|Year : 2017 | Volume
| Issue : 1 | Page : 24-27
Efficacy and safety of viscosupplementation in symptomatic knee osteoarthritis: An experience from a Tertiary Care Center in Mumbai
Anuj Singhal1, Vishal Marwaha2, Vivek Hande VSM 3, Ajay Deep Sud4
1 Associate Professor, Department of Medicine, Pune, India
2 Professor (Medicine), Amrita Institute of Medicine at Kochi, Kerala, India
3 Head of Department (Medicine), INHS Asvini, Mumbai, Maharashtra, India
4 Surg and Orthopedics, Command Hospital, Chandimandir, Haryana, India
|Date of Web Publication||17-Aug-2017|
Surg Cdr Anuj Singhal
Department of Medicine, AFMC, Pune - 411 040, Maharashtra
Source of Support: None, Conflict of Interest: None
Objective: To report on our clinical experience (safety and efficacy) of intraarticular injection of high molecular weight hyaluronic acid in symptomatic knee osteoarthritis. Methods: In this prospective, experimental pre post efficacy, non-comparative study, 39 patients with symptomatic knee osteoarthritis (OA) were treated with single intra-articular injection of high molecular weight (HMW) hyaluronic acid (Hylan G-F20). Pain visual analogue scale (VAS) and WOMAC scores were evaluated at baseline, after three and six months. The study as completed over one year. The change in VAS and WOMAC score from baseline was calculated for patients who completed all three visits. Results: The mean age of participants was 55.5 (+10.9) years; mean duration of OA was 4.8 (+3.1) years. Of the 39 patients, 12 patientshad grade 2 OA, 26 patients had grade 3 OA and one patient had grade 4 OA. Thirteen patients completed all three visits, and seven patients completed baseline and three month evaluation. The median VAS score reduced from 6.5 (+2.1) at baseline to 3.5 (+2.1) at 3 months and 4.5 (+2.2) at 6 months, P = 0.01 (vs Baseline). The median WOMAC score reduced from 52.5 (+18.5) baseline to 23 (+13.5) at 3 months and 33 (+17.5) at 6 months, P = 0.0004 (vs baseline). Study medication was well tolerated. None of the patients reported any adverse event. Conclusion: In our experience intra-articular HMW hyaluronic acid (Hylan G-F20) is a good and safe therapeutic option for patients with mild to moderate knee OA to reduce pain.
Keywords: Hyaluronic acid, osteoarthritis, quality of life, viscosupplementation, visual analog scale, Western Ontario and McMaster Universities Osteoarthritis Index score
|How to cite this article:|
Singhal A, Marwaha V, Hande V, Sud AD. Efficacy and safety of viscosupplementation in symptomatic knee osteoarthritis: An experience from a Tertiary Care Center in Mumbai. J Mar Med Soc 2017;19:24-7
|How to cite this URL:|
Singhal A, Marwaha V, Hande V, Sud AD. Efficacy and safety of viscosupplementation in symptomatic knee osteoarthritis: An experience from a Tertiary Care Center in Mumbai. J Mar Med Soc [serial online] 2017 [cited 2019 Jan 17];19:24-7. Available from: http://www.marinemedicalsociety.in/text.asp?2017/19/1/24/213108
| Introduction|| |
Osteoarthritis (OA) is a degenerative joint disease and the most common form of arthritis worldwide., The knee is the most common joint to be involved in OA, causes significant disability and impairs the patients' quality of life (QOL).,,
Hyaluronan or hyaluronic acid (HA), a nonsulfated glycosaminoglycan, is a critical component of normal synovial fluid and an important contributor to joint homeostasis. In OA, both the concentration and molecular weight of endogenous intra-articular hyaluronans are decreased. Viscosupplementation with high molecular weight (HMW) HA is an attempt to replace diseased synovial fluid and restore rheotoric properties of the joint. Viscosupplementation is an approved therapeutic option for OA and may be offered when pain relief is inadequate with nonsteroidal anti-inflammatory drugs (NSAIDs) or the patient cannot tolerate NSAIDs. In this setting, intra-articular HMW-hyaluronan provides additional advantage by decreasing the dosage frequency of NSAIDs. They also help in downregulating genes expressing cytokines and enzymes in fibroblast-like synoviocytes of early osteoarthritic patients which may explain their therapeutic efficacy.
