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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., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Altamirano et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Digital symptom-checkers (SCs) have potential to improve rheumatology triage and reduce diagnostic delays. In addition to being accurate, SCs should be user friendly and meet patient's needs. Here, we examined usability and acceptance of Rheumatic? -a new and freely available online SC (currently with >44 000 users)-in a real-world setting., Methods: Study participants were recruited from an ongoing prospective study, and included people ≥18 years with musculoskeletal complaints completing Rheumatic? online. The user experience survey comprised five usability and acceptability questions (11-point rating scale), and an open-ended question regarding improvement of Rheumatic? Data were analysed in R using t-test or Wilcoxon rank test (group comparisons), or linear regression (continuous variables)., Results: A total of 12 712 people completed the user experience survey. The study population had a normal age distribution, with a peak at 50-59 years, and 78% women. A majority found Rheumatic? useful (78%), thought the questionnaire gave them an opportunity to describe their complaints well (76%), and would recommend Rheumatic? to friends and other patients (74%). Main shortcoming was that 36% thought there were too many questions. Still, 39% suggested more detailed questions, and only 2% suggested a reduction of questions., Conclusion: Based on real-world data from the largest user evaluation study of a digital SC in rheumatology, we conclude that Rheumatic? is well accepted by women and men with rheumatic complaints, in all investigated age groups. Wide-scale adoption of Rheumatic? , therefore, seems feasible, with promising scientific and clinical implications on the horizon., Competing Interests: Competing interests: RK is an editorial board member of RMD Open. She has not been involved in handling of the manuscript at RMD Open, or in communication with the journal regarding the study. LUMC and KI are research collaborators with Elsa Science AB. Elsa Science AB has contributed to the collaboration with in-kind contributions to the design, development and hosting of the digital symptom-checker Rheumatic? KL was part-time employed by Elsa Science, January 2022–February 2023. All other authors declare no commercial or financial conflict of interest in relation to the study., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To investigate cartilage tissue turnover in response to a supervised 12-week exercise-related joint loading training program followed by a 6-month period of unsupervised training in patients with knee osteoarthritis (OA). To study the difference in cartilage tissue turnover between high- and low-resistance training., Method: Patients with knee OA were randomized into either high-intensity or low-intensity resistance supervised training (two sessions per week) for 3 months and unsupervised training for 6 months. Blood samples were collected before and after the supervised training period and after the follow-up period. Biomarkers huARGS, C2M, and PRO-C2, quantifying cartilage tissue turnover, were measured by ELISA. Changes in biomarker levels over time within and between groups were analyzed using linear mixed models with baseline values as covariates., Results: huARGS and C2M levels increased after training and at follow-up in both low- and high-intensity exercise groups. No changes were found in PRO-C2. The huARGS level in the high-intensity resistance training group increased significantly compared to the low-intensity resistance training group after resistance training (p = 0.029) and at follow-up (p = 0.003)., Conclusion: Cartilage tissue turnover and cartilage degradation appear to increase in response to a 3-month exercise-related joint loading training program and at 6-month follow-up, with no evident difference in type II collagen formation. Aggrecan remodeling increased more with high-intensity resistance training than with low-intensity exercise. These exploratory biomarker results, indicating more cartilage degeneration in the high-intensity group, in combination with no clinical outcome differences of the VIDEX study, may argue against high-intensity training., (© 2023. The Author(s).)

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., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Osteoarthritis, rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, all have one clear common denominator; an altered turnover of bone. However, this may be more complex than a simple change in bone matrix and mineral turnover. While these diseases share a common tissue axis, their manifestations in the area of pathology are highly diverse, ranging from sclerosis to erosion of bone in different regions. The management of these diseases will benefit from a deeper understanding of the local versus systemic effects, the relation to the equilibrium of the bone balance (i.e., bone formation versus bone resorption), and the physiological and pathophysiological phenotypes of the cells involved (e.g., osteoblasts, osteoclasts, osteocytes and chondrocytes). For example, the process of endochondral bone formation in chondrocytes occurs exists during skeletal development and healthy conditions, but also in pathological conditions. This review focuses on the complex molecular and cellular taxonomy of bone in the context of rheumatological diseases that alter bone matrix composition and maintenance, giving rise to different bone turnover phenotypes, and how biomarkers (biochemical markers) can be applied to potentially describe specific bone phenotypic tissue profiles.

Background: The blood metabolome incorporates cues from the environment and the host's genetic background, potentially offering a holistic view of an individual's health status., Methods: We have compiled a vast resource of proton nuclear magnetic resonance metabolomics and phenotypic data encompassing over 25 000 samples derived from 26 community and hospital-based cohorts., Results: 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 with 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., Conclusions: 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 cardiometabolic health.

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 1 H-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.

