nine studies (n = 283,036) were included with nineteen randomized control trials, fourteen prospective cohort, and thirty-six retrospective cohort studies (included studies ranged from 1987 to 2019). When compared to the posterior approach, the risk for dislocation was significantly lower in the anterior (RR 0.66, 95% CI 0.54–0.77, p < 0.01), anterolateral (RR 0.50, 95% CI 0.32–0.77, p = 0.03) and lateral (RR 0.74, 95% CI 0.58–0.96, p = 0.02). When compared to the posterior approach, we found higher risk of loosening in the anterolateral (RR 1.89, 95% CI 1.59–2.25, p < 0.01) and lateral (RR 1.21, 95% CI 1.02–1.44, p = 0.03). Overall, evidence was deemed very low and low-quality following GRADE assessment.
Our findings reveal that the posterior approach was associated with a higher risk of dislocation (compared to the anterior, lateral, and anterolateral) but lower risk of loosening (compared to the lateral and anterolateral approach). However, the large number of cohorts and imprecision due to low sample size for most pooled comparisons was still insufficient to confidently conclude that one approach is superior to another. Each approach has its own strengths and weaknesses, and surgeons can use the approach they are most comfortable with.
Effusion-synovitis is related to pain and progression in knee osteoarthritis (OA), but current gold standard ultrasound (US) measures are limited to semi-quantitative grading of joint distension or ...1-dimensional thickness measures. A novel quantitative 2-dimensional image analysis methodology is applied to US images of effusion-synovitis; reliability and concurrent validity was assessed in patients with knee OA.
Cross sectional analysis of US images collected from 51 patients with symptomatic knee OA were processed in ImageJ and segmented in 3DSlicer to produce a binary mask of the supra-patellar synovitis region of interest (ROI). Area measures (mm2) of total synovitis, effusion and hypertrophy components were exported. Intra-rater reliability and test-retest reliability (1–14 days washout) were estimated with intra-class correlation coefficients (ICCs). Concurrent validity was measured by Spearman correlations between quantitative measures and gold standard OMERACT and caliper measurements of synovitis.
Intra-rater reliability for hypertrophy area was estimated at 0.98, 0.99 for effusion area, and 0.99 for total synovitis area. The test-retest reliability for total synovitis area was 0.63 (SEM 87.8 mm2), 0.59 for hypertrophy area (SEM 21.0 mm2), and 0.64 for effusion area (SEM 73.8 mm2). Correlation between total synovitis area and OMERACT grade was 0.84, 0.81 between total synovitis area and effusion-synovitis calipers, and 0.81 between total effusion area and effusion calipers.
This new research tool for image analysis demonstrated excellent intra-rater reliability, good concurrent validity, and moderate test-retest reliability. Quantitative 2D US measures of effusion-synovitis and its individual components may enhance the study and management of knee OA.
Joint neuropathic pain occurs in a subset of arthritis patients, and lysophosphatidic acid (LPA) has been implicated as a mediator of joint neuropathy. The mechanism by which LPA promotes neuropathic ...pain is unknown but may be related to altered signalling of the voltage-gated sodium channel Nav1.8 located on nociceptors. Because arthritis and neuropathic pain are more prevalent in females, this study aimed to explore potential sex differences in the development of LPA-induced joint neuropathy and whether Nav1.8 played a role in the associated neuropathic pain. Joint neuropathy was induced in male and female Wistar rats (179-284 g) by intra-articular injection of 50-µg LPA. Pain behaviour was assessed over 21 days using von Frey hair algesiometry. On day 21, electrophysiological recordings of joint primary afferents were conducted to measure peripheral sensitisation. Saphenous nerve morphology and expression of the nerve-damage marker ATF3 and Nav1.8 in ipsilateral dorsal root ganglions were compared on the basis of sex. The analgesic properties of the selective Nav1.8 antagonist A-803467 was determined in pain behaviour and electrophysiology experiments. Females developed more severe mechanical allodynia than males after LPA treatment. Lysophosphatidic acid caused more pronounced demyelination of the saphenous nerve in females, but no sex differences were observed in the expression of ATF3 or Nav1.8 in dorsal root ganglion neurones. Blockade of Nav1.8 channels with A-803467 resulted in a decrease in joint mechanosensitivity and secondary allodynia with females exhibiting a greater response. These findings suggest that LPA has sex-specific effects on joint neuropathy and Nav1.8 gating, which should be considered when treating neuropathic arthritis patients.
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