Total Hip Arthroplasty Versus Education and Exercise: A Propensity-Matched Analysis of 266 Patients Who Have Hip Osteoarthritis.

BACKGROUND: Total hip arthroplasty (THA) for osteoarthritis (OA) is a major health system cost. Education and exercise (Edu+Ex) programs may reduce the number of THAs needed, but supporting data is limited. This study aimed to estimate the treatment effect of THA versus Edu+Ex on pain, function, and quality of life outcomes 3- and 12-months after treatment initiation for hip OA. METHODS: Patients who had hip OA who underwent THA or an Edu+Ex program were included in this propensity-matched study. In 778 patients (Edu+Ex n = 303; THA n = 475), propensity scores were based on pre-treatment characteristics, and patients were matched on a 1:1 ratio. Between-group treatment effects (pain, function, and quality of life) were estimated as the mean difference in change from pre-treatment to 3- and 12-month follow-up using linear mixed models. RESULTS: The matched sample consisted of 266 patients (Edu+Ex n = 133; THA n = 133) that were balanced on all pre-treatment characteristics except opioid use. At 12-month follow-up, THA resulted in significantly greater improvements in pain (mean difference [MD] 35.4; 95% CI [confidence interval] 31.4 to 39.4), function (MD 30.5; 95% CI 26.3 to 34.7), and quality of life (MD 33.6; 95% CI 28.8 to 38.4). Between 17 and 30% of patients receiving Edu+Ex experienced a surgical threshold for clinically meaningful improvement in outcomes, compared to 84 and 90% of THA patients. CONCLUSIONS: A THA provides greater improvements in pain, function, and quality of life. A significant proportion of Edu+Ex patients had clinically meaningful improvements, suggesting Edu+Ex may result in THA deferral in some patients, but confirmatory trials are needed.

The impact of diabetes on physical and mental health status and patient satisfaction after total hip and knee arthroplasty.

OBJECTIVE: To assess the impact of diabetes on physical and mental health status, as well as patient satisfaction, one-year following knee and hip total joint arthroplasty (TJA) for osteoarthritis (OA). METHODS: Participants were 626 hip and 754 knee TJA patients. Pre-surgery data were collected on socio-demographics and health status. The 12-item Short Form Health Survey (SF-12) was collected pre- and one year post-surgery, and physical (PCS) and mental component (MCS) summary scores computed. One-year patient satisfaction was also recorded. Four regression models tested the effect of diabetes on: 1) PCS change score; 2) MCS change score; 3) achieving minimal clinically important improvement (MCII) on PCS; and 4) patient satisfaction ('Somewhat or Very Satisfied' vs. 'Somewhat or Very Dissatisfied'). An interaction between surgical joint and diabetes was tested in each model. RESULTS: Self-reported diabetes prevalence was 13.0% (95% CI: 11.2%-14.7%) and was more common in knee 16.1% (95% CI: 13.4%-18.7%) than hip 9.3% (95% CI: 7.0%-11.5%) patients. In adjusted analyses, change scores were 2.3 units less on the PCS for those with diabetes compared to those without (p = 0.005). Patients with diabetes were about half as likely to achieve MCII as patients without diabetes (p = 0.004). Diabetes was not significantly associated with satisfaction or changes in MCS scores. Diabetes effects did not differ by surgical joint. CONCLUSIONS: Findings support that diabetes has a negative impact on improvements in physical health after TJA. Considering the growing prevalence of OA and diabetes in the population, our findings support the importance of perioperative screening and management of diabetes in patients undergoing TJA.

Total Knee Arthroplasty Versus Education and Exercise for Knee Osteoarthritis: A Propensity-Matched Analysis.

OBJECTIVE: We estimate the treatment effect of total knee arthroplasty (TKA) versus an education and exercise (Edu+Ex) program on pain, function, and quality of life outcomes 3 and 12 months after treatment initiation for knee osteoarthritis (OA). METHODS: Patients with knee OA who had undergone TKA were matched on a 1:1 ratio with participants in an Edu+Ex program based on a propensity score fitted to a range of pretreatment covariates. After matching, between-group differences in improvement (the treatment effect) in Knee Injury and Osteoarthritis Outcome Score 12-item version (0, worst to 100, best) pain, function, and quality of life from baseline to 3 and 12 months were estimated using linear mixed models, adjusting for unbalanced covariates, if any, after matching. RESULTS: The matched sample consisted of 522 patients (Edu+Ex, n = 261; TKA, n = 261) who were balanced on all pretreatment characteristics. At 12-month follow-up, TKA resulted in significantly greater improvements in pain (mean difference [MD] 22.8; 95% confidence interval [95% CI] 19.7-25.8), function (MD 21.2; 95% CI 17.7-24.4), and quality of life (MD 18.3; 15.0-21.6). Even so, at least one-third of patients receiving Edu+Ex had a clinically meaningful improvement in outcomes at 12 months compared with 75% of patients with TKA. CONCLUSION: TKA is associated with greater improvements in pain, function, and quality of life, but these findings also suggest that Edu+Ex may be a viable alternative to TKA in a meaningful proportion of patients, which may reduce overall TKA need. Confirmatory trials are needed.

