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.
Summary Objective Whether meniscal extrusion and bone marrow lesions (BMLs) are independently associated with the risk of knee osteoarthritis (OA) is unknown. Methods Data was extracted from the ...Osteoarthritis Initiative (OAI) cohort. Participants were grouped according to the absence (Kellgren–Lawrence (KL) grade ≤ 1, n = 2120) or presence (KL ≥ 2, n = 2249) of radiographic OA (ROA). Baseline meniscal extrusion and tibial BMLs were assessed. Tibial plateau cartilage volume was assessed at baseline and 72 months, while radiographic disease was assessed at baseline and 48 months. Total knee replacement (TKR) was assessed at 72 months. Results In those with ROA, the presence of a baseline meniscal extrusion (independent of BMLs) was associated with accelerated cartilage volume loss (medial tibia: −2.1%/annum vs −1.5%; lateral: −2.6%/annum vs −1.6%; both P < 0.001), progressive ROA and TKR (Odds ratio (OR) range 1.4–1.8; 95% CI range 1.1–2.9). The presence of a baseline BML was associated with accelerated cartilage volume loss (medial tibia: −2.1%/annum vs −1.6%; lateral: −1.9%/annum vs −1.6%; P ≤ 0.02), progressive ROA and joint replacement (OR range 1.5–2.4; 95% CI range 1.1–3.4). In those with no ROA, a baseline medial meniscal extrusion was associated with accelerated cartilage volume loss (medial tibia: −2.1%/annum vs −1.2%, P < 0.001), and a baseline medial BML with incident ROA (OR 1.7, 95% CI 1.1 to 2.9). Conclusions The presence of baseline meniscal extrusion and BMLs are associated with incident and progressive knee of each other (OA) and represent important structural targets for the treatment and prevention of knee OA.
Summary Hand osteoarthritis (OA) is a very frequent disease, but yet understudied. However, a lot of works have been published in the past 10 years, and much has been done to better understand its ...clinical course and structural progression. Despite this new knowledge, few therapeutic trials have been conducted in hand OA. The last OARSI recommendations for the conduct of clinical trials in hand OA dates back to 2006. The present recommendations aimed at updating previous recommendations, by incorporating new data. The purpose of this expert opinion, consensus driven exercise is to provide evidence-based guidance on the design, execution and analysis of clinical trials in hand OA, where published evidence is available, supplemented by expert opinion, where evidence is lacking, to perform clinical trials in hand OA, both for symptom and for structure-modification. They indicate core outcome measurement sets for studies in hand OA, and list the methods and instruments that should be used to measure symptoms or structure. For both symptom- and structure-modification, at least pain, physical function, patient global assessment, HR-QoL, joint activity and hand strength should be assessed. In addition, for structure-modification trials, structural progression should be measured by radiographic changes. We also provide a research agenda listing many unsolved issues that seem to most urgently need to be addressed from the perspective of performing “good” clinical trials in hand OA. These updated OARSI recommendations should allow for better standardizing the conduct of clinical trials in hand OA in the next future.
Emergence of more autonomous roles for physiotherapists warrants more evidence regarding their diagnostic capabilities. Therefore, we aimed to evaluate diagnostic and surgical triage concordance ...between a physiotherapist and expert physicians and to assess the diagnostic validity of the physiotherapist's musculoskeletal examination (ME) without imaging.
This is a prospective diagnostic study where 179 consecutive participants consulting for any knee complaint were independently diagnosed and triaged by two evaluators: a physiotherapist and one expert physician (orthopaedic surgeons or sport medicine physicians). The physiotherapist completed only a ME, while the physicians also had access to imaging to make their diagnosis. Raw agreement proportions and Cohen's kappa (k) were calculated to assess inter-rater agreement. Sensitivity (Se) and specificity (Sp), as well as positive and negative likelihood ratios (LR+/-) were calculated to assess the validity of the ME compared to the physicians' composite diagnosis.
Primary knee diagnoses included anterior cruciate ligament injury (n = 8), meniscal injury (n = 36), patellofemoral pain (n = 45) and osteoarthritis (n = 79). Diagnostic inter-rater agreement between the physiotherapist and physicians was high (k = 0.89; 95% CI:0.83-0.94). Inter-rater agreement for triage recommendations of surgical candidates was good (k = 0.73; 95% CI:0.60-0.86). Se and Sp of the physiotherapist's ME ranged from 82.0 to 100.0% and 96.0 to 100.0% respectively and LR+/- ranged from 23.2 to 30.5 and from 0.03 to 0.09 respectively.
There was high diagnostic agreement and good triage concordance between the physiotherapist and physicians. The ME without imaging may be sufficient to diagnose or exclude common knee disorders for a large proportion of patients. Replication in a larger study will be required as well as further assessment of innovative multidisciplinary care trajectories to improve care of patients with common musculoskeletal disorders.
Although the atomic structure of amorphous alloys, which lacks long-range translational symmetry, may appear homogeneous at the macroscopic scale, their local dynamic and/or static properties however ...vary significantly according to the recent experimental and simulation results. In the literature of amorphous alloys, the nature of such local heterogeneities is currently an issue under debate. More importantly, since amorphous alloys are in a thermodynamically nonequilibrium state, their local structures constantly evolve during structural relaxation, physical aging and mechanical deformation. As such, local structural heterogeneities, which vary with the thermal and mechanical history of amorphous alloys, could provide a key to understand the structural origin of their mechanical behavior, such as anelasticity, viscoelasticity, plasticity and fracture. In this review article, we first review mechanical spectroscopy or dynamic mechanical analyses as an important tool to study the relaxation dynamics in amorphous alloys, with a focus on the possible correlation between the secondary (also called β) relaxation and the local structural heterogeneities of amorphous alloys. After that, we discuss the recent advances on the understanding of structural heterogeneities in metallic supercooled liquids and the influence of the structural heterogeneities on the overall mechanical properties of the corresponding amorphous alloys. Finally, we briefly discuss the further development of research on this subject.
