Purpose The inflammatory, angiogenic and neurogenic pathways of osteoarthritis (OA) might already be present in patients with patellofemoral pain (PFP), a supposed precursor of OA. In this study, differences in serum levels of biomarkers of inflammation, angiogenesis and neurogenesis were compared between PFP patients and healthy controls. Furthermore, we aimed to determine the associations between serum marker levels and both clinical and MRI based inflammatory features. Methods In a post hoc analysis of data from a prospective case-control study, a wide range of serum levels of markers of inflammation, angiogenesis and neurogenesis were measured in 44 PFP patients and 50 healthy controls aged 18-40 years. Clinical measures included the NRS for knee pain intensity, duration of complaints and pressure pain thresholds. Morphologic and dynamic contrast enhanced MRI of the knee were performed to assess inflammatory features and quantitative perfusion parameters. Differences in biomarker levels between patients and controls were assessed and additional analyses in the patient group were performed to study associations between serum biomarkers and inflammatory MR features and clinical parameters. Results There were no significant differences between patients and controls in serum biomarker levels. Additional analyses in the patient group revealed no associations between serum markers and inflammatory MR features and clinical parameters. Conclusion Our results were unable to confirm the hypothesis that inflammation, angiogenesis or neurogenesis plays a role in PFP pathophysiology.

OBJECTIVE:To gain better understanding of osteoarthritis (OA) heterogeneity and its predictors for distinguishing OA phenotypes. This could provide the opportunity to tailor prevention and treatment strategies and thus improve care.DESIGN:Ten year follow-up data from CHECK (1002 early-OA subjects with first general practitioner visit for complaints ≤6 months before inclusion) was used. Data were collected on WOMAC (pain, function, stiffness), quantitative radiographic tibiofemoral (TF) OA characteristics, and semi-quantitative radiographic patellofemoral (PF) OA characteristics. Using functional data analysis, distinctive sets of trajectories were identified for WOMAC, TF and PF characteristics, based on model fit and clinical interpretation. The probabilities of knee membership to each trajectory were used in hierarchical cluster analyses to derive knee OA phenotypes. The number and composition of potential phenotypes was selected again based on model fit (silhouette score) and clinical interpretation.RESULTS:Five trajectories representing different constant levels or changing WOMAC scores were identified. For TF and PF OA, eight and six trajectories respectively were identified based on (changes in) joint space narrowing, osteophytes and sclerosis. Combining the probabilities of knees belonging to these different trajectories resulted in six clusters ('phenotypes') of knees with different degrees of functional (WOMAC) and radiographic (PF) parameters; TF parameters were found not to significantly contribute to clustering. Including baseline characteristics as well resulted in eight clusters of knees, dominated by sex, menopausal status and WOMAC scores, with only limited contribution of PF features.CONCLUSIONS:Several stable and progressive trajectories of OA symptoms and radiographic features were identified, resulting in phenotypes with relatively independent symptomatic and radiographic features. Sex and menopausal status may be especially important when phenotyping knee OA patients, while radiographic features contributed less. Possible phenotypes were identified that, after validation, could aid personalized treatments and patients selection.

Objectives: To assess the associations of biomarkers in serum [highsensitivity C-reactive protein (hs-CRP), serum cartilage oligomeric protein (sCOMP), serum propeptide of type I procollagen (sPINP) and serum osteocalcin (sOC)] and urine [urinary type II collagen telopeptide (uCTX-2)] with the extent and progression of nocturnal pain, pain while walking, and fatigue in participants with hip and/or knee pain suspected to be early stage osteoarthritis (OA). Methods: hs-CRP, uCTX-2, sCOMP, sPINP and sOC were measured at baseline in 1,002 participants of the Cohort Hip and Cohort Knee (CHECK). Nocturnal pain, pain while walking and fatigue were assessed by self-reported questionnaires at baseline and 2-year follow-up. Associations between these biomarkers and symptoms were examined using logistic and linear regression analyses. Results: hs-CRP was significantly associated with mild nocturnal pain (OR 1.18 95% CI 1.01-1.37), with mild and moderate pain while walking (OR 1.17 95% CI 1.01-1.35 and OR 1.56 95% CI 1.29-1.90, respectively) and with progression of nocturnal pain (OR 1.25 95% CI 1.07-1.46). uCTX-2 was associated with mild nocturnal pain (OR 1.40 95% CI 1.05-1.85) and with mild and severe-extreme pain while walking (OR 1.35 95% CI 1.04-1.75 and OR 2.55 95% CI 1.03-6.34, respectively). sPINP was associated with severe-extreme nocturnal pain (OR 0.45 95% CI 0.25-0.82). No significant associations were found for sCOMP and sOC, nor for any of the biomarkers and fatigue. Conclusion: This study of biomarkers in a large cohort of participants with hip and/or knee pain suspected to reflect early stage hip and/or knee OA suggests that inflammation and cartilage matrix degeneration play a role in pain, but not in fatigue. (c) 2022 The Author(s). Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/).

