Health Economic Assessments of Hyaluronic Acid Treatments for Knee Osteoarthritis: A Systematic Review.

INTRODUCTION: Hyaluronic acid (HA) use to treat knee osteoarthritis (OA) has been extensively investigated in the literature. There are also multiple economic assessments comparing intra-articular HAs with oral anti-inflammatory medicines and other conservative measures (NSAIDs), as well as different types and formulations of HA. Owing to the broad landscape of evidence across this area, it is important to further understand the empirical data comparing HA products, as well as the health economic implications that exist between commercially available HAs. This systematic review aims to identify and summarize the available evidence comparing commercially available HA products in the USA, as well as the health economic evidence and socioeconomic outcomes associated with HA use for knee OA. METHODS: A systematic literature review within the OVID Medline, Embase, HealthStar, and Cochrane EBM HTA databases was conducted. Articles were screened for eligibility, and a qualitative summary of the findings was provided based on specific themes: (1) trials comparing the safety and/or efficacy of two or more HA products in knee OA, (2) economic/cost analyses of HA use in knee OA, and (3) studies investigating healthcare resource utilization in patients treated with HA for knee OA. RESULTS: The search strategy identified 398 studies, 27 of which were deemed eligible: 21 health economic analyses with US relevance and six head-to-head trials of HA products available in the USA, cumulatively assessing 5,782,156 patients with knee OA. The evidence demonstrates a clear distinction between high and low molecular weight HAs, as both efficacy and cost analyses provided favorable results for the high molecular weight options. In all but one cost analysis, HA use was a cost-effective option when compared to routine nonoperative care, captured in administrative databases, which typically included NSAID use and/or corticosteroids. HA saw benefits in delaying the need for total knee arthroplasty (TKA), decreasing the use of rescue medication, and limiting the need for additional corticosteroid injection. The included evidence highlights that the treatment's cost-effectiveness is improved when HA is utilized in earlier stages of the disease, as opposed to when HA is reserved for late stages of knee OA. Additionally, among HAs, Bio-HA and Hylan G-F 20 evidence made up the majority of available literature with beneficial efficacy and cost outcomes. Head-to-head evidence between them indicated similar pain outcomes; however, Bio-HA required less rescue with acetaminophen and had fewer joint effusions in this comparison. CONCLUSIONS: The available efficacy and safety data as well as health economic analyses on the use of HA for knee OA management suggest that there are economic benefits of this treatment option. From a healthcare system perspective, the body of HA literature summarizes favorable costs profile, decreased opioid and corticosteroid use as rescue medication, and a delay to the need for TKA in patients who have HA included in their treatment regimen.

Association Between Bio-Fermentation Derived Hyaluronic Acid and Healthcare Costs Following Knee Arthroplasty.

Background: Limiting access to intra-articular knee injections, including hyaluronic acid (HA), has been advocated as a cost-containment measure in the treatment of knee osteoarthritis. The association between presurgical injections and post-surgical complications such as early periprosthetic joint infection and revision remained to be investigated. This study evaluated pre- and post-surgical costs and rates of post-surgical complications in knee arthroplasty (KA) patients with or without prior HA use. Methods: Commercial and Medicare Supplemental Claims Data (IBM MarketScan Research Databases) from January 1, 2012 to December 31, 2018 were used to identify unilateral KA patients. Those who completed a course of bio-fermentation derived HA (Bio-HA) as the first-line HA therapy comprised of the test group (n = 4091), while the control group did not use HA prior to KA (n = 118,659). Using multivariable regression with propensity score (PS) weighting, overall healthcare costs, readmission rates, and revision rates were assessed at six months following KA. Results: Healthcare costs following KA were significantly lower for the Bio-HA group ($10,021 ± $22,796) than No HA group ($12,724 ± $32,966; PS p < 0.001). Bio-HA patients had lower readmission rates (8.9% vs 14.0%; PS p < 0.001) and inpatient costs per readmitted patient ($43,846 ± $50,648 vs $50,533 ± $66,150; PS p = 0.005). There were no differences in revision rate for any reason (Bio-HA: 0.78% vs No HA: 0.67%; PS p = 0.361) and with PJI (Bio-HA: 0.42% vs No HA: 0.33%; PS p = 0.192). Costs in the six months up to and including the KA were similar for both groups (Bio-HA: $49,759 ± $40,363 vs No HA: $50,532 ± $43,183; PS p = 0.293). Conclusion: Bio-HA use prior to knee arthroplasty did not appear to increase overall healthcare costs in the six months before and after surgery. Allowing access to HA injections provides a non-surgical therapeutic option without increasing cost or risk of post-surgical complications.

