Three Weekly Intra-Articular Injections of Hylan G-F 20 vs Arthrocentesis in Patients with Chronic Idiopathic Knee Osteoarthritis: A Multicenter, Evaluator- and Patient-Blinded, Randomized Controlled Trial.

Background: Knee osteoarthritis is a leading cause of disability worldwide. Symptoms can vary over time, leading to episodes of worsened symptoms known as flares. Intra-articular injection of hyaluronic acid has demonstrated long-term symptomatic relief in the broader knee osteoarthritis population, although its use in the flare population has not been extensively examined. Objective: To assess the efficacy and safety of 3 once-weekly intra-articular injections of hylan G-F 20 (as single and repeat courses) in patients with chronic knee osteoarthritis, including a subpopulation that experienced flare. Methods: Prospective randomized controlled, evaluator- and patient-blinded, multicenter trial with 2 phases: hylan G-F 20 vs arthrocentesis only (control) and 2 courses vs single-course hylan G-F 20. Primary outcomes were visual analog scale (0-100 mm) pain scores. Secondary outcomes included safety and synovial fluid analysis. Results: Ninety-four patients (104 knees) were enrolled in Phase I, with 31 knees representing flare patients. Seventy-six patients (82 knees) were enrolled in Phase II. Long-term follow-up was 26 to 34 weeks. In flare patients, hylan G-F 20 showed significantly more improvement than the controls for all primary outcomes except pain at night (P = 0.063). Both 1 and 2 courses of hylan G-F 20 showed significant improvements from baseline for primary outcomes with no differences in efficacy between groups in the intention-to-treat population at the end of Phase II. Two courses of hylan G-F 20 showed better improvement in pain with motion (P = 0.0471) at long-term follow-up. No general side effects were reported, and local reactions (pain/swelling of the injected joint) resolved within 1 to 2 weeks. Hylan G-F 20 was also associated with reduced effusion volume and protein concentration. Conclusions: Hylan G-F 20 significantly improves pain scores vs arthrocentesis in flare patients with no safety concerns. A repeat course of hylan G-F 20 was found to be well tolerated and efficacious.

Efficacy and safety of a single intra-articular injection of 6 ml Hylan G-F 20 compared to placebo in Chinese patients with symptomatic knee osteoarthritis : C-SOUND study, a 26-week multicenter double-blind randomized placebo-controlled trial in China.

BACKGROUND: Single 6 ml Hylan G-F 20 injection, is indicated for knee osteoarthritis patients who have failed to respond to non-pharmacologic therapy and/or simple analgesics. To obtain more thorough understanding of the clinical efficacy and safety, a randomized clinical trial was conducted comparing intra-articular (IA) administration of single 6 ml Hylan G-F 20 injection versus placebo in knee OA patients of Chinese ethnicity. METHODS: This was a randomized, multi-center, double-blind, placebo-controlled clinical trial conducted in 21 centers across China. Four hundred forty adults with knee OA received a single 6 ml Hylan G-F 20 or placebo injection and were evaluated for clinical efficacy and safety outcomes over 26 weeks. Western Ontario and McMaster Universities OA (WOMAC) A1 index, treatment-emergent adverse events (TEAEs) and standard safety parameters were measured at pre-injection, and at weeks 1, 4, 8, 12, 16, 20 and 26 post-injection. RESULTS: Four hundred forty patients (male: 98 [22.3%]; female: 342 [77.7%]) were randomized. The mean age [standard deviation (SD)] was 61.5 (7.9) years. All patients were of East Asian ethnicity. Mean WOMAC A1 score at baseline was 5.3 (1.2) and 5.2 (1.3) in single 6 ml Hylan G-F 20 injection and placebo groups, respectively. Significant reductions of WOMAC A1 score were observed in both treatment groups when compared to baseline at 26 weeks post-injection, with the mean reduction of [standard error (SE)/percentage] -2.146 (0.108)/- 40.5% and - 2.271 (0.110) /- 43.7% in the single 6 ml Hylan G-F 20 injection and the placebo groups, respectively. Additionally, clinically important reductions in pain at 26 weeks was reported in 67.0 and 68.2% in single 6 ml Hylan G-F 20 injection and placebo groups (p = 0.36). Regarding safety, TEAEs were similar between the two treatment groups (hylan G-F 20 single: 61.5%; placebo: 64.5%). CONCLUSIONS: While the magnitude of the effect of a single 6 ml Hylan G-F 20 injection in this study is consistent with previously published literature with respect to the efficacy and safety of the drug, the current study shows a strong IA placebo effect and did not established superiority of single 6 ml Hylan G-F 20 injection over IA placebo in Chinese knee OA patients. TRIAL REGISTRATION: Prospectively registered Jun 16, 2017 at www.clinicaltrials.gov ( NCT03190369 ).