Purpose: Frequent and debilitating symptoms of hip osteoarthritis are pain while walking, fatigue and nocturnal pain. The aim of the present study was to assess associations of five biochemical markers of joint tissue turnover and inflammation (hs-CRP, CTX-II, COMP, PINP and OC) with the presence and 2-year progression of pain while walking, fatigue and nocturnal pain. CTX-II and COMP are markers of cartilage and bone metabolism. CRP is a nonspecific marker of inflammation. PINP (aminoterminal propeptide of type I procollagen) and OC (osteocalcin) are bone synthesis markers.

Purpose: Patellofemoral pain (PFP) is a common knee condition among adolescents and a supposed precursor of knee osteoarthritis (OA). In OA pathophysiology, the inflammatory pathway of cytokine release by the infrapatellar fat pad (IPFP) is of great importance. It was, therefore, hypothesized that this inflammatory pathway is also already active in patients with PFP. We determined whether serological biomarker levels of inflammation, angiogenesis and neurogenesis differed between PFP patients and healthy controls.

Objective: To design an automated workflow for hip radiographs focused on joint shape and tests its prognostic value for future hip osteoarthritis. Design: We used baseline and 8-year follow-up data from 1,002 participants of the CHECK-study. The primary outcome was definite radiographic hip osteoarthritis (rHOA) (KellgreneLawrence grade >= 2 or joint replacement) at 8-year follow-up. We designed a method to automatically segment the hip joint from radiographs. Subsequently, we applied machine learning algorithms (elastic net with automated parameter optimization) to provide the Shape-Score, a single value describing the risk for future rHOA based solely on joint shape. We built and internally validated prediction models using baseline demographics, physical examination, and radiologists scores and tested the added prognostic value of the Shape-Score using Area-Under-the-Curve (AUC). Missing data was imputed by multiple imputation by chained equations. Only hips with pain in the corresponding leg were included. Results: 84% were female, mean age was 56 (+/- 5.1) years, mean BMI 26.3 (+/- 4.2). Of 1,044 hips with pain at baseline and complete follow-up, 143 showed radiographic osteoarthritis and 42 were replaced. 91.5% of the hips had follow-up data available. The Shape-Score was a significant predictor of rHOA (odds ratio per decimal increase 5.21, 95%-CI (3.74-7.24)). The prediction model using demographics, physical examination, and radiologists scores demonstrated an AUC of 0.795, 95%-CI (0.757-0.834). After addition of the Shape-Score the AUC rose to 0.864, 95%-CI (0.833-0.895). Conclusions: Our Shape-Score, automatically derived from radiographs using a novel machine learning workflow, may strongly improve risk prediction in hip osteoarthritis. (C) 2019 The Authors. Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International.

