Osteoarthritis
■ PathophysiologyandClassification Several theoretical explanations underlie the pathophysiology of OA. As stated above, occasionally there is a clear explanation of the development of OA (i.e., following joint trauma, infection, etc.), but in most cases the cause is not clear.
At a basic level, two major factors are involved in the development of OA: mechanical load and tissue turnover or metabolism. In many cases of OA, it is likely that both of these factors play a role in the etio- pathogenesis, and to consider them separately is likely an oversimplification. For example, a normal load placed on a joint that has increased catabolic processes will eventually lead to the development of OA as that “normal load” overwhelms the repair capacity of that specific joint. Conversely, an abnormal load placed on a normal joint (i.e., balanced catabolic and anabolic processes) will also eventually develop OA, in part due to eventual increased turnover of components of the joint resulting in an inability for that joint to repair itself. For the purposes of this chapter, however, these processes will be considered independently.ABNORMAL BIOMECHANICAL LOAD. Examples of an abnormal mechanical load that overwhelms a joint's capacity for repair can be an obvious acute injury resulting in instability. Examples of these types of injuries include injury to collateral ligaments and other supporting structures of joints, fractures involving the articular surface, and injuries in the contralateral limb resulting in increased weight bearing.10 Importantly, these examples represent a single traumatic event resulting in joint instability and eventual development of OA if not managed appropriately or, in some cases, even if managed appropriately. The other broad category of biomechanical load resulting in OA is repeated low-grade damage that occurs with routine use, resulting in repeated microdamage to the structure of a joint.
At no one point are these low-grade injuries apparent, but over time this microdamage overwhelms a joint's capacity for repair and ultimately leads to development of OA. A primary example of this phenomenon is the changes that occur within the metacarpophalangeal joints of racehorses.11 In this context, there is a wealth of evidence suggesting that stress placed on the distal end of the third metacarpal bone results in increased stiffness of the subchondral bone and eventual microcracks that may progress to condylar fractures.12 Even if condylar fractures do not develop, the structural and molecular alterations induced by repetitive trauma lead to changes in the articular cartilage and predispose these horses to developing OA.13 Similarly, abnormal biomechanical forces are placed on joints when there are anatomic abnormalities such as severe angular limb deformities and hip dysplasia in calves, among others. Although the underlying causes in these situations are obvious, this too represents a form of repetitive injury, albeit one more obvious than what occurs with the microdamage associated with performance or the forces placed on joints on a regular basis due to the shear size of many large animal species. Irrespective of the underlying biomechanical cause, the result is initiation of a series of complex biochemical and metabolic events that result in an imbalance of anabolic and catabolic processes in the joint, eventually overwhelming the repair processes. This culmination of events leads to fibrillated and ulcerated articular cartilage, eburnation and sclerosis of the subchondral bone, hyperplasia of the synovial membrane, and development of periarticular osteophytes and enthesophytes.TISSUE METABOLISM. All tissues have capacity for turnover and repair, and the tissues in the joint are no exception. OA can be thought of as an imbalance between anabolic processes (repair) and catabolic processes (turnover).14 As discussed, factors that can upset this balance include biomechanical factors (see above), other trauma, inflammation, and sepsis.
Much of the discussion examining these factors focuses on the articular cartilage, but other tissues associated with joints are also important, including synovial membrane, ligaments, and subchondral bone. Recall that synovial fluid is an ultrafiltrate of plasma, thus the synovial membrane is the bidirectional interface between the joint and the remainder of the animal. Equine synoviocytes have recently been shown to be an important player in the development of OA in horses by regulating several pathways in cartilage associated with the progression of OA.2,15 In addition, synoviocytes are responsible for the production of several elements of synovial fluid, the critical component that along with articular cartilage is responsible for maintaining frictionless motion in joints. Taken together, these findings suggest that synoviocytes play an important role in development of OA, although their exact role and the clinical implications of these findings remain unclear.Loss of articular cartilage is a hallmark of OA, and therefore clearly the balance of anabolic and catabolic processes in this tissue is an important aspect of OA Articular cartilage is composed of cells, primarily chondrocytes, and an extracellular matrix (ECM) produced by these chondrocytes. The ECM consists of water (>70%), collagen (>90% type II), proteoglycan (aggrecan and aggrecan aggregates linked to hyaluronan). Loss of any of these components is critical, as inherent repair capacity of large (>3 to 5 mm), full-thickness defects is minimal and restoration of the critically important hyaline cartilage is difficult. Loss of articular cartilage is due to either biomechanical disruption (see above) or proteolytic enzymes synthesized by chondrocytes, synoviocytes, or other cell types that have invaded the joint in response to injury (e.g., neutrophils following joint sepsis). A major class of proteolytic enzymes involved in cartilage destruction include the matrix metalloproteinases (MMP), which are a family of more than 25 different enzymes, each with some degree of specificity to a component of the ECM.
