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Objectives: The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) sought to revisit the 2014 algorithm recommendations for knee osteoarthritis (OA), in light of recent efficacy and safety evidence, in order to develop an updated stepwise algorithm that provides practical guidance for the prescribing physician that is applicable in Europe and internationally., Methods: Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) process, a summary of evidence document for each intervention in OA was provided to all members of an ESCEO working group, who were required to evaluate and vote on the strength of recommendation for each intervention. Based on the evidence collected, and on the strength of recommendations afforded by consensus of the working group, the final algorithm was constructed., Results: An algorithm for management of knee OA comprising a stepwise approach and incorporating consensus on 15 treatment recommendations was prepared by the ESCEO working group. Both "strong" and "weak" recommendations were afforded to different interventions. The algorithm highlights the continued importance of non-pharmacological interventions throughout the management of OA. Benefits and limitations of different pharmacological treatments are explored in this article, with particular emphasis on safety issues highlighted by recent literature analyses., Conclusions: The updated ESCEO stepwise algorithm, developed by consensus from clinical experts in OA and informed by available evidence for the benefits and harms of various treatments, provides practical, current guidance that will enable clinicians to deliver patient-centric care in OA practice., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the validity of diagnostic clusters combining history elements and physical examination tests to diagnose or exclude patellofemoral pain (PFP)., Design: Prospective diagnostic study., Settings: Orthopedic outpatient clinics, family medicine clinics, and community-dwelling., Participants: Consecutive patients (N=279) consulting one of the participating orthopedic surgeons (n=3) or sport medicine physicians (n=2) for any knee complaint., Interventions: Not applicable., Main Outcome Measures: History elements and physical examination tests were obtained by a trained physiotherapist blinded to the reference standard: a composite diagnosis including both physical examination tests and imaging results interpretation performed by an expert physician. Penalized logistic regression (least absolute shrinkage and selection operator) was used to identify history elements and physical examination tests associated with the diagnosis of PFP, and recursive partitioning was used to develop diagnostic clusters. Diagnostic accuracy measures including sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios with associated 95% confidence intervals (CIs) were calculated., Results: Two hundred seventy-nine participants were evaluated, and 75 had a diagnosis of PFP (26.9%). Different combinations of history elements and physical examination tests including the age of participants, knee pain location, difficulty descending stairs, patellar facet palpation, and passive knee extension range of motion were associated with a diagnosis of PFP and used in clusters to accurately discriminate between individuals with PFP and individuals without PFP. Two diagnostic clusters developed to confirm the presence of PFP yielded a positive likelihood ratio of 8.7 (95% CI, 5.2-14.6) and 3 clusters to exclude PFP yielded a negative likelihood ratio of .12 (95% CI, .06-.27)., Conclusions: Diagnostic clusters combining common history elements and physical examination tests that can accurately diagnose or exclude PFP compared to various knee disorders were developed. External validation is required before clinical use., (Copyright © 2017 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) published a treatment algorithm for the management of knee osteoarthritis (OA) in 2014, which provides practical guidance for the prioritization of interventions. Further analysis of real-world data for OA provides additional evidence in support of pharmacological interventions, in terms of management of OA pain and function, avoidance of adverse events, disease-modifying effects and long-term outcomes, e.g., delay of total joint replacement surgery, and pharmacoeconomic factors such as reduction in healthcare resource utilization. This article provides an updated assessment of the literature for selected interventions in OA, focusing on real-life data, with the aim of providing easy-to-follow advice on how to establish a treatment flow in patients with knee OA in primary care clinical practice, in support of the clinicians' individualized assessment of the patient. In step 1, background maintenance therapy with symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) is recommended, for which high-quality evidence is provided only for the prescription formulations of patented crystalline glucosamine sulfate and chondroitin sulfate. Paracetamol may be added for rescue analgesia only, due to limited efficacy and increasing safety signals. Topical non-steroidal anti-inflammatory drugs (NSAIDs) may provide additional symptomatic treatment with the same degree of efficacy as oral NSAIDs without the systemic safety concerns. Oral NSAIDs maintain a central role in step 2 advanced management of persistent symptoms. However, oral NSAIDs are highly heterogeneous in terms of gastrointestinal and cardiovascular safety profile, and patient stratification with careful treatment selection is advocated to maximize the risk:benefit ratio. Intra-articular hyaluronic acid as a