Table of contentsNon-steroidal anti-inflammatory drugs (NSAIDs)Non-steroidal anti-inflammatory drugs (NSAIDs)Intra-articular corticosteroidsHyaluronanPentosan polysulfateBiological therapiesStem cellsOral joint supplements in equine joint diseasesOsteoarthritis is the most common chronic joint disease causing lameness in mature equines (60%) and humans (21%).160-162 Pain associated with chronic joint disease is the main contributing factor associated with lameness and decreased performance in horses. companion and sport horses.163 As the understanding of the complex etiology and pathogenesis of this disease has grown over the past several decades, so has the number of treatment options available to equine veterinarians. Therapies directed against osteoarthritis (OA) aim to alleviate both pain and the progression of this degenerative disease. Simply put, the mechanisms of a given therapy can be divided into symptom-modifying (e.g., decreasing pain or degree of lameness) and disease-modifying (e.g., preventing further cartilage breakdown) mechanisms. . The majority of recent literature refers to therapies used for osteoarthritis as symptom-modifying drugs of osteoarthritis (SMOAD) and disease-modifying drugs of osteoarthritis (DMAOD), where any given treatment can exert the characteristics of one or both. This concept is particularly important in the equine athlete, as career longevity is paramount to the successful treatment of equine joint diseases. As such, the clinician must always consider SMAOD and DMOAD effects downstream of a chosen equine joint disease treatment. Say no to plagiarism. Get a tailor-made essay on “Why Violent Video Games Should Not Be Banned”? Get an original essay Today's market offers an ever-increasing number of options available to the equine clinician. Treatments, including nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, hyaluronan, polysulfated glycosaminoglycans, pentosan polysulfate, biologic therapies including stem cells, and a number of supplements, are often administered intra -articular, systemic or oral. and the scientific and clinical evidence for each will be discussed in the following review. The majority of information presented has been 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 agents that inhibit certain components of the enzyme system responsible for of the conversion of arachidonic acid into prostaglandins and thromboxane (arachidonic acid cascade). Inhibition is important. Osteoarthritis is the most common chronic joint disease causing lameness in mature equines (60%) and humans (21%).160-162 Pain associated with chronic joint disease is the main contributing factor associated with lameness and to reduced performance in horses. both companion and sport horses.163 As understanding of the complex etiology and pathogenesis of this disease has grown in recent decades, the number of treatment options available to equine veterinarians also increased. Therapies directed against osteoarthritis (OA) aim to alleviate both pain and the progression of this degenerative disease. Simply put, the mechanisms of a given therapy can be divided into symptom-modifying mechanisms (e.g., reductionpain or degree of lameness) and disease modifying (e.g. prevention of further cartilage breakdown). The majority of recent literature refers to therapies used for osteoarthritis as symptom-modifying drugs of osteoarthritis (SMOAD) and disease-modifying drugs of osteoarthritis (DMAOD), where any given treatment can exert the characteristics of one or both. This concept is particularly important in the equine athlete, as career longevity is paramount to the successful treatment of equine joint diseases. As such, the clinician must always consider SMAOD and DMOAD effects downstream of a chosen treatment for equine joint disease. Today's market offers an ever-increasing number of options available to the equine clinician. Treatments, including nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, hyaluronan, polysulfated glycosaminoglycans, pentosan polysulfate, biologic therapies including stem cells, and a number of supplements, are often administered intra -articular, systemic or oral. and the scientific and clinical evidence for each will be discussed in the following review. The majority of information presented has been 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 agents that inhibit certain components of the enzyme system responsible for of the conversion of arachidonic acid into prostaglandins and thromboxane (arachidonic acid cascade). Inhibition of the prostanoid series of prostaglandins E (PGE) is important, as they are intimately involved in pain, changes in cartilage metabolism, and persistent inflammation in diseased joints. Specifically, elevations in synovial prostaglandin E2 (PGE2) concentrations are known to be associated with synovial inflammation and decreased cartilage matrix in horses with osteoarthritis. Currently, NSAIDs remain the mainstay of treatment in cases of acute injury, primarily due to their potent, but