Association between synovial tissue damage and pain in late-stage knee osteoarthritis: A cross-sectional study.

OBJECTIVE: To identify the presence and distribution of histopathological features of synovial inflammation and tissue damage, and to test their associations with ultrasound (US) imaging measures of synovitis and patient-reported measures of pain in knee osteoarthritis (OA). DESIGN: In the cross-sectional study of 122 patients undergoing surgery for painful late-stage (Kellgren-Lawrence Grade 3 or 4) knee OA, we compared 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. RESULTS: Histopathological features of inflammation were associated with higher odds of moderate/severe US synovitis (odds ratio [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]). CONCLUSIONS: 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.

A scoping review of how early-stage knee osteoarthritis has been defined.

BACKGROUND: Early-stage knee osteoarthritis (KOA) classification criteria will enable consistent identification and trial recruitment of individuals with knee osteoarthritis (OA) at an earlier stage of the disease when interventions may be more effective. Toward this goal, we identified how early-stage KOA has been defined in the literature. METHODS: We performed a scoping literature review in PubMed, EMBASE, Cochrane, and Web of Science, including human studies where early-stage KOA was included as a study population or outcome. Extracted data included demographics, symptoms/history, examination, laboratory, imaging, performance-based measures, gross inspection/histopathologic domains, and the components of composite early-stage KOA definitions. RESULTS: Of 6142 articles identified, 211 were included in data synthesis. An early-stage KOA definition was used for study inclusion in 194 studies, to define study outcomes in 11 studies, and in the context of new criteria development or validation in six studies. The element most often used to define early-stage KOA was Kellgren-Lawrence (KL) grade (151 studies, 72%), followed by symptoms (118 studies, 56%), and demographic characteristics (73 studies, 35%); 14 studies (6%) used previously developed early-stage KOA composite criteria. Among studies defining early-stage KOA radiographically, 52 studies defined early-stage KOA by KL grade alone; of these 52, 44 (85%) studies included individuals with KL grade 2 or higher in their definitions. CONCLUSION: Early-stage KOA is variably defined in the published literature. Most studies included KL grades of 2 or higher within their definitions, which reflects established or later-stage OA. These findings underscore the need to develop and validate classification criteria for early-stage KOA.

Are we missing the target? Are we aiming too low? What are the aerobic exercise prescriptions and their effects on markers of cardiovascular health and systemic inflammation in patients with knee osteoarthritis? A systematic review and meta-analysis.

OBJECTIVES: We systemically reviewed published studies that evaluated aerobic exercise interventions in patients with knee osteoarthritis (OA) to: (1) report the frequency, intensity, type and time (FITT) of exercise prescriptions and (2) quantify the changes in markers of cardiovascular health and systemic inflammation. DATA SOURCES: PubMed, CINAHL, Scopus; inception to January 2019. ELIGIBILITY CRITERIA: Randomised clinical trials (RCT), cohort studies, case series. DESIGN: We summarised exercise prescriptions for all studies and calculated effect sizes with 95% CIs for between-group (RCTs that compared exercise and control groups) and within-group (pre-post exercise) differences in aerobic capacity (VO2), heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and inflammatory markers (interleukin-6 (IL-6), tumour necrosis factor-alpha). We pooled results where possible using random effects models. RESULTS: Interventions from 49 studies were summarised; 8% (4/49) met all FITT guidelines; 16% (8/49) met all or most FITT guidelines. Fourteen studies (10 RCTs) reported at least one marker of cardiovascular health or systemic inflammation. Mean differences (95% CI) indicated a small to moderate increase in VO2 (0.84 mL/min/kg; 95% CI 0.37 to 1.31), decrease in HR (-3.56 beats per minute; 95% CI -5.60 to -1.52) and DBP (-4.10 mm Hg; 95% CI -4.82 to -3.38) and no change in SBP (-0.36 mm Hg; 95% CI -3.88 to 3.16) and IL-6 (0.37 pg/mL; 95% CI -0.11 to 0.85). Within-group differences were also small to moderate. CONCLUSIONS: In studies of aerobic exercise in patients with knee OA, very few interventions met guideline-recommended dose; there were small to moderate changes in markers of cardiovascular health and no decrease in markers of systemic inflammation. These findings question whether aerobic exercise is being used to its full potential in patients with knee OA. PROSPERO REGISTRATION NUMBER: CRD42018087859.

