Safety and Tolerability of Intra-Articular Hyaluronic Acid Injection (Sinovial®) in Experimental and Clinical Practice

Osteoarthritis (OA) requires long-term treatment, therefore, tolerability is a key factor in treatment choice. Hyaluronic acid (HA), a glycosaminoglycan with viscoelastic properties, a major component of synovial fluid and the extracellular matrix of the joint cartilage, plays key roles in synovial fluid viscosity and maintaining normal cartilage. Viscosupplementation is an intra-articular (IA) injection of exogenous HA in an effort to delay joint mobility loss. Commercially available viscosupplementation includes HA of different average molecular weight (MW), concentration and origins, with varying tolerability. This review describes the tolerability and safety profile of Sinovial® in knee and hip OA. A literature search of PubMed using the search queries [Sinovial® OR hyaluronic acid OR hyaluronan] and [intra-articular OR osteoarthritis] was performed using terms as medical subject headings and free text searches. Studies were selected manually for inclusion in this review. Sinovial® is a low-medium MW HA of non-avian origin, produced by biofermentation to ensure the product is pure and free of allergenic animal proteins. We analyzed data regarding the tolerability of Sinovial® in OA patients. This formulation has a favorable tolerability profile; no systemic reactions have been reported and most adverse events (AEs) are mild, transient and easily managed local injection site reactions. Reactions — pain and burning at the injection site - are typical of IA injections. AEs with Sinovial® used in the hip are similar to knee OA.

Related papers:

title: Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II.
abstract: To provide a single source for the best available estimates of the US prevalence of and number of individuals affected by osteoarthritis, polymyalgia rheumatica and giant cell arteritis, gout, fibromyalgia, and carpal tunnel syndrome, as well as the symptoms of neck and back pain. A companion article (part I) addresses additional conditions.



The National Arthritis Data Workgroup reviewed published analyses from available national surveys, such as the National Health and Nutrition Examination Survey and the National Health Interview Survey. Because data based on national population samples are unavailable for most specific rheumatic conditions, we derived estimates from published studies of smaller, defined populations. For specific conditions, the best available prevalence estimates were applied to the corresponding 2005 US population estimates from the Census Bureau, to estimate the number affected with each condition.



We estimated that among US adults, nearly 27 million have clinical osteoarthritis (up from the estimate of 21 million for 1995), 711,000 have polymyalgia rheumatica, 228,000 have giant cell arteritis, up to 3.0 million have had self-reported gout in the past year (up from the estimate of 2.1 million for 1995), 5.0 million have fibromyalgia, 4-10 million have carpal tunnel syndrome, 59 million have had low back pain in the past 3 months, and 30.1 million have had neck pain in the past 3 months.



Estimates for many specific rheumatic conditions rely on a few, small studies of uncertain generalizability to the US population. This report provides the best available prevalence estimates for the US, but for most specific conditions more studies generalizable to the US or addressing understudied populations are needed.

title: The epidemiology, etiology, diagnosis, and treatment of osteoarthritis of the knee.
abstract: Osteoarthritis is the most common joint disease of adults worldwide. Its incidence rises with age. Both intrinsic and extrinsic risk factors promote its development. In men aged 60 to 64, the right knee is more commonly affected; in women, the right and left knees are affected with nearly equal frequency.



The PubMed, Medline, Embase and Cochrane Library databases were selectively searched for current studies (up to September 2009; case reports excluded) on the epidemiology, etiology, diagnosis, staging, and treatment of osteoarthritis of the knee. The search terms were "gonarthrosis," "prevention," "conservative treatment," "joint preservation," "physical activity," "arthroscopy," "osteotomy," "braces," "orthoses," and "osteoarthritis knee joint."



Osteoarthritis is not yet a curable disease, and its pathogenesis remains unclear. The best treatment for osteoarthritis of the knee is prevention. The goal of therapy is to alleviate clinical manifestations. The therapeutic spectrum ranges from physiotherapy and orthopedic aids to pharmacotherapy and surgery.

title: EULAR recommendations for the non-pharmacological core management of hip and knee osteoarthritis
abstract: The objective was to develop evidence -based recommendations and a research and educational agenda for the non-pharmacological management of hip and knee osteoarthritis (OA). The multidisciplinary task force comprised 21 experts: nurses, occupational therapists, physiotherapists, rheumatologists, orthopaedic surgeons, general practitioner, psychologist, dietician, clinical epidemiologist and patient representatives. After a preliminary literature review, a first task force meeting and five Delphi rounds, provisional recommendations were formulated in order to perform a systematic review. A literature search of Medline and eight other databases was performed up to February 2012. Evidence was graded in categories I–IV and agreement with the recommendations was determined through scores from 0 (total disagreement) to 10 (total agreement). Eleven evidence-based recommendations for the non-pharmacological core management of hip and knee OA were developed, concerning the following nine topics: assessment, general approach, patient information and education, lifestyle changes, exercise, weight loss, assistive technology and adaptations, footwear and work. The average level of agreement ranged between 8.0 and 9.1. The proposed research agenda included an overall need for more research into non-pharmacological interventions for hip OA, moderators to optimise individualised treatment, healthy lifestyle with economic evaluation and long-term follow-up, and the prevention and reduction of work disability. Proposed educational activities included the required skills to teach, initiate and establish lifestyle changes. The 11 recommendations provide guidance on the delivery of non-pharmacological interventions to people with hip or knee OA. More research and educational activities are needed, particularly in the area of lifestyle changes.

title: EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT).
abstract: To update the EULAR recommendations for management of knee osteoarthritis (OA) by an evidence based medicine and expert opinion approach.



