Abstract 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.
Objective
To assess the efficacy and safety of the anti–interleukin‐1α/β (anti–IL‐1α/β) dual variable domain immunoglobulin lutikizumab (ABT‐981) in patients with knee osteoarthritis (OA) and ...evidence of synovitis.
Methods
Patients (n = 350; 347 analyzed) with Kellgren/Lawrence grade 2–3 knee OA and synovitis (determined by magnetic resonance imaging MRI or ultrasound) were randomized to receive placebo or lutikizumab 25, 100, or 200 mg subcutaneously every 2 weeks for 50 weeks. The coprimary end points were change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at week 16 and change from baseline in MRI‐assessed synovitis at week 26.
Results
The WOMAC pain score at week 16 had improved significantly versus placebo with lutikizumab 100 mg (P = 0.050) but not with the 25 mg or 200 mg doses. Beyond week 16, the WOMAC pain score was reduced in all groups but was not significantly different between lutikizumab‐treated and placebo‐treated patients. Changes from baseline in MRI‐assessed synovitis at week 26 and other key symptom‐ and most structure‐related end points at weeks 26 and 52 were not significantly different between the lutikizumab and placebo groups. Injection site reactions, neutropenia, and discontinuations due to neutropenia were more frequent with lutikizumab versus placebo. Reductions in neutrophil and high‐sensitivity C‐reactive protein levels plateaued with lutikizumab 100 mg, with further reductions not observed with the 200 mg dose. Immunogenic response to lutikizumab did not meaningfully affect systemic lutikizumab concentrations.
Conclusion
The limited improvement in the WOMAC pain score and the lack of synovitis improvement with lutikizumab, together with published results from trials of other IL‐1 inhibitors, suggest that IL‐1 inhibition is not an effective analgesic/antiinflammatory therapy in most patients with knee OA and associated synovitis.
Abstract 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.
Osteoarthritis (OA) is associated with cartilage destruction, subchondral bone remodeling and inflammation of the synovial membrane, although the etiology and pathogenesis underlying this ...debilitating disease are poorly understood. Secreted inflammatory molecules, such as proinflammatory cytokines, are among the critical mediators of the disturbed processes implicated in OA pathophysiology. Interleukin (IL)-1β and tumor necrosis factor (TNF), in particular, control the degeneration of articular cartilage matrix, which makes them prime targets for therapeutic strategies. Animal studies provide support for this approach, although only a few clinical studies have investigated the efficacy of blocking these proinflammatory cytokines in the treatment of OA. Apart from IL-1β and TNF, several other cytokines including IL-6, IL-15, IL-17, IL-18, IL-21, leukemia inhibitory factor and IL-8 (a chemokine) have also been shown to be implicated in OA and could possibly be targeted therapeutically. This Review discusses the current knowledge regarding the role of proinflammatory cytokines in the pathophysiology of OA and addresses the potential of anticytokine therapy in the treatment of this disease.
Objective
By using machine learning, our study aimed to build a model to predict risk and time to total knee replacement (TKR) of an osteoarthritic knee.
Methods
Features were from the Osteoarthritis ...Initiative (OAI) cohort at baseline. Using the lasso method for variable selection in the Cox regression model, we identified the 10 most important characteristics among 1,107 features. The prognostic power of the selected features was assessed by the Kaplan‐Meier method and applied to 7 machine learning methods: Cox, DeepSurv, random forests algorithm, linear/kernel support vector machine (SVM), and linear/neural multi‐task logistic regression models. As some of the 10 first‐found features included similar radiographic measurements, we further looked at using the least number of features without compromising the accuracy of the model. Prediction performance was assessed by the concordance index, Brier score, and time‐dependent area under the curve (AUC).
Results
Ten features were identified and included radiographs, bone marrow lesions of the medial condyle on magnetic resonance imaging, hyaluronic acid injection, performance measure, medical history, and knee‐related symptoms. The methodologies Cox, DeepSurv, and linear SVM demonstrated the highest accuracy (concordance index scores of 0.85, Brier score of 0.02, and an AUC of 0.87). DeepSurv was chosen to build the prediction model to estimate the time to TKR for a given knee. Moreover, we were able to decrease the features to only 3 and maintain the high accuracy (concordance index of 0.85, Brier score of 0.02, and AUC of 0.86), which included bone marrow lesions, Kellgren/Lawrence grade, and knee‐related symptoms, to predict risk and time of a TKR event.