Evaluating the use of intra-articular injections as a treatment for painful hip osteoarthritis: a randomized, double-blind, multicenter, parallel-group study comparing a single 6-mL injection of hylan G-F 20 with saline.

OBJECTIVE: Hip osteoarthritis (OA) is difficult to treat. Steroid injections reduce pain with short duration. With widespread adoption of office-based, image-guided injections, hyaluronic acid is a potentially relevant therapy. In the largest clinical trial to-date, we compared safety/efficacy of a single, 6-mL image-guided injection of hylan G-F 20 to saline in painful hip OA. METHOD: 357 patients were enrolled in a multicenter, double-blind, randomized saline placebo- controlled trial. Subjects were ≥35 years of age, with painful (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]-A1:5.0-8.0; numeric rating scale [NRS]: 0-10) mild-to-moderate hip OA (Kellgren-Lawrence grade II/III) and minimal contralateral hip pain (WOMAC-A1 < 4). Outcome measures included "pain on walking" (WOMAC-A1 and -A), Patient Global Self-Assessment (PTGA), WOMAC-A1 responder rate (+≥2 points on NRS), and adverse events (AEs) over 26 weeks. RESULTS: 357 patients (hylan G-F 20 single:182; saline:175) were enrolled. Both groups demonstrated significant pain improvement from baseline over 26 weeks (P < 0.0001); saline-induced pain reduction was a remarkable 35%. WOMAC-A and PTGA scores also significantly improved (P < 0.0001). No statistically significant difference was observed between groups in WOMAC-A1 scores (hylan G-F 20 single:-2.19 ± 0.16; saline:-2.26 ± 0.17) or WOMAC-A1 responders (41-52%). Treatment-related AE rates at target hip were similar (hylan G-F 20 single:23 patients [12.8%]; saline:12 [7.0%]). Posthoc analysis found, despite protocol requirements, many patients had psychological (31%) or potential neuropathic pain (27.5%) conditions. CONCLUSION: A single 6-mL hylan G-F 20 injection or saline for painful hip OA resulted in similar, statistically significant/clinically relevant pain and function improvements up to 6 months following injection; no differences between hylan G-F 20 and saline placebo were observed.

Weekly injections of Hylan G-F 20 delay cartilage degeneration in partial meniscectomized rat knees.

BACKGROUND: Cross-linked hyaluronan--also called Hylan G-F 20--is a medical device developed to treat osteoarthritis of the knee. However, it is still controversial whether Hylan G-F 20 has a cartilage protective effect in trauma-induced osteoarthritis. We investigated whether Hylan G-F 20 delayed osteoarthritis progression in a partial meniscectomized rat model. METHODS: Lewis rats were used for the experiments. The anterior medial meniscus was resected at the level of the medial collateral ligament in both knees. From 1 week after the surgery, 50 µl of Hylan G-F 20 was injected weekly into the left knee and phosphate buffered saline was injected into the right knee. Cartilage was evaluated for macroscopic findings, histology with safranin-o, and expression of type II collagen at 2, 4, and 8 weeks. Synovitis was also evaluated, and immunohistochemical analysis was performed for ED1. RESULTS: Macroscopic findings demonstrated that India ink positive area, representing fibrillated cartilage, was significantly smaller in the Hylan G-F 20 group than in the control group at 2, 4, and 8 weeks (n = 5). There were no significant differences in osteophyte score between the Hylan G-F 20 group and the control group at 2, 4, and 8 weeks. Histologically, the cartilage in the medial tibial plateau was destroyed at 8 weeks in the control group, while type II collagen expression was still observed at 8 weeks in the Hylan G-F 20 group. OARSI score for cartilage histology was significantly lower in the Hylan G-F 20 group than in the control group at 4 and 8 weeks (n = 5). There were no significant differences in synovial cell number or modified synovitis score between the Hylan G-F 20 group and the control group at 2, 4, and 8 weeks (n = 5). In the Hylan G-F 20 group, foreign bodies surrounded by ED1 positive macrophages were observed in the synovium. CONCLUSION: Weekly injections of Hylan G-F 20 starting 1 week after surgery delayed cartilage degeneration after meniscectomy in a rat model. Synovitis induced by meniscectomy was not alleviated by Hylan G-F 20. Insoluble gels were observed in the synovium after the Hylan G-F 20 injection.

Three once-weekly intra-articular injections of Hylan G-F 20 significantly improve pain relief compared with placebo in patients with chronic idiopathic knee osteoarthritis: a single-centre, evaluator-blinded and patient-blinded, randomized controlled trial.

