Search

Objective: To investigate how running, cycling, and sedentary cardiovascular stress impact biomarkers of cartilage turnover acutely in subjects with knee osteoarthritis (OA)., Design: This was a sequential, cross-over, clinical study. Forty subjects with primary knee OA underwent moderate-to-high-intensity cycling, running, and adrenaline infusion on separate days. Blood was sampled before, during, and at 6-time points after intervention. On a control day, similar samples were taken. Biomarkers of type II collagen degradation (C2M, T2CM, Coll2-1, Coll2-1NO2), formation (PRO-C2), and aggrecan degradation (ARGS) were measured., Results: Mean age was 60.4 years, 40% were male, 45% had cumulated Kellgren-Lawrence (KL)-grade (Right + Left knee) of 2 to 3 and 55% had 4 to 6. Analyzing overall changes, area under the curve was significantly lower compared with resting values for ARGS and C2M after cycling and for ARGS after running. Considering individual time points, peak changes in biomarker levels showed reduction in C2M shortly following cycling (T 20min = -12.3%, 95% confidence interval [CI]: -19.3% to -5.2%). PRO-C2 increased during cycling (T 10min = 14.0%, 95% CI = 4.1% to 23.8%) and running (T 20min = 16.5%, 95% CI = 4.3% to 28.6%). T2CM decreased after cycling (T 50min = -19.9%, 95% CI = -29.2% to -10.6%), running (T 50min = -22.8%, 95% CI = -32.1% to -13.5%), and infusion of adrenaline (peak, T 50min = -9.8%, 95% CI = -20.0% to 0.4%). A latent increase was seen in Coll2-1 240 minutes after running (T 260min = 21.7%, 95% CI = -1.6% to 45.1%)., Conclusion: Exercise had an impact on cartilage markers, but it did not suggest any detrimental effect on cartilage. Changes following adrenaline infusion suggest a sympathomimetic influence on the serological composition of biomarkers., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J.J.B.-B. was funded by the Danish Research Fund, employee at NBCD A/S and of Sanos Clinic A/S. J.R.A. and A.R.B. are employees and shareholders of NBCD A/S. Y.H. is president of Artialis SA. M.U. is employee at Artialis SA. C.S.T. is employee at Nordic Bioscience A/S. CS., N.H.S., H.B.N., M.B., G.D., V.F., P.K., and C.-C.K. have nothing to declare.

Rationale: Viscosupplementation (VS) with hyaluronic acid is widely used in the management of knee osteoarthritis. There is no clear recommendation on the decision-making to achieve VS., Design: Based on extensive research of the literature and expert opinion, the members of the EUROVISCO (European Viscosupplementation Consensus Group) task force were asked to give their degree of agreement with 60 issues, using a Delphi method., Results: The expert panel achieved unanimous agreement in favor of the following statements: It is recommended to assess pain on a visual or 10-point numeric scale before considering VS. VS can be considered for patients with pain scores between 3 and 8. A standard x-ray must be obtained before the decision of VS. If the x-ray is normal, osteoarthritis must be confirmed by MRI or computed tomography (CT) arthrogram before considering VS. The aims of VS are relieving pain, improving function, and reducing non-steroidal anti-inflammatory drug (NSAID) consumption. The use of VS must not be considered for treating an osteoarthritis flare. VS can be envisaged as a first-line pharmacological treatment in patients having a contra-indication to NSAIDs or analgesics. VS can be considered in patients with contra-indications to arthroplasty. In the case of severe comorbidities (diabetes, hypertension, gastrointestinal disorders, renal failure), VS can avoid the use of potentially dangerous treatments. VS can be considered in patients receiving antiplatelet agents, vitamin K antagonists, and direct factor Xa or thrombin inhibitors. Five other statements obtained a high level of consensus., Conclusion: These recommendations, illustrated in a decision algorithm, have been established to help practitioners in the decision-making of knee VS.

