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TechTalk Issue 2 RANDLAB

Veterinary Medicines

Welcome to Randlab’s TechTalkIn this issue, well known specialist equine surgeon, Dr Nicholas Kannegieter takes a fresh look at an old faithful as he gives an update on the use of hyaluronic acid (HA) for the treatment of joint disease.

For access to a comprehensive library of journal articles on joint disease and other topics, check out the Randlab library at www.randlab.com.au/library.html. Access to the library is free and there are hundreds of key scientific publications available for reading on selected topics.

Hyaluronic acid (HA) is the major component of synovial fluid and is essential in providing the viscoelastic and shock absorbing properties to joint fluid that help protect cartilage from damage. Damage to articular cartilage that occurs in association with joint disease invariably results in changes in HA composition and content which can cause further damage to the joint.

The viscoelastic properties of

exogenous HA can provide good

improvement in the viscoelastic and

protective properties of joint fluid

and joint function that can last for

many months following treatment.

There is also the potential that exogenous HA will stimulate the production by synoviocytes of high molecular weight HA which not only prolongs the duration of action of any medication but also increases the efficacy.

Update on the use of Hyaluronic Acid in the management of joint disease in the horse.Assoc Professor Nicholas KannegieterBVSc, DVCS, PhD, FACVScKannegieter Equine Specialists

Hyaluronic acid, often in combination with corticosteroids, has long been the mainstay in the treatment of joint disease in the horse. Despite a growing number of alternative treatments being available for treating joint disease combination of corticosteroids and hyaluronic acid still remains the gold standard by which other treatments must be judged. There are many different exogenous HA‘s currently available and it is important that the practitioner is aware that there is considerable difference between available HA’s which can impact on both their efficacy and safety.

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There have been many studies in many species, including horses, evaluating the efficacy of HA in the management of joint disease (see reference list below). As is found with all products used to treat joint disease it is very difficult to create a standardised scientific protocol, either clinical or experimental, which allows accurate comparison and evaluation of these products.

Consequently, there are some apparently conflicting accounts regarding the efficacy of HA treatments in the horse. By way of example, some recent studies have suggested that HA may be less effective than had previously been documented in a large volume of scientific data over the past 40 years. It is likely that if these studies were repeated that different results would be obtained due to the usual variability encountered when using clinical material for such studies.

In one such study (Grauw et al 2016) it was reported that horses treated with a combination of HA and triamcinolone performed worse at three weeks compared to triamcinolone alone. However, this study had severe limitations including being a multicentre trial with lameness evaluation undertaken by many different veterinarians, multiple joints affected, results were subjective using owner-reported telephone follow-up, an unusually high portion of adverse reactions following injection and in particular the average age of the horses was approximately 13 years and small case numbers which included one horse whose intended use was breeding.

There were also no radiographic or ultrasonographic studies undertaken. Although results of the two groups were again equivalent by 3 months, there is no obvious reason that adding HA to the medication would result in a decrease in success rate at three weeks. It would seem imperative that the authors of the

paper look for problems in the design of the study and most importantly case selection which would be far more likely to contribute to any potential skewed results rather than the detrimental effect of HA.

Another recent study by Niemelä et al (2016) reported that while horses receiving HA intra-articularly had significantly less pain on flexion at 2 week follow up there was no difference in lameness scores between treated and control groups. However there were only 27 horses in the entire study and saline, which was injected as the control, can have an influence on results. The lameness score improvement with HA was almost statistically significantly and had more horses been included in the study it is likely different results would have been obtained.

Despite these recent studies there is a large volume of scientific data as well as clinical experience that supports the use of HA in the clinical management of joint disease in horses.

It is important when considering the use of HA to remember that there is a considerable difference in the quality and type of HA available for use in equine practice. There are both animal derived and newer synthetic products which are Streptococcus equi fermentation products. Other factors that veterinarians should consider when selecting a hyaluronic acid are the viscosity, protein content, molecular weight and origin of the HA. Unfortunately not all this data is readily

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available when selecting the HA of choice. High viscosity is paramount to efficacy, while high protein content may mean more foreign proteins which may contribute to the flair reactions seen after injection of many intra-articular products. The significance of molecular weight in exogenous HA is still unclear but there is evidence that very low molecular weight products may be less effective while very high molecular weight products may also cause adverse problems within the joint. It seems likely that middle to high molecular weight exogenous HA may be most suitable for equine use.

There are different levels of adverse reactions following use of any intra-articular medication and there is considerable difference in reaction rates between different HA’s. Using a high quality HA from an established manufacturer will result in less, or potentially no, flair reactions.

Given recent changes to the Australian Rules of Racing in regard to the use of intra-articular medication with corticosteroids close to race time, more attention is being given to medicating joints using HA alone, which is not impacted by these changes.

HA without corticosteroids

can provide significant anti-

inflammatory and analgesic effect

to joints.

Careful case selection is one of the keys to ensuring the best results are obtained when using hyaluronic acid, either with or without corticosteroids. Those cases with severe clinical and radiographic signs will of course respond the least, particularly in the short term, while those cases that have primary synovitis or low grade inflammatory joint disease are the best candidates for HA therapy.

