Osteoarthritis and Cartilage 28 (2020) S15eS19

Abstracts from Invited Speakers

I-1FROM GUT TO OA

M.J. Zuscik. Univ. of Colorado, Anschutz Med. Campus, Aurora, CO, USA

Purpose: As well all know, osteoarthritis (OA) is a disease of dia-rthrodial joints that leads to joint degeneration, inflammation, and pain.OA is the most prevalent disabling disease globally. Despite efforts todevelop a disease modifying treatment, the only accepted and availableclinical approaches involve palliation. While many factors contribute tothe development of OA, the gut microbiome has recently emerged as animportant pathogenic factor in OA initiation and progression, partic-ularly in the context of obesity. This presentationwill provide an up-to-date review of the literature regarding the link between the gutmicrobiome and OA.Literature and Data to be Discussed: Studies showing correlationsbetween serum levels of bacterial metabolites and joint degenerationwere the first links connecting a dysbiosis of the gut microbiome withOA. Further investigations have demonstrated that microbial com-munity shifts induced by antibiotics, a germ-free environment or highfat diet are important underlying factors in joint homeostasis and OA. Infact, key pro-inflammatory species have been linked to joint pain inhumans with knee OA. Data will also be presented that suggests theaction of ‘joint protective’ nutraceuticals may be via shifts in the gutmicrobiome. It follows that strategies to manipulate the microbiomehave demonstrated efficacy in mitigating joint degeneration in OA, andmay represent a new strategic approach to address disease modificationfor this disease.Summary: While role of the microbiome in OA is an area of intensestudy, no clear mechanism of action has been determined. Increasedunderstanding of how the two factors interact may provide mechanisticinsight into OA and lead to disease modifying treatments.

I-2WHAT RARE DISEASES CAN TELL US ABOUT OA

J.A. Gallagher. Univ. of Liverpool, Liverpool, United Kingdom

Purpose: Rare cartilage diseases are a neglected area of study inosteoarthritis (OA). This presentation puts forward the proposition thatmore emphasis on studying rare cartilage syndromes could lead toaccelerated progress in understanding OA and age-related jointdegeneration. OA is one of the major causes of disability globally, yetdespite the resources which have been channelled into research, thereare no current therapies for OA and only a limited number ofbiomarkers.Methods: Research on the extreme phenotypes observed in rare dis-eases can help elucidate the pathogeneses of more common disorders, aphenomenon recognised by William Harvey as long ago as the 17 th

century. Harvey wrote to a colleague “/ nor is there any better way toadvance the proper practice of medicine than to give our minds to thediscovery of the usual law of nature, by careful investigation of cases ofrarer forms of disease”. In monogenic disorders, the phenotypes areoften very severe and disease progress is rapidmaking it easy to identifypathological changes, both structural and biochemical. Several thera-pies for common diseases, including the blockbuster drugs statins and

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bisphosphonates, were discovered in part through the study of raresyndromes.Results: Rare disease research is making a significant contribution tounderstanding bone turnover and to the development of new ther-apeutic agents to regulate bone formation and bone resorption. Whilstthe potential impact on OA of studying rare cartilage syndromes hasbeen less explored, recent research has revealed new insights into OAdisease mechanisms. Analysis of rare mutations responsible for chon-drodysplasias has identified genes such as GDF5, which plays a key rolein skeletal development. Polymorphisms in this gene are associatedwith OA susceptibility. Mutation of the ANKH gene in chondrocalcinosishas highlighted the role that this gene plays in the physiological andpathological mineralisation of cartilage. The expression of ANKH, whichcodes for a pyrophosphate transporter is known to be dysregulated inOA. Investigation of the rare autosomal recessive disorder CACP hasrevealed the disease-causing mutation in the PRG4 gene which codesfor the secretedmucin-like proteoglycan, lubricin.Alkaptonuria (AKU) isan autosomal recessive disease of tyrosine metabolism that inevitablyleads to early onset, aggressive arthropathy. Joint destruction in AKU iscaused by the deposition of ochronotic pigment in cartilage, but thereare several parallels with the pathophysiology of OA. Studies on tissuesamples from patients with AKU, and from mouse models of the dis-ease, have revealed previously unrecognised microanatomical andbiochemical changes in joints which have been subsequently detectedin human OA. These include early changes in the integrity of collagenfibrils, the role of calcified cartilage in the initiation of OA, thinning andcracking of the subchondral plate and the formation of novel micro-anatomical structures including trabecular excrescences, templated byadipocytes, and high density mineralised protrusions (HDMPs). Allthese features are abundant and easily recognisable in the severephenotype of AKU but have subsequently been found in common OA,where they contribute to joint destruction.Conclusions: Studying rare cartilage diseases with extreme phenotypescan help elucidate pathophysiological mechanisms in OA.