Purpose: Exercise therapy with a focus on muscle strengthening has proven to be effective for the management of knee osteoarthritis (OA). Yet it is not known whether high-intensity resistance training (RT) is more effective in improving upper leg muscle strength and physical performance than low-intensity RT. Still, there is some controversy regarding the effectiveness of high-intensity RT and whether or not it is harmful, for instance by accelerating cartilage degeneration, osteophyte formation, or increasing synovitis. Any catabolic or anabolic response of musculoskeletal tissue to RT might first be visible on a biochemical level before changes in clinical symptoms are measurable. Serum biomarkers can objectively measure early biochemical changes and assess whether RT leads to a more anabolic or catabolic response. The aim of this study is to assess (i) whether high-intensity RT elicits a different response (e.g. catabolic) on systemic inflammation and musculoskeletal tissues in and surrounding the joint, including bone, cartilage, muscle, and synovial tissue compared to low-intensity RT; and (ii) whether there is an association between changes in serum levels of inflammatory and musculoskeletal tissue-derived biomarkers and improvements in clinical outcomes (performance-based tests and self-reported outcomes on pain and activity limitations). Methods: In a randomized controlled trial, 177 participants with knee OA conducted a high-intensity (70%-80% of the Repetition Maximum (1RM)) or low-intensity (40%-50% 1RM) RT program 3 times a week for 12 weeks. Measures of clinical outcomes and serum samples were collected at the start of RT (pre-intervention), after 3 months at the end of RT (post-intervention), and 6 months after RT (follow-up). As a reflection of systemic inflammation (CRP), synovitis (CRPM, C3M), bone turnover (OC, CTX-I), cartilage turnover (PRO-C2, C2M, huARGS), muscle turnover (PRO-C3, PRO-C6), and cell behaviour (col10neo) a total of eleven serum biomarkers were analysed. With the exception of CRP, which was determined with an immunoturbidimetric assay, ELISA assays were used to quantify serum levels of the other 10 serum biomarkers. The primary outcome measures are the changes in serum biomarker levels. Other outcome measures include upper leg muscle strength, performance-based tests, and self-reported outcomes on pain and activity limitations. Results: High-intensity RT resulted in greater improvements in muscle strength compared to low-intensity RT when measured by the estimated 1RM. No significant differences between groups were found for upper leg muscle strength (Nm/kg) when measured with an isokinetic dynamometer. Both groups showed similar improvements in pain and physical functioning. Although there is no difference between groups in clinical outcomes, except for the estimated 1RM, we expect that participants in the high-intensity RT group are more likely to have enhanced serum levels of catabolic biomarkers than participants in the low-intensity RT group. Since both the high-intensity RT group and low-intensity RT group improved over time, we expect that changes in serum biomarker levels are associated with overall improvements in clinical outcomes. Almost all participants had normal CRP values (<10 mg/L) at baseline. No significant differences between the intensity RT groups in CRP levels at baseline, at 3 months, and 6 months were found. In both groups, there was no evidence that RT influenced CRP serum levels. Conclusions: The work to date on CRP serum levels suggests that RT did not influence CRP levels. This result may be explained by the high percentage of participants with normal CRP levels (<10 mg/L). We are currently in the process of analyzing the remaining 10 neo-epitope biomarkers. We expect that our remaining 10 assays have the potential to measure changes in serum biomarker levels in response to RT. This will be the first study to investigate the effects of high-intensity versus low-intensity RT on musculoskeletal tissue turnover in individuals with knee OA. With this, we aim to determine whether high-intensity RT can improve upper leg muscle strength and physical performance without worsening systemic inflammation or causing adverse effects on musculoskeletal knee OA-related tissues.

BACKGROUND:The concept of osteoarthritis (OA) heterogeneity is evolving and gaining renewed interest. According to this concept, distinct subtypes of OA need to be defined that will likely require recognition in research design and different approaches to clinical management. Although seemingly plausible, a wide range of views exist on how best to operationalize this concept. The current project aimed to provide consensus-based definitions and recommendations that together create a framework for conducting and reporting OA phenotype research. METHODS:A panel of 25 members with expertise in OA phenotype research was composed. First, panel members participated in an online Delphi exercise to provide a number of basic definitions and statements relating to OA phenotypes and OA phenotype research. Second, panel members provided input on a set of recommendations for reporting on OA phenotype studies. RESULTS:Four Delphi rounds were required to achieve sufficient agreement on 11 definitions and statements. OA phenotypes were defined as subtypes of OA that share distinct underlying pathobiological and pain mechanisms and their structural and functional consequences. Reporting recommendations pertaining to the study characteristics, study population, data collection, statistical analysis, and appraisal of OA phenotype studies were provided. CONCLUSIONS:This study provides a number of consensus-based definitions and recommendations relating to OA phenotypes. The resulting framework is intended to facilitate research on OA phenotypes and increase combined efforts to develop effective OA phenotype classification. Success in this endeavor will hopefully translate into more effective, differentiated OA management that will benefit a multitude of OA patients.