Objectives: To investigate a 6-month intervention with an olive leaf extract (OLE) on knee functionality and biomarkers of bone/cartilage metabolism and inflammation., Design: This randomized, double-blind, placebo-controlled, multi-centric trial included 124 subjects with knee pain or mobility issues. Subjects received twice a day one capsule of placebo or 125 mg OLE (Bonolive ™ , an OLE containing 50 mg of oleuropein) for 6 months. The co-primary endpoints were Knee injury and Osteoarthritis Outcome Score (KOOS) and serum Coll2-1NO2. The secondary endpoints were the subscales of the KOOS, knee pain VAS at rest and at walking, OARSI core set of performance-based tests and multiple inflammatory and bone or cartilage remodeling serum biomarkers and concentration of oleuropein's metabolites in urine., Results: At 6 months, OLE group was not efficient on global KOOS score, changes of inflammatory and cartilage remodeling biomarkers compared to placebo. Post hoc analyses demonstrated a large and significant treatment effect of OLE in a sub-group of subjects with high walking pain at baseline ( p  = 0.03). This was observed at 6 months for the global KOOS score, and each different subscale and for pain at walking ( p  = 0.02). OLE treatment was well tolerated., Conclusion: OLE was not effective on joint discomfort excepted in a sub-group of subjects with high pain at treatment initiation. As oleuropein is well tolerated, OLE can be used to relieve knee joint pain and enhance mobility in subjects with articular pain., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: YH is the founder and chairman of Artialis SA, a spin-off company of the University of Liège developing biomarkers. MNH, MB, NS, LP, and MS are employees of Société des produits Nestlé SA. ACH, BC, and LG are employees of the Artialis’company., (© The Author(s), 2022.)

Objective: To assess the cross-sectional association between serum levels of Coll2-1 and Coll2-1NO2, two cartilage degradation biomarkers; the burden of magnetic resonance imaging (MRI) features and clinical outcomes; and to evaluate the predictive value of these biomarkers on progression., Design: A total of 121 subjects with knee osteoarthritis (OA) were followed during 1 year with pain, function, and MRI assessment (PRODIGE study). Type II collagen-specific biomarker Coll2-1 and its nitrated form Coll2-1NO2 were directly measured in serum using immunoassays at baseline and after 3-, 6-, and 12-month follow-up., Results: Serum Coll2-1 and Coll2-1NO2 were correlated with several baseline knee features quantified with Whole-Organ Magnetic Resonance Imaging Score (WORMS). Coll2-1 was significantly correlated with periarticular cysts/bursitis (ρ = 0.29, P < 0.01), subarticular bone attrition (ρ = 0.25, P = 0.01), subarticular cysts (ρ = 0.24, P = 0.02), and articular cartilage integrity (ρ = 0.23, P = 0.03) WORMS subscores for the whole joint as well as with the medial femorotibial joint sum score (ρ = 0.26, P = 0.01) and medial femorotibial joint cartilage (ρ = 0.23, P = 0.02). Coll2-1NO2 correlated with WORMS total score (ρ = 0.23, P = 0.02), WORMS scores in the patellofemoral (ρ = 0.23, P = 0.02) and medial femorotibial compartments (ρ = 0.21, P = 0.03), with osteophytes scores (ρ = 0.27, P < 0.01), subarticular cysts (ρ = 0.24, P = 0.019), and intraarticular loose bodies (ρ = 0.27, P = 0.007). Baseline Coll2-1NO2 was higher in subjects with a pain worsening (426.4 pg/mL [278.04-566.95]) as compared to non-progressors (306.84 pg/mL [200.37-427.84]) over 1 year (AUC = 0.655, P = 0.015)., Conclusion: Serum cartilage biomarkers Coll2-1 and Coll2-1NO2 are associated with several knee OA features quantified with WORMS. Our study also shows that the baseline value of Coll2-1NO2 is positively associated with pain worsening.

Objective: Syndecan-4 plays a critical role in cartilage degradation during osteoarthritis (OA). The aim of this study was to investigate the expression and localization of syndecan-4 in different OA joint tissues., Design: Syndecan-4 mRNA levels were quantified by reverse transcription-polymerase chain reaction in human OA primary cells. Syndecan-4 was localized by immunohistochemistry in knee, hip, or shoulder OA bone/cartilage biopsies. Syndecan-4 was quantified by immunoassay in chondrocytes culture supernatant and cell fraction., Results: Using immunochemistry, syndecan-4 was observed in chondrocytes clusters in the superficial zone of OA knee, but not in OA hip or shoulder cartilage. No significant difference was detected in syndecan-4 expression level in sclerotic compared with nonsclerotic osteoblasts or in inflamed synoviocytes compared to normal/reactive ones. Differentiated hypertrophic chondrocytes from knee, but not from hip cartilage, expressed more syndecan-4 than nonhypertrophic cells. Using an immunoassay for the extracellular domain of syndecan-4, we found 68% of the syndecan-4 in the culture supernatant of OA chondrocytes culture, suggesting that a large majority of the syndecan-4 is shed and released in the extracellular medium. The shedding rate was not affected by hypertrophic differentiation state of the chondrocytes or their joint origin., Conclusions: Even if chondrocytes clusters are seen in OA knee, hip and shoulder cartilage and hypertrophic differentiation appears in knee and hip OA articular chondrocytes, syndecan-4 synthesis only increased in knee. These findings suggest the presence of biochemical difference between articular cartilage according to their location and that syndecan-4 could be a biochemical marker specific for knee OA.