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., Competing Interests: Competing interests: EMvH has nothing to disclose; WEvS reports grants from The Innovative Medicines Initiative Joint Undertaking under Grant Agreement no 115770, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution, during the conduct of the study; MPJ has nothing to disclose; PMJW has nothing to disclose. MK reports grants from IMI-APPROACH, grants from Dutch Arthritis Association, during the conduct of the study; other from GlaxoSmithKline, Pfizer, Merck-Serono, Kiniksa, Abbvie, outside the submitted work; ML reports grants from Inovative Medicines Initative, during the conduct of the study; FJB reports grants from Gebro Pharma, grants from BIOIBERICA, grants from AB Science, grants from Abbvie, grants from Ablynx N.V., grants from Amgen, grants from Archigen Biotech, grants from Boehringer, grants from Bristol-Myers, grants from Celgene Int., grants from Eli Lilly and Company, grants from F. Hoffmann- La Roche, grants from Galapagos, grants from Gedeon, grants from Genentech, grants from Gideal Sciences, NC, grants from Glaxosmithkline, grants from Hospira, grants from INC Research UK, grants from Inventiv Health Clinical, grants from Janssen, grants from Lilly, grants from Nichi-IKO Pharmaceutical, grants from Novartis, grants from ONO Pharma, grants from Pfizer, grants from Pharmaceutical Research, grants from Regeneron, grants from Roche, grants from SA UCB Pharma, grants from Sanofi, grants from TRB Chemedica, grants from UCB Biosciences GMBH, outside the submitted work; In addition, FJB has a patent Molecular block-matching method for gel image analysis issued, a patent Targeting A Specific Receptor On Cells With A Specific Compound For Use In The Treatment And/Or The Prevention Of Osteoarthritis And Rheumatoid Arthritis pending, a patent Genetic markers for osteoarthritis issued, a patent Method for the diagnosis of osteoarthritis issued, a patent Genetic markers for osteoarthritis pending, a patent Method for the diagnosing Arthrosis pending, a patent Method for diagnosing Arthrosis pending, a patent Method for the diagnosis of osteoarthritis pending, and a patent Anti-connexin compounds for use in the prevention and/or treatment of degenerative joint diseases. pending; IKH reports personal fees from AbbVie, grants from Pfizer, outside the submitted work; FB reports personal fees from Boehringer, Bone Therapeutics, Expanscience, Galapagos, Gilead, GSK, Merck Sereno, MSD, Nordic, Novartis, Pfizer, Regulaxis, Roche, Sandoz, Sanofi, Servier, UCB, Peptinov, TRB Chemedica, 4P Pharma, outside the submitted work; CHL reports other from Merck KGaA, during the conduct of the study; JLo has nothing to disclose; ACB-J reports non-financial support from Nordic Bioscience, personal fees from Nordic Bioscience, during the conduct of the study; AM has nothing to disclose; JLa reports personal fees and other from GlaxoSmithKline, outside the submitted work; and Current employee and shareholder of GlaxoSmithKline; JBo reports grants from Innovative Medicines Initiative (IMI-1), during the conduct of the study; and one of Lygature's other project receives part of its funding directly from Merck KgaA. This project is in the field of schistosomiasis and has no relationship whatsoever with the APPROACH project; HHW has nothing to disclose; ACAM has nothing to disclose; FPJGL has nothing to disclose., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

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.

Objective: To provide an insightful summary of studies on biochemical markers for osteoarthritis (OA)., Design: Two 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., Results: Out 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., Conclusions: This 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., (Copyright © 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

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) (Kellgren-Lawrence 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., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Recent research in the field of osteoarthritis (OA) has focused on understanding the underlying molecular and clinical phenotypes of the disease. This narrative review article focuses on recent advances in our understanding of the phenotypes of OA and proposes that the disease represents a diversity of clinical phenotypes that are underpinned by a number of molecular mechanisms, which may be shared by several phenotypes and targeted more specifically for therapeutic purposes. The clinical phenotypes of OA supposedly have different underlying etiologies and pathogenic pathways and they progress at different rates. Large OA population cohorts consist of a majority of patients whose disease progresses slowly and a minority of individuals whose disease may progress faster. The ability to identify the people with relatively rapidly progressing OA can transform clinical trials and enhance their efficiency. The identification, characterization, and classification of molecular phenotypes of rapidly progressing OA, which represent patients who may benefit most from intervention, could potentially serve as the basis for precision medicine for this disabling condition. Imaging and biochemical markers (biomarkers) are important diagnostic and research tools that can assist with this challenge., Competing Interests: Competing interests: Anne-Christine Bay-Jensen and Morten A. Karsdal are full-time employees and shareholders of Nordic Bioscience, a small–medium enterprise involved in biomarker identification, validation, and development. Ali Mobasheri has consulted for the following companies in the last three years: Abbvie, Aché Laboratórios Farmacêuticos S.A., AlphaSights, Galapagos, Guidepoint Global, Kolon TissueGene, Pfizer Consumer Health (PCH), Servier, Bioiberica S.A. and Science Branding Communications. No competing interests were disclosed.No competing interests were disclosed., (Copyright: © 2019 Mobasheri A et al.)

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., (Copyright © 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

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., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the ability of radiography-based bone texture variables in proximal femur and acetabulum to predict incident radiographic hip osteoarthritis (rHOA) over a 10 years period., Design: Pelvic radiographs from CHECK at baseline (987 hips) were analyzed for bone texture using fractal signature analysis (FSA) in proximal femur and acetabulum. Elastic net (machine learning) was used to predict the incidence of rHOA (including Kellgren-Lawrence grade (KL) ≥ 2 or total hip replacement (THR)), joint space narrowing score (JSN, range 0-3), and osteophyte score (OST, range 0-3) after 10 years. Performance of prediction models was assessed using the area under the receiver operating characteristic curve (ROC AUC)., Results: Of the 987 hips without rHOA at baseline, 435 (44%) had rHOA at 10-year follow-up. Of the 667 hips with JSN grade 0 at baseline, 471 (71%) had JSN grade ≥ 1 at 10-year follow-up. Of the 613 hips with OST grade 0 at baseline, 526 (86%) had OST grade ≥ 1 at 10-year follow-up. AUCs for the models including age, gender, and body mass index (BMI) to predict incident rHOA, JSN, and OST were 0.59, 0.54, and 0.51, respectively. The inclusion of bone texture variables in the models improved the prediction of incident rHOA (ROC AUC 0.68 and 0.71 when baseline KL was also included in the model) and JSN (ROC AUC 0.62), but not incident OST (ROC AUC 0.52)., Conclusion: Bone texture analysis provides additional information for predicting incident rHOA or THR over 10 years., (Copyright © 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Background: 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)., Methods/design: 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., Discussion: 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., Trial Registration: Dutch Trial Register, NTR6388. Registered on 6 April 2017 ( NL50026.041.14 ). Protocol version 3.0, 19-01-2017.

