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Objective: Osteoarthritis (OA) is a highly prevalent chronic condition. The subchondral bone plays an important role in onset and progression of OA making it a potential treatment target for disease-modifying therapeutic approaches. However, little is known about changes of periarticular bone mineral density (BMD) in OA and its relation to meniscal coverage and meniscal extrusion at the knee. Thus, the aim of this study was to describe periarticular BMD in the Applied Public-Private Research enabling OsteoArthritis Clinical Headway (APPROACH) cohort at the knee and to analyze the association with structural disease severity, meniscal coverage and meniscal extrusion. Design: Quantitative CT (QCT), MRI and radiographic examinations were acquired in 275 patients with knee osteoarthritis (OA). QCT was used to assess BMD at the femur and tibia, at the cortical bone plate (Cort) and at the epiphysis at three locations: subchondral (Sub), mid-epiphysis (Mid) and adjacent to the physis (Juxta). BMD was evaluated for the medial and lateral compartment separately and for subregions covered and not covered by the meniscus. Radiographs were used to determine the femorotibial angle and were evaluated according to the Kellgren and Lawrence (KL) system. Meniscal extrusion was assessed from 0 to 3. Results: Mean BMD differed significantly between each anatomic location at both the femur and tibia (p < 0.001) in patients with KL0. Tibial regions assumed to be covered with meniscus in patients with KL0 showed lower BMD at Sub (p < 0.001), equivalent BMD at Mid (p = 0.07) and higher BMD at Juxta (p < 0.001) subregions compared to regions not covered with meniscus. Knees with KL2-4 showed lower Sub (p = 0.03), Mid (p = 0.01) and Juxta (p < 0.05) BMD at the medial femur compared to KL0/1. Meniscal extrusion grade 2 and 3 was associated with greater BMD at the tibial Cort (p < 0.001, p = 0.007). Varus malalignment is associated with significant greater BMD at the medial femur and at the medial tibia at all anatomic locations. Conclusion: BMD within the epiphyses of the tibia and femur decreases with increasing distance from the articular surface. Knees with structural OA (KL2-4) exhibit greater cortical BMD values at the tibia and lower BMD at the femur at the subchondral level and levels beneath compared to KL0/1. BMD at the tibial cortical bone plate is greater in patients with meniscal extrusion grade 2/3.

To assess patient perspective and professional practice of intraarticular therapies (IATs) across Europe, an expert international multidisciplinary panel designed two open web-based surveys: one targeting people who had experienced at least two IATs (44 items); and one targeting health care providers (HCPs) (160 items). Surveys were disseminated via patient and professional associations and social media. A descriptive analysis was performed. The surveys were answered by 200 patients and 186 HCPs from 26 countries, showing that IAT is routinely performed by rheumatologists (97%) and orthopaedic surgeons (89%), with specific training being compulsory in a few countries. The most frequent indications for IAT are arthritis (76%), osteoarthritis (74%), crystal arthritis (71%) and bursitis (70%); the most frequently injected joints are knee (78%) and shoulder (70%); and the most used compounds are glucocorticoids. The majority of HCPs report informing patients about side-effects (73%), benefits (72%), and the nature of the procedure (72%), which coincides with 27% of patients reporting that they had not been informed about benefits or potential complications of IATs; 73% of patients had not been asked whether they wanted an anaesthetic. Few HCPs (10%) obtain written consent (56% get oral consent, being mandatory for 32%), a procedure deemed necessary by 41% of the patients. 50% of patients reported a clear benefit of IAT and 20% experienced complications including pain, impaired mobility, rashes, or swelling. In summary, the practice of IAT is variable across Europe, and although patients perceive it as relatively safe and usually effective procedure, some gaps were identified.

Introduction: Combining measures of key core domains (especially pain and function) into a composite endpoint that requires each patient to meet a threshold of improvement for each domain provides information on multiple aspects of osteoarthritis within individual patients. This pooled analysis of two phase 3 studies (NCT02697773, NCT02709486) explored single and composite endpoints for assessing within-patient improvement in knee or hip osteoarthritis symptoms following subcutaneous administration of tanezumab or placebo. Methods: Endpoints at week 16 included proportions of responders (C 30% improvement) in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function, WOMAC Pain/Function composite, and weekly average pain; and patient acceptable symptom state (PASS) composite responders, minimal clinically important improvement (MCII) composite responders, IntroductionCombining measures of key core domains (especially pain and function) into a composite endpoint that requires each patient to meet a threshold of improvement for each domain provides information on multiple aspects of osteoarthritis within individual patients. This pooled analysis of two phase 3 studies (NCT02697773, NCT02709486) explored single and composite endpoints for assessing within-patient improvement in knee or hip osteoarthritis symptoms following subcutaneous administration of tanezumab or placebo.MethodsEndpoints at week 16 included proportions of responders (≥ 30% improvement) in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function, WOMAC Pain/Function composite, and weekly average pain; and patient acceptable symptom state (PASS) composite responders, minimal clinically important improvement (MCII) composite responders, Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) responders, and sustained weekly average pain responders.ResultsPooled population comprised 1545 patients. Of patients who had a ≥ 30% improvement in WOMAC Pain and/or WOMAC Physical Function, 88.5% were WOMAC Pain/Function composite responders, 7.0% were WOMAC Pain (but not Function) responders, and 4.4% were WOMAC Function (but not Pain) responders. Of weekly average pain responders, 43.1% were PASS composite responders. Odds ratios (tanezumab 2.5 mg and 5 mg groups, respectively, vs placebo) were 1.75 and 1.86 (WOMAC Pain/Function composite responders), 1.41 and 1.65 (weekly average pain responders), 1.60 and 1.73 (PASS composite responders), 1.52 and 1.68 (MCII composite responders), 1.75 and 1.88 (OMERACT-OARSI responders), and 1.85 and 1.48 (sustained weekly average pain responders). Subgroup analyses suggested a greater magnitude of effect for patients with a knee index joint compared with hip on some endpoints.ConclusionResponders on single pain endpoints were in many cases also responders on function or composite endpoints. Separation of tanezumab from placebo was similar and consistent across single and composite endpoints.

ObjectivesTo establish evidence-based recommendations to guide health professionals using intra-articular therapies (IAT) in adult patients with peripheral arthropathies.MethodsA multidisciplinary international task force established the objectives, users and scope and the need for background information, including systematic literature reviews) and two surveys addressed to healthcare providers and patients throughout Europe. The evidence was discussed in a face-to-face meeting, recommendations were formulated and subsequently voted for anonymously in a three-round Delphi process to obtain the final agreement. The level of evidence was assigned to each recommendation with the Oxford levels of evidence.ResultsRecommendations focus on practical aspects to guide health professionals before, during and after IAT in adult patients with peripheral arthropathies. Five overarching principles and 11 recommendations were established, addressing issues related to patient information, procedure and setting, accuracy, routine and special aseptic care, safety issues and precautions to be addressed in special populations, efficacy and safety of repeated joint injections, use of local anaesthetics and aftercare.ConclusionWe have developed the first evidence and expert opinion-based recommendations to guide health professionals using IAT. We hope that these recommendations will be included in different educational programmes, used by patient associations and put into practice via scientific societies to help improve uniformity and quality of care when performing IAT in peripheral adult joints.