I-3APPLICATIONS OF RAPID MRI, HOW TO IMPROVE PATIENT CARE

B.A. Hargreaves. Stanford Univ., Standord, CA, USA

Magnetic resonance imaging (MRI) is routinely used in Osteoarthritis(OA) assessment, both clinically and in research studies. Numerousdifferent MRI contrast mechanisms highlight abnormalities or changesover time, with increasing tendency toward quantitative techniquesand true 3D imaging. Scan protocols can include multiple contrasts,often resulting in exam protocols of 20-30 minutes for clinical imaging,and even longer for research studies, which can limit utilization orstudy sizes due to cost. Rapid MRI protocols are being explored usingonly a few scans, to offer exam times in just 5-10minutes, and includingboth knees. This has potential to rival X-ray imaging, as it can offercomprehensive joint information in a comparable time and perhaps at acomparable cost. Benefits include scanning many more subjects instudies, acquiring quantitative information in both knees in patients,and being able to scan at earlier stages of disease. Combined withadvances in data science, rapid quantitative MRI protocols could offermuch better understanding of the onset and progression of different OA

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phenotypes as well as the ability to offer quantitative endpoints for drugdevelopment and ultimately triage to different minimally invasive OAtreatments.

I-4MACHINE LEARNING AND ARTIFICIAL INTELLIGENCE

V. Pedoia. UCSF, San Francisco, CA, USA

In the past, there have been efforts to relate OA outcomes tomedical image features extracted from MRI and clinical measure-ments; however, these were limited by using either non-imagepredictors or manually extracted predictors. The application ofimaging biomarkers defined a priori limited the prediction abilityof the resulting models, and the time-consuming process ofextracting such predictors often restricted the sample size. Onetechnique that has shown promise in creating models that canpredict outcome and learn features directly from the data is deeplearning (DL). DL, especially convolutional neural networks (CNNs),has made strides in several domains as speech recognition, visualobject detection, classification, drug discovery and genomics. DLshines when afforded large datasets, as its automated featureextraction allows one to solve problems too complex for conven-tional approaches. CNNs are representation learning methodscharacterized by the usage of multiple, simple, but non-linear unitsto build several interconnected layers. Each layer aggregates theinformation at increasing levels of abstraction starting with simpleimage elements, as edges or contrast, to more complex andsemantic aggregations, uncovering latent patterns able to accom-plish pattern recognition tasks. Another advantage of DL is thatonce its training completed, by summarizing the data-driven rep-resentation of information, it offers the opportunity to inspectwhat it has learned, often revealing unsuspected relationships thatlead researchers to abetter understanding complex problems. DLcan then be used to predict future outcomes; by interpreting thefeatures learned, it is possible to discover new biomarkers over-looked by the classical analysis. The CNN framework allows astraightforward definition of classical classification and/or regres-sion problems. Few examples in OA imaging are tissue segmenta-tion, OA diagnosis from plain radiograph, detection of jointabnormality from MRI Additionally, we can build multi-modalintegrated frameworks by using biochemical and morphologicalfeatures extracted from MR imaging, demographics, family historyand genetic data simultaneously, to predict future outcomes anddisease trajectories. For a clinically feasible translation of thedeveloped models and to achieve the unmet challenge of a com-prehensive, quantitively, automatic and data-driven imaging eval-uation of the musculoskeletal system, efficient simultaneous dataacquisition and processing are necessary. In this workshop somebasics on the usage of deep learning to study OA will be coveredby reviewing the current state of the art on diagnostic and prog-nostic application of deep learning on OA. We will also cover someapplications of deep learning to MRI acceleration and automatedprocessing.