Purpose The Applied Public-Private Research enabling OsteoArthritis Clinical Headway (APPROACH) consortium intends to prospectively describe in detail, preselected patients with knee osteoarthritis (OA), using conventional and novel clinical, imaging, and biochemical markers, to support OA drug development. Participants APPROACH is a prospective cohort study including 297 patients with tibiofemoral OA, according to the American College of Rheumatology classification criteria. Patients were (pre)selected from existing cohorts using machine learning models, developed on data from the CHECK cohort, to display a high likelihood of radiographic joint space width (JSW) loss and/or knee pain progression. Findings to date Selection appeared logistically feasible and baseline characteristics of the cohort demonstrated an OA population with more severe disease: age 66.5 (SD 7.1) vs 68.1 (7.7) years, min-JSW 2.5 (1.3) vs 2.1 (1.0) mm and Knee injury and Osteoarthritis Outcome Score pain 31.3 (19.7) vs 17.7 (14.6), except for age, all: p<0.001, for selected versus excluded patients, respectively. Based on the selection model, this cohort has a predicted higher chance of progression. Future plans Patients will visit the hospital again at 6, 12 and 24 months for physical examination, pain and general health questionnaires, collection of blood and urine, MRI scans, radiographs of knees and hands, CT scan of the knee, low radiation whole-body CT, HandScan, motion analysis and performance-based tests. After two years, data will show whether those patients with the highest probabilities for progression experienced disease progression as compared to those wit lower probabilities (model validation) and whether phenotypes/endotypes can be identified and predicted to facilitate targeted drug therapy. Trial registration number NCT03883568

Higher body mass index (BMI) is associated with osteoarthritis (OA) in both weight-bearing and non-weight-bearing joints, suggesting a link between OA and poor metabolic health beyond mechanical loading. This risk may be influenced by systemic factors accompanying BMI. Fluctuations in concentrations of metabolites may mark or even contribute to development of OA. This study explores the association of metabolites with radiographic knee/hip OA prevalence and progression. A 1H-NMR-metabolomics assay was performed on plasma samples of 1564 cases for prevalent OA and 2,125 controls collected from the Rotterdam Study, CHECK, GARP/NORREF and LUMC-arthroplasty cohorts. OA prevalence and 5 to 10 year progression was assessed by means of Kellgren-Lawrence (KL) score and the OARSI-atlas. End-stage knee/hip OA (TJA) was defined as indication for arthroplasty surgery. Controls did not have OA at baseline or follow-up. Principal component analysis of 227 metabolites demonstrated 23 factors, of which 19 remained interpretable after quality-control. Associations of factor scores with OA definitions were investigated with logistic regression. Fatty acids chain length (FALen), which was included in two factors which associated with TJA, was individually associated with both overall OA as well as TJA. Increased Fatty Acid chain Length is associated with OA.

Background Chondrocytes are exposed to an inflammatory micro-environment in the extracellular matrix (ECM) of articular cartilage in joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA). In OA, degenerative changes and low-grade inflammation within the joint transform the behaviour and metabolism of chondrocytes, disturb the balance between ECM synthesis and degradation, and alter the osmolality and ionic composition of the micro-environment. We hypothesize that chondrocytes adjust their physiology to the inflammatory microenvironment by modulating the expression of cell surface proteins, collectively referred to as the ‘surfaceome’. Therefore, the aim of this study was to characterize the surfaceome of primary equine chondrocytes isolated from healthy joints following exposure to the pro-inflammatory cytokines interleukin-1-beta (IL-1β) and tumour necrosis factor-alpha (TNF-α). We employed combined methodology that we recently developed for investigating the surfaceome in stem cells. Membrane proteins were isolated using an aminooxy-biotinylation technique and analysed by mass spectrometry using high throughput shotgun proteomics. Selected proteins were validated by western blotting. Results Amongst the 431 unique cell surface proteins identified, a high percentage of low-abundance proteins, such as ion channels, receptors and transporter molecules were detected. Data are available via ProteomeXchange with identifier PXD014773. A high number of proteins exhibited different expression patterns following chondrocyte stimulation with pro-inflammatory cytokines. Low density lipoprotein related protein 1 (LPR-1), thrombospondin-1 (TSP-1), voltage dependent anion channel (VDAC) 1–2 and annexin A1 were considered to be of special interest and were analysed further by western blotting. Conclusions Our results provide, for the first time, a repository for proteomic data on differentially expressed low-abundance membrane proteins on the surface of chondrocytes in response to pro-inflammatory stimuli.

