Effect of Resveratrol on Serum Levels of Type II Collagen and Aggrecan in Patients with Knee Osteoarthritis: A Pilot Clinical Study

Treatment of knee osteoarthritis (OA) remains a challenging concern. Preclinical studies provided accumulating evidence on resveratrol efficacy in ameliorating degenerative articular damage. The present study was conducted to evaluate the effects of resveratrol as monotherapy on the serum level of type II collagen (Coll 2-1) and aggrecan in patients with knee osteoarthritis. The study was an open-labeled noncontrolled clinical trial. Resveratrol 500 mg/day in a single oral dose was given to the patients with knee osteoarthritis for 90 days. The serum levels of Coll-2-1, aggrecan, and biomarkers of inflammation were measured pre- and posttreatment. Hematological profiles and both hepatic and renal function markers were investigated at the baseline and at the end of the treatment for evaluating the tolerability and safety of resveratrol. Visual Analog Scale (VAS) for pain and Knee injury and Osteoarthritis Outcome Score (KOOS) for disease activity were clinically assessed monthly. Administration of 500 mg resveratrol for three months led to a nonsignificant decrease in the serum level of Coll 2-1 while a significant increase in aggrecan serum level. Resveratrol significantly improves pain score measured by VAS and KOOS after 30 days. Improvements in patients’ activity and functional status were also evident at day 30 and kept on for three months which was reflected by KOOS subscale scores and with a significant improvement in all KOOS areas. In conclusion, oral administration of resveratrol as a monotherapy provides a remarkable improvement in the clinical status of the patients but has no significant effect on serum levels of Coll 2-1.

Acute Arthritis in Children: How to Discern between Septic and Non-Septic Arthritis?

The term septic arthritis refers to an infection of the synovial space. This is an infrequent condition in healthy children, but it should be considered a medical emergency potentially leading to irreversible articular damage. Therefore, prompt diagnosis and antimicrobial treatment play a crucial role in improving the prognosis. Although septic arthritis is the most common cause of acute arthritis, many other diseases may mimic a similar clinical picture, constituting a diagnostic challenge for the clinician who first approaches the patient. Herein we analyze the main features of septic arthritis, offering an overview of the main conditions involved in the differential diagnosis and suggesting a diagnostic workup plan.

Clinically suspect arthralgia – are we going towards a new shift in the therapeutic paradigm of rheumatoid arthritis?

Background. There is a time sensitive window of opportunity in rheumatoid arthritis (RA) in which therapeutic intervention is more effective, the disease being more susceptible to the immunomodulatory effects of the remissive medication. The goal is to prevent osteo-articular damage, which causes severe functional deficit, and to raise the chance to lead the disease in remission. Evolution towards RA represents a multi-step process. In other medical fields prevention has the same important role as treatment, so could we in the future switch again the therapeutic paradigm in RA, from early treatment to prevention of RA, by treating patients with high risk of developing disease? Initiating treatment in the pre-RA phases could potentially lead to a better immune modulation or even preventing disease development by acting on less mature pathogenic processes. Treating in the initial symptomatic phase of the disease could potentially be more effective in reducing disease persistence and the development of structural lesions. The clinically suspect arthralgia (CSA) definition offers a support of clinical parameters for future longitudinal studies, where together with para clinical parameters, laboratory studies and imagistic studies, could lead to the development of imminent RA classification criteria. Currently there are more ongoing studies that have the primary objective to prove this concept with different subpopulations and treatments, but most of them have inclusion criteria based on the presence of autoantibodies. The publication of this trials results in the next decade will help to better understand the efficacy of therapeutic intervention with the scope of preventing chronic arthritis and what subset of patients at risk to treat. There are no recommendations for management of CSA, but current practice is symptomatic treatment with nonsteroidal anti-inflammatory drugs, pain relievers and of course monitoring.