The extracellular matrix (ECM) of articular cartilage is a three-dimensional network mainly constituted of entangled collagen fibrils and interfibrillar aggrecan aggregates. During the development of osteoarthritis (OA), the most common musculoskeletal disorder, the ECM is subjected to a combination of chemical and structural changes that play a pivotal role in the initiation and the progress of the disease. While the molecular mechanisms involved in the pathological remodelling of the ECM are considered as decisive, they remain, however, not completely elucidated. Herein, we report a relevant way for unravelling the role and nature of OA progress on human cartilage tissues, in terms of chemical composition and morphological and mechanical properties at the level of supramolecular assemblies constituting the cartilage ECM. For this purpose, we used X-ray photoelectron spectroscopy (XPS), and developed an innovative methodological approach that provides the molecular composition of the ECM. Moreover, we used atomic force microscopy (AFM) to probe the tissues at the level of individual collagen fibrils, both imaging and force spectroscopy modes being explored to this end. Taken together, these nanoscale characterization studies reveal the existence of two stages in the OA progress. At the early stage, a marked increase in the aggrecan and collagen content is observed, reflecting the homeostatic chondrocyte activity that tends to repair the cartilage ECM. At the late stage, we observe a failed attempt to stabilize and/or restore the tissue, yielding significant degradation of the supramolecular assemblies. This suggests an imbalance in the chondrocyte activity that turns in favor of catabolic events. Chemical changes are also accompanied by ECM structural changes and stiffening. Interestingly, we showed the possibility to mimic the imbalanced activities of chondrocytes by applying enzymatic digestions of healthy cartilage, through the combined action of hyaluronidase and collagenase. This yields damage strictly analogous to that observed at high OA severity. These findings bring mechanistic insights leading to a better understanding of the mechanism by which OA is initiated and progresses in the cartilage ECM. They offer guidelines for the development of curative treatments, such as targeting the homeostatic balance of chondrocyte metabolism through the control of enzymatic reactions involved in catabolic processes.

International audience; Objective: The innate immune system plays a central role in osteoarthritis (OA). We identified 14-3-3ε as a novel mediator that guides chondrocytes toward an inflammatory phenotype. 14-3-3ε shares common characteristics with alarmins. These endogenous molecules, released into extracellular media, are increasingly incriminated in sustaining OA inflammation. Alarmins bind mainly to toll-like receptor 2 (TLR2) and TLR4 receptors and polarize macrophages in the synovium. We investigated the effects of 14-3-3ε in joint cells and tissues and its interactions with TLRs to define it as a new alarmin involved in OA.Design: Chondrocyte, synoviocyte and macrophage cultures from murine or OA human samples were treated with 14-3-3ε. To inhibit TLR2/4 in chondrocytes, blocking antibodies were used. Moreover, chondrocytes and bone marrow macrophage (BMM) cultures from knockout (KO) TLRs mice were stimulated with 14-3-3ε. Gene expression and release of inflammatory mediators [interleukin 6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNFα)] were evaluated via reverse transcription quantitative polymerase chain reaction (RT-qPCR) and ELISA.Results: In vitro, 14-3-3ε induced gene expression and release of IL6 and MCP1 in the treated cells. The inflammatory effects of 14-3-3ε were significantly reduced following TLRs inhibition or in TLRs KO chondrocytes and BMM.Conclusions: 14-3-3ε is able to induce an inflammatory phenotype in synoviocytes, macrophages and chondrocytes in addition to polarizing macrophages. These effects seem to involve TLR2 or TLR4 to trigger innate immunity. Our results designate 14-3-3ε as a novel alarmin in OA and as a new target either for therapeutic and/or prognostic purposes.

Osteoarthritis (OA) is the most common joint condition and, with a burgeoning ageing population, is due to increase in prevalence. Beyond conventional medical and surgical interventions, there are an increasing number of ‘alternative’ therapies. These alternative therapies may have a limited evidence base and, for this reason, are often only afforded brief reference (or completely excluded) from current OA guidelines. Thus, the aim of this review was to synthesize the current evidence regarding autologous chondrocyte implantation (ACI), mesenchymal stem cell (MSC) therapy, platelet-rich plasma (PRP), vitamin D and other alternative therapies. The majority of studies were in knee OA or chondral defects. Matrix-assisted ACI has demonstrated exceedingly limited, symptomatic improvements in the treatment of cartilage defects of the knee and is not supported for the treatment of knee OA. There is some evidence to suggest symptomatic improvement with MSC injection in knee OA, with the suggestion of minimal structural improvement demonstrated on MRI and there are positive signals that PRP may also lead to symptomatic improvement, though variation in preparation makes inter-study comparison difficult. There is variability in findings with vitamin D supplementation in OA, and the only recommendation which can be made, at this time, is for replacement when vitamin D is deplete. Other alternative therapies reviewed have some evidence (though from small, poor-quality studies) to support improvement in symptoms and again there is often a wide variation in dosage and regimens. For all these therapeutic modalities, although controlled studies have been undertaken to evaluate effectiveness in OA, these have often been of small size, limited statistical power, uncertain blindness and using various methodologies. These deficiencies must leave the question as to whether they have been validated as effective therapies in OA (or chondral defects). The conclusions of this review are that all alternative interventions definitely require clinical trials with robust methodology, to assess their efficacy and safety in the treatment of OA beyond contextual and placebo effects. Electronic supplementary material The online version of this article (10.1007/s40520-020-01515-1) contains supplementary material, which is available to authorized users.

Objective: Physical function is one of the Outcome Measures in Rheumatology (OMERACT) core outcome domains for hand osteoarthritis studies. Our aim was to select appropriate instrument(s) to measure this domain, as part of the development of a core outcome measurement set.Methods: Following the OMERACT Filter 2.1 instrument selection process, the (function subscale of) the Australian/Canadian Hand Osteoarthritis Index (AUSCAN), Functional Index for Hand Osteoarthritis (FIHOA) and Michigan Hand Outcomes Questionnaire (MHQ) were assessed for domain match, feasibility, truth and discrimination. Data gathered from available literature, working group and patient surveys, and additional analyses in two hand osteoarthritis cohorts were used to inform a consensus process.Results were summarized in Summary of Measurements Properties tables and reviewed by the OMERACT technical advisory group. Results: MHQ passed the assessment of domain match and feasibility by the working group and patient research partners. For AUSCAN important limitations in feasibility were noted, but domain match was good. FIHOA did not pass the assessment and was not taken through the follow-up assessment. Based on published literature, reliability and construct/longitudinal validity of both MHQ and AUSCAN fulfilled OMERACT standards. While clinical trial discrimination and thresholds of meaning were good for AUSCAN, results for MHQ were ambiguous.Conclusion: MHQ was provisionally endorsed as OMERACT core outcome measure for the core domain physical function. While AUSCAN may have better metric properties than MHQ, it received provisional endorsement as a second measure of function due to important feasibility issues. A research agenda to merit full endorsement was set. (c) 2021 The Author(s). Published by Elsevier Inc.

ObjectivesOsteoarthritis (OA) patients with a neuropathic pain (NP) component may represent a specific phenotype. This study compares joint damage, pain and functional disability between knee OA patients with a likely NP component, and those without a likely NP component.MethodsBaseline data from the Innovative Medicines Initiative Applied Public-Private Research enabling OsteoArthritis Clinical Headway knee OA cohort study were used. Patients with a painDETECT score ≥19 (with likely NP component, n=24) were matched on a 1:2 ratio to patients with a painDETECT score ≤12 (without likely NP component), and similar knee and general pain (Knee Injury and Osteoarthritis Outcome Score pain and Short Form 36 pain). Pain, physical function and radiographic joint damage of multiple joints were determined and compared between OA patients with and without a likely NP component.ResultsOA patients with painDETECT scores ≥19 had statistically significant less radiographic joint damage (p≤0.04 for Knee Images Digital Analysis parameters and Kellgren and Lawrence grade), but an impaired physical function (pConclusionsOA patients with a likely NP component, as determined with the painDETECT questionnaire, may represent a specific OA phenotype, where local and overall joint damage is not the main cause of pain and disability. Patients with this NP component will likely not benefit from general pain medication and/or disease-modifying OA drug (DMOAD) therapy. Reserved inclusion of these patients in DMOAD trials is advised in the quest for successful OA treatments.Trial registration numberThe study is registered under clinicaltrials.gov nr: NCT03883568.

