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Home , Betamethasone acetate, Isoflupredone

IN-DEPTH: CHOOSING JOINT THERAPIES FOR THE BEST RESULTS

Use of

C. Wayne McIlwraith, BVSc, PhD, DSc, FRCVS, Diplomate ACVS, ACVSMR

The use of certain intra-articular corticosteroids for equine joint disease are still appropriate but the use of has deleterious effects on articular cartilage and its use should be questioned. The duration of action of each is still poorly defined and pharmacogenomic methods provide the potential of a more global assessment for pharmacodynamic responses after intra-articular corticosteroid injection. Author’s address: Gail Holmes Equine Orthopaedic Re- search Center, Colorado State University, College of Veterinary Medicine and Biomedical Sciences, 300 West Drake, Fort Collins, CO 80523; e-mail: [email protected]. © 2011 AAEP.

1. Introduction toplasmic receptors. In addition to the well-known The first report of intra-articular corticosteroids general effect of reducing capillary dilation, margin- used in the treatment of musculoskeletal conditions ation, migration, and accumulation of inflammatory in horses and cattle was in 1955.1 The use has cells, inhibit the synthesis and re- become frequent since that time. Although the use lease of several soluble mediators, including acting of intra-articular corticosteroids has been cited as on the prostaglandin cascade, and they have been harmful in the horse,2,3 more recent research has shown to inhibit interleukin-1 (IL-1), considered the identified variations in therapeutic effects, with most important mediator of cartilage degradation some having beneficial effects and one commonly and tumor necrosis factor (TNF␣) at low concentra- used product having deleterious effects.4–6 tions.9 Pain relief is attributed to inhibition of prostaglandin synthesis in large measure, specifi- 2. Mechanism of Action cally by inhibiting the enzyme phospholipase A and The use of intra-articular corticosteroids for equine 2 7 cyclooxygenase (COX)-2 expression in the arachi- joint disease was extensively reviewed in 1996, and donic cascade.10 the specific benefits and deleterious side effects of intra-articular corticosteroids in the horse have 3. Indications been clarified more since that time. Corticosteroids are potent anti-inflammatory agents, and they The use of intra-articular corticosteroids is primar- inhibit the inflammatory process at all levels. Al- ily indicated for the treatment of traumatic synovitis though traditional thinking has ascribed corticoste- and capsulitis.11 Traumatic synovitis and capsuli- roid anti-inflammatory effects to stabilization of tis are significant because of the direct functional lysosomal membranes with a concomitant release of effects, including pain and restrictive function, in lysosomal enzymes, the anti-inflammatory effect is the joint as well as the release of deleterious now known to be much more complex and far-reach- mediators, including IL-1, metalloproteinases, 8 ing. Glucocorticoids exert their effects through cy- aggrecanases, prostaglandin E2 (PGE2), and free

NOTES

AAEP PROCEEDINGS ր Vol. 57 ր 2011 107 IN-DEPTH: CHOOSING JOINT THERAPIES FOR THE BEST RESULTS

Fig. 1. Design of experiments to assess the value of direct intra-articular injection of a corticosteroid into an osteoarthritic joint (ST TX) and injection of an intra-articular corticosteroid in a remote joint (ST CNT) compared with a saline-injected control (CNT).