High health care use prior to elective surgery for osteoarthritis is associated with poor postoperative outcomes: A Canadian population-based cohort study.

BACKGROUND: The characterization and influence of preoperative health care use on quality-of-care indicators (e.g., readmissions) has received limited attention in populations with musculoskeletal disorders. The purpose of this study was to characterize preoperative health care use and examine its effect on quality-of-care indicators among patients undergoing elective surgery for osteoarthritis. METHODS: Data on health care use for 124,750 patients with elective surgery for osteoarthritis in Ontario, Canada, from April 1, 2015 to March 31, 2018 were linked across health administrative databases. Using total health care use one-year previous to surgery, patients were grouped from low to very high users. We used Poisson regression models to estimate rate ratios, while examining the relationship between preoperative health care use and quality-of-care indicators (e.g., extended length of stay, complications, and 90-day hospital readmissions). We controlled for covariates (age, sex, neighborhood income, rural/urban residence, comorbidities, and surgical anatomical site). RESULTS: We found a statistically significant trend of increasing worse outcomes by health care use gradients that persisted after controlling for patient demographics and comorbidities. Findings were consistent across surgical anatomical sites. Moreover, very high users have relatively large numbers of visits to non-musculoskeletal specialists. CONCLUSIONS: Our findings highlight that information on patients' preoperative health care use, together with other risk factors (such as comorbidities), could help decision-making when benchmarking or reimbursing hospitals caring for complex patients undergoing surgery for osteoarthritis.

Hospital spending and length of stay attributable to perioperative adverse events for inpatient hip, knee, and spine surgery: a retrospective cohort study.

BACKGROUND: The incremental hospital cost and length of stay (LOS) associated with adverse events (AEs) has not been well characterized for planned and unplanned inpatient spine, hip, and knee surgeries. METHODS: Retrospective cohort study of hip, knee, and spine surgeries at an academic hospital in 2011-2012. Adverse events were prospectively collected for 3,063 inpatient cases using the Orthopaedic Surgical AdVerse Event Severity (OrthoSAVES) reporting tool. Case costs were retrospectively obtained and inflated to equivalent 2021 CAD values. Propensity score methodology was used to assess the cost and LOS attributable to AEs, controlling for a variety of patient and procedure factors. RESULTS: The sample was 55% female and average age was 64; 79% of admissions were planned. 30% of cases had one or more AEs (82% had low-severity AEs at worst). The incremental cost and LOS attributable to AEs were $8,500 (95% confidence interval [CI]: 5100-11,800) and 4.7 days (95% CI: 3.4-5.9) per admission. This corresponded to a cumulative $7.8 M (14% of total cohort cost) and 4,290 bed-days (19% of cohort bed-days) attributable to AEs. Incremental estimates varied substantially by (1) admission type (planned: $4,700/2.4 days; unplanned: $20,700/11.5 days), (2) AE severity (low: $4,000/3.1 days; high: $29,500/11.9 days), and (3) anatomical region (spine: $19,800/9 days; hip: $4,900/3.8 days; knee: $1,900/1.5 days). Despite only 21% of admissions being unplanned, adverse events in these admissions cumulatively accounted for 59% of costs and 62% of bed-days attributable to AEs. CONCLUSIONS: This study comprehensively demonstrates the considerable cost and LOS attributable to AEs in orthopaedic and spine admissions. In particular, the incremental cost and LOS attributable to AEs per admission were almost five times as high among unplanned admissions compared to planned admissions. Mitigation strategies focused on unplanned surgeries may result in significant quality improvement and cost savings in the healthcare system.

Individual participant data meta-analysis of metabolomics on sustained knee pain in primary osteoarthritis patients.