ObjectivesOsteoarthritis (OA) patient stratification is an important challenge to design tailored treatments and drive drug development. Biochemical markers reflecting joint tissue turnover were measured in the IMI-APPROACH cohort at baseline and analysed using a machine learning approach in order to study OA-dominant phenotypes driven by the endotype-related clusters and discover the driving features and their disease-context meaning.MethodData quality assessment was performed to design appropriate data preprocessing techniques. The k-means clustering algorithm was used to find dominant subgroups of patients based on the biochemical markers data. Classification models were trained to predict cluster membership, and Explainable AI techniques were used to interpret these to reveal the driving factors behind each cluster and identify phenotypes. Statistical analysis was performed to compare differences between clusters with respect to other markers in the IMI-APPROACH cohort and the longitudinal disease progression.ResultsThree dominant endotypes were found, associated with three phenotypes: C1) low tissue turnover (low repair and articular cartilage/subchondral bone turnover), C2) structural damage (high bone formation/resorption, cartilage degradation) and C3) systemic inflammation (joint tissue degradation, inflammation, cartilage degradation). The method achieved consistent results in the FNIH/OAI cohort. C1 had the highest proportion of non-progressors. C2 was mostly linked to longitudinal structural progression, and C3 was linked to sustained or progressive pain.ConclusionsThis work supports the existence of differential phenotypes in OA. The biomarker approach could potentially drive stratification for OA clinical trials and contribute to precision medicine strategies for OA progression in the future.Trial registration numberNCT03883568.

ObjectiveThe aim of this systematic literature review was to provide a comprehensive and exhaustive overview of the use of machine learning (ML) in the clinical care of osteoarthritis (OA).MethodsA systematic literature review was performed in July 2021 using MEDLINE PubMed with key words and MeSH terms. For each selected article, the number of patients, ML algorithms used, type of data analysed, validation methods and data availability were collected.ResultsFrom 1148 screened articles, 46 were selected and analysed; most were published after 2017. Twelve articles were related to diagnosis, 7 to prediction, 4 to phenotyping, 12 to severity and 11 to progression. The number of patients included ranged from 18 to 5749. Overall, 35% of the articles described the use of deep learning And 74% imaging analyses. A total of 85% of the articles involved knee OA and 15% hip OA. No study investigated hand OA. Most of the studies involved the same cohort, with data from the OA initiative described in 46% of the articles and the MOST and Cohort Hip and Cohort Knee cohorts in 11% and 7%. Data and source codes were described as publicly available respectively in 54% and 22% of the articles. External validation was provided in only 7% of the articles.ConclusionThis review proposes an up-to-date overview of ML approaches used in clinical OA research and will help to enhance its application in this field.

AIM To assess the impact of pre-specified patient characteristics on efficacy and safety of subcutaneous tanezumab in patients with osteoarthritis (OA). METHODS Data were pooled from two (efficacy; N = 1545) or three (safety; N = 1754) phase 3 placebo-controlled trials. Change from baseline to week 16 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function and patient global assessment of OA (PGA-OA) scores was compared between tanezumab (2.5 and 5 mg) and placebo groups via analysis of covariance. Treatment-emergent adverse events (TEAEs) were summarised descriptively. Analyses were done in patient subgroups (men or women; age

OBJECTIVE: Develop a generic trans-disciplinary, skills-based capability framework for health professionals providing care for people with OA.DESIGN: e-Delphi survey. An international inter-professional Delphi Panel (researchers; clinicians; consumer representatives) considered a draft framework (adapted from elsewhere) of 131 specific capabilities mapped to 14 broader capability areas across four domains (A: person-centred approaches; B: assessment, investigation and diagnosis; C: management, interventions and prevention; D: service and professional development). Over three rounds, the Panel rated their agreement (Likert or numerical rating scales) on whether each specific capability in Domains B and C was essential (core) for all health professionals when providing care for all people with OA. Those achieving consensus (≥80% of Panel) rating of ≥ seven out of ten (Round 3) were retained. Generic domains (A and D) were included in the final framework and amended based on Panel comments.RESULTS: 173 people from 31 countries, spanning 18 disciplines and including 26 consumer representatives, participated. The final framework comprised 70 specific capabilities across 13 broad areas i) communication; ii) person-centred care; iii) history-taking; iv) physical assessment; v) investigations and diagnosis; vi) interventions and care planning; vii) prevention and lifestyle interventions; viii) self-management and behaviour change; ix) rehabilitative interventions; x) pharmacotherapy; xi) surgical interventions; xii) referrals and collaborative working; and xiii) evidence-based practice and service development).CONCLUSION: Experts agree that health professionals require an array of skills in person-centred approaches; assessment, investigation and diagnosis; management, interventions and prevention; and service and professional development to provide optimal care for people with OA.

Objective: To assess the efficacy and safety of the anti–interleukin‐1α/β (anti–IL‐1α/β) dual variable domain immunoglobulin lutikizumab (ABT‐981) in patients with knee osteoarthritis (OA) and evidence of synovitis. Methods: Patients (n = 350; 347 analyzed) with Kellgren/Lawrence grade 2–3 knee OA and synovitis (determined by magnetic resonance imaging [MRI] or ultrasound) were randomized to receive placebo or lutikizumab 25, 100, or 200 mg subcutaneously every 2 weeks for 50 weeks. The coprimary end points were change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at week 16 and change from baseline in MRI‐assessed synovitis at week 26. Results: The WOMAC pain score at week 16 had improved significantly versus placebo with lutikizumab 100 mg (P = 0.050) but not with the 25 mg or 200 mg doses. Beyond week 16, the WOMAC pain score was reduced in all groups but was not significantly different between lutikizumab‐treated and placebo‐treated patients. Changes from baseline in MRI‐assessed synovitis at week 26 and other key symptom‐ and most structure‐related end points at weeks 26 and 52 were not significantly different between the lutikizumab and placebo groups. Injection site reactions, neutropenia, and discontinuations due to neutropenia were more frequent with lutikizumab versus placebo. Reductions in neutrophil and high‐sensitivity C‐reactive protein levels plateaued with lutikizumab 100 mg, with further reductions not observed with the 200 mg dose. Immunogenic response to lutikizumab did not meaningfully affect systemic lutikizumab concentrations. Conclusion: The limited improvement in the WOMAC pain score and the lack of synovitis improvement with lutikizumab, together with published results from trials of other IL‐1 inhibitors, suggest that IL‐1 inhibition is not an effective analgesic/antiinflammatory therapy in most patients with knee OA and associated synovitis.