Changes in prescription pain medication and intra-articular corticosteroid utilization after intra-articular bio-fermentation derived hyaluronic acid use in patients undergoing multimodal pain management.

BACKGROUND: Multiple interventions may be used to treat symptomatic knee osteoarthritis (OA), but concerns have been raised about the safety and efficacy of some therapies. Clinical trials have shown that hyaluronic acid (HA) can provide pain relief up to 6 months and possibly to 12 months, while real-world data has shown that pain medication and intra-articular corticosteroid (CS) injection utilization are reduced within 6 months after HA. OBJECTIVE: To examine changes in prescription pain medication and CS utilization during 1 year after multimodal therapy that included high molecular weight, bio-fermentation derived HA (Bio-HA) use for knee OA. METHODS: Commercial and Medicare Supplemental claims data (IBM MarketScan Research Databases) (1 January 2012, through 31 December 2018) was used to identify unilateral Bio-HA patients using multimodal therapy (any combination of CS injection, opioids, and non-opioid pain medication). Monthly therapy utilization was compared in the 12 months after Bio-HA therapy initiation to the 4-month intra-multimodal period. RESULTS: A total of 13,999 patients underwent Bio-HA therapy with concurrent multimodal therapy. The number of filled opioid prescriptions decreased from 2,913.0/month to 2,861.5/month after Bio-HA, with a reduction in mean monthly prescriptions from 0.60 to 0.43 per user (p < 0.001). A number of opioid days supplied also decreased from 48,914/month to 39,730/month, with a decrease from 10.1/month to 6.0/month per user (p < 0.001). Bio-HA patients had prescription pain medication-free days for 71% of the time post-multimodal period compared to 53% during the intra-multimodal period (p < 0.001). The proportion of patients with CS injections after Bio-HA decreased from 53.8% to 29.6% (p < 0.001). Total monthly CS injections decreased from 2,292 to 663. CONCLUSIONS: Our data suggest that high molecular weight Bio-HA, as part of multimodal therapy, may be effective in providing longer-term pain relief with the reduction in pain therapy (CS injections and opioids) and increase in prescription pain medication-free days.

Delay to TKA in Patients Treated with a Multimodal Approach Using High Molecular Weight, Biologically Derived Hyaluronic Acid.

BACKGROUND: The primary objective of this study was to determine the effect of single versus multiple rounds of intra-articular hyaluronic acid (IA-HA) in delaying the need for total knee arthroplasty (TKA) in patients with knee OA, and if additional benefits were seen when used in conjunction with other multimodal treatment options. METHODS: This study was a retrospective claims analysis of a large commercial database containing more than 100 million patients with continuous coverage from October 1, 2010 through September 30, 2015. Time to TKA for patients who received one course of Euflexxa (IA-BioHA) were compared to patients who received two or more courses of IA-BioHA and patients who received no IA-HA. Assessment of multimodal treatment effects was done between the following groups: IA-BioHA injections alone, IA-BioHA and bracing, IA-BioHA and corticosteroid injection, and IA-BioHA with both corticosteroids and bracing. RESULTS: A total of 26,727 patients were included in the analysis of treatment courses, and 31,034 in the analysis of multimodal treatment combinations. The use of IA-BioHA demonstrated a delay of TKA that was prolonged with repeated courses of treatment (1.411 years, interquartile range [IQR]: 1.44). The greatest delay to TKA was observed for the patients who had received all three treatment options (1.5 years, IQR: 1.52) in the multimodal analysis. CONCLUSIONS: These results confirm that treatment of knee OA should consider the use of multimodal therapy instead of focusing on individual treatment options. Additionally, the use of repeated courses of IA-BioHA should be considered for prolonged benefit for patients with symptomatic knee OA.

Insights from Real-World Analysis of Treatment Patterns in Patients with Newly Diagnosed Knee Osteoarthritis.