variable, attenuation of pain and inflammation locally and at the spinal cord level.3 However, the potential to Well-recognized adverse effects including renal and gastrointestinal toxicity preclude their use as a long-term treatment for 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 Despite this, controversy based on current knowledge and lack of Evidence in horses makes it unlikely that the clinical use of NSAIDs should be modified. All NSAIDs inhibit cyclooxygenase (COX) to some extent and their action may be nonspecific or limited to inhibition of a single isozyme 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 diseases. It's not as simple as COX-1 is good and COX-2 is bad, however. Constitutive COX-2 production has been demonstrated in normal physiological processes in several organ systems, including the brain, kidney, pancreas, and bone. Additionally, in a mouse model, suppression of COX-2 delayed gastric ulcer healing. Phenylbutazone and flunixin meglumine are the most common NSAIDscommonly used 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-COX-selective mechanism of action and is considered one of the NSAIDs most potent for its symptom-modifying effects. Thus, it is commonly chosen as a treatment for acute musculoskeletal diseases of equines. This is supported by research showing decreased PGE2 concentrations in synovial fluid following experimental induction of OA, although results have been variable in the treatment of naturally occurring OA.5, 6 Generally, it is recommended that phenylbutazone be administered 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 materials, although its plasma half-life was 5.5 hours in horses and ponies. .9-12. 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. The data on whether or not phenylbutazone is harmful to articular cartilage are conflicting. Two in vitro studies found no evidence that phenylbutazone was harmful to cartilage. However, a recent in vitro study showed a decrease in proteoglycan synthesis in cartilage explants exposed to serum from horses that had previously received phenylbutazone for 14 days. 7, 8, 21. These adverse effects led to the development NSAIDs more selective for COX-2, such as firocoxib. It has been approved for use in horses for the control of pain and inflammation associated with osteoarthritis, the idea being that the selective action should improve the safety profile of long-term administration. Second, there is now a topical NSAID in the United States containing 1% diclofenac sodium. Extrapolating from the human literature, it is believed that topical NSAIDs may be clinically beneficial while reducing systemic side effects. Regarding joint diseases, recent work has demonstrated DMOAD effects of this drug in equine osteoarthritis, characterized by increased proteoglycan staining and GAG content of cartilage.5 Anecdotal and objective evaluations show the clinical ability of NSAIDs to improve lameness. The proposed mechanism by which NSAIDs provide pain reduction is by reversing alterations in nociceptive threshold, both locally and peripherally, via inhibition of prostaglandin production.14 Many studies testing the effectiveness of 4, 4 mg/kg phenylbutazone to alleviate pain in different models showed significant results. reduction in lameness ranging from 2 to 24 hours after treatment.13,15 Interestingly, a study comparing 4.4 mg/kg to 8.8 mg/kg showed no benefit from the higher dose. elevated compared to the lowest dose.16 Flunixin meglumine, often given at a dose of 1.1 mg/kg, can provide analgesia as quickly as 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 resulted in improvement in the degree of lameness and maximum vertical strength. , with no significant difference between the two.18 However, when administered simultaneously for 5 days (oral administration of phenylbutazone and IV administration of flunixin) in 29 horses withnatural lameness, the combination showed better clinical improvement 12 hours after the last dose compared to phenylbutazone alone.6 It is important to note that one horse in the group receiving both NSAIDs died from necrotizing colitis, which highlights the importance of clinical discretion. Firocoxib is the only selective COX-2 inhibitor approved for use in horses in the United States. Compared to oral phenylbutazone in 253 horses in a randomized controlled trial, there was no difference in clinical lameness scores between groups.19 These results were supported by another study which showed that approximately 80% of 390 horses with osteoarthritis had improved lameness scores after 14 days of oral firocoxib. Improvement was most rapid during the first 7 days, but continued at a slower rate until day 14.20 NSAIDs are commonly used to reduce inflammation in sport horses. It is therefore important to consider their potential analgesic effects in terms of withdrawal from competition. Extensive literature reviews have been conducted with varying interpretations. Although there are reports of a link between NSAID use and musculoskeletal injuries, additional