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Osteoarthritis (OA) drug development is hampered by a number of challenges. One of the main challenges is the apparent discordance between pain and structure, which has had a significant impact on drug development programs and has led to hesitance among stakeholders. Since 2017, the Clinical Trials Symposium (CTS) has been hosted under the Osteoarthritis Research Society International (OARSI) leadership. OARSI and the CTS steering committee yearly invite and encourage discussions on selected special subject matter between regulators, drug developers, clinicians, clinical researchers, biomarker specialists, and basic scientists to progress drug development in the OA field. The main topic for the 2022 OARSI CTS was to elucidate the many facets of pain in OA and to enable a discussion between regulators (Food and Drug Administration (FDA) and the European Medicines Agency (EMA)) and drug developers to clarify outcomes and study designs for OA drug development. Signs or symptoms indicative of nociceptive pain occur in 50–70% of OA patients, neuropathic-like pain in 15–30% of patients, and nociplastic pain in 15–50% of patients. Weight-bearing knee pain is associated with bone marrow lesions and effusions. There are currently no simple objective functional tests whose improvements correlate with patient perceptions. The CTS participants, in collaboration with the FDA and EMA, raised several suggestions that they consider key to future clinical trials in OA including the need for more precise differentiation of pain symptoms and mechanisms, and methods to reduce placebo responses in OA trials. [ABSTRACT FROM AUTHOR]

To determine if baseline biomarkers are associated with longitudinal changes in the worsening of disc space narrowing (DSN), vertebral osteophytes (OST), and low back pain (LBP). Paired baseline (2003–2004) and follow-up (2006–2010) lumbar spine radiographs from the Johnston County Osteoarthritis Project were graded for severity of DSN and OST. LBP severity was self-reported. Concentrations of analytes (cytokines, proteoglycans, and neuropeptides) were quantified by immunoassay. Pressure-pain threshold (PPT), a marker of sensitivity to pressure pain, was measured with a standard dolorimeter. Binary logistic regression models were used to estimate odd ratios (OR) and 95% confidence intervals (CI) of biomarker levels with DSN, OST, or LBP. Interactions were tested between biomarker levels and the number of affected lumbar spine levels or LBP. We included participants (n = 723) with biospecimens, PPT, and paired lumbar spine radiographic data. Baseline Lumican, a proteoglycan reflective of extracellular matrix changes, was associated with longitudinal changes in DSN worsening (OR = 3.19 [95% CI 1.22, 8.01]). Baseline brain-derived neuropathic factor, a neuropeptide, (OR = 1.80 [95% CI 1.03, 3.16]) was associated with longitudinal changes in OST worsening, which may reflect osteoclast genesis. Baseline hyaluronic acid (OR = 1.31 [95% CI 1.01, 1.71]), indicative of systemic inflammation, and PPT (OR = 1.56 [95% CI 1.02, 2.31]) were associated with longitudinal increases in LBP severity. These findings suggest that baseline biomarkers are associated with longitudinal changes occurring in structures of the lumbar spine (DSN vs OST). Markers of inflammation and perceived pressure pain sensitivity were associated with longitudinal worsening of LBP. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this overview of osteoarthritis (OA) biomarkers is to provide the non-specialist with a toolbox, based on experience acquired by biomarker researchers over many years, to understand biomarkers in general and their use in the OA field.Methods: We provide an update on this subject since the OARSI Primer on osteoarthritis (OA) nearly a decade ago.Results: Since the last update, the importance of molecular biomarkers has been increasingly recognized in the field, but no OA-related biomarkers have been adopted for routine use in clinical practice. The current lack of chondroprotective treatments for OA impairs the assessment, validation and qualification of the potential role of biomarkers as tools for monitoring disease status and patient responses to treatment of OA. Yet there is no lack of an evolving compendium of OA-related biomarkers, ever more fit-for-purpose, that could currently facilitate drug development for OA. We provide an abbreviated update and overview of specific soluble OA-related biomarkers for this new OARSI Primer on OA with OA-relevant examples encompassing the concepts of biomarker nomenclature, qualification, interpretation, measurement, reporting requirements, application to research, drug discovery and clinical care, and future needs for biomarker advancement.Conclusion: Appropriate biomarkers should play a role at all stages of OA diagnosis, prognosis, drug development, and treatment. The future of OA biomarker research and development holds great promise as its foundation is increasingly robust. [ABSTRACT FROM AUTHOR]

Objectives: To reveal the heterogeneity of different cell types of osteoarthritis (OA) synovial tissues at a single-cell resolution, and determine by novel methodology whether bulk-RNA-seq data could be deconvoluted to create in silico scRNA-seq data for synovial tissue analyses.Methods: OA scRNA-seq data (102,077 synoviocytes) were provided by 17 patients undergoing total knee arthroplasty; 9 tissues with matched scRNA-seq and bulk RNA-seq data were used to evaluate six in silico gene deconvolution tools. Predicted and observed cell types and proportions were compared to identify the best deconvolution tool for synovium.Results: We identified seven distinct cell types in OA synovial tissues. Gene deconvolution identified three (of six) platforms as suitable for extrapolating cellular gene expression from bulk RNA-seq data. Using paired scRNA-seq and bulk RNA-seq data, an "arthritis" specific signature matrix was created and validated to have a significantly better predictive performance for synoviocytes than a default signature matrix. Use of the machine learning tool, Cell-type Identification By Estimating Relative Subsets of RNA Transcripts x (CIBERSORTx), to analyze rheumatoid arthritis (RA) and OA bulk RNA-seq data yielded proportions of T cells and fibroblasts that were similar to the gold standard observations from RA and OA scRNA-seq data, respectively.Conclusion: This novel study revealed heterogeneity of synovial cell types in OA and the feasibility of gene deconvolution for synovial tissue. [ABSTRACT FROM AUTHOR]

Objective: Macrophages play an important part in the pathogenesis of osteoarthritis (OA). Our objective was to determine the effects of α-defensin-1 on macrophage polarization and consequently OA.Methods: OA synovial tissue and synovial fluid were assessed for the presence of M1 (CD68+CD16+CD206-) and M2 (CD68+CD206+CD16-) macrophages by flow cytometry. M0, M1, and M2 macrophages were co-cultured with OA chondrocytes to determine their influence on chondrogenic phenotype. Polarization of THP-1 activated monocytes from M1 to M2 in response to α-defensin-1 was evaluated by flow cytometry, RT-PCR and RNA sequencing. Effects of intra-articular α-defensin-1 in vivo were evaluated in a rat meniscal/ligamentous injury (MLI) model.Results: The quantity of M1 exceeded M2 polarized macrophages in human OA synovial tissue (mean difference 26.1% [13.6-38.6%], P < 0.001) and fluid (mean difference 10.5% [5.0-16.1%], P = 0.003). M1 to M2 polarization in vitro was most effectively promoted with 10 ng/mL α-defensin-1. Compared with untreated macrophages, the α-defensin-1 polarized macrophages modified co-cultured OA chondrocytes from a pro-catabolic state to a pro-anabolic (regenerative-like) state based on expression of COL2A1, ACN, MMP3, MMP13 and ADAMTS5. Intra-articular α-defensin-1 decreased severity of cartilage damage and synovitis in the MLI rat model. RNAseq analyses suggested insulin and Toll-like receptor signaling pathways in the chondroprotective α-defensin-1 mechanism of action.Conclusion: α-defensin-1 promotes M1 to M2 macrophage polarization in vitro, has beneficial effects on chondrocytes indirectly via M2 macrophage polarization, and attenuates the severity of OA in vivo, suggesting it might be a candidate treatment for OA. [ABSTRACT FROM AUTHOR]