Background: Clinical trials on the use of viscosupplementation with hyaluronic acid (HA) in patients with knee osteoarthritis (KOA) are inconsistent, making it challenging to determine its value in clinical practice. One issue is the availability of various HA products on the market; differences in their chemical features can impact patient outcomes. Herein, we assess the efficacy and safety of three once-weekly intra-articular (IA) injections of Hylan G-F 20, a high-molecular-weight and highly crosslinked HA product, in patients with KOA. We hypothesized that Hylan G-F 20 would provide significant pain relief with no increased safety risk compared with IA saline (placebo). Methods: This was a 26-week, patient-blinded and evaluator-blinded, single-centre, randomized placebo- controlled trial. Men or women ≥18 years of age with Larsen grade II or III KOA were included. Patients received IA injections of either Hylan G-F 20 or placebo once a week for 3 weeks. The primary endpoints were the week 12 and 26 visits. Primary efficacy outcomes included visual analogue scale (VAS) pain scores, patient activity level and an overall assessment of clinical condition. Secondary outcomes included adverse events (AEs) that emerged during treatment. The primary analysis included the intention-to-treat population. An alpha level of 0.05 was used in the statistical analysis. Results: Thirty patients were included in the intention-to-treat population (15 per group). All efficacy outcomes were statistically significant in favour of Hylan G-F 20, except night pain and inactivity stiffness, for both patient- assessed (all p=0.0001 at week 12) and evaluator-assessed (all p=0.0001 at week 12 and p=0.0004-0.0180 at week 26) measurements. There was also a greater proportion of symptom-free patients and those with a >50% improvement in their VAS scores, except night pain, in the Hylan G-F 20 group (p=0.001-0.003 in patient-assessed scores and p<0.0001 to 0.002 in evaluator-assessed scores at week 12). Two patients, one in each group, experienced an AE; no sequelae occurred, and no special treatment was required for either AE. No patients withdrew from the study prematurely due to an AE. Conclusion: In patients with chronic idiopathic KOA, Hylan G-F 20 provides significant improvements in pain relief compared with placebo with no added safety concerns.

Hyaluronic Acid Therapy in Hip OA Does Not Perform Equally in Osteoarthritis Secondary to Juvenile Idiopathic Arthritis When Compared to Primary Osteoarthritis: A 2-Year Preliminary Evaluation.

OBJECTIVE: Hip involvement in juvenile idiopathic arthritis (JIA) is one of most important causes of pain and disability. Total hip arthroplasty (THA) is considered the standard when medical approaches fail to relieve pain. However, THA is problematic for many reasons. As current literature lacks studies valuating medical management of osteoarthritis (OA) secondary to JIA, we assessed the long-term pain relief effect of US-guided intra-articular viscosupplementation in hip osteoarthritis secondary to JIA versus primary OA under different etiological conditions. METHODS: Patients in both groups received intra-articular Hylan G-F 20 2 ml once a month for 3 consecutive months and every 6 months for 2 years as maintenance. Effectiveness (VAS and WOMAC), NSAID/analgesic consumption, tolerability, withdrawals and reason for discontinuation were collected at each time point. An inverse probability weighting was used to balance the two groups. RESULTS: We retrospectively retrieved data of 14 JIA patients and 26 primary OA. Weighting successfully accounted for differences between the disease groups supporting the results. Viscosupplementation led to an early and significant improvement of pain and function and concomitant decrease in NSAIDs consumption, while the response diverged over 1 year with loss of benefits in JIA. The worst outcome was observed in active JIA. CONCLUSIONS: Duration of symptom relief after intra-articular injection of hyaluronic acid depends on the nature of arthritis. Multiple courses of viscosupplementation are required to maintain low-dose NSAIDs consumption in patients responsive to treatment while shortening the time between consecutive injections might provide persistent positive results in patients suffering from JIA.

One-year efficacy and safety of single or one to three weekly injections of hylan G-F 20 for knee osteoarthritis: a systematic literature review and meta-analysis.