For example, MMP-1 is also called collagenase 1 and is capable of cleaving type II collagen molecules. Similarly, a disintegrin and metalloproteinase (ADAM) class of enzymes, which are closely related to MMPs, is responsible for enzymatic destruction of aggrecan molecules. Although not always clear, these enzymes are produced by chondrocytes, synoviocytes, and other cells found in joints in response to various cytokines. The principal cytokines associated with stimulating production of these enzymes are the proinflammatory cytokines interleukin (IL)-1 and tumor necrosis factor (TNF)-α. These cytokines not only induce production of these enzymes but also encourage production of other mediators of joint destruction, including prostaglandin E2, oxygen free radicals, and nitric oxide. In a normal joint under normal condition, production of these catabolic compounds is countered by production of anabolic compounds that inhibit cartilage degradation. For example, tissue inhibitors of MMPs (TIMPs) are produced by several cell types within the joint, as is IL-1 receptor antagonist, which binds to IL-1 receptors thus preventing signal transduction. Delving into the host of mediators that regulate cartilage destruction is beyond the scope of this chapter; suffice it to say that the process is complex and involves the interaction of a wealth of mediators. Identification of these mediators of OA, along with their natural inhibitors, is important as this information offers a plethora of potential therapeutic targets to prevent progression of OA (see the Treatment section later). Ultimately, however, OA develops when catabolic mediators outpace anabolic mediators, resulting in loss of ECM components, loss of chondrocytes, and eventual cartilage fibrillation and exposure of subchondral bone. In most cases the exact cause of this imbalance is not clear and is likely multifactorial. Typically the rate of disease progression and severity of OA are related to the nature and severity of the primary insult, the animal's age, the joint location, and the animal's type and level of activity.■ Clinical Signs OA can affect any joint, and therefore the clinical signs will vary greatly depending on which joint is affected. We focus primarily on OA of the appendicular skeleton, but OA is common in the axial skeleton and any diarthrodial joint. Lameness in horses is a major problem that costs the horse industry hundreds of millions of dollars each year. Lameness is also highly prevalent in other large animal species, resulting in decreased production and welfare concerns.16 Undoubtedly, much of the lameness in horses is due to OA, although the exact locations, severity, and clinical implications of OA in horses depends on the age, use, severity, and individual response to the pathology associated with OA.17,18 In other large animal species, lameness is the primary clinical sign of OA, although the exact manifestation of the lameness will be related to species, animal size, and severity of disease. The pain, resulting in lameness, in OA comes from several sources. As stated, the primary area of pathology is the articular cartilage. Cartilage is devoid of innervation, so the pain arises from sensory nerves in periarticular structures, including synovium, joint capsule, subchondral bone, and surrounding ligaments. Either mechanical stimuli or chemical mediators of pain stimulate these sensory nerves. An example of a mechanical stimulus resulting in pain is increased synovial fluid stretching the joint capsule and synovium. It remains unclear in both animals and people if osteophytes or bone spurs result in pain or are merely a radiographic manifestation of joint disease. Theoretically, periarticular osteophytes could result in stretching of the richly innervated periosteum, causing pain, but in people this has not been conclusively demonstrated and in some cases has been refuted.19 In addition to lameness, other clinical signs associated with OA include synovial effusion of the affected joint, decreased range of motion, and angular limb deformities with visually obvious periarticular new bone formation as the disease becomes more severe.
■ Diagnosis Perineural anesthesia and intraarticular anesthesia can be useful for localizing the source of lameness and is a mainstay for the diagnosis of OA in large animals as, in most cases, physical examination alone is insufficient to confidently localize the source of pain resulting in lameness.20 Determining the origin of lameness, however, does not confirm the cause of lameness. Diagnostic imaging demonstrating articular changes consistent with OA is the primary means of confirming a diagnosis of OA. Diagnostic tests that can accurately identify OA prior to the onset of irreparable articular changes have clear clinical benefit over diagnostic imaging after these changes have occurred.
