Novel Hyaluronan Injection Shows Superior Reduction in Osteoarthritis Knee Pain, Stiffness

Novel viscous gel-based formulation of hyaluronan more effective in reducing pain and stiffness in patients with moderate knee osteoarthritis.

In patients with moderate tibiofemoral osteoarthritis (Kellgren-Lawrence grade 2 or 3), a single intra-articular injection of Hya-Joint Plus might provide improved relief of pain and stiffness compared with a single injection of Synvisc-One, as indicated in a prospective, randomized, controlled, double-blind trial  recently published in The Journal of Bone and Joint Surgery.1 Both hyaluronan-based injections were found to be safe and effective for 6 months in patients with knee osteoarthritis. The study is reported to be the first to compare the safety and efficacy of single-injection hyaluronan preparations in a well-controlled trial ( Identifier: NCT02686047).1

“Viscosupplementation with hyaluronan is a well-established treatment option for knee osteoarthritis. The goal of viscosupplementation is to reduce pain and improve viscoelasticity of synovial fluid. Hyaluronan may provide biological actions, including anti-inflammatory, antinociceptive, and anabolic effects,” the researchers wrote. They also noted that evidence has shown hyaluronan viscosupplementation to promote endogenous hyaluronan synthesis via CD44 receptor binding.

Unlike earlier hyaluronan preparations, which require multiple injections, Hya-Joint Plus and Synvisc-One contain chemically cross-linked hyaluronan, resulting in increased viscoelasticity, and enabling administration via a single injection. The agents are synthesized using different cross-linking processes and provide distinct concentrations of hyaluronan. Hya-Joint Plus is a cross-linker of 1,4-butanediol diglycidyl ether and Synvisc-One crosslinks avian-derived hyaluronic acids with formaldehyde and divinyl sulfone. A 3-mL injection of Hya-Joint Plus delivers 60 mg of hyaluronate (2% hyaluronan, 20 mg/mL) as a viscous gel, whereas a 6-mL injection of Synvisc-One delivers 48 mg of hyaluronate (0.8% hyaluronan, 8 mg/mL).

In the study, patients were randomly assigned to receive a 3-mL intra-articular injection of Hya-Joint Plus (n = 66), or a 6-mL injection of Synvisc-One (n = 66). All patients were recruited through advertisements placed in a rehabilitation department of a university-affiliated tertiary-care medical center, and treated at the Kaohsiung Veterans General Hospital in Kaohsiung City, Taiwan. During the study, patients were not permitted to take regular analgesics, glucosamine and/or chondroitin, non-steroidal anti-inflammatory drugs, or to receive physical therapy for their knee. Acetaminophen was allowed as a rescue medication, but could not be taken in the 24-hours preceding each study visit, which occurred at 1, 3, and 6 months. Upon study completion, 121 patients were available for the intention-to-treat analysis.

The primary outcome measure was pain scores (assessed using the visual analog scale [VAS)]) changes from baseline at 6 months. Although both injections led to improvements in VAS pain scores, the improvements were more significant in patients receiving Hya-Joint Plus vs Synvisc-One: 34.2 mm, 34.6 mm, and 33.3 mm vs 19.9 mm, 22.8 mm, and 23.4 mm at 1, 3, and 6 months, respectively, with adjusted mean differences of -12.0 (P =.001), -8.5 (P =.033), and -6.6 (P =.045), respectively.  

The secondary outcome measures, including the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Lequesne index for knee osteoarthritis severity, timed up and go test (TUG), single-limb stance (SLS), use of rescue analgesics, and patient satisfaction, were comparable between injection groups. However, those receiving Hya-Joint Plus demonstrated a small but statistically significant improvement in WOMAC stiffness subscale scores at 6 months (1.7 ± 1.2 vs 2.3 ± 1.7 for Synvisc-One; P =.043).

Although TUG time did not change significantly in either group, and both showed significant improvements in SLS time, there was some indication that patients with poor physical activity might derive greater benefit from Hya-Joint Plus. “We found that patients with an initial poor performance on the TUG test (>18.8 s) could benefit more, with regard to their performance at 3 months post-injection, if they were treated with Hya-Joint Plus. Similarly, patients with an initial poor performance on the SLS test could benefit more, with regard to their performance at 1 and 3 months, if they were treated with Hya-Joint Plus,” the researchers wrote. They were unsure of the mechanism behind this finding, but suspected a volume effect of Synvisc-One might cause excessive capsular distension, affecting patients’ physical activity.

Both injections were well tolerated, as reported by patients and/or observed by treating physicians during study appointments. Most adverse effects were considered mild or moderate, lasted ≤3 days, and resolved without intervention or upon use of simple analgesics. The most severe adverse event was joint effusion, occurring in 9 patients in the Synvisc-One group and 3 in the Hya-Joint Plus group, with 2 in the Synvisc-One group requiring arthrocentesis for pain relief. No patients discontinued treatment due to an adverse event.

Summary and Clinical Applicability

The current study provides additional evidence that viscosupplementation with hyaluronan is safe and efficacious for the treatment of knee osteoarthritis, but that there are enough differences even between single-injection cross-linked hyaluronan products to warrant consideration when treating individual patients. “Additional studies to elucidate the mechanism of [the] possible superiority [of Hya-Joint Plus] are warranted. The cost-effectiveness of single-injection regimens of hyaluronan should be explored,” they concluded.     

Limitations and Disclosures

There were several study limitations:

The study was small and restricted to patients with moderate knee osteoarthritis treated at one facility, limiting generalizability.

Administering physicians could not be blinded because of differences in the products, but they were not involved in outcome assessments.

The study did not have a placebo group, and the injections had different volumes, fluid viscosity, and dosages of hyaluronan, which could have affected outcomes.

Finally, Hya-Joint Plus requires intra-articular injection, but no imaging was undertaken to confirm adequate administration.

The study was funded by SciVision Biotech, manufacturer of Hya-Joint Plus, but it was reported not to be involved in patient enrollment, data collection, data analysis, or manuscript preparation.

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  1. Sun SF, Hsu CW, Lin HS, Liou IH, Chen YH, Hung CL. Comparison of single intra-articular injection of novel hyaluronan (HYA-JOINT Plus) with Synvisc-One for knee osteoarthritis: a randomized, controlled, double-blind trial of efficacy and safety. J Bone Joint Surg Am. 2017;99(6):462-471. doi: 10.2106/JBJS.16.00469