Objectives To assess underlying domains measured by GaitSmartTMparameters and whether these are additional to established OA markers including patient reported outcome measures (PROMs) and radiographic parameters, and to evaluate if GaitSmart analysis is related to the presence and severity of radiographic knee OA. Methods GaitSmart analysis was performed during baseline visits of participants of the APPROACH cohort (n = 297). Principal component analyses (PCA) were performed to explore structure in relationships between GaitSmart parameters alone and in addition to radiographic parameters and PROMs. Logistic and linear regression analyses were performed to analyse the relationship of GaitSmart with the presence (Kellgren and Lawrence grade ≥2 in at least one knee) and severity of radiographic OA (ROA). Results Two hundred and eighty-four successful GaitSmart analyses were performed. The PCA identified five underlying GaitSmart domains. Radiographic parameters and PROMs formed additional domains indicating that GaitSmart largely measures separate concepts. Several GaitSmart domains were related to the presence of ROA as well as the severity of joint damage in addition to demographics and PROMs with an area under the receiver operating characteristic curve of 0.724 and explained variances (adjusted R2) of 0.107, 0.132 and 0.147 for minimum joint space width, osteophyte area and mean subchondral bone density, respectively. Conclusions GaitSmart analysis provides additional information over established OA outcomes. GaitSmart parameters are also associated with the presence of ROA and extent of radiographic severity over demographics and PROMS. These results indicate that GaitsmartTM may be an additional outcome measure for the evaluation of OA.

Objective: Despite its prevalence, there are few worldwide hand osteoarthritis (HOA) cohorts. The main objective of DIGItal COhort Design (DIGICOD) cohort is to investigate prognostic clinical, biological, genetic and imaging factors of clinical worsening after 6 years follow-up.Methods: DIGICOD is a hospital-based prospective cohort including patients > 35 years-old with symptomatic HOA fulfilling: (i) ACR criteria for HOA with > 2 symptomatic joints among proximal/distal interphalangeal joints or 1st interphalangeal joint with Kellgren-Lawrence (KL) > 2; or (ii) symptomatic thumb base OA with KL > 2. Main exclusion criteria were inflammatory arthritis and crystal arthropathies. Annual clinical evaluations were scheduled with imaging (X-rays of the hands and of other OA symptomatic joints) and biological sampling every 3 years. Hand radiographs are scored using KL and anatomical Verbruggen-Veys scores. Follow-up visits are ongoing. Cohort methodology and baseline characteristics are presented.Results: Between April 2013 and June 2017, from the 436 HOA included patients, 426 have been analysed of whom 357 (84%) are women. Mean age +/- standard deviation was 66.7 +/- 7.3 years and mean disease duration was 12.6 +/- 9.6 years. Metabolic syndrome affected 151 (36.5%) patients. Mean Visual Analog Scale (VAS) hand pain (0-100 mm) was 44.4 +/- 26.7 mm at activity. Mean FIHOA (0-100) was 19.9 + 18.6. Elevated serum CRP level (>= 5 mg/L) involved 10% patients. Mean KL score (0-128) was 46.7 +/- 18 and the mean number ofjoint with KL >= 2 was 15.1 +/- 6.3. Erosive HOA (defined as >= 1 Erosive or Remodeling phase joint according to Verbruggen-Veys score) involved 195/426 (45.8%) patients and the median number (interquartile range) of erosive joints in erosive patients was 3.0 (1.0-5.0).Conclusion: DIGICOD is a unique prospective HOA cohort with a long-term 6 years standardized assessment and has included severe radiologically HOA patients with a high prevalence of erosive disease. 2021 Societe francaise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.

ObjectiveTo summarise the evidence on intra-articular therapies (IAT) to inform the 2020 EULAR recommendations.MethodsAn overview of systematic reviews (SR) including randomised-controlled trials (RCTs) of IAT in adults with arthropathies was performed up to July 2020. Pain, function, and frequency of adverse events were the main efficacy and safety outcomes, respectively. Quality was assessed with the A MeaSurement Tool to Assess Systematic Reviews (AMSTAR)-2 tool.ResultsOf 184 references identified, 16 met the inclusion criteria, and a search of their reference lists identified 16 additional SRs. After quality assessment, 29 were finally included. Of these, 18 focused on knee osteoarthritis (KOA), 6 on hip osteoarthritis (HOA), 3 on shoulder capsulitis (SC), and 3 on rheumatoid arthritis. Overall, hyaluronic acid showed a small effect on pain and function in KOA but not in HOA or shoulder capsulitis. Intra-articular glucocorticoids showed a small effect in pain and function in KOA and function in HOA and SC. Platelet-rich plasma showed benefit in pain and function in KOA but not in HOA. Mesenchymal stem cells behaved similarly. Most SR results were of moderate quality and RCTs included often presented a high risk of bias, mainly due to inadequate blinding and heterogeneous results. All interventions were well tolerated with no clear safety differences.ConclusionsThis overview underlines that most IAT currently used in KOA, HOA, and SC exert small effects and are well tolerated. However, no firm conclusions can be drawn for inflammatory arthritis due to the limited data found.

Objective.To investigate the metabolic syndrome (MetS) association with radiographic and symptomatic hand osteoarthritis (HOA).Methods.Using 1:2 propensity score matching for relevant confounders, we included 2509 participants (896 MetS positive and 1613 MetS negative) from the Osteoarthritis Initiative dataset. MetS and its components, according to the International Diabetes Federation criteria, were extracted from baseline data, and included hypertension, abdominal obesity, dyslipidemia, and diabetes. We scored distinct hand joints based on the modified Kellgren-Lawrence (mKL) grade of baseline radiographs, with HOA defined as mKL ≥ 2. In the cross-sectional analysis, we investigated the association between MetS and its components with radiographic HOA and the presence of nodal and erosive HOA phenotypes using regression models. In the longitudinal analysis, we performed Cox regression analysis for hand pain incidence in follow-up visits.Results.MetS was associated with higher odds of radiographic HOA, including the number of joints with OA (OR 1.32, 95% CI 1.08–1.62), the sum of joints mKLs (OR 2.42, 95% CI 1.24–4.71), mainly in distal interphalangeal joints (DIPs) and proximal interphalangeal joints (PIPs; OR 1.52, 95% CI 1.08–2.14 and OR 1.38, 95% CI 1.09–1.75, respectively), but not metacarpophalangeal (MCP) and first carpometacarpal (CMC1) joints. Hand pain incidence during follow-up was higher with MetS presence (HR 1.25, 95% CI 1.07–1.47). The erosive HOA phenotype and joints’ nodal involvement were more frequent with MetS (OR 1.40, 95% CI 1.01–1.97 and OR 1.28, 95% CI 1.02–1.60, respectively).Conclusion.MetS, a potentially modifiable risk factor, is associated with radiographic DIP and PIP OA and longitudinal hand pain incidence while sparing MCPs and CMC1s. Nodal and erosive HOA phenotypes are associated with MetS, suggestive of possible distinct pathophysiology.