Intravenous HA therapy works best in horses with low-grade joint disease particularly where multiple joints are affected or if close to competition. Frequently 20 to 40 mg is given IV 24 to 48 hours before any strenuous athletic activity and can have a significant anti-inflammatory effect on joint disease.

Horses following joint surgery for traumatic arthritis can also benefit greatly from regular HA treatment, either intra-articularly and/or intravenously starting 1 to 3 weeks following surgery. My regular protocol following carpal or fetlock arthroscopic surgery in athletic horses is to administer 20 mg of HA into each of affected joint any time from 1 to 3 weeks post operatively and then every 3 to 4 weeks for a total of four treatments.

The beneficial effects of combining corticosteroids with the intra-articular administration of HA has been well documented. Most commonly triamcinolone is added in the same syringe. For most joints 10mg triamcinolone and 10-20 mg HA is adequate. For larger joints, such as a stifle or shoulder, then 20 mg HA and up to 40 mg triamcinolone can be used if injecting a single joint.

Recommended Medication for Joint Disease (based on using HA 10mg/ml)

• IV: 2 or 4mls once weekly or

1-2 days prior to event (ensure

compliance with event rules)

And/or

• IA: 2ml alone or in combination

with steroids (as noted in key

points)

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Key Points

HA can be used effectively either intravenously or intra-articularly.

HA intra-articularly can be used alone or in combination with corticosteroids.

HA provides anti-inflammatory and analgesic properties in appropriate cases.

Exogenous HA can enhance the quality of joint fluid and improve ongoing production of natural HA.

Not all exogenous HA’s are the same. There are considerable differences in viscosity, protein levels, purity, molecular weight and safety and efficacy between different brands.

Regular use of intra-articular HA can greatly improve joint function in the longer term.

The combined use of HA and corticosteroids is still the gold standard by which other joint treatments are judged.

HA administration when using a high quality HA either intra-articularly or intravenously is known to be a safe, reliable and cost-effective means of assisting in the management of joint disease.

HA used following joint surgery in appropriate cases can decrease the amount of synovial effusion and increase flexibility within the joint.

Compared to many newer treatments for joint disease, HA is still very effective, safe, simple to use and cost-effective.

Intra-articular HA and Corticosteroids (ensure compliance with event rules)

Dose

20 mg HA and

Either 20mg Dexamethasone

OR 10-20 mg Triamcinolone

OR10 -40 mg Triamcinolone and 15 mg Dexamethasone

OR15 mg Voren Depot (potential prolonged excretion)

OR40-120mg Depomedrol (potential prolonged excretion)

Assoc Prof Nicholas KannegieterBVSC, DVCS, PhD, FACVSc

Specialist Equine Surgeon

Graduating in veterinary science at the University of Sydney in 1983, Nick undertook an internship at the Rural Veterinary Centre, University of Sydney in

1984. He spent the next four years at Massey University in New Zealand undertaking a PhD in laryngeal hemiplegia and receiving post-graduate training in equine surgery. In 1988, he was admitted as a member of the Australian College of Veterinary scientists in equine surgery.

Nick took up the position of registrar/senior registrar in equine surgery at the University of Sydney from 1989 until 1995. He obtained fellowship of the Australian College of Veterinary Scientists in equine surgery in 1990 and was granted specialist registration in equine surgery in 1991. He was a member of the executive of the Australian Equine Veterinary Association (AEVA) from 1990-2001 (president in 1994) and on the AVA board of directors from 1996-2001.

Nick has published approximately 40 scientific papers with special interests in the respiratory tract, orthopaedic surgery, joint disease and particularly arthroscopic surgery. Since 1996 he has been a consultant equine surgeon in private practice, providing surgical services and second opinions on cases and radiographs for veterinarians in equine clinics throughout NSW, the ACT, Queensland and other parts of Australia.

In 1997, he was awarded the AEVA VMS Award for excellence in the equine veterinary field. Nick was made an Adjunct Associate Professor Department of Animal and Veterinary Sciences, Charles Sturt University, Wagga Wagga, NSW in 2012. He currently works with Dr Hadley Willsallen providing specialist services to veterinarians around Australia.

References:

Auer JA, Fackelman GE, Gingerich DA, Fetter AW (1980) Effect of hyaluronic acid in naturally occurring and experimentally induced osteoarthritis. Are J Vet Res 41:568-74?