Objective: Human and in vivo animal research implicates inflammation following articular fracture as contributing to post-traumatic arthritis. However, relevant immune cell subsets present following injury are currently undefined. Immunophenotyping human and murine synovial fluid may help to identify immune cell populations that play key roles in the response to articular fracture.Methods: Immunophenotyping by polychromatic flow cytometry was performed on human and mouse synovial fluid following articular fracture. Specimens were collected in patients with closed ankle fracture at the time of surgical fixation and from C57BL/6 mice with closed articular knee fracture. Immune cells were collected from injured and uninjured joints in mice via a novel cell isolation method. Whole blood samples were also collected. Immunohistochemistry (IHC) was performed on mouse synovial tissue to assess for macrophages and T cells.Results: Following intra-articular fracture, the prominent human synovial fluid immune cell subset was CD3+ T cells, containing both CD4+ and CD8+ T cells. In mice, infiltration of CD45+ immune cells in synovial fluid of the fractured limb was dominated by CD19+ B cells and CD3+ T cells at 7 days after intra-articular fracture. We also detected adaptive immune cells, including macrophages, NK cells, dendritic cells and monocytes. Macrophage and T cell findings were supported by IHC of murine synovial tissue.Conclusions: Determining specific cell populations that mediate the immune response is essential to elucidating the chain of events initiated after injury and may be an important step in identifying potential immune signatures predictive of PTA susceptibility or potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the anti-inflammatory effects of clinically relevant naproxen sodium (Nx) concentrations on human monocyte-derived macrophages in a controlled in vitro system and human primary synovial fluid (SF) cells.Design: Using phorbol 12-myristate 13-acetate, THP-1 human monocytic cells were differentiated into mature monocyte-derived macrophages in vitro then treated with Nx pre- or post-activating an inflammatory response with lipopolysaccharide (LPS) and hyaluronan (HA) fragments (n = 8/group). Cell culture supernatants were assessed for NF-κB activity and prostaglandin E2 (PGE2), indicating cyclooxygenase enzyme activity. Under Duke IRB approval, primary human SF cells were collected at the time of knee joint replacement (n = 19 individuals) for osteoarthritis (OA), and cultured with LPS, HA and Nx; SF cells were characterized by polychromatic flow cytometry for cell surface markers and intracellular cytokines.Result: Compared to placebo treatment of THP-1 cells, low dose Nx (corresponding 27.5-440 mg/L orally) added both pre- and post-activation with LPS/HA, significantly reduced NF-κB activity and PGE2: mean reduction to 73%, 61%, 17% and 10% of placebo, respectively. LPS/HA treatment of primary OA SF cells significantly increased the number of IL-1β producing primary monocytes and macrophages, and by 24 h the overall production of secreted cytokines (IL-1β, IL-6, IL8, and TNF-α). Low dose Nx reduced the percentage of IL-1β producing primary monocytes and macrophages.Conclusion: LPS/HA induced inflammation of THP-1 monocytic and primary human SF cells. Low dose Nx both prevented and reduced inflammatory responses of a human monocytic cell line and reduced IL-1β production by primary human SF monocytes and macrophages. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the degree of knee fat pad abnormalities after acute anterior cruciate ligament (ACL) tear via magnetic resonance fat pad scoring and to assess cross-sectionally its association with synovial fluid biomarkers and with early cartilage damage as quantified via T1ρ and T2 relaxation time measurements.Design: 26 patients with acute ACL tears underwent 3T MR scanning of the injured knee prior to ACL reconstruction. The presence and degree of abnormalities of the infrapatellar (IPFP) and the suprapatellar (SPFP) fat pads were scored on MR images along with grading of effusion-synovitis and synovial proliferations. Knee cartilage composition was assessed by 3T MR T1ρ and T2 mapping in six knee compartments. We quantified concentrations of 20 biomarkers in synovial fluid aspirated at the time of ACL reconstruction. Spearman rank partial correlations with adjustments for age and gender were employed to evaluate correlations of MR, particularly cartilage composition and fat pad abnormalities, and biomarker data.Results: The degree of IPFP abnormality correlated positively with the synovial levels of the inflammatory cytokine markers IFN-γ (ρpartial = 0.64, 95% CI (0.26-0.85)), IL-10 (ρpartial = 0.47, 95% CI (0.04-0.75)), IL-6 (ρpartial = 0.56, 95% CI (0.16-0.81)), IL-8 (ρpartial = 0.49, 95% CI (0.06-0.76)), TNF-α (ρpartial = 0.55, 95% CI (0.14-0.80)) and of the chondrodestructive markers MMP-1 and -3 (MMP-1: ρpartial = 0.57, 95% CI (0.17-0.81); MMP-3: ρpartial = 0.60, 95% CI (0.21-0.83)). IPFP abnormalities were significantly associated with higher T1ρ and T2 values in the trochlear cartilage (T1ρ: ρpartial = 0.55, 95% CI (0.15-0.80); T2: ρpartial = 0.58, 95% CI (0.18-0.81)) and with higher T2 values in the medial femoral, medial tibial as well as in patellar cartilage (0.45 ≤ ρpartial ≤ 0.59). Correlations between SPFP abnormalities and synovial markers were not significant except for IL-6 (ρpartial = 0.57, 95% CI (0.17-0.81)).Conclusions: This exploratory study suggests that acute ACL rupture can be associated with damage to knee tissues such as the inferior fat pad of the knee. Such fat pad injury could be partially responsible for the apparent post-injury pro-inflammatory response noted in ACL-injured individuals. However, future longitudinal studies are needed to link ACL-rupture associated fat pad injury with important patient outcomes such as the development of posttraumatic osteoarthritis. [ABSTRACT FROM AUTHOR]

Objective: To update and expand upon prior Osteoarthritis Research Society International (OARSI) guidelines by developing patient-focused treatment recommendations for individuals with Knee, Hip, and Polyarticular osteoarthritis (OA) that are derived from expert consensus and based on objective review of high-quality meta-analytic data.Methods: We sought evidence for 60 unique interventions. A systematic search of all relevant databases was conducted from inception through July 2018. After abstract and full-text screening by two independent reviewers, eligible studies were matched to PICO questions. Data were extracted and meta-analyses were conducted using RevMan software. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Evidence Profiles were compiled using the GRADEpro web application. Voting for Core Treatments took place first. Four subsequent voting sessions took place via anonymous online survey, during which Panel members were tasked with voting to produce recommendations for all joint locations and comorbidity classes. We designated non-Core treatments to Level 1A, 1B, 2, 3, 4A, 4B, or 5, based on the percentage of votes in favor, in addition to the strength of the recommendation.Results: Core Treatments for Knee OA included arthritis education and structured land-based exercise programs with or without dietary weight management. Core Treatments for Hip and Polyarticular OA included arthritis education and structured land-based exercise programs. Topical non-steroidal anti-inflammatory drugs (NSAIDs) were strongly recommended for individuals with Knee OA (Level 1A). For individuals with gastrointestinal comorbidities, COX-2 inhibitors were Level 1B and NSAIDs with proton pump inhibitors Level 2. For individuals with cardiovascular comorbidities or frailty, use of any oral NSAID was not recommended. Intra-articular (IA) corticosteroids, IA hyaluronic acid, and aquatic exercise were Level 1B/Level 2 treatments for Knee OA, dependent upon comorbidity status, but were not recommended for individuals with Hip or Polyarticular OA. The use of Acetaminophen/Paracetamol (APAP) was conditionally not recommended (Level 4A and 4B), and the use of oral and transdermal opioids was strongly not recommended (Level 5). A treatment algorithm was constructed in order to guide clinical decision-making for a variety of patient profiles, using recommended treatments as input for each decision node.Conclusion: These guidelines offer comprehensive and patient-centered treatment profiles for individuals with Knee, Hip, and Polyarticular OA. The treatment algorithm will facilitate individualized treatment decisions regarding the management of OA. [ABSTRACT FROM AUTHOR]