KCB-Net: A 3D Knee Cartilage and Bone Segmentation Network via Sparse Annotation

<div>Knee cartilage and bone segmentation is critical for physicians to analyze and diagnose articular damage and knee osteoarthritis (OA). Deep learning (DL) methods for medical image segmentation have largely outperformed traditional methods, but they often need large amounts of annotated data for model training, which is very costly and time-consuming for medical experts, especially on 3D images. In this paper, we report a new knee cartilage and bone segmentation framework, KCB-Net, for 3D MR images based on sparse annotation. KCB-Net selects a small subset of slices from 3D images for annotation, and seeks to bridge the performance gap between sparse annotation and full annotation. Specifically, it first identifies a subset of the most effective and representative slices with an unsupervised scheme; it then trains an ensemble model using the annotated slices; next, it self-trains the model using 3D images containing pseudo-labels generated by the ensemble method and improved by a bi-directional hierarchical earth mover’s distance (bi-HEMD) algorithm; finally, it fine-tunes the segmentation results using the primal-dual Internal Point Method (IPM). Experiments on two 3D MR knee joint datasets (the Iowa dataset and iMorphics dataset) show that our new framework outperforms state-of-the-art methods on full annotation, and yields high quality results even for annotation ratios as low as 5%.<br></div>

KCB-Net: A 3D Knee Cartilage and Bone Segmentation Network via Sparse Annotation

<div>Knee cartilage and bone segmentation is critical for physicians to analyze and diagnose articular damage and knee osteoarthritis (OA). Deep learning (DL) methods for medical image segmentation have largely outperformed traditional methods, but they often need large amounts of annotated data for model training, which is very costly and time-consuming for medical experts, especially on 3D images. In this paper, we report a new knee cartilage and bone segmentation framework, KCB-Net, for 3D MR images based on sparse annotation. KCB-Net selects a small subset of slices from 3D images for annotation, and seeks to bridge the performance gap between sparse annotation and full annotation. Specifically, it first identifies a subset of the most effective and representative slices with an unsupervised scheme; it then trains an ensemble model using the annotated slices; next, it self-trains the model using 3D images containing pseudo-labels generated by the ensemble method and improved by a bi-directional hierarchical earth mover’s distance (bi-HEMD) algorithm; finally, it fine-tunes the segmentation results using the primal-dual Internal Point Method (IPM). Experiments on two 3D MR knee joint datasets (the Iowa dataset and iMorphics dataset) show that our new framework outperforms state-of-the-art methods on full annotation, and yields high quality results even for annotation ratios as low as 5%.<br></div>

The Anti-Arthritic Efficacy of Khellin Loaded in Ascorbyl Decanoate Nanovesicles after an Intra-Articular Administration

Osteoarthritis is the most widespread joint-affecting disease. The management of persistent pain remains inadequate and demands new therapeutic strategies. In this study, we explored the pain relieving and protective properties of a single intra-articular (i.a.) injection of khellin loaded in nanovesicles (K-Ves) based on ascorbyl decanoate plus phosphatidylcholine in a rat model of osteoarthritis (OA) induced by monosodium iodoacetate (MIA) treatment. The developed nanovesicles (approximately 136 nm) had a narrow size distribution (PdI 0.26), a good recovery (about 80%) and a worthy encapsulation efficiency (about 70%) with a ζ-potential of about −40 mV. The stability of K-Ves was assessed in simulated synovial fluid. Seven days after the articular damage with MIA, both K-Ves and a suspension of khellin (K, 50 μL) were i.a. injected. K-Ves significantly counteracted MIA-induced hypersensitivity to mechanical noxious (paw pressure test) and non-noxious stimuli (von Frey test) and significantly reduced the postural unbalance related to spontaneous pain (incapacitance test) and the motor alterations (beam balance test) 7 and 14 days after the i.a. injection. K was partially active only on day 7 after the treatment. The histology emphasized the improvement of several morphological factors in MIA plus K-Ves-treated animals. In conclusion, K-Ves could be successfully used for the local treatment of osteoarthritis.