OBJECTIVES: Knee pain is the major driver for OA patients to seek healthcare, but after pursuing both conservative and surgical pain interventions, ∼20% of patients continue to report long-term pain following total knee arthroplasty (TKA). This study aimed to identify a metabolomic signature for sustained knee pain after TKA to elucidate possible underlying mechanisms. METHODS: Two independent cohorts from St John's, NL, Canada (n = 430), and Toronto, ON, Canada (n = 495) were included in the study. Sustained knee pain was assessed using the WOMAC pain subscale (five questions) at least 1 year after TKA for primary OA. Those reporting any pain on all five questions were considered to have sustained knee pain. Metabolomic profiling was performed on fasted pre-operative plasma samples using the Biocrates Absolute IDQ p180 kit. Associations between metabolites and pair-wise metabolite ratios with sustained knee pain in each individual cohort were assessed using logistic regression with adjustment for age, sex and BMI. Random-effects meta-analysis using inverse variance as weights was performed on summary statistics from both cohorts. RESULTS: One metabolite, phosphatidylcholine (PC) diacyl (aa) C28:1 (odds ratio = 0.66, P = 0.00026), and three metabolite ratios, PC aa C32:0 to PC aa C28:1, PC aa C28:1 to PC aa C32:0, and tetradecadienylcarnitine (C14:2) to sphingomyelin C20:2 (odds ratios = 1.59, 0.60 and 1.59, respectively; all P < 2 × 10-5), were significantly associated with sustained knee pain. CONCLUSIONS: Though further investigations are needed, our results provide potential predictive biomarkers and drug targets that could serve as a marker for poor response and be modified pre-operatively to improve knee pain and surgical response to TKA.

Identification of a differential metabolite-based signature in patients with late-stage knee osteoarthritis.

Objective: Multiple disease phenotypes have been identified in knee osteoarthritis (OA) patients based on anthropometric, sociodemographic and clinical factors; however, differential systemic metabolite-based signatures in OA patients are not well understood. We sought to identify differential plasma metabolome signatures in a cross-sectional sample of late-stage knee OA patients. Methods: Plasma from 214 (56.5% female; mean age â€‹= â€‹67.58 years) non-diabetic, non-obese (BMI <30 â€‹kg/m2, mean â€‹= â€‹26.25 â€‹kg/m2), radiographic KL 3/4 primary knee OA patients was analyzed by metabolomics. Patients with post-traumatic OA and rheumatoid arthritis were excluded. Hierarchical clustering was used to identify patient clusters based on metabolite levels. A refined metabolite signature differentiating patient clusters was determined based on ≥ 10% difference, significance by FDR-adjusted t-test (q-value < 0.05), and random forests importance score ≥1, and analyzed by AUROC. Bioinformatics analysis was used to identify genes linked to ≥2 annotated metabolites. Associated enriched pathways (q â€‹< â€‹0.05) were determined. Results: Two patient clusters were determined based on the levels of 151 metabolites identified. Metabolite signature refinement found 24 metabolites could accurately predict cluster classification within the sample (AUC â€‹= â€‹0.921). Fifty-six genes were linked to at least 2 â€‹KEGG annotated metabolites. Pathway analysis found 26/56 genes were linked to enriched pathways including tRNA acylation and B-vitamin metabolism. Conclusion: This study demonstrates systemic metabolites can classify a cross-sectional cohort of OA patients into distinct clusters. Links between metabolites, genes and pathways can help determine biological differences between OA patients, potentially improving precision medicine and decision-making.

Restricting Branched-Chain Amino Acids within a High-Fat Diet Prevents Obesity.

Obesity is a global pandemic, but there is yet no effective measure to control it. Recent metabolomics studies have identified a signature of altered amino acid profiles to be associated with obesity, but it is unclear whether these findings have actionable clinical potential. The aims of this study were to reveal the metabolic alterations of obesity and to explore potential strategies to mitigate obesity. We performed targeted metabolomic profiling of the plasma/serum samples collected from six independent cohorts and conducted an individual data meta-analysis of metabolomics for body mass index (BMI) and obesity. Based on the findings, we hypothesized that restriction of branched-chain amino acids (BCAAs), phenylalanine, or tryptophan may prevent obesity and tested our hypothesis in a dietary restriction trial with eight groups of 4-week-old male C57BL/6J mice (n = 5/group) on eight different types of diets, respectively, for 16 weeks. A total of 3397 individuals were included in the meta-analysis. The mean BMI was 30.7 ± 6.1 kg/m2, and 49% of participants were obese. Fifty-eight metabolites were associated with BMI and obesity (all p ≤ 2.58 × 10-4), linked to alterations of the BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways. The restriction of BCAAs within a high-fat diet (HFD) maintained the mice's weight, fat and lean volume, subcutaneous and visceral adipose tissue weight, and serum glucose and insulin at levels similar to those in the standard chow group, and prevented obesity, adipocyte hypertrophy, adipose inflammation, and insulin resistance induced by HFD. Our data suggest that four metabolic pathways, BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways, are altered in obesity and restriction of BCAAs within a HFD can prevent the development of obesity and insulin resistance in mice, providing a promising strategy to potentially mitigate diet-induced obesity.

