IndexNon-steroidal anti-inflammatory drugs (NSAIDs)Non-steroidal anti-inflammatory drugs (NSAIDs)Intra-articular corticosteroidsHyaluronanPentosan polysulphateBiological therapiesStem cellsOral joint supplements in equine joint diseaseOsteoarthritis is the most common chronic joint disease which causes lameness in mature equine (60%) and human (21%) populations.160-162 Pain associated with chronic joint disease is the primary contributing factor to lameness and decreased performance in both companion and sport horses. 163 How Understanding of the complex etiology and pathogenesis of this disease has increased in recent decades, as has the number of therapeutic options available to equine veterinarians. Therapies directed against osteoarthritis (OA) aim to mitigate both the pain and the progression of this degenerative disease. Simply put, the mechanisms of any therapy can be divided into symptom modifiers (e.g. decreased pain or degree of lameness) and disease modifiers (e.g. prevention of further cartilage degradation). Most of the recent literature refers to therapies used against OA such as symptom-modifying osteoarthritis drugs (SMOAD) and disease-modifying osteoarthritis drugs (DMAOD), where any treatment can exert the characteristics of one or both. This concept is particularly important in the equine athlete, as career longevity is critical to successful treatment of equine joint disease. Therefore, the clinician should always consider SMAOD and DMOAD effects downstream of a chosen treatment for equine joint disease. Say no to plagiarism. Get a tailor-made essay on "Why Violent Video Games Shouldn't Be Banned"? Get an Original Essay Today's market offers an ever-increasing number of options available to the equine doctor. Treatments, including nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, hyaluronic acid, polysulfated glycosaminoglycans, pentosan polysulfate, biologic therapies including stem cells, and a variety of supplements are often administered intra-articularly, systemically, or orally, and scientific evidence and clinics of each will be discussed in the following review. Most of the information presented was adapted from the second edition of Joint Disease in the Horse.159Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) The term nonsteroidal anti-inflammatory drugs (NSAIDs) refers to those agents that inhibit certain components of the enzyme system responsible for conversion of arachidonic acid into prostaglandins and thromboxane (arachidonic acid cascade). Of important importance is inhibition. Osteoarthritis is the most common chronic joint disease causing lameness in mature equine (60%) and human (21%) populations.160-162 Pain associated with chronic joint disease is the primary contributing factor to lameness and reduced performance in both companion and sport horses.163 As understanding of the complex etiology and pathogenesis of this disease has increased in recent decades, the number of treatment options available to equine veterinarians has also grown. Therapies directed against osteoarthritis (OA) aim to mitigate both the pain and the progression of this degenerative disease. Simply put, the mechanisms of any therapy can be divided into symptom modifiers (e.g. decreased pain or degree of lameness) and disease modifiers (e.g. prevention of further cartilage degradation). Most of the recent literature refers to therapiesused against OA as symptom-modifying osteoarthritis drugs (SMOAD) and disease-modifying osteoarthritis drugs (DMAOD), where any treatment can exert the characteristics of one or both. This concept is particularly important in the equine athlete, as career longevity is critical to successful treatment of equine joint disease. Therefore, the doctor should always consider the SMAOD and DMOAD effects downstream of the chosen treatment against equine joint diseases. Today's market offers an ever-increasing number of options available to the equine doctor. Treatments, including nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, hyaluronic acid, polysulfated glycosaminoglycans, pentosan polysulfate, biologic therapies including stem cells, and a variety of supplements are often administered intra-articularly, systemically, or orally, and scientific evidence and clinics of each will be discussed in the following review. Most of the information presented was adapted from the second edition of Joint Disease in the Horse.159Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) The term nonsteroidal anti-inflammatory drugs (NSAIDs) refers to those agents that inhibit certain components of the enzyme system responsible for conversion of arachidonic acid into prostaglandins and thromboxane (arachidonic acid cascade). Of important importance is the inhibition of the prostaglandin E (PGE) series of prostanoids, as they are intimately involved in pain, changes in cartilage metabolism, and persistent inflammation in diseased joints. Specifically, increases in synovial concentrations of prostaglandin E2 (PGE2) are known to be associated with synovial inflammation and decreased cartilage matrix in horses with OA. Currently, NSAIDs persist as a mainstay of treatment in acute injury cases, primarily due to their potent, but variable, mitigation of pain and inflammation locally and at the spinal cord level.3 However, the potential for side effects well known, including renal and gastrointestinal toxicity, prevent its use as a long-term treatment of joint diseases. This may, however, be in favor of clinicians, as recent research suggests that PGE2 inhibition may have long-term adverse effects on cartilage metabolism.4 Nonetheless, controversies based on current knowledge and the lack of evidence in the horse make it unlikely that the clinical use of NSAIDs needs to be modified. All NSAIDs inhibit cyclooxygenase (COX) to some extent and their action may be nonspecific or limited to the inhibition of a single isoenzyme of the COX pathway (COX-1 and COX-2). 