Hylans are derivatives of HA; they are cross-linked hyaluronan which have higher elastoviscosity than purified hyaluronan. Two to four hyaluronan molecules are covalently coupled together to produce Hylan A, which is completely water soluble.,,, More extensive, continuous cross-linking of the hyaluronan molecules produces a polymer gel known as Hylan B. Combination of Hylan A and Hylan B in an 80:20 volume ratio results in a product known as Hylan G-F 20.,, Herein, we report our clinical experience on the effectiveness and safety of intra-articular HMW-HA (Hylan G-F20) among patients with symptomatic knee OA.
| Methods|| |
This was a prospective, nonrandomized, experimental pre-post efficacy study conducted in a tertiary care naval hospital located in South Mumbai. The hospital caters to service personnel, ex-service men, and their families. All investigations and treatment are offered free of cost. The inclusion criteria were patients with OA of the knee who had persistent knee pain despite paracetamol (maximum 4 g/day) and ibuprofen 400 mg thrice daily or etoricoxib 90 mg twice daily or diclofenac 50 mg thrice daily and whose pain on 100 mm visual analog scale (VAS) scale of 60 or more. Informed consent was obtained from all patients enrolled in the study explaining them the purpose of the study.
The exclusion criteria were patients with grade IV changes on radiography, functional impairment of the knee, associated OA of other joint that might affect assessment of the knee, psoriasis, OA secondary to rheumatoid arthritis or other joint diseases, joint infection, serious medical illness, skin infections overlying the joint, or intra-articular use of steroids or radiocolloids in the previous 3 months, and if patient has a history of egg allergy.
Over a period of 1 year, 39 patients fulfilled the inclusion criteria and received a single intra-articular injection of HMW-HA (Hylan G-F 20, Synvisc-One) on to the affected knee.
The intra-articular injection was done as an outpatient procedure in a dedicated joint injection room. In brief, the affected knee was prepared with 100% alcohol rub; Hylan G-F 20 contained in a sterile prefilled syringe was injected in to the affected knee by the lateral approach. Local anesthesia was not required (except for the anxious and apprehensive patients). Postinjection, the patient was observed for 30 min and discharged on the same day.
Baseline pain score on a 100 mm VAS and baseline Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was recorded before the joint injection was given. Follow-up was done at 3 months and at 6 months to assess for pain relief on a 100 mm VAS for pain and WOMAC score.
With alpha error of 5% and power of 90% to detect a difference in VAS score postintervention of 4 (7) and WOMAC score of 30 (7), a minimum of 5 patients are required.
Data were analyzed using SPSS software version 19 hylan 20 G by Sanofi. Both descriptive and inferential statistics were used. Paired t-test was carried out to compare the mean difference in VAS and WOMAC score at baseline and at 6 months. P <0.05 was considered statistically significant.
| Results|| |
Over a period of 2 years, a total of 350 patients with knee OA were seen in medicine outpatient, rheumatology clinic, and orthopedic outpatient departments. Out of these 350 patients, 39 patients satisfied the inclusion criteria and received a single intra-articular injection of Hylan G-F 20. There were 10 men (25.64%) and 19 (74.36%) women [Flow Chart 1]. The baseline characteristics of the patients who received intra-articular injection are given in [Table 1]. Of the 39 patients, 13 patients completed all three visits, 7 patients completed baseline and 3-month evaluation, while the remaining 19 had only a baseline evaluation and were lost to follow-up.
|Table 1: Baseline characteristics of the knee osteoarthritis study patients|
Click here to view
Follow-up pain as assessed by VAS scale reduced from 6.9 ± 2.2 at baseline to 3.4 ± 2.1 (at 3 months) and 4.7 ± 2.5 at 6 months, P = 0.01 [Figure 1]. The reduction in VAS at 6 months was 44.7%. Similarly, the WOMAC score reduced from a baseline of 51.8 ± 19.5 to 22.3 ± 12.5 at 3 months and 32.1 ± 17.3 at 6 months (P = 0.0004). The reduction in WOMAC from baseline to 6 months was 38.2% [Figure 2].
|Figure 1: Pain visual analog scale of 13 patients at baseline, at 3 months, and at 6 months after intra-articular injection of high molecular weight hyaluronic acid. Note that there is greater reduction in pain visual analog scale at 3 months compared to at 6 months.|
Click here to view
|Figure 2: Western Ontario and McMaster Universities Osteoarthritis Index scores of 13 patients at baseline, at 3 months, and at 6 months after intra-articular injection of high molecular weight hyaluronic acid. Note that the decrease in Western Ontario and McMaster Universities Osteoarthritis Index scores is maximum at 3 months.|
Click here to view
None of the patients had any adverse event.