I-5PATIENT ORIENTED KNOWLEDGE TRANSLATION IN REHABILITATION

L.C. Li 1,2. 1Univ. of British Columbia, Vancouver, BC, Canada; 2ArthritisRes. Canada, Richmond, BC, Canada

Background: Billions of dollars have been invested globally in healthresearch, but the knowledge is unlikely to translate into health benefitsif it is not being used in clinical practice or by individuals to inform theiraction. For instance, there is ample evidence that physical activityimproves pain, mobility and quality of life in people with osteoarthritis

(OA). Yet, physical inactivity in this population is a known public healthconcern. The purpose of this presentation is to discuss recent researchthat aims to modernize the process of knowledge translation andenhance health of people with OA.Discussion: The presentation consists of two parts. First, recentresearch on digital tools for promoting physical activity and supportingpatients in making evidence-informed treatment decisions will bediscussed. Second, it will explore strategies to meaningfully engagepatients in the development and evaluation of these tools for OArehabilitation. Studies evaluating physical activity counselling with theuse of a wearable device, and the use of online patient decision aids inOA management will be discussed. To illustrate the important roles ofpatients in these studies, results from About Us will be presented. Thisis a qualitative study co-developed with four people with arthritis toexamine patients’ experiences as research partners. About Us providesthe foundation for the Patient Engagement in Research Framework(PEIR Framework) and PEIR Scale, a new outcome measure forassessing quality of patient engagement in research teams.This presentation will highlight the potential of digital patient-orientedknowledge translation tools for promoting physical activity and shared-decision making in rehabilitation. It will also illustrate opportunitiesand challenges of involving patients as partners in health research.

I-6ADDITIONAL USE OF SYNOVIAL MESENCHYMAL STEM CELLTRANSPLANTATION FOLLOWING SURGICAL REPAIR OF A COMPLEXDEGENERATIVE TEAR OF THE MEDIAL MENISCUS OF THE KNEE

I. Sekiya. Tokyo Med. and Dental Univ., Tokyo, Japan

Purpose: Complex degenerative tears of themedial meniscus in the kneeareusually treatedusingmeniscectomy.However, thisprocedure increasesthe risk of osteoarthritis, while other treatments aimed atmeniscal repairremainchallengingdue to thehighpossibilityof failure. Theuseof synovialmesenchymal stem cells (MSCs) is an attractive additional approach formeniscal repair, as these cells have high proliferative and chondrogenicpotential.Wesurgically repairedacomplexdegenerative tearof themedialmeniscus and then transplanted autologous synovial MSCs. We evaluatedclinical outcomes at two years and assessed adverse events.Methods: We enrolled patients with clinical symptoms that included afeeling of instability in addition to pain caused by their complexdegenerative tears of the medial meniscus. Two weeks after surgicalrepair of the torn meniscus, autologous synovial MSCs were trans-planted onto the menisci of five patients.Results: The total Lysholm knee score, the Knee Injury and Osteo-arthritis Outcome Scale (KOOS) scores for “pain,” “daily living,” “sportsactivities,” and the numerical rating scale were significantly increasedafter two years. Three adverse events, an increase in c-reactive protein(CRP), joint effusion, and localized warmth of the knee were recorded,although these could have been due to the meniscal repair surgery.Conclusions: This first-in-human study confirmed that the combina-tion of surgical repair and synovial MSC transplantation improved theclinical symptoms in patients with a complex degenerative tear of themedial meniscus. No adverse events occurred that necessitated treat-ment discontinuation. After this clinical study, we started a clinical trial.

I-7THE POTENTIAL FOR DIETARY FACTORS TO PREVENT OR TREAT OA

I.M. Clark 1, R.K. Davidson 1, A. Cassidy 2, A.J. MacGregor 1. 1Univ. of EastAnglia, Norwich, United Kingdom; 2Queen's Univ. Belfast, Belfast, UnitedKingdom

Purpose: Osteoarthritis (OA) is a degenerative joint disease for whichthere are no disease-modifying drugs. It is a leading cause of disability.Increasing age and obesity are both major risk factors for OA and thehealth and economic burden of this disease will increase in the future.