1,2 COX-1 is produced constitutively and functions to help maintain normal physiological parameters of the gastrointestinal and renal systems. COX-2 is inducible and is primarily associated with mononuclear and synovial cell-mediated inflammation in equine joint disease. However, it is not that simple as COX-1 is good and COX-2 is bad. Constitutive production of COX-2 has been demonstrated in normal physiological processes in multiple organ systems including the brain, kidney, pancreas, and bone. Furthermore, in a mouse model, suppression of COX-2 delayed gastric ulcer healing. Phenylbutazone and flunixin meglumine are the most commonly used NSAIDs in equine veterinary medicine and can be administered intravenously or orally. Phenylbutazone, often administered at a dose of 4.4 mg/kg once or 2.2 mg/kg twice daily, has a non-selective mechanism of action for COX and is considered one of the most potent NSAIDs due to its symptom modifying effects.Therefore, it is commonly chosen as a treatment for acute equine musculoskeletal disease. This is supported by research showing decreased PGE2 concentrations in synovial fluid following experimental induction of OA, although results have been variable when treating natural OA.5,6 In general, it is recommended to administer the phenylbutazone at a dose of 4.4 mg/kg. once a day. This is primarily the result of a study showing that the elimination half-life of phenylbutazone is 24 hours in exudative material, although its plasma half-life has been shown to be 5.5 hours in horses and ponies.9-12 Due to its non-selective action of COX, long-term administration of phenylbutazone has been associated with the development of adverse effects in vivo, such as elevated serum creatinine levels and diarrhea. Data investigating whether or not phenylbutazone is harmful to articular cartilage are contradictory. Two in vitro studies found no evidence that phenylbutazone was harmful to cartilage. However, a recent in vitro study showed decreased proteoglycan synthesis in cartilage explants exposed to serum from horses that had previously been administered phenylbutazone for 14 days.7, 8, 21 These side effects have led to the development of more selective for COX-2, such as firocoxib. It has been approved for use in horses to control pain and inflammation associated with OA, with the idea that selective action should improve the safety profile of long-term administration. Second, a topical NSAID that contains 1% diclofenac sodium is now available in the United States. Extrapolating from the human literature, it is believed that topical NSAIDs could be clinically beneficial while reducing systemic side effects. Regarding joint diseases, recent work has demonstrated the DMOAD effects of this drug in equine OA, characterized by an increase in the staining of proteoglycans and the GAG ​​content of the cartilage.5 Anecdotal and objective evaluations show the clinical capacity of NSAIDs to improve lameness. The proposed mechanism by which NSAIDs provide pain reduction involves the reversal of alterations in nociceptive thresholds, both locally and peripherally, through the inhibition of prostaglandin production.14 Numerous studies have tested the efficacy of 4 .4 mg/kg phenylbutazone for pain relief in various models has shown significant reductions in lameness 2 to 24 hours after treatment.13, 15 Interestingly, one study compared 4.4 mg/kg with 8.8 mg/kg showed no advantage of the higher dose over the lower dose.16 Flunixin Meglumine, often administered at a dose of 1.1 mg/kg, can provide analgesia rapidly for up to 2 hours after administration and persist for up to 30 hours.17 When phenylbutazone and flunixin meglumine were compared in horses with navicular syndrome, both provided an improvement in the degree of lameness and peak vertical force, with no significant difference between the two.18 However, when administered simultaneously for 5 days (oral administration of phenylbutazone and intravenous administration of flunixin) in 29 naturally lame horses, the combination showed better clinical improvement 12 hours after the last dose compared to phenylbutazone alone.6 It is important to note that a horse in the group that received both NSAIDs died of necrotizing colitis, highlighting the importance of clinical discretion. Firocoxib is the only selective COX-2 inhibitor licensed for use in horses in the United States. Compared to oral phenylbutazone in 253 horses in one studyrandomized controlled trial, no difference in clinical lameness scores was observed between groups.19 These findings were supported by another study which demonstrated that approximately 80% of 390 horses with OA had improved lameness scores after 14 days of oral firocoxib. Improvement was most rapid in the first 7 days, although it continued at a slower rate until day 14.20 NSAIDs are commonly used to reduce inflammation in performance horses. Therefore, it is important to consider their potential analgesic effects regarding withdrawal from competition. Extensive literature reviews with different interpretations were conducted. Although there are reports supporting an association between NSAID use and musculoskeletal injuries, further studies need to be conducted to determine whether horses with higher plasma NSAID concentrations have an altered risk of musculoskeletal injuries compared to other horses.22 This is mainly due to the fact that no study investigating this association has normalized for other possible risk factors (age, discipline, surface, duration of performance, sex, training program, pre-existing pathological conditions, etc.) contributing to musculoskeletal injuries in horses. Therefore, the actual role of NSAIDs as a possible risk factor for musculoskeletal injuries remains a matter of debate. In summary, NSAIDs remain the standard of care for first-line treatment of trauma-induced inflammation, of which phenylbutazone and flunixin meglumine are the most commonly used. Newer preferential COX-2 inhibitors are available, but should not be considered substitutes for phenylbutazone and flunixin meglumine. Although NSAIDs and corticosteroids work to prevent or reduce the inflammatory response, they are not the same thing, as they exert their effects at different levels in the inflammatory cascade. COX-1 is primarily responsible for protective prostaglandins, while COX-2 plays an accessory role but is more important than previously thought. These facts, however, may still not offset the beneficial effects of selective COX-2 inhibition in joint diseases. Intra-articular Corticosteroids Intra-articular (IA) use of corticosteroids to treat musculoskeletal conditions was reported as early as 1955, and remains an important tool for professionals caring for the equine athlete.23 Corticosteroids they are powerful anti-inflammatory agents through the inhibition of inflammatory processes at all levels. The anti-inflammatory effect of glucocorticoids occurs through the alteration of cytoplasmic receptors, while pain relief is attributed to the inhibition of the enzyme phospholipase A2 and the expression of cyclooxygenase 2 (COX-2) in the arachidonic acid cascade. 