The literature search and guidelines were restricted to treatments for knee OA pertaining to clinical and/or radiological OA of any compartment of the knee. Papers for combined treatment of knee and other types of OA were excluded. Medline and Embase were searched using a combination of subject headings and key words. Searches for those treatments previously investigated were conducted for January 1999 to February 2002 and for those treatments not previously investigated for 1966 to February 2002. The level of evidence found for each treatment was documented. Quality scores were determined for each paper, an effect size comparing the treatment with placebo was calculated, where possible, and a toxicity profile was determined for each treatment modality.



497 new publications were identified by the search. Of these, 103 were intervention trials and included in the overall analysis, and 33 treatment modalities were identified. Previously identified publications which were not exclusively knee OA in the initial analysis were rejected. In total, 545 publications were included. Based on the results of the literature search and expert opinion, 10 recommendations for the treatment of knee OA were devised using a five stage Delphi technique. Based on expert opinion, a further set of 10 items was identified by a five stage Delphi technique as important for future research.



The updated recommendations support some of the previous propositions published in 2000 but also include modified statements and new propositions. Although a large number of treatment options for knee OA exist, the evidence based format of the EULAR Recommendations continues to identify key clinical questions that currently are unanswered.

title: Viscosupplementation with Hyaluronans for Osteoarthritis of the Knee
abstract: Treatment with intra-articular viscosupplementation with hyaluronan (hyaluronic acid) and its derivatives is an important component of the management of osteoarthritis (OA) of the knee. Several intra-articular hyaluronan formulations are now available that vary in their physical properties, duration of effect and treatment schedules.Although aspects regarding their mechanism of action are not completely understood, numerous clinical trials, systematic reviews and meta-analyses have confirmed the efficacy of intra-articular hyaluronan therapies for relieving OA-related pain and improving joint function. Data indicate that intra-articular hyaluronan preparations provide OA pain relief that is comparable to or greater than that observed with conventional treatment, NSAID medications, intra-articular corticosteroids, arthroscopic lavage, physical therapy and exercise. Other studies indicate that multiple courses of hyaluronan are effective.Intra-articular hyaluronan formulations are well tolerated and are associated with a low incidence of adverse effects, usually localised to the injected joint. Local adverse events associated with intra-articular hyaluronan products are typically mild to moderate in severity, benign and transient, although their aetiology is unknown.The cost effectiveness of intra-articular hyaluronan has been demonstrated, but only in a limited number of studies. Cost savings with intra-articular hyaluronan can also be realised with reduction of NSAID medication use and the possibility of delaying total knee replacement, which can reduce the need for costly revision procedures. Because different intra-articular hyaluronan formulations require different numbers of injections and office visits, are associated with variable treatment costs, and provide varying degrees of efficacy, not all intra-articular hyaluronan formulations may be equally cost effective over time.

title: Viscosupplementation: a new concept in the treatment of osteoarthritis.
abstract: Viscosupplementation is a new medical concept that has as its therapeutic goal the restoration of rheological homeostasis in pathological structures such as osteoarthritic joints. When the normal viscoelasticity of a solid tissue compartment or the elastoviscosity of a liquid tissue compartment is decreased under pathological conditions, normal function and regenerative processes are impaired. By introducing viscosupplementary devices, the normal rheological state of such compartments is restored or augmented. These devices stay in the tissue compartment for various periods of time, depending on the nature of the viscosupplement and the pathophysiology of the tissue compartment.

title: Intra-articular hyaluronans in knee osteoarthritis: rationale and practical considerations.
abstract: Intra-articular hyaluronans are used to treat pain associated with osteoarthritis of the knee. Many controlled clinical studies have demonstrated their efficacy for this indication. The rationale for the use of hyaluronans therapeutically is based on observations that hyaluronic acid is an important component of the synovial fluid acting as a cushion and lubricant for the joint and also serving as a major component of the extracellular matrix of the cartilage, helping to enhance the ability of cartilage to resist shear and maintain a resiliency to compression. While intra-articular hyaluronans are indicated at this time only for the treatment of pain in osteoarthritis of the knee, there are data to suggest that they may also be useful in treating degenerative disease of other articular joints, as well as have an impact on disease progression. The mechanisms by which hyaluronans mediate their clinical benefit seem to be multifactorial and biologically related, in contrast to the notion that they provide only viscous fluid replacement. The safety profile of intra-articular hyaluronans is very favorable and, because they are used as a local therapy, there are no known drug interactions-an advantage for patients receiving treatment for comorbid conditions. Some adverse effects, such as pseudosepsis, have been associated with cross-linked hyaluronan agents and do not appear to be class related.

title: Intra-articular use of hyaluronic acid in the treatment of osteoarthritis
abstract: Osteoarthritis is one of the leading causes of disability in the elderly. The changes in the lubricating properties of synovial fluid lead to significant pain and loss of function. More than ten years have passed from the first studies. Up till now many authors have supported intra-articular hyaluronan (HA) therapy as not only a symptom-modifying therapy but also a treatment which may significantly decrease the rate of deterioration of joint structure. In this review we report data relative to knee and hip treatment. The ongoing studies continue to further our understanding of the fundamental mechanisms that likely underlie the therapeutic benefits of this treatment but, despite recent progress, many unresolved issues require further study. Large scale double blind controlled studies must be carried out to confirm these promising data and produce meaningful guidelines.

title: The synthesis of hyaluronic acid by human synovial fibroblasts is influenced by the nature of the hyaluronate in the extracellular environment
abstract: SummaryVarious cell lines of human synovial fibroblasts derived from synovium obtained at the time of biopsy or total joint-replacement surgery have been established. The synthesis of 3H-labelled hyaluronic acid (HA) in these cells has been determined, and the effects of adding HA of varying molecular size to the cultured cells examined. The results obtained clearly show that the in vitro synthesis of HA by these cells is influenced by the concentration and molecular weight (MW) of the HA in their extracellular environment. Synovial fibroblasts derived from an osteoarthritic joint demonstrated the most marked response on exposure to exogenous HA, showing a stimulation of HA synthesis with preparations of weight-average molecular weight (Mw)>5×105 in a concentration dependent manner. HA preparations with Mw<5×105 showed little or no effect except at high concentrations where a suppression of biosynthesis was observed. A model to explain these findings is proposed.

title: Viscosupplementation for the treatment of osteoarthritis of the knee.
abstract: Osteoarthritis (OA) is the most prevalent chronic joint disorder worldwide and is associated with significant pain and disability.