next step provides sustained clinical benefit with effects lasting up to 6 months after a short-course of weekly injections. As a last step before surgery, the slow titration of sustained-release tramadol, a weak opioid, affords sustained analgesia with improved tolerability., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Non-steroidal anti-inflammatory drugs (NSAIDs) are at the cornerstone of treatment for osteoarthritis (OA). In recent years, the widespread use of oral NSAIDs has been called into question due to the appearance of significant upper gastrointestinal (GI) complications and cardiovascular (CV) adverse events (AEs). However, NSAIDs are non-homogeneous, and there are noticeable differences between them in AE risk for GI and CV events. Nevertheless, if properly prescribed oral NSAIDs can provide an effective and safe treatment for OA in real-life situations. The identification of patients with significant CV and/or GI risk is critical, and the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) treatment algorithm provides guidance on appropriate treatments for OA patients with elevated risk. Among non-selective NSAIDs, ibuprofen and naproxen seem preferable to diclofenac, the latter being associated with higher CV risk. Recommendation has been made by some that naproxen may be the preferred agent in patients at high CV risk because of its lower risk of CV events. Low dose celecoxib (200mg/day) is also associated with a lower risk of CV events compared with other coxibs. In addition, drugs with a demonstrated low GI risk profile may be of benefit, such as coxibs and nabumetone. Among patients who fail to respond adequately to sequential ESCEO algorithm Step 1 and Step 2 treatments, the short-term use of weak opioids, such as tramadol, for severely symptomatic OA patients is recommended. Although studies exploring the efficacy of tramadol in OA are limited, there is good evidence that tramadol works if prescribed properly. The sustained-release (SR) formulation of tramadol is preferred as it avoids the peak plasma concentrations reached with immediate-release tramadol, and is believed to reduce the incidence of AEs. Furthermore, slow upwards titration of tramadol SR is recommended to improve tolerability and minimize treatment discontinuations., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Topical non-steroidal anti-inflammatory drugs (NSAIDs) are recommended in international and national guidelines as an early treatment option for the symptomatic management of knee and hand osteoarthritis (OA), and may be used ahead of oral NSAIDs due to their superior safety profile. The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) treatment algorithm recommends topical NSAIDs for knee OA in addition to the pharmacological background of symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) and rescue analgesia with paracetamol and non-pharmacological treatment, if the patient is still symptomatic. Topical NSAIDs have a moderate effect on pain relief, with efficacy similar to that of oral NSAIDs, with the advantage of a better risk:benefit ratio. In real-life studies, topical and oral NSAIDs demonstrate an equivalent effect on knee pain over 1 year of treatment, with fewer adverse events due to lower systemic absorption of topical NSAIDs compared with oral NSAIDs. As a result, topical NSAIDs may be the preferred treatment option, especially in OA patients aged ≥75 years, and those with co-morbidities or at an increased risk of cardiovascular, gastrointestinal, or renal side effects. Furthermore, using topical NSAIDs in inflammatory rheumatic diseases leads to a 40% reduction in the need for concomitant oral NSAIDs. When selecting a topical NSAID, absorption and bioavailability are important because of heterogeneity among topical drug formulations. Molecules like etofenamate have a bioavailability of >20% and evidence for accumulation in synovial tissues, with efficacy demonstrated as improvement in pain and function in real-life studies of OA patients. Diclofenac also shows good efficacy alongside evidence that diclofenac accumulates in the synovium., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: In the perspective of personalized management of osteoarthritis (OA), a clinically relevant concern is the impact of meniscal extrusion (Ext) on response to treatment. This study aimed at determining the effects of conventional OA pharmacological treatments and those of the combination of glucosamine and chondroitin sulfate (Glu/CS) on knee structural changes in the presence or absence of Ext, using data from the progression cohort of the Osteoarthritis Initiative., Methods: In this longitudinal study, knee OA participants were stratified based on whether (+) or not (-) they received analgesics/NSAIDs (+ and -analgesics/NSAIDs) and/or Glu/CS (+ and -Glu/CS) for 24 consecutive months and on the presence (Ext+) or absence (Ext-) of medial meniscal extrusion at baseline. The main outcomes were knee structural changes including the loss of joint space width (JSW) and cartilage volume loss measured by quantitative MRI., Results: In both - and +analgesics/NSAIDs groups (n = 300 each), the Ext+ participants had more-advanced disease at baseline (T0) and more JSW loss and cartilage volume loss in the medial compartment (p ≤ 0.003, univariate; p ≤ 0.049, multivariate analyses) at both 12 (T12) and 24 (T24) months compared to Ext- participants. In the -analgesics/NSAIDs group, Ext+ participants taking Glu/CS had significantly less cartilage volume loss in the medial plateau at T24 (p ≤ 0.010, univariate and multivariate analyses). In the +analgesics/NSAIDs group at T24, Ext- participants taking Glu/CS had less cartilage volume loss