31 Other well-recognized effects include reduction of capillary vessel dilation, margin migration and accumulation of inflammatory cells, and inhibition of soluble mediators including IL-1 and tumor necrosis factor alpha (TNFα).32, 33Hydrocortisone was the first reported corticosteroid (1955) used in horses and showed profound improvements in clinical signs in the majority of cases.23 In subsequent decades, corticosteroid use for musculoskeletal conditions increased, along with reports indicating that corticosteroids could be harmful in horses.24 Specifically, they were accused of producing laminitis, catastrophic exhaustion, and steroids. However, to the author's knowledge, there has never been any scientific demonstration of a comparable response associated with corticosteroid use in horses, but some authors continue to perpetuate the concept. Cases of illnessdegenerative joint disease caused by corticosteroids have been presented without evidence of such pathogenesis.25 Likewise, data on the potential of TA to produce laminitis conclude that there is no association between the onset of laminitis and AI use of TA.45 Overall, the literature supports the use of total body doses of 45 mg as safe in an otherwise healthy horse. Regarding catastrophic rupture injury, a role for corticosteroids in the pathogenesis has never been demonstrated. This is supported by work showing that TA and MPA are not harmful to the subchondral bone, but that it is more likely “that microdamage in the subchondral bone occurs early in the exercising athlete and this microdamage can lead to pathological fractures ”. 38, 43, 47, 48Today the modern doctor has various corticosteroids at his disposal. Those most commonly used in equine practice include methylprednisolone acetate (MPA), dexamethasone, betamethasone, and triamcinolone acetonide (TA). A long-standing debate surrounds the use of AI corticosteroids, as some individuals argue that their pain-modifying effects can lead to overuse and subsequent cartilage degradation. Early research on the intra-articular use of MPA investigated doses ranging from 80 to 120 mg/joint (high by clinical standards) in normal horses and those with induced OA, both with and without subsequent exercise.26-30 These studies have mainly focused on the intra-articular use of MPA. middle carpal and antebrachiocarpal joints. Each of them, to a different extent and largely depending on the selected dose and severity of the model, showed negative effects on joint and cartilage metabolism. Deleterious findings included decreased glycosaminoglycan (GAG) and proteoglycan staining, chondrocyte necrosis, hypocellularity, and cartilage fibrillation. Since many of the models selected were drastically more severe than those currently used, it is likely that some of these effects were exacerbated by induced trauma and instability. Currently, an osteochondral fragment model (OFM) of traumatic osteoarthritis serves as the gold standard for the in vitro study of the SMOAD and DMOAD effects of joint therapy in the horse.35-37More recent studies examining the effect of corticosteroids on equine cartilage have shown more beneficial results by attenuating cartilage degradation. In equine cartilage explants, this action was achieved with dexamethasone and TA through decreased degradation driven by interleukin 1 (IL-1) and activator protein C (APC). Previous work has demonstrated that IL-1 and APC (synthesized by chondrocytes at sites of cartilage fibrillation) act synergistically to promote degradation of articular cartilage.34 Controlled in vivo studies further clarify the therapeutic response of intra-articular corticosteroids in the horse. A landmark study investigating joint therapies in the osteochondral fragment model (OFM) found that two injections of 15 mg betamethasone 21 days apart into the middle carpal joint caused no deleterious effects on articular cartilage compared to saline. 35 Interestingly, this study also compared exercise to nonexercise in the injected joints and concluded that there are no harmful effects of exercise in the presence of corticosteroids. Although not significant, beneficial effects were noted, as often reported clinically. Over time, the OFM was modified to allow one joint to function as an internal control, creating a fragment in only one of the two jointsmiddle carpals of an individual. When MPA was studied in the OFM (the only controlled in vivo study in the horse), lameness, synovial PGE2 concentrations, and synovial membrane staining were slightly improved. However, cartilage histopathology scores were significantly worse, confirming that the deleterious effects of MPA on articular cartilage outweigh the benefits of inhibiting inflammation.37 These findings are supported by numerous other investigators demonstrating that multiple injections of clinical concentrations of AI MPA inhibit the development and maturation of tissue repair, are harmful to the synovial membrane, and degrade articular cartilage.39-41 It is important to highlight, however, that in one study, a single dose of MPA did not cause harmful effects to long-term on the quality of cartilage repair tissues.39 In equine practice, AI corticosteroids and local anesthetics are often used together (or on the same day). Current evidence from a recent study investigating the effects of MPA and lidocaine on bovine articular cartilage showed that when chondrocytes were exposed to both at the same time, no cells survived. The combined use of local anesthetics and corticosteroids in vivo in horses has not been studied. Unlike the results obtained with MPA, when the effects of TA were studied in OFM, the results were quite different. IA administration of 12 mg TA resulted in decreased lameness scores, decreased total synovial fluid protein (TP), and higher concentrations of hyaluronate (HA) and GAG compared to controls. Interestingly, TP, HA, and GAG concentrations improved regardless of the joint treated (fragment versus no fragment), indicating a remote DMOAD effect. It is important to remember that this remote effect also applies when using MPA, so the deleterious effects of repeated use of this drug may still cause adverse effects on joints other than the one directly treated. Overall, the findings support the favorable effects of AT on the degree of clinically detectable lameness, synovial