No conclusive evidence that histologically found granulomas and acute local reactions following hylan G-F 20 injections are related or have clinical significance.

Osteoarthritic (OA) knee pain can be successfully treated with hylan G-F 20 (Synvisc, Sanofi Biosurgery, Cambridge, MA) with few local adverse events. However, a few studies have identified hyaluronate positive (HA+) granulomas in the synovial tissue of patients treated with hylan G-F 20 raising the question of their relationship and clinical significance. To understand the potential relationship of HA+ granulomas with the occurrence of acute local reactions (ALRs), we evaluated the synovial tissue of OA patients undergoing total knee replacement that had previously been treated with hylan G-F 20 (n = 101) or had not been treated (n = 20). Granulomas were observed in nine patients, of which eight were in the hylan G-F 20 group (7.9%); HA+ granulomas were identified in six of these eight patients (5.9%). Three of the six patients with HA+ granulomas experienced an ALR within 30 days of administering an injection. Overall, we found no consistent relationship between histologically found HA+ granulomas and the occurrence of an ALR following hylan G-F 20 treatment. These microscopic granulomas were not associated with any symptoms and likely have little clinical significance. The low occurrence of granulomas and/or ALRs should not preclude use of hylan G-F 20 for the treatment of knee pain associated with OA.

The use of hyaluronan after arthroscopic surgery of the knee.

Viscosupplementation is defined as the use of intra-articular hyaluronan therapy for symptomatic osteoarthritis (OA). Originally used for the treatment of ophthalmic disorders, viscosupplementation has been available for over a decade in the United States for the treatment of pain secondary to OA of the knee in patients who have not responded adequately to conservative oral pharmaceuticals including nonsteroidal anti-inflammatories and simple analgesics. The majority of patients with symptomatic knee OA will have evidence of meniscal and/or articular surface pathology, and most orthopaedic surgeons include arthroscopic surgery as a possible treatment modality for the symptomatic patient. Although arthroscopic meniscectomy is the most commonly performed orthopaedic procedure in the United States, in patients with concomitant OA, disease-related pain can persist after arthroscopic surgery. This article reviews some of the more recent evidence recommending the use of viscosupplementation for the management of symptomatic knee OA and pain relief after arthroscopy.

Viscosupplementation with hyaluronans for osteoarthritis of the knee: clinical efficacy and economic implications.

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.

Total knee replacement delayed with Hylan G-F 20 use in patients with grade IV osteoarthritis.

BACKGROUND: Total knee replacement (TKR), a last resort for treating knee pain due to osteoarthritis (OA), is not always medically indicated or preferred by many patients. Hylan G-F 20 is a cross-linked hyaluronan derivative approved for the treatment of pain due to OA of the knee after other conservative approaches have failed. OBJECTIVE: The objectives of this study were to (1) determine the effect of hylan G-F 20 on patient need for TKR as measured by time from hylan G-F 20 injection to TKR, and (2) assess patient factors that might influence time from hylan G-F 20 therapy to TKR. METHODS: This is a retrospective case series review of the medical records of patients seen in 1 orthopedic specialty practice. The incidence and time to TKR in patients who were TKR candidates (100% grade IV OA [severe]) treated with 1 or more courses of intra-articular hylan G-F 20 injections (3 weekly injections per course) were determined from October 1997 to November 2003. Survival analysis was used to evaluate time to TKR and the effects of age, gender, ethnicity, body mass index (BMI), and presence of effusion on this outcome. Logistic regression was also used to assess these covariates. RESULTS: The incidence of TKR in hylan G-F 20-treated knees (1,187 knees; 863 patients) was 19% (n=225 knees). The median time to TKR in these patients was 638 days (1.8 years; minimum of 14 days, maximum of 2,147 days). For patients in whom a TKR had not yet occurred during the observation time, the median time of hylan G-F 20 treatment and patient follow-up was 810 days (2.2 years; minimum of 7 days, maximum of 2,222 days). A total of 1,978 courses of hylan G-F 20 given to 1,187 knees (average 1.67 courses per knee) resulted in an average cost of $1,419.76 per knee to delay TKR by a median of 2.1 years (772 days, minimum 7, maximum 2,222), the median time of all knees to either TKR or time of last observation. Survival analysis showed that 75% of knees had not had a TKR by 1,370 days (3.8 years). Survival analysis and logistic regression indicated that of age, gender, ethnicity, BMI, and presence of effusion, only age significantly affected time to TKR. CONCLUSION: In patients who are candidates for TKR, the need for TKR can be delayed with hylan G-F 20 when used for the treatment of OA knee pain.

Chronic knee effusions in patients with advanced osteoarthritis: implications for functional outcome of viscosupplementation.