Dual 5-LOX/COX inhibitors are potential new drugs to treat inflammation. They act by blocking the formation of both prostaglandins and leucotrienes but do not affect lipoxin formation. Such combined ...inhibition avoids some of the disadvantages of selective COX-2 inhibitors and spares the gatrointestinal mucosa.
To compare the efficacy and safety of chondroitin sulfate plus glucosamine hydrochloride (CS+GH) versus celecoxib in patients with knee osteoarthritis and severe pain.
Double-blind Multicentre ...Osteoarthritis interVEntion trial with SYSADOA (MOVES) conducted in France, Germany, Poland and Spain evaluating treatment with CS+GH versus celecoxib in 606 patients with Kellgren and Lawrence grades 2-3 knee osteoarthritis and moderate-to-severe pain (Western Ontario and McMaster osteoarthritis index (WOMAC) score ≥301; 0-500 scale). Patients were randomised to receive 400 mg CS plus 500 mg GH three times a day or 200 mg celecoxib every day for 6 months. The primary outcome was the mean decrease in WOMAC pain from baseline to 6 months. Secondary outcomes included WOMAC function and stiffness, visual analogue scale for pain, presence of joint swelling/effusion, rescue medication consumption, Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) criteria and EuroQoL-5D.
The adjusted mean change (95% CI) in WOMAC pain was -185.7 (-200.3 to -171.1) (50.1% decrease) with CS+GH and -186.8 (-201.7 to -171.9) (50.2% decrease) with celecoxib, meeting the non-inferiority margin of -40: -1.11 (-22.0 to 19.8; p=0.92). All sensitivity analyses were consistent with that result. At 6 months, 79.7% of patients in the combination group and 79.2% in the celecoxib group fulfilled OMERACT-OARSI criteria. Both groups elicited a reduction >50% in the presence of joint swelling; a similar reduction was seen for effusion. No differences were observed for the other secondary outcomes. Adverse events were low and similarly distributed between groups.
CS+GH has comparable efficacy to celecoxib in reducing pain, stiffness, functional limitation and joint swelling/effusion after 6 months in patients with painful knee osteoarthritis, with a good safety profile.
NCT01425853.
Summary Significant advances have occurred in our understanding of the pathogenesis of knee osteoarthritis (OA) and some recent trials have demonstrated the potential for modification of the disease ...course. The purpose of this expert opinion, consensus driven exercise is to provide detail on how one might use and apply knee imaging in knee OA trials. It includes information on acquisition methods/techniques (including guidance on positioning for radiography, sequence/protocol recommendations/hardware for magnetic resonance imaging (MRI)); commonly encountered problems (including positioning, hardware and coil failures, sequences artifacts); quality assurance (QA)/control procedures; measurement methods; measurement performance (reliability, responsiveness, validity); recommendations for trials; and research recommendations.
12/15-Lipoxygenase (12/15-LOX) catalyzes the generation of various anti-inflammatory lipid mediators, and has been implicated in several inflammatory and degenerative diseases. However, there is ...currently no evidence that 12/15-LOX has a role in osteoarthritis (OA). The aim of this study was to investigate the role of 12/15-LOX in the pathogenesis of OA.
The development of aging-associated and destabilization of the medial meniscus (DMM)-induced OA were compared in 12/15-LOX-deficient (12/15-LOX−/−) and wild-type (WT) mice. The extent of cartilage damage was evaluated by histology. The expression of OA markers was evaluated by immunohistochemistry and RT-PCR. Cartilage explants were stimulated with IL-1α in the absence or presence of the 12/15-LOX metabolites, 15-hydroxyeicosatetraenoic acids (15-HETE), 13-hydroxyoctadecadienoic acid (13-HODE) or lipoxin A4 (LXA4), and the levels of matrix metalloproteinases-13 (MMP-13), Nitric oxide (NO) and prostaglandin E2 (PGE2) were determined. The effect of LXA4 on the progression of OA was evaluated in wild type (WT) mice.
The expression of 12/15-LOX in cartilage increased during the progression of DMM-induced OA and with aging in WT mice. Cartilage degeneration was more severe in 12/15-LOX−/− mice compared to WT mice in both models of OA, and this was associated with increased expression of MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs, aggrecanases (ADAMTS5), inducible NO synthases (iNOS), and mPGES-1. Treatment of cartilage explants with 12/15-LOX metabolites, suppressed IL-1α-induced production of MMP-13, NO and PGE2, with LXA4 being the most potent. Intra-peritoneal injection of LXA4 reduced the severity of DMM-induced cartilage degradation.
These data suggest an important role of 12/15-LOX in the pathogenesis of OA. They also suggest that activation of this pathway may provide a novel strategy for prevention and treatment of OA.
Summary Imaging of hip in osteoarthritis (OA) has seen considerable progress in the past decade, with the introduction of new techniques that may be more sensitive to structural disease changes. The ...purpose of this expert opinion, consensus driven recommendation is to provide detail on how to apply hip imaging in disease modifying clinical trials. It includes information on acquisition methods/techniques (including guidance on positioning for radiography, sequence/protocol recommendations/hardware for magnetic resonance imaging (MRI)); commonly encountered problems (including positioning, hardware and coil failures, artifacts associated with various MRI sequences); quality assurance/control procedures; measurement methods; measurement performance (reliability, responsiveness, and validity); recommendations for trials; and research recommendations.
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