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To identify and synthesise the content of knee bracing interventions in randomised controlled trials (RCTs) of knee osteoarthritis (OA). In this scoping review, three electronic databases (PubMed, Web of Science, Cochrane) were searched up to 10th June 2024. Nineteen previous systematic reviews of knee bracing for knee OA and four recent international clinical practice guidelines were also hand searched. Identified studies were screened for eligibility by two independent reviewers. Information on bracing interventions was extracted from included RCT reports, informed by Template for Intervention Description and Replication (TIDieR) guidelines. Data were synthesised narratively. Thirty-one RCTs testing 47 different bracing interventions were included. Braces were broadly grouped as valgus/varus, patellofemoral, sleeve, neutral hinged, or control/placebo knee braces. Brace manufacturer and models varied, as did amount of recommended brace use. Only three interventions specifically targeted brace adherence. Information on brace providers, setting, number of treatment sessions, and intervention modification over time was poorly reported. Adherence to brace use was described for 32 (68%) interventions, most commonly via self-report. Several mechanisms of action for knee braces were proposed, broadly grouped as biomechanical, neuromuscular, and psychological. Many different knee brace interventions have been tested for knee OA, with several proposed mechanisms of action, a lack of focus on adherence, and a lack of full reporting. These issues may be contributing to the heterogeneous findings and inconsistent guideline recommendations about the clinical effectiveness of knee bracing for knee OA to date.

Objective: To determine the reliability and agreement of manual and automated morphological measurements, and agreement in morphological diagnoses. Methods: Thirty pelvic radiographs were randomly selected from the World COACH consortium. Manual and automated measurements of acetabular depth-width ratio (ADR), modified acetabular index (mAI), alpha angle (AA), Wiberg center edge angle (WCEA), lateral center edge angle (LCEA), extrusion index (EI), neck-shaft angle (NSA), and triangular index ratio (TIR) were performed. Bland-Altman plots and intraclass correlation coefficients (ICCs) were used to test reliability. Agreement in diagnosing acetabular dysplasia, pincer and cam morphology by manual and automated measurements was assessed using percentage agreement. Visualizations of all measurements were scored by a radiologist. Results: The Bland-Altman plots showed no to small mean differences between automated and manual measurements for all measurements except for ADR. Intraobserver ICCs of manual measurements ranged from 0.26 (95%-CI 0–0.57) for TIR to 0.95 (95%-CI 0.87–0.98) for LCEA. Interobserver ICCs of manual measurements ranged from 0.43 (95%-CI 0.10–0.68) for AA to 0.95 (95%-CI 0.86–0.98) for LCEA. Intermethod ICCs ranged from 0.46 (95%-CI 0.12–0.70) for AA to 0.89 (95%-CI 0.78–0.94) for LCEA. Radiographic diagnostic agreement ranged from 47% to 100% for the manual observers and 63%–96% for the automated method as assessed by the radiologist. Conclusion: The automated algorithm performed equally well compared to manual measurement by trained observers, attesting to its reliability and efficiency in rapidly computing morphological measurements. This validated method can aid clinical practice and accelerate hip osteoarthritis research.

OBJECTIVE: The aim of this work was to report the prevalence of computed tomography (CT)-detected intra-articular mineralization. DESIGN: We included participants from the Multicenter Osteoarthritis (MOST) Study. At the 12th year visit of the MOST study, bilateral knee CTs were first obtained. All participants also had posteroanterior and lateral radiographs of bilateral knees and completed standard questionnaires. Knee radiographs were assessed for Kellgren & Lawrence grade (KLG) and radiographic evidence of intra-articular mineralization. CT images were scored using the Boston University Calcium Knee Score (BUCKS) for cartilage, menisci, ligaments, capsule, and vasculature. Prevalence of intra-articular mineralization was computed for the total sample, and stratified by age, sex, race, Body Mass Index (BMI), presence of frequent knee pain, and KLG. We also determined distribution of mineralization in the cartilage and meniscus, and co-localization. RESULTS: 4140 bilateral knees from 2070 participants were included (56.7% female, mean age 61.1 years, mean BMI: 28.8 kg/m2). On radiographs 240 knees (5.8%) had intraarticular mineralization, while CT-detected mineralization was present in 9.8% of knees. Prevalence of hyaline articular and meniscus mineralization increased with age and KL grade, and was similar by sex, BMI categories, and comparable in subjects with and without frequent knee pain. Mineralization tended to be ubiquitous in the joint, most commonly involving all three (medial/lateral tibiofemoral and patellofemoral) compartments (3.1%), while the patellofemoral compartment was the most involved compartment in isolation (1.4%). CONCLUSIONS: CT of the knee provides greater visualization of intra-articular mineralization than radiographs and allows better localization of the crystal deposition within the joint. Further studies should focus on the co-localization of intra-articular crystal deposition and corresponding magnetic resonance imaging (MRI

ObjectivesTo determine how many persons with knee pain have subsequent pain resolution and what factors are associated with resolution, focusing especially on types of physical activity.MethodsUsing data from MOST, an NIH funded longitudinal cohort study of persons with or at risk of knee osteoarthritis, we studied participants who at baseline reported knee pain on most days at both a telephone interview and clinic visit. We defined pain resolution if at 30 and 60 month exams, they reported no knee pain on most days and compared these participants to those who reported persistent pain later. In logistic regression analyses, we examined the association of baseline risk factors including demographic factors, BMI, depressive symptoms, isokinetic quadriceps strength and both overall physical activity (using the PASE survey) and specific activities including walking, gardening, and different intensities of recreational activities with pain resolution.ResultsOf 1,304 participants with knee pain on most days at baseline, 265 (20.3%) reported no knee pain at 30 and 60 months. Lower BMI and stronger quadriceps were associated with higher odds of pain resolution while overall physical activity was not. Of activities, walking decreased the odds of pain resolution (adjOR = 0.86 (95% CI 0.76, 0.98)), but gardening (adjOR = 1.59 (1.16, 2.18)) and moderate intensity recreational activities ((adjOR = 1.24 (1.05, 1.46)) increased it.ConclusionPain resolution is common in those with knee pain. Factors increasing the odds of pain resolution include lower BMI, greater quadriceps strength and gardening and moderately intensive recreational activities.