The aim of this study was to evaluate the long-term efficacy and safety of single or 1-3 weekly injections of hylan G-F 20 at 1 year following the first injection for knee osteoarthritis (OA). Searches were conducted in PubMed/MEDLINE, Embase, and CENTRAL and included relevant conference proceedings (January 1, 1995-August 17, 2020). Randomized controlled trials (RCTs), non-randomized trials, and observational studies investigating 1-year efficacy and safety of 1-3 weekly injections or single hylan G-F 20 injection for knee OA were included. Primary outcomes were WOMAC pain, physical function, and stiffness. Meta-analyses of RCTs and non-randomized studies were conducted separately. Our search identified 24 eligible studies. Hylan G-F 20, in the meta-analyses of RCTs, showed statistically significant improvement in WOMAC pain (SMCC - 0.98, 95% CI - 1.50, - 0.46), physical function (SMCC - 1.05, 95% CI - 1.28, - 0.83), and stiffness (SMCC - 1.07, 95% CI -1.28, -0.86). Improvement was also seen for VAS pain, SF-36 MCS (mental component summary), and SF-36 PCS (physical component summary). Analyses of non-randomized studies showed similar efficacy estimates. There were no significant differences in efficacy based on injection schedule, nor between RCT and non-randomized studies. Rates of adverse events (AEs) were low for most types of AEs. Hylan G-F 20 (either as single or 1-3 weekly injections) showed improvement in 1-year efficacy outcomes in comparison to baseline and was generally well tolerated. While further research will inform the medical field regarding viscosupplementation treatment options for knee OA, these findings show that hylan G-F 20 at both frequencies/dosages are efficacious and generally well tolerated for long-term use.

Intra-articular Injections of Cross-linked Hyaluronic Acid in Japanese Patients with Symptomatic Osteoarthritis of the Hip.

OBJECTIVES: We investigated the efficacy and safety of Hylan G-F 20 for the treatment of hip osteoarthritis in Japanese patients. METHODS: Twenty-nine patients with hip osteoarthritis (OA) received Hylan G-F 20 injection into the hip. The visual analog scale of pain during gait (VAS-G), VAS of pain at rest, hip joint function evaluated by the Japanese Orthopaedic Association (JOA) score, health-related quality of life (HRQoL), and adverse events were evaluated before, immediately after, and at 4, 8, and 12 weeks after injection. Patients were categorized according to the severity of OA (mild and severe OA groups) and dysplasia (dysplastic and non-dysplastic groups) and these groups were compared. RESULTS: After the injection, VAS-G improved significantly for 12 weeks. VAS-G was lower (less pain) in the mild OA group than in the severe OA group at each time point. There were no differences in VAS-G between the dysplastic and non-dysplastic groups throughout the observation period. VAS-G improved significantly in the dysplastic group after the injection. The JOA score and HRQoL demonstrated the same tendency as VAS-G. Three patients experienced worsening of local pain immediately after the injection; however, the pain on the following day was less than that before the injection in all three hips. CONCLUSIONS: Hylan G-F 20 injection into the hip joint was effective in reducing hip pain and can be used as a non-operative treatment option for hip OA in the Japanese population.

Retrospective Comparative Analysis of Opioid Use and Intra-Articular Corticosteroid Injections Before and After Initial Treatment of Knee Osteoarthritis with Hylan G-F 20.

BACKGROUND: Knee osteoarthritis (OA) is a painful condition affecting >250 million people worldwide and is a leading cause of disability. Intra-articular (IA) corticosteroids and/or oral opioids are often recommended for the management of knee OA pain. There are, however, concerns regarding their safety and tolerability. STUDY QUESTION: Do patients diagnosed with knee OA show a decrease in opioids or IA corticosteroid injections prescribed/administered in hospitals following hylan G-F 20 treatment? STUDY DESIGN: This case-crossover, retrospective study using Health Facts®, a de-identified electronic health records database, enrolled patients ≥18 years with knee OA treated with hylan G-F 20 between January 1, 2000 and March 31, 2016, with data within 6 months before/after treatment. MEASURES AND OUTCOMES: Primary endpoints compared days on opioids, amounts of opioids, and number of IA corticosteroid injections before/after hylan G-F 20 treatment via paired t-tests. RESULTS: A total of 513 patients were qualified for analysis. In the opioid cohort, the average total number of days on opioids (N = 50; 5.0 vs 13.5 days; P = 0.007) and average total amount of opioids (N = 44; 165.4 morphine mg equivalents [MME] vs 493.7 MME; P = 0.013) were lower 6 months after hylan G-F 20 treatment than 6 months before treatment. In the IA corticosteroid cohort, the average number of IA corticosteroid injections decreased after hylan G-F 20 treatment (N = 36; 0.56 in the 6-month follow-up vs 1.39 before treatment; P < 0.0001). Additional time frames of 1-5 months before and after treatment were examined; similar conclusions were drawn for patients with >2 months of data. CONCLUSION: Patients with knee OA previously treated with opioids or IA corticosteroid injections who received hylan G-F 20 demonstrated statistically significant decreases in these medications >2 months following hylan G-F 20 treatment versus >2 months before treatment.

Hylan G-F20 and galactomannan joint flares are associated to acute synovitis and release of inflammatory cytokines.

