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Background: Some controversy exists regarding the safety of intra-articular hyaluronic acid (IAHA) in the management of osteoarthritis (OA)., Objective: The objective of this study was to re-assess the safety profile of IAHA in patients with OA, through a comprehensive meta-analysis of randomized, placebo-controlled trials., Methods: A comprehensive literature search was undertaken in the databases MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and Scopus. Randomized, double-blind, placebo-controlled, parallel-group trials that assessed adverse events (AEs) with IAHA in patients with OA were eligible for inclusion. Authors and/or study sponsors were contacted to obtain the full report of AEs. The primary outcomes were overall severe and serious AEs, as well as the following MedDRA System Organ Class (SOC)-related AEs: gastrointestinal, cardiac, vascular, respiratory, nervous system, skin and subcutaneous tissue disorders, musculoskeletal, renal and urinary disorders, infections and infestations, and hypersensitivity reaction., Results: Database searches initially identified 1481 records. After exclusions according to the selection criteria, 22 studies were included in the qualitative synthesis, and nine studies having adequate data were ultimately included in the meta-analysis. From the studies excluded according to the pre-specified selection criteria, 21 with other pharmacological OA treatments permitted during the trials were a posteriori included in a parallel qualitative synthesis, from which eight studies with adequate data were finally included in a parallel meta-analysis. Since this meta-analysis was designed to assess safety, the exclusion criterion on concomitant anti-OA medication was crucial. However, due to the high number of studies that allowed mainly concomitant oral non-steroidal anti-inflammatory drugs (NSAIDs), we decided to include them in a post hoc parallel analysis in order to compare the results from the two analyses. No statistically significant difference in odds was found between IAHA and placebo for all types of SOC-related disorders, except for infections and infestations, for which significantly lower odds were found with IAHA compared with placebo, both overall (odds ratio [OR] = 0.61, 95% confidence interval [CI] 0.40-0.93; I 2  = 0%) and in studies without concomitant anti-OA medication (OR = 0.49, 95% CI 0.27-0.89). There were significant increased odds of reporting serious AEs with IAHA compared with placebo, both overall (OR = 1.78, 95% CI 1.21-2.63; I 2  = 0%) and in studies with concomitant anti-OA medication (OR = 1.78, 95% CI 1.10-2.89), but not in studies without concomitant anti-OA medication (OR = 1.78, 95% CI 0.92-3.47)., Conclusions: Using the available data on studies without any concomitant anti-OA medication permitted during clinical trials, IAHA seems not to be associated with any safety issue in the management of OA. However, this evidence was associated with only a "low" to "moderate" certainty. A possible association with increased risk of serious AEs, particularly when used with concomitant OA medications, requires further investigation.

Introduction: International guidelines recommend that the management of knee osteoarthritis (OA) combine both nonpharmacological and pharmacological interventions. Intra-articular (IA) therapies are considered part of this multimodal approach and are well-established Food and Drug Administration (FDA) and European Medicines Agency (EMA)-approved treatments. Areas covered: Safety data for knee OA, including IA corticosteroids, hyaluronic acid, platelet-rich plasma and botulinum toxin are critically reviewed, and evidence- and pratice-based measures to improve safety of IA therapies are discussed. Expert opinion: The incidence of AEs attributable to IA therapies across clinical trials in knee OA is very low, and barely reaches significance when compared to the incidence of AEs in the comparator group. These events are exceptionally serious. Mild differences between products have been inconsistently reported mainly for IA HA. One can distinguish self-limited AEs such as post-injection pain and swelling that are the most frequently reported AEs, from AEs that are not self-limited but rare such as septic arthritis. The safety of IA therapies can be improved by applying simple measures designed to prevent AEs. However, even though no specific safety concerns have been raised to date about IA therapies, the quality of evidence is low, and there is a need to improve the monitoring and reporting of safety data from clinical trials and post-marketing surveillance.

