Introduction Viscosupplementation by intra-articular injection of hyaluronic acid (HA) is a widely used treatment for lower limb osteoarthritis. However, the injected HA is rapidly degraded by reactive oxygen species (ROS), limiting its time of intra-articular residence. Optimizing clinical effectiveness of viscosupplementation by reducing HA degradation in situ, and therefore increasing the time of contact with the diseased tissue, is a challenging research approach. Mannitol, a powerful ROS scavenger, is a good candidate for this. The aim of this study was to compare in vitro the resistance to ROS-mediated degradation of two marketed viscosupplements (one linear and one cross-linked) to that of two novel viscosupplements combining HA and mannitol. Methods A HA viscosupplement at a concentration of 10 g/L (HA 1%), was compared to a HANOX-M, a novel viscosupplement made of a mixture of HA and mannitol. In a second experiment, Hylan G-F 20, a partially cross-linked viscosupplement, was compared to a HANOX-M-XL, a novel cross-linked viscosupplement made of a HA and mannitol (35 g/L). The four HA viscosupplements were subjected to oxidative stress generated by the addition of hydrogen peroxide (H₂O₂) and their rheological behavior (elastic moduli [G′], viscous moduli [G″], and complex viscosity [|η*|]) were compared before and after the oxidative stress exposure. Results The two viscosupplements not containing mannitol HA were rapidly degraded by H₂O₂, as demonstrated by the dramatic decrease of |η*|. On the other hand, the rheological properties of HA containing mannitol were not substantially modified in the presence of H₂O₂. Conclusion This in vitro study demonstrates that mixing mannitol with HA protects the viscosupplement from ROS-mediated degradation and might therefore increase its intra-articular residence time without substantially modifying its rheological behavior. This in vitro study has to be followed by clinical trials designed to assess whether the addition of mannitol to HA might improve the efficiency and/or the duration of action of viscosupplementation.

The objective of this pilot study was to identify biological, clinical or structural biomarkers of an intra-articular hyaluronic acid injection efficacy (HYMOVIS®) for the design of a larger placebo-controlled clinical trial studying the disease-modifying activity of this treatment. Forty six patients with symptomatic knee Osteoarthritis (OA) were enrolled in this open-label, prospective, multicenter, pilot study. Patients received two treatment cycles of intra-articular injections (3 mL) of HYMOVIS® (8 mg/mL of hyaluronic acid hexadecylamide) at 6 months interval. Each treatment cycle involved two intra-articular injections 1 week apart. All patients had Magnetic Resonance Imaging (MRI) of the target knee at baseline and 1 year, and blood samples to assess joint biomarkers. The primary outcome was the change in type II collagen-specific biomarkers (Coll2–1, Coll2–1NO2 and CTX-II) after HYMOVIS® treatment versus baseline. Secondary endpoints included levels changes in aggrecan chondroitin sulfate 846 epitope (CS-846), Cartilage Oligomeric Matrix Protein (COMP), procollagen type II N-terminal propeptide (PIIANP), Matrix Metalloprotease (MMP)-3, Myeloperoxidase (MPO) and Interleukin (IL)-6 serum biomarkers, the ratio Coll2–1/PIIANP, CTX-II/PIIANP, variation of MRI cartilage volume, and Knee injury and Osteoarthritis Outcome Score (KOOS) index. Coll2–1 serum levels significantly increased overtime while Coll2–1NO2 levels were only increased at D360. Serum PIIANP levels also progressively and significantly enhanced with time. In contrast, other serum biomarker levels including CTX-II, CS-846, COMP, MMP-3, MPO or IL-6 did not change significantly overtime. Interestingly, the ratios Coll2–1/PIIANP and CTX-II/PIIANP decreased, indicating a decrease of cartilage catabolism. Compared to baseline value, MRI cartilage volume and thickness increased in lateral femoral and lateral trochlea compartments and not in medial compartment. These results, in addition to an improvement of T2 mapping score suggest a positive structural effect of the product. Interestingly, WORMS effusion score, an indicator of synovitis, significantly decreased. Finally, global KOOS score and subscales significantly increased overtime while pain at rest, walking pain and patients or investigators global assessment of disease activity decreased. The safety profile was favorable with a low incidence of injection-site pain. HYMOVIS®, a well-tolerated intra-articular treatment, significantly enhanced type II collagen turnover as suggested by the increase in Coll2–1 and PIIANP levels and cartilage volume observed by MRI in lateral knee compartment. Importantly, this study provides critical information for the design of a larger phase III clinical trial investigating Disease Modifying effect of HYMOVIS®. http://www.isrctn.com/ISRCTN12227846 11/02/2015.