ADAMTS-7 forms a positive feedback loop with TNF-α in the pathogenesis of osteoarthritis.

OBJECTIVE: To examine the expression of ADAMTS-7 during the progression of osteoarthritis (OA), defining its role in the pathogenesis of OA, and elucidating the molecular events involved. METHODS: ADAMTS-7 expression in cartilage of a rat OA model was assayed using immunohistochemistry. Cartilage-specific ADAMTS-7 transgenic mice and ADAMTS-7 small interfering (si)RNA knockdown mice were generated and used to analyse OA progression in both spontaneous and surgically induced OA models. Cartilage degradation and OA was evaluated using Safranin-O staining, immunohistochemistry, ELISA and western blotting. In addition, mRNA expression of tumour necrosis factor (TNF)-α and metalloproteinases known to be involved in cartilage degeneration in OA was analysed. Furthermore, the transactivation of ADAMTS-7 by TNF-α and its downstream NF-κB signalling was measured using reporter gene assay. RESULTS: ADAMTS-7 expression was elevated during disease progression in the surgically induced rat OA model. Targeted overexpression of ADAMTS-7 in chondrocytes led to chondrodysplasia characterised by short-limbed dwarfism and a delay in endochondral ossification in 'young mice' and a spontaneous OA-like phenotype in 'aged' mice. In addition, overexpression of ADAMTS-7 led to exaggerated breakdown of cartilage and accelerated OA progression, while knockdown of ADAMTS-7 attenuated degradation of cartilage matrix and protected against OA development, in surgically induced OA models. ADAMTS-7 upregulated TNF-α and metalloproteinases associated with OA; in addition, TNF-α induced ADAMTS-7 through NF-κB signalling. CONCLUSIONS: ADAMTS-7 and TNF-α form a positive feedback loop in the regulation of cartilage degradation and OA progression, making them potential molecular targets for prevention and treatment of joint degenerative diseases, including OA.

Changes and associations between synovial fluid and magnetic resonance imaging markers of osteoarthritis after high tibial osteotomy.

BACKGROUND: Mechanobiological mechanisms of osteoarthritis (OA) are unclear. Our objectives were to explore: 1) changes in knee joint physiology using a large panel of synovial fluid biomarkers from before to one year after high tibial osteotomy (HTO) surgery, and 2) the association of changes in the synovial fluid biomarkers with the changes in MRI measures of knee effusion-synovitis and articular cartilage composition. METHODS: Twenty-six patients with symptomatic knee OA and varus alignment underwent synovial fluid aspirations and 3 T MRI before and one year after medial opening wedge HTO. Cytokine and growth factor levels in synovial fluid were measured with multiplex assays. Ontology and pathway enrichment was assessed using data protein sets with gene set enrichment analysis (GSEA), and analyzed using linear mixed effects models. MRIs were analyzed for effusion-synovitis and T2 cartilage relaxation time using manual segmentations. Changes in biomarker concentrations were correlated to changes in MRI effusion-synovitis volume and articular cartilage T2 relaxation times. RESULTS: Decreased enrichment in Toll-like receptor and TNF-α signalling was detected one year after HTO. The leading contributors to this reduction included IL-6, TNF-α and IL-1ß, whereas the highest contributors to positive enrichment were EGF, PDGF-BB and FGF-2. Effusion-synovitis volume decreased (mean [95%CI]) one year after HTO (-2811.58 [-5094.40, -528.76mm3]). Effusion-synovitis volume was moderately correlated (r [95% CI]) with decreased MMP-1 (0.44 [0.05; 0.71]), IL-7 (0.41 [0.00; 0.69]) and IL-1ß (0.59 [0.25; 0.80]) and increased MIP-1ß (0.47 [0.10; 0.73]). Medial tibiofemoral articular cartilage T2 relaxation time decreased (mean [95% CI]) one year after HTO (-0.33 [-2.69; 2.05]ms). Decreased T2 relaxation time was moderately correlated to decreased Flt-3L (0.61 [0.28; 0.81]), IL-10 (0.47 [0.09; 0.73]), IP-10 (0.42; 0.03-0.70) and increased MMP-9 (-0.41 [-0.7; -0.03]) and IL-18 (-0.48 [-0.73; -0.10]). CONCLUSIONS: Decreased aberrant knee mechanical loading in patients with OA is associated with decreased biological and imaging measures of inflammation (measured in synovial fluid and on MRI) and increased anabolic processes. These exploratory findings suggest that improvement in knee loading can produce long-term (one year) improvement in joint physiology.