In 1992, the Food and Drug Administration (FDA) instituted the accelerated approval regulations that allow drugs or biologics for serious conditions that fill an unmet medical need to be approved on the basis of a surrogate endpoint or an intermediate clinical endpoint. The current definition of a serious condition includes chronic disabling conditions, such as osteoarthritis (OA), and thereby provides expanded opportunities for the use of biomarkers for regulatory approval of drugs for OA. The use of surrogates or intermediate clinical endpoints for initial regulatory approval of a drug or biologic requires confirmation in a post-marketing study of a drug effect on a clinically relevant outcome, such as on how a patient feels, functions or survives. Current FDA guidance requires that the post-marketing approval (PMA) study be ongoing during the time of initial drug approval. This white paper arose out of the need to brainstorm trial designs that might be suitable for PMA of drugs initially approved, on the basis of a surrogate or intermediate clinical endpoint, for treatment of OA to alter disease progression, abnormal function or pathological changes in the morphology of the joint. In this white paper we define the concept and regulations regarding accelerated approval and propose two major study design scenarios for PMA trials in OA. The long-term goal is to discuss and refine these designs in consultation with regulatory agencies in order to facilitate development of drugs to fill the large unmet need in OA. [ABSTRACT FROM AUTHOR]

Objective: There are few guidelines for clinical trials of interventions for prevention of post-traumatic osteoarthritis (PTOA), reflecting challenges in this area. An international multi-disciplinary expert group including patients was convened to generate points to consider for the design and conduct of interventional studies following acute knee injury.Design: An evidence review on acute knee injury interventional studies to prevent PTOA was presented to the group, alongside overviews of challenges in this area, including potential targets, biomarkers and imaging. Working groups considered pre-identified key areas: eligibility criteria and outcomes, biomarkers, injury definition and intervention timing including multi-modality interventions. Consensus agreement within the group on points to consider was generated and is reported here after iterative review by all contributors.Results: The evidence review identified 37 studies. Study duration and outcomes varied widely and 70% examined surgical interventions. Considerations were grouped into three areas: justification of inclusion criteria including the classification of injury and participant age (as people over 35 may have pre-existing OA); careful consideration in the selection and timing of outcomes or biomarkers; definition of the intervention(s)/comparator(s) and the appropriate time-window for intervention (considerations may be particular to intervention type). Areas for further research included demonstrating the utility of patient-reported outcomes, biomarkers and imaging outcomes from ancillary/cohort studies in this area, and development of surrogate clinical trial endpoints that shorten the duration of clinical trials and are acceptable to regulatory agencies.Conclusions: These considerations represent the first international consensus on the conduct of interventional studies following acute knee joint trauma. [ABSTRACT FROM AUTHOR]

Objective: To evaluate systemic inflammatory biomarkers in symptomatic knee osteoarthritis (OA) and their association with radiographic and biochemical OA progression.Methods: Lipopolysaccharide (LPS) binding protein (LBP), soluble Toll-like receptor 4 (sTLR4) and interleukin 6 (IL-6) were measured in plasma of 431 knee OA patients from the doxycycline (DOXY) trial at baseline and 18 months. Plasma lipopolysaccharide and lipopolysaccharide binding protein (LBP) were also measured at 12 months. As a biochemical indicator of disease activity and OA progression, urinary (u) C-telopeptide of Type II collagen (uCTX-II) was measured in samples collected at baseline and 18 months. Change over 16 months in radiographic tibiofemoral joint space width (JSW in mm) and joint space narrowing (JSN≥0.5 mm) were used to indicate radiographic OA progression. Change over 18 months for uCTX-II was used as a secondary outcome. Both univariate and multivariable regression analyses were performed to test the association between Z-score transformed biomarkers and outcomes.Results: Baseline LBP and time-integrated concentration (TIC) of LBP over 12 and 18 months were associated with worsening joint space width (JSW) (parameter estimates: -0.1 to -0.07) and JSN (OR: 1.32 to 1.42) adjusting for treatment group, age, body mass index (BMI) and corresponding baseline radiographic measures. Baseline sTLR4 and TIC over 18 months were associated with change in uCTX-II over 18 months (adjusted parameter estimates: 0.0017 to 0.0020). Results were not modified by treatment with doxycycline.Conclusion: Plasma LBP and sTLR4 were associated with knee OA progression over 16-18 months. These results lend further support for a role of systemic low-grade inflammation in the pathogenesis of knee OA progression. [ABSTRACT FROM AUTHOR]

Summary Objective Our study analyzes the association between chemokine-ligand-2 (CCL2) serum concentrations at baseline and knee radiographic osteoarthritis (OA) (knee-rOA), knee-rOA progression, individual radiographic features and knee symptomatic OA at 5-year follow-up. Design OA outcomes were analyzed in a community-based cohort including a baseline enrollment and a 5-year follow-up. Baseline CCL2 serum concentrations were assessed by multiplex assay and associated with presence or progression of individual radiographic features at 5-year follow-up. Separate multiple logistic regression models were used to examine adjusted associations between baseline CCL2 and each of the knee OA variables at follow-up. CCL2 at baseline was modeled as an explanatory variable, whereas each of the knee OA variables at follow-up served as the response variables. Models were adjusted for age, BMI, race, and sex. Trend tests were conducted to assess any linear effect on outcomes across CCL2 tertiles. Results Participants ( n = 168) had a median age of 57-years and median BMI of 29 kg/m2. About 63% of all participants were women, and 58% Caucasian (42% African American). In adjusted logistic models, continuous log-CCL2 was significantly associated with knee-rOA. For each unit increase in log CCL2, the odds of having knee-rOA at follow-up was increased by 72%. CCL2 tertiles showed significant linear associations with presence and progression of knee-rOA and medial joint space narrowing (JSN), but not with presence or progression of osteophytes, bone sclerosis, knee symptoms, or symptomatic knee-rOA. Conclusions Serum CCL2 may help to elucidate some mechanisms of joint destruction and identify individuals with higher odds of structural knee changes. [ABSTRACT FROM AUTHOR]

Objectives: Uric acid may activate an innate immune response in osteoarthritis (OA), contributing to disease pathology and progression. We evaluated the effectiveness of colchicine on pain and function in symptomatic knee OA (KOA) and the underlying mechanism of action.Methods: Colchicine effectiveness in symptoms and inflammation modification in knee osteoarthritis (COLKOA) was a double-blind, placebo-controlled, randomized trial comparing 16 weeks of treatment with 0.5 mg twice-daily oral colchicine to placebo for knee osteoarthritis (KOA). The primary endpoint was ≥30% improvement in total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score at week 16. Secondary endpoints included improvement in pain (0-10 Likert scales); WOMAC pain; patient global assessment (0-100); physical function; the OARSI-OMERACT response; quality of life; and change in serum, urine, synovial fluid (SF) biomarkers of cartilage metabolism and inflammation, and plasma/SF colchicine concentrations.Results: Of 109 randomly assigned participants, 39% (95% confidence interval (CI) 27-52%) and 49% (95% CI 36-62%) in the colchicine and placebo arms respectively met the primary endpoint at study end (P = 0.284, odds ratio 0.66, 95% CI 0.31-1.41). No strong evidence of treatment differences was identified on clinical secondary endpoints. Treatment significantly reduced mean serum hs-CRP (P = 0.008) and SF CTXI (P = 0.002); treatment tended to reduce inflammatory markers (SF IL-6, IL8, TNFα, CD14 and IL-18), but these differences were not statistically significant.Conclusion: Colchicine (0.5 mg twice-daily orally) reduced inflammation and high bone turnover biomarkers known to be associated with OA severity and progression risk, but did not reduce KOA symptoms over a 16-week study period. A longer-term study to evaluate for slow-acting disease modifying effects is warranted.Trial Registration: The trial has been registered at clinicaltrials.gov as NCT02176460. Date of registration: June 26, 2014. [ABSTRACT FROM AUTHOR]