Intra-articular injection of exogenous hyaluronan (viscosupplementation) is an effective treatment for knee pain due to osteoarthritis, but the amount of dilution of the viscosupplement by the synovial fluid, which could affect efficacy, has not been previously considered. In this study, the synovial fluid volume was measured in patients with advanced osteoarthritis and the variation in viscosupplement concentration that would have occurred had the patients received that treatment was calculated. A closed aspiration was performed under anesthesia in this consecutive, prospective series of patients undergoing total joint arthroplasty for advanced osteoarthritis. Any remaining synovial fluid was collected by means of open aspiration following an arthrotomy. Overall, 27.0 +/- 15.5 mL (range: 10-70 mL) of synovial fluid was present in the joints. Irrespective of the particular proprietary hyaluronan product, the viscosupplement concentration would have varied by an approximate factor of 6. Interpatient variation in volume of synovial fluid may explain some of the observed variations in efficacy in patients treated with viscosupplementation. Stricter attention to the possibility of a joint effusion and aspiration of the joint where indicated might lead to improved results.

Clinical experience with the effectiveness and tolerability of hylan G-F 20 in 1047 patients with osteoarthritis of the knee.

This retrospective review evaluates the effectiveness and tolerability of hylan G-F 20 for relief of pain due to knee osteoarthritis in a large orthopedic practice over a 5-year period. Prospectively collected data from patients who initiated intra-articular hylan G-F 20 (3 weekly injections) for osteoarthritis knee pain treatment were analyzed. Efficacy variables included physician visual analogue scale (VAS: 100 mm), and patient rating of pain, mobility, and amount of pain medication taken after treatment. Patients (n=1047; 1489 knees) were an average age of 65.3 years, 60% female, and 71% had radiologic osteoarthritis grade IV. Mean VAS scores significantly improved with hylan G-F 20 compared to baseline at all time points (P<.0001). Most knees (62%-89%) responded positively with hylan G-F 20. Pain and mobility improved and less pain medication was needed after therapy. The incidences of local adverse events were 5.2% per patient and 1.2% per injection; most local adverse events were mild or moderate, with severe local events in 0.3% of injections. Our clinical experience shows that hylan G-F 20 effectively relieves osteoarthritis knee pain (as indicated) and reduces pain medication needed for up to 6 months with a low incidence of local adverse events.

Hylan G-F 20 tolerability with repeat treatment in a large orthopedic practice: a retrospective review.

The objective of this study was to determine the incidence of local adverse events (AEs) with repeat treatment of hylan G-F 20 for osteoarthritis (OA) knee pain relief in the authors' practice. Prospectively collected patient data (5-year period) was retrospectively reviewed from patients who initiated multiple courses of three weekly hylan G-F 20 injections. All local AEs (knee pain and swelling) were qualitatively and quantitatively assessed. The incidence of treatment-related local AEs was 3.4% of patients (0.8% of injections) at course 1, 13.1% of patients (4.3% of injections) at course 2, and 17.3% of patients (5.4% of injections) at course 3. The majority of related local AEs were mild to moderate and persisted for < or = 48 hours. The number of patients who discontinued injections because of local AEs was low. While the incidence of local AEs with hylan G-F 20 tends to slightly increase with subsequent courses of therapy, physicians should educate patients regarding this possibility rather than preclude them from the benefit of continued OA pain relief with repeat hylan G-F 20 therapy.

Delayed Total Knee Replacement with Hylan G-F 20.

We retrospectively examined prospective data on the incidence and time to total knee replacement (TKR) in (1) patients with grade IV osteoarthritis (OA) treated with hylan G-F 20 from 1997 to 2010 (full cohort; 1,863 knees) and (2) a patient subset treated from 1997 to 2003 (original cohort; 1,187 knees) to determine any continued hylan G-F 20 influence on TKR delay. In both the cohorts, 25 to 28% knees underwent a TKR, with an average of 2.8 to 3.1 years occurring between hylan G-F 20 and surgery. Age was a significant predictor of time to TKR. Knee synovitis increased slightly with repeat courses; most cases considered mild or moderate. Survival analysis showed that TKR was delayed for > 7 years in 75% of 1,863 grade IV OA knees (1,342 patients) treated with hylan G-F 20 in an orthopedic practice. Consistent with our previous report (Waddell and Bricker, 2007), we show hylan G-F 20 continues to delay the need for TKR.

A second course of hylan G-F 20 for the treatment of osteoarthritic knee pain: 12-month patient follow-up.