radicals that can lead to degradation of articular polyionic fluid. The corticosteroid control group cartilage and consequent osteoarthritis (OA). horses (ST CNT) were injected with corticosteroid in the middle carpal joint without an osteochondral 4. Available Choices fragment, and the opposite middle carpal joint was The most commonly used intra-articular corticoste- injected with a similar volume of polyionic fluid. roids are acetate–betamethasone The corticosteroid-treated group horses (ST TX) sodium phosphate,a acetonideb (TA), were treated with corticosteroid in the joint that methylprednisolone acetatec (MPA), and isoflupre- contained the osteochondral fragment, and the op- done acetated. Experimental studies of the three posite middle carpal joint was injected with a single most commonly used intra-articular corticosteroids, volume of polyionic fluid. All horses were treated namely betamethasone esters, MPA, and TA, have intra-articularly on days 14 and 28 after surgery been performed using an osteochondral fragment and exercised on a high-speed treadmill for 6 wk model of OA developed at Colorado State University starting on day 15. (CSU).4–6 In joints containing an osteochondral fragment The first product studied was betamethasone so- and treated with MPA, there was reduction, al- dium phosphate-betamethasone acetatea. Osteo- though not a significant one, in the degree of lame- chondral fragments were created arthroscopically ness; however, there were significant PGE2 trends on the distal aspect of both middle carpal joints in 12 in the synovial fluid and lower scores for intimal horses, and one joint was treated with 2.5 ml beta- hyperplasia and vascularity (no effect on cellular sodium phosphate-betamethasone ace- infiltration in the synovial membrane compared tate at 14 days after surgery, which was repeated in with placebo-treated joints).6 Of more importance, 35 days.4 The opposite joint was injected with sa- modified Mankin scores (a score of negative histo- line as a control. No deleterious side effects to the pathological change in the articular cartilage) were articular cartilage (based on histology, histochemis- significantly increased in association with MPA, try, and uronic acid content) were shown. In addi- confirming deleterious effects of intra-articular ad- tion, comparison of exercise versus non-exercise on ministration of MPA on articular cartilage.6 All of injected joints showed that exercise also did not these changes were observed at 70 days, which was have any harmful effects in the presence of cortico- 42 days after the second and last injection of MPA. administration. It was also noted that synovial aspiration was diffi- In subsequent studies with intra-articular cortico- cult (low volume and high viscosity) after treatment (as well as other treatments), the model was with MPA, and this was not seen with the other modified so that the opposite joint was not used as a corticosteroids that were tested. In other work, re- control, and also, the CSU chip fragment model was petitive intra-articular administration of MPA to modified to more effectively produce early OA exercising horses has been shown to alter the me- change. MPA and TA were tested using three chanical integrity of articular cartilage, but there groups, and the test system is depicted in Figure was no effect on subchondral or cancellous bone.12 1.5,6 Eighteen horses were randomly assigned to In an earlier publication investigating joint function each of three groups (six horses per group). Both and healing after intra-articular administration of middle carpal joints in the placebo control group 120 mg MPA, it inhibited the development and mat- (ST) horses were injected intra-articularly with uration of repair tissue of surgically created full-