Purpose: To summarize last year's important and novel findings on biochemical markers relevant to osteoarthritis (OA), with a particular emphasis on their potential relevance to OA phenotyping studies. OA phenotypes are defined as subtypes of OA that share distinct underlying pathobiological and pain mechanisms and their structural and functional consequences. Methods: Electronic medical databases (PubMed, EMBASE, Scopus) were searched for relevant publications between 01-04-2018 and 01-03-2019. Publications describing biochemical markers in blood, urine and/or synovial fluid were included. The search was restricted to human data, English language and full text publications. Results: This review will highlight a selection of the thus identified publications based on their perceived importance to the OA field as a whole and OA phenotype research in particular, based on expert opinion. Conclusions: Key findings and the potential implications thereof for OA phenotyping studies will be discussed.

ObjectiveTo provide an insightful summary of studies on biochemical markers for osteoarthritis (OA).DesignTwo investigators systematically searched the electronic PubMed database for clinical studies into soluble biochemical markers for OA in humans that were published between 01-03-2018 and 01-03-2019. Data from selected publications were systematically extracted and tabulated and were summarized in a narrative review.ResultsOut of 1,279 publications, 124 fulfilled all selection criteria and were selected for data extraction. The majority were around knee OA, cross-sectional in design, relatively small, and/or focused on one or a few biochemical markers. Among the intervention studies, relatively many were on non-pharmacological interventions, used clinical outcomes and/or were rather short. Some leads that were provided by this year's studies pertained to less conventional inflammatory mediators, oxidative stress, acidosis, angiogenesis and/or autoantibody formation.ConclusionsThis year's biochemical marker studies did provide potential leads for therapeutic targets or other biochemical marker applications that require robust and strategic follow-up research to be validated.

Objective: To describe the radiographic and symptomatic course in subjects with hip or knee complaints suspected of early osteoarthritis (OA). Design: CHECK (Cohort Hip and Cohort Knee) is a multicenter, prospective observational cohort study of 1,002 subjects with first complaints in knee(s) and/or hip(s) (age 56 +/- 5 years; 79% female; body mass index (BMI) 26 +/- 4 kg/m(2)). Visits took place at baseline and at 2, 5, 8, and 10 year follow-up. At each visit, questionnaires were administered, physical examination performed, and X-ray images obtained. Clinical OA was defined according to the clinical American College of Rheumatism (ACR) criteria. Radiographic OA (ROA) was defined as Kellgren and Lawrence score (K&L) >= 2. Results: 83% of the subjects reported knee pain, 59% hip pain, and 42% reported both hip and knee pain at baseline. 85% of the subjects completed 10-year follow-up. Pain scores remained rather stable over time, although individual scores fluctuated. A total of 138 subjects never fulfilled the clinical American College of Rheumatology (ACR) criteria. 60% (n = 601) had ROA in one or both knees, and 51% (n = 513) had ROA in one or both hips at 10 years. Only 13.5% of the subjects did not develop ROA after 10 years. Most joint replacements (n = 52 (57%)) took place in subjects with multiple affected joints. Conclusions: The symptomatic course in subjects with hip or knee complaints suspected of OA remained fairly stable on population level, though individual scores fluctuated. The radiological course was progressive, with joint replacements particularly in subjects with both hip and knee OA. (C) 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Purpose: It is suggested that zoledronic acid (ZA) and other bone-active agents might serve as disease-modifying osteoarthritis drugs (DMOADs) in the subgroup of knee osteoarthritis (OA) with bone marrow lesions (BMLs). Clinical studies have already suggested pain reduction from ZA, but its structural effects remain unclear so far. The current two-year trial will study the efficacy of ZA over placebo for reducing articular cartilage loss, pain and disability in knee OA patients with BMLs. Methods: 86 Persons fulfilling the clinical and radiographic ACR criteria for tibiofemoral knee OA and aged between 40 and 75 years at the time of inclusion will be selected. They should report pain in the index knee on at least 50% of the days of the previous month (numeric rating scale, NRS, between 4/10 and 8/10). When two knees are eligible, the most painful knee is designated the index knee. At least one BML should be present on a MRI scan of the most affected tibiofemoral compartment (MAC) of the index knee (either medial or lateral, based on radiographs). Major exclusion criteria pertain to contraindications for ZA or MRI, grade 3 (i.e. complete) radiographic joint space loss according to the OARSI atlas, concurrent pharmacological interventions with potential to significantly influence pain and/or structure (except for oral analgesics), and/or expected surgical treatment of the index knee within 2 years. Patients will be randomized in a 1:1 ratio to either four semiannual intravenous gifts of 4 mg ZA or placebo (saline). Patients and researchers will be blinded to study arm allocation. Structural outcomes will be assessed at two years after the first infusion. Clinical outcomes will be collected at every study visit (i.e. baseline and 6, 12, 18 and 24 months). The primary outcome measure is total mean cartilage thickness in the tibial and load-bearing femoral regions of the MAC of the index knee on MRI (mm) at two years versus baseline. Secondary outcome measures are pain (NRS and Knee injury and Osteoarthritis Outcome Score, KOOS), oral analgesic use, disability (KOOS), BML size (mm2), minimum and mean tibiofemoral joint space width of the MAC on radiographs of the index knee (mm), total mean cartilage thickness in the tibial and load-bearing femoral regions of the tibiofemoral compartment contralateral to the MAC of the index knee and of both tibiofemoral compartments combined, and safety. The study is powered to detect a difference of 0.18 mm (based on a medium effect size of 0.67) in total mean cartilage thickness in the tibial and load-bearing femoral regions of the MAC of the index knee of ZA over placebo (primary outcome), with 80% power and an alpha of 0.05 and accounting for 15% dropout or loss to follow-up. The study protocol was approved by the institutional review board of the University Medical Center Utrecht, The Netherlands. Results: Inclusion started on 17 August 2018. Conclusions: This study is expected to further clarify the potential disease-modifying ability of ZA in knee OA patients with BMLs. EudraCT number 2017-001157-14.