Healthcare Utilization and Costs for Musculoskeletal Disorders in Ontario, Canada.

OBJECTIVE: To examine the magnitude and costs of ambulatory primary care, specialist physician care, and hospital service use for musculoskeletal disorders (MSDs) in Canada's largest province, Ontario. METHODS: Administrative health databases were analyzed for fiscal year 2013-2014 for adults aged ≥ 18 years, including data on physician services, emergency department (ED) visits, and hospitalizations. International Classification of Diseases diagnostic codes were used to identify MSD services. A validated algorithm was used to estimate direct medical costs. Person-visit rates and numbers of persons and visits were tabulated by care setting, age, sex, and physician specialty. Data were examined for all MSDs combined, as well as for specific diagnostic groupings. RESULTS: Overall, 3.1 million adult Ontarians (28.5%) made over 8 million outpatient physician visits associated with MSDs. These included 5.6 million primary care visits. MSDs accounted for 560,000 (12.3%) of all adult ED visits. Total costs for MSD-related care were $1.6 billion, with 12.6% of costs attributed to primary care, 9.2% to specialist care, 8.6% to ED care, 8.5% to day surgery, and 61.2% associated with inpatient hospitalizations. Costs due to arthritis accounted for 40% of total MSD care costs ($639 million). MSD-related imaging costs were $169 million, yielding a total cost estimate of $1.8 billion for MSDs overall. CONCLUSION: MSDs place a significant and costly burden on the healthcare system. Health system planning needs to consider the large and escalating demand for care to reduce both the individual and population burden.

MicroRNA-34a-5p Promotes Joint Destruction During Osteoarthritis.

OBJECTIVE: MicroRNA-34a-5p (miR-34a-5p) expression is elevated in the synovial fluid of patients with late-stage knee osteoarthritis (OA); however, its exact role and therapeutic potential in OA remain to be fully elucidated. This study was undertaken to examine the role of miR-34a-5p in OA pathogenesis. METHODS: Expression of miR-34a-5p was determined in joint tissues and human plasma (n = 71). Experiments using miR-34a-5p mimic or antisense oligonucleotide (ASO) treatment were performed in human OA chondrocytes, fibroblast-like synoviocytes (FLS) (n = 7-9), and mouse OA models, including destabilization of the medial meniscus (DMM; n = 22) and the accelerated, more severe model of mice fed a high-fat diet and subjected to DMM (n = 11). Wild-type (WT) mice (n = 9) and miR-34a-knockout (KO) mice (n = 11) were subjected to DMM. Results were expressed as the mean ± SEM and analyzed by t-test or analysis of variance, with appropriate post hoc tests. P values less than 0.05 were considered significant. RNA sequencing was performed on WT and KO mouse chondrocytes. RESULTS: Expression of miR-34a-5p was significantly increased in the plasma, cartilage, and synovium of patients with late-stage OA and in the cartilage and synovium of mice subjected to DMM. Plasma miR-34a-5p expression was significantly increased in obese patients with late-stage OA, and in the plasma and knee joints of mice fed a high-fat diet. In human OA chondrocytes and FLS, miR-34a-5p mimic increased key OA pathology markers, while miR-34a-5p ASO improved cellular gene expression. Intraarticular miR-34a-5p mimic injection induced an OA-like phenotype. Conversely, miR-34a-5p ASO injection imparted cartilage-protective effects in the DMM and high-fat diet/DMM models. The miR-34a-KO mice exhibited protection against DMM-induced cartilage damage. RNA sequencing of WT and KO chondrocytes revealed a putative miR-34a-5p signaling network. CONCLUSION: Our findings provide comprehensive evidence of the role and therapeutic potential of miR-34a-5p in OA.

Healthcare utilization and costs for spinal conditions in Ontario, Canada - opportunities for funding high-value care: a retrospective cohort study.