Objective: To determine whether optical spectral transmission (OST) can be used to assess synovitis in hand and wrist joints of patients with hand osteoarthritis (OA)., Design: Hand and wrist joints of 47 primary hand OA patients with at least one clinically inflamed hand or wrist joint were assessed for synovitis by OST and ultrasound (US). Associations between standardized OST and US synovitis were studied in linear mixed effects models, across all joint types together and individually for wrist, proximal interphalangeal (PIP), and distal interphalangeal (DIP) joints, and were adjusted for OA features that showed associations with US synovitis. Diagnostic performance was determined using receiver operator characteristic (ROC) curves analysis, with US as reference standard., Results: Altogether, 6.7% of joints showed US synovitis. Statistically significant associations between OST scores and US synovitis were found for all joints combined (Δ0.37SD, p<0.001) and PIP joints (Δ0.81SD, p<0.001), but not for DIP (Δ0.14SD, p = 0.484) or wrist joints (Δ0.37SD, p = 0.178). All associations were independent of other OA features, i.e. osteophytes and dorsal vascularity. Analysis of diagnostic performance of OST, revealed an area under the ROC curve (AUC-ROC) of 0.74 for all joints together (p<0.001), 0.69 for PIP joints (p<0.001), 0.54 for DIP joints (p = 0.486), and 0.61 for wrist joints (p = 0.234)., Conclusions: OST scores and US synovitis are statistically significantly associated, independent of osteophytes and dorsal vascularity. At this stage, OST performs fair in the assessment of synovitis in PIP joints of hand OA patients., Competing Interests: Data sharing restrictions apply to the HandScan software. This software is is proprietary third party software and therefore cannot be made available as open source software. An unrestricted research grant was provided by Hemics to finance the salaries of NB and PvdM. The authors have no patent applications, ownership and possess no stocks or shares of the company Hemics, nor receive any gift, consulting fee, royalty, travel grant, or honorarium for speaking or participation at meetings, or the like. The authors have no other potential conflicts of interest to disclose.

Objective: There is significant variability in the trajectory of structural progression across people with knee osteoarthritis (OA). We aimed to identify distinct trajectories of femorotibial cartilage thickness over 2 years and develop a prediction model to identify individuals experiencing progressive cartilage loss., Methods: We analysed data from the Osteoarthritis Initiative (OAI) (n = 1,014). Latent class growth analysis (LCGA) was used to identify trajectories of medial femorotibial cartilage thickness assessed on magnetic resonance imaging (MRI) at baseline, 1 and 2 years. Baseline characteristics were compared between trajectory-based subgroups and a prediction model was developed including those with frequent knee symptoms at baseline (n = 686). To examine clinical relevance of the trajectories, we assessed their association with concurrent changes in knee pain and incidence of total knee replacement (TKR) over 4 years., Results: The optimal model identified three distinct trajectories: (1) stable (87.7% of the population, mean change -0.08 mm, SD 0.19); (2) moderate cartilage loss (10.0%, -0.75 mm, SD 0.16) and (3) substantial cartilage loss (2.2%, -1.38 mm, SD 0.23). Higher Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) pain scores, family history of TKR, obesity, radiographic medial joint space narrowing (JSN) ≥1 and pain duration ≤1 year were predictive of belonging to either the moderate or substantial cartilage loss trajectory [area under the curve (AUC) 0.79, 95% confidence interval (CI) 0.74, 0.84]. The two progression trajectories combined were associated with pain progression (OR 1.99, 95% CI 1.34, 2.97) and incidence of TKR (OR 4.34, 1.62, 11.62)., Conclusions: A minority of individuals follow a progressive cartilage loss trajectory which was strongly associated with poorer clinical outcomes. If externally validated, the prediction model may help to select individuals who may benefit from cartilage-targeted therapies., (Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Purpose of Review: This review focuses on the molecular taxonomy of osteoarthritis from the perspective of molecular biomarkers. We discuss how wet biochemical markers may be used to understand disease pathogenesis and progression and define molecular endotypes of osteoarthritis and how these correspond to clinical phenotypes., Recent Findings: Emerging evidence suggests that osteoarthritis is a heterogeneous and multifaceted disease with multiple causes, molecular endotypes and corresponding clinical phenotypes. Biomarkers may be employed as tools for patient stratification in clinical trials, enhanced disease management in the primary care centres of the future and for directing more rational and targeted osteoarthritis drug development. Proximal molecular biomarkers (e.g synovial fluid) are more likely to distinguish between molecular endotypes because there is less interference from systemic sources of biomarker noise, including comorbidities., Summary: In this review, we have focused on the molecular biomarkers of four distinct osteoarthritis subtypes including inflammatory, subchondral bone remodelling, metabolic syndrome and senescent age-related endotypes, which have corresponding phenotypes. Progress in the field of osteoarthritis endotype and phenotype research requires a better understanding of molecular biomarkers that may be used in conjunction with imaging, pain and functional assessments for the design of more effective, stratified and individualized osteoarthritis treatments.