Targeting STAT6-mediated synovial macrophage activation improves pain in experimental knee osteoarthritis.

BACKGROUND: Pain from osteoarthritis (OA) is one of the top causes of disability worldwide, but effective treatment is lacking. Nociceptive factors are released by activated synovial macrophages in OA, but depletion of synovial macrophages paradoxically worsens inflammation and tissue damage in previous studies. Rather than depleting macrophages, we hypothesized that inhibiting macrophage activation may improve pain without increasing tissue damage. We aimed to identify key mechanisms mediating synovial macrophage activation and test the role of STAT signaling in macrophages on pain outcomes in experimental knee OA. METHODS: We induced experimental knee OA in rats via knee destabilization surgery, and performed RNA sequencing analysis on sorted synovial tissue macrophages to identify macrophage activation mechanisms. Liposomes laden with STAT1 or STAT6 inhibitors, vehicle (control), or clodronate (depletion control) were delivered selectively to synovial macrophages via serial intra-articular injections up to 12 weeks after OA induction. Treatment effects on knee and hindpaw mechanical pain sensitivity were measured during OA development, along with synovitis, cartilage damage, and synovial macrophage infiltration using histopathology and immunofluorescence. Lastly, crosstalk between drug-treated synovial tissue and articular chondrocytes was assessed in co-culture. RESULTS: The majority of pathways identified by transcriptomic analyses in OA synovial macrophages involve STAT signaling. As expected, macrophage depletion reduced pain, but increased synovial tissue fibrosis and vascularization. In contrast, STAT6 inhibition in macrophages led to marked, sustained improvements in mechanical pain sensitivity and synovial inflammation without worsening synovial or cartilage pathology. During co-culture, STAT6 inhibitor-treated synovial tissue had minimal effects on healthy chondrocyte gene expression, whereas STAT1 inhibitor-treated synovium induced changes in numerous cartilage turnover-related genes. CONCLUSION: These results suggest that STAT signaling is a major mediator of synovial macrophage activation in experimental knee OA. STAT6 may be a key mechanism mediating the release of nociceptive factors from macrophages and the development of mechanical pain sensitivity. Whereas therapeutic depletion of macrophages paradoxically increases inflammation and fibrosis, blocking STAT6-mediated synovial macrophage activation may be a novel strategy for OA-pain management without accelerating tissue damage.

Strength in numbers: growth of Canadian clinician investigator training in the 21st century.

PURPOSE: Enhancing clinician-investigator (CI) training at Canadian medical schools is urgently needed to bolster the dwindling work force of medical professionals carrying out patient-oriented research in a wide array of medical fields. The purpose of this study is to obtain, from the 15 Canadian medical schools that offer one or more CI training programs, data on the number of trainees, funding levels, attrition rates or other important metrics to evaluate the outcomes of such training efforts. METHODS: All Canadian CI programs were surveyed to collect demographic information for the academic year 2010-2011 and compared this to historical data collected by the Association of Faculties of Medicine of Canada (AFMC) and MD/PhD program funding data from the Canadian Institutes of Health Research (CIHR). RESULTS: Over the past decade, enrolment in Canadian CI training programs has increased approximately four-fold. Program-specific funding (CIHR) has also increased, but nearly 50% of MD/PhD trainees are still not supported through dedicated CIHR funding. CONCLUSION: It is too early to know to what extent this increase in both CI and funding will sustain the workforce of Canadian researchers carrying out patient-oriented research. Monitoring of CI training demographics across Canada, beyond this baseline study, will be essential to measure outcomes from CI training programs and to guide response from funding bodies and policy-makers.

Human osteoarthritis knee joint synovial fluids cleave and activate Proteinase-Activated Receptor (PAR) mediated signaling.