BACKGROUND: Several nonpharmacologic and pharmacologic treatments are available for the management of knee osteoarthritis (OA)-related pain and for improving functionality; however, clinical guideline recommendations vary on their use. OBJECTIVE: To compare the treatment patterns in a real-world setting versus the guideline recommendations for the treatment of newly diagnosed patients with knee OA. METHODS: This retrospective analysis used data from the electronic health records of the Geisinger Health System between January 1, 2010, and December 2018 to identify adults with newly diagnosed knee OA who had not received previous therapy with intra-articular corticosteroids, opioids, intra-articular hyaluronic acid, or prescription nonsteroidal anti-inflammatory drugs (NSAIDs). Eligible patients were evaluated for the mutually exclusive treatment categories after diagnosis, including prescription NSAIDs, intra-articular corticosteroids, intra-articular hyaluronic acid (specifically an intra-articular bioengineered hyaluronic acid), opioids, physical therapy, bracing, and total knee arthroplasty. These 7 treatment categories were evaluated for utilization patterns in the real-world setting. RESULTS: A total of 8776 patients with a new diagnosis of knee OA were identified; 88.2% of them received 1 of the 7 evaluated treatments. The most frequently prescribed first treatment was intra-articular corticosteroids (26%), followed by opioids (17.6%), and intra-articular bioengineered hyaluronic acid (14.9%). The most often prescribed second treatment was opioids (15.8%), followed by physical therapy (14%), NSAIDs (11.8%), and intra-articular bioengineered hyaluronic acid (9.6%). Of note, 22.9% of the patients received only 1 evaluated therapy during the study period and did not receive a second treatment. CONCLUSIONS: Real-world treatment patterns in patients with newly diagnosed knee OA indicate that prescribers are using the spectrum of the available therapies that, at times, are different from the current treatment guideline recommendations.

Delay to TKA and Costs Associated with Knee Osteoarthritis Care Using Intra-Articular Hyaluronic Acid: Analysis of an Administrative Database.

BACKGROUND: Total knee arthroplasty (TKA) is a surgical treatment for patients with knee osteoarthritis (KOA) that no longer experience symptom relief from non-operative or pharmacologic treatments. Non-operative KOA management aims to address patient symptoms and improve function, as well as forestall or mitigate the large costs associated with TKA. The primary objective of this study was to examine the relationship between intra-articular hyaluronic acid (IA-HA) treatment and delaying TKA in patients with KOA compared to patients not receiving IA-HA, as well as to identify differences in KOA-related costs incurred among patients who received or did not receive IA-HA. METHODS: This was a retrospective analysis of an administrative claims database from October 1st, 2010 through September 30th, 2015. Kaplan-Meier survival analysis was conducted to determine the TKA-free survival of patients who received IA-HA, stratified by the number of injection courses received versus those who did not receive any IA-HA. Median KOA-related costs per year were calculated for 2 comparisons: (1) patients who received IA-HA versus patients who did not receive IA-HA, among patients who eventually had TKA, and (2) patients who received IA-HA versus patients who did not receive IA-HA, among patients who did not have TKA. RESULTS: A total of 744 734 patients were included in the analysis. A delay to TKA was observed after IA-HA treatment for patients treated with IA-HA compared to those who did not receive IA-HA. At 1 year, the TKA-free survival was 85.8% (95% CI: 85.6%-86.0%) for patients who received IA-HA and 74.1% (95% CI: 74.0%-74.3%) for those who did not receive IA-HA. At 2 years, the TKA free survival was 70.8% (70.5%-71.1%) and 63.7% (63.5%-63.9%) in the 2 groups, respectively. Patients treated with multiple courses of IA-HA demonstrated an incremental increase in delay to TKA with more courses of IA-HA, suggesting that the risk of TKA over the study time period is reduced with additional IA-HA courses. The hazard ratio for the need of TKA was 0.85 (95% CI 0.84-0.86) for a single course and 0.27 (95% CI 0.25-0.28) for ⩾5 courses, both compared to the no IA-HA group. In patients that eventually had TKA, the median KOA-related costs were lower among those who received IA-HA before their TKA ($860.24, 95% CI: 446.65-1722.20), compared to those who did not receive IA-HA ($2659.49, 95% CI: 891.04-7480.38). For patients who did not have TKA, the median and interquartile range (IQR) KOA-related costs per year were similar for patients who received IA-HA compared with those who did not. CONCLUSION: These results demonstrate that within a large cohort of KOA patients, individuals who received multiple courses of IA-HA had a progressively greater delay to TKA compared to patients who did not receive IA-HA treatment. Also, for patients who progressed to TKA, IA-HA treatment was associated with a large reduction in KOA-related healthcare costs. Based on these results, multiple, repeat courses of IA-HA may be beneficial in substantially delaying TKA in KOA patients, as well as minimizing KOA-related healthcare costs.

Knee Osteoarthritis Treatment Costs in the Medicare Patient Population.