Assessment of disease activity is a critical component of tight-control, treat-to-target treatment strategies of rheumatoid arthritis (RA). Recently, the HandScan has been validated as a novel method for objectively assessing RA disease activity in only 1.5 min, using optical spectral transmission (OST) in hands and wrists. We describe the protocol of a randomized controlled clinical trial (RCT) to investigate whether HandScan-guided treatment aimed at ‘HandScan remission’ (HandScan arm) is at least as effective as and more cost-effective than clinically guided treatment aimed at ACR/EULAR 2011 Boolean remission (DAS arm). The study is a multi-center, double-blind, non-inferiority RCT of 18 months duration. Patients ≥ 18 years with newly diagnosed, disease-modifying antirheumatic drug (DMARD)-naïve RA according to the ACR 2010 classification criteria, will be randomized to the DAS arm or the HandScan arm. The efficacy of the arms will be compared by evaluating Health Assessment Questionnaire (HAQ) scores (primary outcome) after 18 months of DMARD therapy, aimed at remission. The equivalence margin in HAQ scores between study arms is 0.2. Secondary outcomes are differences in cost-effectiveness and radiographic joint damage between treatment arms. The non-inferiority sample size calculation to obtain a power of 80% at a one-sided p value of 0.05, with 10% dropouts, resulted in 61 patients per arm. In both arms, DMARD strategy will be intensified monthly according to predefined steps until remission is achieved; in both arms DMARDs and treatment steps are identical. If sustained remission, defined as remission that persists consistently over three consecutive months, is achieved, DMARD therapy will be tapered. The study protocol and the specifically designed decision-making software application allow for implementation of this RCT. To test a novel method of assessing disease activity and comparing (cost-)effectiveness with the contemporary method in treat-to-target DMARD strategies in early RA patients. Dutch Trial Register, NTR6388. Registered on 6 April 2017 ( NL50026.041.14 ). Protocol version 3.0, 19-01-2017.