This prospective open-label study evaluated the efficacy and tolerability of a second course of hylan G-F 20 for the treatment of osteoarthritic knee pain over a 12-month period in patients who previously experienced a beneficial initial course of therapy. Men or women aged > or = 40 years with knee osteoarthritis received 3 weekly injections of hylan G-F 20. Consecutive patients requesting a second course of therapy were enrolled from October 2000 to January 2001. The mean time between the first and second courses of hylan G-F 20 was 19.6 months. All efficacy parameters significantly improved (P<.001) from baseline at weeks 1, 2, 4, 8, 12, 26, and 52. Improvements from baseline to weeks 26 and 52 for the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) index question A1, WOMAC domain C, and total WOMAC were 1.39+/-0.11 and 1.1+/-0.12, 18.50+/-1.43 and 13.69+/-1.54, and 26.77+/-1.97 and 19.8+/-2.13, respectively. Significant improvements from baseline were maintained for patient and physician VAS to week 26 (patient: 48.66+/-2.52; investigator: 51.51+/-2.34) and week 52 (patient: 46.10+/-2.73; investigator: 47.23+/-2.52). A second course of hylan G-F 20 therapy was generally well-tolerated; the types of local events observed in this study were not qualitatively different from those in the current product information and published literature. For continued relief of osteoarthritic knee pain, this study supports repeat use of hylan G-F 20 in patients who had a previous successful course of therapy.

Comparison of Efficacy and Tolerability of Hylan G-F 20 in Patients with and without Effusions at the Time of Initial Injection.

An effusion at the onset of viscosupplementation has been thought to diminish the efficacy and increase adverse event rates. This study compares efficacy of hylan G-F 20 in patients with and without an effusion. Patients with knee osteoarthritis (OA) received three weekly injections of hylan G-F 20. A total of 50 patients with an effusion requiring aspiration were compared with 50 matched patients without an effusion. Outcome measurements included Western Ontario and McMaster's Universities Osteoarthritis index (WOMAC) and visual analog scale (VAS). Patients were followed for 26 weeks. Both effusion and control group VAS was significantly lowered at all time points. WOMAC scores improved (p < 0.025) at all visits in the effusion group except for WOMAC A-1 week 14. Control WOMAC scores also significantly improved at all visits (p < 0.027), except for full WOMAC and WOMAC A-1 at week 1. Neither group experienced an adverse event. Presence of an effusion at onset of viscosupplementation requiring aspiration does not negatively impact efficacy of hylan G-F 20 or increase adverse event rates.

The tolerability of viscosupplementation: low incidence and clinical management of local adverse events.

Hylan G-F 20 (Synvisc, Genzyme Biosurgery, Ridgefield, NJ) is a visco supplement indicated for the treatment of pain due to osteoarthritis (OA) of the knee. Overall, the therapy is well tolerated with a low incidence of local and systemic adverse events (AEs). In our large clinical practice, our overall rate of local pain and swelling with treatment is consistent with that of previous reports and the product labeling. Local AEs that do occur with therapy are mostly mild to moderate in nature, transient, and resolve spontaneously or with symptomatic treatment. Local AEs thought to be related to the treatment are clinically manageable and do not result in long-term sequelae, such that their occurrence should not preclude patients from the benefit of OA pain relief with therapy, including continued pain relief with repeat treatment. Based on previous published reports of hylan G-F 20 and our extensive clinical experience, relief of OA knee pain with hylan G-F 20 far outweighs the low risk of local AEs for patients who do not respond to other therapies indicated for the treatment of OA knee pain.

An open-label study of a second course of hylan G-F 20 for the treatment of pain associated with knee osteoarthritis.

OBJECTIVE: To evaluate the efficacy and tolerability of a second course of hylan G-F 20 for the treatment of osteoarthritic knee pain in patients who experienced a clinical benefit with an initial course of therapy. RESEARCH DESIGN AND METHODS: In this prospective, open-label study, men or women (>/=40 years of age) with knee osteoarthritis (OA) received three weekly injections of hylan G-F 20. Consecutive patients who requested a second course of hylan G-F 20 therapy due to OA knee pain subsequent to pain relief with a first course of therapy were enrolled between October 26, 2000 and January 18, 2001. MAIN OUTCOME MEASURES: Pain while walking on a flat surface (Western Ontario and McMaster's Universities Osteoarthritis Index, WOMAC, question A1), WOMAC domain C (physical functioning), full WOMAC, and patient and investigator overall visual analog scales (VAS). Efficacy variables were measured at baseline and at weeks 1, 2, 4, 8, 12 and 26. An analgesic washout was required before all efficacy evaluations. RESULTS: Patients receiving at least one injection of hylan G-F 20 (n = 71) were predominantly Caucasian (84.5%) and female (64.8%), with a mean age of 65.5 years and mean weight of 200.1 pounds. The mean time between the first and second courses of hylan G-F 20 was 19.6 months (median 17.6 months). With hylan G-F 20, pain while walking on a flat surface was significantly lower (p < 0.001) than baseline at all time points up to week 26 (mean +/- SEM: -1.40 +/- 0.10 at week 26). Actual scores decreased from 2.4 +/- 0.10 at baseline to 0.97 +/- 0.11 at week 26. Scores for the WOMAC domain C, full WOMAC and patient and investigator overall VAS also significantly improved (p < 0.001) at all time points. A second course of hylan G-F 20 was generally well-tolerated, based on the low incidence of local adverse events (AEs) - only one patient (1.4%) experienced a severe event, the types of AEs, and the fact that no patients discontinued the study due to these AEs. The types of related AEs observed were not qualitatively different from those listed in the current product information and published literature. CONCLUSION: A second course of hylan G-F 20 therapy is an appropriate therapy for the treatment of OA knee pain in patients who had a previous favorable clinical response. For continued relief of osteoarthritis knee pain, this study supports repeat use of hylan G-F 20 in these patients.

