Hyaluronic acid injections & arthritis

Osteoarthritis

Click here for a HA knee injection leaflet as a downloadable file. [pdf opens in a new window]


Osteoarthritis (OA) is a major cause of disability. Patients with OA have pain that typically worsens with weight-bearing and activity and improves with rest. Unlike the rheumatoid arthritis (RA) inflammation is usually mild and localised in the affected joint. Although the cause of OA remains unknown, biomechanical stresses and biochemical changes in the articular cartilage, sub-chondral bone and synovial membrane, and genetic factors, are all important in its pathogenesis.

In joints affected by OA, the synovial fluid's capacity to lubricate and to absorb impact are typically reduced. These changes are partly due to a reduction in the size and concentration of hyaluronic acid (hyaluronan) molecules naturally present in synovial fluid.

Medical management of OA of the knee is effective for many patients, but significant morbidity is common for those using non-steroidal anti-inflammatory medication (NSAIDs). Gastrointestinal toxicity has been a major problem for many patients on NSAIDs, especially for geriatric patients who need to take them for extended periods to treat chronic conditions. Although only a minority of patients using NSAIDs appear to develop serious GI problems, because of widespread usage it is estimated that there are at least 16,500 NSAID-related deaths each year in the United States among patients with osteo- and rheumatoid arthritis (1, 2). Another 76,000 end up in the hospital. The economic burden of NSAID-associated gastrointestinal disorders is enormous, with an estimated cost of $500 million.

Surgical treatment of the knee OA is effective but it is not appropriate for all stages of the disease or for all patients. It is also costly and not without risks.

With increased understanding of the pathogenesis of OA, new therapies are being developed, one of which is viscosupplementation with hyaluronic acid. A new approach in the management of OA of the knee is to inject hyaluronan or derivatives of this molecule (hylans) into the joint. In recent years, the concept of viscosupplementation has gained widespread acceptance as a new treatment for the management of OA of the knee. The safety of this treatment has been well documented in numerous clinical trials, but controversy persists regarding efficacy and cost-benefit concerns (3).

Viscosupplementation
The use of viscosupplementation is based on observation that there is a decrease in viscosity and elasticity of the synovial fluid in osteoarthritis and that the native hyaluronic acid in osteoarthritic knees has a lower molecular weight than that found in normal healthy knees.  Replenishing the hyaluronic acid component of normal synovial fluid may play a role in supplementing the elastic and viscous properties of synovial fluid, which may help relieve the signs and symptoms related to osteoarthritis and improve function. Studies of human synoviocytes from osteoarthritic joints have revealed that exogenous hyaluronic acid stimulates de novo synthesis of hyaluronic acid, inhibits release of arachidonic acid, and inhibits interleukin-1α induced prostaglandin E2 synthesis by human synoviocytes. (4).

Hyaluronic acid (HA) is a glycosaminoglycan that is composed of glucuronic acid and N-acetylglucosamine. It differs from other glycosaminoglycans in that it is unsulfated; also, it does not bind covalently with proteins to form proteoglycan monomers, serving instead as the backbone of proteoglycan aggregates. It is the only glycosaminoglycan that is not limited to animal tissues, being found also in bacteria. It serves as a lubricant and shock absorber in the synovial fluid, and is found in the vitreous humor of the eye. HA is not well absorbed orally, but has been widely used intraarticularly in the treatment of OA in animals and, more recently, in humans. HA is well tolerated with no demonstrable toxicity and few side effects. Because it is injected directly into the joint, its onset of action is rapid. Conversely, its route of administration does limit its therapeutic applications to some degree, and high cost is also a factor (5).

Biochemistry
Glycosaminoglycans (GAGs) are carbohydrate polymers that are among the most abundant components of the ground substance of connective tissue throughout the body. GAG molecules are long, homogeneous, unbranched polysaccharide chains that are formed by repeating disaccharide subunits. Hyaluronate is the most abundant GAG in synovial fluid. It is produced and secreted by synoviocytes. Hyaluronate is also prevalent in the extracellular matrix of articular cartilage, where it is produced by chondrocytes and where it forms the foundation for proteoglycan aggregates. The recurring disaccharide subunit of hyaluronate consists of N-acetylglucosamine and glucuronate. These sugar subunits are joined by glycosidic bonds. These bonds are extremely flexible in solution; therefore, hyaluronate has no defined tertiary structure. The carboxylate group on the glucuronate sugar is negatively charged. Thus, hyaluronate is a polyanion chain. The recurring electronegative charges along the chain repel one another and attract water molecules. Hence, hyaluronate has been likened to a "molecular sponge." These properties account for the viscosity and elasticity of the hyaluronate macromolecule.