To assess the effects of viscosupplementation in the treatment of OA of the knee. The products were hyaluronan and hylan derivatives (Adant, Arthrum H, Artz (Artzal, Supartz), BioHy (Arthrease, Euflexxa, Nuflexxa), Durolane, Fermathron, Go-On, Hyalgan, Hylan G-F 20 (Synvisc Hylan G-F 20), Hyruan, NRD-101 (Suvenyl), Orthovisc, Ostenil, Replasyn, SLM-10, Suplasyn, Synject and Zeel compositum).


SEARCH STRATEGY
MEDLINE (up to January (week 1) 2006 for update), EMBASE, PREMEDLINE, Current Contents up to July 2003, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched. Specialised journals and reference lists of identified randomised controlled trials (RCTs) and pertinent review articles up to December 2005 were handsearched.



RCTs of viscosupplementation for the treatment of people with a diagnosis of OA of the knee were eligible. Single and double-blinded studies, placebo-based and comparative studies were eligible. At least one of the four OMERACT III core set outcome measures had to be reported (Bellamy 1997).



Each trial was assessed independently by two reviewers for its methodological quality using a validated tool. All data were extracted by one reviewer and verified by a second reviewer . Continuous outcome measures were analysed as weighted mean differences (WMD) with 95% confidence intervals (CI). However, where different scales were used to measure the same outcome, standardized mean differences (SMD) were used. Dichotomous outcomes were analyzed by relative risk (RR).



Seventy-six trials with a median quality score of 3 (range 1 to 5) were identified. Follow-up periods varied between day of last injection and eighteen months. Forty trials included comparisons of hyaluronan/hylan and placebo (saline or arthrocentesis), ten trials included comparisons of intra-articular (IA) corticosteroids, six trials included comparisons of nonsteroidal anti-inflammatory drugs (NSAIDs), three trials included comparisons of physical therapy, two trials included comparisons of exercise, two trials included comparisons of arthroscopy, two trials included comparisons of conventional treatment, and fifteen trials included comparisons of other hyaluronans/hylan. The pooled analyses of the effects of viscosupplements against 'placebo' controls generally supported the efficacy of this class of intervention. In these same analyses, differential efficacy effects were observed for different products on different variables and at different timepoints. Of note is the 5 to 13 week post injection period which showed a percent improvement from baseline of 28 to 54% for pain and 9 to 32% for function. In general, comparable efficacy was noted against NSAIDs and longer-term benefits were noted in comparisons against IA corticosteroids. In general, few adverse events were reported in the hyaluronan/hylan trials included in these analyses.



Based on the aforementioned analyses, viscosupplementation is an effective treatment for OA of the knee with beneficial effects: on pain, function and patient global assessment; and at different post injection periods but especially at the 5 to 13 week post injection period. It is of note that the magnitude of the clinical effect, as expressed by the WMD and standardised mean difference (SMD) from the RevMan 4.2 output, is different for different products, comparisons, timepoints, variables and trial designs. However, there are few randomised head-to-head comparisons of different viscosupplements and readers should be cautious, therefore, in drawing conclusions regarding the relative value of different products. The clinical effect for some products, against placebo, on some variables at some timepoints is in the moderate to large effect-size range. Readers should refer to relevant tables to review specific detail given the heterogeneity in effects across the product class and some discrepancies observed between the RevMan 4.2 analyses and the original publications. Overall, the analyses performed are positive for the HA class and particularly positive for some products with respect to certain variables and timepoints, such as pain on weight bearing at 5 to 13 weeks postinjection. In general, sample-size restrictions preclude any definitive comment on the safety of the HA class of products; however, within the constraints of the trial designs employed no major safety issues were detected. In some analyses viscosupplements were comparable in efficacy to systemic forms of active intervention, with more local reactions but fewer systemic adverse events. In other analyses HA products had more prolonged effects than IA corticosteroids. Overall, the aforementioned analyses support the use of the HA class of products in the treatment of knee OA.

title: Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis--meta-analysis.
abstract: To evaluate the therapeutic trajectory of intra-articular hyaluronic acid (IAHA) vs placebo for knee osteoarthritis (OA).



Our data sources include Medline, EMBASE, CINAHL, BIOSIS, Web of Science, Google Scholar, Cochrane database; hand searched reviews, manuscripts, and, supplements; author contacts for unpublished data. Randomized trials that reported effects of IAHA vs placebo on knee OA were selected based on inclusion criteria. We computed effect sizes for change from baseline at 4, 8, 12, 16, 20 and 24 weeks, using Bayesian random effects model. We performed multivariate analyses adjusting for correlation between time points. Meta-regressions were performed adjusting for potential confounders.



The 54 eligible trials included 7545 participants. The conduct and quality of these trials varied in number of aspects. The effect size (ES) favored IAHA by week 4 (0.31; 95% CI 0.17, 0.45), reaching peak at week 8 (0.46; 0.28, 0.65), and then trending downwards, with a residual detectable effect at week 24 (0.21; 0.10, 0.31). This therapeutic trajectory was consistent among the subset of high quality trials and on multivariate analysis adjusting for correlation between time points.