OBJECTIVE: The effect of physical activity on the risk of developing knee osteoarthritis (OA) is unclear. We undertook this study to examine the relationship between recreational physical activity and incident knee OA outcomes using comparable physical activity and OA definitions. METHODS: Data were acquired from 6 global, community-based cohorts of participants with and those without knee OA. Eligible participants had no evidence of knee OA or rheumatoid arthritis at baseline. Participants were followed up for 5-12 years for incident outcomes including the following: 1) radiographic knee OA (Kellgren-Lawrence [K/L] grade ≥2), 2) painful radiographic knee OA (radiographic OA with knee pain), and 3) OA-related knee pain. Self-reported recreational physical activity included sports and walking/cycling activities and was quantified at baseline as metabolic equivalents of task (METs) in days per week. Risk ratios (RRs) were calculated and pooled using individual participant data meta-analysis. Secondary analysis assessed the association between physical activity, defined as time (hours per week) spent in recreational physical activity and incident knee OA outcomes. RESULTS: Based on a total of 5,065 participants, pooled RR estimates for the association of MET days per week with painful radiographic OA (RR 1.02 [95% confidence interval (95% CI) 0.93-1.12]), radiographic OA (RR 1.00 [95% CI 0.94-1.07]), and OA-related knee pain (RR 1.00 [95% CI 0.96-1.04]) were not significant. Similarly, the analysis of hours per week spent in physical activity also showed no significant associations with all outcomes. CONCLUSION: Our findings suggest that whole-body, physiologic energy expenditure during recreational activities and time spent in physical activity were not associated with incident knee OA outcomes.

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.

OBJECTIVES: To assess the relation of obesity to opioid use in people with or at risk of knee osteoarthritis (OA), and the extent to which this association is mediated by number of painful joints or depressive symptoms. METHODS: We used data from the Multicenter Osteoarthritis Study, a longitudinal cohort of older adults with or at risk of knee OA. Opioid use was identified by prescription medications and self-report. Obesity was defined as BMI ≥ 30 kg/m2. Multi-joint pain was assessed using a standardized body homunculus, and depressive symptoms using the Center for Epidemiological Studies Depression scale. We quantified the direct and indirect effect of obesity on opioid use through the number of painful joints or depressive symptoms using causal mediation analysis by natural-effects models. RESULTS: We studied 2,335 participants (mean age: 68; mean BMI 31 kg/m2; 60% women). Persons with obesity had ∼50% higher odds of opioid use than those without. Estimates of indirect (mediated) effect by the number of painful joints and depressive symptoms suggested an increased odds of opioid use by 34% (odds ratio [OR] = 1.34, 95% CI: 1.04, 1.70) and 35% (OR 1.35, 95% CI: 1.05, 1.71), respectively, in obese vs non-obese individuals. The total effect of obesity on opioid use was higher in women than in men. CONCLUSIONS: Multi-joint pain and depressive symptoms partially explained greater opioid use among obese persons with knee OA, demonstrating that the negative impact of obesity on knee OA extends beyond its influence on knee pain and structural progression.

Objective: To summarize proceedings of a workshop convened to discuss the current state of science in the disease of osteoarthritis (OA), identify the knowledge gaps, and examine the developmental and regulatory challenges in bringing these products to market. Design: Summary of the one-day workshop held virtually on June 22nd, 2021. Results: Speakers selected by the Planning Committee presented data on the current approach to assessment of OA therapies, biomarkers in OA drug development, and the assessment of disease progression and long-term benefit. Conclusions: Demonstrated by numerous failed clinical trials, OA is a challenging disease for which to develop therapeutics. The challenge is magnified by the slow time of onset of disease and the need for clinical trials of long duration and/or large sample size to demonstrate the effect of an intervention. The OA science community, including academia, pharmaceutical companies, regulatory agencies, and patient communities, must continue to develop and test better clinical endpoints that meaningfully reflect disease modification related to long-term patient benefit.

INTRODUCTION: Higher intake of fiber has been associated with lower risk of incident symptomatic osteoarthritis (OA). We examined whether levels of alkylresorcinol (AR), a marker of whole grain intake, were associated with OA in subjects in The Multicenter Osteoarthritis (MOST) Study. METHOD: Knee x-rays and knee pain were assessed at baseline and through 60-months. Stored baseline fasting plasma samples were analyzed for AR homologues (C17:0, C19:0, C21:0, C23:0, C25:0) and total AR levels (AR sum). Two nested case-control studies, one for incident radiographic OA and one for incident symptomatic OA were performed with participants re-assessed at 15, 30 and 60 months. Multivariable conditional logistic regression with baseline covariates including age, sex, BMI, physical activity, quadriceps strength, race, smoking, depressive symptoms, diabetes and knee injury tested the association of log transformed AR levels with OA outcomes. RESULTS: Seven hundred seventy-seven subjects were, on average, in their 60s, and most were women. For 60-month cumulative incidence, there was no significant association between quartiles of AR concentration and incident radiographic (e.g., for incident radiographic OA, highest vs lowest quartile of AR sum showed RR = 0.93 (95% CI 0.59, 1.47), and for symptomatic OA RR was 1.22 (95% CI 0.76, 1.94). In secondary analyses examining 30-month incidence, high AR levels were associated with a reduced risk of X-ray OA (RR = 0.31 (95% CI 0.15, 0.64). CONCLUSION: In primary analyses, AR levels were not associated with risk of OA, but secondary analyses left open the possibility that high AR levels may protect against OA.

