Kortison

Intra-articular Corticosteroids

Corticosteroids are the most controversial drug used in treating joint injury and synovitis and capsulitis in the horse. Statements have been made in the popular press that have no scientific basis. It has been implied by some that intra-articular corticosteroids have been replaced by hyaluronic acid and polysulfated glycosaminoglycan but this is not the case. Many clinicians have returned to or persisted in the use of corticosteroids and in athletic horses this use is common. The first report of intra-articular corticosteroid use in the horse was in 1955. Since then, the untoward effects of intra-articular corticosteroids have been documented by some and questioned by others. More recently, we have attempted to critically evaluate the specific effects of corticosteroids in equine joints and these results are helping us identify a more definite role for these agents in the management of joint disease. Corticosteroids are the most potent anti-inflammatory drug we have and many beneficial effects have been recognized (discussed further below). The big problem has been the emphasis on the deleterious effects.

The first paper indicting corticosteroids as harmful in the horse was written by O’Connor in 1968. The report was based on some papers in the human literature. The statement, «An endless destructive cycle is set into motion which, if continued, will produce a steroid arthropathy which can render the horse useless» was referenced and the reference was an abstract written by an anonymous author. Six other human-based references were quoted in this paper to compare corticosteroids to Charcot-like arthropathy. Charcot’s arthropathy is a neurogenic disease that results in the loss of sensation, loss of proprioceptive control, instability and arthritis (most often seen as a sequel to syphilis). There has never been any scientific demonstration of a comparable response associated with corticosteroid use in horses. The insinuation that corticosteroids «deaden» the joint is dangerous and has caused considerable alarm. A noted veterinary pharmacologist made statements in a chapter on corticosteroids in his textbooks that included «A patient on corticosteroids can walk all the way to the autopsy room» and «A horse can wear a joint surface right down to the bone running on a glucocorticoid-injected joint».

It has recently been questioned whether corticosteroids alter the destructive course of joint disease in humans and in horses. More recent studies looking at the histologic and biochemical changes in equine articular cartilage under the influence of corticosteroids with or without the added effect of exercise have questioned some of the previous dogma.

Figure 13. Click to enlarge.

Effect of corticosteroids – Corticosteroid effects are exerted through an interaction with steroid-specific receptors in the cellular cytoplasm of steroid-responsive tissues. The corticosteroid binds to the receptor and induces changes in the transcription of genes coding various proteins that produce the hormonal effects. Corticosteroids are potent anti-inflammatory agents and inhibit inflammatory processes at virtually all levels. The major effect is their inhibition of movement of inflammatory cells (including neutrophils and monocyte-macrophages) into a site of inflammation. They also inhibit lysosomal enzyme release. They greatly inhibit prostaglandin E2 production by cells and this may be the dominant mechanism for their anti-inflammatory effects. It is now felt that they inhibit the generation of prostaglandins by producing proteins called lipocortins. They exert their effect on the prostaglandin cascade above the level of where NSAIDs affect it (Fig 13). There is also evidence for anti-IL-1 and anti TNF effects. There is also evidence for decreased expression for collagenase and stromelysin by inflamed synovial cells. Low doses of corticosteroids have also been associated with inhibition of plasminogen activator.

Clinical use of corticosteroids in the horse – The three most commonly used corticosteroids are 1) betamethasone (Betavet Soluspan or Celestone, Schering), 2) triamcinolone acetonide (Vetalog, Squibb), 3) 6_-methylprednisolone acetate (Depo-Medrol, Upjohn). All drugs are administered intra-articularly. Veterinary preferences vary as to which drug is used. The length of duration of action varies between the drugs but so might the side effects. The clinical use as well as scientific research will now be detailed.

Depo-Medrol (methylprednisolone acetate) – This drug has been used for the longest period of time and therefore has received the most attention with regard to research. It is also the longest acting of the commonly used corticosteroids. The drug can be detected in the joint 30 days after administration. It is injected at a dose rate of 80 to 100 mg for a carpal joint, for instance. Some veterinarians use a lower dose rate to avoid side effects but recent in vitro work suggests that a dose rate of 80 mg may be necessary for complete effectiveness.

A number of studies have evaluated the effects of methylprednisolone acetate injected into normal joints. In the first study reported in 1977, there were not any toxic effects demonstrated. A second study involved injecting both upper and lower joints of the carpus (knee) with 120 mg per joint on eight occasions one week apart. The opposite joints were used as untreated controls. Although there were no obvious gross differences in the cartilage, histologically there were decreased cartilage cells (chondrocytes) and decreased rates of proteoglycan and collagen synthesis. This did indicate some deleterious effects of Depo-Medrol, but the dosage regimen was far above what would be used in clinical practice. In a third study at CSU we injected 100 mg of Depo-Medrol three times at twice weekly intervals. We showed decreased amounts of proteoglycans (glycosaminoglycans) in the cartilage but there was no histologic damage. Horses remained clinically normal during the study and significant radiographic changes were not observed.

We are currently investigating the effect of Depo-Medrol in a less severe osteochondral fragment model (arthroscopic) that we have developed at CSU and the results of this study are pending.