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Focusing on compounds from the habitual diet that may prevent theonset or slow the progression of OA is a strategy that has been under-investigated to date. An approach that relies on dietary modification isclearly attractive in terms of risk/benefit and more likely to be imple-mentable at the population level. However, detailed molecular studiesahead of a full clinical trial are required in order to establish modes ofaction (which are different from traditional single target pharmaceut-icals) at dietary achievable levels and to optimise the design of trials togain an evidence-base of efficacy.Methods: There are currently limited data on the interrelationshipbetween diet and OA. Data come from a variety of studies: in vitrocell and tissue explant models, animal models, population-basedstudies using habitual intakes and risk factors/disease incidence andintervention trials. There is a large variability between studies, e.g. inanimal models, a dietary intake approach would be optimal in orderto relate to human exposure, but some studies use intra-articularinjection and/or concentrations not achievable through the diet. Thesmall and short-term intervention trials conducted to date havemany different designs, number of patients, time length and out-come measures.Results and Conclusions: There are however, a number of pertinentstudies in the literature and this presentation will review these. It willalso comment on our own experience developing sulforaphane, acompound derived from the consumption of cruciferous vegetables,particularly broccoli, in OA from laboratory models into proof of prin-ciple patient trials, as well as the identification of other bioactive diet-derived compounds.

I-8PROTEOMIC PROFILING OF THE ECM IN HEALTH AND DISEASE

A. Naba. Univ. of Illinois at Chicago, Chicago, IL, USA

Purpose: The ECM is a complex meshwork of proteins providingarchitectural support to cells and conferring biomechanical propertiesto tissues. In addition, it provides chemical cues that orchestrate cellularfunctions such as proliferation and survival, adhesion, and migration.Degradation, hyper-production or alteration of the composition of theECM cause or accompany numerous pathologies such as musculo-skeletal and cardio-vascular diseases, cancers, and fibroses. Thus, abetter characterization of ECM composition, metabolism, and biologycan lead to the identification of novel prognostic and diagnosticmarkers and offer novel therapeutic opportunities.Methods: We have devised a unique mass-spectrometry-based pro-teomic pipeline coupled to computational tools to profile the ECMcomposition, or "matrisome", of normal and diseased tissues.Results: In this presentation, I will first discuss how proteomics hasemerged in recent years as the method of choice to characterize theECM composition of normal and pathological samples. I will thenillustrate how proteomic profiling has led to the identification of novelproteins playing causal role in the etiology of diseases. Last, I will dis-cuss the latest release and new features of the second version ofMatrisomeDB, a searchable compendium of proteomic data on the ECMproduced by cells in culture or in vivo that we have made available tothe broad scientific community.Conclusions:We propose that the ECM is an underexplored reservoir ofpotential diagnostic and prognostic markers as well as therapeutictargets, and that its exploration using proteomics will pave the way forthe development of novel approaches to better care patients.

I-9MEDIATION ANALYSIS: UNDERSTANDING CAUSAL PATHWAYS TODISEASE OUTCOMES

S. Jafarzadeh. Boston Univ. Sch. of Med., Boston, MA, USA

Purpose: To understand causal pathways to disease outcomes and toquantify the potential mechanisms of an intervention-diseaserelationship.Methods: This workshop discusses recent advances in mediationanalysis that are based on modern causal inference methods. It startswith an introduction to the key concepts in mediation analysis anddiscusses how to assess the importance of the causal mechanisms bywhich an intervention/exposure affects an outcome.Results: The workshop enables the implementation of the state-of-the-art techniques for decomposing an intervention effect into natural

direct and indirect/mediated effects as well as quantifying interven-tional direct and indirect effects.Conclusions: Mediation analysis provides the framework to test causalhypotheses that could ultimately inform utilizing more optimal inter-ventions.