Objective: To summarize available evidence on the association between hip shape as quantified by statistical shape modeling (SSM) and the incidence or progression of hip osteoarthritis. Design: We conducted a systematic search of five electronic databases, based on a registered protocol (available: PROSPERO CRD42020145411). Articles presenting original data on the longitudinal relationship between radiographic hip shape (quantified by SSM) and hip OA were eligible. Quantitative meta-analysis was precluded because of the use of different SSM models across studies. We used the Newcastle–Ottawa Scale (NOS) for risk of bias assessment. Results: Nine studies (6,483 hips analyzed with SSM) were included in this review. The SSM models used to describe hip shape ranged from 16 points on the femoral head to 85 points on the proximal femur and hemipelvis. Multiple hip shape features and combinations thereof were associated with incident or progressive hip OA. Shape variants that seemed to be consistently associated with hip OA across studies were acetabular dysplasia, cam morphology, and deviations in acetabular version (either excessive anteversion or retroversion). Conclusions: Various radiographic, SSM-defined hip shape features are associated with hip OA. Some hip shape features only seem to increase the risk for hip OA when combined together. The heterogeneity of the used SSM models across studies precludes the estimation of pooled effect sizes. Further studies using the same SSM model and definition of hip OA are needed to allow for the comparison of outcomes across studies, and to validate the found associations.

Background Brace effectiveness for knee osteoarthritis (OA) remains unclear and international guidelines offer conflicting recommendations. Our trial will determine the clinical and cost-effectiveness of adding knee bracing (matched to patients' clinical and radiographic presentation and with adherence support) to a package of advice, written information and exercise instruction delivered by physiotherapists. Methods and analysis A multicentre, pragmatic, two-parallel group, single-blind, superiority, randomised controlled trial with internal pilot and nested qualitative study. 434 eligible participants with symptomatic knee OA identified from general practice, physiotherapy referrals and self-referral will be randomised 1:1 to advice, written information and exercise instruction and knee brace versus advice, written information and exercise instruction alone. The primary analysis will be intention-to-treat comparing treatment arms on the primary outcome (Knee Osteoarthritis Outcomes Score (KOOS)-5) (composite knee score) at the primary endpoint (6 months) adjusted for prespecified covariates. Secondary analysis of KOOS subscales (pain, other symptoms, activities of daily living, function in sport and recreation, knee-related quality of life), self-reported pain, instability (buckling), treatment response, physical activity, social participation, self-efficacy and treatment acceptability will occur at 3, 6, and 12 months postrandomisation. Analysis of covariance and logistic regression will model continuous and dichotomous outcomes, respectively. Treatment effect estimates will be presented as mean differences or ORs with 95% CIs. Economic evaluation will estimate cost-effectiveness. Semistructured interviews to explore acceptability and experiences of trial interventions will be conducted with participants and physiotherapists delivering interventions. Ethics and dissemination North West Preston Research Ethics Committee, the Health Research Authority and Health an

Background Brace effectiveness for knee osteoarthritis (OA) remains unclear and international guidelines offer conflicting recommendations. Our trial will determine the clinical and cost-effectiveness of adding knee bracing (matched to patients' clinical and radiographic presentation and with adherence support) to a package of advice, written information and exercise instruction delivered by physiotherapists. Methods and analysis A multicentre, pragmatic, two-parallel group, single-blind, superiority, randomised controlled trial with internal pilot and nested qualitative study. 434 eligible participants with symptomatic knee OA identified from general practice, physiotherapy referrals and self-referral will be randomised 1:1 to advice, written information and exercise instruction and knee brace versus advice, written information and exercise instruction alone. The primary analysis will be intention-to-treat comparing treatment arms on the primary outcome (Knee Osteoarthritis Outcomes Score (KOOS)-5) (composite knee score) at the primary endpoint (6 months) adjusted for prespecified covariates. Secondary analysis of KOOS subscales (pain, other symptoms, activities of daily living, function in sport and recreation, knee-related quality of life), self-reported pain, instability (buckling), treatment response, physical activity, social participation, self-efficacy and treatment acceptability will occur at 3, 6, and 12 months postrandomisation. Analysis of covariance and logistic regression will model continuous and dichotomous outcomes, respectively. Treatment effect estimates will be presented as mean differences or ORs with 95% CIs. Economic evaluation will estimate cost-effectiveness. Semistructured interviews to explore acceptability and experiences of trial interventions will be conducted with participants and physiotherapists delivering interventions. Ethics and dissemination North West Preston Research Ethics Committee, the Health Research Authority and Health an

Background Despite recent advances in the understanding of the genetic architecture of osteoarthritis (OA), only two genetic loci have been identified for OA of the hand, in part explained by the complexity of the different hand joints and heterogeneity of OA pathology. Methods We used data from the Rotterdam Study (RSI, RSII and RSIII) to create three hand OA phenotypes based on clustering patterns of radiographic OA severity to increase power in our modest discovery genome-wide association studies in the RS (n=8700), and sought replication in an independent cohort, the Framingham Heart Study (n=1203). We used multiple approaches that leverage different levels of information and functional data to further investigate the underlying biological mechanisms and candidate genes for replicated loci. We also attempted to replicate known OA loci at other joint sites, including the hips and knees. Results We found two novel genome-wide significant loci for OA in the thumb joints. We identified WNT9A as a possible novel causal gene involved in OA pathogenesis. Furthermore, several previously identified genetic loci for OA seem to confer risk for OA across multiple joints: TGFa, RUNX2, COL27A1, ASTN2, IL11 and GDF5 loci. Conclusions We identified a robust novel genetic locus for hand OA on chromosome 1, of which WNT9A is the most likely causal gene. In addition, multiple genetic loci were identified to be associated with OA across multiple joints. Our study confirms the potential for novel insight into the genetic architecture of OA by using biologically meaningful stratified phenotypes.