studies need to be conducted to determine whether horses with higher plasma concentrations of NSAIDs are at risk. higher musculoskeletal injuries compared to other horses.22 This is mainly because no studies examining this association have standardized for other possible risk factors (age, discipline, surface, duration of performance, gender, training program, pre-existing pathological conditions, etc.) contributing to musculoskeletal injuries in horses. Thus, the actual role of NSAIDs as a possible risk factor for musculoskeletal injuries remains under debate. In summary, NSAIDs remain the standard of care for first-line treatment of trauma-induced inflammation, with phenylbutazone and flunixin meglumine being the most commonly used. New 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 because they exert their effects at different levels of the inflammatory cascade. COX-1 is primarily responsible for protective prostaglandins, while COX-2 plays an accessory but more important role than previously thought. These facts, however, may not outweigh the beneficial effects of selective COX-2 inhibition in joint diseases. Intra-articular corticosteroids The intra-articular (IA) use of corticosteroids for the treatment of musculoskeletal conditions was reported as early as 1955, and remains an important tool for practitioners caring for the equine athlete.23 Corticosteroids are powerful anti-inflammatory agents via 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 expression of the enzyme phospholipase A2 and cyclooxygenase 2 (COX-2 ) in the arachidonic acid cascade.31 Other well-recognized effects include reduction of capillaries. dilatation, margination migration and accumulation of inflammatory cells, and inhibition of soluble mediators including IL-1 and tumor necrosis factor alpha (TNFα). 32, 33 Hydrocortisone was the first reported corticosteroid (1955) used in horses andshowed profound improvements in clinical signs. in most cases.23 Over the following decades, the use of corticosteroids for musculoskeletal conditions increased, alongside reports that corticosteroids might be harmful in horses.24 Specifically, they were accused to produce laminitis, catastrophic breakdown and steroid arthropathy. However, to the author's knowledge, there has never been a scientific demonstration of a comparable response associated with corticosteroid use in the horse, but some authors continue to perpetuate the concept. Cases of degenerative joint disease caused by corticosteroids have been presented without evidence of such pathogenesis.25 Similarly, data on the potential of AT to produce laminitis conclude that there is no association between the onset of laminitis and the use of AT by AI.45 In general, the literature supports the use of total body doses of 45 mg as safe in an otherwise healthy horse. Regarding catastrophic injuries, the role of corticosteroids in the pathogenesis has never been proven. This is supported by work showing that TA and MPA are not harmful to subchondral bone, but that it is more likely "that microdamage in subchondral bone occurs early in the athlete in exercise and that these microdamages can lead to pathological fractures. 38, 43, 47, 48 Today, several corticosteroids are available to the modern practitioner. Those most commonly used in equine practice are methylprednisolone acetate (MPA), dexamethasone, betamethasone, and triamcinolone acetonide (TA). A long-standing debate surrounds the use of AI corticosteroids, as some people argue that their pain-modifying effects can lead to overuse and subsequent cartilage breakdown. Early research into the intra-articular use of MPA studied doses of 80 to 120 mg/joint (high by clinical standards) in normal horses and in those with induced osteoarthritis, with or without subsequent exercise.26 -30 These studies have focused primarily on the intra-articular use of MPA. middle carpal and antebrachiocarpal joints. Each, to varying degrees and largely depending on the selected dose and severity of the model, showed negative effects on joint and cartilage metabolism. Deleterious outcomes included decreased glycosaminoglycan (GAG) and proteoglycan staining, chondrocyte necrosis, hypocellularity, and cartilage fibrillation. As most of the models selected were considerably more severe than those currently used, it is likely that some of these effects were compounded by induced trauma and instability. Currently, an osteochondral fragment (OFM) model of traumatic osteoarthritis serves as a reference for the in vitro study of the SMOAD and DMOAD effects of joint therapy in horses.35-37More recent studies investigating the effect of corticosteroids on equine cartilage further showed beneficial results in mitigating cartilage degradation. In equine cartilage explants, this action was achieved with dexamethasone and TA through a reduction in degradation induced by interleukin 1 (IL-1) and activator protein C (APC). Previous work has shown that IL-1 and APC (synthesized by chondrocytes at sites of cartilage fibrillation) act