Introduction: Randomised clinical trials to date investigating the efficacy of bisphosphonates in knee osteoarthritis (OA) have found divergent results, with a recent meta-analysis finding no superiority of these drugs over placebo. Whether particular patient subgroups are more likely to benefit from this therapy than others is still unclear. We aim to investigate the effects of bisphosphonates compared with a control group (placebo, no treatment, another active treatment) on clinical and structural outcomes in specific knee OA subpopulations with possible distinct rates of subchondral bone turnover., Methods and Analysis: Medline, Embase, Scopus, Web of Sciences and Cochrane Central Register of Controlled Trials will be searched from inception to February 2018. Randomised clinical trials will be eligible if they reported at least one potential treatment effect modifier at baseline: gender, menopausal status, age, body mass index, radiographic stage, knee pain severity, presence of bone marrow lesions, levels of biochemical markers of bone turnover (serum and/or urinary) and systemic bone mineral density status. Authors of original trials will be contacted to obtain individual patient data from each study. Risk of bias will be assessed using the Cochrane Collaboration's tool. The primary outcomes will include pain and radiographic joint space width loss. Studies using other MRI-based assessment of disease progression will also be eligible. Outcomes will be grouped into short-term (≤3 months), intermediate-term (>3 months; ≤12 months) and long-term (>12 months). Regression models will be used, adding an interaction term for each subgroup of interest to determine possible subgroup effects. There was no source of funding for this study., Ethics and Dissemination: Dissemination of our findings is planned to occur through conference presentations, publication in peer-reviewed journals and social media. No formal ethics approval is generally required as no new data collection will be undertaken., Prospero Registration Number: CRD42018093327., Competing Interests: Competing interests: Professor David Hunter reports personal fees from consulting fees from Merck Serono, Flexion and Tissuegene, outside the submitted work. Prof. Bierma-Zeinstra reports grants from the European Union, The Netherlands Organisation for Health Research and Development, Dutch Arthritis Foundation, CZ, Nuts Ohra, Stichting Coolsingel, personal fees from Infirst Healthcare and from Osteoarthritis and Cartilage, outside the submitted work. All other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: On a population level, the incidence of knee prostheses (KPs) has increased, but excess health care costs per patient, compared to matched controls without a KP, in the years surrounding these procedures and their determinants are largely unknown. We therefore aimed to provide estimates of age- and sex-specific incidence of KPs, revision KPs, and prosthesis complications in patients with knee osteoarthritis (OA) and to determine excess health care costs in the years surrounding surgery compared with matched controls., Methods: All KPs in OA patients in the Achmea Health Database were identified as well as up to four controls. Incidence rates of KPs, revisions, and complications from 2006 to 2013 were determined. Annual health care cost and excess costs (over matched controls) preceding, during, and after surgery were calculated and their determinants were evaluated., Results: The increased incidence of KPs, revisions, and complications was strongest in younger age categories and men. The average costs per patient were relatively stable between 2006 and 2012. KP patient's annual health care costs increased towards the year of surgery. After surgery, costs decreased, but remained higher as compared to costs prior to surgery. High post-surgery costs were mainly associated with subsequent revisions or additional KPs, but costs were also higher in females, lower age categories, and lower social economic status., Conclusion: These results underscore the increasing burden and medical need associated with end-stage OA, especially in younger age categories. Improvement of guidelines tailored to individual patient groups aimed at avoiding complications and revisions is required to counteract this increasing burden., (Copyright © 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objectives: There is sparse evidence for a relationship between cardiovascular disease (CVD) and osteoarthritis (OA). We investigated the association between incidence of arterial calcifications and incidence of radiographic knee and/or hip OA., Design: We used baseline and 8-year follow-up data of Cohort Hip and Cohort Knee (CHECK). Knees and hips were either Kellgren-Lawrence (KL) grade 0 or 1 at baseline. Arterial calcifications were scored on hip and knee radiographs using a four-grade scale. Scores were summed for patient-level analyses. To investigate incidence, participants with arterial calcifications at baseline or missing follow-up were excluded. Incident OA was defined per joint as KL ≥ 2 or prosthesis at year eight. The association between incidenct of arterial calcifications and incident OA was studied using mixed-effects logistic regression., Results: Of 763 participants included, 623 (82%) were women. Mean (sd) age was 56 (5.1) years, mean (sd) body mass index (BMI) 26.2 (4.1) kg/m 2 . Arterial calcifications developed in 174 participants (283 joints). OA developed in 456 participants (778 joints). Sex modified the association between arterial calcification and OA. In women, incident arterial calcification around a joint was positively associated with incident OA in that joint (adjusted OR 2.51 (95% CI 1.57-4.03)). In men, no association was observed on joint-level, but at patient-level the arterial calcification sum score was negatively associated with incident OA (adjusted OR per point increase 0.70 (95% CI 0.54-0.90)) indicating a systemic effect., Conclusions: We observed sex-dependent associations between incident arterial calcification and incident radiographic knee and/or hip OA, which differs between joint- and patient-level., (Copyright © 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Purpose: The aim of this "Year in Review" article is to summarize and discuss the implications of biochemical marker related articles published between the Osteoarthritis Research Society International (OARSI) 2015 Congress in Seattle and the OARSI 2016 Congress in Amsterdam., Methods: The PubMed/MEDLINE bibliographic database was searched using the combined keywords: 'biomarker' and 'osteoarthritis'. The PubMed/MEDLINE literature search was conducted using the Advanced Search Builder function (http://www.ncbi.nlm.nih.gov/pubmed/advanced)., Results: Over two hundred new biomarker-related papers were published during the literature search period. Some papers identified new biomarkers whereas others explored the biological properties and clinical utility of existing markers. There were specific references to several adipocytokines including leptin and adiponectin. ADAM Metallopeptidase with Thrombospondin Type 1 motif 4 (ADAMTS-4) and aggrecan ARGS neo-epitope fragment (ARGS) in synovial fluid (SF) and plasma chemokine (CeC motif) ligand 3 (CCL3) were reported as potential new knee biomarkers. New and refined proteomic technologies and novel assays including a fluoro-microbead guiding chip (FMGC) for measuring C-telopeptide of type II collagen (CTX-II) in serum and urine and a novel magnetic nanoparticle-based technology (termed magnetic capture) for collecting and concentrating CTX-II, were described this past year., Conclusion: There has been steady progress in osteoarthritis (OA) biomarker research in 2016. Several novel biomarkers were identified and new technologies have been developed for measuring existing biomarkers. However, there has been no "quantum leap" this past year and identification of novel early OA biomarkers remains challenging. During the past year, OARSI published a set of recommendations for the use of soluble biomarkers in clinical trials, which is a major step forward in the clinical use of OA biomarkers and bodes well for future OA biomarker development., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Knee joint distraction (KJD) is a surgical joint-preserving treatment in which the knee joint is temporarily distracted by an external frame. It is associated with joint tissue repair and clinical improvement. Initially, patients were submitted to an eight-week distraction period, and currently patients are submitted to a six-week distraction period. This study evaluates whether a shorter distraction period influences the outcome., Methods: Both groups consisted of 20 patients. Clinical outcome was assessed by WOMAC questionnaires and VAS-pain. Cartilaginous tissue repair was assessed by radiographic joint space width (JSW) and MRI-observed cartilage thickness., Results: Baseline data between both groups were comparable. Both groups showed an increase in total WOMAC score; 24±4 in the six-week group and 32±5 in the eight-week group (both p<0.001). Mean JSW increased 0.9±0.3mm in the six-week group and 1.1±0.3mm in the eight-week group (p=0.729 between groups). The increase in mean cartilage thickness on MRI was 0.6±0.2mm in the eight-week group and 0.4±0.1mm in the six-week group (p=0.277)., Conclusions: A shorter distraction period does not influence short-term clinical and structural outcomes statistically significantly, although effect sizes tend to be smaller in six week KJD as compared to eight week KJD., (Copyright © 2016 Elsevier B.V. All rights reserved.)

