Use of Corticosteroids

The use of certain intra-articular corticosteroids for equine joint disease are still appropriate but the use of methylprednisolone acetate has deleterious effects on articular cartilage and its use should be questioned. The duration of action of each corticosteroid 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 Research 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

The first report of intra-articular corticosteroids used in the treatment of musculoskeletal conditions in horses and cattle was in 1955.¹  The use has become frequent since that time. Although the use of intra-articular corticosteroids has been cited as harmful in the horse,^2,3  more recent research has identified variations in therapeutic effects, with some having beneficial effects and one commonly used product having deleterious effects.^4–6

2. Mechanism of Action

The use of intra-articular corticosteroids for equine joint disease was extensively reviewed in 1996,⁷ and the specific benefits and deleterious side effects of intra-articular corticosteroids in the horse have been clarified more since that time. Corticosteroids are potent anti-inflammatory agents, and they inhibit the inflammatory process at all levels. Although traditional thinking has ascribed corticosteroid anti-inflammatory effects to stabilization of lysosomal membranes with a concomitant release of lysosomal enzymes, the anti-inflammatory effect is now known to be much more complex and far-reaching.⁸  Glucocorticoids exert their effects through cytoplasmic receptors. In addition to the well-known general effect of reducing capillary dilation, margination, migration, and accumulation of inflammatory cells, glucocorticoids inhibit the synthesis and release of several soluble mediators, including acting on the prostaglandin cascade, and they have been shown to inhibit interleukin-1 (IL-1), considered the most important mediator of cartilage degradation and tumor necrosis factor (TNFα) at low concentrations.⁹  Pain relief is attributed to inhibition of prostaglandin synthesis in large measure, specifically by inhibiting the enzyme phospholipase A₂ and cyclooxygenase (COX)-2 expression in the arachidonic cascade.¹⁰

3. Indications

The use of intra-articular corticosteroids is primarily indicated for the treatment of traumatic synovitis and capsulitis.¹¹ Traumatic synovitis and capsulitis are significant because of the direct functional effects, including pain and restrictive function, in the joint as well as the release of deleterious mediators, including IL-1, metalloproteinases, aggrecanases, prostaglandin E₂ (PGE²), and free radicals that can lead to degradation of articular cartilage and consequent osteoarthritis (OA).
 

4. Available Choices

The most commonly used intra-articular corticosteroids are betamethasone acetate–betamethasone sodium phosphate,^a triamcinolone acetonide^b (TA), methylprednisolone acetate^c (MPA), and isoflupredone acetate^d. Experimental studies of the three most commonly used intra-articular corticosteroids, namely betamethasone esters, MPA, and TA, have been performed using an osteochondral fragment model of OA developed at Colorado State University (CSU).^4-6

The first product studied was betamethasone sodium phosphate-betamethasone acetate^a. Osteochondral fragments were created arthroscopically on the distal aspect of both middle carpal joints in 12 horses, and one joint was treated with 2.5 ml betamethasone sodium phosphate-betamethasone acetate at 14 days after surgery, which was repeated in 35 days.⁴ The opposite joint was injected with saline as a control. No deleterious side effects to the articular cartilage (based on histology, histochemistry, and uronic acid content) were shown. In addition, comparison of exercise versus non-exercise on injected joints showed that exercise also did not have any harmful effects in the presence of corticosteroid administration.

In subsequent studies with intra-articular corticosteroids (as well as other treatments), the model was modified so that the opposite joint was not used as a control, and also, the CSU chip fragment model was modified to more effectively produce early OA change. MPA and TA were tested using three groups, and the test system is depicted in Figure 1.^5,6 Eighteen horses were randomly assigned to each of three groups (six horses per group). Both middle carpal joints in the placebo control group (ST) horses were injected intra-articularly with polyionic fluid. The corticosteroid control group horses (ST CNT) were injected with corticosteroid in the middle carpal joint without an osteochondral fragment, and the opposite middle carpal joint was injected with a similar volume of polyionic fluid. The corticosteroid-treated group horses (ST TX) were treated with corticosteroid in the joint that contained the osteochondral fragment, and the opposite middle carpal joint was injected with a single volume of polyionic fluid. All horses were treated intra-articularly on days 14 and 28 after surgery and exercised on a high-speed treadmill for 6 wk starting on day 15.

In joints containing an osteochondral fragment and treated with MPA, there was reduction, although not a significant one, in the degree of lameness; however, there were significant PGE₂ trends in the synovial fluid and lower scores for intimal hyperplasia and vascularity (no effect on cellular infiltration in the synovial membrane compared with placebo-treated joints).⁶ Of more importance, modified Mankin scores (a score of negative histopathological change in the articular cartilage) were significantly increased in association with MPA, confirming deleterious effects of intra-articular administration of MPA on articular cartilage.⁶ All of these changes were observed at 70 days, which was 42 days after the second and last injection of MPA. It was also noted that synovial aspiration was difficult (low volume and high viscosity) after treatment with MPA, and this was not seen with the other corticosteroids that were tested. In other work, repetitive intra-articular administration of MPA to exercising horses has been shown to alter the mechanical integrity of articular cartilage, but there was no effect on subchondral or cancellous bone.¹² [...]