Objective: To summarize available evidence on the association between hip shape as quantified by statistical shape modeling (SSM) and the incidence or progression of hip osteoarthritis. Design: We conducted a systematic search of five electronic databases, based on a registered protocol (available: PROSPERO CRD42020145411). Articles presenting original data on the longitudinal relationship between radiographic hip shape (quantified by SSM) and hip OA were eligible. Quantitative meta-analysis was precluded because of the use of different SSM models across studies. We used the Newcastle–Ottawa Scale (NOS) for risk of bias assessment. Results: Nine studies (6,483 hips analyzed with SSM) were included in this review. The SSM models used to describe hip shape ranged from 16 points on the femoral head to 85 points on the proximal femur and hemipelvis. Multiple hip shape features and combinations thereof were associated with incident or progressive hip OA. Shape variants that seemed to be consistently associated with hip OA across studies were acetabular dysplasia, cam morphology, and deviations in acetabular version (either excessive anteversion or retroversion). Conclusions: Various radiographic, SSM-defined hip shape features are associated with hip OA. Some hip shape features only seem to increase the risk for hip OA when combined together. The heterogeneity of the used SSM models across studies precludes the estimation of pooled effect sizes. Further studies using the same SSM model and definition of hip OA are needed to allow for the comparison of outcomes across studies, and to validate the found associations.

Objective: To summarize available evidence on the association between hip shape as quantified by statistical shape modeling (SSM) and the incidence or progression of hip osteoarthritis. Design: We conducted a systematic search of five electronic databases, based on a registered protocol (available: PROSPERO CRD42020145411). Articles presenting original data on the longitudinal relationship between radiographic hip shape (quantified by SSM) and hip OA were eligible. Quantitative meta-analysis was precluded because of the use of different SSM models across studies. We used the Newcastle–Ottawa Scale (NOS) for risk of bias assessment. Results: Nine studies (6,483 hips analyzed with SSM) were included in this review. The SSM models used to describe hip shape ranged from 16 points on the femoral head to 85 points on the proximal femur and hemipelvis. Multiple hip shape features and combinations thereof were associated with incident or progressive hip OA. Shape variants that seemed to be consistently associated with hip OA across studies were acetabular dysplasia, cam morphology, and deviations in acetabular version (either excessive anteversion or retroversion). Conclusions: Various radiographic, SSM-defined hip shape features are associated with hip OA. Some hip shape features only seem to increase the risk for hip OA when combined together. The heterogeneity of the used SSM models across studies precludes the estimation of pooled effect sizes. Further studies using the same SSM model and definition of hip OA are needed to allow for the comparison of outcomes across studies, and to validate the found associations., Biomaterials & Tissue Biomechanics

OBJECTIVES: Further knowledge about typical hand osteoarthritis (OA) characteristics is needed for the development of new classification criteria for hand OA. METHODS: In a cross-sectional multi-centre international study, a convenience sample of patients from primary and secondary/tertiary care with a physician-based hand OA diagnosis (n = 128) were compared with controls with hand complaints due to inflammatory or non-inflammatory conditions (n = 70). We examined whether self-reported, clinical, radiographic and laboratory findings were associated with hand OA using logistic regression analyses. Discrimination between groups was assessed by calculating the area under receiver operating curves (AUC). RESULTS: Strong associations with hand OA were observed for radiographic osteophytes (OR = 1.62, 95% CI 1.40 to 1.88) and joint space narrowing (JSN) (OR = 1.57, 95% CI 1.36 to 1.82) in the distal interphalangeal (DIP) joints with excellent discrimination (AUC = 0.82 for both). For osteophytes and JSN, we found acceptable discrimination between groups in the proximal interphalangeal joints (AUC = 0.77 and 0.78, respectively), but poorer discrimination in

Objective In rheumatoid arthritis, composite outcomes constructed from a combination of outcome measures are widely used to enhance responsiveness (sensitivity to change) and comprehensively summarize response. WOMAC pain is the primary outcome measure in many osteoarthritis (OA) trials. Information from other outcomes, such as rescue medication use, and other WOMAC subscales, could be added to create composite outcomes, but the sensitivity of such a composite has not been tested. Method We used data from a completed trial of Tanezumab for knee OA (NCT00733902). The WOMAC questionnaire and rescue medication use were measured at multiple time points, up to 16 weeks. Pain and rescue medication outcomes were standardised and combined into 3 composite outcomes via principal components analysis to produce one score (composite outcome) and their responsiveness was compared to WOMAC pain, the standard. We pooled all treatment doses of Tanezumab into one ‘treatment’ group, for simplicity, and compared this to the control group (placebo). Results The composite outcomes showed modestly but not statistically significantly greater responsiveness when compared to WOMAC pain alone. Adding information on rescue medication to the composite improved responsiveness. While improvements in sensitivity were modest, the required sample sizes for trials using composites was 20- 40% less than trials using WOMAC pain alone Page 4 of 55 Page 4 of 23 Conclusion Combining information from related, but distinct, outcomes considered relevant to a particular treatment improved responsiveness, could reduce sample size requirements in OA trials and might offer a way to better detect treatment efficacy in OA trials.

ObjectivePopulation-based osteoarthritis (OA) cohorts provide vital data on risk factors and outcomes of OA, however the methods to define OA vary between cohorts. We aimed to provide recommendations for combining knee and hip OA data in extant and future population cohort studies, in order to facilitate informative individual participant level analyses.MethodInternational OA experts met to make recommendations on: 1) defining OA by X-ray and/or pain; 2) compare The National Health and Nutrition Examination Survey (NHANES)-type OA pain questions; 3) the comparability of the Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) scale to NHANES-type OA pain questions; 4) the best radiographic scoring method; 5) the usefulness of other OA outcome measures. Key issues were explored using new analyses in two population-based OA cohorts (Multicenter Osteoarthritis Study; MOST and Osteoarthritis Initiative OAI).ResultsOA should be defined by both symptoms and radiographs, with symptoms alone as a secondary definition. Kellgren and Lawrence (K/L) grade ≥2 should be used to define radiographic OA (ROA). The variable wording of pain questions can result in varying prevalence between 41.0% and 75.4%, however questions where the time anchor is similar have high sensitivity and specificity (91.2% and 89.9% respectively). A threshold of 3 on a 0-20 scale (95% CI 2.1, 3.9) in the WOMAC pain subscale demonstrated equivalence with the preferred NHANES-type question.ConclusionThis research provides recommendations, based on expert agreement, for harmonising and combining OA data in existing and future population-based cohorts.