Vitamin K is best known for its role in blood coagulation. The reduced form of vitamin K is a necessary cofactor for the γ-carboxylase enzyme that converts specific glutamic acid residues to γ-carboxyglutamic acid (Gla) in the coagulation factors II, XII, IX, X and protein C and protein S.1 Proteins containing one or more Gla residues are often referred to as vitamin K-dependent proteins. The presence of calcium-binding Gla residues is critical to the structure and function of the vitamin K-dependent coagulation proteins. The anticoagulant drugs warfarin and acenocoumarol interfere with the reduction of vitamin K to its active form by inhibiting vitamin K epoxide reductase complex 1 (VKORC1) and so are known as vitamin K antagonists (VKAs).1 These drugs are widely used clinically to treat patients with blood clots or at high risk of blood clots, although newer anticoagulants are available that do not act by inhibiting vitamin K function. These are often referred to as direct oral anticoagulants (DOACs) or non-vitamin K oral anticoagulants (NOACs). The vitamin K-dependent coagulation proteins are produced primarily in the liver and function within the systemic circulation and vasculature. However, there are a number of vitamin K-dependent proteins not involved in blood coagulation, including several found in joint tissues.2–5 The latter include matrix Gla protein (MGP), Gla-rich protein (GRP) and growth arrest specific gene 6 (Gas6) found in cartilage, the bone proteins bone Gla protein (osteocalcin) and transforming growth factor β (TGFβ)-induced protein, and periostin found in cartilage and the periosteum.5–10 Periostin and TGFβ-induced protein may not be γ-carboxylated in all tissues,11 and their γ-carboxylation status has not been determined in the joint. Although the precise function of the vitamin K-dependent proteins in the joint is not known, MGP and GRP have been shown to inhibit mineralisation, Gas6 …

Objective: To determine the prevalence, distribution and characteristics associated with radiographic metacarpophalangeal (MCP) osteoarthritis (OA). Methods: This is a cross‐sectional study of baseline data from the DIGItal Cohort Osteoarthritis Design, a French monocentric cohort including patients with symptomatic hand OA (HOA). We evaluated the prevalence of radiographic MCP OA defined as ≥2 MCP joints with a Kellgren and Lawrence score ≥2. We compared the prevalence of MCP OA in the dominant and non‐dominant hands. Associations between radiographic MCP OA and patient characteristics were studied using univariable and multivariable logistic regression. Results: Radiographic MCP OA was present in 138 of the 425 patients (32.5%) but was not severe. Patients with MCP OA had a mean age of 69.2±6.9 years, a BMI of 25±4.2 kg/m2, and 86.2% were women. MCP OA was more frequent in the dominant hand and predominated at the 1st and 2nd MCP joints. In the multivariable analysis, MCP OA was associated with older age (OR 1.05, 95%CI [1.01,1.10] for each year), manual occupation (OR 3.74, 95%CI [1.21,11.54]), scaphotrapezial OA (OR 2.18, 95%CI [1.27,3.72]), and a high number of proximal interphalangeal joints with radiographic OA. MCP OA was not associated with metabolic syndrome or HOA symptoms. Conclusion: In this cross‐sectional study using a hospital‐based HOA cohort, radiographic MCP OA was frequent and associated with structural HOA features rather than with symptom severity. Our results suggest that the involvement of MCP joints in HOA is predominantly related to mechanical rather than systemic factors in this population.

International audience; The role of the gutl microbiome within a "gut-joint" axis is increasingly studied in osteoarthritis. The gut microbiome, particularly via its role in low-grade systemic inflammation, could be involved in joint destruction and osteoarthritic pain. Its mechanisms of action in osteoarthritis remain complex, with on the one hand a direct action of intestinal dysbiosis on osteoarthritis involving systemic inflammation, and on the other hand an indirect effect via the promotion of metabolic syndrome and obesity. The published works in mice have mainly focused on the role of the intestinal microbiota in joint destruction in metabolic models of osteoarthritis. In humans, works have focused on indirect markers of the gut microbiota, such as lipopolysaccharide, or metabolites, such as tryptophan-and related metabolites. Also, intestinal dysbiosis could be one of the explanatory factors of osteoarthritic pain. A better understanding of the role of the gut microbiom in osteoarthritis in humans and from experimental models could lead to new therapeutic insights in osteoarthritis.

ObjectivesTo describe the relations between baseline clinical characteristics of the Applied Public-Private Research enabling OsteoArthritis Clinical Headway (IMI-APPROACH) participants and their predicted probabilities for knee osteoarthritis (OA) structural (S) progression and/or pain (P) progression.MethodsBaseline clinical characteristics of the IMI-APPROACH participants were used for this study. Radiographs were evaluated according to Kellgren and Lawrence (K&L grade) and Knee Image Digital Analysis. Knee Injury and Osteoarthritis Outcome Score (KOOS) and Numeric Rating Scale (NRS) were used to evaluate pain. Predicted progression scores for each individual were determined using machine learning models. Pearson correlation coefficients were used to evaluate correlations between scores for predicted progression and baseline characteristics. T-tests and χ2 tests were used to evaluate differences between participants with high versus low progression scores.ResultsParticipants with high S progressions score were found to have statistically significantly less structural damage compared with participants with low S progression scores (minimum Joint Space Width, minJSW 3.56 mm vs 1.63 mm; pConclusionsThe baseline minJSW of the IMI-APPROACH participants contradicts the idea that the (predicted) course of knee OA follows a pattern of inertia, where patients who have progressed previously are more likely to display further progression. In contrast, for pain progressors the pattern of inertia seems valid, since participants with high P score already have more pain at baseline compared with participants with a low P score.

International audience; Osteoarthritis (OA) is a whole-joint disease characterized by subchondral bone perfusion abnormalities and neovascular invasion into the synovium and articular cartilage. In addition to local vascular disturbance, mounting evidence suggests a pivotal role for systemic vascular pathology in the aetiology of OA. This Review outlines the current understanding of the close relationship between high blood pressure (hypertension) and OA at the crossroads of epidemiology and molecular biology. As one of the most common comorbidities in patients with OA, hypertension can disrupt joint homeostasis both biophysically and biochemically. High blood pressure can increase intraosseous pressure and cause hypoxia, which in turn triggers subchondral bone and osteochondral junction remodelling. Furthermore, systemic activation of the renin-angiotensin and endothelin systems can affect the Wnt-β-catenin signalling pathway locally to govern joint disease. The intimate relationship between hypertension and OA indicates that endothelium-targeted strategies, including re-purposed FDA-approved antihypertensive drugs, could be useful in the treatment of OA.

International audience; Purpose of review: Epidemiologic studies reveal that the link between obesity and osteoarthritis cannot be uniquely explained by overweight-associated mechanical overload. For this reason, much attention focuses on the endocrine activity of adipose tissues. In addition to the systemic role of visceral and subcutaneous adipose tissues, many arguments highlight the involvement of local adipose tissues in osteoarthritis.Recent findings: Alteration in MRI signal intensity of the infrapatellar fat pad may predict both accelerated knee osteoarthritis and joint replacement. In this context, recent studies show that mesenchymal stromal cells could play a pivotal role in the pathological remodelling of intra-articular adipose tissues (IAATs) in osteoarthritis. In parallel, recent findings underline bone marrow adipose tissue as a major player in the control of the bone microenvironment, suggesting its possible role in osteoarthritis.Summary: The recent description of adipose tissues of various phenotypes within an osteoarthritic joint allows us to evoke their direct involvement in the initiation and progression of the osteoarthritic process. We can expect in the near future the discovery of novel molecules targeting these tissues.