To make an advanced decision about resuscitation it is important to know what its outcomes are. In-hospital resuscitation cannot always be compared with out-of-hospital resuscitation; furthermore, outcomes of in-hospital resuscitation vary between hospital wards and patient populations. Age plays a role in the outcome of a resuscitation procedure. However, older patients who leave hospital alive have a reasonable prognosis as far as survival and neurological function are concerned. Data on quality of life and self-reliance after resuscitation are scarce or non-existent. Comorbidities and ADL status also contribute to the outcome of resuscitation, independent of age. One of the goals of Emergency Intervention Systems is to limit the number of in-hospital resuscitations. Although these systems are probably successful at this point, this cannot be demonstrated in all studies. Much of our knowledge about in-hospital resuscitation is based solely on American research.

Objective: First, to study how markers of matrix metabolism, inflammation markers, and adipokines relate to (superior) cam deformity and (possible) cam impingement of the hip. Second, to investigate whether they can identify subjects with cam deformity that are at risk of future hip osteoarthritis (OA)., Method: In a cohort of 1002 subjects (CHECK), (superior) cam deformity was defined by an alpha angle >60° on anteroposterior pelvic radiographs and (possible) cam impingement by a cam deformity together with internal hip rotation ≤20°. Hip OA at 5-year follow-up was defined by Kellgren and Lawrence grade ≥2 or total hip replacement., Results: Subjects with (superior) cam deformity and (possible) cam impingement showed lower levels of bone turnover markers (uCTX-I, uNTX-I, sPINP, sOC) than those without. Cam deformity was positively associated with future hip OA, but associations were weaker at high levels of bone turnover. sCOMP and sHA levels were higher in subjects with cam deformity, while other cartilage and synovium markers were not. Some markers of inflammation (pLeptin, pAdiponectin, and erythrocyte sedimentation rate) were lower in presence of cam deformity and cam impingement, but high-sensitivity C-reactive protein was not. Most associations depended largely on gender differences., Conclusion: Bone metabolism may be relevant in the pathogenesis of (superior) cam deformity and in the development of (superior) cam deformity into hip OA. Subjects with cam deformity and cam impingement surprisingly showed lower levels of inflammation markers and adipokines. Associations of cartilage turnover markers with cam deformity and cam impingement were less obvious., (Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To relate systemic biochemical markers of joint metabolism to presence, incidence, and progression of early-stage radiographic knee and/or hip osteoarthritis (OA)., Method: The cartilage markers uCTX-II, sCOMP, sPIIANP, and sCS846, bone markers uCTX-I, uNTX-I, sPINP, and sOC, and synovial markers sHA and sPIIINP were assessed by enzyme-linked immunosorbent assay or radioactive immunoassay in baseline samples of CHECK (Cohort Hip and Cohort Knee), a cohort study of early-stage symptomatic knee and/or hip OA. Knee and hip radiographs were obtained at baseline and 5-year follow-up. Presence of OA at baseline was defined as Kellgren and Lawrence (K&L) = 1 (maximum observed). Incidence of OA was defined as K&L = 0 at baseline and K&L ≥ 1 at 5-year follow-up. Progression of OA was defined as K&L = 1 at baseline and K&L ≥ 2 at 5-year follow-up., Results: Data were available for 801 subjects at baseline and for 723 subjects at both baseline and 5-year follow-up. Multiple cartilage and synovial markers showed positive associations with presence and progression of knee and hip OA and with incidence of hip OA, except for negative associations of uCTX-II and sCOMP with incidence of knee OA. uCTX-II and sCOMP showed multiple interactions with other biomarkers in their associations with knee and hip OA. Bone markers were positively associated with presence of radiographic knee OA, but negatively associated with progression of radiographic hip OA., Conclusion: Especially metabolism in cartilage and synovial matrix appear to be of relevance in knee and hip OA. The role of bone metabolism appears to differ between knee and hip OA., (Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Immunocompromised patients are at increased risk of disseminated cryptococcal infection, often presenting as a primary respiratory infection with yeast cells originating from bird excreta. Because Cryptococcus neoformans has a tropism for cerebrospinal fluid, most patients suffer from meningitis or meningoencephalitis. Symptoms of cryptococcal meningitis are non-specific: headache, fever, nausea, or altered mental state and behaviour. Case descriptions of a renal transplant recipient and an HIV patient illustrate the non-specific presentation of cryptococcal meningitis. Lumbar puncture seemed to be critical in establishing the diagnosis. Cerebrospinal fluid, blood and other tissues were tested for C. neoformans by microscopy, culture and antigen tests. The patients were successfully treated with amphotericin B or liposomal amphotericin B intravenously and flucytosine intravenously or orally, followed by long-term fluconazole. The mortality rate for cryptococcal meningitis is 41% among renal transplant recipients and 20% in HIV patients.

