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.

Adherence to the OARSI recommendations for designing, conducting, and reporting of clinical trials in knee osteoarthritis: a targeted literature review.

BACKGROUND: The Osteoarthritis Research Society International (OARSI) updated their guideline for clinical trials on knee osteoarthritis (KOA) in 2015, which contains recommendations for the conduct, design, and reporting of clinical trials. The purpose of this study was to assess the quality of clinical trials published between 2010 and 2020 investigating intra-articular interventions in patients with KOA using the OARSI recommendations. METHODS: A targeted literature review was conducted to identify randomized controlled trials in patients with KOA receiving intra-articular interventions, published between 2010 and 2020. Included studies were assessed using the OARSI recommendations. For a comparison between the time periods before and after the introduction of the new OARSI recommendations, the year 2016 was selected as the cut-off. RESULTS: One hundred forty-eight publications, representing 139 unique trials, were included in this review. Included studies adhered to between 9 and 24 recommendations (median: 19). The highest increase in adherence from studies published in 2016 or earlier compared to after 2016 was seen in the reporting and registration of trials and the use of structural outcome measures. Overall, adherence to the recommendations related to the collection of biochemical biomarkers and the use of structural outcome measures remained low. CONCLUSION: An improvement can be made in the conduct, design, and reporting of clinical trials for intra-articular therapies in KOA. Despite proper guidelines, quality of clinical trials varies, and the methodological deficiencies found are preventable and can be corrected. The quality of research should be considered when making treatment decisions for patients with KOA in clinical practice.

High molecular weight Intraarticular hyaluronic acid for the treatment of knee osteoarthritis: a network meta-analysis.

BACKGROUND: The 2013 American Academy of Orthopaedic Surgeons (AAOS) guidelines made strong recommendations against intraarticular hyaluronic acid (IAHA) for patients with knee osteoarthritis (OA), as evidence supporting improvements in pain did not meet the minimal clinically important improvement (MCII) threshold. However, there may be important distinctions based on IAHA molecular weight (MW). Hence our objective was to evaluate the efficacy of IAHAs in knee OA based on molecular weight. METHODS: Randomized controlled trials were searched within MEDLINE, Embase, and CENTRAL and selected based on AAOS criteria. A pain measure hierarchy and longest follow-up were used to select one effect size from each trial. Mean differences between interventions were converted to standardized mean differences (SMDs) and incorporated into a random-effects Bayesian network meta-analysis. High MW (HMW) was defined as ≥6000 kDa, and low MW (LMW) as < 750 kDa. RESULTS: HMW IAHA was associated with a statistically significant and possibly clinically significant improvement in pain (SMD - 0.57 (95% credible interval [Crl]: - 1.04, - 0.11), exceeding the - 0.50 MCII threshold. LMW IAHA had a lesser, non-significant improvement (- 0.23, 95% Crl: - 0.67, 0.20). Back-transforming SMDs to the WOMAC pain scale indicated a 14.65 (95% CI: 13.93, 15.62) point improvement over IA placebo, substantially better than the 8.3 AAOS MCII threshold. CONCLUSIONS: Unlike LMW IAHA, HMW IAHA exceeded the MCII threshold for pain relief, suggesting that improvements can be subjectively perceived by the treated patient. Amalgamation of LMW and HMW may have blurred the benefits of IAHA in the past, leading to negative recommendations. Differentiation according to MW offers refined insight for treatment with IAHA.

Intraarticular Hyaluronic Acid Preparations for Knee Osteoarthritis: Are Some Better Than Others?

OBJECTIVE: This literature review summarizes evidence on the safety and efficacy of intraarticular hyaluronic acid (IAHA) preparations approved in the United States for the treatment of osteoarthritis of the knee. DESIGN: A systematic literature search was performed in PubMed, Ovid MEDLINE, and SCOPUS databases. Only studies in which clinical outcomes of individual IAHA preparations alone could be assessed when compared to placebo, no treatment, other standard knee osteoarthritis treatments, and IAHA head-to-head studies were selected. RESULTS: One hundred nine articles meeting our inclusion criteria were identified, including 59 randomized and 50 observational studies. Hylan G-F 20 has been the most extensively studied preparation, with consistent results confirming efficacy in placebo-controlled studies. Efficacy is also consistently reported for Supartz, Monovisc, and Euflexxa, but not for Hyalgan, Orthovisc, and Durolane. In the head-to-head trials, high-molecular-weight (MW) Hylan G-F 20 was consistently superior to low MW sodium hyaluronate preparations (Hyalgan, Supartz) up to 20 weeks, whereas one study reported that Durolane was noninferior to Supartz. Head-to-head trials comparing high versus medium MW preparations all used Hylan G-F 20 as the high MW preparation. Of the IAHA preparations with strong evidence of efficacy in placebo-controlled studies, Euflexxa was found to be noninferior to Hylan G-F 20. There are no direct comparisons to Monovisc. One additional IAHA preparation (ie, Synovial), which has not been assessed in placebo-controlled studies, was also noninferior to Hylan G-F 20. CONCLUSION: IAHA efficacy varies widely across preparations. High-quality studies are required to assess and compare the safety and efficacy of IAHA preparations.

Evaluation of Hylan G-F 20 Treatment with Opioid Prescriptions and Intraarticular Corticosteroid Injections in Patients with Osteoarthritis of the Knee Using a Claims Database.