[Abstract] Background: To evaluate if early improvements in pain and function with subcuta-neous tanezumab are meaningful and sustained over 24 weeks. Methods: Patients with moderate- to- severe osteoarthritis (hip or knee) in Europe and Japan were randomized to placebo, tanezumab 2.5 mg or tanezumab 5 mg (baseline, Week 8 and Week 16). Outcomes included: average daily index joint pain score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscales, rescue medication use, WOMAC responders (within- patient ≥30% reduction in WOMAC Pain or Physical Function), Outcome Measures in Rheumatology- Osteoarthritis Research Society International (OMERACT- OARSI) responders (within- patient) and Patient- reported Treatment Impact Assessment- Modified questionnaire. Results: Patients received placebo (n = 282), tanezumab 2.5 mg (n = 283) or tanezumab 5 mg (n = 284). Changes from baseline in average daily index joint pain (within the first week) and WOMAC subscales (Week 2 through Week 24) were greater for each tanezumab group versus placebo (least squares [LS] mean, unadjusted p ≤ .05). Rescue medication use (days/week) was lower for each tan-ezumab group versus placebo from Week 2 through Week 12 (LS mean, unad-justed p ≤ .05) but not at Week 16 or 24. A higher proportion of each tanezumab group than placebo achieved ≥30% reduction from baseline in WOMAC Pain or Physical Function, or OMERACT- OARSI response (Week 2 through Week 24, unadjusted p ≤ .05), or were satisfied with treatment at Week 24 (unadjusted p ≤ .05). Conclusions: Subcutaneous tanezumab, compared with placebo, reduced pain within the first week, and pain and function were improved throughout 24 weeks. The propor-tions of responders and patients satisfied were higher with tanezumab than placebo. ClinicalTrials.gov:NCT02709486. Significance: This exploratory analysis of data from a placebo- controlled, Phase 3 study of patients with moderate- to- severe osteoarthritis of the hip or knee for whom standard analgesics were not effective or could not be taken, found that onset of efficacy of subcutaneous tanezumab was within the first week, and efficacy was maintained through the 24- week treatment period. Tanezumab was effective in those patients with the most radiologically severe osteoarthritis.

Summary Objective TGFβ is a key player in cartilage homeostasis and OA pathology. However, few data are available on the role of TGFβ signalling in the different OA phenotypes. Here, we analysed the TGFβ pathway by transcriptomic analysis in six mouse models of OA. Method We have brought together seven expert laboratories in OA pathophysiology and, used inter-laboratories standard operating procedures and quality controls to increase experimental reproducibility and decrease bias. As none of the available OA models covers the complexity and heterogeneity of the human disease, we used six different murine models of knee OA: from post-traumatic/mechanical models (meniscectomy (MNX), MNX and hypergravity (HG-MNX), MNX and high fat diet (HF-MNX), MNX and seipin knock-out (SP-MNX)) to aging-related OA and inflammatory OA (collagenase-induced OA (CIOA)). Four controls (MNX-sham, young, SP-sham, CIOA-sham) were added. OsteoArthritis Research Society International (OARSI)-based scoring of femoral condyles and ribonucleic acid (RNA) extraction from tibial plateau samples were done by single operators as well as the transcriptomic analysis of the TGFβ family pathway by Custom TaqMan® Array Microfluidic Cards. Results The transcriptomic analysis revealed specific gene signatures in each of the six models; however, no gene was deregulated in all six OA models. Of interest, we found that the combinatorial Gdf5-Cd36-Ltbp4 signature might discriminate distinct subgroups of OA: Cd36 upregulation is a hallmark of MNX-related OA while Gdf5 and Ltbp4 upregulation is related to MNX-induced OA and CIOA. Conclusion These findings stress the OA animal model heterogeneity and the need of caution when extrapolating results from one model to another.

To establish recommendations for pharmacological treatment of knee osteoarthritis specific to France.On behalf of the French Society of Rheumatology (SFR), a bibliography group analyzed the literature on the efficacy and safety of each pharmacological treatment for knee osteoarthritis. This group joined a multidisciplinary working group to draw up recommendations. Strength of recommendation and quality of evidence level were assigned to each recommendation. A review committee gave its level of agreement.Five general principles were established: 1) need to combine pharmacological and non-pharmacological treatments, 2) personalization of treatment, 3) symptomatic and/or functional aim of pharmacological treatments, 4) need to regularly re-assess the treatments and 5) discussion about arthroplasty if medical treatment fails. Six recommendations involved oral treatments: 1) paracetamol should not necessarily be prescribed systematically and/or continuously, 2) NSAIDs, possibly as first-line, 3) weak opioids, 4) strong opioids, 5) symptomatic slow-acting drugs of osteoarthritis, and 6) duloxetine (off-label use). Two recommendations involved topical agents (NSAIDs and capsaicin1%). Three recommendations involved intra-articular treatments: corticosteroid or hyaluronic acid injections that can be proposed to patients. The experts did not draw a conclusion about the benefits of platelet-rich plasma injections.These are the first recommendations of the SFR on the pharmacological treatment of knee osteoarthritis.

OBJECTIVE The non-neuronal cholinergic system represents non-neuronal cells that have the biochemical machinery to synthetize de novo and/or respond to acetylcholine (ACh). We undertook this study to investigate this biochemical machinery in chondrocytes and its involvement in osteoarthritis (OA). METHODS Expression of the biochemical machinery for ACh metabolism and nicotinic ACh receptors (nAChR), particularly α7-nAChR, in human OA and murine chondrocytes was determined by polymerase chain reaction and ligand-binding. We investigated the messenger RNA expression of the human duplicate α7-nACh subunit, called CHRFAM7A, which is responsible for truncated α7-nAChR. We assessed the effect of nAChR on chondrocytes activated by interleukin-1β (IL-1β) and the involvement of α7-nAChR using chondrocytes from wild-type (WT) and α7-deficient Chrna7-/- mice. The role of α7-nAChR in OA was explored after medial meniscectomy in WT and Chrna7-/- mice. RESULTS Human and murine chondrocytes express the biochemical partners of the non-neuronal cholinergic system and a functional α7-nAChR at their cell surface (n = 5 experiments with 5 samples each). The expression of CHRFAM7A in human OA chondrocytes (n = 23 samples) correlated positively with matrix metalloproteinase 3 (MMP-3) (r = 0.38, P < 0.05) and MMP-13 (r = 0.48, P < 0.05) expression. Nicotine decreased the IL-1β-induced IL-6 and MMP expression, in a dose-dependent manner, in WT chondrocytes but not in Chrna7-/- chondrocytes. Chrna7-/- mice that underwent meniscectomy (n = 7) displayed more severe OA cartilage damage (mean ± SD Osteoarthritis Research Society International [OARSI] score 4.46 ± 1.09) compared to WT mice that underwent meniscectomy (n = 9) (mean ± SD OARSI score 3.05 ± 0.9; P < 0.05). CONCLUSION The non-neuronal cholinergic system is functionally expressed in chondrocytes. Stimulation of nAChR induces antiinflammatory and anticatabolic activity through α7-nAChR, but the anticatabolic activity may be mitigated by truncated α7-nAChR in human chondrocytes. In vivo experiments strongly suggest that α7-nAChR has a protective role in OA.

International audience; In this opinion article, we would like to draw attention to the fact that COVID-19 has a significant impact not only on immune-mediated arthritis but also on osteoarthritis (OA), the most common rheumatic disease. We suggest herein strategies for pain relief and symptom prevention in patients with OA during COVID-19 pandemic.

Background Considering the role of metabolic diseases in osteoarthritis (OA), we investigated whether biomarkers of adipose tissue dysfunction could be associated with OA-related pain. Design We cross-sectionally analyzed patients with knee and/or hip OA at inclusion in the KHOALA cohort. We used visual analogic scale (VAS) for pain, the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and Osteoarthritis Knee and Hip Quality of Life (OAKHQOL) pain subscores. At inclusion, we measured ultra-sensitive CRP (usCRP), leptin and adiponectin for calculation of leptin:adiponectin ratio (LAR), a marker of adipose tissue dysfunction associated with central adiposity, high-molecular-weight adiponectin, visfatin and apolipoproteins. Univariate and multivariable analyses using stepwise linear regression models were performed to search for correlation between pain assessments and these biomarkers, with systematic adjustment on age. Results In 596 women with hip and/or knee OA, multivariable analyses indicated that higher pain intensity was associated with higher LAR (VAS pain: β=0.49; p = 0.0001, OAKHQOL pain: β=-0.46; p = 0.0002, WOMAC pain: β=0.30; p = 0.001) in the whole group as well as in hip or knee OA patients considered separately. Pain intensity correlated also with usCRP level (VAS pain: β= 0.27; p = 0.02, OAKHQOL pain: β =-0.30; p = 0.01) and Kellgren-Lawrence score. In 267 men, no correlation between biomarkers and pain was found. Conclusion Serum LAR and usCRP level are associated with pain level, independently of radiographic structural severity in women with hip and/or knee OA, emphasizing the role of adipose tissue dysfunction and of meta-inflammation in pain experience in the female population.

