Equine Osteoarthritis Update and New Targeted Therapies
One of the world's leading clinicians and researchers in equine joints is C. Wayne McIlwraith, BVSc, PhD, DSc, FRCVS, Dipl. ACVS, University Distinguished Professor, Barbara Cox Anthony Chair in Orthopedics, and director of Orthopaedic Research at Colorado State University (CSU). At WEVA he presented an update on new therapies for osteoarthritis, a condition previously known as degenerative joint disease.
One of his main points in the general discussion is that we need to think of the joint as an organ, realizing there are a number of ways in which damage can occur to the joint, and a number of ways the joint can respond.
What is Osteoarthritis?
McIlwraith said osteoarthritis (OA) results from an interaction of a number of complex mechanical and biological processes. "The major characteristic of OA is progressive degradation and destruction of the articular cartilage (or cartilage in a joint)," he said.
While much more has become known in recent years about what causes arthritis, he said there is still a lot that needs to be studied and discovered in order to successfully prevent and treat OA.
"The loss of articular cartilage represents a culmination of failure of the articular cartilage to withstand the cyclic trauma of athletic activity, and this may be complicated by aging changes," noted McIlwraith. "Traumatic arthritis includes a number of conditions, but these can generally be divided into 1) synovitis and capsulitis (inflammation of the synovial membrane of the joint and inflammation of the joint capsule); 2) instability causing injury such as intra-articular and collateral ligament injury, intra-articular fracture, subchondral bone disease, and meniscal injury (stifle); and 3) osteoarthritis."
He said there are different causes of OA, but generally they come down to either abnormal forces on normal cartilage or normal forces on damaged cartilage.
Abnormal forces could include heavy athletic activity and loss of joint or limb stability due to fractures or tendon/ligament problems. "Abnormal cartilage can be created with normal stresses when synovitis and capsulitis cause degradation of articular cartilage or there is pathologic change in the underlying subchondral bone," McIlwraith said.
What Should Treatment Do?
"The aims of all therapeutic procedures are to prevent the progressive loss of articular cartilage," said McIlwraith. "Many instances of early joint disease mainly manifest as synovitis and capsulitis, and their appropriate treatment will delay or prevent the cartilage loss of OA. On the other hand, timely and appropriate surgery for intra-articular fractures, osteochondritis dissecans (OCD), and other traumatic injuries to joints is also a necessary part of preventing OA."
McIlwraith stressed that research has shown the significance of understanding the inflammatory cascade that leads up to OA. His group at Colorado State University and others have been delving into when and how the inflammation starts, and how to stop the progression. "The principle factor of significance at the top of the inflammatory cascade in equine OA is interleukin-1 (IL-1, a deleterious cytokine, or inflammatory mediator)," stated McIlwraith. "When considering therapies, attention to inhibition to this molecule is critical."
Advances in Therapies
McIlwraith then discussed the latest research on conventional OA therapies and introduced newer biological therapies.
Physical therapy and rehabilitation McIlwraith said he feels just using stall confinement or turnout is not enough to properly rehabilitate horses being treated for OA or to avoid OA in injured animals. "Experimental data is lacking, but currently a study is ongoing at the CSU Orthopaedic Research Center examining the value of underwater treadmilling in an experimental model of OA," he said.
Shock wave therapy More is being learned about the applications for this therapy in humans and equines. "Shock wave therapy has been used as a treatment for a number of conditions," said McIlwraith. "Most recently the value of shock wave therapy has been demonstrated with experimental OA in the horse. The major usefulness is in decreasing the inflammatory response from synovial membrane and joint capsule, as well as symptomatic decrease in lameness."
Non-steroidal anti-inflammatory drugs (NSAIDs) McIlwraith said generalized cyclooxygenase (COX, a type of enzyme) inhibitors, such as phenylbutazone (Bute) and flunixin meglumine, have been used for a long time, but side effects in ponies and young foals, and at larger doses in adults, have been noted. Then came the new cyclooxygenase-2 (COX-2) inhibitors. "These can potentially provide focused inhibition of inflammatory-mediated cyclooxygenase production while preserving the normal physiologic COX-1 activities and thereby reducing side effects," said McIlwraith. He stressed there is only one licensed COX-2 product in the United States, firocoxib (Equioxx), although there are other products (such as meloxicam) available elsewhere. "Most recently the value of the topical liposomal-based 1% cream of diclofenac (Surpass) has been demonstrated in an experimental model of synovitis," said McIlwraith. He noted Surpass had symptom-modifying as well as disease-modifying effects, "and the topical use (of Surpass) for 30 days provided more benefit than systemic phenylbutazone in another experimental group."