Our meta-analysis highlights a therapeutic trajectory of IAHA for knee OA pain over 6 months post-intervention. With this additional perspective, we are able to infer that IAHA is efficacious by 4 weeks, reaches its peak effectiveness at 8 weeks and exerts a residual detectable at 24 weeks. On the other hand, the peak effect size (0.46; 0.28, 0.65), is greater than published effects from other OA analgesics [acetaminophen (ES=0.13; 0.04, 0.22); NSAIDs (ES=0.29; 0.22, 0.35); COX-2 inhibitors (ES=0.44; 0.33, 0.55)]. An effect size above 0.20 is considered to be clinically relevant on an individual patient basis in chronic pain conditions such as knee OA. Thus, its properties could have utility for certain clinical situations, or in combination with other therapies.

title: Therapeutic trajectory of hyaluronic acid versus corticosteroids in the treatment of knee osteoarthritis: a systematic review and meta-analysis.
abstract: To compare the efficacy of intraarticular hyaluronic acid with corticosteroids for knee osteoarthritis (OA).



Our data sources were Medline, EMBASE, CINAHL, BIOSIS, and the Cochrane database, as well as hand- searched reviews, manuscripts, and supplements. For unpublished data we used author contacts. Randomized trials that reported effects of intraarticular hyaluronic acid versus corticosteroids on knee OA were selected based on inclusion criteria. Two reviewers extracted data independently. Using a random-effects model, we computed effect sizes for pain change from baseline at 2, 4, 8, 12, and 26 weeks. We also performed multivariate analyses accounting for within and between-study covariance. We performed sensitivity analyses for trials that reported intent-to-treat (ITT) analysis and blinding, and directly compared Hyalgan with methylprednisolone.



The 7 eligible trials included 606 participants. Five reported ITT analyses. At week 2 the effect size was -0.39 (95% confidence interval [95% CI], -0.65, -0.12) favoring corticosteroids; at week 4 it was -0.01 (95% CI -0.23, 0.21) suggesting equal efficacy. At week 8 the effect size was 0.22 (95% CI -0.05, 0.49) favoring hyaluronic acid, and at week 12 it was 0.35 (95% CI 0.03, 0.66) favoring hyaluronic acid. At week 26 the effect size was 0.39 (95% CI 0.18, 0.59), favoring hyaluronic acid. The multivariate analyses and sensitivity analyses generated consistent results.



From baseline to week 4, intraarticular corticosteroids appear to be relatively more effective for pain than intraarticular hyaluronic acid. By week 4, the 2 approaches have equal efficacy, but beyond week 8, hyaluronic acid has greater efficacy. Understanding this trend is useful to clinicians when treating knee OA.

title: American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee
abstract: To update the American College of Rheumatology (ACR) 2000 recommendations for hip and knee osteoarthritis (OA) and develop new recommendations for hand OA.

title: Assessment of Immunologic Mechanisms for Flare Reactions to Synvisc®
abstract: Intraarticular injection of Synvisc® for treatment of knee pain sometimes results in an acute local reaction (flare). We tested the hypothesis that the flare was a Type-1 hypersensitivity reaction as manifested by the presence of Synvisc® antibodies in the synovial fluid and serum and by an increase in the concentration of the mast-cell enzyme tryptase in the synovial fluid. Our second objective was to determine whether the ratio of CD4+ to CD8+ lymphocytes in the synovial fluid was increased, as would be expected in a Type-4 hypersensitivity reaction. The study population was a prospective, consecutive series of 16 patients who had a flare, and 20 control patients. We found no differences in product-specific antibodies in the synovial fluid or serum between patients with flares and patients without flares. The mean tryptase level in the synovial fluid of patients with flares, 3.8 ± 0.8 μg/L, was not different from the corresponding level in the control patients. The CD4+/CD8+ ratio in the synovial fluid was more than eight times greater in patients with flares. Flares that sometimes occur after treatment with Synvisc® are probably not Type-1 (antibody-mediated) hypersensitivity reactions, but may be Type-4 (cell-mediated) hypersensitivity reactions.

title: Antalgic effect and clinical tolerability of hyaluronic acid in patients with degenerative diseases of knee cartilage: an outpatient treatment survey.
abstract: A total of 40 outpatients (28 men and 12 women) aged between 18 and 82 years with primary or secondary symptomatic knee osteoarthritis (OA) were selected for this retrospective study. The patients were treated weekly with an intra-articular injection of hyaluronic acid of biofermentative origin. A total of five injections were given, with a follow-up visit at week 7. The aims of this study were to analyze the antalgic effect and tolerability of the procedure, evaluated by overall tolerance, Lequesne's Algo-Functional Index (AFI), pain level evolution and analgesic consumption. No systemic adverse effects related with the device were reported. Global tolerability was judged as excellent/good by almost all the patients and the investigator; 16 patients reported a mild burning sensation at the injection site, which was more frequent during the first injection and resolved within a few minutes. The mean value of the AFI decreased from 7.9 at the initial visit to 3.2 at the final visit, parallel to a decrease into the relative scores of the pain scale. We can thus conclude that intra-articular injection of hyaluronic acid of biofermentative origin appears to be a safe and effective therapy for gonarthritic pain.