Objective: To investigate associations of biochemical markers of joint metabolism and inflammation with minimum joint space width (JSW) and osteophyte area (OP area) of knees showing no or doubtful radiographic osteoarthritis (OA) and to investigate whether these differed between painful and non-painful knees., Design: Serum (s-) and urinary (u-) levels of the cartilage markers uCTX-II, sCOMP, sPIIANP, and sCS846, bone markers uCTX-I, uNTX-I, sPINP, and sOC, synovial markers sPIIINP and sHA, and inflammation markers hsCRP and erythrocyte sedimentation rate (ESR) were assessed in subjects from CHECK (Cohort Hip and Cohort Knee) demonstrating Kellgren and Lawrence grade ≤1 OA on knee radiographs. Minimum JSW and OP area of these knees were quantified in detail using Knee Images Digital Analysis (KIDA)., Results: uCTX-II levels showed negative associations with minimum JSW and positive associations with OP area. sCOMP and sHA levels showed positive associations with OP area, but not with minimum JSW. uCTX-I and uNTX-I levels showed negative associations with minimum JSW and OP area. Associations of biochemical marker levels with minimum JSW were similar between painful and non-painful knees, associations of uCTX-II, sCOMP, and sHA with OP area were only observed in painful knees., Conclusions: In these subjects with no or doubtful radiographic knee OA, uCTX-II might not only reflect articular cartilage degradation but also endochondral ossification in osteophytes. Furthermore, sCOMP and sHA relate to osteophytes, maybe because synovitis drives osteophyte development. High bone turnover may aggravate articular cartilage loss. Metabolic activity in osteophytes and synovial tissue, but not in articular cartilage may be related to knee pain., (Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Osteoarthritis affects the whole joint structure with progressive changes in cartilage, menisci, ligaments and subchondral bone, and synovial inflammation. Biomarkers are being developed to quantify joint remodelling and disease progression. This article was prepared following a working meeting of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis convened to discuss the value of biochemical markers of matrix metabolism in drug development in osteoarthritis. The best candidates are generally molecules or molecular fragments present in cartilage, bone or synovium and may be specific to one type of joint tissue or common to them all. Many currently investigated biomarkers are associated with collagen metabolism in cartilage or bone, or aggrecan metabolism in cartilage. Other biomarkers are related to non-collagenous proteins, inflammation and/or fibrosis. Biomarkers in osteoarthritis can be categorised using the burden of disease, investigative, prognostic, efficacy of intervention, diagnostic and safety classification. There are a number of promising candidates, notably urinary C-terminal telopeptide of collagen type II and serum cartilage oligomeric protein, although none is sufficiently discriminating to differentiate between individual patients and controls (diagnostic) or between patients with different disease severities (burden of disease), predict prognosis in individuals with or without osteoarthritis (prognostic) or perform so consistently that it could function as a surrogate outcome in clinical trials (efficacy of intervention). Future avenues for research include exploration of underlying mechanisms of disease and development of new biomarkers; technological development; the 'omics' (genomics, metabolomics, proteomics and lipidomics); design of aggregate scores combining a panel of biomarkers and/or imaging markers into single diagnostic algorithms; and investigation into the relationship between biomarkers and prognosis.

Osteoarthritis affects the whole joint structure with progressive changes in cartilage, menisci, ligaments and subchondral bone, and synovial inflammation. Biomarkers are being developed to quantify joint remodelling and disease progression. This article was prepared following a working meeting of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis convened to discuss the value of biochemical markers of matrix metabolism in drug development in osteoarthritis. The best candidates are generally molecules or molecular fragments present in cartilage, bone or synovium and may be specific to one type of joint tissue or common to them all. Many currently investigated biomarkers are associated with collagen metabolism in cartilage or bone, or aggrecan metabolism in cartilage. Other biomarkers are related to non-collagenous proteins, inflammation and/or fibrosis. Biomarkers in osteoarthritis can be categorised using the burden of disease, investigative, prognostic, efficacy of intervention, diagnostic and safety classification. There are a number of promising candidates, notably urinary C-terminal telopeptide of collagen type II and serum cartilage oligomeric protein, although none is sufficiently discriminating to differentiate between individual patients and controls (diagnostic) or between patients with different disease severities (burden of disease), predict prognosis in individuals with or without osteoarthritis (prognostic) or perform so consistently that it could function as a surrogate outcome in clinical trials (efficacy of intervention). Future avenues for research include exploration of underlying mechanisms of disease and development of new biomarkers; technological development; the 'omics' (genomics, metabolomics, proteomics and lipidomics); design of aggregate scores combining a panel of biomarkers and/or imaging markers into single diagnostic algorithms; and investigation into the relationship between biomarkers and prognosis.