BACKGROUND: Several nonoperative options have been recommended for the treatment of knee osteoarthritis (OA), with varying degrees of evidence. Adhering to the American Academy of Orthopaedic Surgeons clinical practice guidelines has been suggested to decrease direct treatment costs by 45% in the year before knee arthroplasty, but this does not consider the cost of the entire episode of care, including the cost of surgery and postsurgery care. OBJECTIVES: To analyze the total treatment costs after a diagnosis of knee OA, as well as the proportion of arthroplasty interventions as part of the total knee OA-related costs, and whether the total costs differed for patients who received intra-articular hyaluronic acid and/or had knee arthroplasty. METHODS: We identified patients newly diagnosed with knee OA using the 5% Medicare data sample from January 2010 to December 2015. Patients were excluded if they were aged <65 years, had incomplete claim history, did not reside in any of the 50 states, had claim history <12 months before knee OA diagnosis, or did not enroll in Medicare Part A and Part B. The study analyzed knee OA-related costs from a payer perspective in terms of reimbursements provided by Medicare, as well as the time from the diagnosis of knee OA to knee arthroplasty for patients who had knee arthroplasty, and the time from the first hyaluronic acid injection to knee arthroplasty for those who received the injection. We compared patients who received hyaluronic acid and those who did not receive hyaluronic acid injections. Patients who received hyaluronic acid injection who subsequently had knee arthroplasty were also compared with those who did not have subsequent knee arthroplasty. RESULTS: Of the 275,256 patients with knee OA, 45,801 (16.6%) received a hyaluronic acid injection and 35,465 (12.9%) had knee arthroplasty during the study period. The median time to knee arthroplasty was 16.4 months for patients who received hyaluronic acid versus 5.7 months for those who did not receive hyaluronic acid. Non-arthroplasty-related therapies and knee arthroplasty accounted for similar proportions of knee OA-related costs, with hyaluronic acid injection comprising 5.6% of the total knee OA-related costs. For patients who received hyaluronic acid injections and subsequently had knee arthroplasty, hyaluronic acid injection contributed 1.8% of the knee OA-related costs versus 76.6% of the cost from knee arthroplasty. Patients who received hyaluronic acid injections and did not have knee arthroplasty incurred less than 10% of the knee OA-related costs that patients who had surgery incurred. CONCLUSION: Although limiting hyaluronic acid use may reduce the knee OA-related costs, in this study hyaluronic acid injection only comprised a small fraction of the overall costs related to knee OA. Among patients who had knee arthroplasty, those who received treatment with hyaluronic acid had surgery delayed by a median of 10.7 months and associated costs for a significant period. The ability to delay or avoid knee arthroplasty altogether can have a substantial impact on healthcare costs.

Decrease in opioid and intra-articular corticosteroid burden after intra-articular hyaluronic acid for knee osteoarthritis treatment.

Aim: We studied changes in opioid prescriptions and corticosteroid injection use for knee osteoarthritis patients before and after intra-articular hyaluronic acid (HA) use and opioid prescriptions before and after knee arthroplasty (KA). Materials & methods: A total of 1,017,578 knee osteoarthritis members were ascertained from a commercial claims database (Health Intelligence Company LLC, IL, USA) using ICD9/ICD10 diagnosis codes. Results: Eighty two percent of HA patients did not fill opioid prescriptions postinjection, with 54% of opioid users discontinuing fills. Two-thirds of KA patients filled opioid prescriptions within 6 months postsurgery, with 78% of opioid users continuing fills and 62% of nonusers initiating use. Conclusion: Alternative therapies, such as HA, that reduce opioid use may alleviate opioid addiction risks for KA patients who use opioids in the pre- and postoperative periods.

Knee OA cost comparison for hyaluronic acid and knee arthroplasty.

BACKGROUND: Limiting treatment to those recommended by the American Academy of Orthopaedic Surgeon Clinical Practice Guidelines has been suggested to decrease costs by 45% in the year prior to total knee arthroplasty, but this only focuses on expenditures leading up to, but not including, the surgery and not the entire episode of care. We evaluated the treatment costs following knee osteoarthritis (OA) diagnosis and determined whether these are different for patients who use intra-articular hyaluronic acid (HA) and/or knee arthroplasty. METHODS: Claims data from a large commercial database containing de-identified data of more than 100 million patients with continuous coverage from 2012 to 2016 was used to evaluate the cumulative cost of care for over 2 million de-identified members with knee OA over a 4.5-year period between 2011 and 2015. Median cumulative costs were then stratified for patients with or without HA and/or knee arthroplasty. RESULTS: Knee OA treatment costs for 1,567,024 patients over the 4.5-year period was $6.60 billion (mean $4210/patient) as calculated by the authors. HA and knee arthroplasty accounted for 3.0 and 61.5% of the overall costs, respectively. For patients who underwent knee arthroplasty, a spike in median costs occurred sooner for patients without HA use (around the 5- to 6-month time point) compared to patients treated with HA (around the 16- to 17-month time point). CONCLUSIONS: Non-arthroplasty therapies, as calculated by the authors, accounted for about one third of the costs in treating knee OA in our cohort. Although some have theorized that limiting the use of HA may reduce the costs of OA treatment, HA only comprised a small fraction (3%) of the overall costs. Among patients who underwent knee arthroplasty, those treated with HA experienced elevated costs from the surgery later than those without HA, which reflects their longer time to undergoing knee arthroplasty. The ability to delay or avoid knee arthroplasty altogether can have a substantial impact on the cost to the healthcare system.