fluid, synovial membrane, and articular cartilage, without deleterious effects on subchondral bone.36 A 2009 survey of 831 members of the American Association of Equine Practitioners (AAEP) revealed that MPA and TA are the most commonly used corticosteroids for the treatment of equine musculoskeletal diseases in the United States.46 These drugs are often combined with hyaluronic acid (HA) for intra-articular use and are used by convention in low- and high-motion joints, respectively. The most current research does not provide clear evidence of the beneficial effect of adding HA to MPA or TA for intra-articular injection. In fact, a recent publication was conducted which investigated the reduction in the degree of lameness following IA treatment with HA plus TA or TA alone. It was concluded that the success rate of IA TA three weeks after treatment was 87.8% while that of TA plus HA was 64.1%. This study, however, only analyzed the SMOAD (lameness) effects of each therapy and did not provide information on the inflammatory state of the joint after treatment. In other studies evaluating the combination of MPA plus HA versus no treatment on cartilage explants, a slight increase in proteoglycan synthesis was found. It is unclear whether this is beneficial or not, as increased proteoglycan synthesis may be an indicator of early OA.44 Does treatment with one corticosteroid last longer than another? Traditionally, it was thought that durationof response to corticosteroid injection had an inverse correlation with its water solubility, however others have proposed that the duration of action is more a reflection of the rate of hydrolysis of the drug and binding affinity to receptors in the joint .49, 50 However, the complete mechanism determining the duration of action remains unresolved, it is likely that there is a combination of these processes, as well as the total dose administered, the duration of treatment and the crystal size of the suspension.32, 50, 53 Insoluble compounds can persist in the joint for a longer period of time, however they do not activate their anti-inflammatory properties until they are hydrolyzed into their biologically active (prodrug) forms to bind to the appropriate receptors. Historically, MPA has been recognized as having the most rapid onset of action compared to other commonly selected corticosteroids. Indeed, MPA has been shown to be hydrolyzed to methylprednisolone in as little as 2 hours and persists as a prodrug in synovial fluid for up to 39 days.51 A clinical SMOAD effect has been shown to persist for up to 42 days after administration of IA MPA. 37 In contrast, AT is absorbed very rapidly from the joint into the bloodstream. Following AI administration of 6 mg TA, synovial fluid concentrations peaked 1 day after administration and were undetectable by day 15.52 In the author's opinion, the onset of clinically relevant improvement of pain occurs more rapidly with TA than with MPA, and the duration of improvement is slightly in favor of MPA (i.e. longer duration with MPA). In practice, veterinarians often recommend varying convalescence periods after administration of corticosteroids. In human patients receiving this treatment, multiple sources report a prolonged clinical response when rest from exercise is allowed following the injection. Therefore, as one author mentioned, “a period of limited joint motion would likely reduce drug clearance and allow for better IA tissue penetration,” although other research exists. 31 The authors generally use 24 hours of rest after IA injection of TA and 4–7 days when using MPA. In summary, when used intra-articularly, corticosteroids provide potent anti-inflammatory effects. There are differences in the profiles of beneficial versus deleterious effects between products. According to the author, betamethasone has no deleterious side effects, AT can promote cartilage health, and MPA has been shown to have some deleterious effects. The duration of clinical response to each product is multifactorial, although prolonged long-term effects have been documented and are likely due to downstream effects of interaction with cytoplasmic receptors. A period of rest following AI administration may increase local tissue absorption, although exercise has not been shown to be harmful. There is no good evidence linking corticosteroids to the induction of laminitis in otherwise healthy horses. Finally, there is no evidence that HA in combination with corticosteroids reduces adverse effects, however research showing the chondroprotective nature of HA justifies the appropriateness of combined therapy with TA or betamethasone. HyaluronanHyaluronan (HA) is a disaccharide molecule composed of d-glucuronic acid and N-acetyl-d-glucosamine, and is produced by synoviocytes and chondrocytes. It functions to form the backbone of the polyglycan aggrecan and is integral to the proper function of both synovial fluid and articular cartilage. HA, like other disaccharides, is made up of repeating units and therefore can be produced in severallengths. Therefore, the length determines the molecular weight (degree of polymerization) and, together with the overall concentration, is responsible for normal functioning. HA acts to lubricate the joint and to form a barrier at the synovial membrane to regulate fluid exchange.53, 54 In a diseased joint, this barrier formation minimizes white blood cells (WBC), free radicals and pro-inflammatory substances. infiltration of cytokines into the joint.55 Much research has been conducted on the effectiveness of HA as a treatment for joint diseases. There are multiple products in today's market, and while they contain relatively the same active ingredient, they differ in several key aspects, including protein concentration, cross-linking, and molecular weight. Based on an extensive literature review, HA with a molecular weight greater than approximately 500,000 Daltons consistently shows benefits.56 Most available commercial products have a molecular weight between 1 and 3 million Daltons, but, as mentioned above, it can vary in cross-linking and protein content. Those products that are synthetically cross-linked are marketed as providing “viscosupplementation,” in an attempt to restore the viscoelastic properties of the synovial fluid in a diseased joint to normal levels. In turn, as the synthetic cross-linking of an HA product increases, the molecular weight, free radical resistance, and retention time in the synovial space also increase.55 