title: Intra-Articular Ultrasound-Guided Injection of Sinovial® Forte 1.6% in Patients Affected by Symptomatic Hip Osteoarthritis: Effectiveness and Safety in a Large Cohort of Patients
abstract: The aim of this prospective observational study is to assess the efficacy and safety profile of intraarticular Sinovial® Forte 1.6% administered under ultrasound-guidance in a large cohort of patients affected by symptomatic hip osteoarthritis (OA). Patients with symptomatic hip OA referred to our clinic in 2008–2010 received one 4 ml (2 vials) intra-articular injection of Sinovial® Forte 1.6% under ultrasound guidance. Patients were followed-up every 3 months for a total of 6 months and were offered an optional, additional injection at the 3-month follow-up visit if clinically justified. At each visit, pain scores [0–10 Visual Analogue Scale (pain VAS)], Lequesne index scores and NSAID intake were recorded. Adverse events (AEs) were recorded throughout the study. An effect size of 30% and 50% reduction in Lequesne index and Pain VAS scores was evaluated for each patient to ascertain the number of patients achieving partial remission of symptoms and functional impairment by the use of intra-articular hyaluronic acid in hip osteoarthritis. One hundred and fourteen patients completed the 6-month follow-up and received a total of 142 injections. A statistically significant reduction in Lequesne index scores, VAS pain scores and NSAID consumption was observed at all time-points (p < 0.05). No systemic, severe or even moderate side effects were observed. Only 7 patients reported mild local reaction at the injection site, consisting of mild pain and localized warmth, which resolved spontaneously without any additional medication. This study provides evidence of the efficacy and tolerability of Sinovial® Forte 1.6% in the treatment of patients affected by symptomatic hip OA. Sinovial® Forte may also offer economical benefits, owing to the reduction in NSAID consumption associated with this treatment. The percentage of patients achieving the effect size of 30% and 50% reduction in Lequesne index and pain VAS scores encourages the use of intra-articular hyaluronic acid in patients with hip osteoarthritis.

title: Efficacy evaluation of highly purified intra-articular hyaluronic acid (Sinovial(®)) vs hylan G-F20 (Synvisc(®)) in the treatment of symptomatic knee osteoarthritis. A double-blind, controlled, randomized, parallel-group non-inferiority study.
abstract: Knee osteoarthritis is a major cause of disability and pain. This phase III, double-blind (patient and observer blinded,) multicenter, randomized, non-inferiority study was conducted to demonstrate the non-inferiority of the highly purified intra-articular injection of hyaluronic acid (Sinovial(®)) in comparison to Hylan G-F20 (Synvisc(®)) in the treatment of knee osteoarthritis.



A total of 381 patients were randomly assigned to receive either the test drug, 16 mg/2 ml (0.8%) highly purified ia hyaluronic acid of biofermentative origin (Sinovial(®)), or the comparative drug, 16 mg/2 ml of 0.8% hylan G-F20 (Synvisc(®)). The duration of the treatment was 2 weeks (three injections at 1-week interval), followed by an observation period of 6 months. The primary efficacy variable was the improvement in mean Western Ontario and McMaster Universities (WOMAC) pain subscore from baseline to the final visit (week 26), compared between the two treatment groups. The acceptable margin for non-inferiority was chosen to be 8 mm.



At week 26, WOMAC pain subscores decreased by a mean of 32.5 for both Sinovial(®) and Synvisc(®). These results met prespecified criteria for non-inferiority for both the Intent-to-Treat and Per-Protocol populations. There were no statistically significant differences between groups at 26 weeks, although Sinovial(®)-treated patients tended to have a slightly better outcome for select variables, as they did at earlier time-points, some of which reached statistical significance. Both hyaluronic acid preparations were well-tolerated, with no statistically significant differences in tolerability profile between groups.



Sinovial(®) and Synvisc(®) treatments were found to be equivalent, both in terms of efficacy and safety.

title: Overall tolerability and analgesic activity of intra-articular sodium hyaluronate in the treatment of knee osteoarthritis
abstract: Viscosupplementation with intra-articular hyaluronic acid (HA) is an alternative to the treatment of symptomatic knee osteoarthritis (OA) with pain relieving drugs. Sinovial*, is a sterile, non-pyrogenic 0.8% solution of highly purified sodium hyaluronate for intra-articular application. The aim of the present study was to investigate the safety and tolerability profile of this preparation in patients with symptomatic knee OA over 24 weeks.  Sinovial is a registered trade name of IBSA Institut Biochimique SA, Lugano, Switzerland Research design and methods: This was a single group, open-label study, including outpatients of both sexes, aged between 18 and 85 years, with symptomatic knee OA. All patients underwent weekly intra-articular injections of HA for 5 consecutive weeks and were followed-up for 19 additional weeks. The safety and tolerability profile (primary endpoint) was assessed by adverse event (AE) reporting. The secondary endpoint was efficacy evaluated by changes in the Western Ontario and McMaster Universities (WOMAC) score vs. baseline. Patient and physician satisfaction were also recorded.  Intra-articular HA was generally well tolerated. The most frequent AE was pain at the injection site (5.8% of the injections); no serious treatment-related AE was reported. The WOMAC score was significantly reduced within the first 2 weeks of treatment (from 4.02 ± 1.90 to 3.55 ± 2.04, p = 0.0011), further decreased by the end of the injection series (week 6: 2.59 ± 1.90; p < 0.0001) and maintained during the follow-up (week 24: 2.44 ± 1.88; p < 0.0001). The WOMAC subscores were also significantly reduced from week 4 for ‘pain’ and from week 6 for ‘stiffness’ and ‘physical function’.  In the present study, intra-articular HA was well tolerated and safe in patients with symptomatic knee OA. Based on the sustained improvements in WOMAC score and subscores, a carry-over effect lasting for at least 19 weeks after the last injection may be proposed. These results further confirm the evidence of efficacy and safety of intra-articular HA in the management of knee OA.