ADIPOCYTOKINES IN RHEUMATOID ARTHRITIS: LATENT RELATIONASHIP BETWEEN INFLAMMATION AND CARDIOMETABOLIC COMORBIDITIES

Rheumatoid arthritis is a chronic autoimmune disease that affects the synovial membrane of the joints and leads to progressive articular damage, disability and reduced quality of life. Despite the emergence of more innovative therapeutic strategies that have improved the duration of remission, rheumatoid arthritis is associated with high levels of comorbidities, infections, malignancies and cardiovascular disease. It is known that some pathogenic proinflammatory mediators in rheumatoid arthritis, such as interleukin-1β (IL-1β) and tumour necrosis factor, may play a central role in the development of cardiovascular disease. Interestingly, various preclinical and clinical studies have shown that biologic agents, who are widely used in the therapy of patients with rheumatoid arthritis, may be effective in the therapy of cardiovascular diseases as well. For this purpose we have studied adipocytokines. Adipocytokines are pleiotropic molecules that are mainly released by white adipose tissue and immune cells. Adipocytokines modulate the function of different tissues and cells, and, in addition to energy homeostasis and metabolism, enhance inflammation, immune response and tissue damage. Adipocytokines may contribute to the proinflammatory conditions in patients with rheumatoid arthritis and the development of bone damage. In addition, they may be associated with the development of cardiovascular disease. In this study, we considered the already known evidence about adipocytokines in the pathogenesis of rheumatoid arthritis, because they are also actively involved in the pathogenesis of cardiovascular disease and are possible biomarkers of prognosis and treatment outcomes, because of their potential, as a possible new therapeutic target.

Anatomy of the Intermetatarsal Facets of the Fourth and Fifth Metatarsals

Background: The intermetatarsal joint between the fourth and fifth metatarsals (4-5 IM) is important in defining fifth metatarsal fractures. The purpose of the current study was to quantify this joint in order to determine the mean cartilage area, the percentage of the articulation that is cartilage, and to give the clinician data to help understand the joint anatomy as it relates to fifth metatarsal fracture classification. Methods: Twenty cadaver 4-5 IM joints were dissected. Digital images were taken and the articular cartilage was quantified by calibrated digital imaging software. Results: For the lateral fourth proximal intermetatarsal articulation, the mean area of articulation was 188 ± 49 mm2, with 49% of the area composed of articular cartilage. The shape of the articular cartilage had 3 variations: triangular, oval, and square. A triangular variant was the most common (80%, 16 of 20 specimens). For the medial fifth proximal intermetatarsal articulation, the mean area of articulation was 143 ± 30 mm2, with 48% of the joint surface being composed of articular cartilage. The shape of the articular surface was oval or triangular. An oval variant was the most common (75%, 15 of 20 specimens). Conclusion: This study supports the notion that the 4-5 IM joint is not completely articular and has both fibrous and cartilaginous components. Clinical Relevance: The clinical significance of this study is that it quantifies the articular surface area and shape. This information may be useful in understanding fifth metatarsal fracture extension into the articular surface and to inform implant design and also help guide surgeons intraoperatively in order to minimize articular damage.

Role of Adiponectin in the Pathogenesis of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a systemic chronic inflammatory autoimmune joint disease, characterized by progressive articular damage and joint dysfunction. One of the symptoms of this disease is persistent inflammatory infiltration of the synovial membrane, the principle site of inflammation in RA. In the affected conditions, the cells of the synovial membrane, fibroblast-like synoviocytes and macrophage-like synovial cells, produce enzymes degrading cartilage and underlining bone tissue, as well as cytokines increasing the infiltration of immune cells. In patients with RA, higher levels of adiponectin are measured in the serum and synovial fluid. Adiponectin, a secretory product that is mainly white adipose tissue, is a multifunctional protein with dual anti-inflammatory and pro-inflammatory properties. Several studies underline the fact that adiponectin can play an important pro-inflammatory role in the pathophysiology of RA via stimulating the secretion of inflammatory mediators. This narrative review is devoted to the presentation of recent knowledge on the role played by one of the adipokines produced by adipose tissue—adiponectin—in the pathogenesis of rheumatoid arthritis.

Neutrophil-mediated carbamylation promotes articular damage in rheumatoid arthritis

Formation of autoantibodies to carbamylated proteins (anti-CarP) is considered detrimental in the prognosis of erosive rheumatoid arthritis (RA). The source of carbamylated antigens and the mechanisms by which anti-CarP antibodies promote bone erosion in RA remain unknown. Here, we find that neutrophil extracellular traps (NETs) externalize carbamylated proteins and that RA subjects develop autoantibodies against carbamylated NET (cNET) antigens that, in turn, correlate with levels of anti-CarP. Transgenic mice expressing the human RA shared epitope (HLADRB1* 04:01) immunized with cNETs develop antibodies to citrullinated and carbamylated proteins. Furthermore, anti–carbamylated histone antibodies correlate with radiographic bone erosion in RA subjects. Moreover, anti–carbamylated histone–immunoglobulin G immune complexes promote osteoclast differentiation and potentiate osteoclast-mediated matrix resorption. These results demonstrate that carbamylated proteins present in NETs enhance pathogenic immune responses and bone destruction, which may explain the association between anti-CarP and erosive arthritis in RA.