The cholinergic system plays a major anti-inflammatory role in many diseases through acetylcholine (Ach) release after vagus nerve stimulation. Osteoarthritis (OA) is associated with local low-grade inflammation, but the regulatory mechanisms are unclear. Local Ach release could have anti-inflammatory activity since articular cells express Ach receptors involved in inflammatory responses. Using the 3DISCO clearing protocol that allows whole-sample 3-dimensional (3D) analysis, we cleared human OA cartilage-subchondral bone samples to search for cholinergic nerve fibres able to produce Ach locally. We analysed 3 plugs of knee cartilage and subchondral bone from 3 OA patients undergoing arthroplasty. We found no nerves in the superficial and intermediate articular cartilage layers, as evidenced by the lack of Peripherin staining (a peripheral nerves marker). Conversely, peripheral nerves were found in the deepest layer of cartilage and in subchondral bone. Some nerves in the subchondral bone samples were cholinergic because they coexpressed peripherin and choline acetyltransferase (ChAT), a specific marker of cholinergic nerves. However, no cholinergic nerves were found in the cartilage layers. It is therefore feasible to clear human bone to perform 3D immunofluorescence. Human OA subchondral bone is innervated by cholinergic fibres, which may regulate local inflammation through local Ach release.

Background Osteoarthritis (OA) causes pain, disability and impaired quality of life. Tanezumab, a monoclonal antibody against nerve growth factor, is in development for the management of OA pain. Two randomised, placebo-controlled studies with a primary aim of assessing the efficacy and safety of subcutaneously administered tanezumab were recently completed as part of a phase 3 OA programme, and the data reported, separately. Here we report pooled analyses of secondary efficacy outcomes from these two trials: Outcome Measures in Rheumatology - Osteoarthritis Research Society International (OMERACT-OARSI) treatment response and EuroQol 5 Dimension (EQ-5D-5L) questionnaire. Methods Both studies enrolled patients with moderate-to-severe OA of the hip or knee, for whom standard care was inadequate or unsuitable. In study one (NCT02709486) with primary endpoint at Week 24, patients received three doses of placebo, tanezumab 2.5 mg or tanezumab 5 mg (at baseline/Week 8/Week 16). Study two was a dose-titration study (NCT02697773) with primary endpoint at Week 16, where patients received two doses of: placebo at baseline/Week 8 (pooled with study one placebo group), tanezumab 2.5 mg at baseline/Week 8 (pooled with study one tanezumab 2.5 mg group) or tanezumab 2.5 mg at baseline/tanezumab 5 mg at Week 8 (pooled with study one tanezumab 5 mg group). The current analysis assessed differences between pooled groups in OMERACT-OARSI treatment response, and EQ-5D-5L questionnaire responses and overall utility scores, at Week 16. Results A total of 1,545 patients were evaluated. At Week 16 in the pooled analyses, more patients in the tanezumab 2.5 mg (76.0%, 390/513) or tanezumab 5 mg (77.4%, 400/517) groups than the placebo group (64.7%, 332/513) met the criteria for OMERACT-OARSI response (each p < 0.0001 versus placebo). Patients in the pooled placebo, tanezumab 2.5 mg and 5 mg groups, respectively, recorded their baseline pain/discomfort (EQ-5D-5L) as none (1.8%, 1.0%, 0.6%), slight (7.6%, 9.7%, 8.9%), moderate (52.6%, 50.7%, 50.7%), severe (35.1%, 36.3%, 36.4%) or extreme (2.9%, 2.3%, 3.5%). At Week 16, patients recorded their pain/discomfort as none (12.8%, 15.4%, 15.8%), slight (37.3%, 44.3%, 44.8%), moderate (40.6%, 33.9%, 32.0%), severe (8.8%, 6.4%, 6.4%) or extreme (0.4%, 0.0%, 1.0%). Improvements in mobility, self-care, usual activities and anxiety/depression were also seen. At Week 16, the change from baseline in EQ-5D-5L utility score was greater for the pooled tanezumab 2.5 mg group (difference in least squares means [95% confidence interval], 0.03 [0.01, 0.05], p = 0.0083) or tanezumab 5 mg group (0.04 [0.01, 0.06], p = 0.0015) compared with placebo. Conclusion Together, pooled analyses from these studies show that significant improvements in the composite measure OMERACT-OARSI response are accompanied by significant improvements in overall health status as assessed by the EQ-5D-5L utility score at Week 16 for tanezumab-treated patients compared with placebo. These studies were sponsored by Pfizer and Eli Lilly and Company. Disclosures D. Walsh: Consultancies; consulting fees (non-personal, pecuniary interest) from Pfizer, Lilly, GlaxoSmithKline, AbbVie, Medscape Education, Love Productions. T.J. Schnitzer: Consultancies; TJS has received consulting fees from Pfizer, Lilly, AbbVie, Aptinyx, Genzyme, Regeneron, and Vertex. Grants/research support; TJS has engaged in clinical research for AbbVie, Grünenthal, and Radius. F. Berenbaum: Consultancies; Consulting fees/remuneration from AbbVie, Merck, Regulaxis, 4P Pharma, Bone Therapeutics, Galapagos, Peptinov, Expanscience, Flexion, Janssen, MerckSerono, Novartis, Roche, Gilead, Sanofi, GlaxoSm. S. Howland: Corporate appointments; SH is an employee of Pfizer Ltd. Shareholder/stock ownership; SH holds Pfizer stock options. S. Wilhelm: Corporate appointments; SW is a Lilly employee. Shareholder/stock ownership; SW holds Lilly stock and/or stock options. R. Junor: Corporate appointments; RJ is an employee of Pfizer Ltd. Shareholder/stock ownership; RJ holds Pfizer stock and/or stock options.

Over the past year many studies and clinical trials have been published in the osteoarthritis (OA) field. This review is based on systematic literature review covering the period May 1st, 2018 to April 19th , 2019; the final selection of articles was subjective. Specifically those articles considered to be presenting novel insights and of potential importance for clinical practice, are discussed.Further evidence has emerged that OA is a serious disease with increasing impact worldwide. Our understanding of development of pain in OA has increased. Detailed studies investigating widely used pharmacological treatments have shown the benefits to be limited, whereas the risks seem higher than expected, suggesting further studies and reconsideration of currently used guidelines. Promising new pharmacological treatments have been developed and published, however subsequent studies are warranted. While waiting for new treatment modalities to appear joint replacement is an effective alternative; new data have become available on how long they might last. (C) 2020 The Authors. Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International.