I-10FROM OA RISK GENES TO UNDERLYING DISEASE MECHANISMS

J. Loughlin. Newcastle Univ., Newcastle upon Tyne, United Kingdom

The mapping of risk loci for polygenic traits is now a relativelystraightforward procedure; the next major step in complex trait anal-ysis is transitioning from association signal to functional character-isation. This offers a realistic means of generating clinically-relevantmechanistic insight that will assist new treatment development. OA is ahighly polygenic disease and so far, just over 100 OA risk-conferringassociation signals have been mapped in the human genome. Anoverwhelming majority of the associated DNA variants reside in non-protein-coding regions of the genome and, as such, OA genetic sus-ceptibility is presumed to act principally via changes to gene expression.The availability of excised tissue following arthroplasty of an OA jointoffers the opportunity to experimentally test this in disease-relevantcells, including cartilage chondrocytes, the single cell type in this tissue.In this session, I will describe the experiments that are undertaken tomove from the association signals toward a functional analysis of thegenetic risk and how these studies contribute to our understanding ofOA disease mechanisms. The session will encompass in-silico analysesand lab-based experimental studies, and will cover genetics, epi-genetics, genomics and functional studies in disease-relevant primarycells, tissues and cell lines.

I-11IN VIVO LOAD-INDUCED OA IN THE MOUSE

M. van der Meulen 1, F.C. Ko 2, O.O. Adebayo 3, D.T. Holyoak 4,S. Ziemian 1. 1Cornell Univ., Ithaca, NY, USA; 2Rush Univ., Chicago, IL, USA;3Univ. of Massachusetts, Amherst, MA, USA; 4 Exponent, Philadelphia, PA,USA

Purpose: Musculoskeletal tissues not only bear joint loads, but activelyadapt their structure and composition to the mechanical environment.However, our understanding of the mechanisms of this functionaladaptation is limited, particularly in complex systems such as synovialjoints. For example, adaptive changes in articular cartilage and under-lying subchondral bone are both key contributors to osteoarthritis (OA)pathogenesis. Using well-controlled mechanical loading, we have beenstudying the in vivo response of joint tissues to mechanical stimuli.Non-invasive in vivo compression of the mouse tibia can induce bothadverse and beneficial effects in bone, cartilage and synoviumdepending on the experimental conditions. My laboratory has focusedon understanding load-induced joint damage and the role of bone tis-sue properties in this process.Methods: Our primary experimental model is in vivo loading of themouse tibia. Under IACUC approval, we apply cyclic compression to theleft tibia of the mouse, 5 d/wk for 5 min (4 Hz, 1200 cycles). This loadingresults in consistent, repeatable kinematics inducing combined com-pression and shear motions at the joint surface. The loadmagnitude andduration depend on the experimental question being studied. Highloads are selected to induce 1200 me on the mid-diaphyseal cortex. Alljoint ligaments and surrounding soft tissues remain intact. Right limbsare not loaded and serve as contralateral controls. This approach can becombined with other treatments and mice of different genetic back-grounds to alter joint tissue properties or signaling pathways. Forexample, to understand the role of bone and cartilage tissue propertiesload-induced OA, my laboratory has used pharmacologic treatments(alendronate, PTH) and examined different mouse strains (C57Bl/6, cho/þ, pOC-ERa, FVB).Outcome assays to assess cartilage damage, bonechanges and other joint responses include histology, immunohis-tochemistry and microCT. Tibial cartilage damage is quantified inSafranin-O stained tissues using OARSI scoring. Bone morphology ismeasured by microCT. Synovial inflammation can be scored from H&E-stained sections. If osteophytes are present, width is measured andmaturity scored based on the relative calcification of the osteophyte.Other assays depend on the research question, mouse strain and otherexperimental manipulations.

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Results: Both adverse and beneficial effects of loading on joint healthare present. High magnitude loading results in OA-like pathologyincluding cartilage damage, osteophytes and bone sclerosis. At themetaphysis, high magnitude loading induces anabolic bone formation,which stiffens the bone structure and also may contribute to thechanges present at the joint surface. On the other hand, the sameapproach with low magnitude loading can be beneficial to joint tissuesand attenuate cartilage damage and osteophyte formation followingjoint injury by destabilization of the medial meniscus. These findingsdemonstrate the importance of the loading environment to joint healthand the differential tissue responses.Conclusions: The development and progression of cartilage damageand OA is complex and multifactorial. Load-induced damage is onecontributing mechanism. Loading models are valuable tools to identifythe relationship between sub-failure mechanical forces and progressivetissue changes in OA, without the confounding effects of surgery. Inaddition, thisapproach allows the interaction of joint loading with othertissues including subchondral bone to be studied, to address keyquestions in developing preventative strategies and disease modifyingtherapies for OA.