Purpose: To explore mechanisms underlying the association of TSG-6 with osteoarthritis (OA) progression.Methods: TSG-6-mediated heavy chain (HC) transfer (TSG-6 activity) and its association with inflammatory mediators were quantified in knee OA (n=25) synovial fluids (SFs). Paired intact and damaged cartilages from the same individuals (20 tibial and 12 meniscal) were analyzed by qRT-PCR and immunohistochemistry (IHC) for gene and protein expression of TSG-6 and components of Inter-alpha-Inhibitor (IαI) and TSG-6 activity ± spiked in IαI. Primary chondrocyte cultures (n=5) ± IL1β or TNFα were evaluated for gene expression. The effects of TSG-6 activity on cartilage extracellular matrix (ECM) assembly were explored using quantitative hyaluronan (HA)-aggrecan binding assays.Results: TSG-6 activity was significantly associated (R > 0.683, P < 0.0002) with inflammatory mediators including TIMP-1, A2M, MMP3, VEGF, VCAM-1, ICAM-1 and IL-6. Although TSG-6 protein and mRNA were highly expressed in damaged articular and meniscal cartilage and cytokine-treated chondrocytes, there was little or no cartilage expression of components of the IαI complex (containing HC1). By IHC, TSG-6 was present throughout lesioned cartilage but HC1 only at lesioned surfaces. TSG-6 impaired HA-aggrecan assembly, but TSG-6 mediated HA-HC formation reduced this negative effect.Conclusions: TSG-6 activity is a global inflammatory biomarker in knee OA SF. IαI, supplied from outside cartilage, only penetrates the cartilage surface, restricting TSG-6 activity (HC transfer) to this region. Therefore, unopposed TSG-6 in intermediate and deep regions of OA cartilage could possibly block matrix assembly, leading to futile synthesis and account for increased risk of OA progression. [ABSTRACT FROM AUTHOR]

Objective To propose draft classification criteria for early stage osteoarthritis (OA) of the knee for use in a primary care setting. Methods A group of basic scientists, physician-scientists, rheumatologists, orthopedic surgeons, and physiotherapists in a workshop setting discussed potential classification criteria for early osteoarthritis of the knee. The workshop was divided into sessions around relevant topics with short state of the art presentations followed by breakout sessions, consensus discussions, and consolidation into a consensus document. Results Three classes of criteria were agreed: (1) Pain, symptoms/signs, self-reported function, and quality of life using tools such as KOOS: scoring ≤85% in at least 2 out of these 4 categories; (2) Clinical examination: at least 1 present out of joint line tenderness or crepitus; (3) Knee radiographs: Kellgren & Lawrence (KL) grade of 0 or 1. MRI is at present not recommended as an aid to identify or define early OA in routine clinical practice or primary care, in light of the absence of validated consensus criteria and the high population prevalence of structural joint changes detected by this method. Biomarkers may have future utility in early OA classification, but no individual or set of biomarkers is yet robust enough. Conclusion Based on our consensus proposal, draft classification criteria for early OA of the knee for use in clinical studies should include patient reported outcomes such as pain and function, together with clinical signs and KL grade 0-1 on radiographs. [ABSTRACT FROM AUTHOR]

Objective: Intra-articular (IA) corticosteroids relieve osteoarthritis (OA) pain, but rapid absorption into systemic circulation may limit efficacy and produce untoward effects. We compared the pharmacokinetics (PK) of IA triamcinolone acetonide (TA) delivered as an extended-release, microsphere-based formulation (FX006) vs a crystalline suspension (TAcs) in knee OA patients.Method: This Phase 2 open-label study sequentially enrolled 81 patients who received a single IA injection of FX006 (5 mL, 32 mg delivered dose, N = 63) or TAcs (1 mL, 40 mg, N = 18). Synovial fluid (SF) aspiration was attempted in each patient at baseline and one post-IA-injection visit (FX006: Week 1, Week 6, Week 12, Week 16 or Week 20; TAcs: Week 6). Blood was collected at baseline and multiple post-injection times. TA concentrations (validated LC-MS/MS, geometric means (GMs)), PK (non-compartmental analysis models), and adverse events (AEs) were assessed.Results: SF TA concentrations following FX006 were quantifiable through Week 12 (pg/mL: 231,328.9 at Week 1; 3590.0 at Week 6; 290.6 at Week 12); post-TAcs, only two of eight patients had quantifiable SF TA at Week 6 (7.7 pg/mL). Following FX006, plasma TA gradually increased to peak (836.4 pg/mL) over 24 h and slowly declined to <110 pg/mL over Weeks 12-20; following TAcs, plasma TA peaked at 4 h (9628.8 pg/mL), decreased to 4991.1 pg/mL at 24 h, and was 149.4 pg/mL at Week 6, the last post-treatment time point assessed. AEs were similar between groups.Conclusion: In knee OA patients, microsphere-based TA delivery via a single IA injection prolonged SF joint residency, diminished peak plasma levels, and thus reduced systemic TA exposure relative to TAcs. [ABSTRACT FROM AUTHOR]

Objective: To determine differences in biomarker levels between radiographic phenotypes of facet joint osteoarthritis (FOA) only, spine OA only ((disc space narrowing (DSN) and vertebral osteophytes (OST)) or the combination of FOA and spine OA.Design: A cross-sectional analysis of data from 555 participants in the Johnston County Osteoarthritis Project was performed. Lumbar spine levels were graded by severity (OST and DSN) and presence (FOA) of degeneration. Biomarkers included hyaluronan (HA) and type II collagen (CTX-II). Adjusted risk ratios (aRRR) were estimated using multinomial regression, with adjustment for age, race, sex, body mass index (BMI), and radiographic OA (knee, hip, hand). Interactions were tested between sex, race and low back symptoms.Results: FOA only was present in 22.4%, 14.5% had spine OA only, and 34.6% had the combination of FOA and spine OA. Compared to the reference group of neither FOA or spine OA, a one unit higher ln HA level was associated with 31% higher relative risk ratio (RRR = 1.31 (95% 1.03, 1.67)) of having FOA only, while, a one unit higher lnuCTX-II level was associated with 84% higher relative risk ratio (RRR = 1.84 (95% CI 1.19, 2.84)) of having spine OA only. No significant interactions were identified.Conclusion: Interestingly, OA affecting the synovial facet joint was associated with a marker of inflammation (HA). Spine OA, affecting intervertebral discs that contain collagen type II, was associated with a marker reflecting collagen type II degradation (CTX-II). These findings suggest that biomarkers may reflect the different pathophysiologic processes of lumbar spine OA phenotypes. [ABSTRACT FROM AUTHOR]