Betamethasone (Celestone) – The author first questioned some of the dogma regarding the deleterious effects of corticosteroids when first operating racing Quarter Horses with arthroscopic surgery for the removal of osteochondral chip fractures. During these surgeries and after discussion with the referring veterinarians, it was found that the amount of secondary articular cartilage damage in no way correlated with the number of times the joint had been injected. In fact, some joints had been injected 20 times or more yet had no secondary articular cartilage damage. Because of this, we then went ahead and developed a study using arthroscopic surgery to create chip fragments and exercising the horses on a high speed treadmill. One intercarpal joint of each horse was injected with betamethasone 14 days after surgery and the procedure was repeated at 35 days. We also investigated the effect of exercise (it had been proposed that if one did use corticosteroids, then no exercise should be done because the cartilage was vulnerable to injury). Six of the horses were maintained in box stalls throughout the study as nonexercised controls and six were exercised five days per week on a high speed treadmill with a regimen of two minutes trot, two minutes gallop, two minutes trot. Three weeks after the second injection, horses were clinically examined for lameness and synovial effusion and radiographs were taken. The results of examination of the articular cartilage grossly and histologically showed that there were no consistent detrimental effects of betamethasone with or without exercise. Histochemical staining for the GAGs showed a decrease in the steroid-treated limbs of rested horses, although the decrease was not significant. What was particularly interesting was that in the exercised horses there were similar levels of GAGs in treated versus control joints. Biochemical assays showed no significant difference in water content or uronic acid concentration (a measure of GAG content) in the treated versus control joints. This data demonstrated that exercise had no deleterious effects on joints injected with corticosteroids and in fact may be somewhat protective (presumably associated with increased synthesis due to exercise).

The research work supported our clinical observations that betamethasone did not have significant deleterious effects in the cartilage of horses. We certainly do not advocate treating carpal chip fractures with corticosteroids but at least in the short term, it appears that it does not have significant deleterious effects. Betavet Soluspan, the veterinary product of betamethasone, has become unavailable in the last year. We now use the human preparation, celestone.

Triamcinolone acetonide (Vetalog) – There has been considerable opinion variation on how potent triamcinolone is and also how long acting it is. It is generally agreed that it is a potent corticosteroid but that the length of action (or at least detection) is shorter than previously thought. Because of its common usage and the anecdotal opinions of some veterinarians that it was the best corticosteroid to use, we tested this drug using the arthroscopic chip-treadmill model. We tested not only the deleterious effects of triamcinolone when injected into a joint with a carpal chip fragment and exercise, but also any effects that remotely-injected (into the other joint) triamcinolone might have. We had three groups of horses–one that was treated with control fluid in both midcarpal joints, six that were treated with 12 mg triamcinolone acetonide intra-articularly in the midcarpal joint without an osteochondral fragment, and six horses that were treated with 12 mg triamcinolone acetonide in the joint that contained the fragment. Triamcinolone and placebo treatments were repeated at days 14 and 28 and treadmill exercise proceeded at five days per week beginning on day 15 and ending on day 72. Horses that were treated intra-articularly with triamcinolone in a joint containing a fragment (Group 3) were less lame than horses in Groups 1 and 2. Synovial membrane from Groups 2 and 3 joints (treated with triamcinolone) had less inflammatory cell infiltration, intimal hyperplasia and subintimal fibrosis indices of synovial membrane inflammation. Analysis of articular cartilage with a standardized scoring system showed that the cartilage was significantly better in Groups 2 and 3, irrespective of which joint received triamcinolone. In addition, horses treated with TA in either joint had lower protein and higher hyaluronic acid concentrations in the joint fluid. Staining for glycosaminoglycan was greatest in Group 3. The results of this study showed positive direct and indirect effects of intra-articular corticosteroid administration. There were favorable effects of triamcinolone on various parameters and support for a chondroprotective effect in a controlled model of osteoarthritis. This is in marked contrast to the detrimental effects of corticosteroids on articular cartilage seen in other models with other drugs.

Summary – Based on our research, it seems that we can use both betamethasone and triamcinolone without substantial detrimental effects and in the case of triamcinolone, some chondroprotective effects on articular cartilage. There are obvious differences between the drugs used and the dosages and generalizations are difficult. However, we seem to be coming up with drugs that can offer considerable benefit without deleterious side effects. We are particularly interested in seeing the results of Depo-Medrol in the same model that we have tested betamethasone and triamcinolone.

Clinical use – It is unfortunate that the lay public has been told that corticosteroids purely inhibit pain and therefore permit horses to continue to run and degenerate their joints, because this is not the case. It is also a particular concern that it has been implied by some that corticosteroids can lead horses to «break down». It is also important, however, that we continue to try to find better treatments of the arthritic conditions. The ideal treatment for intra-articular fractures of the joint is definitely arthroscopic surgery.

In the meantime, we know that corticosteroids have specific activity against a number of deleterious products produced by synovitis and previously discussed:
Collagenase production
Proteoglycanase (stromelysin) production
Prostaglandin production
Synovial membrane-induced interleukin-1 production

At the moment we are investigating what is the minimally effective dose for each corticosteroid in the hope that we can use less drug and further minimize the chance of side effects. If our current research demonstrates that Depo-Medrol does have deleterious effects compared to the other corticosteroids, then we would make the recommendation that the latter drug should not be used. The development of specific equine interleukin-1 through molecular biology (that has happened here recently) could not only lead to more specific testing of corticosteroid dose rate and effectiveness but also potentially lead to specific inhibitors that block the mediators at the time of initial formation.

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