The increase in molecular weight, however, is not directly related to clinical efficacy. In a study comparing multiple treatments with low-to-medium molecular weight HA formulations (a product with an average molecular weight of 0.8-1.5 million Daltons versus a product with a low molecular weight of 0.5- 0.7 million Daltons), the medium weight product showed statistical superiority in reducing pain in patients with knee OA by up to 50% for 6 months after injection.57 It may therefore be reasonable to recommend the use of HA-based products with a molecular weight of 1-3 million Daltons (average molecular weight), as they ensure a lower monetary cost for the patient and show clinical superiority. In the horse, a dose of at least 20 mg in the middle carpal joint was required to evoke clinical improvement based on force plate analysis.58 Extrapolation of this dose to other joints should be treated with caution, as each joint has a different articulation. total surface area and volume of synovial fluid. Does HA have SMAOD and DMOAD effects in the equine joint? The limited number and quality of studies investigating this question leave the answer unanswered. However, in human medicine, a comprehensive study compiling published human studies showed a 28% to 54% reduction in pain and a 9% to 32% improvement in function for up to 18 months compared to baseline values.59 These effects SMOADs were not observed. been confirmed in the horse. DMOAD effects in the equine joint have been confirmed, characterized by a decrease in histological fibrillation of the articular cartilage and improvements in synovial membrane parameters.62 This is supported by evidence from the human literature demonstrating that medium-weight HA provides preservation of cartilage volume and no significant cartilage loss compared to controls.60 In a second human study, patients received 4 courses of medium molecular weight HA treatments with 5 weekly injections each course of treatment. Responders showed an improvement in knee OA symptoms and a significant long-term effect that islasted for at least 1 year after the final treatment.61 Human clinical studies, as well as the previously mentioned equine study, provide good evidence that the DMOAD action of HA administered weekly exists for three or more treatments.55 When l 'HA is compared with other joint therapies, such as corticosteroids, the results are variable. A comparison of high-molecular-weight HA and betamethasone in patients with human knee OA showed no significant differences between the groups.63 Interestingly, when low-molecular-weight HA was compared to MPA, the results short-term showed no difference between the two, however at 45 days after treatment, pain scores were lower in the HA group compared to MPA.64 Similarly, high molecular weight HA compared to triamcinolone esotonide revealed faster pain relief with corticosteroid treatment, but OA and pain scores were significantly lower at long-term follow-up. -up (12 and 26 weeks) in joints receiving HA alone.65 Nearly 60% of equine practitioners in one survey reported routinely combining HA and corticosteroids for intra-articular administration.66 In vivo research supports this notion, as a study conducted in a rabbit model of OA showed an 88% reduction in pathology with the combination of corticosteroids and HA, compared to 53% and 72% respectively with HA or TA alone.67 Again, in humans who received a combination of AI HA and TA for knee OA, the findings revealed that the combination therapy provided faster improvement in pain, had beneficial effects during one year after treatment, and showed no signs of deleterious effects on joint structure.68 Combination therapy, based on current peer-reviewed literature, supports the hypothetical notion that synergistic action may exist between HA and AT and that routine use may be justified. In today's equine athlete population, HA is also often administered intravenously as a prophylactic effort. When 40 mg HA administered intravenously once weekly for three weeks in an equine OA model, clinical lameness, synovial membrane histology, and synovial fluid parameters improved compared to controls at 42 days after the last treatment .69 HA has been shown to moderately reduce OA. associated pain in humans and is not refuted by work conducted on equine models. There are reports of beneficial effects from intra-articular administration of combined HA and AT, and a literature-based guideline for use is 20 to 22 mg of medium molecular weight HA with 3 to 5 mg of triamcinolone acetonide in a dose of 10 to 15 mL in a single injection.55 There is evidence of beneficial effects of HA alone (2 serial injections 1 week apart), and intravenous administration of HA for prophylaxis may be beneficial. Polysulfated glycosaminoglycan Polysulfated glycosaminoglycan (PSGAG) is a polysulfated polysaccharide with DMOAD activity, consisting mainly of the GAG ​​chondroitin sulfate. It can be given IA or IM and is used primarily in joint disease when damage to the articular cartilage is suspected and aims to prevent or reverse cartilage degeneration. Recent evidence also supports its application for the mitigation of synovitis.70 Early in vitro studies of PSGAG showed contradictory results, with one study finding inhibition of matrix metalloproteinase 3 (MMP-3) production and others finding showed an increase in collagen and GAG synthesis with a dose dependent nature. inhibitionof proteoglycan synthesis.71, 72 In vivo in the horse, AI PSGAG provided a significant reduction in cartilage fibrillation, erosion, chondrocyte death, and GAG staining in a carpal synovitis model using sodium monoiodoacetate, but it did nothing to improve the pre-existing joint fixation. cartilaginous lesions.73 When applied intra-articularly in equine OFM with OA, PSGAG significantly reduced synovial vascularity and subintimal fibrosis compared to HA or saline.74 When PSGAG was combined with low dosage, some adverse effects have been noted and therefore this combination is not recommended based on in vivo experimental work in the horse.75 A 2011 survey of equine professionals revealed that the majority of individuals (84.1%) using PSGAG do administered intramuscularly (IM). However, when comparing IA to IM administration, it was concluded that greater potency was achieved via the IA route.76 Due to early reports of enhanced IA PSGAG joint infection, the IM route likely has clinical acceptance more general. It is important to note that with