I-12METABOLIC DISORDERS AND TRANSCRIPTIONAL REPROGRAMMINGIN OA PATHOGENESIS

J.-S. Chun. Gwangju Inst. of Sci. and Technology, Gwangju, Republic ofKorea

Although osteoarthritis (OA) is currently considered to be associatedwith metabolic disorders and metabolic syndrome (MetS), direct evi-dence for this is lacking. Because MetS is associated with abnormalcholesterol levels and production of oxysterol metabolites, we aim tocharacterize the role of abnormal cholesterol metabolism in OA patho-genesis. We present evidences that the CH25H-CYP7B1-RORa axis ofcholesterol metabolism in chondrocytes is a crucial catabolic regulatorof the pathogenesis of OA. OA chondrocytes had increased levels ofcholesterol because of enhanced uptake, upregulation of cholesterolhydroxylases (CH25H and CYP7B1) and increased production of oxy-sterol metabolites. Adenoviral overexpression of CH25H or CYP7B1 inmouse joint tissues caused experimental osteoarthritis, whereasknockout or knockdown of these hydroxylases abrogated the patho-genesis of osteoarthritis. Moreover, retinoic acid-related orphanreceptor alpha (RORa) was found to mediate the induction of osteo-arthritis by alterations in cholesterol metabolism. These results indicatethat OA is a disease associatedwithmetabolic disorders and suggest thattargeting the CH25H-CYP7B1-RORa axis of cholesterol metabolismmayprovide a therapeutic avenue for treating osteoarthritis. We will alsopresent evidences that various metabolic disorders and transcriptionalreprogramming regulates OA pathogenesis in mouse models of OA.

I-13PREVENTION OF OA, UNDER THE LIGHT OF PHENOTYPES

F. Berenbaum. Sorbonne Universit�e Saint-Antoine Hosp., Paris, France

Given our inability to cure osteoarthritis (OA) today, the only way to acteffectively is the primary/secondary prevention of the illness. However,it is a real challenge to disseminate prevention messages early in lifewhen the disease itself often only appears late in life. Current researchto try to phenotype the disease is an opportunity to improve preventionby delivering specific messages to specific populations. The purpose ofthis lecture is to discuss the optimization of OA prevention based on therecent attempts to delineate OA phenotypes.

I-14CARTILAGE/BONE CROSSTALK IN JOINT HEALTH AND DISEASE

T. Alliston. Univ. of California San Francisco, San Francisco, CA, USA

Purpose: Understanding the mechanisms that maintain cartilagehomeostasis and disease requires consideration of how spatial andphysical features of the joint, across multiple length scales, shift theactivity of biological signaling pathways. With a focus on well-knownparticipants in cartilage health and disease, TGF-beta and MMP13, thistalk will explore these concepts in joint crosstalk between cartilage andbone.

Methods: This study examines bone and cartilage outcomes in severalmodels, including human surgical specimens, mouse models, and invitro systems, with a range of biological and mechanobiologicapproaches.Results: Our results shed light on the mechanisms by which TGF-betaboth supports joint homeostasis, and by which disruption of TGF-betasignaling can exacerbate joint disease, through its cell intrinsic effects inbone and in cartilage.Conclusions: Understanding the compartment and cell type specificeffects of TGF-beta, and how this signaling pathway is regulated byphysical cues, is essential for understanding the important and multi-faceted role of this signaling pathway in joint crosstalk.