OBJECTIVE:To determine the relationship of meniscal damage to magnetic resonance imaging (MRI) features of compartment-specific patellofemoral joint (PFJ) osteoarthritis (OA) at baseline and 2 years later. METHOD:Individuals from a prospective cohort of individuals aged 50-79 with or at risk of knee OA were included. At the 60-month and 84-month study visit, Whole-Organ MRI Score (WORMS) was used to assess meniscal tears and extrusions as well as cartilage damage and bone marrow lesions (BMLs) in the medial and lateral patella and trochlea. Worsening of structural features was defined as any increase in WORMS score from 60 to 84 months. Logistic regression was used to determine the cross-sectional and longitudinal relation of meniscus damage to features of compartment-specific PFJ OA. RESULTS:Relative to knees without lateral meniscal pathology at baseline, those with grades 3-4 lateral meniscal tear and extrusion had greater risk of worsening of cartilage damage in the lateral PFJ 2 years later (Risk ratio: 1.7 [95% CI: 1.1-2.7) and (1.7 [1.2-2.5]), respectively. Relative to those without medial meniscal pathology at baseline, those with grades 1-2 (0.6 [0.4-0.9]) and 3-4 (0.7 [0.5-1.0]) medial meniscal tears had lower risk of worsening of BMLs in the medial PFJ 2 years later. CONCLUSION:Meniscal tear and extrusion are associated with increased risk of medial and lateral PFJ OA and more severe meniscal pathology is associated with worsening of PFJ OA 2 years later. Lateral meniscal pathology appears to be more detrimental to the lateral PFJ.

Objective In rheumatoid arthritis, composite outcomes constructed from a combination of outcome measures are widely used to enhance responsiveness (sensitivity to change) and comprehensively summarize response. WOMAC pain is the primary outcome measure in many osteoarthritis (OA) trials. Information from other outcomes, such as rescue medication use, and other WOMAC subscales, could be added to create composite outcomes, but the sensitivity of such a composite has not been tested. Method We used data from a completed trial of Tanezumab for knee OA (NCT00733902). The WOMAC questionnaire and rescue medication use were measured at multiple time points, up to 16 weeks. Pain and rescue medication outcomes were standardised and combined into 3 composite outcomes via principal components analysis to produce one score (composite outcome) and their responsiveness was compared to WOMAC pain, the standard. We pooled all treatment doses of Tanezumab into one ‘treatment’ group, for simplicity, and compared this to the control group (placebo). Results The composite outcomes showed modestly but not statistically significantly greater responsiveness when compared to WOMAC pain alone. Adding information on rescue medication to the composite improved responsiveness. While improvements in sensitivity were modest, the required sample sizes for trials using composites was 20- 40% less than trials using WOMAC pain alone Page 4 of 55 Page 4 of 23 Conclusion Combining information from related, but distinct, outcomes considered relevant to a particular treatment improved responsiveness, could reduce sample size requirements in OA trials and might offer a way to better detect treatment efficacy in OA trials.

Objective Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability in the elderly. Of all the joints, genetic predisposition is strongest for OA of the hand; however, only few genetic risk loci for hand OA have been identified. Our aim was to identify novel genes associated with hand OA and examine the underlying mechanism. Methods We performed a genome-wide association study of a quantitative measure of hand OA in 12 784 individuals (discovery: 8743, replication: 4011). Genome-wide significant signals were followed up by analysing gene and allele-specific expression in a RNA sequencing dataset (n=96) of human articular cartilage. Results We found two significantly associated loci in the discovery set: at chr12 (p=3.5 × 10 -10) near the matrix Gla protein (MGP) gene and at chr12 (p=6.1×10 -9) near the CCDC91 gene. The DNA variant near t

Knee osteoarthritis (OA) is believed to be highly prevalent today because of recent increases in life expectancy and body mass index (BMI), but this assumption has not been tested using long-term historical or evolutionary data. We analyzed long-term trends in knee OA prevalence in the United States using cadaver-derived skeletons of people aged ≥50 y whose BMI at death was documented and who lived during the early industrial era (1800s to early 1900s; n = 1,581) and the modern postindustrial era (late 1900s to early 2000s; n = 819). Knee OA among individuals estimated to be ≥50 y old was also assessed in archeologically derived skeletons of prehistoric hunter-gatherers and early farmers (6000–300 B.P.; n = 176). OA was diagnosed based on the presence of eburnation (polish from bone-on-bone contact). Overall, knee OA prevalence was found to be 16% among the postindustrial sample but only 6% and 8% among the early industrial and prehistoric samples, respectively. After controlling for age, BMI, and other variables, knee OA prevalence was 2.1-fold higher (95% confidence interval, 1.5–3.1) in the postindustrial sample than in the early industrial sample. Our results indicate that increases in longevity and BMI are insufficient to explain the approximate doubling of knee OA prevalence that has occurred in the United States since the mid-20th century. Knee OA is thus more preventable than is commonly assumed, but prevention will require research on additional independent risk factors that either arose or have become amplified in the postindustrial era.