synergistically to promote articular cartilage degradation.34 Controlled in vivo studies further clarify the answer corticosteroid therapyintra-articular in the horse. A fundamental review of the body of work on joint therapies in the osteochondral fragment model (OFM) found that two injections of 15 mg of betamethasone 21 days apart into the middle carpal joint caused no effect deleterious on articular cartilage compared to saline.35 Interestingly, this study also compared exercise to non-exercise in the injected joints and concluded that there were no harmful effects of the exercise in the presence of corticosteroids. Although not significant, beneficial effects were noted, as is often reported clinically. Over time, OFM has been modified to allow one joint to function as an internal control, creating a fragment in only one of an individual's two middle carpal joints. When MPA was studied in OFM (the only controlled in vivo study in horses), lameness, synovial PGE2 concentrations, and synovial membrane staining were slightly improved. However, the histopathological scores of the cartilage were significantly worse, confirming that the deleterious effects of MPA on articular cartilage outweigh the benefits of inhibiting inflammation.37 These results are supported by several other investigators showing that multiple injections of high concentrations AI clinical MPA inhibits the development and maturation of repair. tissues, are harmful to the synovial membrane and degrade articular cartilage.39-41 It is important to emphasize, however, that in one study, a single dose of MPA did not cause long-term adverse effects on the quality cartilage repair tissue. .39 In equine practice, IA 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 simultaneously, 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 AT were studied in OFM, the result was very different. IA administration of 12 mg TA produced decreased lameness scores, decreased synovial fluid total protein (TP), and higher concentrations of hyaluronan (HA) and GAG compared to controls. Interestingly, TP, HA, and GAG concentrations were improved regardless of the joint treated (fragment vs. no fragment), indicating a remote DMOAD effect. It is important to mention that this remote effect also applies when using MPA, so the deleterious effects of repeated use of this medication may still cause negative effects on joints other than the one directly treated. Overall, the results 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 survey conducted in 2009 among 831 members of the American Association of Equine Practitioners (AAEP) found that MPA and TA are the most commonly used corticosteroids to treat equine musculoskeletal diseases in the United States.46 These medications are often combined with hyaluronic acid (HA) for intra-articular use and are used by convention in low and high movement joints respectively. Most recent research does not provide clear evidence of the beneficial effect of adding HA to MPA or TA forintra-articular injection. In fact, there was a recent publication looking at reducing the degree of lameness after AI treatment with HA plus TA or TA alone. It concluded that the success rate of AI TA three weeks after treatment was 87.8%, while that of AT plus HA was 64.1%. This study, however, only investigated the SMOAD (lameness) effects of each therapy and provided no insight into the inflammatory state of the joint after treatment. In other studies examining MPA plus HA versus no treatment in cartilage explants, a slight elevation in proteoglycan synthesis was observed. It is unclear whether this is beneficial or not, as increased proteoglycan synthesis may be an indicator of early osteoarthritis.44Does treatment with one corticosteroid last longer than another? Traditionally, the duration of response to corticosteroid injection was thought to have an inverse correlation with its water solubility, but others have proposed that the duration of action more closely reflects the rate of hydrolysis of the drug and its binding affinity to the receptor in the joint.49,50 Although the complete mechanism determining the duration of action remains unresolved, it is likely a combination of these processes, as well as the total dose administered, the duration of treatment and the size of the crystals in the suspension.32, 50, 53 Insoluble compounds may persist in the joint. for a longer period of time, however, they only activate their anti-inflammatory properties after being hydrolyzed into their biologically active (prodrug) forms to bind to the appropriate receptors. Historically, MPA has been recognized as having the fastest onset of action compared to other commonly selected corticosteroids. In fact, MPA has been shown to be hydrolyzed to methylprednisolone in just 2 hours and persist 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 IA administration of MPA.37 On the other hand, TA is very quickly absorbed from the joint into the blood circulation. Following IA administration of 6 mg TA, synovial fluid concentrations peaked 1 day after dosing and were undetectable by day 15.52 In the author's opinion, the occurrence of a clinically significant improvement in Pain occurs more quickly 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 variable convalescence periods after AI administration of corticosteroids. In human patients receiving this treatment, several sources report a prolonged clinical response when rest from exercise is allowed after injection. Thus, as one author mentions, "a period of restriction of joint movement would likely reduce drug clearance and allow better penetration of IA tissues", although further research exists. 