title: Femoroacetabular impingement: is hyaluronic acid effective?
abstract: PurposeFemoroacetabular impingement may predispose to the development of hip osteoarthritis. Conservative treatments are effective in the short term, but surgery is often required. Aim of this paper was to report the short-term results on hip pain and function after ultrasound-guided injections of hyaluronic acid.MethodsIn this open prospective trial, twenty patients suffering from mild femoroacetabular impingement were enrolled. Each patient received a 2-ml intra-articular ultrasound-guided injection of hyaluronic acid at baseline and after 40 days; the same dosing schedule was repeated after 6 months. The clinical evaluation was performed at baseline and after 6 and 12 months of follow-up. Pain score, Lequesne Index, Harris Hip Score and anti-inflammatory medication consumption were measured. Adverse events were also registered.ResultsTwenty-three hips (3 bilateral cases) were treated. Pain decreased from 6.7 ± 1.3 to 3.7 ± 1.8 and to 1.7 ± 1.8 after 6 and 12 months, respectively; Lequesne Index was reduced and the mean Harris Hip Score improved from 83.3 ± 6 before treatment to 88.2 ± 4.7 at 12 months. Consumption of anti-inflammatory drugs was also reduced, from 14 to 4 subjects and from 3.6 ± 2.2 to 1.3 ± 1.3 tablets/week. Local side effects after injection were observed only in 2 cases.ConclusionsHyaluronic acid is safe and effective in the treatment of mild femoroacetabular impingement, with significant pain reduction and function improvement.

title: The role of viscosupplementation with hylan G-F 20 (Synvisc) in the treatment of osteoarthritis of the knee: a Canadian multicenter trial comparing hylan G-F 20 alone, hylan G-F 20 with non-steroidal anti-inflammatory drugs (NSAIDs) and NSAIDs alone.
abstract: To determine the safety and efficacy of viscosupplementation with hylan G-F 20, a cross-linked hyaluronan preparation, used either alone or in combination with continuous non-steroidal anti-inflammatory drug (NSAID) therapy, a randomized, controlled, multicenter clinical trial, assessed by a blinded assessor, was conducted in 102 patients with osteoarthritis (OA) of the knee. All patients were on continuous NSAID therapy for at least 30 days prior to entering the study. Patients were randomized into three parallel groups: (1) NSAID continuation plus three control arthrocenteses at weekly intervals; (2) NSAID discontinuation but with three weekly intra-articular injections of hylan G-F 20; and (3) NSAID continuation plus three injections, one every week, intra-articular injections of hylan G-F 20. Outcome measures of pain and joint function were evaluated by both the patients and an evaluator at baseline and weeks 1, 2, 3, 7 and 12, with a follow-up telephone evaluation at 26 weeks. At 12 weeks all groups showed statistically significant improvements from baseline, but did not differ from each other. A statistical test for the equivalence, the q-statistic, demonstrated that viscosupplementation with hylan G-F 20 was at least as good or better than continuous NSAID therapy for all outcome measurements except activity restriction. At 26 weeks both groups receiving hylan G-F 20 were significantly better than the group receiving NSAIDs alone. A transient local reaction was observed in three patients after hylan G-F 20 injection; only one patient withdrew from the study as a result and all recovered without any sequela. Hylan G-F 20 is a safe and effective treatment for OA of the knee and can be used either as a replacement for or an adjunct to NSAID therapy.

title: Intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee: systematic review and meta-analysis
abstract: Osteoarthritis of the knee affects up to 10% of the elderly population. The condition is frequently treated by intra-articular injection of hyaluronic acid. We performed a systematic review and meta-analysis of randomized controlled trials to assess the effectiveness of this treatment.  We searched MEDLINE, EMBASE, CINAHL, BIOSIS and the Cochrane Controlled Trial Register from inception until April 2004 using a combination of search terms for knee osteoarthritis and hyaluronic acid and a filter for randomized controlled trials. We extracted data on pain at rest, pain during or immediately after movement, joint function and adverse events.  Twenty-two trials that reported usable quantitative information on any of the predefined end points were identified and included in the systematic review. Even though pain at rest may be improved by hyaluronic acid, the data available from these studies did not allow an appropriate assessment of this end point. Patients who received the intervention experienced a reduction in pain during movement: the mean difference on a 100-mm visual analogue scale was –3.8 mm (95% confidence interval [CI] –9.1 to 1.4 mm) after 2–6 weeks, –4.3 mm (95% CI –7.6 to –0.9 mm) after 10–14 weeks and –7.1 mm (95% CI –11.8 to –2.4 mm) after 22–30 weeks. However, this effect was not compatible with a clinically meaningful difference (expected to be about 15 mm on the visual analogue scale). Furthermore, the effect was exaggerated by trials not reporting an intention-to-treat analysis. No improvement in knee function was observed at any time point. Even so, the effect of hyaluronic acid on knee function was more favourable when allocation was not concealed. Adverse events occurred slightly more often among patients who received the intervention (relative risk 1.08, 95% CI 1.01 to 1.15). Only 4 trials explicitly reported allocation concealment, had blinded outcome assessment and presented intention-to-treat data.  According to the currently available evidence, intra-articular hyaluronic acid has not been proven clinically effective and may be associated with a greater risk of adverse events. Large trials with clinically relevant and uniform end points are necessary to clarify the benefit–risk ratio.