BACKGROUND CONTEXT: An important step in improving spinal care is understanding how current health-care resources and associated cost are being utilized and distributed across a health-care system. PURPOSE: Our objective was to examine the magnitude and distribution of direct health care costs for spinal conditions across physician type and hospital setting. DESIGN/SETTING: Cross-sectional analysis of administrative health data for the fiscal year 2013-2014 from the province of Ontario, Canada. PATIENT SAMPLE: Adult population aged 18+ years (N=10,841,302). OUTCOME MEASURES: Person visit rates and total number of people and visits by specific care settings were calculated for all spinal conditions as well as stratified by nontrauma and trauma-related conditions. Variation in rates by age and sex was examined. The proportion of patients seeing physicians of different specialties was calculated for each condition grouping. Direct medical costs were estimated and their percentage distribution by care setting calculated for nontrauma and trauma-related conditions. Additionally, costs for spinal imaging overall and stratified by type of scan were determined. METHODS: Administrative health databases were analyzed, including data on physician services, emergency department visits, and hospitalizations. ICD-9 and -10 diagnostic codes were used to identify nontraumatic (degenerative or inflammatory) and traumatic spinal disorders. A validated algorithm was used to estimate direct medical costs. RESULTS: Overall, 822,000 adult Ontarians (7.6%) made 1.6 million outpatient physician visits for spinal conditions; the majority (1.1 million) of these visits were for nontrauma conditions. Approximately, 86% of outpatient visits were in primary care. Emergency Department (ED) visits for nontrauma spinal conditions (130,000 out of 156,000 ED visits) accounted for 2.8% of all ED visits in the province. Total costs for spine-related care were $264 million (CDN) with 64% of costs due to nontrauma conditions. For these nontrauma conditions, ED visits cost $28 million for 130,000 visits ($215 per visit). For $32 million spent in primary care, 890,000 visits were made ($36 per visit). Spine imaging costs were $66.5 million, yielding a combined total of $330 million in health care spending for spinal conditions. CONCLUSIONS: Spinal conditions place a large and costly burden on the health-care system. The disproportionate annual cost associated with ED visits represents a potential opportunity to redirect costs to fund more clinically and cost-effective models of care for nontraumatic spinal conditions.

Sex-Modified Effects of Depression, Low Back Pain, and Comorbidities on Pain After Total Knee Arthroplasty for Osteoarthritis.

OBJECTIVE: The influence of sex on post-total knee arthroplasty (TKA) outcomes has been variable in the literature. Though sex is often reported as an averaged effect, we undertook this study to investigate whether sex modified the influence of presurgery characteristics on post-TKA knee pain. METHODS: This was a prospective study with data derived from 477 TKA osteoarthritis patients (279 women, 198 men). Questionnaires were completed presurgery and at 3 months postsurgery. The association between 3-month post-TKA knee pain and presurgery covariates (body mass index, comorbidity count, symptomatic joint count, low back pain, knee pain, and depressive symptoms) was assessed by linear regression. Sex-specific effects were evaluated using interactions. RESULTS: Women had significantly worse presurgery knee pain, joint count, and depressive symptoms, and worse postsurgery knee pain, than men. With simple covariate adjustment, no sex effect on pain was found. However, sex was found to moderate the effects of comorbidities (worse for women [P = 0.013]), presence of low back pain (worse for men [P = 0.003]), and depressive symptoms (worse for men [P < 0.001]) on postsurgery pain. Worse presurgery pain was associated with worse postsurgery pain similarly for women and men. CONCLUSION: The influence of some patient factors on early post-TKA pain cannot be assumed to be the same for women and men; average effects may mask underlying associations. Results suggest a need to consider sex differences in understanding TKA outcomes, which may have important implications for prognostic tool development in TKA.

Patterns of Depressive Symptoms Before and After Surgery for Osteoarthritis: A Descriptive Study.