31 Authors generally use 24 hours of rest after IA TA injection, and 4 to 7 days when using MPA. In summary, when used intra-articularly, corticosteroids provide potent anti-inflammatory effects. There are differences between products in their beneficial and harmful effect profiles. In the author's opinion, betamethosone has no deleterious side effects, TA may 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 areprobably due to downstream effects of interaction with cytoplasmic receptors. A period of rest after AI administration may increase local tissue absorption, although exercise has not been shown to be harmful. There is no strong evidence linking corticosteroids to the induction of laminitis in otherwise healthy horses. Finally, there is no evidence that HA in combination with corticosteroids alleviates negative effects, but research showing the chondroprotective nature of HA supports that combination therapy with TA or betamethasone is appropriate. HyaluronanHyaluronan (HA) is a disaccharide molecule composed of d-glucuronic acid and N-acetyl-d-glucosamine, produced by synoviocytes and chondrocytes. It forms the backbone of the aggrecan polyglycan and is integral to the proper functioning of synovial fluid and articular cartilage. HA, like other disaccharides, is made up of repeating units and can therefore be produced in different lengths. As such, length dictates molecular weight (degree of polymerization) and, in conjunction with overall concentration, is responsible for normal function. HA lubricates the joint and forms 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 effects. infiltration of cytokines into the joint.55Much research has been conducted on the effectiveness of HA as a treatment for joint diseases. Several products exist in today's market and, although 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 review of the literature, HA with a molecular weight greater than approximately 500,000 Daltons consistently provides benefits.56 The majority of commercial products available have a molecular weight between 1 and 3 million Daltons, but as mentioned before, it can vary. in crosslinking and protein content. Synthetically cross-linked products are marketed as providing "viscosupplementation", with the aim of returning the viscoelastic properties of the synovial fluid of 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 not directly correlated with clinical effectiveness. In a study comparing several treatments with medium to low molecular weight HA formulations (0.8 to 1.5 million Daltons product to a 0.5 to 0.7 million Daltons product), the product of average weight showed statistical superiority in reducing pain in patients with knee osteoarthritis by up to 50% for 6 months after injection.57 It may then be reasonable to recommend the use of HA products with a molecular weight of 1 to 3 million Daltons (average molecular weight), as this results in a lower monetary cost to the patient. , and shows clinical superiority. In horses, a dose of at least 20 mg to 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 effect. 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 addressing this question leave the answer unclear.suspense. However, in human medicine, a comprehensive study compiling published human trials showed a 28-54% reduction in pain and a 9-32% improvement in function for up to 18 months compared to normal values. baseline.59 These SMOAD effects were not observed. been confirmed in horses. The effects of DMOAD in the equine joint have been confirmed, characterized by a decrease in histological fibrillation of articular cartilage and improvements in synovial membrane parameters.62 This is supported by evidence from the human literature showing that HA of medium weight ensures the preservation of cartilage volume and no significant effect. loss of cartilage compared to controls.60 In a second human study, patients received 4 treatments of medium molecular weight HA with 5 weekly injections during each treatment course. Responders showed improvement in knee osteoarthritis symptoms and a significant long-term effect that lasted at least 1 year after final treatment.61 Human clinical trials, as well as the previously mentioned equine study, provide There is good evidence for the DMOAD action of HA administered weekly for three or more treatments.55 When HA is compared to other joint therapies, such as corticosteroids, results