NON-IMAGING-BASED DIAGNOSTICS. Routine synovial fluid analysis of affected joints can distinguish pain and lameness associated with septic arthritis from OA, but in cases of OA, routine synovial analysis reveals only nonspecific changes. Therefore there has been a great deal of effort to identify specific biomarkers of early OA. Sources of these biomarkers have included serum, synovial fluid, and urine.21 The idea of serum biomarkers is attractive, as such samples are more easily collected than synovial fluid. Examples of biomarkers that have been examined include glycosaminoglycans (GAGs), collagen degradation markers and fragments of collagen, osteocalcin, C-terminal of bone type I collagen (CTX1), and cartilage oligomeric matrix protein (COMP).22,23 Many of these markers have shown promise in both naturally occurring OA and in vivo models of OA, but none has yet demonstrated sufficient evidence or feasibility for routine clinical use.
IMAGING-BASED DIAGNOSTICS. After identification of an involved joint, many imaging strategies can be used to confirm the cause of pain, evaluate the extent of injury, and determine which treatment approaches may be warranted in light of the exact pathology found within that joint. Radiographic evaluation has been the mainstay of these approaches for decades. Radiographic changes associated with OA can include loss of joint space, subchondral bone sclerosis, subchondral cystic lesions, periarticular marginal osteophyte formation, periosteal new bone production at sites of joint capsules and ligamentous attachments (enthesophytes), and occasionally subchondral lysis. These findings can progress from no abnormalities early in the course of disease to complete fusion or ankylosis of the joint as the disease progresses. The association of radiographic findings with clinical signs is not always clear, with severe pain occasionally being associated with minimal radiographic changes and, conversely, severe radiographic changes being associated with minimal to no pain. A well-studied example of this is OA of the distal metatarsal (i.e., tarsometatarsal and distal intertarsal) joints of horses.24 Thus more advanced imaging modalities, including cross-sectional imaging, have been attempted to more accurately assess these joints. High-field magnetic resonance imaging (MRI) is superior to low-field imaging for evaluating articular cartilage, although both approaches can provide useful information. MRI is superior to radiographs for detecting early changes associated with OA in both the cartilage and the periarticular structures, including subchondral bone.25 Scintigraphy can be particularly valuable in early disease states when other diagnostic methods have not revealed bone or soft tissue changes; anatomic detail, however, will be lacking. Computed tomography is an excellent imaging modality to examine increased density of subchondral bone, a major component of the pathophysiology of OA, especially in the context of repetitive trauma.26 The use of sonographic imaging to aid in the diagnosis of OA in horses is rapidly expanding due to the utility of this imaging technique and to the inability of perform cross-sectional imaging of many large animal species due to size. Ultrasonographic evidence of OA is limited to evaluation of the contours of the bone, as the sound beam cannot penetrate bone. Effusion, presence of osteophytes, periarticular soft tissue structures, and in some cases limited views of articular cartilage can be obtained.27,28 Finally, surgical arthroscopic evaluation of the articular surface likely provides the best ability to evaluate the articular cartilage of joints where arthroscopic evaluation is possible. This technique provides the added therapeutic benefit of simultaneous joint lavage and is used for these purposes in all large animal species.29,30
■ Treatment Because of the importance of lameness and OA in horses and other large animal species, there has been a great deal of research into developing effecting treatment approaches. As a result, there are many choices, with seemingly more each day. Clearly the choice will depend on the inciting cause of OA, stage of disease, joint involved, species involved, and use of that animal. In general, treatment of OA should be directed at eliminating any primary causes, halting disease progression, and encouraging repair and regeneration of damaged articular cartilage. An important point is to make the diagnosis early so that effective interventions can be implemented prior to the onset of irreparable joint damage. Examples of primary causes that should be addressed include recognition and surgical intervention of osteochondritis dissecans lesions, joint sepsis, and other underlying causes amenable to treatment. Specific treatments for OA are discussed in broad categories of treatment options, recognizing that there is a great deal of overlap among these options.
ANTIINFLAMMATORY AGENTS. NSAIDs are a mainstay of this class of drugs and are used ubiquitously in equine veterinary medicine in the management of OA. Prostaglandin E2 (PGE2) contributes to the pain, inflammation, and cartilage destruction that accompanies OA. Thus inhibition of the cyclooxygenase (COX) enzyme that is responsible for the breakdown of arachidonic acids into various prostaglandins is desirable from both a pain and a disease-modifying perspective. Because inhibition of COX-1, the constitutively expressed isoform of the COX enzyme, contributes to damage to the gastrointestinal (GI) tract by NSAIDs, great effort has been made to generate NSAIDs that selectively inhibit COX-2, the inducible isoform considered to cause inflammation.31 The effectiveness of this approach remains unclear in terms of safety, but likely both classes induce the desired antiinflammatory effect in OA.