OBJECTIVE: To examine patterns of depressive symptoms before and over the year following osteoarthritis (OA) surgery, stratified by joint and postsurgical outcome. METHODS: Participants were hip (n = 287), knee (n = 360), and lumbar spine (n = 100) OA patients scheduled for joint replacement or decompression surgery with or without fusion. One pre- and 4 postsurgery questionnaires were completed. Depressive symptoms were quantified using the Hospital Anxiety and Depression Scale (HADS). One-year outcomes were based on Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores for hip and knee patients and Oswestry Disability Index (ODI) scores for spine patients and were categorized as "worse" (top score tertile) vs. "better" outcomes (first, second tertiles). Plots over time were generated by joint and outcome: 1) mean pain/disability and depression scores and 2) percentage of patients meeting HADS cut-off for depression "caseness," reporting depression diagnosis and treatment. RESULTS: There were notable decreases in depression scores for patients with better outcomes. For those with worse outcomes, decreases were smaller for hip patients and were not significant for knee and spine patients. Among those with poorer outcomes, 25% of spine and knee patients were depression "cases" pre- and postsurgery; an additional 16% of spine and 10% of knee patients developed new "caseness" postsurgery. The proportion of these patients deemed depression cases by score was much higher than the proportion reporting diagnosis/treatment. CONCLUSION: Although depressive symptoms decrease overall in OA patients postsurgery, degrees of change vary by joint and surgical outcome. Greater attention to mental health postsurgery is warranted and may lead to improved surgical outcomes, particularly among knee and spine patients.

Bone Marrow Mesenchymal Stromal Cell Treatment in Patients with Osteoarthritis Results in Overall Improvement in Pain and Symptoms and Reduces Synovial Inflammation.

Patients with late-stage Kellgren-Lawrence knee osteoarthritis received a single intra-articular injection of 1, 10, or 50 million bone marrow mesenchymal stromal cells (BM-MSCs) in a phase I/IIa trial to assess safety and efficacy using a broad toolset of analytical methods. Besides safety, outcomes included patient-reported outcome measures (PROMs): Knee Injury and Osteoarthritis Outcome Score (KOOS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC); contrast-enhanced magnetic resonance imaging (MRI) for cartilage morphology (Whole Organ MRI Scores [WORMS]), collagen content (T2 scores), and synovitis; and inflammation and cartilage turnover biomarkers, all over 12 months. BM-MSCs were characterized by a panel of anti-inflammatory markers to predict clinical efficacy. There were no serious adverse events, although four patients had minor, transient adverse events. There were significant overall improvements in KOOS pain, symptoms, quality of life, and WOMAC stiffness relative to baseline; the 50 million dose achieved clinically relevant improvements across most PROMs. WORMS and T2 scores did not change relative to baseline. However, cartilage catabolic biomarkers and MRI synovitis were significantly lower at higher doses. Pro-inflammatory monocytes/macrophages and interleukin 12 levels decreased in the synovial fluid after MSC injection. The panel of BM-MSC anti-inflammatory markers was strongly predictive of PROMs over 12 months. Autologous BM-MSCs are safe and result in significant improvements in PROMs at 12 months. Our analytical tools provide important insights into BM-MSC dosing and BM-MSC reduction of synovial inflammation and cartilage degradation and provide a highly predictive donor selection criterion that will be critical in translating MSC therapy for osteoarthritis. Stem Cells Translational Medicine 2019;8:746&757.

Synovial fluid monocyte/macrophage subsets and their correlation to patient-reported outcomes in osteoarthritic patients: a cohort study.

BACKGROUND: Chronic, low-grade inflammation of the synovium (synovitis) is a hallmark of osteoarthritis (OA), thus understanding of OA immunobiology, mediated by immune effectors, is of importance. Specifically, monocytes/macrophages (MΦs) are known to be abundantly present in OA joints and involved in OA progression. However, different subsets of OA MΦs have not been investigated in detail, especially in terms of their relationship with patient-reported outcome measures (PROMs). We hypothesized that levels of synovial fluid (SF) MΦ subsets are indicative of joint function and quality of life in patients with OA, and can therefore serve as biomarkers and therapeutic targets for OA. METHODS: In this cohort study, synovial fluid leukocytes (SFLs, N = 86) and peripheral blood mononuclear cells (n = 53) from patients with knee OA were characterized. Soluble MΦ receptors and chemokine (sCD14, sCD163, CCL2, CX3CL1) levels were detected in SF using immunoassays. Linear models, adjusted for sex, age and body mass index, were used to determine associations between SF MΦs and soluble factors with PROMs (N = 83). Pearson correlation was calculated to determine correlation between MΦ subsets, T cells and soluble factors. RESULTS: SF MΦs were the most abundant SFLs. Within these, the double-positive CD14+CD16+-MΦ subset is enriched in knee OA SF compared to the circulation. Importantly, MΦ subset ratios correlated with PROMs, specially stiffness, function and quality of life. Interestingly, the SF CD14+CD16+-MΦ subset ratio correlated with SF chemokine (C-C motif) ligand 2 (CCL2) levels but not with levels of sCD163 or sCD14; we found no association between PROMs and either SF CCL2, sCD163, sCD14 or CX3CL1 (which was below detection levels). All SF MΦs displayed high levels of HLA-DR, suggesting an activated phenotype. Correlation between OA SF MΦ subsets and activated CD4+ T cell subsets suggests modulation of CD4+ T cell activation by MΦs. CONCLUSION: SF MΦ subsets are associated with knee OA PROMs and display an activated phenotype, which may lead to modulation of CD4+ T cell activation. Knee OA SF MΦ subsets could serve as knee OA function biomarkers and as targets of novel therapeutics.