Background: Viscosupplementation is a symptomatic treatment of the knee osteoarthritis based on the intra-articular injection of hyaluronic acid (IAHA). Although many studies have investigated its effect on symptoms, few clinical studies have focused on its effects on biologicals markers of cartilage metabolism. In this study, we assessed the effect of an intra-articular injection of a reticulated hyaluronic acid compound on the level of a specific biomarker of type II collagen degradation., Methods: Eighty one patients with symptomatic knee osteoarthritis were included in this randomized placebo controlled trial testing a reticulated hyaluronic acid (HA) with mannitol (KARTILAGE® CROSS, 16 mg/ml, one single injection of 2.2 mL; IAHA) versus saline solution. Primary outcome was the percentage of patients with a reduction of at least 10 nmol/l of serum Coll2-1 between baseline and day 90 (D90, 3 months after injection). Secondary outcomes concerned clinical evaluation and tolerance to the study product., Results: A significant effect of IAHA was revealed by the sensitivity analysis of the decrease in cartilage marker. In the intention-to-treat population, the percentage of patients showing a decrease in the levels of serum Coll2-1 between inclusion and D90 showed was higher in HA (56.8%) than in placebo group (28.6%; P = 0.01). The same significant difference was observed between groups in the per protocol population (57.1% vs 29.0%; P = 0.02) corresponding to all patients having received the intra-articular injection (IA), being evaluated for the primary outcome on D-10 and D90, and with no major defined deviation. No significant differences between groups were observed on the changes in function (Lequesne index) or pain and on the number of adverse events., Conclusions: This is the first randomized double-blind placebo controlled trial showing that IA injection of reticulated HA with mannitol in knee osteoarthritis patients can reduce the serum levels of Coll2-1, a marker specific of type II collagen degradation. This finding suggests that IAHA may have a beneficial effect on cartilage degradation and that Coll2-1 could be used for the assessment of a single intra-articular treatment in clinical trials., Trial Registration: NCT02951585 ; clinicaltrial.gov. Retrospectively registered on October 28, 2016.

Pharmacological treatments are widely recommended in international guidelines for management of osteoarthritis (OA). However, the use of intra-articular (IA) therapies of diverse active drugs remains controversial. We critically reviewed studies of the efficacy and safety of IA injections of corticosteroids (CS), hyaluronic acid (HA), platelet-rich plasma (PRP), and botulinum toxin A (BTA) and evidence-based international recommendations for their use in treating knee OA. The process of article selection was unsystematic. Articles were selected on the basis of authors' expertise, self-knowledge, and reflective practice. Only studies assessing knee OA were included. IA CS and HA injections were conditionally to fully recommended for treating knee OA. No recommendations have been formulated for IA PRP or BTA. The evidence remains inconsistent and controversial for the use of IA therapies for knee OA. The characteristics of and selection criteria for the OA population that would likely benefit from these therapies need to be identified. Accurately phenotyping and selecting patients is mandatory in future randomized controlled trials. Therefore, efficacy and safety meta-analyses should be performed, as should qualitative and sensitivity analyses of published trial results., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) treatment algorithm recommends intra-articular (IA) hyaluronic acid (HA) for management of knee osteoarthritis (OA) as second-line treatment in patients who remain symptomatic despite use of non-steroidal anti-inflammatory drugs (NSAIDs). This recommendation is based upon accumulating evidence that IA HA provides a significant benefit in knee OA. There is good evidence that IA HA injections reduce pain and increase function in knee OA, and the benefits are long-lasting as compared with IA corticosteroids. Evidence from real-life studies of repeat courses of IA HA demonstrates an improvement in pain or function lasting up to 40 months (12 months after the last injection cycle), a reduction in use of concomitant analgesia by up to 50%, and suggests that there may be a delay in the need for total knee replacement (TKR) of around 2 years. The clinical benefit of IA HA on knee OA may be 2-fold: (i) mechanical viscosupplementation of the joint (allowing lubrication and shock absorption) and (ii) the re-establishment of joint homeostasis through induction of endogenous HA production, which continues long after the exogenous injection has left the joint. The magnitude of the clinical effect may be different for different HA products, but this has not been proven so far and requires further investigation. IA HA injections are generally considered to be safe, although a slightly higher number of cases of local reactions and post-injection non-septic arthritis has been reported with high molecular weight cross-linked HAs. The use of IA HA in knee OA patients with mild-moderate disease, and for more severe patients wishing to delay TKR surgery, is recommended by the ESCEO task force. Further investigation into the OA patient types most likely to benefit from IA HA is warranted. Viscosupplementation with IA HA is a safe and effective component of the multi-modal management of knee OA., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