© 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY licenseBackground Non-fatal outcomes of disease and injury increasingly detract from the ability of the world's population to live in full health, a trend largely attributable to an epidemiological transition in many countries from causes affecting children, to non-communicable diseases (NCDs) more common in adults. For the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015), we estimated the incidence, prevalence, and years lived with disability for diseases and injuries at the global, regional, and national scale over the period of 1990 to 2015. Methods We estimated incidence and prevalence by age, sex, cause, year, and geography with a wide range of updated and standardised analytical procedures. Improvements from GBD 2013 included the addition of new data sources, updates to literature reviews for 85 causes, and the identification and inclusion of additional studies published up to November, 2015, to expand the database used for estimation of non-fatal outcomes to 60?900 unique data sources. Prevalence and incidence by cause and sequelae were determined with DisMod-MR 2.1, an improved version of the DisMod-MR Bayesian meta-regression tool first developed for GBD 2010 and GBD 2013. For some causes, we used alternative modelling strategies where the complexity of the disease was not suited to DisMod-MR 2.1 or where incidence and prevalence needed to be determined from other data. For GBD 2015 we created a summary indicator that combines measures of income per capita, educational attainment, and fertility (the Socio-demographic Index [SDI]) and used it to compare observed patterns of health loss to the expected pattern for countries or locations with similar SDI scores. Findings We generated 9·3 billion estimates from the various combinations of prevalence, incidence, and YLDs for causes, sequelae, and impairments by age, sex, geography, and year.

Purpose: To explore the association of baseline trabecular bone structure with incident tibiofemoral (TF) osteoarthritis (OA) and with increase in joint space narrowing (JSN) score. Methods: The Multicenter Osteoarthritis Study (MOST) includes subjects with or at risk for knee OA. Knee radiographs were scored for Kellgren–Lawrence (KL) grade and JSN at baseline, 30, 60 and 84 months. Knees (KL = 1) at baseline were assessed for incident OA (KL = 2) and increases in JSN score. For each knee image at baseline, a variance orientation transform method (VOT) was applied to subchondral tibial bone regions of medial and lateral compartments. Seventeen fractal parameters were calculated per region. Associations of each parameter with OA incidence and with medial and lateral JSN increases were explored using logistic regression. Analyses were stratified by digitized film (DF) vs computer radiography (CR) and adjusted for confounders. Results: Of 894 knees with CR and 1158 knees with DF, 195 (22%) and 303 (26%) developed incident OA. Higher medial bone roughness was associated with increased odds of OA incidence at 60 and 84 months and also, medial and lateral JSN increases (primarily vertical). Lower medial and lateral anisotropy was associated with increased odds of medial and lateral JSN increase. Compared to DF, CR had more associations and also, similar results at overlapping scales. Conclusion: Baseline trabecular bone texture was associated with incident radiographic OA and increase of JSN scores independently of risk factors for knee OA. Higher roughness and lower anisotropy were associated with increased odds for radiographic OA change.

BackgroundPrevious studies suggest that the antioxidants vitamins C and E may protect against development of knee osteoarthritis (OA). We examined the association of circulating levels of vitamin C and E with incident whole knee radiographic OA (WKROA).MethodsWe performed a nested case-control study of incident WKROA in MOST, a cohort of 3,026 men and women aged 50-79 years with, or at high risk of, knee OA. Incident cases were knees without either tibiofemoral (TF) or patellofemoral (PF) OA at baseline that developed TF and/or PF OA by 30-month follow-up. Two control knees per case were selected from those eligible for WKROA that did not develop it. Vitamin C and E (alpha-tocopherol) assays were done on baseline supernatant plasma (PCA) and serum samples, respectively. We examined the association of gender-specific tertiles of vitamin C and E with incident WKROA using logistic regression with GEE, adjusting for age, gender, and obesity.ResultsSubjects without WKROA at baseline who were in the highest tertile of vitamin C had a higher incidence of WKROA [adjusted OR = 2.20 (95% CI: 1.12-4.33); P-value = 0.021], with similar results for the highest tertile of vitamin E [adjusted OR = 1.89 (1.02-3.50); P-value = 0.042], compared to those in the lowest tertiles. P-values for the trend of vitamin C and E tertiles and incident WKROA were 0.019 and 0.030, respectively.ConclusionsHigher levels of circulating vitamin C and E did not provide protection against incident radiographic knee OA, and may be associated with an increased risk of knee OA.

Objective To assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA. Methods A total of 199 candidate genes for association with OA were identified using Human Genome Epidemiology (HuGE) Navigator. All of their single-nucleotide polymorphisms (SNPs) with an allele frequency of >5% were assessed by fixed-effects meta-analysis of 9 genome-wide association studies (GWAS) that included 5,636 patients with knee OA and 16,972 control subjects and 4,349 patients with hip OA and 17,836 control subjects of European ancestry. An additional 5,921 individuals were genotyped for significantly associated SNPs in the meta-analysis. After correction for the number of independent tests, P values less than 1.58 × 10-5 were considered significant. Results SNPs at only 2 of the 199 candidate genes (COL11A1 and VEGF) were associated with OA in the meta-analysis. Two SNPs in COL11A1 showed association with hip OA in the combined analysis: rs4907986 (P = 1.29 × 10-5, odds ratio [OR] 1.12, 95% confidence interval [95% CI] 1.06-1.17) and rs1241164 (P = 1.47 × 10-5, OR 0.82, 95% CI 0.74-0.89). The sex-stratified analysis also showed association of COL11A1 SNP rs4908291 in women (P = 1.29 × 10-5, OR 0.87, 95% CI 0.82-0.92); this SNP showed linkage disequilibrium with rs4907986. A single SNP of VEGF, rs833058, showed association with hip OA in men (P = 1.35 × 10-5, OR 0.85, 95% CI 0.79-0.91). After additional samples were genotyped, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened. Conclusion Two candidate genes, COL11A1 and VEGF, were significantly associated with OA in this focused meta-analysis. The remaining candidate genes were not associated. Copyright