BACKGROUND: Injection of Hylan G-F20 (HY) into joints may provoke local flares, which mechanisms may involve reaction to protein contaminants. We have previously developed a protein-free saline-soluble galactomannan derived from guar gum (GM) that displays both analgesia and chondroprotection in experimental osteoarthritis (OA). We now demonstrate that both GM and Hylan G-F20 (HY) promote mild synovitis with cytokine release after intra-articular injection. METHODS: Mice received 100 µg/25 µL GM or HY or saline into the knees. Joint pain was evaluated using von Frey test; cell influx, interleukin (IL)-1, IL-6, and CXCL-1 (pg/mL) levels were assessed in joint lavage at 6 h. Synovia were excised for histopathology. RESULTS: Neither GM nor HY after being given into mice knee joints induced pain albeit promoting mild cell influx into joint washings as well as mild synovitis at histology, with no damage to the underlying cartilage. HY but not GM promoted IL-1 release into mice joints. Both compounds induced IL-6 and CXCL-1 release. CONCLUSION: Intra-articular injection of HY or GM promote acute transient synovitis whilst not provoking detectable significant joint damage. Local administration of these polysaccharides induces acute intra-articular release of inflammatory cytokines, which may account for joint flares following viscosupplementation.

Intra-articular Injections With Either Triamcinolone Hexacetonide, Stanozolol, Hylan G-F 20, or a Platelet Concentrate Improve Clinical Signs in Police Working Dogs With Bilateral Hip Osteoarthritis.

Objectives: To compare the effect of intra-articular treatment with triamcinolone hexacetonide (TH), stanozolol, hyaluronan, and a platelet concentrate in police working dogs with bilateral hip osteoarthritis (OA). Study Design: Prospective, longitudinal, double-blinded, negative controlled study. Sample Population: Fifty police working dogs with naturally occurring hip OA. Methods: Animals were randomly assigned to a control group (CG, n = 10), TH group (THG, n = 10), platelet concentrate group (PCG, n = 10), stanozolol group (SG, n = 10), and Hylan G-F 20 group (HG). On days 0 (T0), 8, 15, 30, 90, and 180 days post-treatment, weight-bearing distribution was evaluated. In those days, and on days 60, 120, and 150, four clinical metrology instruments were completed. Kaplan-Meier estimators were conducted and compared with the log-rank test. Cox proportional hazard regression analysis was performed to determine treatment survival. Significance was set at p < 0.05. Results: Patients had a mean age of 6.5 ± 2.4 years and body weight of 26.7 ± 5.2 kg. At T0, hips were classified as mild (n = 35), moderate (n = 10), and severe (n = 5), according to the Orthopedic Foundation for Animals grading scheme. No differences were found between groups at that moment considering age, body weight, OFA hip score, and all assessments performed. All treatments improved clinical signs in various OA dimensions in some groups, with a broad effect interval. PCG showed a lower range of variation while maintaining a positive result for more extended periods (p < 0.01 for symmetry index and 0.01 < p < 0.04 in the majority of scores). Breed, age, sex, and OFA grade did not significantly influence response to treatment. Conclusions and Clinical Relevance: This is the first prospective, negative controlled, double-blinded study to compare the effect of a single administration of these IA treatments in dogs with hip OA. HG and PCG recorded more significant improvements throughout the 180-day follow-up. In particular, PCG also registered a lower variation in results, seemingly the best therapeutic option. Nevertheless, improvements were still observed in THG and SG, and these treatment options can be considered, mainly when the first two treatments are not available.

Methylobacterium infection of an arthritic knee.

INTRODUCTION: Osteoarthritis (OA) is a common cause of knee pain in older adults. OA is primarily caused by deterioration of cartilage in the knee, which decreases the ability of synovial fluid to absorb shock and increases the opportunity for bones of the joint to rub together. Hylan G-F 20 (Synvisc-One) is a compound that can be injected directly into the knee to help combat the pain associated with OA by lubricating and cushioning the joint. CASE PRESENTATION: A 92-year-old male reported to his primary care provider with complaints of pain due to OA. An ultrasound-guided injection of Hylan G-F 20 was administered without complication; however, the patient presented to an emergency department approximately 10 h after the injection complaining of stabbing pain and swelling in the same knee. Specimens submitted for culture 12 h post-injection yielded a Methylobacterium spp. that was identified following biochemical testing, MALDI-TOF (matrix-assisted laser desorption/ionization-time of flight) MS analysis and bacterial sequencing. Interestingly, symptoms began to subside following aspiration of synovial fluid, and new cultures of synovial fluid collected 24 h post-Hylan G-F 20 injection were negative for the presence of Methylobacterium. The patient's knee returned to baseline with diminished pain due to OA approximately 1 week after the initial injection without antibiotic treatment. CONCLUSION: We report short-term complications following treatment of OA with a Methylobacterium-contaminated lot of Hylan G-F 20.