Conclusion
For the first time, we developed a model using the OAI cohort to predict with high accuracy if a given osteoarthritic knee would require TKR, when a TKR would be required, and who would likely progress fast toward this event.
Abstract 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 (200 mg/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.
Osteoarthritis (OA) is an extremely common musculoskeletal disease. However, current guidelines are not well suited for diagnosing patients in the early stages of disease and do not discriminate ...patients for whom the disease might progress rapidly. The most important hurdle in OA management is identifying and classifying patients who will benefit most from treatment. Further efforts are needed in patient subgrouping and developing prediction models. Conventional statistical modelling approaches exist; however, these models are limited in the amount of information they can adequately process. Comprehensive patient-specific prediction models need to be developed. Approaches such as data mining and machine learning should aid in the development of such models. Although a challenging task, technology is now available that should enable subgrouping of patients with OA and lead to improved clinical decision-making and precision medicine.
Mammalian target of rapamycin (mTOR) (a serine/threonine protein kinase) is a major repressor of autophagy, a cell survival mechanism. The specific in vivo mechanism of mTOR signalling in OA ...pathophysiology is not fully characterised. We determined the expression of mTOR and known autophagy genes in human OA cartilage as well as mouse and dog models of experimental OA. We created cartilage-specific mTOR knockout (KO) mice to determine the specific role of mTOR in OA pathophysiology and autophagy signalling in vivo.
Inducible cartilage-specific mTOR KO mice were generated and subjected to mouse model of OA. Human OA chondrocytes were treated with rapamycin and transfected with Unc-51-like kinase 1 (ULK1) siRNA to determine mTOR signalling.
mTOR is overexpressed in human OA cartilage as well as mouse and dog experimental OA. Upregulation of mTOR expression co-relates with increased chondrocyte apoptosis and reduced expression of key autophagy genes during OA. Subsequently, we show for the first time that cartilage-specific ablation of mTOR results in increased autophagy signalling and a significant protection from destabilisation of medial meniscus (DMM)-induced OA associated with a significant reduction in the articular cartilage degradation, apoptosis and synovial fibrosis. Furthermore, we show that regulation of ULK1/adenosine monophosphate-activated protein kinase (AMPK) signalling pathway by mTOR may in part be responsible for regulating autophagy signalling and the balance between catabolic and anabolic factors in the articular cartilage.
This study provides a direct evidence of the role of mTOR and its downstream modulation of autophagy in articular cartilage homeostasis.
Abstract 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.
Skeletal muscle aging is associated with a progressive decline in muscle mass and strength, a process termed sarcopenia. Evidence suggests that accumulation of mitochondrial dysfunction plays a ...causal role in sarcopenia, which could be triggered by impaired mitophagy. Mitochondrial function, mitophagy and mitochondrial morphology are interconnected aspects of mitochondrial biology, and may coordinately be altered with aging. However, mitochondrial morphology has remained challenging to characterize in muscle, and whether sarcopenia is associated with abnormal mitochondrial morphology remains unknown. Therefore, we assessed the morphology of SubSarcolemmal (SS) and InterMyoFibrillar (IMF) mitochondria in skeletal muscle of young (8-12wk-old) and old (88-96wk-old) mice using a quantitative 2-dimensional transmission electron microscopy approach. We show that sarcopenia is associated with larger and less circular SS mitochondria. Likewise, aged IMF mitochondria were longer and more branched, suggesting increased fusion and/or decreased fission. Accordingly, although no difference in the content of proteins regulating mitochondrial dynamics (Mfn1, Mfn2, Opa1 and Drp1) was observed, a mitochondrial fusion index (Mfn2-to-Drp1 ratio) was significantly increased in aged muscles. Our results reveal that sarcopenia is associated with complex changes in mitochondrial morphology that could interfere with mitochondrial function and mitophagy, and thus contribute to aging-related accumulation of mitochondrial dysfunction and sarcopenia.
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