Pharmacology of Viscosupplementation
The notion of supplementing osteoarthritic synovial fluid with exogenous hyaluronate stems from the fact that the molecular weight and concentration of hyaluronate in osteoarthritic synovial fluid are reduced. This phenomenon diminishes the viscosity of osteoarthritic synovial fluid. Appropriate synovial fluid viscosity is believed to be critical for maintaining normal joint lubrication and is also believed to have chondroprotective effects. It is hypothesized that the reduced concentration and decreased molecular weight of hyaluronate in osteoarthritic synovial fluid renders articular cartilage more vulnerable to mechanical and enzymatic injury.

The goal of viscosupplementation
To increase the molecular weight and concentration of hyaluronate in arthritic joints so that the intra-articular environment more closely resembles that of healthy synovial fluid.

The mechanism of action
The way viscosupplementation alleviates arthritic knee pain is a subject of debate. It has been proposed that exogenous viscoelastic substances act biomechanically by providing a "cushioning" or layer effect. It forms a viscous coating over the synovial and cartilage linings, acting as a mechanical barrier over pain receptors and inflammatory cells.

However, some authors have suggested that viscosupplements are eliminated from the knee too rapidly to exert a significant and lasting biomechanical effect. Indeed, the half-life of hyaluronate in sheep is less than 24 hours. In vitro research suggests that exogenous hyaluronate may stimulate endogenous production of additional hyaluronate by human synoviocytes. This could lead to more durable biomechanical consequences. Other studies suggest that hyaluronate supplementation has a direct anti-inflammatory effect on synoviocytes by inhibiting arachidonic acid release or by blocking prostaglandin-E2 production. It has also been suggested that exogenous hyaluronate inhibits damage mediated by oxygen free radicals and phagocytosis. Research has also found that hyaluronate may exert a direct analgesic effect on articular nociceptors. Possible mechanisms by which HA may act therapeutically include: providing additional lubrication of the synovial membrane, and controlling permeability of the synovial membrane, thereby controlling effusions. Other possible, though less certain, mechanisms include: promotion of cartilage matrix synthesis and reaggregation of preoteoglycans. Several studies have suggested that viscosupplements with higher molecular weights have greater therapeutic efficacy (6, 7).

Anti-inflammatory Effect
Hyaluronic acid has both in vivo and in vitro effects on leukocyte function. These include inhibition of phagocytosis, adherence and mitogen-induced stimulation. These properties are dependant on the molecular size of hyaluronic acid. Intra-articular administration of hyaluronic acid reduces levels of inflammatory mediators, including prostaglandin and cyclic adenosine monophosphate, in the synovial fluid of patients with arthritis (3).

Analgesic Activity
It seems that intra-articular hyaluronic acid modulates pain perception directly through inhibition of nociceptors or indirectly through binding of substance P - a small peptide involved in the transmission of pain signals (3).

Chondroprotective Potential
There is some data from human and animal studies to suggest that viscosupplementation could have a chondroprotective effect. Listrat et al. suggest that repeated intra-articular injections of hyaluronan might delay the structural progression of osteoarthritis. (7). However, the chondroprotective effect of hyaluronic acid remains unproved.

Clinical Effectiveness
Viscosupplementation is a proven adjunct to the treatment armamentarium of general practitioners and surgeons. A number of recent clinical  trials  have evaluated the efficacy and safety of intra-articular hyaluronic acid injections (8, 9, 10, 11, 12, 13, 14, 15). The reports of these studies were among those presented to the Food and Drug Administration (FDA) in the course of the process that resulted in the release of this treatment modality. The American College of Rheumatology has included viscosupplementation in the treatment algorithm for osteoarthritis of the knee (4, 16, 17).

Cost-effectiveness
In clinical trials of intraarticular hyaluronan preparations, pain relief among those who completed the study was significantly greater than that seen after intraarticular injection of placebo, and comparable with that seen with oral NSAIDs. In addition, pain relief among those who completed the study was comparable with greater than that with intraarticular glucocorticoids. Although pain relief is achieved more slowly with hyaluronan injections than with intraarticular glucocorticoid injections, the effect may last considerably longer with hyaluronan injections (17).

Safety
The risk of introducing infection into an OA joint is extremely low if standard aseptic technique is used. The lack of systemic side effects make the use of viscosupplementation an appealing option for the management of the knee OA. Extensive safety and toxicity tests were performed on Ostenil™ before the first clinical trials. Preclinical studies showed that Ostenil™ is nonantigenic, nontoxic, noninflammatory, and does not elicit foreign body reactions. Hyaluronan, from which hylan is derived, has been safely used in ophthalmic and orthopedic applications in millions of patients. There have been no systemic side effects attributed to Ostenil. No cases of anaphylaxis or anaphylactoid reactions have been reported in connection with Ostenil™ treatment. However, anaphylactic-like reactions have been reported following intra-articular Hyalgan™ injections (18).

Unwanted Effects
In clinical trials, transient redness, local pain, warmth, and effusion, usually lasting up to three to four days, may occur. Occasionally, severe synovitis may occur requiring treatment with intra-articular corticosteroids.