Objective: The role of inflammation and pain in osteoarthritis (OA) is not fully understood. We evaluated the association between pro-inflammatory biomarkers and pain.Methods: We used baseline data and samples from a randomized controlled trial of colchicine for symptomatic knee OA. Severity of pain of the more symptomatic knee was assessed by National Health and Nutrition Examination Survey-I (NHANES-I) criterion and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain index. Pains on movement and at rest were self-reported on an 11-point Likert scale. Severity of radiographic tibiofemoral OA was assessed by Kellgren and Lawrence (KL) grade. Concentrations of synovial fluid (sf) IL-1β, IL-6, IL-8, TNFα, C-terminal telopeptides of Type I collagen (CTXI) and C-telopeptide of Type II collagen (CTXII), as well as urinary (u) CTXII were measured.Results: Of the 109 patients enrolled in the study, 70 patients (70% women) with synovial fluid obtained by direct aspiration were included for analysis. The mean ± SD age and body mass index (BMI) of the patients were 57.6 ± 8.3 years and 28.8 ± 5.2 kg/m2. After adjustment for age, sex, and BMI, sf IL-6 and IL-8 were statistically significantly associated with 11-point pain on movement, but not with pain at rest. No significant associations were observed with WOMAC pain scores. sf IL-1β (analyzed as detectable/non-detectable) was inversely associated with pain. In contrast, after adjustment, Sf TNFα was associated with WOMAC total pain and both pain on movement and at rest. sf/u CTXII was associated with radiographic severity, but not with knee pain.Conclusions: This study provides indication that OA pain mechanisms may differ according to the characteristics of the pain. [ABSTRACT FROM AUTHOR]

Objectives: To investigate serum biomarkers, tartrate resistant acid phosphatase 5b (TRAcP5b) and cathepsin K (cath-K), indicative of osteoclastic bone resorption, and their relationship to pain and pain change in knee osteoarthritis (OA).Methods: Sera and clinical data were collected from 129 people (97 with 3-year follow-up) with knee OA from the Prediction of Osteoarthritis Progression (POP) cohort. Knee OA-related outcomes in POP included: WOMAC pain, National Health and Nutrition Examination Survey (NHANES) I (pain, aching and stiffness), subchondral sclerosis, and radiographically determined tibiofemoral and patellofemoral OA. Two putative osteoclast biomarkers were measured in sera: TRAcP5b and cath-K. Medial tibia plateaux were donated at knee arthroplasty for symptomatic OA (n = 84) or from 16 post mortem (PM) controls from the Arthritis Research UK (ARUK) Pain Centre joint tissue repository. Osteoclasts were stained for tartrate resistant acid phosphatase (TRAcP) within the subchondral bone of the medial tibia plateaux.Results: Serum TRAcP5b activity, but not cath-K-immunoreactivity, was associated with density of TRAcP-positive osteoclasts in the subchondral bone of medial tibia plateaux. TRAcP-positive osteoclasts were more abundant in people with symptomatic OA compared to controls. Serum TRAcP5b activity was associated with baseline pain and pain change.Conclusions: Our observations support a role for subchondral osteoclast activity in the generation of OA pain. Serum TRAcP5b might be a clinically relevant biomarker of disease activity in OA. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the anti-inflammatory mechanism of action of Chondroitin Sulphate (CS).Design: THP-1 macrophages were cultured with a range of sizes and concentrations of HA fragments with TLR4 (LPS in a physiologically relevant concentration determined by analyses of sera of a community clinic ascertained knee osteoarthritis (OA) cohort) or TLR2 (heat killed listeria bacteria) agonists and varying concentrations of CS in a physiologically relevant range (10-200 μg/ml). We measured IL-1β release, intracellular IL-1β, proIL-1β, caspase-1 and NF-κB activity and DNA binding activity of NF-κB transcription factors from nuclear and cytoplasmic extracts.Results: Serum LPS was significantly associated with radiographic knee joint space narrowing (JSN) (P = 0.02) in the OA cohort (n = 40). The priming dose of LPS used for these experiments (10 ng/ml) was below the lowest serum concentration of the OA cohort (median 47.09, range 14.43-81.36 ng/ml). Priming doses of LPS and HA fragments alone did not elicit an inflammatory response. However, primed with LPS, HA fragments produced large dose-dependent increases in IL-1β that were inhibitable by CS. CS did not inhibit caspase-1 activity but in physiologically achievable concentrations, attenuated NF-κB activity induced by either the TLR4 (LPS 1000 ng/ml) or TLR2 agonists alone or in combination with HA fragments. LPS induced and CS significantly reduced activity of canonical NF-κB transcription factors, p65, p50, c-Rel and RelB.Conclusions: Subinflammatory concentrations of pathogenic (LPS, listeria) and damage associated (HA) molecules interact to induce macrophage-related inflammation. CS works upstream of the inflammasome by inhibiting activation of NF-κB transcription factors. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is the biggest unmet medical need among the many musculoskeletal conditions and the most common form of arthritis. It is a major cause of disability and impaired quality of life in the elderly. We review several ambitious but failed attempts to develop joint structure-modifying treatments for OA. Insights gleaned from these attempts suggest that these failures arose from unrealistic hypotheses, sub-optimal selection of patient populations or drug dose, and/or inadequate sensitivity of the trial endpoints. The long list of failures has prompted a paradigm shift in OA drug development with redirection of attention to: (1) consideration of the benefits of localized vs systemic pharmacological agents, as indicated by the increasing number of intra-articularly administered compounds entering clinical development; (2) recognition of OA as a complex disease with multiple phenotypes, that may each require somewhat different approaches for optimizing treatment; and (3) trial enhancements based on guidance regarding biomarkers provided by regulatory agencies, such as the Food and Drug Administration (FDA), that could be harnessed to help turn failures into successes. [ABSTRACT FROM AUTHOR]

Objective: The microbiome is recognized as a new frontier in medicine with connections to a variety of diseases. We aimed to evaluate the association of lipopolysaccharide (LPS), a key pro-inflammatory product of the microbiome, with severity of inflammation, symptoms and radiographic abnormalities of knee osteoarthritis (OA).Design: LPS was measured using a recombinant Factor C (rFC) assay, carefully optimized for systemic and synovial fluid (SF) analyses. LPS binding protein (LBP) was tested in both serum and SF of 25 patients (31 knees) from the Etarfolatide cohort for association with OA phenotypic outcomes. Models were adjusted for age, gender and body mass index.Results: Based on LPS spike-and-recovery, both serum and SF dilutions of 0.1% were required to achieve recovery rates of at least 75% in all test specimens. Low coefficients of variation (CVs) (<10%) were achieved with both serum and SF dilutions <0.2%. Serum LPS and LBP were associated with the abundance of activated macrophages in the knee joint capsule and synovium. SF LPS and LBP were associated with the abundance of activated macrophages in the synovium. Serum LPS, LBP and SF LPS were associated with knee osteophyte severity. SF LPS was positively associated with knee joint space narrowing (JSN) severity and total WOMAC score. SF LBP was positively associated with self-reported knee pain score.Conclusion: These data strongly support a role for LPS in the pathogenesis and severity of structural abnormalities and symptoms of knee OA. [ABSTRACT FROM AUTHOR]