Factors Associated With Opioid Use in Presurgical Knee, Hip, and Spine Osteoarthritis Patients.

OBJECTIVE: To evaluate rates of prescription opioid use among patients with presurgical knee, hip, and spine osteoarthritis (OA) and associations between use and sociodemographic and health status characteristics. METHODS: Participants were patients with presurgical, end-stage OA of the knee (n = 77), hip (n = 459), and spine (n = 168). Data were collected on current use of opioids and other pain medications, as well as measures of sociodemographic and health status variables and depression and pain (0-10 numeric rating scale). Rates of opioid use were calculated by sex, age, and surgical site. Multivariable logistic regression was used to examine associations between opioid use (sometimes/daily versus never) and other study variables. RESULTS: The mean age of participants was 65.6 years; 55.5% were women, 15% of patients reported "sometimes" using opioids, and 15% reported "daily use." Use of opioids was highest among patients with spine OA (40%) and similar among patients with knee and hip OA (28% and 30%, respectively). Younger women (ages <65 years) reported the greatest use of opioids overall, particularly among patients with spine OA. From multivariable logistic regression, greater likelihood of opioid use was significantly associated with spine OA (versus knee OA), obesity, being a current or former smoker, higher symptomatic joint count, greater depressive symptoms, greater pain, and current use of other prescription pain medication. CONCLUSION: Nearly one-third of patients with presurgical OA used prescription opioid medication. Given the questionable efficacy of opioids in OA and risk of adverse effects, higher opioid use among younger individuals and those with depressive symptoms is of concern and warrants further investigation.

microRNA-181a-5p antisense oligonucleotides attenuate osteoarthritis in facet and knee joints.

OBJECTIVES: We recently identified microRNA-181a-5p (miR-181a-5p) as a critical mediator involved in the destruction of lumbar facet joint (FJ) cartilage. In this study, we tested if locked nucleic acid (LNA) miR-181a-5p antisense oligonucleotides (ASO) could be used as a therapeutic to limit articular cartilage degeneration. METHODS: We used a variety of experimental models consisting of both human samples and animal models of FJ and knee osteoarthritis (OA) to test the effects of LNA-miR-181a-5p ASO on articular cartilage degeneration. Histopathological analysis including immunohistochemistry and in situ hybridisation were used to detect key OA catabolic markers and microRNA, respectively. Apoptotic/cell death markers were evaluated by flow cytometry. qPCR and immunoblotting were applied to quantify gene and protein expression. RESULTS: miR-181a-5p expression was increased in human FJ OA and knee OA cartilage as well as injury-induced FJ OA (rat) and trauma-induced knee OA (mouse) cartilage compared with control cartilage, correlating with classical OA catabolic markers in human, rat and mouse cartilage. We demonstrated that LNA-miR-181a-5p ASO in rat and mouse chondrocytes reduced the expression of cartilage catabolic and chondrocyte apoptotic/cell death markers in vitro. Treatment of OA-induced rat FJ or mouse knee joints with intra-articular injections of in vivo grade LNA-miR-181a-5p ASO attenuated cartilage destruction, and the expression of catabolic, hypertrophic, apoptotic/cell death and type II collagen breakdown markers. Finally, treatment of LNA-miR-181a-5p ASO in cultures of human knee OA chondrocytes (in vitro) and cartilage explants (ex vivo) further demonstrated its cartilage protective effects. CONCLUSIONS: Our data demonstrate, for the first time, that LNA-miR-181a-5p ASO exhibit cartilage-protective effects in FJ and knee OA.

Presurgery osteoarthritis severity over 10 years in 2 Ontario prospective total knee replacement cohorts: a cohort study.