Introduction Patients with erosive hand osteoarthritis (EHOA) experience pain and inflammation, two features that can be targeted by vagus nerve stimulation using electrical auricular transcutaneous vagus nerve stimulation (tVNS). A pilot study demonstrated the feasibility of the procedure, so we designed a randomised sham-controlled trial to determine the safety and efficacy of tVNS in EHOA. Methods and analysis ESTIVAL Study (Essai randomisé comparant la STImulation auriculaire transcutanée du nerf Vague versus sham stimulation dans l’Arthrose DigitaLe Érosive symptomatique et inflammatoire) is a superiority, randomised, double-blind sham-controlled trial comparing two parallel arms: active and sham tVNSs in a 1:1 ratio. Patients with symptomatic EHOA (score ≥40/100 mm on a visual analogue scale (VAS) for pain of 0–100 mm) and inflammatory EHOA (≥1 clinical and ultrasonography-determined interphalangeal synovitis) are included in 18 hospital centres (17 rheumatology and 1 rehabilitation departments) in France. Active and sham tVNSs use an auricular electrode connected to the Vagustim device, with no electric current delivered in the sham group. Patients undergo stimulation for 20 min/day for 12 weeks. The follow-up visits take place at weeks 4, 8 and 12. The enrolment duration is 2 years and started in April 2021; 156 patients are scheduled to be included. The primary outcome is the difference in self-reported hand pain in the previous 48 hours measured on a VAS of 0–100 mm between baseline and week 12. Secondary outcomes include other pain outcomes, function, quality of life, serum biomarker levels, compliance and tolerance. For a subset of patients, MRI of the hand is performed at baseline and week 12 to compare the change in Outcome Measures in Rheumatology/Hand Osteoarthritis MRI Scoring System subscores. The primary analysis will be performed at the end of the study according to the intent-to-treat principle. Ethics and dissemination Ethics approval was obtained from the institutional review board (Comité de Protection des Personnes, 2020-A02213-36). All participants will be required to provide written informed consent. The findings will be published in peer-reviewed journals. Trial registration number NCT04520516; Pre-results. Protocol version and number V.2 of 11 March 2021.

ObjectiveTo assess the efficacy, safety, pharmacokinetics and pharmacodynamics of the anti-interleukin (IL)-1α/β dual variable domain immunoglobulin lutikizumab (ABT-981) in erosive hand osteoarthritis (HOA).MethodsPatients with ≥1 erosive and ≥3 tender and/or swollen hand joints were randomised to placebo or lutikizumab 200 mg subcutaneously every 2 weeks for 24 weeks. The primary endpoint was change in Australian/Canadian Osteoarthritis Hand Index (AUSCAN) pain subdomain score from baseline to 16 weeks. At baseline and week 26, subjects had bilateral hand radiographs and MRI of the hand with the greatest number of baseline tender and/or swollen joints. Continuous endpoints were assessed using analysis of covariance models, with treatment and country as main factors and baseline measurements as covariates.ResultsOf 132 randomised subjects, 1 received no study drug and 110 completed the study (placebo, 61/67 (91%); lutikizumab, 49/64 (77%)). AUSCAN pain was not different among subjects treated with lutikizumab versus placebo at week 16 (least squares mean difference, 1.5 (95% CI –1.9 to 5.0)). Other clinical and imaging endpoints were not different between lutikizumab and placebo. Lutikizumab significantly decreased serum high-sensitivity C reactive protein levels, IL-1α and IL-1β levels, and blood neutrophils. Lutikizumab pharmacokinetics were consistent with phase I studies and not affected by antidrug antibodies. Injection site reactions and neutropaenia were more common in the lutikizumab group; discontinuations because of adverse events occurred more frequently with lutikizumab (4/64) versus placebo (1/67).ConclusionDespite adequate blockade of IL-1, lutikizumab did not improve pain or imaging outcomes in erosive HOA compared with placebo.

International audience; The prevalence of osteoarthritis (OA) is rising for reasons that are not fully understood. In this Opinion article, we review the possibility that OA is an evolutionary mismatch disease, which is a disease more common today than in the past because genes inherited from previous generations are inadequately or imperfectly adapted to modern environmental conditions. We focus on four major environmental factors in OA pathogenesis that have become ubiquitous within the past half-century: obesity, metabolic syndrome, dietary changes and physical inactivity. Because a cure for OA does not yet exist, prevention strategies that target these modifiable environmental factors are needed to curb further increases in OA prevalence.

Background: Intra-articular corticosteroids relieve osteoarthritis pain, but rapid systemic absorption limits efficacy. FX006, a novel, microsphere-based, extended-release triamcinolone acetonide (TA) formulation, prolongs TA joint residence and reduces systemic exposure compared with standard TA crystalline suspension (TAcs). We assessed symptomatic benefits and safety of FX006 compared with saline-solution placebo and TAcs. Methods: In this Phase-3, multicenter, double-blinded, 24-week study, adults ≥40 years of age with knee osteoarthritis (Kellgren-Lawrence grade 2 or 3) and average-daily-pain (ADP)-intensity scores of ≥5 and ≤9 (0 to 10 numeric rating scale) were centrally randomized (1:1:1) to a single intra-articular injection of FX006 (32 mg), saline-solution placebo, or TAcs (40 mg). The primary end point was change from baseline to week 12 in weekly mean ADP-intensity scores for FX006 compared with saline-solution placebo. Secondary end points were area-under-effect (AUE) curves of the change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with saline-solution placebo, AUE curves of the change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with TAcs, change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with TAcs, and AUE curves of the change in weekly mean ADP-intensity scores from baseline to week 24 for FX006 compared with saline-solution placebo. Exploratory end points included week-12 changes in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Knee Injury and Osteoarthritis Outcome Score Quality of Life (KOOS-QOL) subscale scores for FX006 compared with saline-solution placebo and TAcs. Adverse events were elicited at each inpatient visit. Results: The primary end point was met. Among 484 treated patients (n = 161 for FX006, n = 162 for saline-solution placebo, and n = 161 for TAcs), FX006 provided significant week-12 improvement in ADP intensity compared with that observed for saline-solution placebo (least-squares mean change from baseline: −3.12 versus −2.14; p < 0.0001) indicating ∼50% improvement. FX006 afforded improvements over saline-solution placebo for all secondary and exploratory end points (p < 0.05). Improvements in osteoarthritis pain were not significant for FX006 compared with TAcs using the ADP-based secondary measures. Exploratory analyses of WOMAC-A, B, and C and KOOS-QOL subscales favored FX006 (p ≤ 0.05). Adverse events were generally mild, occurring at similar frequencies across treatments. Conclusions: FX006 provided significant, clinically meaningful pain reduction compared with saline-solution placebo at week 12 (primary end point). Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

International audience; Osteoarthritis (OA) is a whole joint disease characterized by an important remodeling of the osteochondral junction. It includes cartilage mineralization due to chondrocyte hypertrophic differentiation and bone sclerosis. Here, we investigated whether gremlin-1 (Grem-1) and its BMP partners could be involved in the remodeling events of the osteochondral junction in OA. We found that Grem-1, BMP-2, and BMP-4 immunostaining was detected in chondrocytes from the deep layer of cartilage and in subchondral bone of knee OA patients, and was positively correlated with cartilage damage. ELISA assays showed that bone released more Grem-1 and BMP-4 than cartilage, which released more BMP-2. In vitro experiments evidenced that compression stimulated the expression and the release of Grem-1 and BMP-4 by osteoblasts. Grem-1 was also overexpressed during the prehypertrophic to hypertrophic differentiation of murine articular chondrocytes. Recombinant Grem-1 stimulated Mmp-3 and Mmp-13 expression in murine chondrocytes and osteoblasts, whereas recombinant BMP-4 stimulated the expression of genes associated with angiogenesis (Angptl4 and osteoclastogenesis (Rankl and Ccl2). In conclusion, Grem-1 and BMP-4, whose expression at the osteochondral junction increased with OA progression, may favor the pathological remodeling of the osteochondral junction by inducing a catabolic and tissue remodeling program in hypertrophic chondrocytes and osteoblasts.