Effectiveness and Tolerability of Repeated Courses of Viscosupplementation in Symptomatic Hip Osteoarthritis: A Retrospective Observational Cohort Study of High Molecular Weight vs. Medium Molecular Weight Hyaluronic Acid vs. No Viscosupplementation.

Background: Nonsurgical management of symptomatic hip osteoarthritis needs real-world evidence. We evaluated the effectiveness and tolerability of US-guided intra-articular treatment of two hyaluronic acids (HAs) commercially available in Italy and investigated predictors of response. Methods: Outpatient records including three cohorts: 122 subjects treated with medium (1,500-3,200 kDa; Hyalubrix®) molecular weight (MW) or high (hylan G-F20; Synvisc®) MW HAs and 20 controls taking NSAIDs/analgesics on demand were retrospectively analyzed. Pain VAS score, WOMAC, NSAID/analgesic consumption, and causes of suspension were available at 1, 6, 12, and 24 months after first administration. As selection bias usually affects observational retrospective studies, a quasi-randomization process was attained by performing propensity score approach. Results: Propensity score adjustment successfully allowed comparisons among balanced groups of treatments. VAS and WOMAC considerably decreased over time in treated groups independently of the radiological grade (p<0.001). On the other hand, the control group showed only a slight and rather uneven variation in VAS. Mean score changes were comparable in both HA cohorts from the earliest stages (ΔVAS(HA1,500-3,200kDa)T1vsT0 = -20%; ΔVAS(hylan G-F20)T1vsT0 = -23%/ΔWOMAC(HA1,500-3,200kDa)T1vsT0 = -17%; ΔWOMAC(hylan G-F20)T1vsT0 = -19%), reaching a further substantial reduction after 12 months (ΔVAS(HA1,500-3,200kDa)T12vsT0 = -52%; ΔVAS(hylan G-F20)T12vsT0 = -53%/ΔWOMAC(HA1,500-3,200kDa)T12vsT0 = -45%; and ΔWOMAC(hylan G-F20)T12vsT0 = -47%). Almost 11% (=13/122) of ineffectiveness and few moderate local side effects 3% (=4/122) were detected. Conclusions: Viscosupplementation in a real-life setting seems to provide a sound alternative in pain management in comparison to oral NSAIDs/analgesics, guaranteeing a reduced intake of pain killer medications. Analgesic effectiveness, functional recovery, and reduced joint stiffness extend and improve over 12 and 24 months, suggesting that repeated administrations achieve an additive effect.

Cost-effectiveness and budget impact analysis of viscosupplementation with hylan G-F 20 for knee and hip osteoarthritis.

PURPOSE: To estimate the cost-effectiveness and budget impact of viscosupplementation with one intra-articular (IA) injection of 6 mL hylan G-F 20 (Synvisc-One®) and with three injections of 2 mL hylan G-F 20 (Synvisc®3×2) in knee osteoarthritis (OA) patients compared with conventional support therapy (CST - eg, NSAIDs and acetaminophen) and the cost-effectiveness of one IA injection of 2 mL hylan G-F 20 (Synvisc®1×2) in hip OA patients compared with CST from an Italian Health System perspective. METHODS: The model used was a Markov model with states for stages II-IV on the Kellgren-Lawrence scale and runs on 6-month cycles over a 5-year time horizon. A 3.5% discount was applied to both costs and utilities. Direct costs were determined from the perspective of the Italian National Health Service. A one-way and probabilistic sensitivity analysis was conducted for both comparisons. RESULTS: Hylan G-F 20 1×6 mL and hylan G-F 20 3×2 mL for knee OA were very likely to be cost-effective when compared to acetaminophen (ICER = €3,160.61 and €3,845.81 per QALY, respectively) and NSAIDs as both ICERs are below €25,000. The hip OA treatment by hylan G-F 20 1×2 mL was dominant compared to NSAIDs and very likely compared to acetaminophen. The results of the cost-effectiveness analysis were confirmed by one-way sensitivity analysis. The budget impact analysis for knee and hip OA showed a small increase in expenditure during 5 years. CONCLUSIONS: Hylan G-F 20 1×6 mL/hylan G-F 20 is a cost-effectiveness treatment compared to NSAIDs and acetaminophen in the treatment of knee/hip OA in Italy. The treatment of hip and knee OA resulted in cost-saving with hylan G-F 20 1×2 mL and economically sustainable with hylan G-F 20 1×6 mL. However, Real Word Evidence studies should be conducted in order to estimate costs associated with both prosthetics and to understand the reduction of physiotherapy and medication due to hylan G-F 20.

Viscosupplementation for knee osteoarthritis: a focus on Hylan G-F 20.