Objectives: This work studied if and how current clinical practice agrees with European Viscosupplementation Consensus Group (EUROVISCO) recommendations and how this agreement might be different according to physician's specialization. In addition, this work aimed to identify key decision factors that practitioners consider in their decision to retreat or not a patient with hyaluronic acid viscosupplementation., Methods: Practitioners have been invited by e-mail to participate in an online exercise on viscosupplementation retreatment. They received a fictional patient case at random among a set of predefined fictional cases. The platform asked the practitioner if he/she would retreat the patient with viscosupplementation or not. To take a decision, the practitioner could select questions among a list of predefined questions. Among them, some were related to criteria used in the EUROVISCO decision tree and others served as confounding factors., Results: A total of 506 practitioners participated to the exercise, of which 399 gave their decision about the case assigned to them by the platform. The observed agreement between practitioner decisions and EUROVISCO recommendations was 58.89 ± 4.95% (95% confidence interval [CI]). Overall, the decision to retreat was taken in 47.87% of the cases, while the EUROVISCO guidelines follow-up would have led to 55.89% retreatment for the same cases ( P = 0.03)., Conclusions: In current practice, physicians tended to reinject their patients less than recommended, although EUROVISCO guidelines for viscosupplementation retreatment consider decision criteria that clearly correspond to those of practitioners in real life. These include the patients' willingness to be treated or the patients' perception of the effectiveness of the treatment.

Objective: The aim of this study was to evaluate the effects of a lyophilized inactivated culture (LIC) from Bifidobacterium longum CBi0703 in a spontaneous model of osteoarthritis (OA) in Dunkin Hartley guinea pigs. Histology of cartilage and synovial membrane was the primary outcome. Biomarkers were also considered to evaluate the treatment efficacy., Design: LIC (1 µg/kg) with or without vitamin C (1 mg/kg) were tested in Dunkin Hartley guinea pigs spontaneously developing OA and compared with control (sterile water; CTL). Treatment was initiated orally in 16-week-old animals over a period of 12 weeks. Histological lesions of articular cartilage and synovial membrane were scored according to the OARSI (Osteoarthritis Research Society International) recommendations. Four biomarkers (Coll2-1, PIINAP, Fib3-2, and osteocalcin) were measured in animal sera., Results: The global OARSI score increased with time in all group but no significant difference between groups was observed. When score items were analyzed individually, a significant lower score of cartilage structure was observed in the LIC + vitamin C group compared with CTL ( P < 0.0001). Synovial membrane showed a mild inflammatory reaction that was not affected by the treatment. LIC significantly decreased serum levels of Coll2-1 ( P = 0.0004 vs. CTL), a marker of type II collagen degradation and LIC + vitamin C significantly increased PIINAP ( P = 0.0003), a marker of type II collagen synthesis. The ratio Coll2-1/PIINAP was significantly decreased in both LIC groups ( P < 0.001)., Conclusion: Lyophilized inactivated culture of B. longum CBi0703 administrated orally over a period of 12 weeks decreased cartilage structure lesions and decreased type II collagen degradation suggesting a potential prophylactic effect on OA development.

Objective: To assess intraindividual biological variability of serum cartilage specific biomarker Coll2-1 and define the best standardized conditions for blood sampling., Design: Blood samples were taken from 116 subjects with knee osteoarthritis (OA) at a single time point (PRODIGE study) and from 15 healthy subjects under various conditions, including fasting condition, sampling time and season, blood treatment, and type of blood collection tube (COVAR study). Type II collagen-specific biomarker Coll2-1 was directly measured in serum using an immunoassay., Results: There was no significant difference on Coll2-1 values between samples collected at any of the 5 sampling times or at any of the sampling days measured. None of the sampling parameters tested had a significant impact on Coll2-1 value (clotting time, clotting temperature and temperature of blood centrifugation, type of tube). On the contrary, differences were found in between subjects and between subjects with knee OA and healthy subjects., Conclusion: Coll2-1 measurement is not affected by sampling specific conditions, circadian rhythm or seasons but was found elevated in subject with knee OA indicating that Coll2-1 serum variation is not linked to the study environment, but to cartilage degradation in OA. Coll2-1 assay is sufficiently robust for use in OA clinical trials.