in the global (p ≤ 0.002, univariate and multivariate analyses) and medial and lateral plateaus (p = 0.034 and p = 0.013, respectively, multivariate analysis). No significant difference in JSW loss was found between the groups., Conclusion: This study is the first to demonstrate, using qMRI, that meniscal extrusion can modify the response to Glu/CS treatment in knee OA patients, depending on the severity of the disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: General recommendations for a reference case for economic studies in rheumatic diseases were published in 2002 in an initiative to improve the comparability of cost-effectiveness studies in the field. Since then, economic evaluations in osteoarthritis (OA) continue to show considerable heterogeneity in methodological approach., Objectives: To develop a reference case specific for economic studies in OA, including the standard optimal care, with which to judge new pharmacologic and non-pharmacologic interventions., Methods: Four subgroups of an ESCEO expert working group on economic assessments (13 experts representing diverse aspects of clinical research and/or economic evaluations) were charged with producing lists of recommendations that would potentially improve the comparability of economic analyses in OA: outcome measures, comparators, costs and methodology. These proposals were discussed and refined during a face-to-face meeting in 2013. They are presented here in the format of the recommendations of the recently published Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement, so that an initiative on economic analysis methodology might be consolidated with an initiative on reporting standards., Results: Overall, three distinct reference cases are proposed, one for each hand, knee and hip OA; with diagnostic variations in the first two, giving rise to different treatment options: interphalangeal or thumb-based disease for hand OA and the presence or absence of joint malalignment for knee OA. A set of management strategies is proposed, which should be further evaluated to help establish a consensus on the "standard optimal care" in each proposed reference case. The recommendations on outcome measures, cost itemisation and methodological approaches are also provided., Conclusions: The ESCEO group proposes a set of disease-specific recommendations on the conduct and reporting of economic evaluations in OA that could help the standardisation and comparability of studies that evaluate therapeutic strategies of OA in terms of costs and effectiveness., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Existing practice guidelines for osteoarthritis (OA) analyze the evidence behind each proposed treatment but do not prioritize the interventions in a given sequence. The objective was to develop a treatment algorithm recommendation that is easier to interpret for the prescribing physician based on the available evidence and that is applicable in Europe and internationally. The knee was used as the model OA joint., Methods: ESCEO assembled a task force of 13 international experts (rheumatologists, clinical epidemiologists, and clinical scientists). Existing guidelines were reviewed; all interventions listed and recent evidence were retrieved using established databases. A first schematic flow chart with treatment prioritization was discussed in a 1-day meeting and shaped to the treatment algorithm. Fine-tuning occurred by electronic communication and three consultation rounds until consensus., Results: Basic principles consist of the need for a combined pharmacological and non-pharmacological treatment with a core set of initial measures, including information access/education, weight loss if overweight, and an appropriate exercise program. Four multimodal steps are then established. Step 1 consists of background therapy, either non-pharmacological (referral to a physical therapist for re-alignment treatment if needed and sequential introduction of further physical interventions initially and at any time thereafter) or pharmacological. The latter consists of chronic Symptomatic Slow-Acting Drugs for OA (e.g., prescription glucosamine sulfate and/or chondroitin sulfate) with paracetamol at-need; topical NSAIDs are added in the still symptomatic patient. Step 2 consists of the advanced pharmacological management in the persistent symptomatic patient and is centered on the use of oral COX-2 selective or non-selective NSAIDs, chosen based on concomitant risk factors, with intra-articular corticosteroids or hyaluronate for further symptom relief if insufficient. In Step 3, the last pharmacological attempts before surgery are represented by weak opioids and other central analgesics. Finally, Step 4 consists of end-stage disease management and surgery, with classical opioids as a difficult-to-manage alternative when surgery is contraindicated., Conclusions: The proposed treatment algorithm may represent a new framework for the development of future guidelines for the management of OA, more easily accessible to physicians., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: There is an important need to evaluate therapeutic approaches for osteoarthritis (OA) in terms of cost-effectiveness as well as efficacy., Methods: The ESCEO expert working group met to discuss the epidemiological and economic evidence that justifies the increasing concern of the impact of this disease and reviewed the current state-of-the-art in health economic studies in this field., Results: OA is a debilitating disease; it is increasing in frequency and is associated with a substantial and growing burden on society, in terms of both burden of illness and cost of illness. Economic evaluations in this field are