The success of disease-modifying osteoarthritis drug (DMOAD) development is still elusive. While there have been successes in preclinical and early clinical studies, phase 3 clinical trials have failed so far and there is still no approved, widely available DMOAD on the market. The latest research suggests that, among other causes, poor trial outcomes might be explained by the fact that osteoarthritis (OA) is a heterogeneous disease with distinct phenotypes. OA trials might be more successful if they would address and target a specific phenotype. The increasing availability of advanced techniques to detect particular OA characteristics expands the possibilities to distinguish between such potential OA phenotypes. Magnetic resonance imaging is among the key imaging techniques to stratify and monitor patients with changes in bone, cartilage and inflammation. Biochemical markers have mainly used as secondary parameters and could further delineate phenotypes. Moreover, post-hoc analyses of trial data have suggested the existence of distinct pain phenotypes and their relevance in the design of clinical trials. Although ongoing work in the field supports the concept of OA heterogeneity, this has not yet resulted in more effective treatment options. This paper reviews the current knowledge about potential OA phenotypes and suggests that combining patient clinical data, quantitative imaging, biochemical markers and utilizing data-driven approaches in patient selection and efficacy assessment will allow for more successful development of effective DMOADs.

Purpose: Disease modifying therapy of osteoarthritis (OA) represents an unmet clinical need, and appropriate outcome measures are required that can robustly identify patients with different OA phenotypes who may benefit from specific therapies. APPROACH is an exploratory, European, 5-centre, 2-year prospective follow-up cohort study. It entails extensive clinical, imaging, biomechanical and biochemical parameters, in a cohort recruited using machine learning models based on retrospective patient data to display a high likelihood of radiographic joint space width loss and/or knee pain over the course of the study. The purpose of the current work was to report the baseline test-retest reliability for measures of cartilage thickness and composition (T2) by MRI, and to identify potential differences between the participating sites. Methods: For the current pilot study, 3 volunteers had both knees imaged at 4 of the 5 sites (two with 1.5T MRI: A Coruña and Oslo; and two with 3.0T: Leiden and Utrecht; Table 1). Eventually, 30 participants (6 at each of the 5 sites) will have test-retest MRI acquisitions with repositioning of the knee, with 13 patients at 3 sites having currently completed this exercise (Table 2). Sagittal 3D WATS, 3D FFE, or FLASH VIBE sequences with water excitation or fat suppression (57-120 1.5 mm contiguous slices; 0.31 mm in-plane resolution; TR 17ms, TE 7ms, FA 12-15°) are acquired to determine cartilage thickness; multi echo spin echo (MESE) sequences (21 3.0 mm slices with 3.5 mm gap; 0.27-0.31 mm in-plane resolution; TR 2700ms, 5-7 echos between 0-70ms) are obtained to generate T2 maps (Figure). For cartilage thickness, segmentation of the total weight-bearing femorotibial cartilage plates was performed using Works 3.0 software (Chondrometrics GmbH, Ainring, Germany). For the T2 analysis, 3 central slices were analyzed in the medial (MFTC) and lateral femorotibial compartments (LFTC), due to lack of complete anatomical coverage of the MESE MRIs (Figure). Sets of intersite comparison images, and test-retest pairs, were read by the same reader in one session, with reference to each other. The root-mean square (RMS) standard deviation (SD) and coefficient of variation (CV%) were computed to estimate measurement variability. Results: One participant of the inter-site calibration study displayed motion in most images, so that only 4 knees of 2 participants were available for comparison. The mean cartilage thickness in the MFTC varied between 3.00 and 3.11 mm across the 4 sites, and that in the LFTC between 3.33 and 3.47 mm (Table 1).Table 1Intersite Comparison: Mean+/-SD at each site, and RMS SD (and CV%) across all 4 sitesThick / T2 n=Cart. ThicknessCart. Superficial T2Cart. Deep T2Medial femorotibial compartmentA Coruña4 / 43.10 +/- 0.09 mm50.7 +/- 3.2 ms40.6 +/- 0.7 msOslo4 / 43.11+/- 0.07 mmT2 not acquiredLeiden4 / 43.00 +/- 0.07 mm43.7 +/- 0.8 ms28.8 +/- 1.5 msUtrecht4 / 43.08 +/- 0.11 mm47.3 +/- 3.3 ms28.0 +/- 1.1 msRMS SD (CV %)16 / 1679 um (2.6%)4.5 ms (9.4%)7.1 ms (22%)Lateral femorotibial compartmentA Coruña3 / 43.33 +/- 0.13 mm54.6 +/- 4.1 ms42.3 +/- 2.1 msOslo4 / 43.42 +/- 0.14 mmT2 not acquiredLeiden4 / 43.40 +/ - 0.10 mm48.2 +/- 0.8 ms33.4 +/- 2.6 msUtrecht4 / 43.47 +/- 0.10 mm49.1 +/- 3.6 ms30.9 +/- 2.6 msRMS SD (CV%)16 / 1678 um (2.3%)4.1 ms (7.9%)6.2 ms (17%) Open table in a new tab The test-retest reliability was 46μm (RMS SD) or 1.5% (RMS CV%) in the MFTC, with a range of 1.2 to 1.7% across the 3 sites. Test-retest errors in the LFTC were similar but somewhat more variable across the sites (Table 2).Table 2RMS SD (and CV%) of test retest acquisitions at each site, and across all 3 sitesThick / T 2 n=Cart. ThicknessCart. Superficial T2Cart. Deep T2Medial femorotibial compartmentA Coruña3 / 047 um (1.6%)NANALeiden6 / 550 um (1.7%)0.71 ms (1.6%)1.52 ms (4.4%)Utrecht4 / 440 um (1.2%)1.38 ms (2.8%)1.91 ms (5.9%)ALL13 / 946 um (1.5%)1.06 ms (2.2%)1.70 ms (5.1%)Lateral femorotibial compartmentA Coruña3 / 057 um (2.1%)NANALeiden6 / 531 um (1.0%)0.98 ms (2.1%)0.50 ms (1.4%)Utrecht4 / 410 um (0.3%)0.43 ms (1.0%)1.45 ms (4.8%)ALL13 / 935 um (1.2%)0.79 ms (1.7%)1.04 ms (3.3%) Open table in a new tab The inter-site variability (RMS SD and CV%) for cartilage thickness was only marginally greater than the test-retest errors (Table 1, Table 2). The cartilage T2 was consistently longer in the superficial than in the deep layer (both in the MFTC and LFTC), and consistently longer in the LFTC than in MFTC (both in the superficial and deep layer) at all 4 sites (Table 1). However, there were obvious differences in the absolute values between sites that exceeded the variability across the 4 knees. Notably, longer TEs were apparent for 1.5T (A Coruña) compared with 3.0T MRI (Leiden and Utrecht; Table 1). Test-retest errors of superficial and deep cartilage T2 were substantially smaller than the inter-site variability, and were only somewhat greater than those for cartilage thickness (Table 2). Conclusions: In this pilot study, we have explored inter-site differences and test-retest reliability of cartilage thickness and composition analysis (T2) by MRI, in a multicenter European exploratory trial. An obvious limitation of the pilot analysis is the small sample size, but few multicenter studies have thus far made any effort to determine measurement variability across and within sites. Cartilage thickness measures only displayed small differences between sites and were well reproduced with repositioning. Cartilage T2 also showed relatively high test-retest reliability, but yielded notable differences between sites, particularly between 1.5 and 3.0T. Hence, in contrast to measurements of cartilage thickness, T2 measurements should not be pooled across sites for cross-sectional statistical analysis. Acknowledgment: This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (APPROACH grant n° 115770). This communication reflects the views of the authors and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.

ABSTRACT The blood metabolome incorporates cues from the environment as well as the host’s genetic background, potentially offering a holistic view of an individual’s health status. We have compiled a vast resource of 1 H-NMR metabolomics and phenotypic data encompassing over 25,000 samples derived from 26 community and hospital-based cohorts. Using this resource, we constructed a metabolomics-based age predictor (metaboAge) to calculate an individual’s biological age. Exploration in independent cohorts demonstrates that being judged older by one’s metabolome, as compared to one’s chronological age, confers an increased risk on future cardiovascular disease, mortality and functionality in older individuals. A web-based tool for calculating metaboAge ( metaboage.researchlumc.nl ) allows easy incorporation in other epidemiological studies. Access to data can be requested at bbmri.nl/samples-images-data . In summary, we present a vast resource of metabolomics data and illustrate its merit by constructing a metabolomics-based score for biological age that captures aspects of current and future cardio-metabolic health.