Hyalgan

Rheumatologists and orthopaedists have used the intra-articular administration of hyaluronate for several years in the non-operative management of patients with degenerative joint diseases1,2. Because synovial fluid naturally contains hyaluronate at a concentration of 3 mg/ml3 and viscosity is broken down in arthropathies, the notion of restoring synovial fluid with full length2 and cross-linked hyaluronate polymers4,5 seems plausible. Prior to its approval by the Food and Drug Administration (PDA) as a device in 1997, viscosupplementation with hyaluronate polymers was also used in veterinary applications (Hylart-Vet® and Hyvisc®,) for lame joints6 due to episodic traumatic arthritis in race horses. This latter application continues today with great anecdotal success,7 in contrast to the later human applications. Recent reviews8 and meta-analyses9,10 of viscosupplement double-blind placebo controlled trials in controlling pain from osteoarthritis (OA) show divergent results. The therapeutic benefit of these multiple intra-articular injections may be comparable to that of nonsteroidal anti-inflammatory drugs (NSAIDs) over that of acetaminophen.9

Hyalgan®, Artzal®, Suplazyn®, BioHy®, and Orthovisc®, are preparations of high molecular weight hyaluronate polymers. Successive versions of these products from different manufacturers have progressively increased viscosity. Chemically cross-linked hyaluronate monomers, a hylan (Synvisc®), possesses a molecular weight larger than the native synovial hyaluronate polymer. Accordingly, viscosity of hylans exceed normal physiologic synovial viscosity. The presumption here is that a more highly viscous preparation would result in a longer intra-articular residence time and an increased chance of restored synovial homeostasis. The above marginal therapeutic benefit is associated with the fact that placebo groups receiving sham injections also had improvement in pain. Manipulation of the joint via irrigation or injection appears to confound these studies."

Viscosupplementation has its origin in our early understanding of articular lubrication provided by synovial fluid. Hyaluronic acid was thought to add viscoelastic effects to synovial fluid which would be important in enabling hydrodynamic lubrication during periods of fast joint reciprocation. Under these circumstances some of the load from locomotion is borne by wedges of fluid between the articular surfaces. This effect restores 'shock absorber' characteristics to the diseased synovial fluid. Naturally occurring hyaluronate from human umbilical cord and rooster comb were used. Transformation into hyalns was performed by cross-linking hydroxyl groups (Figure 1) creating high molecular weight polymer networks.12

An unintended consequence of meshed polymers is the creation of excluded volume which inhibit small molecule movement. For example, a 0.3 mg/ml solution of cross-linked hyaluronate requires 1 liter of aqueous solvent in order to be fully solvated.1 (Each polymer is touching another.) This concentration is 10 times less than normal synovial hyaluronate concentration. Understandably, injection of 0.3 mg of a viscosupplement into a confined knee joint would have significant effects on the rheological properties of a patient's synovial fluid. Arresting small molecule movement by utilization of all available solvent. Solvation requirements would exclude cytokines and nociceptive mediators from triggering pain while restoring viscoelasticity. In this regard, viscosupplements, as a device, may serve a pseudopharmacologic anti-inflammatory role which is now being investigated.13

Chondroprotection is served by a very different mechanism in synovial fluid. Synovial fluid is present to provide for lubrication of apposed and pressurized cartilaginous surfaces and to also nourish chondrocytes, as these highly specialized cells have no supportive blood supply. Digesting synovial fluid with hyaluronidase results in a non-viscous fluid which continues to lubricate.14 Synovial fluid digested with trypsin results in a viscous fluid which fails to lubricate.15,16 The phenomenon of lubricating in the absence of viscosity is termed boundary lubrication and is a major feature of synovial fluid which is finally the subject of NIH sponsored research.

The modicum of therapeutic value in the intra-articular administration of viscosupplements may be appropriate for those patients unable to tolerate NSAIDs.9 This conclusion was also supported by a medicoeconomic analysis.17 This approach is endorsed by the American College of Rheumatology.18 However, the routine use of these devices in treating OA effectively is not well established because their mechanism of action is unclear. Multiple injections are required and therapeutic value is typically not seen until 3-6 months later, but can last longer than intra-articular steroid administration.19 There have been anecdotal reports20 of local inflammatory reactions at the site of injection, which are transient.21 The overall adverse event rate is 2-4%22 which is typically localized swelling. Utility in joints, other than the knee, is not PDA-approved.23 Rheumatologists and orthopaedists should reserve viscosupplementation for patients with OA on a case by case basis. Appreciating that viscosupplements are not articular lubricants and more likely work as retardants of pro-inflammatory factors24 may assist in this selection process. This effect may be more pronounced as the molecular weight of the hyaluronate is increased.

If this mechanism of action is correct, I would argue that perhaps the wrong patient population has been served. The human joint disease group most closely aligned with race horses are active patients with inflammatory joint conditions25 and not those with advanced OA. Deficient lubricating ability among patients with synovitis stands paradoxically in contrast to synovial fluid aspirated from joints of patients afflicted with OA.26 These former patients demonstrate absent lubricating ability. By contrast, patients with OA have normal lubricating ability. These intriguing observations are partly explained by the fact that the lubricating moiety is produced by superficial zone articular chondrocytes27 and synovial fibroblasts,28,secreting superficial zone protein (SZP) and lubricin respectively. Both are highly homologous protein products of megakaryocyte stimulating factor gene expression.29 Patients with advanced OA undoubtedly may lack superficial zone chondrocytes and yet continue to have normal synovial fluid lubricating ability, suggesting that the synovial fibroblast contribution continues. Disease states such as traumatic synovitis and RA, exemplified by synovial fluid deficient in lubricating ability, have both cell types affected. The histopathologic appearance of traumatic synovitis is similar to RA but less intense and extensive.30 Inflammatory processes can lead to IL-1 expression which in the case of superficial zone articular chondrocytes27, down regulates expression of SZP/lubricin and can ultimately lead to proteolysis. Arresting this process while at the same time restoring some of the mechanical features of synovial fluid (even the viscoelasticity by itself) makes some physiologic sense. The implication is that an unlubricated joint will result in cartilage injury and premature wear, consequently leading to the fibrillation of cartilage and appearance OA.