Intra-articular corticosteroids McIlwraith said corticosteroids have gotten a bad rap from the general industry, and not all corticosteroids have the same negative effects on joint cartilage. "Recent work has identified deleterious effects with methylprednisolone acetate (Depo-Medrol), but marked beneficial effects from triamcinolone acetonide (Vetalog) and betamethasone esters (Celestone)," stressed McIlwraith. "They are still the most potent anti-inflammatory drugs and are still commonly used in combination therapies, primarily with hyaluronan.
"I like to use this as an example of clinical observation leading to questioning of dogma and scientific investigation," he added.
Hyaluronic acid (HA) McIlwraith said recent research using the CSU equine OA model demonstrated that intra-articular HA had disease-modifying osteoarthritic drug effects, which supports the long-term value of this treatment. He said their research showed decreased synovitis with use of intra-articular HA. "We have also done research with intravenous HA in the model and there were positive effects as well," he noted. "The main use of intravenous HA has been prophylactic. Horses that have no apparent problems get regular maintenance injections with HA. Two studies in racing Quarter Horses found those that were treated raced better. A study in normal Thoroughbreds showed no difference in biomarkers (that indicate joint health). It's still an unproven area."
There also are oral HA products. He said if you feed HA you get a higher level of the molecule in blood, but higher HA in blood is a marker for OA.
"We still haven't figured it out," he admitted, but he added that there is one study in Kentucky showing a positive benefit with oral HA reducing synovial effusion following arthroscopic surgery for OCD in the hock.
Polysulfated glycosaminoglycans (PSGAGs, trade name Adequan) Recent research has shown there are different uses for PSGAGs administered intra-articularly and intramuscularly. "Intra-articular Adequan was recently shown to be highly beneficial for inhibiting acute inflammation in the synovial membrane and fibrous joint capsule in the CSU equine OA model," said McIlwraith.
On the other hand, he said, intramuscular Adequan has been tested in the experimental OA model and minimal effectiveness was demonstrated. "Use of Adequan on a 'prophylactic' based continues, and it is certainly agreed that no harm is done," stated McIlwraith. "The beneficial effects still need to be demonstrated, but this is difficult."
Pentosan polysulfate McIlwraith said while this drug is not available in the United States, it is available in other parts of the world as Pentosan Equine. "This is an intramuscular product that has been demonstrated as beneficial in the CSU OA model, implying superiority of this product to intramuscular Adequan," he said.
Autologous conditioned serum (interleukin-1 receptor antagonist protein, or IRAP) This product is based on processing blood from a horse to be used in that same horse (a biologic therapy to produce IRAP and other pro-inflammatory proteins to combat pro-inflammatory molecules, such as interleukin-1). "Research has shown upregulation of interleukin-1 receptor antagonist/IL-1 ratio as well as upregulation of other growth factors to a lesser degree," noted McIlwraith. Testing in the CSU OA model has shown beneficial effects that were symptom-modifying and disease-modifying. "The principle clinical use is post-surgery and also for OA that is no longer responsive to HA/Vetalog combination therapy."
Platelet-Rich Plasma (PRP) Tendons are composed of large amounts of extracellular matrix (ECM). Growth factors enhance tendon and ligament healing by increasing the synthesis of the ECM. The use of PRP is based on the high growth factor content of platelets. "The concentration of platelets allows for a growth factor-rich medium, and PRP has received considerable use in the treatment of tendon and ligamentous injuries," noted McIlwraith. He said use of this product intra-articularly is being evaluated.
Gene therapy with interleukin-1 receptor antagonist (IL-1ra) Initial research has shown gene therapy using an adenoviral vector containing the equine IL-1ra gene could shut down experimental osteoarthritis in the horse, said McIlwraith. Repeat injections of the vector caused immunologic responses, so work has continued in the development of a better vector. "Work by Goodrich et al. at CSU on an adenoassociated viral vector (aaV) is proving promising, and there is hope that gene therapy (for treating OA) will soon become a clinical reality."
Oral joint supplements "My overall feeling is there is very little proof these are effective," said McIlwraith. "That doesn't mean they aren't useful, but no one has done any scientific studies. They are a thorn in the side of companies who pay money to get regulated products licensed."
Other products There is some information that omega-3 fatty acids can help OA, noted McIlwraith. He said in humans, three to four months of supplementation reduced joint pain. He mentioned a Platinum Performance product with omega-3 fatty acids in it as an example of one of the products on the market.
A clinical trial at CSU with unsaponified avocado soy (Vetoquinol) concluded that the product significantly reduced the severity of joint damage and significantly increased the synthesis of cartilage glycosaminoglycans (i.e., the "building blocks" of articular cartilage) in joints with OA, compared to horses treated with a placebo. McIlwraith said this was the "first well-controlled equine study demonstrating a positive effect with an oral nutraceutical." He said controlled studies of the product in humans also were positive.
About the Author
Kimberly S. Brown was the Publisher/Editor of The Horse: Your Guide To Equine Health Care from June 2008 to March 2010, and she served in various positions at Blood-Horse Publications since 1980.