Aviad AD, Houpt JB (1994) the molecular weight of therapeutic hyaluronan (sodium hyaluronate): how significant is it? J Rheumatol 21:297-301

Barr, A. R. S. Duance, V. C. Wotton, S. F. Waterman, A. E. (1994) Influence of intra-articular sodium hyaluronate and polysulphated glycosaminoglycans on the biochemical composition of equine articular surface repair tissue. Equine Veterinary Journal. 26: 1, 40-42

Bolt DM, Ishihara A, Weisbrode SE, Bertone AL (2008) Effects of triamcinolone acetonide, sodium hyaluronate, amikacin sulfate, and mepivacaine hydrochloride, alone and in combination, on morphology and matrix composition of lipopolysaccharide-challenged and unchallenged equine articular cartilage explants. Am J Vet Res. 69(7):861-7

Butler J, Rydell NW, Balazs EA (1970) Hyaluronic acid in synovial fluid. VI. Effect of intra-articular injection of hyaluronic acid on the clinical symptoms of arthritis in track horses. Acta Vet Scand 11:139-55 Equine Veterinary Science. 5:147-148

Dabareiner RM, Carter GK, Honnas CM. (2003) Injection of corticosteroids, hyaluronate, and amikacin into the navicular bursa in horses with signs of navicular area pain unresponsive to other treatments: 25 cases (1999-2002) J Am Vet Med Assoc. 15;223:1469-74

Doyle AJ, Stewart AA, Constable PD, et al. (2005) Effects of sodium hyaluronate and methylprednisolone acetonide on proteoglycan synthesis in equine articular cartilage explants. Am J Vet Res;66:48–53

Frisbie DD, Kawcak CE, McIlwraith CW, Werpy NM (2009) Evaluation of polysulfated glycosaminoglycan or sodium hyaluronan administered intra-articularly for treatment of horses with experimentally induced osteoarthritis Am J Vet Res.70(2):203-9

... continued over

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IN OUR NExt IssUE

Gaustad G, Larsen S (1995) Comparison of polysulphated glycosaminoglycan and sodium hyaluronate with placebo in treatment of traumatic arthritis in horses. Equine Vet J 27:356-62

Gingerich DA, Auer JA, Fackelman GE (1981) Effect of exogenous hyaluronic acid on joint function in experimentally induced equine osteoarthritis: dosage titration studies. Res Vet Sci 30:192-7

Gingerich, D. A. Auer, J. A. Fackelman, G. E. (1979) Force plate studies on the effect of exogenous hyaluronic acid on joint function in equine arthritis. Journal of Veterinary Pharmacology & Therapeutics. 2: 291-298

Grauw et al (2016) Intra-articular treatment with triamcinolone compared with triamcinolone with hyaluronate: A randomised open-label multicentre clinical trial in 80 lame horses EVJ Volume 48, Issue 2 Pages 152–158

Kannegieter N.J. (2006) Arthrology, in The Equine Manual 2nd edition, eds Higgins A and Snyder J. Elselvier Saunders

Kawcak CE, Frisbie DD, Trotter GW, McIlwraith CW, Gillette SM, Powers BE, Walton RM (1997) Effects of intravenous administration of sodium hyaluronate on carpal joints in exercising horses after arthroscopic surgery and osteochondral fragmentation. Am J Vet Res;58:1132-40

Niemelä et al. (2016) A randomised, double-blinded, placebocontrolled clinical study on intra-articular hyaluronan treatment in equine lameness originating from the metacarpophalangeal joint. BMC Veterinary Research 12:60

Nizolek DJ, White KK (1981) Corticosteroid and hyaluronic acid treatments in equine degenerative joint disease. A review. Cornell Vet 71:355-75

Popot MA, Bonnaire Y, Guéchot J, Toutain PL. (2004) Hyaluronan in horses: physiological production rate, plasma and synovial fluid concentrations in control conditions and following sodium

hyaluronate administration. Equine Vet J. 36(6):482-7 Prieto JG,

Roneus B, Lindblad A, Lindholm A, Jones B (1993) Effects of intraarticular corticosteroid and sodium hyaluronate injections on synovial fluid production and synovial fluid content of sodium hyaluronate and proteoglycans in normal equine joints.

Ruth, D. T. Swites, B. J.(1985) Comparison of the effectiveness of intra-articular hyaluronic acid and conventional therapy for the treatment of naturally occurring arthritic conditions in horses. Equine Practice. 7: 25-29

Schaefer EC, Stewart AA, Durgam SS, Byron CR, Stewart MC (2009) Effects of sodium hyaluronate and triamcinolone acetonide on glucosaminoglycan metabolism in equine articular chondrocytes treated with interleukin-1. Am J Vet Res. Dec;70(12):1494-501

Schwenzer, K. Gerhards, H. (1999) Intra-articular and intravenous application of sodium hyaluronate to horses with chronic joint disease. Pferdeheilkunde. 15: 3, 221-232. 39 ref.

Uden, P. C., Lavoie, L. M. (1997) Laboratory evaluation of commercial hyaluronate sodium products. Journal of Equine Veterinary Science. 17:123-125

Valentine S. W (2007) Intra-articular Hyaluronic Acid Supplementation in the Horse: The Role of Molecular Weight. Journal of Equine Veterinary Science 27:7298-303

White, G. W. Stites, T. Hamm, J. Pool, R. (1999) Evaluation of the efficacy of various preparations of sodium hyaluronate in an induced equine carpitis model. Journal of Equine Veterinary Science. 19: 5, 331-337

Yates AC, Stewart AA, Byron CR, et al. (2006) Effects of sodium hyaluronate and methylprednisolone acetonide on proteoglycan metabolism in equine articular chondrocytes treated with interleukin-1. Am J Vet Res;67:1980–1986