Viscosupplementation (VS) is a symptomatic treatment for knee and other joint osteoarthritis (OA). Despite a long history of use, conflicting opinions remain on the best clinical indications and the most appropriate patients to be treated with intra-articular hyaluronic acid (IA-HA), the optimal dosing regimen and the modalities of retreatment. A multidisciplinary committee of European experts on OA (EUROVISCO) was constituted to formulate recommendations, aimed at helping physicians in the decision-making and the optimal achievement of VS. Before each session members were tasked to collate an exhaustive literature review. Level of evidence and strength of recommendation were based on the level of agreement for each item according to the Delphi method. In 2015, a consensus position was proposed for 24 statements. Among those that obtained a consensual agreement, the working group stressed that VS is effective in mild/moderate knee OA but is not an alternative to surgery in advanced OA, and that dosing regimen must be supported by controlled trials. In 2018, two decision algorithms for the retreatment with IA-HA in knee OA were published. Among the key recommendations, the experts recommended to re-treat every year patients with high risk of OA progression, even if not symptomatic. In 2020, EUROVISCO published two sets of recommendations for the design of clinical trials on the disease-modifying effect of VS and for optimizing the results of VS. The working group underlined that an accurate analysis of radiological features and symptoms and a careful clinical examination may improve the chances of success of VS, as well as good technique of injection and the use of imaging guidance. Based on the exhaustive analysis of the literature and their own clinical experience, the EUROVISCO experts offer a wide range of recommendations intended to help practitioners, particularly in certain cases where the specific characteristics of the patients make the therapeutic decision difficult., Competing Interests: Conflict of interest statement: Yves Henrotin: Received honorarium from Menarini, Flexion therapeutics, IBSA, BioIberica, Expansciences, Royal canin, MagPharm, Pfizer, Fidia and LABRHA and Tilman SA, for consultant services. Founder and shareholder of KIOmed pharma. Founder and shareholder of Artialis SA. Raghu Raman: Received honorarium from Sanofi and LABRHA for consultant services. Pascal Richette: Received fees from BioIbérica, Fidia, IBSA, Expanscience, Genévrier, Sanofi, Rottapharm, Servier, Flexion Therapics and Ménarini. Hervé Bard: Received speaker and expert fees from Sanofi, Pfizer, Labrha, Expanscience, TRB Chemedica Jörg Jerosch: Received honorarium from Sanofi for speaker services Thierry Conrozier: Received honorarium from Sanofi, MEDAC, Fidia and Labrha for expert and consultant services Xavier Chevalier: Received fees as a Genevrier Board member, Sanofi-Aventis expert, member of the IBSA foundation, speaker in IBSA meetings, Moebius and Flexion therapics consultant Alberto Migliore: Received consulting fees from Abbvie, BMS, MSD, Fidia, Sanofi, IBSA, Pfizer and Labrha, for national and international studies and courses. Jordy Monfort: Received consulting fees from Sanofi and Bioiberica Dominique Baron: Received speaker fees from LCA and Expansciences, (© The Author(s), 2021.)

Objectives: The 3 aims of the work were to identify population subgroups that can benefit the most from viscosupplementation (VS), to provide recommendations on injection techniques, and to discuss VS appropriateness in clinical situations that are commonplace in daily practice., Methods: The task force members voted on their degree of agreement on 27 statements, 36 recommendations, and 22 clinical scenarios using a 9-point scale. The strength of agreement/appropriateness/recommendation (SOA/SOR) was classified as strong if the median agreement score was ≥8. The level of consensus (LOC) was also obtained., Results: Among the assumed predictors for VS failure, obesity, radiographic severity, large synovial fluid effusion, severe patellofemoral involvement, major malalignment, and gross joint instability received a large majority of agreements. The lateral mid-patellar approach was recommended for knee injection. Imaging guidance was unanimously recommended for hip and ankle. Agreement was achieved to strictly respect the dosing regimen proven by controlled trials. There was agreement for treating with VS patients with mild to moderate knee and hip OA, with normal weight or moderate overweight, insufficiently improved by first-line therapies, or who do not wish get oral treatment or who have contraindications to pain killers. The group considered the patient's wishes as a key element in therapeutic decision making., Conclusion: Based on literature data and clinical experience, the EUROVISCO group proposed a set of recommendations for optimizing the results of VS, aimed to help practitioners, especially in some cases in which the patients' specificities make the therapeutic decision difficult.