relatively rare, and those that do exist, show considerable heterogeneity of methodological approach (such as indicated population, comparator, decision context and perspective, time horizon, modeling and outcome measures used). This heterogeneity makes comparisons between studies problematic., Conclusions: Better adherence to guidelines for economic evaluations is needed. There was strong support for the definition of a reference case and for what might constitute "standard optimal care" in terms of best clinical practice, for the control arms of interventional studies., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of the study was to evaluate by quantitative magnetic resonance imaging the effect of celecoxib 200 mg daily on cartilage volume loss over 12 months in knee osteoarthritis., Methods: The primary outcome of this study was to evaluate cartilage volume loss in the medial compartment of the knee (femoral condyle and tibial plateau) assessed by quantitative magnetic resonance imaging on subjects receiving continuous treatment with celecoxib 200 mg daily for 12 months compared with a modelized historical control cohort, as expressed by the percentage loss from baseline. Safety of the medication was also assessed. Comparison of the observed volume loss to the expected loss was evaluated by a multivariate linear regression model based on a historical cohort., Results: For the primary outcome, the 95% confidence intervals for the mean observed celecoxib cohort joint medial compartment cartilage volume loss (6.81% [6.01; 7.60]) and mean predicted loss (modelized historical cohort) (5.65% [5.10; 6.19]) overlap, indicating no significant difference and hence no effect of celecoxib on the medial compartment cartilage volume loss. Similar findings were demonstrated for the lateral compartment cartilage loss. The safety data reported several minor adverse events similar to those typically seen in a 1-year clinical trial., Conclusions: Although celecoxib was demonstrated to be safe for knee osteoarthritis at a 200 mg daily dose, it did not provide a protective effect on knee cartilage loss. Cohort modelization is an efficient and unbiased way to provide a comparator group for the assessment of novel treatments when classic head-to-head randomized controlled trials are not feasible., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objectives: To provide an overview on: 1) the expression of cyclooxygenase (COX)-2 in articular tissues; 2) the role of prostaglandin E2 (PGE2) in these tissue functions; and 3) clinical trials with COX-2-selective nonsteroidal anti-inflammatory drugs (NSAIDs) (coxibs)., Methods: MEDLINE search was performed using the key words "cyclooxygenase," "prostaglandin," "osteoarthritis" (OA), and "rheumatoid arthritis" (RA). Selected publications related to clinical trials with coxibs also are included., Results: COX-2 is upregulated in inflamed joint tissues and is responsible for elevated PGE2 production. The overexpression of COX-2 is likely induced by proinflammatory mediators such as interleukin-1beta (IL-1beta) and tumor necrosis factor (TNF) alpha. However, the exact molecular mechanisms through which the expression of COX-2 is regulated remain to be elucidated. Several studies suggest that PGE2 is involved in inflammation, apoptosis, angiogenesis, and possibly structural changes that characterize arthritic diseases. NSAIDs are prescribed for the treatment of OA and RA and provide effective relief from symptoms; however, serious gastrointestinal complications occur with their use. The clinical efficacy of NSAIDs is primarily related to the inhibition of COX-2, whereas much of the toxicity is related to COX-1 inhibition. Selective COX-2 inhibitors (coxibs) that spare COX-1 at therapeutic doses are more effective than placebo and as effective as other NSAIDs for relief of symptoms of OA and RA, and have significantly improved gastrointestinal safety and tolerability. However, some studies showed that COX-2-selective inhibitors still have classic NSAID complications., Conclusions: Overexpression of COX-2 protein in articular tissues is a characteristic feature of arthritic diseases. However, the molecular mechanisms involved in the regulation of COX-2 expression and activity are still unclear. Elucidating the mechanisms of COX-2 expression and PGE2 production and action will help identify novel and more selective potential drug targets in the treatment of arthritic diseases.

The putative role and mechanism of action of cytokines in the progression of arthritic diseases such as osteoarthritis (OA) has received particular attention because of the important interaction between articular cartilage and synovium in the pathophysiology of the diseased state. Maintaining matrix homeostasis in the normal adult cartilage phenotype requires normal turnover of matrix components, principally collagen and proteoglycan. Chondrocytes and synovial fibroblasts are targeted, via specific cell-surface receptors, by cytokines like interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) to produce matrix proteases and to suppress the synthesis of collagen and proteoglycan. Thus, cytokines not only favor tissue destruction, but also inhibit tissue repair. A structurally heterogeneous group of factors capable of directly antagonizing cytokine action is described, which acts either by blocking cytokine-receptor binding, inhibiting local cytokine synthesis, or complexing the cytokine into an inactive form. Furthermore, many growth factors, such as transforming growth factor-beta (TGF-beta), can counteract the net effect of cytokines by stimulating the synthesis of matrix components or natural inhibitors of cartilage degrading enzymes.