Objective: Through binding to folate receptor-β (FR-β), the new (99m)Tc-EC20 (Etarfolatide) imaging technique detects activated but not resting macrophages in vivo. The goal of this study was to investigate macrophage-related inflammation in osteoarthritis (OA).Methods: Twenty-five individuals (50 knees) with symptomatic OA of at least one knee underwent SPECT-CT imaging of both knees and planar imaging of the whole body after injection of Etarfolatide. Scans and knee radiographs were scored blinded to clinical information including knee and other joint site pain severity. Measures of association controlled for age, gender, body mass index (BMI) and employed repeated measures to adjust for correlation between knees.Design: Activated macrophages were present in the majority (76%) of knees. The quantity of knee-related macrophages was significantly associated with knee pain severity (R = 0.60, P < 0.0001) and radiographic knee OA severity including joint space narrowing (R = 0.68, P = 0.007), and osteophyte (R = 0.66, P = 0.001). Macrophages were also localized to joints commonly affected by OA including hand finger joints (12%), thumb bases (28%), shoulders (26%), great toes (18%) and ankles (12%). The presence of joint pain at fingers, wrists, ankles and great toes was significantly positively associated with presence of activated macrophages at these sites (P < 0.0001-0.04).Conclusions: This study provides the first direct in vivo evidence for macrophage involvement in OA in a substantial proportion of human knees. The association of quantity of activated macrophages with radiographic knee OA severity and joint symptoms suggests that drugs targeting macrophages and macrophage-associated inflammatory pathways may have the potential to be both symptom and structure modifying. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of pain coping skills training (PCST) and a lifestyle behavioral weight management (BWM) program on inflammatory markers and biomarker associations with pain and function in the OA LIFE study.Method: Serum samples were available from a subset (N = 169) of the overweight or obese knee OA participants in the OA LIFE study that evaluated: PCST, BWM, combined PCST + BWM, or standard care (SC). Inflammatory markers (hsCRP, IL-1ra, IL-1β, IL-6, IL-8, TNF-α, TNFRI, TNFRII, and hyaluronic acid (HA)), and adipokines (leptin and adiponectin) were measured before and after the 24-week treatment period. Biomarkers were assessed for effects of treatment and for associations with change in weight, pain and disability (unadjusted and adjusted for age, race, sex, baseline body mass index (BMI), and baseline biomarker concentration).Results: PCST + BWM was associated with significant reductions in hsCRP (P = 0.0014), IL-6 (P = 0.0075), and leptin (P = 0.0001). After adjustment, there was a significant effect of PCST + BWM on changes in leptin (b = -0.19, P = 0.01) and IL-6 (b = -0.25, P = 0.02) relative to SC. Reductions in leptin and IL-6 were significantly correlated with reductions in weight, BMI and Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain; reductions in IL-6 were correlated with improvements in WOMAC and Arthritis Impact Measurement Scales (AIMS) physical function. By mediation analyses, weight loss was responsible for 54% of the change in IL-6 and all of the change in leptin.Conclusions: OA-related inflammatory markers were reduced by a 24-week combined PCST + BWM intervention. This suggests that the inflammatory state can be successfully modified in the context of a readily instituted clinical intervention with a positive clinical outcome. [ABSTRACT FROM AUTHOR]

Objective: We investigated tissue turnover in healthy and osteoarthritic cartilage. We challenge long held views that osteoarthritis (OA) is dominated by a similar turnover process in all joints and present evidence that hip and knee cartilage respond very differently to OA.Methods: d- and l-Aspartate (Asp) were quantified for whole cartilage, collagen and non-collagenous components of cartilage obtained at the time of joint replacement. We computed the Asp racemization ratio (Asp-RR = d/d + l Asp), reflecting the proportion of old to total protein, for each component.Results: Compared with hip OA, knee OA collagen fibrils (P < 0.0001), collagen (P = 0.007), and non-collagenous proteins (P = 0.0003) had significantly lower age-adjusted mean Asp-RRs consistent with elevated protein synthesis in knee OA. Knee OA collagen had a mean hydroxyproline/proline (H/P) ratio of 1.2 consistent with the presence of type III collagen whereas hip OA collagen had a mean H/P ratio of 0.99 consistent with type II collagen. Based on Asp-RR, the relative age was significantly different in knee and hip OA (P < 0.0005); on average OA knees were estimated to be 30 yrs 'younger', and OA hips 10 yrs 'older' than non-OA.Conclusions: The metabolic response to OA was strikingly different by joint site. Knee OA cartilage evinced an anabolic response that appeared to be absent in hip OA cartilage. These results challenge the long held view that OA cartilage is capable of only minimal repair and that collagen loss is irreversible. [ABSTRACT FROM AUTHOR]

Objective: To develop a radiographic atlas of osteoarthritis (OA) for use as a template and guide for standardized scoring of radiographic features of OA of the ankle and hindfoot joints.Method: Under Institutional Review Board approval, ankle and hindfoot images were selected from a cohort study and from among cases that underwent ankle radiography during a 6-month period at Duke University Medical Center. Missing OA pathology was obtained through supplementation of cases with the assistance of a foot and ankle specialist in Orthopaedic surgery and a musculoskeletal radiologist. Images were obtained and reviewed without patient identifying information. Images went through multiple rounds of review and final images were selected by consensus of the study team. For intra-rater and inter-rater reliability, the kappa statistic was calculated for two readings by three musculoskeletal radiologists, a minimum of two weeks apart, of ankle and hindfoot radiographs from 30 anonymized subjects.Results: The atlas demonstrates individual radiographic features (osteophyte and joint space narrowing (JSN)) and Kellgren-Lawrence grade for all aspects of the talocrural (ankle joint proper) and talocalcaneal (subtalar) joints. Reliability of scoring based on the atlas was quite good to excellent for most features indicated. Additional examples of ankle joint findings are illustrated including sclerosis, os trigonum, subchondral cysts and talar tilt.Conclusions: It is anticipated that this atlas will assist with standardization of scoring of ankle and hindfoot OA by basic and clinical OA researchers. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is highly prevalent and a leading cause of disability worldwide. Despite the global burden of OA, diagnostic tests and treatments for the molecular or early subclinical stages are still not available for clinical use. In recent years, there has been a large shift in the understanding of OA as a "wear and tear" disease to an inflammatory disease. This has been demonstrated through various studies using MRI, ultrasound, histochemistry, and biomarkers. It would of great value to be able to readily identify subclinical and/or sub-acute inflammation, particularly in such a way as to be appropriate for a clinical setting. Here we review several types of biomarkers associated with OA in human studies that point to a role of inflammation in OA. [ABSTRACT FROM AUTHOR]

Objective: Pro- and anti-inflammatory mediators, such as IL-1β and IL1Ra, are produced by joint tissues in osteoarthritis (OA), where they may contribute to pathogenesis. We examined whether inflammatory events occurring within joints are reflected in plasma of patients with symptomatic knee osteoarthritis (SKOA).Design: 111 SKOA subjects with medial disease completed a 24-month prospective study of clinical and radiographic progression, with clinical assessment and specimen collection at 6-month intervals. The plasma biochemical marker IL1Ra was assessed at baseline and 18 months; other plasma biochemical markers were assessed only at 18 months, including IL-1β, TNFα, VEGF, IL-6, IL-6Rα, IL-17A, IL-17A/F, IL-17F, CRP, sTNF-RII, and MMP-2.Results: In cross-sectional studies, WOMAC (total, pain, function) and plasma IL1Ra were modestly associated with radiographic severity after adjustment for age, gender and body mass index (BMI). In addition, elevation of plasma IL1Ra predicted joint space narrowing (JSN) at 24 months. BMI did associate with progression in some but not all analyses. Causal graph analysis indicated a positive association of IL1Ra with JSN; an interaction between IL1Ra and BMI suggested either that BMI influences IL1Ra or that a hidden confounder influences both BMI and IL1Ra. Other protein biomarkers examined in this study did not associate with radiographic progression or severity.Conclusions: Plasma levels of IL1Ra were modestly associated with the severity and progression of SKOA in a causal fashion, independent of other risk factors. The findings may be useful in the search for prognostic biomarkers and development of disease-modifying OA drugs. [ABSTRACT FROM AUTHOR]