I-15SHARING BIOMECHANICAL DATA: CHALLENGES ANDOPPORTUNITIES

M.A. Hunt. Univ. of British Columbia, Vancouver, BC, Canada

Purpose: The purpose of this workshop is to provide the participantwith an understanding of the need for developing large, multi-centredatasets that include movement-based biomechanical outcomes frompeople living with osteoarthritis.Methods: Collection of biomechanics data - loosely defined herein asany kinematic, kinetic, or muscle activity data during humanmovementresulting in direct analysis of global movement characteristics, or usedto drive musculoskeletal modeling to estimate in vivo values - canprovide important insights into the normal and abnormal functioningof muscles, bones, and joints during movement. However, this is anonerous task that is heavy on time, cost, expertise, and personalresources. As a result, there is much difficulty in obtaining datasets withvery large sample sizes, thereby severely limiting the ability to answermany types of research questions that rely on hundreds or even thou-sands of data points. This known limitation presents a clear need towork collaboratively to conduct multi-centre biomechanics studies togrow the field and increase knowledge. Material presented during thisworkshop will focus on some of the unique aspects of biomechanicsdata collection that pose threats to building these large datasets. Datafrom ongoing attempts to conduct multi-centre biomechanics studieswill be reported, and creative solutions and helpful hints to overcomeknown barriers will be provided. Finally, a collaborative discussion ofcommon goals and opportunities for data sharing will provide aframework for the first steps towards an OARSI-based biomechanicsinitiative.Results: Following this workshop, the participant should be able toidentify the research opportunities available, and questions that can bebest answered, through the use of larger, multi-centre biomechanicsdatasets. Further, the participant should be better aware of some of thebarriers and facilitators associated with establishing a large, multi-centre biomechanics dataset.Conclusions: There is a growing interest in, and need for, large datasetsto answer amultitude of basic and clinical research questions including:exploratory associations and mechanisms, long-term changes, andeffectiveness of treatments. These datasets exist in the osteoarthritisfield, but are limited to mainly imaging, biomarkers, symptoms, andsimple measures of physical function. While joint- and whole body-biomechanics are known to play an important role in osteoarthritispathogenesis, yet no large cohort study to-date includes these impor-tant outcomes. An appreciation of the mechanisms and opportunitiesavailable to develop and maintain these large biomechanical cohorts istherefore important.

I-16GUIDELINES AND RECOMMENDATIONS IN TREATING HAND OA

T. Stamm. Med. Univ. of Vienna, Vienna, Austria

Purpose: Hand osteoarthritis has an enormous impact on functioningin daily life. The participants of this workshop will critically appaise therelevant guidelines, recommendations and points to consider andexplore their overlaps and differences.Methods: The participants will discuss potential barriers and facili-tators for the implementation of these on the micro, meso and macrolevels in small groups. We will consider and include the perspective ofpatients and different disciplines and professions.

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Results and conclusions: We will also explore how these guidelines,recommendations and points to consider can lead the way to valuebased healthcare in the future.

I-17BIOLOGICAL AGENTS IN OA - HOPES AND DISAPPOINTMENTS

X. Chevalier, Sr., F. Eymard, Sr.. Hosp. Henri Mondor, Creteil, France

Purpose: To review the trial in humans using biologics in osteoarthritis(OA) which can be can be categorized according to the main target:pain, structure or both.Methods: A literature review (Medline, Cochrane, Embase) of the mostrecent trials in OA using biologicsResults: The analgesic effect of anti-nerve growth factor (NGF) wasinitially dramatic using high dose and intravenous route of admin-istration, but emerging severe arthropathies (in the targeted knee butnot only) have dampened down this enthusiasm. Most recent trialsused anti NGF Mab, administered subcutaneously, with lower dose,shorter interval of administration and without concomitant use ofNSAIDS. The effect on pain is still superior to placebo but with a muchlesser magnitude. Unfortunately, long term follow-up in those trials stillshows a concern in terms safety profile. Thus, Patients who will benefitof this anti NGF therapy should be strictly selected and followed up.Biologics agents targeting main cytokines (interleukines 1 and 6, tumornecrosis alpha) have been tested in knee OA and in hand OA. The firstrandomized controled trial in humans using a single local admin-istration of the antagonist of IL-1, at 2 doses: 50 and 150 mg, failed toshow an analgesic effect, except at day 3 with the highest dose. Thisnegative result has been confirmed in trials using systemic admin-istration of monoclonal antibodies directed against only IL1-b or againstIL-1 a and Il-1 b in patients with knee OA and in patients with hand OA.However, in the CANTOR trial recruiting patients with cardiovasculardisease treated with canakinumab, post hoc analysis indicated that thepatients in the verum group, shows a dramatic decrease in the numberof total joint replacement (hip and knee) (about 50%). This might open adoor for a possible anti IL-1 strategy dedicated to patients with somepart of systemic inflammation. Most of trial with anti TNF inhibitorshave been performed in patients with erosive digital hand OA and allwere negative on pain and on structure (measured by differentparameters on magnetic resonance imaging). Finally the last cytokinethat has been targeted is IL-6. Results of the RCP trial in hand OA areongoing. Taking all together, biologics in OA are really disappointing,raising more questions than answers: choice of the targets, choice ofselected phenotype of pain, selection of the route of administration, tooshort time of intra articular residence of the drug etc. News biologicstargeting WNT, bradykinin or anti sense micro RNA are under devel-opment but so far, the preliminary results needs to be confirmed inlarge trials in humans. Finally, the last option is to try to stimulate thecartilage repair response which is naturally weak. Fibroblast growthfactor 18 (sprifremin), an anabolic and mitogenic factor for the chon-drocyte, has been tested against placebo in an ambitious trial over 5years with 2 years of treatment and 3 years of follow-up. The drug wasintra-articularly delivered every 6 months or every 12 months, with 2different dosages. At the first end point, at year 2, with the highest doseof FGF-18, a statistically significant difference with the placebo wasobserved on the cartilage volumemeasured byMRI in the global, medial