Osteoarthritis (OA) is the most prevalent joint disorder with increasing worldwide incidence. Mechanistic insights into OA pathophysiology are evolving and there are currently no disease-modifying OA drugs. An increase in protease activity is linked to progressive degradation of the cartilage in OA. Proteases also trigger inflammation through a family of G protein-coupled receptors (GPCRs) called the Proteinase-Activated Receptors (PARs). PAR signaling can trigger pro-inflammatory responses and targeting PARs is proposed as a therapeutic approach in OA. Several enzymes can cleave the PAR N-terminus, but the endogenous protease activators of PARs in OA remain unclear. Here we characterized PAR activating enzymes in knee joint synovial fluids from OA patients and healthy donors using genetically encoded PAR biosensor expressing cells. Calcium signaling assays were performed to examine receptor activation. The class and type of enzymes cleaving the PARs was further characterized using protease inhibitors and fluorogenic substrates. We find that PAR1, PAR2 and PAR4 activating enzymes are present in knee joint synovial fluids from healthy controls and OA patients. Compared to healthy controls, PAR1 activating enzymes are elevated in OA synovial fluids while PAR4 activating enzyme levels are decreased. Using enzyme class and type selective inhibitors and fluorogenic substrates we find that multiple PAR activating enzymes are present in OA joint fluids and identify serine proteinases (thrombin and trypsin-like) and matrix metalloproteinases as the major classes of PAR activating enzymes in the OA synovial fluids. Synovial fluid driven increase in calcium signaling was significantly reduced in cells treated with PAR1 and PAR2 antagonists, but not in PAR4 antagonist treated cells. OA associated elevation of PAR1 cleavage suggests that targeting this receptor may be beneficial in the treatment of OA.

Cross-sectional reliability and concurrent validity of a quantitative 2-dimensional ultrasound image analysis of effusion and synovial hypertrophy in knee osteoarthritis.

Objective: 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. Methods: 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. Results: 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 â€‹mm2), 0.59 for hypertrophy area (SEM 21.0 â€‹mm2), and 0.64 for effusion area (SEM 73.8 â€‹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. Conclusion: 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.

Test-Retest Reliability and Sensitivity to Change of Ultrasound-Based Methods of Measuring Synovial Inflammation in Knee Osteoarthritis.

OBJECTIVES: To assess test-retest reliability of musculoskeletal ultrasound (US) measures of inflammation in patients with knee osteoarthritis (OA) and to assess the sensitivity to change of US measures of inflammation in patients with knee OA. METHODS: To mimic a common clinical scenario, 36 patients (n = 70 knees) with symptomatic knee OA who were in stable condition underwent 2 assessments within 14 days by different operators and different US machines, graded by a single rater. Test-retest reliability was measured using Cohen's kappa coefficient, intraclass correlation coefficient (ICC), and absolute agreement parameters. A total of 51 patients (n = 72 knees) were tested immediately before and 21-28 days after intraarticular glucocorticoid injection to investigate sensitivity to change and longitudinal construct validity. Paired t-tests and standardized response mean (SRM) were used to assess sensitivity to change. Multivariate linear regression was used to investigate longitudinal construct validity of US with Knee Injury and Osteoarthritis Outcome Score (KOOS) pain scores, while adjusting for covariates. RESULTS: US measures of inflammation demonstrated moderate (κ = 0.41, 0.60) to substantial (κ = 0.61, 0.80) agreement. Quantitative measures of synovitis and effusion demonstrated good test-retest reliability (ICC2,1 0.71, 0.92). US measures of synovitis and effusion demonstrated low-to-moderate sensitivity to change (SRM -0.29, -0.50). The associations between changes in US measures and KOOS pain scores over time were low, and 95% confidence intervals included zero. CONCLUSION: In a clinical setting, US measures of inflammatory features of knee OA have substantial reliability and low-to-moderate sensitivity to change, whereas measures of structural OA features are less reliable. Longitudinal construct validity of US measures of synovitis and effusion to KOOS pain scores is not strongly supported.

Synovial macrophage diversity and activation of M-CSF signaling in post-traumatic osteoarthritis.