Addition of High Molecular Weight Hyaluronic Acid to Fibroblast-Like Stromal Cells Modulates Endogenous Hyaluronic Acid Metabolism and Enhances Proteolytic Processing and Secretion of Versican.

We have examined the effect of exogenous linear chain high molecular weight hyaluronic acid (HMW HA) on endogenously synthesized hyaluronic acid (HA) and associated binding proteins in primary cultures of fibroblast-like stromal cells that were obtained by collagenase digestion of the murine peripatellar fat pad. The cultures were expanded in DMEM that was supplemented with fetal bovine serum and basic fibroblast growth factor (bFGF) then exposed to macrophage-colony-stimulating factor (MCSF) to induce macrophage properties, before activation of inflammatory pathways using E. coli lipopolysaccharide (LPS). Under all culture conditions, a significant amount of endogenously synthesized HA localized in LAMP1-positive lysosomal vesicles. However, this intracellular pool was depleted after the addition of exogenous HMW HA and was accompanied by enhanced proteolytic processing and secretion of de novo synthesized versican, much of which was associated with endosomal compartments. No changes were detected in synthesis, secretion, or proteolytic processing of aggrecan or lubricin (PRG4). The addition of HMW HA also modulated a range of LPS-affected genes in the TLR signaling and phagocytosis pathways, as well as endogenous HA metabolism genes, such as Has1, Hyal1, Hyal2, and Tmem2. However, there was no evidence for association of endogenous or exogenous HMW HA with cell surface CD44, TLR2 or TLR4 protein, suggesting that its physiochemical effects on pericelluar pH and/or ionic strength might be the primary modulators of signal transduction and vesicular trafficking by this cell type. We discuss the implications of these findings in terms of a potential in vivo effect of therapeutically applied HMW HA on the modification of osteoarthritis-related joint pathologies, such as pro-inflammatory and degradative responses of multipotent mesenchymal cells residing in the synovial membrane, the underlying adipose tissue, and the articular cartilage surface.

Viscosupplementation may preserve tibial cartilage and collagen in osteoarthritis: findings from a preclinical model of osteoarthritis.

PURPOSE: Intraarticular (IA) hyaluronic acid (HA) injection is used to reduce pain and improve mobility in knee osteoarthritis (OA). Little is known about histopathological changes underlying HA efficacy. This study investigated dose-related effects of 1% sodium hyaluronate (BioHA) on knee joint histopathology and pain responses in a medial meniscal tear (MMT) rat model of OA. METHODS: Following MMT surgery, rats were randomized into treatment groups: single IA injection of vehicle, BioHA, or an avian-derived hyaluronic acid (hylan G-F 20) on Day 7; or 3 weekly injections of vehicle or BioHA on Days 7, 14, and 21. On Day 35, joints were evaluated by microscopic histopathology for cartilage degeneration, collagen degeneration, synovitis, and cytokine expression (tumor necrosis factor α, transforming growth factor ß). RESULTS: Joint pathology for control animals was consistent with that expected for the MMT model. Rats treated with 3 injections of IA-BioHA had significantly reduced collagen degeneration (21%) relative to control animals. No significant change in collagen degeneration was observed for rats given a single injection of hylan G-F 20 or IA-BioHA compared to control animals. HA treatment did not affect cytokine expression. CONCLUSIONS: IA-BioHA viscosupplementation in a rat MMT model of OA showed preservation of joint cartilage and collagen. This effect was most pronounced on tibial surfaces having less severe injury, suggesting that treatment should be initiated early in the disease process. A comparison of responses to IA-BioHA or hylan G-F 20 in the MMT rat OA model suggest IA-BioHA may be more effective in preserving joint connective tissue.

Cost-Effectiveness of Treating Early to Moderate Stage Knee Osteoarthritis with Intra-articular Hyaluronic Acid Compared to Conservative Interventions.