BACKGROUND: It has been suggested that total knee replacement is being performed in people with less-severe osteoarthritis. We aimed to determine whether there were differences in the presurgery profile, symptoms and disability of 2 cohorts who underwent total knee replacement over a 10-year period. METHODS: Patients aged 18-85 years undergoing primary total knee replacement for osteoarthritis at 1 of 4 sites in Toronto and Strathroy, Ontario, were recruited in a cohort study during 2006-2008 (cohort 1) and 2012-2015 (cohort 2). Patients undergoing unicompartmental or revision arthroplasty were excluded. Demographic and health (body mass index [BMI], comorbidity) variables and osteoarthritis severity, as assessed with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the disability component of the Late-Life Function and Disability Instrument (LLFDI-D), were collected before surgery. We calculated proportions, means and standard deviations with 95% confidence intervals (CIs) for all data. We constructed density plots by tertile score for the WOMAC pain and physical function subscales and the LLFDI-D limitation scale. RESULTS: There were 494 patients in cohort 1 and 251 patients in cohort 2. There were no differences in age, sex, education, living status, BMI, comorbidity, pain severity or disability between the cohorts based on overlapping 95% CIs and the density plots. More patients in cohort 1 than in cohort 2 were single (176 [35.6%], 95% CI 32.5%-41.1% v. 63 [25.1%], 95% CI 20.3%-31.0%). Patients in cohort 2 reported less limitation in higher-demand activities than did those in cohort 1 (mean score on LLFDI-D 62.3 [95% CI 60.7-63.9] v. 59.2 [95% CI 58.2-60.2]). INTERPRETATION: The patient profile and reported osteoarthritis severity were similar in 2 cohorts that had total knee replacement over a 10-year period. This suggests that increasing total knee replacement volumes over this period likely were not driven by these factors.

Understanding the Relationship Between 3-Month and 2-Year Pain and Function Scores After Total Knee Arthroplasty for Osteoarthritis.

BACKGROUND: Research to understand predictors of poor outcomes after total knee arthroplasty (TKA) has largely focused on presurgery factors. We examined whether pain and function 3-month postsurgery were predictive of longer-term outcomes ascertained 2 years after TKA. METHODS: Western Ontario McMaster University Osteoarthritis Index pain and physical function scores (scaled 0-20 and 0-68; higher = worse) were recorded pre-TKA and 3, 12, and 24 months post-TKA. A sequential series of regression models was used to examine the relative contribution of baseline score and baseline to 3-month and 3 to 12-month change score to explaining variability (R2) in 2-year pain and function scores, with consideration for presurgery covariates. RESULTS: Data from 560 patients were analyzed. Mean pain and function scores improved significantly presurgery to 2 years postsurgery; 10-4 and 33-16 (P < .001), respectively. Considerable variability in 2-year scores was observed. Overall, 80.3% and 79.9% of changes in pain and function scores over the 2 years occurred within the first 3 months. Change over these 3 months explained the greatest proportion of variability in 2-year scores, 16% and 23% for pain and function, respectively. The influences of these early changes were similar to those of baseline status. CONCLUSION: Changes in patient-reported pain and function occurring within the first 3 months post-TKA strongly determine pain and function status at 2 years. Research to identify pre-/intra-/early postoperative factors associated with change in this early postoperative period that may be amenable to modification or used to better inform education and decision-making is warranted.

High-fat diet-induced acceleration of osteoarthritis is associated with a distinct and sustained plasma metabolite signature.

Metabolic changes induced by high fat diet (HFD) that contribute to osteoarthritis (OA) are poorly understood. We investigated longitudinal changes to metabolites and their contribution to OA pathogenesis in response to HFD. HFD-fed mice exhibited acceleration of spontaneous age-related and surgically-induced OA compared to lean diet (LD)-fed mice. Using metabolomics, we identified that HFD-fed mice exhibited a distinct and sustained plasma metabolite signature rich in phosphatidylcholines (PC) and lysophosphatidylcholines (lysoPCs), even after resumption of normal chow diet. Using receiver operator curve analysis and prediction modelling, we showed that the concentration of these identified metabolites could efficiently predict the type of diet and OA risk with an accuracy of 93%. Further, longitudinal evaluation of knee joints of HFD- compared to LD- fed mice showed a greater percentage of leptin-positive chondrocytes. Mechanistic data showed that leptin-treated human OA chondrocytes exhibited enhanced production of lysoPCs and expression of autotaxin and catabolic MMP-13. Leptin-induced increased MMP13 expression was reversed by autotaxin inhibition. Together, this study is the first to describe a distinct and sustained HFD-induced metabolite signature. This study suggests that in addition to increased weight, identified metabolites and local leptin-signaling may also contribute in part, towards the accelerated OA-phenotype observed in HFD mice.