Summary Objective To investigate the efficacy of low-level laser therapy (LLLT) treatment of knee osteoarthritis (KOA) by a systematic literature search with meta-analyses on selected studies. Design MEDLINE, EMBASE, ISI Web of Science and Cochrane Library were systematically searched from January 2000 to November 2014. Included studies were randomized controlled trials (RCTs) written in English that compared LLLT (at least eight treatment sessions) with sham laser in KOA patients. The efficacy effective size was estimated by the standardized mean difference (SMD). Standard fixed or random-effects meta-analysis was used, and inconsistency was evaluated by the I-squared index (I 2 ). Results Of 612 studies, nine RCTs (seven double-blind, two single-blind, totaling 518 patients) met the criteria for inclusion. Based on seven studies, the SMD in visual analog scale (VAS) pain score right after therapy (RAT) (within 2 weeks after the therapy) was not significantly different between LLLT and control (SMD = −0.28 [95% CI = −0.66, 0.10], I 2 = 66%). No significant difference was identified in studies conforming to the World Association of Laser Therapy (WALT) recommendations (four studies) or on the basis of OA severity. There was no significant difference in the delayed response (12 weeks after end of therapy) between LLLT and control in VAS pain (five studies). Similarly, there was no evidence of LLLT effectiveness based on Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain, stiffness or function outcomes (five and three studies had outcome data right after and 12 weeks after therapy respectively). Conclusion Our findings indicate that the best available current evidence does not support the effectiveness of LLLT as a therapy for patients with KOA. [ABSTRACT FROM AUTHOR]

Summary Osteoarthritis (OA) is a heterogeneous disorder. The goals of this review are (1) To stimulate use of standardized nomenclature for OA that could serve as building blocks for describing OA and defining OA phenotypes, in short to provide unifying disease concepts for a heterogeneous disorder; and (2) To stimulate establishment of ROAD (Risk of OA Development) and ROAP (Risk of OA Progression) tools analogous to the FRAX™ instrument for predicting risk of fracture in osteoporosis; and (3) To stimulate formulation of tools for identifying disease in its early preradiographic and/or molecular stages – REDI (Reliable Early Disease Identification). Consensus around more sensitive and specific diagnostic criteria for OA could spur development of disease modifying therapies for this entity that has proved so recalcitrant to date. We fully acknowledge that as we move forward, we expect to develop more sophisticated definitions, terminology and tools. [ABSTRACT FROM AUTHOR]

Summary Objective Kashin-Beck Disease (KBD) is a rare and severe osteoarthropathy endemic to China. We evaluated the frequency and patterns of hand radiographic osteoarthritis (rOA) in adults with and without KBD. Methods Han Chinese ( N = 438) from Yongshou County of central China underwent right hand radiography for determining case status. Presence of KBD was based on characteristic radiographic deformities of articular ends of bones including articular surface depression, carpal crowding, any subchondral bone deformities in the proximal end of phalanges or first metacarpal bone, or the distal ends of metacarpal bones 2–5, and any bony enlargement with deformity of the distal ends of phalanges. Hand rOA severity was determined by osteophyte (OST), joint space narrowing (JSN), and Kellgren and Lawrence (KL) grades. Results This study included 127 KBD and 311 non-KBD adults of similar mean age (39 years) and body mass index (BMI) (21 kg/m 2 ). Inter- and intra-rater reliability for radiographic determination of case status and rOA features was high (kappa 0.72–0.96). Compared to non-KBD, KBD adults had significantly more severe hand rOA of the thumb, distal interphalangeal (DIP), proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints. Only KBD adults had end-stage carpometacapal (CMC) disease. In KBD, DIPs and PIPs were more affected than MCPs and the frequency of OSTs was significantly higher in PIPs than DIPs. Conclusions Compared with age-matched adults from the same area and farming occupation, KBD hand rOA was more widespread and severe, particularly of PIPs and CMCs. The ability to differentiate adult KBD from non-KBD hand rOA will facilitate genetic analyses of the vast majority of affected individuals. [ABSTRACT FROM AUTHOR]

Summary Hand osteoarthritis (OA) is a very frequent disease, but yet understudied. However, a lot of works have been published in the past 10 years, and much has been done to better understand its clinical course and structural progression. Despite this new knowledge, few therapeutic trials have been conducted in hand OA. The last OARSI recommendations for the conduct of clinical trials in hand OA dates back to 2006. The present recommendations aimed at updating previous recommendations, by incorporating new data. The purpose of this expert opinion, consensus driven exercise is to provide evidence-based guidance on the design, execution and analysis of clinical trials in hand OA, where published evidence is available, supplemented by expert opinion, where evidence is lacking, to perform clinical trials in hand OA, both for symptom and for structure-modification. They indicate core outcome measurement sets for studies in hand OA, and list the methods and instruments that should be used to measure symptoms or structure. For both symptom- and structure-modification, at least pain, physical function, patient global assessment, HR-QoL, joint activity and hand strength should be assessed. In addition, for structure-modification trials, structural progression should be measured by radiographic changes. We also provide a research agenda listing many unsolved issues that seem to most urgently need to be addressed from the perspective of performing “good” clinical trials in hand OA. These updated OARSI recommendations should allow for better standardizing the conduct of clinical trials in hand OA in the next future. [ABSTRACT FROM AUTHOR]

Summary The objective of this work was to describe requirements for inclusion of soluble biomarkers in osteoarthritis (OA) clinical trials and progress toward OA-related biomarker qualification. The Guidelines for Biomarkers Working Group, representing experts in the field of OA biomarker research from both academia and industry, convened to discuss issues related to soluble biomarkers and to make recommendations for their use in OA clinical trials based on current knowledge and anticipated benefits. This document summarizes current guidance on use of biomarkers in OA clinical trials and their utility at five stages, including preclinical development and phase I to phase IV trials. As demonstrated by this summary, biomarkers can provide value at all stages of therapeutics development. When resources permit, we recommend collection of biospecimens in all OA clinical trials for a wide variety of reasons but in particular, to determine whether biomarkers are useful in identifying those individuals most likely to receive clinically important benefits from an intervention; and to determine whether biomarkers are useful for identifying individuals at earlier stages of OA in order to institute treatment at a time more amenable to disease modification. [ABSTRACT FROM AUTHOR]

Summary Objective To identify disease relevant genes and pathways associated with knee Osteoarthritis (OA) progression in human subjects using medial and lateral compartment dominant OA knee tissue. Design Gene expression of knee cartilage was comprehensively assessed for three regions of interest from human medial dominant OA ( n = 10) and non-OA ( n = 6) specimens. Histology and gene expression were compared for the regions with minimal degeneration, moderate degeneration and significant degeneration. Agilent whole-genome microarray was performed and data were analyzed using Agilent GeneSpring GX11.5. Significant differentially regulated genes were further investigated by Ingenuity Pathway Analysis (IPA) to identify functional categories. To confirm their association with disease severity as opposed to site within the knee, 30 differentially expressed genes, identified by microarray, were analyzed by quantitative reverse-transcription polymerase chain reaction on additional medial ( n = 16) and lateral ( n = 10) compartment dominant knee OA samples. Results A total of 767 genes were differentially expressed ≥two-fold ( P ≤ 0.05) in lesion compared to relatively intact regions. Analysis of these data by IPA predicted biological functions related to an imbalance of anabolism and catabolism of cartilage matrix components. Up-regulated expression of IL11, POSTN, TNFAIP6, and down-regulated expression of CHRDL2, MATN4, SPOCK3, VIT, PDE3B were significantly associated with OA progression and validated in both medial and lateral compartment dominant OA samples. Conclusions Our study provides a strategy for identifying targets whose modification may have the potential to ameliorate pathological alternations and progression of disease in cartilage and to serve as biomarkers for identifying individuals susceptible to progression. [ABSTRACT FROM AUTHOR]