concomitant use of AI antibiotics (amikacin), the AI ​​route for PSGAGs has been shown to be an acceptable route of administration, and is in fact the preferred route by the authors.77 Although PSGAGs are often used by professionals for prophylactic purposes, there is minimal scientific evidence of effectiveness in this way. Pentosan Polysulfate Pentosan polysulfate (PPS) is isolated from beech wood hemicellulose and has a chemical structure of f(1-4)-linked β-Dxylan-pyranose repeating units.80 When the equine formulation is administered IM or subcutaneously (SQ), blood concentrations reach their peak after approximately 2 hours. Initial studies in animal models have proposed several beneficial mechanisms of PPS for the treatment of OA, including promotion of proteoglycan synthesis, inhibition of proteoglycan degradation, and increased synthesis of chondorprotective signaling molecules.81- 83 Other early studies also highlighted the anticoagulant effects of PPS and hypothesized that it may be useful in the treatment of joint disease through improved perfusion of the subchondral bone.84 Because of these vascular effects, it has been proposed that PPS may delay rate of subchondral bone necrosis and sclerosis.80 However, in a study investigating the anticoagulant effects of IV PPS in horses, a dose-dependent increase in partial thrombin time was demonstrated that persisted for up to 24 hours.87 Therefore some have recommended against giving horses doses of 3 mg/kg or higher within 24 hours. hours of intense activity or where physical injury may pose a risk. The mechanisms of action of PPS relevant to joint diseases are hypothesized to be twofold, as it has been shown to promote HA synthesis in osteoarthritic joints and inhibit the induction of articular cartilage matrix degeneration through inhibition of MMPs and modulation of cytokine receptors, although other research exists.85, 86 The first in vivo study in the horse used the OFM model to compare 3 mg/kg PPS IM with an equivalent volume of saline. Results showed minor DMOAD effects, including reduced articular cartilage fibrillation, increased markers of chondroitin sulfate (CS) synthesis in arthritic and nonarthritic joints of the same individual, and trends toward improved cartilage histology scores. 88 Based on the remote effect on CS synthesis, systemic upregulation of the may occursynthesis of aggrecan.159 When the results of IM administration of a recommended dose (3 mg/kg) of PPS are compared to IM administration of the recommended dose (500 mg) of PSGAG using the same experimental model in a separate study, the PPS produced more favorable results.89 Interestingly, a second study using the OFM model of OA showed beneficial DMOAD effects of IV PPS administered in combination with N-acetyl glucosamine (NAG) and HA. The results were, however, inferior to those demonstrated with PPS alone in the same model.90 Although there is no published confirmation of the SMOAD effects of PPS, clinical application in 39 horses with OA showed that 3 mg/kg of PPS IM improved lameness scores faster and maintained this improvement longer than 500 mg PSGAG IM.159 Clinical reports indicate that 3 mg/kg administered IM once weekly for 4 weeks is anecdotally beneficial. Repeated evaluations confirm that, compared to IM PSGAG, pentosan polysulfate is the only systemically administered DMOAD available to the equine veterinarian. Biological Therapies Biological therapy has become mainstream in the treatment of equine joint disease. Commercially available options include autologous conditioned serum (ACS), platelet-rich plasma (PRP), and stem cells. Each is prescribed various attributes and equine veterinarians tend to use that biological therapy that they feel most comfortable applying based on experience. The production of ACS was first described in 2003 and involves the incubation of whole blood with medical grade glass beads with specific surface characteristics.91 This process is intended to increase the production of anti-inflammatory cytokines, however it cannot be achieved without also allowing the production of proinflammatory cytokines. What is quite important, as has been demonstrated in the horse, is the relationship between the production of anti- and pro-inflammatory cytokines.92 IRAP, as ACS products are called, refers to the interleukin 1 receptor antagonist protein and is the target molecule of upregulation in ACS processing. It is recognized, however, that ACS products contain many proteins other than IRAP alone, and that during incubation many of these (at least 35 different proteins) are at least doubled in concentration (D. Frisbie, unpublished data) . In fact, “using equine blood, IRAP, IL-10, insulin-like growth factor-1, transforming growth factor-β, tumor necrosis factor (TNF)-α, and IL-1β were all significantly upregulated using a kit Commercial ACS versus baseline serum.” 92 This highlights the fact that IRAP is not the only protein present in ACS, but that it is more of a “soup” of biologically active molecules. There is evidence to support the positive role of ACS in the treatment of joint disease. Results from a human study comparing ACS to HA and saline showed significantly superior results when ACS was used to treat knee OA compared to the other two in 376 patients. It also demonstrated that joints treated with ACS had a lower incidence of adverse reactions (23%) compared to saline (28%) and HA (23%).93 In another study, some clinical parameters of OA were decreased up to 1 year after ACS treatment, and IL-1β concentrations were lower in synovial fluid up to 10 days.94 There is one equine in vivo study evaluating ACS in induced equine OA. It demonstrated improvement in lameness, synovial membrane parameters, and cartilage fibrillation, indicating DMOAD and SMOAD effects.95 Interestingly,that IRAP concentrations increased and remained elevated throughout the study period, likely indicating a prolonged beneficial effect that stimulated endogenous production. The clinical use of ACS in the horse for the treatment of joint disease is anecdotal, however, but according to a survey of 791 equine practitioners, the most common indication for use is in joints that are unresponsive to steroids. Today, PRP has multiple recognized uses in medicine, and optimization for a specific application is likely to be the focus of future research. In equine practice, it is often used to treat musculoskeletal conditions related to tendon, ligament and joint injuries. Not