Objective: Synovium is home to immune and stromal cell types that orchestrate inflammation following a joint injury; in particular, macrophages are central protagonists in this process. We sought to define the cellular and temporal dynamics of the synovial immune niche in a mouse model of post-traumatic osteoarthritis (PTOA), and to identify stromal-immune crosstalk mechanisms that coordinate macrophage function and phenotype. Design: We induced PTOA in mice using a non-invasive tibial compression model of anterior cruciate ligament rupture (ACLR). Single cell RNA-seq and flow cytometry were used to assess immune cell populations in healthy (Sham) and injured (7d and 28d post-ACLR) synovium. Characterization of synovial macrophage polarization states was performed, alongside computational modeling of macrophage differentiation, as well as implicated transcriptional regulators and stromal-immune communication axes. Results: Immune cell types are broadly represented in healthy synovium, but experience drastic expansion and speciation in PTOA, most notably in the macrophage portion. We identified several polarization states of macrophages in synovium following joint injury, underpinned by distinct transcriptomic signatures, and regulated in part by stromal-derived macrophage colony-stimulating factor signaling. The transcription factors Pu.1, Cebpα, Cebpß, and Jun were predicted to control differentiation of systemically derived monocytes into pro-inflammatory synovial macrophages. Conclusions: We defined different synovial macrophage subpopulations present in healthy and injured mouse synovium. Nuanced characterization of the distinct functions, origins, and disease kinetics of macrophage subtypes in PTOA will be critical for targeting these highly versatile cells for therapeutic purposes.

Changes and Associations Between Gait Biomechanics and Knee Inflammation After Aspiration and Glucocorticoid Injection for Knee Osteoarthritis.

OBJECTIVE: Although knee inflammation is thought to adversely affect joint function in patients with knee osteoarthritis (OA), the effects of reducing knee inflammation on gait biomechanics and strength are unknown. Our objectives were to compare ultrasound (US) measures of knee inflammation, gait biomechanics, knee extension and flexion strength, and pain before and after knee aspiration and glucocorticoid injection, and to explore associations among changes. METHODS: Forty-nine patients (69 knees) with symptomatic knee OA and synovitis were tested before and 3-4 weeks after US-guided knee aspiration and glucocorticoid injection. At each visit, participants completed US assessments for inflammatory features of knee OA, 3D gait analysis, isokinetic knee extension and flexion strength tests, and Knee Osteoarthritis Outcome Score (KOOS) pain subscales. Linear and polynomial mixed-effects regression models were used to investigate changes and their associations. RESULTS: Changes were observed for the synovitis score (unstandardized ß [post-injection minus pre-injection] -0.55/9 [95% confidence interval (95% CI) -0.97, -0.12]), effusion depth (-1.05 mm [95% CI -1.07, -0.39]), KOOS pain (unstandardized ß 5.91/100 [95% CI 1.86, 9.97]), peak external knee flexion and extension moments (KFM; 3.33 Nm [95% CI 0.45, 6.22]), KEM (-2.99 Nm [95% CI -5.93, -0.05]), and knee extension strength (4.70 Nm [95% CI 0.39, 9.00]) and flexion strength (3.91 Nm [95% CI 1.50, 6.81]). The external KFM increased during 13-38% and 76-89% of stance post-injection. When controlled for time, greater synovitis was associated with lower knee extension strength, while lower pain was associated with increased knee extension and flexion strength. CONCLUSION: In patients with knee OA and synovitis, reduced inflammation and pain after aspiration and glucocorticoid injection are associated with changes in knee gait biomechanics and strength.

Impaired Efferocytosis by Synovial Macrophages in Patients With Knee Osteoarthritis.

OBJECTIVE: Osteoarthritis (OA) exposes all joint tissues to physiologic stresses, increasing the need to clear apoptotic cells from tissues, including the synovium. We undertook this study to assess the burden of apoptotic cells in synovial tissue in patients with late-stage knee OA and to investigate whether OA impairs the macrophage-mediated clearance of apoptotic cells via efferocytosis. METHODS: Synovial tissue was collected from individuals with healthy knees and patients with late-stage knee OA during arthroplasty. Synovial apoptotic cell burden was assessed by immunofluorescence for cleaved caspase 3. Efferocytosis of apoptotic Jurkat cells by CD14+ synovial tissue macrophages and peripheral blood-derived macrophages was quantified using immunofluorescence microscopy. Effects of OA on macrophage-mediated efferocytosis were modeled by stimulating blood-derived macrophages with synovial fluid collected from individuals with healthy knees and patients with early- or late-stage knee OA. RESULTS: Patients with late-stage knee OA had more apoptotic synovial cells compared to healthy individuals. There was a marked reduction in the fraction of synovial tissue macrophages engaging in efferocytosis and the quantity of material efferocytosed by individual macrophages in OA patients. Blood-derived macrophages exposed to synovial fluid from patients with knee OA recapitulated the defective efferocytosis, with the greatest effect from patients with early-stage knee OA and higher disease activity (pain and inflammation). CONCLUSION: Apoptotic cells accumulate in the synovium of patients with late-stage knee OA. Our results suggest that OA impairs critical homeostatic functions of synovial macrophages, leading to accumulation of apoptotic cells.