In 2010, in Osteoarthritis and Cartilage, we published a comprehensive systematic review applying the consensus BIPED criteria (Burden of Disease, Investigative, Prognostic, Efficacy of Intervention and Diagnostic) criteria on serum and urinary biochemical markers for knee and hip osteoarthritis (OA) using publications that were available at that time. It appeared that none of the biochemical markers at that time were sufficiently discriminating to allow diagnosis and prognosis of OA in individual or limited numbers of patients, nor performed so consistently that they could function as primary outcome parameters in clinical trials. Also at present, almost 3 years later, this ultimate goal has not been reached (yet). Frankly, it might be questioned whether we are making the most adequate steps ahead and maybe we have to take a step back to reconsider our approaches. Some reflections are made and discussed: A critical review of molecular metabolism in OA and validation of currently investigated marker molecules in this may be vital and may lead to new and better markers. Creating cohorts in which synovial fluid (SF) is obtained in a systematic way, together with serum and urine, may also bring the field a further step ahead. Thirdly, better understanding of different phenotypes (subtypes) of OA may facilitate identification and validation of biochemical markers. Finally, the systems biology approach as discussed in the last years OA in review on biomarkers, although very complex, might provide steps forward. Looking ahead, we are optimistic but realistic in our expectations, we believe that the field can be brought forward by critically and cautiously reconsidering our approaches, and making changes forward, one step at a time., (Copyright © 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: Soluble mediators in synovial fluid (SF) are acknowledged as key players in the pathophysiology of osteoarthritis (OA). However, a wide-spectrum screening of such mediators in SF is currently lacking. In this study, the levels of 47 mediators in the SF of control donors and osteoarthritic (OA) patients were compared., Materials & Methods: SF was collected from control donors (n = 16) and end-stage knee OA patients (n = 18) and analysed for 47 cytokines, chemokines and growth factors using several multiplex enzyme-linked immunosorbent assays (ELISAs). A Mann-Whitney U test was used to determine differences between OA and control controls. A principal component analysis (PCA) was performed to cluster the 47 mediators., Results: The majority of the mediators could be detected in both control and OA SF. Interleukin (IL)-6, interferon inducible protein (IP)-10, macrophage derived chemokine (MDC), platelet derived growth factor (PDGF)-AA and regulated on activation normal T cell expressed and secreted (RANTES) levels were found to be higher in OA compared to control SF (P < 0.001). Leptin, IL-13, macrophage inflammatory protein (MIP)-1β, soluble CD40 (sCD40L) levels were higher and eotaxin and granulocyte colony-stimulating factor (G-CSF) levels were lower in OA SF than in control SF, albeit borderline significant (P < 0.05). The PCA enabled identification of six clusters of mediators, which explained 76% of the variance., Conclusions: The current study provides the first extensive profile of cytokines, chemokines and growth factors present in control and OA SF. Increased levels of mediators such as MDC and IL-6 imply involvement of inflammatory processes and might be associated with the influx of inflammatory cells in OA synovial tissue. Moreover, the performed cluster analysis indicated multiple clusters, which could indicate different pathophysiological pathways in the joint., (Copyright © 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: CTX-II (C-terminal telopeptide of type II collagen) has been put forward as a marker of collagen type II degradation being part of osteoarthritis. In this study, the authors describe similarities between CTX-II and bone markers arguing against CTX-II as a marker of (solely) cartilage degradation., Methods: uCTX-II, the bone markers uCTX-I, uNTX-I, sPINP, and sOC (C-terminal and N-terminal telopeptides of collagen I, aminoterminal propeptide of type I procollagen, and osteocalcin, respectively), and other (candidate) cartilage markers sCOMP, sCS846, and sPIIANP (cartilage oligomeric matrix protein, chondroitin sulphate 846 and type IIA collagen N-propeptide, respectively) were assessed by ELISA in CHECK (Cohort Hip and Cohort Knee), a cohort of 1002 individuals with early pain and/or stiffness in knee and/or hip., Results: uCTX-II was more strongly associated with the bone markers than with the other cartilage markers, while the other cartilage markers were not so strongly associated with the bone markers. Moreover, both uCTX-II and bone markers but not the other cartilage markers showed an abrupt menopausal shift in women aged 48-53 years, also when adjusted for age and BMI., Conclusion: The similarities between uCTX-II and bone markers could be attributable to a link between cartilage and bone metabolism through metabolic and biomechanical mechanisms. However, other cartilage markers were hardly associated with uCTX-II and did not show such evident associations with bone markers. uCTX-II has unique relations with bone markers as compared to other cartilage markers and might reflect bone rather than cartilage metabolism. More thorough molecular validation of uCTX-II is required.