108 2011 ր Vol. 57 ր AAEP PROCEEDINGS IN-DEPTH: CHOOSING JOINT THERAPIES FOR THE BEST RESULTS thickness articular cartilage defects in exercised low-up study with data on the potential for TA to horses at 42 days and incited potential long-term produce laminitis, and the conclusion was that there (180 days) detrimental synovial membrane in- was no association between the occurrence of lami- flammation.13 However, a single dose of MPA did nitis and the intra-articular use of TA.17 not cause long-term detrimental effects (180 days) A relatively recent legal case in the United King- in the quality of the repair tissue (percentage of dom where a horse developed laminitis after receiv- fibrocartilage). ing 80 mg TA in each tarsus and 20 mg into its back18 led to the develop- 5. Duration of Action ment of a review of the literature19 and a retrospec- Duration of action has been poorly defined. In gen- tive study of one clinician’s cases.20 The review of eral, –betamethasone so- the literature revealed that good evidence linking dium phosphate has been classified as intermediate laminitis to corticosteroid injection was lacking and to long-acting, TA has been classified as intermedi- that a large-scale multicenter trial was needed.19 ate, MPA has been classified as intermediate to long In a third publication, the clinician reported that acting, and isoflupredone acetate has been classified laminitis associated with intra-articular injection of as short to intermediate duration of action.7 corticosteroids had occurred in 3 of 2,000 (0.15%) cases. For the majority of the time, TA was used, 6. Combined Use of Hyaluronan and TA and the upper total dose ranged from 20 to 45 mg.20 There is some support of the combination of TA and hyaluronan (HA) being beneficial from one study of 8. Clinical Effectiveness (Pharmocodynamics) 16 human patients with knee OA. This was a 1-yr, Relative to Pharmacologic Presence (Pharmacokinetics) single-blind, randomized study in which 24 patients and Potential to Quantitate This Activity were treated with intra-articular HA one time per Results of in vivo studies have led to in vitro studies week for 3 wk and then again at 6 mo (total of six of the effects of corticosteroids on articular cartilage injections).14 Sixteen of these patients also had 1.0 to identify specific cellular events. Measuring gene ml triamcinolone before the first and fourth HA in- expression using pharmacogenomic methods, how- jections, and evaluation using the Western Ontario ever, provides the potential of more global assess- and McMaster Universities Arthritis Index ment of all pharmacodynamic responses after intra- (WOMAC) index (used to assess patients with OA of articular corticosteroid injection. An example of the hip or knee using 24 parameters, including 5 this technique has been published using MPA ad- indices of pain, 2 indices of stiffness, 7 indices of ministration in rats.21,22 In this study, MPA was social function, and 10 indices of emotional function) administered using two routes, and the effect on found that the results were better with the combi- mRNA gene expression from muscle cells was mon- nation of these two products. There was no pro- itored over time using microarrays. This work gression of OA on magnetic resonance imaging showed the ability of measuring gene expression (MRI) in either group. (either up- or down-regulated) as a pharmacody- There is indirect evidence that the use of HA namic (pharmacogenomic) method. As expected, a together with TA should provide clinical benefit in host of genes were differentially expressed (up- or the horse. In a recent study, the use of intra-artic- down-regulated) as a consequence of corticosteroid ular HA as well as intra-articular polysulfated gly- administration. Also, differential gene expression cosaminoglycane was assessed in the CSU chip occurred even after the pharmacokinetic effects fragment model.15 Intra-articular injection of 20 were gone. This result may explain why exogenous mg HA was done at 14, 21, and 28 days. There was corticosteroids have both acute and chronic effects. significantly less cartilage fibrillation with HA at day 70, despite less impressive reduction of synovial effusion and synovial membrane vascularity and References and Footnotes subintimal fibrosis compared with polysulfated gly- 1. Wheat JD. The use of in the treatment of cosaminoglycan.15 The combination of the potent joint and tendon disorders in large animals. J Am Vet Med anti-inflammatory corticosteroid TA and the chon- Assoc 1955;127:64–67. 2. O’Conner JT. The untoward effects of the corticosteroids in droprotective HA is, therefore, logical. equine practice. J Am Vet Med Assoc 1968;153:1614–1617. 3. Tobin T. Steroidal anti-inflammatory agents: the corticoste- 7. Laminitis—A Suggested Potential Complication of roids and ACTH. In: Drugs and the Performance Intra-Articular Corticosteroid Use Horse. Tobin T ed, Charles C. Thomas, Springfield IL, 1981: Fear of laminitis has also caused less use of TA by 1981;132–148. 4. Foland JW, McIlwraith CW, Trotter GW, et al. Effect of some equine practitioners, despite scientific studies betamethasone and exercise on equine carpal joints with showing its effectiveness as well as its chondropro- osteochondral fragments. Vet Surg 1994;23:369–376. tective properties. There have been anecdotal as- 5. Frisbie DD, Kawcak CE, Trotter GW, et al. Effects of triam- sociations made and maximum doses established cinolone acetonide on an in vivo equine osteochondral frag- ment exercise model. Equine Vet J 1997;29:349–359. based on a report of no cases of laminitis in 1,200 ␣ 16 6. Frisbie DD, Kawcak CE, Baxter GM, et al. Effects of 6 - horses treated when a dose did not exceed 18 mg. methylprednisolone acetate on an equine osteochondral frag- A more recent publication provides the first fol- ment exercise model. Am J Vet Res 1998;59:1619–1628.