title: Hylan G-F 20 Single-Injection Formulation
abstract: Hylan G-F 20, a cross-linked hyaluronic acid derivative, is an elastoviscous, high-molecular-weight (average 6000 kDa) fluid with rheological properties similar to those of knee synovial fluid of healthy young individuals.In a 26-week, randomized, double-blind, multi-centre study in patients with symptomatic primary osteoarthritis of the knee (n = 253), one intraarticular injection of hylan G-F 20 (single-injection formulation) into the target knee significantly relieved pain (as measured by the Western Ontario and McMaster Universities Osteoarthritis Index pain [WOMAC A] subscale), including pain while walking on a flat surface (as assessed by the WOMAC A1 subscore), compared with placebo.Observer-reported disease status and patient-reported health status were also significantly improved in hylan G-F 20-treated patients compared with placebo-treated patients.A single intra-articular injection of hylan G-F 20 was generally well tolerated, with an adverse event profile similar to that of placebo.Repeat administration of hylan G-F 20 after 6 months had a similar tolerability profile to that of the initial injection. However, no patient who developed a target-knee adverse event after their first injection experienced such an event following their second injection.

title: Septic knee arthritis after intra-articular hyaluronate injection. Two case reports.
abstract: Intraarticular sodium hyaluronate injection to treat osteoarthritis is associated with minor side effects. Infections seem uncommon. We report two cases of septic knee arthritis. One patient was an 80-year-old woman who was admitted for Staphylococcus aureus knee arthritis after several intraarticular injections of sodium hyaluronate and corticosteroids. In the other patient, a 78-year-old woman, Neisseria mucosa knee arthritis occurred after a single sodium hyaluronate injection. Faultless aseptic technique is essential when administering hyaluronate viscosupplementation. Patients should be informed of the risk of septic arthritis.

title: Acute pseudoseptic arthritis after viscosupplementation of the knee: a case report
abstract: Intra-articular injections of hyaluronan are generally well tolerated; the most common adverse event associated with their use is an inflammatory reaction or a flare at the injection site. Naturally derived sodium hyaluronates have not been associated with pseudosepsis; we describe a case of severe arthritis mimicking acute septic arthritis after naturally hyaluronan. A 70-year-old woman had a medial femorotibial and patellofemoral compartment knee osteoarthritis. Hyaluronic acid injection was indicated because of the persistence of a pain while walking and restricted ability to walk 100 m, as well as the installation of a flessum. She was admitted for an evaluation of a joint effusion occurring within 48 h after the first hyaluronic acid intra-articular injection (first course), with no fever or chills. Joint fluid was found to be cloudy and contained 24,000 cells per mm3. A knee aspiration was performed to evaluate the possibility of a joint infection. The examination of synovial fluid under phase contrast and polarizing microscopes showed no crystals, and culture on standard media was negative. Acute septic arthritis was considered to be the most likely diagnosis, and probabilistic antibiotic therapy was started. The result of the bacteriological examinations also returned negative. The absence of general signs, particularly fever and chills, with fast effusion regression in less than 4 days did not plead in favor of a septic origin. In front of this beam of arguments, antibiotic therapy was stopped after 4 days. The nonsteroidal anti-inflammatory drug (Nimésulide) was given. The clinical and laboratory test abnormalities were normalized within 2 weeks. Our case has the particularity to occur after using Curavisc®, which is known as producing no allergenic reactions. Moreover, the described reaction occurred with the very first infiltration within the very first course.

title: Hylan versus hyaluronic acid for osteoarthritis of the knee: a systematic review and meta-analysis.
abstract: To compare the effectiveness and safety of intraarticular high-molecular hylan with standard preparations of hyaluronic acids in osteoarthritis of the knee.



We performed a systematic review and meta-analysis of randomized controlled trials comparing hylan with a hyaluronic acid in patients with knee osteoarthritis. Trials were identified by systematic searches of Central, Medline, EMBase, Cinahl, the Food and Drug Administration, and Science Citation Index supplemented by hand searches of conference proceedings and reference lists (last update November 2006). Literature screening and data extraction were performed in duplicate. Effect sizes were calculated from differences in means of pain-related outcomes between treatment and control groups at the end of the trial, divided by the pooled standard deviation. Trials were combined using random-effects meta-analysis.



Thirteen trials with a pooled total of 2,085 patients contributed to the meta-analysis. The pooled effect size was -0.27 (95% confidence interval [95% CI] -0.55, 0.01), favoring hylan, but between-trial heterogeneity was high (I(2) = 88%). Trials with blinded patients, adequate concealment of allocation, and an intent-to-treat analysis had pooled effect sizes near null. The meta-analyses on safety revealed an increased risk associated with hylan for any local adverse events (relative risk [RR] 1.91; 95% CI 1.04, 3.49; I(2) = 28%) and for flares (RR 2.04; 95% CI 1.18, 3.53; I(2) = 0%).



Given the likely lack of a superior effectiveness of hylan over hyaluronic acids and the increased risk of local adverse events associated with hylan, we discourage the use of intraarticular hylan in patients with knee osteoarthritis in clinical research or practice.

title: Pseudoseptic Reactions to Hylan Viscosupplementation: Diagnosis and Treatment
abstract: Hyaluronans are used widely in the treatment of osteoarthritis of the knee. Three commercial hyaluronan preparations currently are available in the United States: sodium hyaluronate (Hyalgan), sodium hyaluronate (Supartz), and hylan G-F 20 (Synvisc). Although the sodium hyaluronates are derived naturally, hylan is chemically modified to increase its molecular weight. All three products have been shown to be well tolerated in clinical trials, however, there have been reports in the literature of pseudoseptic reactions, or severe acute inflammatory reactions, after injections with hylan. Our study reviewed the reported incidence of pseudosepsis. The pathogenic mechanisms and clinical treatment of this reaction are presented.