Precautions
Patients should consult their doctor or surgeon if they have a history of hypersensitivities to hyaluronan preparations or are allergic to avian proteins, feathers and egg products. Intra-articular viscosupplements should not be given to patients with an infection or skin disease around the injection site, and should not be used if venous or lymphatic stasis is present in the leg, or if the joint is severely inflamed (18).

Click here for a HA knee injection leaflet as a downloadable file. [pdf opens in a new window]

References

1. Singh G, Triadafilopoulos G (1999), Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol 26(suppl 56):18-24.

2. Wolfe MM, Lichtenstein DR, Singh G (1999), Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. N Engl J Med 340(24):1888-1899.

3. Watterson JR, Esdaile JM. Viscosupplementation: Therapeutic Mechanisms and Clinical Potential in Osteoarthritis of the Knee. J Am Acad Orthop Surg 2000;8:277-284.

4. Jackson DW, Sheer MJ, Simon TM: Cartilage Substitutes: Overview of Basic Science and Treatment Options. J Am Acad Orthop Surg 2001;9:37-52.

5. Hungerford DS: Treating Osteoarthritis with Chondroprotective Agents. Orthopaedic Special Edition 1998, January-April.

6. Wright JM, Crockett HC, Dowd M: The Role of Viscosupplementation for the Osteoarthritis of the Knee. Orthopaedic Special Edition 2001;7:15-18.

7. Listrat V, Ayral X, Patarnello F, Bonvarlet JP, Simonnet J, Amor B, Dougados M. Arthroscopic evaluation of potential structure modifying activity of hyaluronan (Hyalgan) in osteoarthritis of the knee. Osteoarthritis Cart 1997;5:153-160.

8. Wöbig M, Bach G, Beks P, Dickhut A, Runzheimer J, Schwieger G, et al. The role of elastoviscosity in the efficacy of viscosupplementation for osteoarthritis of the knee: a comparison of hylan G-F 20 and a lower-molecular-weight hyaluronan. Clint her 1999;21(9):1549-62.

9. Adams ME, Atkinson MH, Lussier AJ, et  al: The  role  of viscosupplementation with hylan G-F 20 (Synvisc) in the treatment of osteoarthritis of the knee: A Canadian  multicenter  trial  comparing  hylan  G-F  20  alone,  hylan  G-F  20 with  non-steroidal  anti-inflammatory drugs (NSAIDs) and NSAIDs alone. Osteoarthritis Cartilage1995;3:213-225.

10. Lussier A, Cividino AA, McFarlane CA, Olszynski WP, Potashner WJ, De Medicis R:  Viscosupplementation with hylan for the treatment of osteo- arthritis: Findings  from  clinical  practice  in  Canada. J  Rheumatol1996:23: 1579-1585.

11. Bellamy N, Torrance GW, Raynauld JP, Goldsmith CH, Tugwell P, Walker V, et al. A randomized controlled trial evaluating effectiveness and cost-effectiveness of Hylan G-F 20 in patients with knee osteoarthritis. Proceedings of the AAOS, 2001.

12. Altman RD, Moskowitz R:  Intraarticular  sodium  hyaluronate  (Hyalgan)  in the  treatment  of  patients  with  osteoarthritis  of  the  knee:  A  randomized clinical trial. Hyalgan Study Group.  J Rheumatol 1998;25:2203-2212.

13. Huskisson EC, Donnelly S:  Hyaluronic acid  in  the  treatment  of  osteoarthritis of  the  knee. Rheumatology (Oxford) 1999;38:602-607.

14. Lohmander LS, Dalen N, Englund G, et al:  Intra-articular hyaluronan injections in the treatment of osteoarthritis of the knee: A randomised, double-blind,  placebo-controlled  multicentre trial. Hyaluronan Multicentre Trial Group. Ann Rheum Dis1996;55:424-431.

15. Petrella RJ, DiSilvestro MD, Hildebrand C.: Effects of hyaluronate sodium on pain and physical functioning in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled clinical trial. Arch Intern Med 2002 Feb 11;162(3):292-8.

16. Miller E H, Correspondence - Viscosupplementation: Therapeutic Mechanisms and Clinical Potential in Osteoarthritis of the Knee, J Am Acad Orthop Surg 2001;9:?.

17. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines: Recommendations for the Medical Management of Osteoarthritis of the Hip and Knee. Arthritis and Rheum, 2000;43:1905-1915. www.rheumatology.org.

18. Hyaluronan or Hylans for Knee Osteoarthritis. DTB, Vol 37, No 9, September 1999, 71-72. BNF 10.1

19. Datamonitor Market Dynamics - Hyaluronic Acid Viscosupplementation, Reference code DMHC1776, Publication date: June 2002. www.datamonitor.com.

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