Responders to Medial Opening Wedge High Tibial Osteotomy for Knee Osteoarthritis.

OBJECTIVE: Medial opening wedge high tibial osteotomy (HTO) aims to improve symptoms for patients with knee osteoarthritis (OA) and varus alignment, yet the likelihood of achieving a minimum clinical threshold of response and the factors predictive of response are unclear. We evaluated the proportion of patients meeting responder criteria based on the Outcome Measures in Rheumatology-Osteoarthritis Research Society International consensus 2 years after medial opening wedge HTO and investigated predictors of response. METHODS: Patients in a prospective cohort with symptomatic knee OA and varus alignment completed the Knee Injury and Osteoarthritis Outcome Score questionnaire < 3 months before and 2 years after HTO. For our primary analysis, we calculated the proportion of responders with ≥ 20% relative improvement and an absolute change of ≥ 10 points in pain and function from baseline. We performed logistic regression to evaluate the association of predictors with response and completed sex-disaggregated analyses. RESULTS: At a mean of 20.3 (SD 6.2) months post-HTO, 406 patients (78%) met the responder criteria. Older age, higher BMI, and larger postoperative mechanical axis angles (ie, slight valgus) were associated with increased odds of achieving responder criteria, although odds ratios were small. When stratified by sex, 316/405 male patients (78%) and 90/118 female patients (76%) met the responder criteria. CONCLUSION: Based on responder criteria for knee OA, 78% of patients undergoing medial opening wedge HTO were responders at 2 years postsurgery. Although patients who are younger, male, and nonobese are viewed as appropriate candidates for HTO, patients who are female, are older, and have a high BMI also achieve sizable improvements in pain and function.

Sex-Differences and Associations Between Complement Activation and Synovial Vascularization in Patients with Late-Stage Knee Osteoarthritis.

Purpose: 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. Methods: 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. Results: 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] p=0.05). Median vasculopathy scores (0.42 [95%CI 0.07, 0.77] p=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] p=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] p=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. Conclusion: 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.

Assessment of Surrogate Markers for Cardiovascular Disease in Familial Mediterranean Fever-Related Amyloidosis Patients Homozygous for M694V Mutation in MEFV Gene.

Cardiovascular disease (CVD) remains underestimated in familial Mediterranean fever-associated AA amyloidosis (FMF-AA). We aimed to compare early markers of endothelial dysfunction and atherosclerosis in FMF-AA with a homozygous M694V mutation (Group 1 = 76 patients) in the Mediterranean fever (MEFV) gene and in patients with other genotypes (Group 2 = 93 patients). Measures of increased risk for future CVD events and endothelial dysfunction, including flow-mediated dilatation (FMD), pentraxin-3 (PTX3), and carotid intima-media thickness (cIMT), and fibroblast growth factor 23 (FGF23) as a marker of atherosclerotic vascular disease were compared between groups. The frequency of clinical FMF manifestations did not differ between the two groups apart from arthritis (76.3% in Group 1 and 59.1% in Group 2, p < 0.05). FMD was significantly lower in Group 1 when compared with Group 2 (MD [95% CI]: −0.6 [(−0.89)−(−0.31)]). cIMT, FGF23, and PTX3 levels were higher in Group 1 (cIMT MD [95% CI]: 0.12 [0.08−0.16]; FGF23 MD [95% CI]: 12.8 [5.9−19.6]; PTX3 MD [95% CI]: 13.3 [8.9−17.5]). In patients with FMF-AA, M694V homozygosity is associated with lower FMD values and higher cIMT, FGF23, and PTX3 levels, suggesting increased CVD risk profiles. These data suggest that a genotype−phenotype association exists in terms of endothelial dysfunction and atherosclerosis in patients with FMF-AA.