In summary, viscosupplements can moderate joint pain from OA and should be considered for those patients unable to tolerate NSAIDs or joint replacement surgery. Their mechanism of action is unclear despite approval by the FDA as a device in knee joint osteoarthritis. There is no clinical evidence that hyaluronate injections will facilitate repair of cartilage defects, however animal studies to this effect exist.24 Administering hyaluronate to patients with arthropathies other than OA will require rigorously performed clinical trials, which correct design flaws of past trials.11,31 This is especially relevant to those young patients with either traumatic or inflammatory arthropathies whom are theoretically more likely to benefit from intra-articular hyaluronate. Viscosupplements are not joint lubricants from a biotribological (study of friction and wear) vantage.

HYALURONIC ACID (HYALURONAN)

Hyaluronic acid (Hyaluronan, HA), is a linear polysaccharide composed of repeating disaccharide units of N-acetyl-glucosamine and D-glucuronic acid. The uronic acid and the amino sugar are linked together by alternating beta-1,4 and beta-1,3 glycosidic bonds. Synvisc®, is a highly viscous preparation of the hyaluronate polymer formed by cross-linked neighboring polymers through hydroxyl groups (circled).

REFERENCES

1. Balazs EA, Denlinger JL. J Rheumatol 1993;(suppl 39)20:3-9.

2. Peyron J. J Rheumatol 1993;(suppl 39)20:10-5.

3. Chmiel IH and Walitza E. On the Rheology of Blood and Synovial Fluids. New York, Research Studies Press 1980; 8-13.

4. Adams ME. J Rheumatol 1993;(suppl 39)20:16-8.

5. Adams ME, Atkinson MH, Lussier AJ, et al. Osteoarthritis and Cartilage 1995;3:213-26.

6. Gaustad G, Larsen S. Equine Vet J 1995;27:356-62.

7. Black JB. Campend Cont Edu Pract Vet 2000;22(5A):10-3.

8. Espallargues M, Pons JM. [Review] [40refs], Int J Technol Assess in Health Care 2003;19(1):41-56.

9. Lo GH, LaValley M, McAdlindon T, Felson D. JAMA 2003; 290(23):3115-21.

10. Aggarwal A, Sempowski IP. Can Fam Physician 2004;50:249-56.

11. Kirwan J. Knee 2001;8:93-01.

12. Pelletier JP, Martel-Pelletier J. J Rheumatol 1993;(suppl 39)20:19-24.

13. Marino AA, Wadell DD, Kolomytkin OV. Trans 50th Orthop Res Soc 2004; 282.

14. McCutchen CW. The factional properties of animal joints. Wear 1962;5:412-5.

15. McCutchen CW. FedProc Fed Am Soc Exp Bio 1966;25:1061-8.

16. Jay GD. Conn Tiss Re 1992;28:71-88.

17. Kahan A, Lleu PL, Salin. Joint, Bone, Spine: Revue du Rehumatisme 2003;70:276-81.

18. Pendleton A, Arden N, Dougados M, et al. Ann Rheum Dis. 2000;59:936-44.

19. Caborn D, Rush J, Lanzer W, et al. J Rheumatol 2004;31:333-43.

20. Noain E, Sancez-Villares JJ, Lasanta PJ, et al. Anales del Sistema Sanitaria de Navarra 2003;26:283-5.

21. Waddell DD. [Review]. Current Medical Research & Opinion 2003;19:575-80.

22. Adams ME, Lussier AJ, Peyron JG. [Review] [81 refs]. Drug Safety 2000;23:115-30.

23. Marshall KW. Intra-articular hyaluronan therapy. [Review] [83 refs]. Foot & Ankle Clinics 2003;8:221-32.

24. Williams JM, Rayan V, Summer DR, Thonar EJ. J Orthop Res. 2003;21:305-11.

25. Vad V, Hong HM, Zazzali M, et al. [Review] [54 refs]. Sports Medicine 2002;32:729-39.

26. Jay GD, Khaled EA, Zack J, et al. J Rheumatol 2004;31:557-64.

27. Flannery CR, Hughes CR, Schumacher BC, et al. Biochem Biophys Res Comm 1999; 234:535-41.

28. Jay GD, Britt D, Cha CJ. J Rheumatol. 2000;27:594-00.

29. Jay GD, Tantravahi U, Britt D, et al. J Orthop Res. 2001;19:677-87.

30. Lindblad S, Wredmark T. Brit J Rheum. 1990;29:422-5.

31. Brandt KD, Smith GN Jr., Simon LS. Arthritis Rheum 2000;43:1192-03.

GREGORY D. JAY, MD, PHD

ACKNOWLEDGEMENT: Dr. Jay's studies are funded by the National Institutes of Health, not by a product manufacturer.

Gregory D. Jay, MD, PhD, is Associate Professor of Medicine and Engineering, Brown Medical School.

CORRESPONDENCE:

Gregory D. Jay, MD, PhD

Medical Simulation Center

One Hoppin St, Suite 106

Providence RI 02903

phone: (401) 444-6237

fax: (401) 444-5456

e-mail: Gjay@lifespan.org

Copyright Rhode Island Medical Society Jul 2004
Provided by ProQuest Information and Learning Company. All rights Reserved