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7. Trotter GW. Intra-articular corticosteroids. In: McIl- 16. Genovese RL. The use of corticosteroids in racetrack prac- wraith CW, Trotter GW, eds. Joint Disease in the Horse. tice, in Proceedings. Symposium on Effective Use of Corti- Philadelphia, PA: WB Saunders, 1996:237–256. costeroids in Veterinary Practice 1983:56–65. 8. Axelrod L. Glucocorticoids. In: Harris ED, Kelley WN, 17. McCluskey MJ, Kavenagh PB. Clinical use of triamcinolone Ruddy S, et al., eds. Textbook of Rheumatology, 4th ed. Phil- acetonide in horses (205 cases) and the incidence of glucocor- adelphia, PA: WB Saunders, 1993:749–796. ticoid-induced laminitis associated with its use. Equine Vet 9. Laufer S, Greim C, Bertsche T. An in vitro screening assay Edu 2004;16:86–89. for the detection of inhibitors of pro-inflammatory cytokine 18. Dutton H. The corticosteroid laminitis story: 1. Duty of synthesis: a useful tool for the development of new anti- care. Equine Vet J 2007;39:5–6. arthritic and disease modifying drugs. Osteoarthritis Carti- 19. Bailey SR, Elliott J. The corticosteroid laminitis story: lage 2002;10:961–967. 2. Science of if, when and how. Equine Vet J 2007;39:7–11. 10. Caron JP. Intra-articular injections for joint disease in 20. Bathe AP. The corticosteroid laminitis story: the clini- horses. Vet Clin North Am [Equine Pract] 2005;21:559–573. cian’s viewpoint. Equine Vet J 2007;39:12–13. 11. McIlwraith CW. Frank Milne lecture: from arthroscopy to 21. Yao Z, Hoffman EP, Ghimbovschi S, et al. Mathematical gene therapy—30 years of looking in joints, in Proceedings. modeling of corticosteroid pharmacogenomics in rat muscle Am Assoc Equine Pract 51:2005;65–113. following acute and chronic methylprednisolone dosing. Mol 12. Murray RC, Znaor N, Tanner KE, et al. The effect of intra- Pharm 2008;5:328–339. articular methylprednisolone acetate and exercise on 22. Yao Z, Dubois DC, Almon RR, et al. Pharmacokinetics/phar- equine carpal subchondral and cancellous bone microhard- macodynamic model of corticosteroine and lipocytopenia by ness. Equine Vet J 2002;34:306–310. methylprednisolone in rats. J Pharm Sci 2008;97:2820– 13. Carter BG, Bertone AL, Weisbrook SE, et al. Influence of 2832. methylprednisolone acetate on osteochondral healing in ex- ercised tarsocrural joints of horses. Am J Vet Res 1996;57: aBetavet Soluspan (now available as Celestone Soluspan), 914–922. Shering-Plough Animal Health Corporation, Union, NJ 07083; 14. Ozturk C, Atamaz F, Hepguler S, et al. The safety and Celestone Soluspan, Schering-Plough/Merck. Whitehouse, NJ efficacy of intra-articular hyaluronan with/without corticoste- 08889. roid in knee osteoarthritis: 1 year, single-blind, randomized bVetalog, Bristol Myers Squibb for Fort Dodge, Fort Dodge, IA study. Rheumatol Int 2006;26:314–319. 50501. 15. Frisbie DD, Kawcak CE, McIlwraith CW, et al. Evaluation cDepo-Medrol, Pharmacia and Upjohn Company, Kalamazoo, of polysulfated glycosaminoglycan or sodium hyaluronan ad- MI 49001. ministered intra-articularly for treatment of horses with ex- dPredef 2X, Pfizer Animal Health, Pfizer Canada Inc., Kirk- perimentally induced osteoarthritis. Am J Vet Res 2006;70: land, QC, Canada H9J2M5. 203–209. eAdequan, Luitpold Pharmaceuticals, Inc., Shirley NY 11967.

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