Objective: To investigate cross-sectional and predictive associations of plasma adipokines with biochemical markers of systemic joint metabolism and radiographic signs of early-stage knee osteoarthritis (OA)., Design: The adipokines pLeptin, pAdiponectin, and pResistin, the cartilage markers C-terminal telopeptide of type II collagen (uCTX-II), N-terminal propeptide of type IIA procollagen (sPIIANP), chondroitin sulfate 846 (sCS846), and cartilage oligomeric matrix protein (sCOMP), and the synovial markers hyaluronic acid (sHA) and N-terminal propeptide of type III procollagen (sPIIINP) were assessed by enzyme-linked immunosorbent assay or radioactive immunoassay in baseline samples of Cohort Hip and Cohort Knee (CHECK), a cohort of 1002 subjects with early-stage symptomatic knee and/or hip OA. Knee radiographs were obtained at baseline and after 2 and 5 years and scored according to Kellgren & Lawrence., Results: pLeptin showed positive associations with uCTX-II, sCOMP, sPIIANP, sHA, and sPIIINP, and with presence and progression of radiographic knee OA. Associations expectedly disappeared after adjustment for body mass index. pResistin showed positive associations with sPIIINP and present and incident radiographic knee OA that were largely independent of BMI. pAdiponectin showed positive associations with uCTX-II and sCOMP. Furthermore, pAdiponectin did not show associations with radiographic knee OA on itself, but associations of pResistin with present radiographic knee OA were stronger in higher pAdiponectin tertiles (P = 0.024 for interaction between pAdiponectin and pResistin). Although statistically significant, all associations were weak., Conclusions: Adipokines may have aggravating, although may be minor, structural effects in early-stage knee OA., (Copyright © 2012 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: Adipose tissue is an endocrine tissue releasing adipokines suggested to be involved in the pathogenesis of osteoarthritis (OA). Nevertheless, their relative contribution and exact mechanisms are still ambiguous. The aim of this study is to compare serum adipokine levels between end-stage knee OA patients and controls and to relate these serum levels to local parameters of cartilage damage and synovial inflammation., Methods: Serum was collected from 172 severe knee OA patients, shortly before total knee replacement (TKR) surgery and from 132 controls without radiographic knee OA [Kellgren & Lawrence (K&L) = 0]. Serum adiponectin, leptin, and resistin levels were measured by enzyme-linked immunosorbent assay (ELISA). Cartilage and synovial tissue were collected at TKR surgery and assessed for cartilage degeneration and synovial inflammation by histochemistry and biochemical analyses., Results: The adipokine levels were all distinctly higher in OA patients as compared to controls. Especially adiponectin and leptin were associated with female gender (stand beta = 0.239 and 0.467, respectively, P < 0.001) and body mass index (BMI) (stand beta = -0.189 and 0.396, respectively, P < 0.001). No associations between serum levels of adipokines and cartilage damage (histochemistry, proteoglycan content) were found whereas weak but positive associations with synovial inflammation were found [adiponectin and interleukin-1β (IL-1β), stand beta = 0.172, P = 0.02; resistin and histology, stand beta = 0.183, P = 0.034, adjusted for demographics]., Conclusion: This study suggests an important involvement of adipokines in OA patients considering their high serum levels compared to controls. Associations of systemic adipokines with local synovial tissue inflammation were found, although not represented by similar relations with cartilage damage, suggesting that adipokines are of relevance in the inflammatory component of OA., (Copyright © 2012 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To assess a wide spectrum of biochemical markers (biomarkers) in a large cohort of individuals with (very) early symptomatic knee and/or hip osteoarthritis (OA). Secondly, to investigate associations between biomarkers and between biomarkers and demographics to demonstrate validity of the obtained dataset and further investigate the involvement and/or role of these biomarkers in OA., Design: Fourteen biomarkers (uCTX-II, uCTX-I, uNTX-I, sCOMP, sPIIANP, sCS846, sC1,2C, sOC, sPINP, sHA, sPIIINP, pLeptin, pAdiponectin, pResistin) were assessed by ELISA or RIA in CHECK (Cohort Hip and Cohort Knee), a 10-year prospective cohort of 1,002 individuals with early symptomatic knee and/or hip OA., Results: Quality controls revealed that gathered data were technically reliable. The majority of biomarkers showed relevant associations with demographic variables, which were expectedly different between genders and/or menopausal status for some. Principal component analysis enabled identification of five clusters, consecutively designated as 'bone-CTX-II', 'inflammation', 'synovium', 'C1,2C-adipokines', and 'cartilage synthesis' cluster. Notably, uCTX-II clustered with biomarkers of bone metabolism, while sCOMP clustered with biomarkers of synovial activity., Conclusions: The identified clusters extended knowledge on individual biomarkers from mostly smaller studies as did the observed associations between biomarker levels and demographics, from which validity of our data was deduced. uCTX-II may not only reflect articular cartilage but also bone metabolism and sCOMP may reflect synovial rather than cartilage metabolism. Major involvement of adipokines in joint metabolism was not identified., (Copyright © 2012 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Background: Azathioprine is used as an immunosuppressant in canine immune-mediated hemolytic anemia (IMHA), but this potentially toxic and carcinogenic drug has not been proven to be beneficial. The aim of this study was to determine the difference in outcome and survival of dogs with idiopathic IMHA treated with a protocol that included azathioprine and prednisolone versus a protocol that included prednisolone alone., Results: The study included 222 dogs with a hematocrit lower than 0.30 L/L and either a positive Coombs' test or spherocytosis and no evidence of diseases that could trigger IMHA. The clinical and laboratory data at the time of diagnosis and the response to therapy and survival were compared in dogs treated according to the prednisolone and azathioprine protocol (AP protocol; n = 149) and dogs treated according to the prednisolone protocol (P protocol; n = 73). At study entry, the two groups were comparable, except that thrombocyte counts were significantly lower and clinical signs had been present significantly longer in the AP protocol group. No significant difference in survival was found between the two groups: the 1-year survival was 64% (95% CI 54 - 77%) in the P protocol group and 69% (95% CI 59-80%) in the AP protocol group, respectively., Conclusions: Azathioprine would appear not to be beneficial as standard treatment for all cases of IMHA; however, a blinded, randomized clinical trial is needed to establish whether outcome is different with the two treatment protocols.

Context: Molecules that are released into biological fluids during matrix metabolism of articular cartilage, subchondral bone, and synovial tissue could serve as biochemical markers of the process of osteoarthritis (OA). Unfortunately, actual breakthroughs in the biochemical OA marker field are limited so far., Objective: By reviewing the status of commercially available biochemical OA markers according to the "Burden of disease, Investigative, Prognostic, Efficacy of intervention, and Diagnostic" ("BIPED") classification, future use of this "BIPED" classification is encouraged and more efficient biochemical OA marker research stimulated., Data Sources: Three electronic databases [PubMed, Scopus, EMBASE (1997-May 2009)] were searched for publications on blood and urinary biochemical markers in human primary knee and hip-OA., Study Selection: Stepwise selection of original English publications describing human studies on blood or urinary biochemical markers in primary knee or hip-OA was performed. Selected articles were fully read to determine whether biochemical markers were investigated on performance within any of the "BIPED" categories. Eighty-four relevant publications were identified., Data Extraction: Data from relevant publications were tabulated according to the "BIPED" classification. Individual analyses within a publication were summarized in general "BIPED" scores., Data Synthesis: An uneven distribution of scores on biochemical marker performance and heterogeneity among the publications complicated direct comparison of individual biochemical markers. Comparison of categories of biochemical markers was therefore performed instead. In general, biochemical markers of cartilage degradation were investigated most extensively and performed well in comparison with other categories of biochemical markers. Biochemical markers of bone metabolism performed less adequately. Biochemical markers of synovial tissue metabolism were not investigated extensively, but performed quite well., Conclusions: Specific biochemical markers and categories of biochemical markers as well as their nature, origin and metabolism, need further investigation. International standardization of future investigations should be pursued to obtain more high-quality, homogenous data on the full spectrum of biochemical OA markers., (Copyright 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)