| Discussion|| |
The viscosupplementation is a proven therapy in animals to treat joint inflammation in many animal trials and subsequently tried in phase I and phase II trials.,,,, This molecule possibly acts by inducing native biosynthesis of HA and other extracellular matrix components in intracellular space and thereby suppresses the inflammatory response.,, The advantage of using this molecule as local therapy is beneficial in avoiding many systemic side effects such as NSAIDs-induced upper gastro-intestinal bleeding and thereby promises to be a better choice in the management of such chronic diseases.
The present study showed that patients with knee OA have significant improvement in pain (VAS) and WOMAC score at 3 months and 6 months. About 67% (18% at 3 months, 49% at baseline) of the patients were lost to follow-up. The primary reasons were good response, patients joining back their service, and patients going back to their hometown. There are no issues of safety which are noted in these patients. The patients who were studied till the end of the study reported a significant improvement in pain and functionality as evaluated by VAS and WOMAC scores. The intervention was also well tolerated. These results are in line with the previous studies on HMW hyaluronan for knee OA. The Cochrane review on viscosupplementation for the treatment of OA of knee which was published in 2005 has reinforced the efficacy of HA in treating OA of knee. In the review, Hylan G-F 20 was significantly better than placebo for pain on weightbearing, pain at night, functionality, and patient global assessment. It was also significantly better than intra-articular steroids and comparable to continuous NSAID treatment at 5–13 and 14–26 weeks after treatment for improving pain and function of knee OA. The review confirmed the overall safety of HA as a class and found that safety favored Hylan G-F 20 compared with NSAIDs because of higher systemic, NSAID-related adverse events. The observations similar to this conducted study were observed with the use of Durolane in fifty patients with gonarthrosis stages I–III (Kellgren score) benefited on the outcomes of knee function, pain intensity, and QOL at the end of 6 months. Apart from the effect on the pain and functionality, the intra-articular Hylan injections also lead to an increase in the HA concentration and complex shear modulus at 3 months. This was seen following a single intra-articular injection of Hylan G-F 20 in a study done by Bagga et al. In the meta-analysis done by Wang and He, the use of intra-articular HA was found to be better than intra-articular corticosteroids over long term (6 months and after). However, there was no statistically significant difference in safety between the two interventions.
The main limitation of this study is the small sample size. More than 50% of patients could not come for repeat assessments at 3 and 6 months. The main reasons for patients losing out to follow-up were (a) good response, (b) patients transferring back to their hometown, (c) transfer of patients on permanent duty. Another limitation is lack of control group, so it is unclear how much of the documented efficacy can be attributed to a placebo response. Placebo arms have been recommended even in surgical randomized controlled trials, and improvement in the placebo arm was documented in surgical procedures.
In our experience, intra-articular HMW-HA is a safe and effective therapeutic option for knee OA to reduce pain, decreases the use of NSAIDs, and consequently may also postpone the need for knee replacement.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Lützner J, Kasten P, Günther KP, Kirschner S. Surgical options for patients with osteoarthritis of the knee. Nat Rev Rheumatol 2009;5:309-16.
Chopra A, Patil J, Billempelly V, Relwani J, Tandle HS; WHO-ILAR COPCORD Study. WHO International League of Associations from Rheumatology Community Oriented Program from Control of Rheumatic Diseases. Prevalence of rheumatic diseases in a Rural population in Western India: A WHO-ILAR COPCORD Study. J Assoc Physicians India 2001;49:240-6.
Registrar General and Census Commissioner of India, Census of India; 2001. Available from: http://www.censusindia.gov.in/
. [Last accessed on 2013 Aug 31].
Felson DT, Zhang Y, Hannan MT, Naimark A, Weissman B, Aliabadi P, et al.
Risk factors for incident radiographic knee osteoarthritis in the elderly: The Framingham Study. Arthritis Rheum 1997;40:728-33.
Jakobsson U, Hallberg IR. Quality of life among older adults with osteoarthritis: An explorative study. J Gerontol Nurs 2006;32:51-60.
Laurent TC, Fraser JR. Hyaluronan. FASEB J 1992;6:2397-404.
Wang CT, Lin J, Chang CJ, Lin YT, Hou SM. Therapeutic effects of hyaluronic acid on osteoarthritis of the knee. A meta-analysis of randomized controlled trials. J Bone Joint Surg Am 2004;86-A: 538-45.