BackgroundPrevious studies suggest that the antioxidants vitamins C and E may protect against development of knee osteoarthritis (OA). We examined the association of circulating levels of vitamin C and E with incident whole knee radiographic OA (WKROA).MethodsWe performed a nested case-control study of incident WKROA in MOST, a cohort of 3,026 men and women aged 50-79 years with, or at high risk of, knee OA. Incident cases were knees without either tibiofemoral (TF) or patellofemoral (PF) OA at baseline that developed TF and/or PF OA by 30-month follow-up. Two control knees per case were selected from those eligible for WKROA that did not develop it. Vitamin C and E (alpha-tocopherol) assays were done on baseline supernatant plasma (PCA) and serum samples, respectively. We examined the association of gender-specific tertiles of vitamin C and E with incident WKROA using logistic regression with GEE, adjusting for age, gender, and obesity.ResultsSubjects without WKROA at baseline who were in the highest tertile of vitamin C had a higher incidence of WKROA [adjusted OR = 2.20 (95% CI: 1.12-4.33); P-value = 0.021], with similar results for the highest tertile of vitamin E [adjusted OR = 1.89 (1.02-3.50); P-value = 0.042], compared to those in the lowest tertiles. P-values for the trend of vitamin C and E tertiles and incident WKROA were 0.019 and 0.030, respectively.ConclusionsHigher levels of circulating vitamin C and E did not provide protection against incident radiographic knee OA, and may be associated with an increased risk of knee OA.

Background Despite the importance of timely management of patients with infl ammatory arthritis (IA), delays exist in its diagnosis and treatment. Objective To perform a systematic literature review to identify strategies addressing these delays to inform an American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) taskforce. Methods The authors searched literature published between January 1985 and November 2010, and ACR and EULAR abstracts between 2007-2010. Additional information was obtained through a grey literature search, a survey conducted through ACR and EULAR, and a hand search of the literature. Results (1) From symptom onset to primary care, community case-finding strategies, including the use of a questionnaire and autoantibody testing, have been designed to identify patients with early IA. Several websites provided information on IA but were of varying quality and insufficient to aid early referral. (2) At a primary care level, education programmes and patient self-administered questionnaires identified patients with potential IA for referral to rheumatology. Many guidelines emphasised the need for early referral with one providing specific referral criteria. (3) Once referred, early arthritis clinics provided a point of early access for rheumatology assessment. Triage systems, including triage clinics, helped prioritise clinic appointments for patients with IA. Use of referral forms standardised information required, further optimising the triage process. Wait times for patients with acute IA were also reduced with development of rapid access systems. Conclusions This review identified three main areas of delay to care for patients with IA and potential solutions for each. A co-ordinated effort will be required by the rheumatology and primary care community to address these effectively.

Background Despite the importance of timely management of patients with infl ammatory arthritis (IA), delays exist in its diagnosis and treatment. Objective To perform a systematic literature review to identify strategies addressing these delays to inform an American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) taskforce. Methods The authors searched literature published between January 1985 and November 2010, and ACR and EULAR abstracts between 2007–2010. Additional information was obtained through a grey literature search, a survey conducted through ACR and EULAR, and a hand search of the literature. Results (1) From symptom onset to primary care, community case-fi nding strategies, including the use of a questionnaire and autoantibody testing, have been designed to identify patients with early IA. Several websites provided information on IA but were of varying quality and insuffi cient to aid early referral. (2) At a primary care level, education programmes and patient self-administered questionnaires identifi ed patients with potential IA for referral to rheumatology. Many guidelines emphasised the need for early referral with one providing specifi c referral criteria. (3) Once referred, early arthritis clinics provided a point of early access for rheumatology assessment. Triage systems, including triage clinics, helped prioritise clinic appointments for patients with IA. Use of referral forms standardised information required, further optimising the triage process. Wait times for patients with acute IA were also reduced with development of rapid access systems. Conclusions This review identifi ed three main areas of delay to care for patients with IA and potential solutions for each. A co-ordinated effort will be required by the rheumatology and primary care community to address these effectively.

ObjectiveStrong associations between radiographic features of knee osteoarthritis (OA) and pain have been demonstrated in persons with unilateral knee symptoms. This study was undertaken to compare radiographic and magnetic resonance imaging (MRI) features of knee OA and assess their ability to discriminate between painful and nonpainful knees in persons with unilateral symptoms.MethodsThe study population included 283 individuals ages 70-79 years with unilateral knee pain who were enrolled in the Health, Aging, and Body Composition Study, a study of weight-related diseases and mobility. Radiographs of both knees were read for Kellgren/Lawrence (K/L) grade and individual radiographic features, and 1.5T MRIs were assessed using the Whole-Organ Magnetic Resonance Imaging Score. The association between structural features and pain was assessed using a within-person case-control design and conditional logistic regression. Receiver operating characteristic (ROC) analysis was then used to test the discriminatory performance of structural features.ResultsIn conditional logistic analyses, knee pain was significantly associated with both radiographic features (any joint space narrowing grade ≥ 1) (odds ratio 3.20 [95% confidence interval 1.79-5.71]) and MRI features (any cartilage defect scored ≥ 2) (odds ratio 3.67 [95% confidence interval 1.49-9.04]). However, in most subjects, MRI revealed osteophytes and cartilage and bone marrow lesions in both knees, and using ROC analysis, no individual structural feature discriminated well between painful and nonpainful knees. The best-performing MRI feature (synovitis/effusion) was not significantly more informative than K/L grade ≥ 2 (P = 0.42).ConclusionIn persons with unilateral knee pain, MRI and radiographic features were associated with knee pain, confirming that structural abnormalities in the knee have an important role in the etiology of pain. However, no single MRI or radiographic finding performed well in discriminating b

ObjectivesThe genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis.MethodsThe authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44,449 individuals), and de novo in 14 534 independent samples, all of European descent.ResultsNone of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects.ConclusionsIdentifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity.

