Intra-articular hyaluronic acid in knee osteoarthritis: clinical data for a product family (ARTHRUM), with comparative meta-analyses.

INTRODUCTION: Viscosupplementation is widely practiced, to reduce pain in osteoarthritis (OA), using intra articular (IA) injections of hyaluronic acid (HA). In Europe, these products are class III medical devices, for which the Medical Device Regulation (MDR) requires clinical assessment, based on specific studies and/or a bibliographical review of equivalent devices. The purpose of this article is to present a comparative review between a family of devices (ARTHRUM, from LCA Pharmaceuticals, Chartres, France) and an extensive group of presumed equivalent IA HA devices or their controls, whose results have been published in Scientific journals. METHODS: To meet the criteria used in most ARTHRUM studies, the Western Ontario and McMaster Universities' index sub-scores were selected for pain (WOMAC A), stiffness (WOMAC B) and function (WOMAC C). The main criterion was the variation of the WOMAC A score from T0 (date of inclusion) to T6 (6 months). The other WOMAC criteria were assessed at T1, T3, T6 and complemented by OMERACT-OARSI rates of responders to the treatment. Fifty articles were selected, containing treatment details on more than 12,000 patients. These were divided into three groups: ARTHRUM, EQUIVALENTS and CONTROLS. To get quantitative comparisons, meta-analyses were performed for each criterion individually. The 95% confidence interval of each difference from baseline, was used to assess the clinical relevance, with reference to a minimum validated in OA literature. Comparisons between groups and tolerance assessment completed the investigation. RESULTS: For the WOMAC A, B and C scores, the full 95% CI was always above the minimal perceptible clinical improvement (MPCI), in the ARTHRUM and EQUIVALENTS groups, but not for all criteria in the CONTROLS group. In the comparisons, both ARTHRUM and EQUIVALENTS groups were significantly better than the CONTROLS group for each criterion. The effect size (ES) on pain, for the ARTHRUM and EQUIVALENTS groups, varied from 0.28 to 0.56 and from 0.23 to 0.27, respectively. Overall, ARTHRUM was estimated always non-inferior to EQUIVALENTS, and sometimes statistically and clinically superior. CONCLUSIONS: The comparison of ARTHRUM clinical studies, with studies selected through bibliographic research, leads to the conclusion that the clinical efficacy of the ARTHRUM medical devices, to reduce pain and improve the function in knee OA, during a six-month period, is at least as great as those of equivalent products. With good tolerance results (lowest rate of adverse events, and none of them serious), the risk benefit ratio favours using viscosupplementation with ARTHRUM.

Exploring the translational potential of clusterin as a biomarker of early osteoarthritis.

BACKGROUND: Clusterin (CLU; also known as apolipoprotein J) is an ATP-independent holdase chaperone that prevents proteotoxicity as a consequence of protein aggregation. It is a ∼60 kDa disulfide-linked heterodimeric protein involved in the clearance of cellular debris and the regulation of apoptosis. CLU has been proposed to protect cells from cytolysis by complement components and has been implicated in Alzheimer's disease due to its ability to bind amyloid-ß peptides and prevent aggregate formation in the brain. Recent studies suggest that CLU performs moonlighting functions. CLU exists in two major forms: an intracellular form and a secreted extracellular form. The intracellular form of CLU may suppress stress-induced apoptosis by forming complexes with misfolded proteins and facilitates their degradation. The secreted form of CLU functions as an extracellular chaperone that prevents protein aggregation. METHODS: In this review, we discuss the published literature on the biology of CLU in cartilage, chondrocytes, and other synovial joint tissues. We also review clinical studies that have examined the potential for using this protein as a biomarker in synovial and systemic fluids of patients with rheumatoid arthritis (RA) or osteoarthritis (OA). RESULTS: Since CLU functions as an extracellular chaperone, we propose that it may be involved in cytoprotective functions in osteoarticular tissues. The secreted form of CLU can be measured in synovial and systemic fluids and may have translational potential as a biomarker of early repair responses in OA. CONCLUSION: There is significant potential for investigating synovial and systemic CLU as biomarkers of OA. Future translational and clinical orthopaedic studies should carefully consider the diverse roles of this protein and its involvement in other comorbidities. Therefore, future biomarker studies should not correlate circulating CLU levels exclusively to the process of OA pathogenesis and progression. Special attention should be paid to CLU levels in synovial fluid. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: There is significant potential for investigating synovial and systemic CLU as a predictive biomarker of osteoarthritis (OA) progression and response to novel treatments and interventions. Given that CLU plays diverse roles in other comorbidities such as rheumatoid arthritis (RA) and obesity, future translational and clinical orthopaedic biomarker studies should not directly correlate circulating CLU levels to the process of OA pathogenesis and progression. However, special attention should be paid to CLU levels in synovial fluid. The cytoprotective properties of CLU may support the implementation of regenerative strategies and new approaches for developing targeted therapeutics for OA.

The human knee: A window on the microvasculature.

In synovial joints, the lining cells do not have tight junctions with their neighboring cells and they have no underlying basement membrane. Therefore, the synovial fluid within the articular cavity is continuous with the interstitial fluid of the synovial intima. These features, combined with ready access to the space via arthrocentesis, permit quantitative studies of microvascular function in the knees of unanesthetized, volunteer, human subjects both with and without chronic arthritis. This brief article reviews the principal findings of such work over ∼40 years at the University of Washington. Examined variables include bidirectional fenestral diffusion of small solutes, effective blood flow, lymphatic drainage, and endothelial pore size and permeability. The latter work introduced a new method using gel filtration chromatography of paired synovial fluid (SF) and serum (S) to obtain essentially continuous SF/S ratios over a range of radii between 1 and 12 nanometers.