Viscosupplementation with hylan g-f 20 in patients with osteoarthrosis of the knee.

Viscosupplementation (VIS) is one of several treatment modalities for osteoarthritis of the knee. It is useful in the treatment of osteoarthritis when other methods of conservative care have failed and it may be a safer method of treatment than oral chemical therapy which can have significant side effects with even short-term usage. The biochemical effects of hyaluronic acid are incompletely understood, however there are several accepted modes of action which result in a positive clinical effect on the function of the knee joint. There is some evidence that hyaluronic acid preparations with a higher molecular weight may be more beneficial to the patient. It is commonly used after arthroscopic meniscectomy and or debridement of the knee in a patient with chondral disease. The clinical effects have been well documented in multiple studies in patients with mild to moderate osteoarthritis in study groups before or after arthroscopic surgery of the knee. Adverse events do occur and are easily treated with only rare case reports of systemic effects. Furthermore, there is some evidence that VIS can prolong the need for total knee arthroplasty in the older patient as well.

Hyaluronan-binding receptors: possible involvement in osteoarthritis.

Our objectives were to compare the expression of the hyaluronan receptors CD44 and RHAMM in knee synovial tissue of patients with and without advanced osteoarthritis (OA). Both receptors were detected immunohistochemically; the staining appeared more intense in the tissues from the patients with advanced OA. Expression of CD44 and RHAMM were each significantly increased (p < 0.05) in synovial tissue from patients with OA, as determined by means of Western-blot analysis. The findings suggested that changes in levels of the HA-binding proteins might be implicated in the development or progression of OA.

Hyaluronan suppresses IL-1beta-induced metalloproteinase activity from synovial tissue.

Intraarticular injection of hyaluronan (viscosupplementation) is commonly used to treat knee pain from osteoarthritis. The therapeutic benefit might derive from hyaluronan inhibition of the activity of the cytokine-regulated catabolic enzymes that attack joint cartilage (matrix metalloproteinases). We tested the hypothesis that hyaluronan inhibited interleukin-1beta-induced matrix metalloproteinase activity secreted by explants of synovial tissue from patients with osteoarthritis and investigated the mechanism of the effect. Hyaluronan with a molecular mass of 12.8 MDa (number average) antagonized induced metalloproteinase activity in proportion to hyaluronan concentration in the clinically relevant range of 2 to 8 mg/mL. The effect was not attributable solely to molecular mass because 1.2-MDa hyaluronan produced comparable inhibition. Based on measurements involving hyaluronans of different average molecular masses, polydispersity and viscosity were similarly ruled out as primary responsible factors. The effect of hyaluronan on induced metalloproteinase activity was mediated partially by CD44, the principal cell surface receptor for hyaluronan. Hyaluronan inhibited interleukin-1beta-induced metalloproteinase production from osteoarthritic synovial tissue by a process that was not solely dependent on hyaluronan molecular mass but that was partly mediated by hyaluronan binding to CD44. The efficacy of viscosupplementation could be explained if hyaluronan also blocked catabolic enzyme activity in the joint.

Assessment of immunologic mechanisms for flare reactions to Synvisc.

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 microg/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.

IL-1beta-induced production of metalloproteinases by synovial cells depends on gap junction conductance.

Synovial cells can form networks connected by gap junctions. The purpose of this study was to obtain evidence for a necessary role of gap junction intercellular communication in protein secretion by synovial cells. We developed a novel assay to measure the enzymatic activity of metalloproteinases (MMPs) produced by synovial cells in response to interleukin-1beta (IL-1beta) and employed the assay to explore the biological function of gap junctions. IL-1beta produced a dose-dependent increase in MMP activity that was blocked by exposure to the gap junction inhibitors 18alpha-glycyrrhetinic acid and octanol for as few as 50 min. The inhibitors produced an immediate and marked reduction in intercellular communication, as assessed by transient current analysis using the nystatin perforated-patch method. These observations suggest that communication through gap junctions early in IL-1beta signal transduction is critical to the process of cytokine-regulated secretion of MMPs by synovial cells.