Objectives: Hyaluronic acid viscosupplementation is a commonly used intra-articular treatment for osteoarthritis (OA). Some recent preclinical and clinical trials have demonstrated a potential for its disease-modifying effects. The goal of this expert opinion, consensus-driven exercise is to provide guidelines for the design and conduct of clinical trials assessing the disease-modifying effect of viscosupplementation in the knee., Methods: The EUROVISCO group constitutes 10 members who had expertise in clinical research methodology in the field of OA and viscosupplementation. They initially drafted issues through an iterative process and had to vote on their degree of agreement on these recommendations. The scores were pooled to generate a median agreement score for each recommendation., Results: The document includes 31 recommendations regarding study population, imaging, clinical and biological assessment of disease-modifying effects of viscosupplementation. Agreements were reached on some recommendations. In particular, the experts reached unanimous agreement on double-blind study design, imaging primary outcomes, time interval between 2 radiographs, x-ray procedure standardization, and the combined use of imaging and biological markers. The group did not recommend the use of ultrasonography, computed tomography (CT) scan and CT arthrography as a tool for OA diagnosis or to assess progression over time., Conclusion: In summary, the working group identified 31 recommendations that represent the current best practices regarding clinical trials that target the assessment of viscosupplementation disease-modifying effects in patients with knee OA. These recommendations integrate new imaging technologies and soluble biomarkers.

Background Viscosupplementation (VS) is a symptomatic treatment of knee osteoarthritis. Although systematic reviews of its repeat use showed favorable benefit/risk ratio, no study has focused on the indication of retreatment. Methods A task force was created to look at issues regarding retreatment with VS in knee osteoarthritis. An attempt was made to reach consensus on several issues: (1) to define treatment "success" and "failure," (2) to determine when to retreat patients successfully treated by a previous VS, (3) to determine how to retreat patients in whom VS failed, (4) to define what to do in case of adverse reaction following previous VS, and (5) to examine the interests of soluble biomarkers to manage retreatment. After debate and review of literature the working group voted on 88 issues. Two "decision trees" were built based on the results of the votes. Results In case of failure, the authors draw attention to the need of a rigorous clinical and radiological analysis, and consider evidence-based medicine. When VS was previously successful, retreatment can be considered after recurrence or increase in pain. However, in subjects with high risk of disease progression, in young patients, and in professional sportsmen, retreatment could be considered systematically, because of the probability of hyaluronic acid to slow osteoarthritis progression. Evidence on soluble biomarkers was not considered as enough strong to support their use as decision tools for patient retreatment. Conclusion The decision algorithms are intended to facilitate consideration of the therapeutic options, in patients with knee osteoarthritis previously treated with VS.

Synovitis is a key feature in osteoarthritis and is associated with symptom severity. Synovial membrane inflammation is secondary to cartilage degradation which occurs in the early stage and is located adjacent to cartilage damage. This inflammation is characterized by the invasion and activation of macrophages and lymphocytes, the release in the joint cavity of large amounts of pro-inflammatory and procatabolic mediators, and by a local increase of synovial membrane vascularity. This latter process plays an important role in the chronicity of the inflammatory reaction by facilitating the invasion of the synovium by immune cells. Therefore, synovial membrane angiogenesis represents a key target for the treatment of osteoarthritis. This paper is a narrative review of the literature referenced in PubMed during the past 5 years. It addresses in particular three questions. What are the mechanisms involved in synovium blood vessels invasion? Are current medications effective in controlling blood vessels formation and invasion? What are the perspectives of research in this area?

Chondroitin sulfate (CS) is recommended as a therapeutic intervention in the multimodal approach of osteoarthritis (OA) management. CS has been studied extensively to describe its pharmacology (pharmacokinetic, in vitro and in vivo effects) and its clinical efficacy. Various results have been reported depending on the system of evaluation (model, dosage and duration) and the source of CS (origin and quality). The purpose of this review was to gather most of the available information about CS and to discuss its potency in OA management.