all PRP products are created equally and variability in platelet concentration, platelet activators, and white blood cell (WBC) concentration may be seen. For musculoskeletal disorders, platelet concentrations 2-6 times those of serum have been shown to produce positive results, however concentrations greater than 6 times suggest adverse effects.96 Additionally, platelet activation may be important in stimulating production and release of biologically active substances. molecules. Three mechanisms of platelet activation have been proposed, including endogenous activation, calcium chloride, and thrombin. In studies comparing each method, only calcium chloride and endogenous activation were found to be non-harmful.96, 97 Second, one author proposed platelet activation via post-injection shock wave therapy. In an in vitro study where platelets were exposed to extracorporeal shock wave therapy, growth factor concentrations were increased compared to non-activated PRP.104 It is important to note that none of the known inflammatory cytokines produced by platelets were analyzed and it is not known whether the platelets were actually activated or simply destroyed as no comparison with platelet lysate has been studied. The appropriate concentration of white blood cells in PRP products is constantly a matter of debate. Currently, studies have shown deleterious effects of PRP preparations high in WBC, although, to date, no evidence of the same effect on preparations low in WBC has been published.98, 99 The presence of WBC may increase the presence of catabolic enzymes. in vivo, although this work has not been done. Equally important is to understand that platelets contain over 200 different preformed biologically active proteins stored in their α granules. Some of these are growth factors, while others may be pro-inflammatory. The clinical manifestation can therefore be dictated by the relationship between beneficial and deleterious molecules. Two systematic reviews have been conducted in the human literature. The first contained 6 studies and compared HA or saline with different PRP preparations in a total of 653 patients with knee OA. Overall, the results indicated a significant improvement in patient functional outcomes, with no significant effects on pain measures.100, 101 The second review was larger and included 1,543 patients with knee OA and again reported significant functional improvements.101 Differences in efficacy based on no centrifugation or activation methods were identified, however results from a single centrifugation did not appear as convincing as those obtained using a double centrifugation technique. This is in contrast to a second study that revealed a higher incidence of pain and swelling after a double centrifugation technique compared to a single one.102Little work has been published on the AI ​​use of PRP in the horse. One study confirmed once again that no activation, or activation via calcium chloride, produced the least clinical reaction, the lowest intra-articular white blood cell concentration, and the best growth factor profile.97 Furthermore, these authors note that ""in normal joints, intra-articular PRP induces a mild to moderate inflammatory response in synovial fluid, lasting approximately 1 day," and that platelets were activated simply by mixing them with synovial fluid. Therefore the addition of activators may not be necessary. A second study analyzing what the author calls autologous protein solution (APS) in 40 horses with natural OA showed significant improvement in lameness 14 years after treatment.103 All reports, both human and equines, suggest that case selection is likely important, and that there is a greater likelihood of beneficial outcomes in milder than severe cases in OA. In summary, there is more published clinical evidence in humans than in horses, and the level of evidence supporting use in horses is currently greater for ACS than for PRP. Stem CellsMesenchymal stem cells (MSCs) are those cells that have the ability to replicate and differentiate into various mesenchymal tissues.105 Their use to treat orthopedic diseases is rapidly becoming more common. Continued use has brought to light several important considerations, including source, dose, timing of treatment, and indications for specific types of musculoskeletal disease/injury. Stem cells can be harvested from different tissue sources in the body, but currently, marrow-derived cells harvested from the ileum show significantly better results based on cell matrix production following chondrocyte differentiation.107 When used to therapeutic purpose, doses in human studies with positive results and anecdotal evidence in horses have used cell numbers ranging from 10 to 50 million.2 When used to treat internal arterial injury or tendons, significantly best when treatment is delayed beyond resolution of the inflammatory phase of the lesion.108 Equine practitioners use stem cells for a variety of different applications, although their therapeutic use in joint disease has been most rigorously studied in the lining of cartilage , in OA and in the treatment of intra-articular soft tissue injuries. Focal cartilage defects have been reported to occur in over 50% of human knee and equine knee arthroscopies.109-112 In an attempt to regenerate functional articular cartilage using mesenchymal stem cells, these are retained over a defect using a matrix or simply injected freely into a joint compartment. The feasibility of implanting MSCs using a matrix has been demonstrated in numerous human clinical studies.113, 114 Most experimental studies using this technique in the horse have been relatively successful and have gained little popularity, as the cells must have been previously collected and expanded before definitive diagnosis of cartilaginous erosion in arthroscopy. One study, however, showed the superiority of autologous-derived cells over allogeneic ones, based on the fact that greater radiographic pathology was noted in defects treated with allogeneic compared to those treated with autologous cells. It is also interesting to note that mesenchymal stem cells can have apropensity for bone formation when combined with a PRP/fibrin matrix compared to cartilage defects.115 The combination of these findings seems to indicate that direct injection may currently be a superior technique to direct matrix implantation. When MSCs are freely injected into a joint compartment, they have been shown to inhabit multiple joint