Knee osteoarthritis is a chronic degenerative joint disease characterized by destruction of articular cartilage with resultant para-articular bone changes. It is a major cause of disability in older persons and is managed by surgical and nonsurgical interventions. Pharmacotherapy includes acetaminophen, nonsteroidal anti-inflammatory agents, and intra-articular steroids. Another treatment option is viscosupplementation with intra-articular injection of hyaluronan (HA). The full mechanism of action of exogenous HA is uncertain, but studies indicate that it may promote endogenous HA production, reduce inflammation, prevent degeneration of cartilage and promote cartilage regeneration. Clinically, HA may improve symptoms of osteoarthritis and delay time to total knee replacement surgery. However, clinical studies are heterogenous and of varying quality, and thus there is a need for more robust studies to determine the place of viscosupplementation in the management of knee osteoarthritis.

Assessing the Impact of a Novel Smartphone Application Compared With Standard Follow-Up on Mobility of Patients With Knee Osteoarthritis Following Treatment With Hylan G-F 20: A Randomized Controlled Trial.

BACKGROUND: Osteoarthritis (OA) is a leading cause of disability in the United States. Although no disease-modifying therapies exist, patients with knee OA who increase walking may reduce risk of functional limitations. OBJECTIVE: The objective of the study is to evaluate the impact of a mobile app (OA GO) plus wearable activity monitor/pedometer (Jawbone UP 24) used for 90 days on the mobility of patients with knee OA treated with hylan G-F 20. METHODS: Patients with knee OA aged 30 to 80 years who were eligible to receive hylan G-F 20 and were familiar with smartphone technology were enrolled in this randomized, multicenter, open-label study. Patients who had a body mass index above 35 kg/m2 were excluded. All patients received a single 6-mL injection of hylan G-F 20 and wore the Jawbone monitor. The patients were then randomized 1:1 to Jawbone and OA GO (Group A; n=107) with visible feedback (unblinded) or Jawbone only (Group B; n=104) with no visible feedback (blinded). The primary endpoint was mean change from baseline in steps per day at day 90 between Groups A and B. RESULTS: Baseline characteristics were similar between groups. There were significant differences between the increases in least squares (LS) mean number of steps per day (1199 vs 467, P=.03) and the mean percentage change (35.8% vs 11.5%, P=.02) from baseline in favor of Group A over Group B. There was a greater reduction in pain from baseline during the 6-minute walk test in Group A versus Group B. (LS mean change: -55.3 vs -33.8, P=.007). Most patients (65.4%) and surveys of physicians (67.3%) reported they would be likely or very likely to use/recommend the devices. Patient Activity Measure-13 scores improved from baseline (LS mean change for Groups A and B: 5.0 vs 6.9), with no significant differences between groups. The occurrence of adverse events was similar in the 2 groups. CONCLUSIONS: Use of a novel smartphone app in conjunction with a wearable activity monitor provided additional improvement on mobility parameters such as steps per day and pain with walking in the 6-minute walk test in patients with knee OA who were treated with hylan G-F 20. Results also highlight the amenability of patients and physicians to using mobile health technology in the treatment of OA and suggest further study is warranted.

Differences among Branded Hyaluronic Acids in Italy, Part 1: Data from In Vitro and Animal Studies and Instructions for Use.

BACKGROUND: The use of hyaluronic acid (HA) for intra-articular (IA) injection is widespread around the world for patients affected by osteoarthritis. AIM: The aim of this study is to identify scientific evidence from in vitro and in vivo studies supporting the use of IA HAs marketed in Italy. We also evaluated the accuracy of indications and contraindications reported in the leaflets of such HAs compared with the available scientific evidence. MATERIALS AND METHODS: An extensive literature search was performed to identify all in vitro and in vivo model studies reporting on the effects of various HAs marketed in Italy for IA use. Data reported in the leaflets of different HA-based products for IA use were extracted and analyzed alongside evidence from in vitro and in vivo model studies. RESULTS: Nine in vitro studies and 11 studies on animal models were examined. Comparing results with what is reported in the leaflets of HAs marketed in Italy, it was observed that many branded formulations are introduced in the market without any reporting of basic scientific evidence. Only 12.82% and 17.95% of branded products had been shown to be effective with scientific evidence from in vitro and in vivo studies, respectively. The rationale of use of these products is based on their nature, as if a class effect existed such that all HAs would yield similar effects. CONCLUSIONS: Data on HAs deriving from in vitro and in vivo studies are scarce and relate to only a small percentage of products marketed in Italy. Many indications and contraindications are arbitrarily reported in Italian HA leaflets without the support of scientific evidence. Larger and brand-specific studies are necessary and should be reported in the leaflets to guide clinicians in making an appropriate choice regarding HA-based IA therapy.