OBJECTIVE: Assess how treatment with the viscosupplement hylan G-F 20 relates to opioid prescriptions and intraarticular corticosteroid injections (IACS) in patients with osteoarthritis of the knee (OAK). DESIGN: Case-crossover; adult patients with OAK identified in a claims database were treated with hylan G-F 20 from July 1, 2007, to June 29, 2017. Opioid or IACS prescriptions in the 6 months before treatment were compared to the 6 months after. Patients with comorbid conditions requiring pain medications were excluded, resulting in a 29,395-patient cohort. Four subgroups were investigated: patients with (1) opioids before hylan G-F 20 (OB; n = 6,609); (2) opioids before and after hylan G-F 20 (OBF; n = 3,320); (3) IACS before hylan G-F 20 (CB; n = 11,162); and (4) IACS before and after hylan G-F 20 (CBF; n = 2,810). All opioids were converted to morphine milligram equivalents (MME). RESULTS: OB subgroup patients had a significant decrease (P < 0.01) in total MME (-14.0%), MME per day (-14.2%) and opioid prescription days (-12.6%) after treatment versus before. Only 50.2% of patients prescribed opioids before hylan G-F 20 were prescribed an opioid after treatment. OBF subgroup patients had a significant increase (P < 0.01) in opioid prescription days (7.8%) before versus after treatment. There was a significant decrease (P < 0.01) in the number of IACS after versus before treatment for the Total Cohort (-56.1%), and subgroups CB (-72.6%) and CBF (-4.1%). A total of 74.8% of patients receiving an IACS before treatment did not receive an IACS after treatment. CONCLUSIONS: Hylan G-F 20 is associated with a reduction in opioid prescriptions and IACS in OAK patients.

Risk of Severe Acute Localized Reactions for Different Intraarticular Hyaluronic Acid Knee Injections in a Real-World Setting.

OBJECTIVE: Case reports of severe acute localized reactions (SALR) following intraarticular (IA) hyaluronic acid (HA) injections for knee osteoarthritis (OA) have been described. We compared surrogate SALR measures between patients using hylan G-F 20 and specific non-hylan G-F 20 HA products. DESIGN: Knee OA patients were identified from the Optum Clinformatics dataset (January 2006 to June 2016), stratified into hylan G-F 20 and non-hylan G-F 20 HA users, matched by single or multiple injection products. Occurrences of surrogate SALR measures including inflammation/infection, intraarticular corticosteroid (CS) injections, arthrocentesis/aspiration, arthrotomy/incision and drainage, and arthroscopy were evaluated within 3 days post-HA. RESULTS: Based on 694,404 HA injections, inflammation/infection rate was rare within 3 days of HA (up to 0.03%), with no statistical differences between hylan G-F 20 and non-hylan G-F 20 groups (matched by single or multiple injection products). The risk of knee arthrotomy/incision and drainage, arthroscopy, or arthrocentesis for hylan G-F 20 (2 mL) 3 weekly injection patients was lower than Hyalgan/Supartz and Orthovisc patients, but greater than Euflexxa patients. Overall, we found that Hylan G-F 20 (2 mL) 3 weekly injection had lower SALR rates compared to Hyalgan/Supartz and Orthovisc. However, Hylan G-F 20 (2 mL) 3 weekly injection had slightly higher rates of SALR when compared to Euflexxa. Among the single injection products, Hylan G-F 20 (6 mL) single injection had lower rates of SALR than Monovisc and Gel-One. CONCLUSIONS: This study shows no clear correlation between avian-derived or cross-linked products and SALR and provides evidence against avian-derived products or crosslinking as a source for these reactions.

Effects of iontophoretic versus injection administration of dexamethasone.

PURPOSE: Sixty-eight skeletally mature New Zealand white rabbits were used to study the effects of iontophoresis- and injection-delivered sodium phosphate dexamethasone (DX) on the morphologic, histologic, microscopic, and biomechanical properties of uninjured rabbit patellar tendons over an initial 14-d period. METHODS: Three control (untreated, placebo iontophoresis, and placebo injection) groups and two treatment (iontophoresis and injection) groups underwent serum, ELISA tendon, histology, electron microscopy, and biomechanical analysis. RESULTS: Serum DX levels were detectable and quantifiable in both treatment groups at 1 h but were significantly greater (P < 0.05) in the injected group (11.29 ng.mL-1) compared with the iontophoresis group (6.34 ng.mL-1). The most significant histologic finding was a lack of a cellular inflammatory response in the DX-treated groups at 24 h. Ultrastructural analysis produced no significant differences between size or size ratio of collagen fibrils among any groups. Morphologic examination revealed only injection puncture marks seen in appropriate tendons. Biomechanical testing produced disruption at the patellar insertion in 81% of the specimens. No injected tendon failed at the injection site. Normalized biomechanical properties included: 1) Stiffness increased in control and iontophoresis groups from 1 to 24 h, then gradually declined; the DX-injected specimens showed a similar but delayed effect. 2) Peak load at failure for iontophoresis and control groups was greatest at 24 h. The DX-injected group again showed a delayed response. 3) In general, total energy to failure revealed no significant differences between groups at any time period. CONCLUSION: It appears that iontophoresis or injection-delivered DX may produce anti-inflammatory effects without significantly altering ultrastructural or biomechanical characteristics of the rabbit patellar tendon within an initial 14-d period.