Summary Objective We investigated the relationship between the molecular weight (MW) distribution of hyaluronan (HA) in synovial fluid (SF) and risk of knee osteoarthritis (OA) progression. Methods HA MW was analyzed for 65 baseline knee SFs. At 3-year follow-up, knees were scored for change in joint space narrowing (JSN), osteophyte (OST) progression, or occurrence of total knee arthroplasty (TKA). HA MW distribution was analyzed using agarose gel electrophoresis (AGE), and its relationship to OA progression was evaluated using logistic regression. The association between HA MW and self-reported baseline knee pain was analyzed using Pearson's correlation coefficients. Results Knee OA was categorized as non-progressing (OST−/JSN−, 26 knees, 40%), or progressing based on OST (OST+/JSN−, 24 knees, 37%), OST and JSN (OST+/JSN+, 7 knees, 11%) or total knee arthroplasty (TKA, 8 knees, 12%). The MW distribution of HA in baseline SFs was significantly associated with the odds of OA progression, particularly for index knees. After adjusting for age, gender, BMI, baseline X-ray grade and pain, each increase of one percentage point in %HA below 1 million significantly increased the odds of JSN (odds ratios (OR) = 1.45, 95% CI 1.02–2.07), TKA or JSN (OR = 1.24, 95%CI 1.01–1.53) and the odds of any progression (OR = 1.16, 95% CI 1.01–1.32). HA MW distribution significantly correlated with pain. Conclusion These data suggest that the odds of knee OA progression increases as HA MW distribution shifts lower and highlight the value of reporting MW distribution rather than just average MW values for HA. [ABSTRACT FROM AUTHOR]

Summary: Objective: To establish whether there is an association between TSG-6 activity and osteoarthritis progression. Design: TSG-6 activity was determined in 132 synovial fluids from patients with OA of the knee, using a novel quantitative TSG-6 activity assay. The association between TSG-6 activities at baseline and four distinct disease progression states, determined at 3-year follow-up, was analyzed using logistic regression. Results: There was a statistically significant relationship between TSG-6 activity at baseline and all OA progression states over a 3-year period. Patient knees with TSG-6 activities in the top tenth percentile, compared to the median activity, had an odds ratio (OR) of at least 7.86 (confidence interval (CI) [3.2, 20.5]) for total knee arthroplasty (TKA) within 3 years, and of at least 5.20 (CI [1.8, 13.9]) after adjustment for confounding factors. Receiver operating characteristic (ROC) analysis for knee arthroplasty yielded a cut-off point of 13.3 TSG-6 activity units/ml with the following parameters: area under the curve 0.90 (CI [0.804, 0.996]), sensitivity 0.91 (CI [0.59, 0.99]), specificity 0.82 (CI [0.74, 0.88]) and a negative predictive value (NPV) of 0.99 (CI [0.934, 0.994]). Conclusion: The TSG-6 activity is a promising independent biomarker for OA progression. Given the high NPV, this assay may be particularly suitable for identifying patients at low risk of rapid disease progression and to assist in the timing of arthroplasty. [Copyright &y& Elsevier]

Summary: For both economic and ethical reasons, identification of the optimal treatment for each individual patient is a pressing concern, not only for the patients and their physician, but also health care payers and the pharmaceutical industry. In the field of osteoarthritis (OA) this is of particular relevance, due to the heterogeneity of the disease and the very large number of affected individuals. There is a need to pair the right patients with the right therapeutic modes of action. At present, the clinical trial failures in OA may be a consequence of both bona fide treatment failures and trial failures due to clinical design deficiencies. Tools are needed for characterization and segregation of patients with OA. Key lessons may be learned from advances with another form of arthritis, namely rheumatoid arthritis (RA). Personalized health care (PHC) may be more advantageous for a number of specific indications which are characterized by costly therapy, low response rates and significant problems associated with trial and error prescription, including the risk of serious side effects. We discuss the use of diagnostic practices guiding RA treatment, which may serve as a source of key insights for diagnostic practices in OA. We discuss the emerging concept of PHC, and outline the opportunities and current successes and failures across the RA field, as the OA field collects further data to support the hypothesis. We attempt to outline a possible path forward to assist patients, physicians, payers and the pharmaceutical industry in assuring the ‘right’ patients are treated with the ‘right drug’ in OA. Finally we highlight methods for possible segregation of OA patients that would allow identification of patient subtypes, such as OA driven by inflammation that may be ideally suited for PHC and for targeted therapies. [Copyright &y& Elsevier]

Summary: Objective: To evaluate ankle joint abnormalities in a knee osteoarthritis (OA) cohort. Methods: Participants (n = 159) with symptomatic and radiographic OA in at least one knee underwent technetium-99m methylene diphosphonate bone scan (scored 0–3) of the ankles and forefeet. Knee radiographs were graded for OA features of joint space narrowing (JSN) and osteophyte (OST). Ankle symptoms and history of ankle injury were assessed by self-report. Knee alignment was measured from a long-limb radiograph. Ankle radiographs were obtained on those who returned for follow-up (n = 138) and were graded for ankle tibiotalar JSN and OST. Design: Ankle scintigraphic abnormalities were frequent (31% of individuals, one-third bilateral). Ankle symptoms were reported by 23% of individuals and history of ankle injury by 24%. Controlling for gender, age, body mass index (BMI), and contralateral predictor, ankle scintigraphic abnormalities were associated with: ipsilateral ankle symptoms (P = 0.005); contralateral knee JSN (P = 0.001), knee OST (P = 0.006) and knee malalignment (P = 0.08); and history of ankle injury or surgery of either ankle (P < 0.0001). At follow-up, scintigraphic abnormalities of the ankle were strongly associated with presence of tibiotalar radiographic OA (P < 0.0001). Conclusions: Although considered rare, we observed a high prevalence of radiographic features of ankle OA in this knee OA cohort. History of overt ankle injury did not appear to account for the majority of ankle abnormalities. These results are consistent with a probable kinematic association of knee OA pathology and contralateral ankle abnormalities and suggest that interventions targeting mechanical factors may be needed to prevent ankle OA in the setting of knee OA. [Copyright &y& Elsevier]

Summary: The sixth Osteoarthritis Research Society International (OARSI) Workshop on Imaging in Osteoarthritis combined with the third osteoarthritis (OA) Biomarkers Workshop is the first to bring together the imaging and molecular biomarker communities to focus on clinical validation and qualification of OA biomarkers. The workshop was held in Hilton Head, SC, USA, from June 12–14, 2012; 138 attendees participated, including representatives from academia, pharmaceutical and magnetic resonance imaging (MRI) industries, Food and Drug Administration (FDA), and National Institutes of Health (NIH). Presentations and discussions raised awareness, consolidated knowledge, and identified strategies to overcome challenges for the development and application of imaging and biochemical biomarkers in OA research studies and clinical trials. Conclusion: The OA research communities need to work alongside regulatory agencies across the world, to qualify and validate new chemical and imaging biomarkers for future research and clinical trials. [Copyright &y& Elsevier]