tissues, including articular cartilage and synovial membrane.116 This is noted in the human literature through two randomized trials, in which multiple doses of blood or marrow bone-derived stem cells were combined with HA and injected into the patients' knee after arthroscopic debridement. In the first study, both imaging and biopsy results showed significant improvement compared to HA alone, however functional scores were not significantly improved.119 The second, on the other hand, showed both the imaging that functional evidence of improvement for 1 to 2 years after the study. last injection.118 Evidence in an equine model with focal cartilage defect in the knee showed improved aggrecan staining (indicating improved repair) at 12 months after a single injection of 20 million bone marrow-derived MSCs 4 weeks after surgery.117For the treatment of OA with MSCs, results vary between models. In a study analyzing bone marrow-derived MSCs in rabbits with dissected anterior cruciate ligaments, the results revealed significantly less cartilage degeneration, osteophyte formation, and subchondral sclerosis compared to control animals.120 In the horse, however , the results confirmed safety, but were not so convincing for the use of MSCs in a knee OA model. The author reports that the timing of the injection (14 days after surgery) may have been inappropriate and may explain the results. It is also important to note, as it addresses clinical concerns, that a combination of studies using allogeneic or bone marrow-derived cells report reaction (flare) rates of no more than 9% in horses.121-123Intra-articular soft tissue injuries may provide the more convincing evidence for the use of AI MSCs. In 2003, a study in which the goat knee was destabilized via anterior cruciate ligament resection and complete medial meniscectomy demonstrated that 6 million AI MSCs provided not only protective effects to the articular cartilage, but also regeneration of 50-70% of the initial meniscal volume.124 The authors defined this as a “neomeniscus” and commented that the decrease in OA scores in the joints treated with MSCs was likely due to partial restabilization of the joint by the newly formed tissue. Subsequent studies in human and rabbit models supported this initial work and showed superior tissue quality with faster tissue regeneration after meniscectomy.125 With positive evidence in other species, research was then conducted in horses with clinical lameness localized to the knee. Initial pilot data in 15 cases of meniscal injury showed that 67% of horses with meniscal injuries that received MSC IA were able to return to their previous level of work. This led to the expansion of the project to include more cases and follow-up up to 36 months, and the results confirmed once again that arthroscopic meniscal debridement combined with the administration of HA plus AI MSC allowed 76% of horses to return to work, with 43% returning to work. their previous level of performance.121 It is important to note that all individuals includedin this study they were refractory to previous medical management. Overall, autologous bone marrow-derived MSCs are most commonly used in AI equine orthopedic research. Again, there are multiple applications for MSCs in the equine patient, including cartilage lesions, OA, and intra-articular soft tissue lesions. A period of at least 4 weeks between surgery/injury and MSC treatment appears to be appropriate. Focal articular cartilage defects may be observed to improve with arthroscopic debridement and MSC plus HA implantation, there is little evidence to support efficacy in cases of equine OA, and in cases of meniscal injury, a long-term improvement. Oral Joint Supplements in Equines Joint Diseases Due to the large costs associated with treating and preventing osteoarthritis, much research and development has been devoted to producing easy-to-administer oral supplements. It is estimated that nearly 50% of horse owners purchase and administer oral nutritional supplements, so the equine veterinarian must be familiar with the myriad of options.126 Most are aimed at supplementing with building blocks of articular cartilage or attenuation of the inflammatory cascade responsible for the progression of osteoarthritis. Most joint supplements contain glucosamine (GU) and chondroitin sulfate (CS). Both are components of articular cartilage and are thought to counteract its degradation through enzyme inhibition and the provision of cartilage precursors.127-140 Commercial products are often manufactured from bovine tracheal tissue and the marine mussel Perna canaliculus. In vitro tests on equine cartilage explants showed a minor reduction in cartilage matrix (GAG) degradation, but only at higher doses. Interestingly, doses of 6.5 to 25 mg/ml have been reported to have detrimental effects on cartilage.142 Obviously, in vitro studies do not accurately represent the clinical application of oral supplements, as the efficacy is highly dependent on the bioavailability of the active ingredients in the gastrointestinal tract. . Absorption must be efficient enough to increase levels in the blood and tissues to a therapeutic level to have any effect. In horses, oral absorption of CS and GU ranges from 22% to 32% and 2.5% to 6.5%, respectively.141, 144 Although these numbers are low, concentrations of GU have been shown increase in synovial fluid following oral administration of clinically selected drugs. doses.141 Furthermore, in the face of joint inflammation, evidence has been produced to suggest increased release of oral GU into synovial fluid compared to normal joints.145 However, the quantities measured in synovial fluid from in vivo studies in the horse they have never reached concentrations equal to those shown to be therapeutic in in vitro models. It appears that the type of GU and CS used, the dose, and the inflammatory state of the joint may dictate delivery to the desired site. Numerous in vivo studies have been conducted in horses and the results are variable. Some, however, support the use of CS and GU for the treatment of OA based on subjective improvements in the degree of lameness, objective increases in ground reaction forces, and decreases in joint injection frequency.146, 147 None of these studies were free from flaws and the evidence for their use is relatively weak. Also commercially available is a proprietary blend of New Zealand green-lipped mussel, shark cartilage, abalone and Biota orientalis lipid extract..