INTRODUCTION: Evidence has demonstrated greater benefit of intra-articular hyaluronic acid (IA-HA) within earlier stages of knee osteoarthritis (OA) rather than waiting for patients to have progressed to later stages of disease progression. High molecular weight (HMW) HA has also been shown to be more effective than low molecular weight (LMW) HA products in mild to moderate knee OA, providing an important distinction to make within the class of IA-HA therapies. The purpose of this study is to evaluate the cost-effectiveness of treating patients with knee OA with HMW HA compared to LMW and conservative treatment, while taking into account disease stage. METHODS: Decision analytic models were created for early/moderate, as well as late stage knee OA. Models for late stage knee OA were created by assuming a range of response rates to IA-HA treatments from 10% to 50%. These models included conservative treatment using physical therapy/exercise, braces/orthosis, and medications such as non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics. The models compared the cost per quality adjusted life year (QALY) gained for these treatments to the use of either LMW or HMW HA. Incremental cost-effectiveness ratios (ICERs) were calculated for each treatment in relation to HMW HA. RESULTS: When evaluating treatment in early to moderate knee OA, HMW HA was dominant over LMW HA and physical therapy/exercise, as it was less expensive and provided greater benefit. HMW HA was cost-effective versus braces/orthosis and NSAID/analgesic medications based on a willingness to pay threshold of $50,000. In the model of 50% response rate to IA-HA for late stage OA, HMW HA remained cost-effective in comparison to physical therapy/exercise and braces/orthosis at a willingness to pay threshold of $50,000; but not NSAID/analgesic medications. In the worst-case scenario of a 10% responder rate to IA-HA, HMW HA was no longer cost-effective in any circumstance. CONCLUSION: IA-HA, particularly HMW formulations, demonstrate cost-effectiveness when compared to conservative treatment options and LMW HA in patients with early/mid stage knee OA. The cost-effectiveness of HMW HA in patients with later stage knee OA was not as apparent, particularly because of the uncertainty in the proportion of patients with late stage OA who have a meaningful improvement after receiving IA-HA. This cost-effectiveness finding supports the use of IA-HA in patients with early and moderate knee OA, as the benefits of IA-HA are apparent within the patient population with mild to moderate knee OA. The findings of this study suggest that there is a potential cost savings benefit as a result of utilizing HMW HA in earlier stages of knee OA as opposed to later stages. FUNDING: Ferring Pharmaceuticals Inc.

Anti-Inflammatory Effects of Intra-Articular Hyaluronic Acid: A Systematic Review.

OBJECTIVE: Osteoarthritis (OA) is one of the leading causes of disability in the adult population. Common nonoperative treatment options include nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular corticosteroids, and intra-articular injections of hyaluronic acid (HA). HA is found intrinsically within the knee joint providing viscoelastic properties to the synovial fluid. HA therapy provides anti-inflammatory relief through a number of different pathways, including the suppression of pro-inflammatory cytokines and chemokines. METHODS: We conducted a systematic review to summarize the published literature on the anti-inflammatory properties of hyaluronic acid in osteoarthritis. Included articles were categorized based on the primary anti-inflammatory responses described within them, by the immediate cell surface receptor protein assessed within the article, or based on the primary theme of the article. Key findings aimed to describe the macromolecules and inflammatory-mediated responses associated with the cell transmembrane receptors. RESULTS: Forty-eight articles were included in this systematic review that focused on the general anti-inflammatory effects of HA in knee OA, mediated through receptor-binding relationships with cluster determinant 44 (CD44), toll-like receptor 2 (TLR-2) and 4 (TLR-4), intercellular adhesion molecule-1 (ICAM-1), and layilin (LAYN) cell surface receptors. Higher molecular weight HA (HMWHA) promotes anti-inflammatory responses, whereas short HA oligosaccharides produce inflammatory reactions. CONCLUSIONS: Intra-articular HA is a viable therapeutic option in treating knee OA and suppressing inflammatory responses. HMWHA is effective in suppressing the key macromolecules that elicit the inflammatory response by short HA oligosaccharides.

The Impact of Excluding Patients with End-Stage Knee Disease in Intra-Articular Hyaluronic Acid Trials: A Systematic Review and Meta-Analysis.