Objectives: The 3 aims of the work were to identify population subgroups that can benefit the most from viscosupplementation (VS), to provide recommendations on injection techniques, and to discuss VS appropriateness in clinical situations that are commonplace in daily practice. Methods: The task force members voted on their degree of agreement on 27 statements, 36 recommendations, and 22 clinical scenarios using a 9-point scale. The strength of agreement/appropriateness/recommendation (SOA/SOR) was classified as strong if the median agreement score was ≥8. The level of consensus (LOC) was also obtained. Results: Among the assumed predictors for VS failure, obesity, radiographic severity, large synovial fluid effusion, severe patellofemoral involvement, major malalignment, and gross joint instability received a large majority of agreements. The lateral mid-patellar approach was recommended for knee injection. Imaging guidance was unanimously recommended for hip and ankle. Agreement was achieved to strictly respect the dosing regimen proven by controlled trials. There was agreement for treating with VS patients with mild to moderate knee and hip OA, with normal weight or moderate overweight, insufficiently improved by first-line therapies, or who do not wish get oral treatment or who have contraindications to pain killers. The group considered the patient’s wishes as a key element in therapeutic decision making. Conclusion: Based on literature data and clinical experience, the EUROVISCO group proposed a set of recommendations for optimizing the results of VS, aimed to help practitioners, especially in some cases in which the patients’ specificities make the therapeutic decision difficult.

Background: Viscosupplementation (VS) is a symptomatic treatment of knee osteoarthritis. Although systematic reviews of its repeat use showed favorable benefit/risk ratio, no study has focused on the indication of retreatment. Methods: A task force was created to look at issues regarding retreatment with VS in knee osteoarthritis. An attempt was made to reach consensus on several issues: (1) to define treatment “success” and “failure,” (2) to determine when to retreat patients successfully treated by a previous VS, (3) to determine how to retreat patients in whom VS failed, (4) to define what to do in case of adverse reaction following previous VS, and (5) to examine the interests of soluble biomarkers to manage retreatment. After debate and review of literature the working group voted on 88 issues. Two “decision trees” were built based on the results of the votes. Results: In case of failure, the authors draw attention to the need of a rigorous clinical and radiological analysis, and consider evidence-based medicine. When VS was previously successful, retreatment can be considered after recurrence or increase in pain. However, in subjects with high risk of disease progression, in young patients, and in professional sportsmen, retreatment could be considered systematically, because of the probability of hyaluronic acid to slow osteoarthritis progression. Evidence on soluble biomarkers was not considered as enough strong to support their use as decision tools for patient retreatment. Conclusion: The decision algorithms are intended to facilitate consideration of the therapeutic options, in patients with knee osteoarthritis previously treated with VS.

To identify predictive factors of response to viscosupplementation (VS) in patients with hip osteoarthritis (HOA). Prospective, multicentre, open-label trial, achieved in daily practice conditions. Patients with HOA were treated with a single intra-articular injection of a cross-linked hyaluronic acid combined with mannitol (HAnox-M-XL), using imaging guidance. WOMAC pain and function scores and patient global assessment (PGA) were assessed at baseline and day 90. Improvement, satisfaction and efficacy were self-assessed at day 90. Hip radiographs at baseline were scored using Kellgren-Lawrence grade and Osteoarthritis Research Society International (OARSI) score. Associations between clinical and radiological features and response to VS (pain improvement > 50% at day 90) were assessed in univariate analysis, and then using logistic regression, adjusted for confounding factors. The intent-to-treat (ITT) population included 97 patients (57 females, mean age 63). Ninety completed the follow-up and 80 had full clinical and radiological data. Response to VS was achieved in 47.8% of patients. In univariate analysis, the only clinical outcome statistically and negatively related to response was PGA at baseline (p = 0.047). Radiologically, response to VS was negatively correlated with joint space narrowing (JSN) score (JSN < 2 vs. JSN ≥ 2, p = 0.01) and was related to the patterns of femoral head migration (p = 0.008). In multivariate analysis, only JSN grade (p = 0.03) remained significantly related to a poor response. This pilot study, which needs further confirmation by larger scale trials, suggests that radiological features might be of importance for the decision of VS in patients with HOA. ID RCB N°2013-A00165-40. Registered 31 January 2013.

No disease-modifying treatments are currently available for osteoarthritis (OA). While many therapeutic approaches are now being investigated it is ethical to resort to alternative solutions as that we already possess. There are many reasons for thinking that, at sufficiently high doses, glucosamine (GlcN) sulphate possesses a clinically relevant effect on OA pain. Wide inter-individual variations in the symptomatic effects of GlcN are explained by the extreme variability of its bioavailability. In studies evaluating its structure-modifying effect, GlcN was more effective than placebo in reducing the rate of joint space narrowing in patients with knee OA. More recent data suggest that GlcN may be effective in the primary prevention of OA in sportsmen. There is no controversy concerning the safety of GlcN which does not differ to that of placebo. Several studies have recently revealed an unexpected effect of GlcN on cardiovascular mortality. After adjusting for confounding factors, the regular consumption of GlcN correlated with a 27% reduction in mortality and a 58% reduction in deaths from cardiovascular causes. These data confirm animal studies demonstrating a protective effect of GlcN against cancer and cardiovascular diseases due to modulation of the O-GlcNAcylation pathway. Disorders in O-GlcNAcylation are involved in diabetes, obesity and cancers, which all feature chronic low-grade inflammation (CLGI). By regulating CLGI, GlcN may be beneficial to the symptoms of OA, its outcome and to that of the concomitant chronic pathologies, making GlcN as a valuable candidate for the treatment of OA in patients with metabolic syndrome, diabetes or cardiovascular diseases.