Intraarticular steroids are the most potent antiinflammatory agents available and widely used in the management of OA in horses and other large animal species.32 These drugs are administered both systemically and intraarticularly for the management of OA, but they have been associated with progressive cartilage damage and chondrocyte cell death both in vivo and in vitro in multiple large animal species.33 These effects seem to be somewhat steroid dependent, with some steroids (i.e., methylprednisolone acetate) being more severe than others (i.e., triamcinolone).34 Moreover, the negative effects of steroids, especially triamcinolone, appear to be mitigated by combining these products with hyaluronan in some contexts. Thus current recommendations are for judicious use of steroids in joints, paying attention to steroid used, mobility of joint (i.e., high-motion versus low-motion), and frequency of injections to mitigate the negative effects of steroids on articular cartilage.
THERAPEUTICS BASED ON REPLACEMENT OF COMPONENTS OF NORMAL JOINTS. Numerous medications that consist of compounds found in joints have been specifically designed and marketed for treating OA in human and veterinary patients. Examples of these include polysulfated glycosaminoglycans (PSGAGs), hyaluronan, GAG peptide complexes, and chondroitin sulfate. These types of products are variably labeled for several routes of administration, including oral, intravenous, intramuscular, and intraarticular. Many of these products exert broad biological function from antiinflammatory properties to providing substrate to support the host repair process. Among these products, hyaluronan is the most widely studied. Most sources agree that larger molecular mass (i.e., >500 kDa) is important for any biological function to exist.35 At masses greater than 500 kDa, hyaluronan is thought to improve the viscoelasticity of synovial fluid and exert antiinflammatory properties.36 Much work remains to be done to clarify the effectiveness of hyaluronan, dose, ideal mass, and route of administration in regard to management of OA in large animals, although evidence exists that it is safe and appears to be beneficial in some contexts. Data on PSGAGS and similar products are equally equivocal regarding mechanisms, effectiveness, ideal product, and dosage. Despite these shortcomings, there are findings suggesting that this class of medications has benefit in the management of OA, primarily by exerting antiinflammatory properties and influencing proteoglycan degradation and production following administration. Importantly, intraarticular PSGAG administration has been shown to lower the number of bacteria required to cause synovial infection, and thus concurrent administration of intraarticular amikacin is recommended when administering PSGAGS in this manner.37,38
REGENERATIVE AND BIOLOGIC THERAPIES. Several regenerative and biologic therapies exist for management of OA, and this is especially true for equine OA. Examples of such therapies include autologous conditioned serum (ACS), also called IL-1 receptor antagonist protein or IRAP; platelet-rich plasma (PRP); and mesenchymal stem cell (MSC) therapy. ACS is thought to inhibit the effects of IL-1 and induce several additional antiinflammatory cytokines within the joint. ACS is widely used for early OA, with both anecdotal and scientific literature supporting its efficacy, although not universally.39,40 PRP is thought to provide a host of growth factors found in platelets to induce a beneficial change in joints affected with OA. Although strong evidence supporting its use for OA is lacking, there are data suggesting beneficial effects either alone or when combined with MSC therapy.41,42 The therapeutic potential of MSC therapy offers an attractive means of regulating inflammation and regeneration of critical tissues lost in OA. As with PRP, data exist suggesting that this approach may offer advantages in the treatment of OA, but much work remains regarding dose, source (i.e., allogenic or autologous), timing of administration, and safety.43,44
In summary, a wealth of treatment options are available for the management of OA in large animals. Unfortunately, many of these approaches are not well understood, and work remains to determine many aspects of the management of OA in large animals. Recognition of disease, treating the underlying cause as early as possible, and making management decisions based on case specifics are a mainstay of therapy to have the best possible outcome.
■ Prognosis Prognosis for large animals with OA depends on the initiating factors, duration and extent of joint destruction, joint affected, species of animals, and intended use of the animal. With early and aggressive treatment, many animals can return to soundness and athletic performance. In other cases, salvage in the form of surgical arthrodesis may provide the most favorable outcome.