Differences Regarding Branded HA in Italy, Part 2: Data from Clinical Studies on Knee, Hip, Shoulder, Ankle, Temporomandibular Joint, Vertebral Facets, and Carpometacarpal Joint.

OBJECTIVES: The aim of the current study is to collect scientific data on all branded hyaluronic acid (HA) products in Italy that are in use for intra-articular (IA) injection in osteoarthritis (OA) compared with that reported in the leaflet. METHODS: An extensive literature research was performed for all articles reporting data on the IA use of HA in OA. Selected studies were taken into consideration only if they are related to products based on HAs that are currently marketed in Italy with the specific joint indication for IA use in patients affected by OA. RESULTS: Sixty-two HA products are marketed in Italy: 30 products are indicated for the knee but only 8 were proved with some efficacy; 9 products were effective for the hip but only 6 had hip indication; 7 products proved to be effective for the shoulder but only 3 had the indication; 5 products proved effective for the ankle but only one had the indication; 6 products were effective for the temporomandibular joint but only 2 had the indication; only 2 proved effective for vertebral facet joints but only 1 had the indication; and 5 products proved effective for the carpometacarpal joint but only 2 had the indication. CONCLUSIONS: There are only a few products with some evidences, while the majority of products remain without proof. Clinicians and regulators should request postmarketing studies from pharmaceuticals to corroborate with that reported in the leaflet and to gather more data, allowing the clinicians to choose the adequate product for the patient.

Hylan G-F20 and galactomannan joint flares are associated to acute synovitis and release of inflammatory cytokines

Abstract Background: Injection of Hylan G-F20 (HY) into joints may provoke local flares, which mechanisms may involve reaction to protein contaminants. We have previously developed a protein-free saline-soluble galactomannan derived from guar gum (GM) that displays both analgesia and chondroprotection in experimental osteoarthritis (OA). We now demonstrate that both GM and Hylan G-F20 (HY) promote mild synovitis with cytokine release after intra-articular injection. Methods: Mice received 100 μg/25 μL GM or HY or saline into the knees. Joint pain was evaluated using von Frey test; cell influx, interleukin (IL)-1, IL-6, and CXCL-1 (pg/mL) levels were assessed in joint lavage at 6 h. Synovia were excised for histopathology. Results: Neither GM nor HY after being given into mice knee joints induced pain albeit promoting mild cell influx into joint washings as well as mild synovitis at histology, with no damage to the underlying cartilage. HY but not GM promoted IL-1 release into mice joints. Both compounds induced IL-6 and CXCL-1 release. Conclusion: Intra-articular injection of HY or GM promote acute transient synovitis whilst not provoking detectable significant joint damage. Local administration of these polysaccharides induces acute intra-articular release of inflammatory cytokines, which may account for joint flares following viscosupplementation.(AU)

Long-Term (1-Year) Safety and Efficacy of a Single 6-mL Injection of Hylan G-F 20 in Indian Patients with Symptomatic Knee Osteoarthritis.

INTRODUCTION: The prevalence of symptomatic knee osteoarthritis (OA) among Asians ≥65 years is estimated to double by 2040. This study was designed to evaluate the safety and efficacy of a single, 6-mL intra-articular injection of hylan G-F 20 in Indian patients with knee OA at 26 weeks through to 52 weeks. METHODS: This study was an open-label, multicentre, phase 4 clinical trial. Enrolled patients (N=394) were ≥30 years old with Kellgren-Lawrence grade 1-3 OA; all patients received hylan G-F 20. WOMAC, SF-12, PTGA, and COGA scores, and OA medication use were evaluated at weeks 1, 4, 12, 26, 39, and 52 (initial treatment phase). At 26, 39, or 52 weeks, eligible patients could participate in a repeat treatment phase. McNemar-Bowkers, paired t-tests and ANOVA analyses were performed (alpha=0.05). RESULTS: At 26 weeks, statistically significant changes from baseline were observed in all efficacy parameters, including the primary efficacy endpoint of WOMAC A1 (p<0.0001). Improvements continued for 52 weeks. No significant changes occurred in concomitant medication use. Eleven patients (2.8%) were re-injected at week 26 or 52. After repeat injection, statistically significant decreases were observed in WOMAC A1, WOMAC C and PTGA scores (p≤0.028). Twenty-three (5.8%) patients reported 26 local target knee AEs. CONCLUSION: Among Indian patients within this study, a 6-mL hylan G-F 20 injection was well tolerated and effective in treating symptomatic knee OA with significant long-term (1 year) improvement of outcomes. When needed, repeat treatment was safe and efficacious for 4 weeks. TRIAL REGISTRATION: Clinical Trial Registry of India (CTRI/2010/091/000052) www.ctri.nic.in/Clinicaltrials/login.php.