To measure the evolution of the serum levels of specific Osteoarthritis (OA) biomarker, Coll2-1 and Coll2-1 NO₂ in knee osteoarthritic patients after viscosupplementation (VS). Fifty-one patients with unilateral symptomatic knee were recruited for this prospective open label study. They received three intra-articular injections of 2 ml of hyaluronic acid (Hylan GF-20) and were followed for 3 months. Walking pain was evaluated and serum samples were taken at each visit. Coll2-1 and Coll2-1 NO₂ were measured in the serum using specific immunoassays. Variations over time of each parameter and predictive factor of response were studied. Forty-five patients were analyzed. The serum concentrations of Coll2-1 and Coll2-1 NO₂ were significantly higher in KL III/IV patients compared to KL I/II patients at baseline and decreased systematically over time after VS. Its effect was ever more pronounced in patients with KL III/IV. The serum concentration of Coll2-1 was significantly lower at baseline in responders than in non-responders. This study suggests a rapid slowdown of type II collagen degradation and joint inflammation after VS with Hylan G-20 and gives additional information for the validation of accurate biomarkers for OA. The serum level of Coll2-1 appeared to be a predictive factor for response to treatment., (Copyright © 2013 Orthopaedic Research Society.)

Introduction: Intra-articular injections of hyaluronic acid (HA) could have potential interest in therapy of acute knee trauma injuries, but few results are available in humans., Objective: We reviewed the literature for animal studies of intra-articular HA injections after knee trauma injury to determine the interest of human clinical research into and/or use of such injections for knee trauma., Methods: Systematic literature search on MEDLINE for studies involving animal models of osteoarthritis created by acute knee trauma injury, with HA injections beginning during the 2 weeks after injury., Results: The search revealed 14 studies with a high methodological quality: 7 related to meniscus injury, 3 ACL injury, 1 combined ACL-meniscus injury and 3 cartilage injury. The animal models were rabbits in 10 studies. Four studies demonstrated positive effects and 3 moderate effects of intra-articular HA injection for meniscus injury; 1 positive effects and 2 no effect for ACL injury; 1 positive effects for combined ACL-meniscus injury; and 2 moderate effects and 1 no effect for cartilage injury., Conclusions: With a high strength of recommendation, intra-articular HA injections in animal models with meniscus injury improved the healing process and/or had a protective role in articular cartilage, a slightly protective role in ACL injury animal models and low or no effect on healing in articular cartilage injury animal models., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objectives: To compare the effects of an intermediate molecular weight (MW) intra-articular hyaluronic acid (HA) with a low MW product on knee osteoarthritis (OA) symptoms., Methods: Patients with symptomatic knee OA were enrolled inarandomised, controlled, double-blind, parallel-group, non-inferiority trial with the possibility to shift to superiority. Patients were randomised to GO-ON(MW 800-1500 kD, 25 mg/2.5 ml) or Hyalgan(MW 500-730 kD, 20 mg/2 ml) injected at 3-weekly intervals. The primary outcome was 6-month change in the WOMAC pain subscale (0-100 mm). Sample size was calculated on a non-inferiority margin of 9 mm, lower than the minimum perceptible clinical improvement. Secondary endpoints included OARSI-OMERACT responder rates, Results: The intention-to-treat (ITT) and per-protocol (PP) populations consisted of 217 and 209 patients and 171 and 172 patients in the GO-ON and Hyalgan groups, respectively. ITT WOMAC pain of 47.5±1.0(SE) and 48.8±1.0 mm decreased by 22.9±1.4 mm with GO-ON and 18.4±1.5 mm with Hyalgan after 6 months. The primary analysis was conducted in the PP population followed by the ITT population.Mean (95% CI) differences in WOMAC pain change were 5.2 (0.9 to 9.6)mm and 4.5 (0.5 to 8.5)mm, respectively,favouring GO-ON, satisfying the claim for non-inferiority (lower limit>-9 mm) and for statistical superiority (95% CI all>0, p=0.021). Ahigher proportion of OARSI/OMERACT responders was observed with GO-ONthan with Hyalgan (73.3% vs58.4%, p=0.001). Both preparations were well tolerated., Conclusions: Treatment with 3-weekly injections of intermediate MW HA may be superior to low MW HA on knee OA symptoms over 6 months, with similar safety.