title: Safety of intra-articular hyaluronates for pain associated with osteoarthritis of the knee.
abstract: Sodium hyaluronate (Hyalgan, and Supartz) and hylan G-F 20 (Synvisc) are hyaluronans (HA) injected intra-articularly for pain relief in osteoarthritis of the knee. Each product has demonstrated a very favorable safety profile in clinical trials and practice. The most common adverse event associated with their use is mild injection site pain and swelling. Rare incidences of pseudogout and anaphylactoid reactions have been reported to be associated with their use. Occasionally, pseudosepsis, also known as a severe acute inflammatory reaction (SAIR) syndrome, has been reported to be associated with these products. Clinical and postmarketing data indicate that HA therapy is a safe treatment for osteoarthritis of the knee.

title: Comparison of avian and nonavian hyaluronic acid in osteoarthritis of the knee
abstract: correspondence: Robert J Petrella 801 commissioners Road, suite 3002, London, On, canada n6c5J1 Tel +1 519 685 4292 Fax +1 519 685 4071 email petrella@uwo.ca  Hyaluronic acid (HA) in knee osteoarthritis (OA) has been shown to be efficacious and safe, but long-term follow up and head-to-head comparison of products, in particular those of avian versus those of nonavian origin, are lacking.  The objective was to compare the efficacy and safety of avian and nonavian origin HA in the treatment of knee OA during a long-term follow-up.  Patients were enrolled on a consecutive basis from all referrals received from 1997 to 2007 at a large primary care referral center in London, Canada. Patients were allocated to commercially available avian and nonavian origin HA based on their own preference for product. Patients were not randomized to therapy nor did the referral center advocate one product versus another. During the period of investigation, three nonavian and two avian products were available in Canada. Injections were given once weekly over three weeks (one series) using a lateral approach. Assessments included body mass index, numbers of medications, number of chronic diseases, duration of knee OA at presentation, visual analog scale (VAS) score (0–10 cm) for rest and weight-bearing pain, patient satisfaction with treatment (5-point categorical scale), numbers of HA series to the point of analysis, previous intra-articular treatment prior to first injection series, adverse events, serious adverse events, and self-payment versus third party payment. Following the first injection series, patients returned to the clinic of their own volition. Inclusion for a second and subsequent injection series was based on a patient request but also requirement of a resting VAS score  4.5 cm. All patients had radiographic evidence of at least grade 1 OA. Patients who crossed over to alternate avian or nonavian product were not included in the analysis following crossover. Patients could switch within class of HA product. Differences were compared using analyses of variance and were considered significant at P  0.05.  Four thousand four hundred twelve patients were evaluated for inclusion. Avian or nonavian HA were received by 1,726 versus 1,971 patients, respectively. There were no significant differences in demographic characteristics between groups. There were no differences in reduction of resting pain between groups between the first and 10th consecutive series of HA injections; however, there was a significantly greater improvement in weight-bearing pain (P  0.01) favoring nonavian HA after the 7th series. There was also a significantly greater number of adverse events (4.8% versus 1.7%; P  0.01) in the aviancompared to nonaviantreated patients.  Both avian and nonavian HA improve pain in patients with osteoarthritis of the knee. Some difference in weight-bearing pain favoring nonavian HA was seen later in the treatment cycle while a significantly greater number of adverse events was observed in avian HA-treated patients.

title: Comparison between High and Low Molecular Weight Hyaluronates in Knee Osteoarthritis Patients: Open-label, Randomized, Multicentre Clinical Trial
abstract: Efficacy and safety of high and low molecular weight hyaluronates in knee osteoarthritis patients were compared in a randomized, open-label trial. Patients in the high molecular weight hyaluronate group were treated once weekly for 3 weeks and in the low molecular weight group once weekly for 5 weeks. We evaluated weight-bearing pain, degree of flexion, swelling and knee tenderness; frequency and amount of rescue medication; patient and investigator global assessment of pain, and safety over 12 weeks after final injection of study medication. Significant improvements in pain and WOMAC-Likert scores were observed in both groups, but not between groups. Knee joint pain improvement was noted in both groups by patients and investigators during follow-up. Close correlation was observed between patient-and investigator-reported data. There was no significant difference in side-effects between the groups. In conclusion, the efficacy and safety of high and low molecular weight hyaluronate are similar.

title: The role of intra-articular hyaluronan (Sinovial®) in the treatment of osteoarthritis
abstract: Osteoarthritis (OA) leads to significant pain and disability. For pain relief, a tailored approach using non-pharmacological and pharmacological therapies is recommended. If adequate symptom relief is not achieved with acetaminophen, other pharmacological options include non-steroidal anti-inflammatory drugs (NSAIDs), topical analgesics, intra-articular corticosteroids and intra-articular hyaluronic acid (HA) viscosupplementation. Most of these therapies generally do not improve functional ability or quality of life or are associated with tolerability concerns. In OA patients, concentration and molecular weight (MW) of HA are reduced, diminishing elastoviscosity of the synovial fluid, joint lubrication and shock absorbancy, and possibly anti-inflammatory, analgesic and chondroprotective effects. In knee OA, viscosupplementation with 3–5 weekly intra-articular HA injections diminishes pain and improves disability, generally within 1 week and for up to 3–6 months and is well tolerated. HAs have comparable efficacy as NSAIDs, with less gastrointestinal adverse events, and compared with intra-articular corticosteroids, benefits last generally longer. High MW hylans provide comparable benefits versus HA, albeit with an increased risk of immunogenic adverse events. In mild-to-moderate hip OA, intra-articular injection of HA moderately improved pain and function, generally for up to 3 months with no serious adverse events. Efficacy in other joints is being evaluated. Viscosupplementation with intra-articular Sinovial® (other trade names: Yaral®, Intragel®) injections (an HA of low-medium MW) relieves pain and improves function in OA of the knee, and other joints including the carpometacarpal joint of the thumb and the shoulder. HA viscosupplementation, including use of Sinovial®, is a valuable treatment approach for OA patients, if other therapies are contraindicated or have failed.