and lateral compartment on the involved knee. Unfortunately, therewas no effect on pain in the ITT population, except in a sub group ofpatients with a minimum threshold of pain and an initial joint spacewidth between 1.5mm and 3.5mm (around one third of the population)show a significant effect on pain reduction compared to placebo. Ifresults of this long term trial are confirmed in others trials, FGF-18 mayconstitute the first real disease modifying drug in OA. ConclusionsConclusion: The trials in humans using biologics are disappointing. Weshould keep in mind that blocking a single mediator will not stop thecatabolic process in OA. Thus in the next future, we should probablyadapt a drug owing to the evolution of the disease, to the profile ofpatient, to the radiological aspect of the disease and to the phenotype ofpain. The story is just starting //

I-18THE ROLE OF SYNOVIUM IN THE ONSET AND PROGRESSION OF OA

N. Fukui 1,2. 1 The Univ. of Tokyo, Tokyo, Japan; 2Clinical Res. Ctr., Natl.Hosp. Organization Sagamihara Hosp., Sagamihara, Japan

Conventionally, the synovial changes in OA are considered to be asecondary event associated with cartilage degeneration. However,recent studies have shown that synovial changes are actively involvedin the pathology of OA. This presentation provides an overview of ourcurrent understanding of the synovial changes in knee OA. Clinically,the significance of synovial changes in OA is two-fold. First, synovialchanges are closely related to the symptoms of knee OA, especially pain.Studies using MRI have revealed that the presence of effusion-synovitisin knee joints is associated with knee pain. Second, synovial changesmay be related to the structural progression of knee OA. The results ofcohort studies have consistently indicated that knees with effusion-synovitis are at higher risk for disease progression. Thus, synovialchanges may play a pivotal role in the pathology of OA by causing painand cartilage degeneration. The severity of synovial changes in OA jointsmay change with time. This may explain some of the clinical features ofOA. For example, the symptoms of knee OA may fluctuate with time,and the progression of OA is often phasic. These features may be relatedto the vacillation of synovial changes. Synovial changes may occurirrespective of the severity of structural changes observed on radio-graphs. Again, this may explain the dissociation between the extent ofstructural changes and the severity of symptoms which is oftenencountered with the disease. While most of the above findings wereobtained from observations of established OA, recent studies havefocused on the knee joints in the very early stage of the disease, or earlyOA, in an attempt to elucidate the initial change(s) that may trigger thedisease. The results of such studies have shown that the synovialchanges may occur prior to the development of radiographic changes,and that such changes may cause pain and structural changes in thejoints of early OA patients, as occurs in established OA. Thus, synovialchanges may be an initial event of OA, which plays a key role in theinitiation of the disease. Despite its significance, the mechanism(s)underlying synovial changes in OA has not yet been elucidated. Again, itis not known why synovial changes are related to pain or structuralprogression. It is therefore necessary to elucidate the mechanism(s)underlying the synovial change in OA since it will be helpful to establisheffective treatments for knee OA.