Wang CT, Lin YT, Chiang BL, Lin YH, Hou SM. High molecular weight hyaluronic acid down-regulates the gene expression of osteoarthritis-associated cytokines and enzymes in fibroblast-like synoviocytes from patients with early osteoarthritis. Osteoarthritis Cartilage 2006;14:1237-47.
Maharjan AS, Pilling D, Gomer RH. High and low molecular weight hyaluronic acid differentially regulate human fibrocyte differentiation. PLoS One 2011;6:e26078.
Lajeunesse D, Delalandre A, Martel-Pelletier J, Pelletier JP. Hyaluronic acid reverses the abnormal synthetic activity of human osteoarthritic subchondral bone osteoblasts. Bone 2003;33:703-10.
Goldberg VM, Coutts RD. Pseudoseptic reactions to hylan viscosupplementation: Diagnosis and treatment. Clin Orthop Relat Res 2004;429:130-7.
Aihara S, Murakami N, Ishii R, Kariya K, Azuma Y, Hamada K, et al.
Effects of sodium hyaluronate on the nociceptive response of rats with experimentally induced arthritis. Nihon Yakurigaku Zasshi 1992;100:359-65.
Gotoh S, Onaya J, Abe M, Miyazaki K, Hamai A, Horie K, et al.
Effects of the molecular weight of hyaluronic acid and its action mechanisms on experimental joint pain in rats. Ann Rheum Dis 1993;52:817-22.
Moore AR, Willoughby DA. Hyaluronan as a drug delivery system for diclofenac: A hypothesis for mode of action. Int J Tissue React 1995;17:153-6.
Peyron JG. A new approach to the treatment of osteoarthritis: Viscosupplementation. Osteoarthritis Cartilage 1993;1:85-7.
Raman R, Dutta A, Day N, Sharma HK, Shaw CJ, Johnson GV. Efficacy of hylan G-F 20 and sodium hyaluronate in the treatment of osteoarthritis of the knee - A prospective randomized clinical trial. Knee 2008;15:318-24.
Wobig M, Dickhut A, Maier R, Vetter G. Viscosupplementation with hylan G-F 20: A 26-week controlled trial of efficacy and safety in the osteoarthritic knee. Clin Ther 1998;20:410-23.
Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev 2006;2:CD005321.
Iannitti T, Elhensheri M, Bingöl AO, Palmieri B. Preliminary histopathological study of intra-articular injection of a novel highly cross-linked hyaluronic acid in a rabbit model of knee osteoarthritis. J Mol Histol 2013;44:191-201.
Iannitti T, Rottigni V, Palmieri B. A pilot study to compare two different hyaluronic acid compounds for treatment of knee osteoarthritis. Int J Immunopathol Pharmacol 2012;25:1093-8.
Strand V, Baraf HS, Lavin PT, Lim S, Hosokawa H. A multicenter, randomized controlled trial comparing a single intra-articular injection of Gel-200, a new cross-linked formulation of hyaluronic acid, to phosphate buffered saline for treatment of osteoarthritis of the knee. Osteoarthritis Cartilage 2012;20:350-6.
Altman RD, Akermark C, Beaulieu AD, Schnitzer T. Durolane International Study Group. Efficacy and safety of a single intra-articular injection of non-animal stabilized hyaluronic acid (NASHA) in patients with osteoarthritis of the knee. Osteoarthritis Cartilage 2004;12:642-9.
Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev 2005;2:CD005321.
Krocker D, Matziolis G, Tuischer J, Funk J, Tohtz S, Buttgereit F, et al
. Reduction of arthrosis associated knee pain through a single intra-articular injection of synthetic hyaluronic acid. Z Rheumatol 2006;65:327-31.
Bagga H, Burkhardt D, Sambrook P, March L. Longterm effects of intraarticular hyaluronan on synovial fluid in osteoarthritis of the knee. J Rheumatol 2006;33:946-50.
Wang F, He X. Intra-articular hyaluronic acid and corticosteroids in the treatment of knee osteoarthritis: A meta-analysis. Exp Ther Med 2015;9:493-500.
Wartolowska K, Judge A, Hopewell S, Collins GS, Dean BJ, Rombach I, et al
. Use of placebo controls in the evaluation of surgery: Systematic review. BMJ 2014;348:g3253.
[Figure 1], [Figure 2]