INTRODUCTION: The Kellgren-Lawrence (K-L) grade is the most commonly used measure of radiographic disease severity in knee osteoarthritis (OA). Studies suggest that intra-articular hyaluronic acid (IA-HA) should only be considered in cases of early stage knee OA. The purpose of this review was to determine if trials administering IA-HA in early-moderate knee OA patients demonstrated greater pain relief than studies that also included patients with end-stage disease. METHODS: We conducted a systematic search of the literature to identify randomized controlled trials (RCT) comparing IA-HA with saline injections and that diagnosed disease severity using the K-L grade criteria. The primary outcome was mean change in pain from baseline at 4-13 weeks and 22-27 weeks. Safety was evaluated on the total number of participants experiencing a treatment-related adverse event (AE). RESULTS: Twenty RCTs were included. In the early-moderate OA subgroup, the mean change in pain scores was statistically significant favoring IA-HA from baseline to 4-13 weeks [SMD = - 0.30, 95% CI - 0.44 to - 0.15, p < 0.0001] and within 22-27 weeks [SMD = - 0.27, 95% CI - 0.39 to - 0.16, p < 0.00001]. No significant differences were observed in the late OA subgroup. IA-HA was associated with a significantly greater risk of treatment-related AEs relative to saline in the late OA subgroup [RR = 1.76, 95% CI 1.16-2.67, p = 0.008]. CONCLUSION: IA-HA provides significant pain relief compared to saline for patients with early-moderate knee OA, compared to cohorts including patients with end-stage OA (KL grade 4), with no increase in the risk of treatment-related AEs, up to 6 months. Patients with end-stage disease had lower levels of pain relief and may be diluting study results if included in the treatment cohort. FUNDING: Ferring Pharmaceuticals.

A Comparison Between Rheological Properties of Intra-articular Hyaluronic Acid Preparations and Reported Human Synovial Fluid.

INTRODUCTION: This study aims to compare the properties of currently available intra-articular hyaluronate (IA-HA) products widely available in the USA to those of healthy knee synovial fluid with respect to their bulk rheological properties. We hypothesize that products would have differing rheological properties, with some more closely resembling the properties and physiological aspects of healthy joint fluid HA. METHODS: We obtained reported HA product molecular weights, as well as measurements of the presence of cross-linking, zero shear rate viscosity, shear thinning ratio, and crossover frequency for the following IA-HA products available in the USA: Euflexxa®, Orthovisc®, Supartz®, Monovisc®, Synvisc®, Synvisc-One®, Gel-One®, and Hyalgan®. RESULTS: Differences were seen between the study products across all of the investigated parameters. Hyalgan, Supartz, Orthovisc, and Euflexxa had a linear chain structure, while Synvisc, Synvisc-One, and Monovisc were cross-linked in structure. Molecular weight, shear rates, and crossover frequencies ranged widely across tested products, with values ranging from below to above those reported for healthy knee synovial fluid HA. When compared to healthy knee parameter values reported within the current literature, observed parameters for Euflexxa and Orthovisc were typically seen to be the most similar to healthy knee synovial fluid. When comparing Euflexxa and Orthovisc directly, Euflexxa was more often similar to the properties of healthy knee synovial fluid with respect to the observed parameters of molecular structure, shear rates, and crossover frequency. CONCLUSION: Available IA-HA products vary with respect to molecular weight, presence of cross-linking, shear rate dependency of viscosity, and crossover frequency. Since IA-HA treatment for osteoarthritis aims to restore synovial fluid back to original HA property characteristics, using HA supplements resembling healthy synovial fluid is a logical approach. Our findings demonstrate that Euflexxa is the most similar to healthy synovial fluid with respect to molecular structure, shear rates, and crossover frequency. FUNDING: Ferring Pharmaceuticals, Inc.

Efficacy and safety of repeated courses of hyaluronic acid injections for knee osteoarthritis: A systematic review.

INTRODUCTION: Hyaluronic acid (HA) is a commonly prescribed intra-articular (IA) therapy for knee osteoarthritis (OA). While a single series of IA-HA has been well studied, the efficacy and safety of repeated courses of IA-HA injection therapy in knee OA patients have not been evaluated as frequently. METHODS: A literature search was conducted using MEDLINE, EMBASE and PubMed databases. The primary outcome measure was knee pain reduction after each treatment course and/or last reported follow-up visit. Secondary outcomes were treatment-related adverse events (AEs) and serious adverse events (SAEs). RESULTS: A total of 17 articles (7 RCTs and 10 cohort studies) met the pre-defined inclusion criteria. Of the RCTs, six were double-blind with two trials including open label extension studies, and one was single-blind. Studies ranged from investigating a single reinjection cycle to four repeat injection cycles. Eleven studies evaluated one reinjection, five studies evaluated ≥2 repeated courses of IA-HA, and one study allowed either one or two repeated courses. All studies reported pain reduction from baseline in the IA-HA treatment group throughout the initial treatment cycle, and either sustained or further reduced pain throughout the repeated courses of treatment. The study with the longest follow-up repeated IA-HA injection every 6 months for 25 months. Pain decreased after the first course and continued to decrease until the end of the study, with an approximate 55% reduction in pain compared to baseline. Common AEs were joint swelling and arthralgia; there were no reported SAEs. All repeated courses were well tolerated, and the number of documented AEs and SAEs was similar to the primary injection regimens. CONCLUSION: Repeated courses of IA-HA injections are an effective and safe treatment for knee OA. Repeat courses were demonstrated to maintain or further improve pain reduction while introducing no increased safety risk.