Objective: To address the need for standardization of osteoarthritis (OA) phenotypes by examining the effect of heterogeneity among symptomatic (SOA) and radiographic osteoarthritis (ROA) phenotypes. Methods: Descriptions of OA phenotypes of the 28 studies involved in the TREAT-OA consortium were collected. We investigated whether different OA definitions result in different association results by creating various hip OA definitions in one large population based cohort (the Rotterdam Study I

ObjectivesThe genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis.MethodsThe authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44,449 individuals), and de novo in 14 534 independent samples, all of European descent.ResultsNone of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects.ConclusionsIdentifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity.

Objective: To address the need for standardization of osteoarthritis (OA) phenotypes by examining the effect of heterogeneity among symptomatic (SOA) and radiographic osteoarthritis (ROA) phenotypes. Methods: Descriptions of OA phenotypes of the 28 studies involved in the TREAT-OA consortium were collected. We investigated whether different OA definitions result in different association results by creating various hip OA definitions in one large population based cohort (the Rotterdam Study I (RSI)) and testing those for association with gender, age and body mass index using one-way ANOVA. For ROA, we standardized the hip-, knee- and hand ROA definitions and calculated prevalence's of ROA before and after standardization in nine cohort studies. This procedure could only be performed in cohort studies and standardization of SOA definitions was not feasible at this moment. Results: In this consortium, all studies with SOA phenotypes (knee, hip and hand) used a different definition and/or assessment of OA status. For knee-, hip- and hand ROA five, four and seven different definitions were used, respectively. Different hip ROA definitions do lead to different association results. For example, we showed in the RSI that hip OA defined as "at least definite joint space narrowing (JSN) and one definite osteophyte" was not associated with gender (P=0.22), but defined as "at least one definite osteophyte" was significantly associated with gender (P=3 x 10(-9)). Therefore, a standardization process was undertaken for ROA definitions. Before standardization a wide range of ROA prevalence's was observed in the nine cohorts studied. After standardization the range in prevalence of knee- and hip ROA was small. Conclusion: Phenotype definitions influence the prevalence of OA and association with clinical variables. ROA phenotypes within the TREAT-OA consortium were standardized to reduce heterogeneity and improve power in future genetics studies. (C) 2010 Osteoarthritis Research Soc

Objective. The American College of Rheumatology and the European League Against Rheumatism have developed new classification criteria for rheumatoid arthritis (RA). The aim of Phase 2 of the development process was to achieve expert consensus on the clinical and laboratory variables that should contribute to the final criteria set. Methods. Twenty-four expert RA clinicians (12 from Europe and 12 from North America) participated in Phase 2. A consensus-based decision analysis approach was used to identify factors (and their relative weights) that influence the probability of "developing RA," complemented by data from the Phase 1 study. Patient case scenarios were used to identify and reach consensus on factors important in determining the probability of RA development. Decision analytic software was used to derive the relative weights for each of the factors and their categories, using choice-based conjoint analysis. Results. The expert panel agreed that the new classification criteria should be applied to individuals with undifferentiated inflammatory arthritis in whom at least 1 joint is deemed by an expert assessor to be swollen, indicating definite synovitis. In this clinical setting, they identified 4 additional criteria as being important: number of joints involved and site of involvement, serologic abnormality, acute-phase response, and duration of symptoms in the involved joints. These criteria were consistent with those identified in the Phase 1 data-driven approach. Conclusion. The consensus-based, decision analysis approach used in Phase 2 complemented the Phase 1 efforts. The 4 criteria and their relative weights form the basis of the final criteria set.

Objective. The 1987 American College of Rheumatology (ACR; formerly, the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticized for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. Methods. A joint working group from the ACR and the European League Against Rheumatism developed, in 3 phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease - this being the appropriate current paradigm underlying the disease construct "rheumatoid arthritis." Results. In the new criteria set, classification as "definite RA" is based on the confirmed presence of synovitis in at least 1 joint, absence of an alternative diagnosis that better explains the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in 4 domains: number and site of involved joints (score range 0-5), serologic abnormality (score range 0-3), elevated acute-phase response (score range 0-1), and symptom duration (2 levels; range 0-1). Conclusion. This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather th

__Objective__ To identify novel genes involved in osteoarthritis (OA), by means of a genome-wide association study. Methods. We tested 500,510 single-nucleotide polymorphisms (SNPs) in 1,341 Dutch Caucasian OA cases and 3,496 Dutch Caucasian controls. SNPs associated with at least 2 OA phenotypes were analyzed in 14,938 OA cases and ∼39,000 controls. Meta-analyses were performed using the program Comprehensive Meta-analysis, with P values <1 x 10-7considered genomewide significant. __Results__ The C allele of rs3815148 on chromosome 7q22 (minor allele frequency 23%; intron 12 of the COG5 gene) was associated with a 1.14-fold increased risk (95% confidence interval 1.09-1.19) of knee and/or hand OA (P = 8 x 10-8) and also with a 30% increased risk of knee OA progression (95% confidence interval 1.03-1.64) (P = 0.03). This SNP is in almost complete linkage disequilibrium with rs3757713 (68 kb upstream of GPR22), which is associated with GPR22 expression levels in lymphoblast cell lines (P = 4 x 10-12). Immunohistochemistry experiments revealed that G protein-coupled receptor protein 22 (GPR22) was absent in normal mouse articular cartilage or synovium. However, GPR22-positive chondrocytes were found in the upper layers of the articular cartilage of mouse knee joints that were challenged with in vivo papain treatment or methylated bovine serum albumin treatment. GPR22-positive chondrocyte-like cells were also found in osteophytes in instability-induced OA. __Conclusion__ Our findings identify a novel common variant on chromosome 7q22 that influences susceptibility to prevalence and progression of OA. Since the GPR22 gene encodes a G protein-coupled receptor, this is potentially an interesting therapeutic target.