The aim of the study was to investigate the effect of hyaluronic acid (HA) intra articular injections (IA) on osteoarthritis (OA) biomarkers in patients with knee OA. Prospective open label study. Fifty-one patients with unilateral symptomatic K-OA received IA injections of 2mL of HA on days (D) 1, 7, 14 and were followed 3 months. At D-15 patients were examined and X-rays performed, to exclude patients with bilateral K-OA, or those with more than three symptomatic OA joints. From 15 days (D-15) before the first injection to D90 concomitant therapies were unchanged. Walking pain (WP) on VAS was obtained at each visit. Urine (U) and serum (S) samples were obtained at D-15, D1, D30, and D90. S-C2C, S-Cartilage oligomeric matrix protein, S-HA, S-CS 846 epitope, S-type II collagen propeptide, and U-type II collagen C telopeptide (U-CTX II/creatinin) were assayed. Predictive factors of response were analyzed using logistic regression. Correlations between variables were obtained using Spearman test. Forty-five patients were analyzed. Between D-15 and D1 there was no difference for any biomarkers At D1, WP (SD) was correlated with U-CTX II/creat (p = 0.006). Between D1 and D90: U-CTX II/creat decreased significantly. After adjustment for confounding variables there was a significant correlation between clinical response and U-CTX II/creat variation. U-CTX II and S-HA at baseline were independently predictive of clinical response. This study showed that 90 days after HA IA injections, U-CTX II levels significantly decrease compared to baseline, suggesting a slowdown of type II collagen degradation., (Copyright © 2011 Orthopaedic Research Society.)

To measure the evolution of the serum levels of specific Osteoarthritis (OA) biomarker, Coll2-1 and Coll2-1 NO2 in knee osteoarthritic patients after viscosupplementation (VS). Fifty-one patients with unilateral symptomatic knee were recruited for this prospective open label study. They received three intra-articular injections of 2 ml of hyaluronic acid (Hylan GF-20) and were followed for 3 months. Walking pain was evaluated and serum samples were taken at each visit. Coll2-1 and Coll2-1 NO2 were measured in the serum using specific immunoassays. Variations over time of each parameter and predictive factor of response were studied. Forty-five patients were analyzed. The serum concentrations of Coll2-1 and Coll2-1 NO2 were significantly higher in KL III/IV patients compared to KL I/II patients at baseline and decreased systematically over time after VS. Its effect was ever more pronounced in patients with KL III/IV. The serum concentration of Coll2-1 was significantly lower at baseline in responders than in non-responders. This study suggests a rapid slowdown of type II collagen degradation and joint inflammation after VS with Hylan G-20 and gives additional information for the validation of accurate biomarkers for OA. The serum level of Coll2-1 appeared to be a predictive factor for response to treatment. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 901-907, 2013 [ABSTRACT FROM AUTHOR]