Rheological Properties of Commercially Available Hyaluronic Acid Products in the United States for the Treatment of Osteoarthritis Knee Pain.

OBJECTIVE: The inconsistent results within the current literature regarding the efficacy of intra-articular-hyaluronic acid (IA-HA) for the treatment of knee osteoarthritis (OA) have been suggested to be due to intrinsic differences between individual HA products. The purpose of this investigation is to define the rheological differences between currently available HA products in the United States at the time of this study for the treatment of knee OA, which will help elaborate on the appropriateness of classifying HA products as a class opposed to as individual agents. METHODS: The rheological parameters for Euflexxa, Orthovisc, Supartz, Monovisc, Synvisc, Synvisc-One, Gel-One, and Hyalgan were obtained with a TA AR 2000 EX Rheometer with a cone-plate geometry (40-mm plate diameter and a 2° cone angle) at room temperature. RESULTS: The bulk rheological parameters of the different products suggest molecular structures traversing the range of dilute solution (Hyalgan, Supartz), semidilute solution (Euflexxa, Orthovisc), entangled solutions (Monovisc, Synvisc, Synvisc-One), and even gel-like (Gel-One) behavior. CONCLUSIONS: Due to the differences in rheological properties between IA-HA products, the universal assessment of these products as a class may not be appropriate. Instead, it may be more appropriate to assess each product individually. Future research should aim to link these differences in rheological properties to the differences in clinical efficacy seen across these IA-HA products.

The efficacy of multiple versus single hyaluronic acid injections: a systematic review and meta-analysis.

BACKGROUND: Intra-articular hyaluronic acid (IA-HA) is a common therapy used to treat knee pain and suppress knee inflammation in knee osteoarthritis (OA), typically prescribed in regimens ranging from a single injection to 5 weekly injections given once weekly. We conducted a systematic review to determine the efficacy of IA-HA, with subgroup analyses to explore the differences in knee pain and adverse events (AEs) across different dosing regimens. METHODS: We conducted a systematic search of the literature to identify studies evaluating IA-HA for the management of knee OA compared to IA-saline. Primary outcome measure was the mean knee pain score at 13 Weeks (3 months) or 26 weeks (6 months). Secondary outcome was the number of treatment-related AEs and treatment-related serious adverse events (SAEs). We evaluated differences in levels of pain and AEs/SAEs between dosing regimens compared to IA-Saline. RESULTS: Thirty articles were included. Overall, IA-HA injections were associated with less knee pain compared to IA-Saline injections for all dosing regimens. 2-4 injections of IA-HA vs. IA-Saline produced the largest effect size at both 3-months and 6-months (Standard mean difference [SMD] = -0.76; -0.98 to -0.53, 95% CI, P < 0.00001, and SMD = -0.36; -0.63 to -0.09 95% CI, P = 0.008, respectively). Additionally, single injection studies yielded a non-significant treatment effect at 3 and 6 months, while ≥5 5 injections demonstrated a significant improvement in pain only at 6 months. Five or more injections of IA-HA were associated with a higher risk of treatment-related AEs compared to IA-Saline (Risk ratio [RR] = 1.67; 1.09 to 2.56 95% CI, p = 0.02), which was a result not seen within the 1 and 2-4 injection subgroups. CONCLUSION: Overall, 2-4 and ≥5 injection regimens provided pain relief over IA-Saline, while single injection did not. Intra-articular injections of HA used in a 2-4 injection treatment regimen provided the greatest benefit when compared to IA-Saline with respect to pain improvement in patients with knee OA, and was generally deemed safe with few to no treatment-related AEs reported across studies. Future research is needed to directly compare these treatment regimens.

The Disease-Modifying Effects of Hyaluronan in the Osteoarthritic Disease State.

Hyaluronic acid (HA) has been a treatment modality for patients with knee osteoarthritis (OA) for many years now. Since HA was first introduced for the treatment of painful knee OA, much has been elucidated regarding both the etiology of this disease and the mechanisms by which HA may mitigate joint pain and tissue destruction. The objectives of this article are to (1) describe the etiology and pathophysiology of OA including both what is known about the genetics and biochemistry, (2) describe the role of HA on disease progression, (3) detail the antinociceptive and anti-inflammatory actions of HA in OA, and (4) present evidence of disease-modifying effects of HA in the preservation and restoration of the extracellular matrix. These data support that HA is not only just a simple device used for viscosupplementation but also a biologically active molecule that can affect the physiology of articular cartilage.