are variable. A comparison between high molecular weight HA and betamethasone in human patients with knee osteoarthritis showed no significant differences between the groups.63 Interestingly, when low molecular weight HA was When compared to MPA, short-term results showed no difference between the two, however at 45 days post-treatment, pain scores were lower in the HA-treated group than in the MPA group.64 Similarly , high molecular weight HA compared to triamcinolone hexotonide revealed more rapid pain relief with corticosteroid treatment, but osteoarthritis and pain scores were significantly lower at follow-up at long term. (12 and 26 weeks) in joints receiving HA only.65 Nearly 60% of equine practitioners in one survey reported that they routinely combine HA and corticosteroids for intra-articular administration.66 In vivo research supports this notion, as shown by a study conducted in a rabbit model of osteoarthritis showing an 88% reduction in pathology with the combination of corticosteroids and HA, compared to 53% and 72% respectively. with HA or AT alone.67 Again, in humans receiving a combination of AI, HA, and AT for knee OA. , findings revealed that the combination therapy led to more rapid improvement in pain, had beneficial effects for one year after treatment, and showed no signs of deleterious effects on joint structure.68 The combination therapy, based on Current peer-reviewed literature, hypothesizes the idea that some synergistic action between HA and TA may exist and that routine use may be warranted. In today's equine athletic population, HA is also often administered intravenously prophylactically. When 40 mg of HA was administered intravenously once a week for three weeks in an equine osteoarthritis model, clinical lameness, synovial membrane histology, and synovial fluid parameters were improved compared to controls 42 days after the last treatment. 69HA has been shown to moderately decrease osteoarthritis. associated pain in humans, and is not refuted by work carried out on equine models. There are reports of beneficial effects linked tointra-articular administration of combined HA and TA, and a guideline for use based on the literature is 20 to 22 mg of medium molecular weight HA with 3 to 5 mg of triamcinolone acetonide in a range 10 to 22 mg. 15 mL joint in a single injection.55 There is evidence of beneficial effects of AI HA alone (2 serial injections 1 week apart), and intravenous administration of HA for prophylactic purposes may be advantageous. Polysulfated GlycosaminoglycanPolysulfated glycosaminoglycan (PSGAG) is a polysulfated polysaccharide with DMOAD activity, consisting primarily of the chondroitin sulfate GAG. It can be administered IA or IM and is primarily used in joint diseases when articular cartilage damage is suspected and aims to prevent or reverse cartilage degeneration. Recently, evidence also supports its application to alleviate synovitis.70 Early in vitro studies of PSGAG showed conflicting results, with one study revealing inhibition of matrix metalloproteinase 3 (MMP-3) production, and others showing an increase in the synthesis of collagen and GAG ​​with a dose-dependent effect. inhibition of proteoglycan synthesis.71,72 In vivo in horses, AI PSGAG caused a significant reduction in cartilage fibrillation, erosion, chondrocyte death and GAG staining in a model of carpal synovitis using sodium monoiodoacetate, but did nothing to improve pre-existing joints. cartilage lesions.73 When applied intra-articularly in equine OFM of osteoarthritis, PSGAG significantly reduced synovial vascularization and subintimal fibrosis compared to HA or solution saline.74 When PSGAG was combined with a low dose of TA, some adverse effects were noted and this combination is therefore not recommended based on in vivo experimental work in horses.75A 2011 survey of equine practitioners revealed that the majority of individuals (84.1%) using PSGAG administer it intramuscularly (IM). However, when comparing IA administration to IM administration, it was concluded that greater potency was achieved via the IA route. 76 Due to early reports of potentiation of joint infection by IA PSGAG , the IM route probably has more general clinical acceptance. It is important to note that with concomitant use of IA antibiotics (amikacin), the IA route of PSGAG has been shown to be an acceptable route of administration and is in fact the preferred route of the authors.77 Although PSGAGs are often used by practitioners prophylactically, there is little scientific evidence of effectiveness in this manner. β-Dxylano-pyranoses.80 When the equine formulation is administered IM or subcutaneously (SQ), blood concentrations peak after approximately 2 hours. Early studies in animal models proposed several beneficial mechanisms of PPS for the treatment of osteoarthritis, including promotion of proteoglycan synthesis, inhibition of proteoglycan degradation, and increased synthesis of chondroprotective signaling molecules.81 -83 Other early studies also highlighted the anticoagulant effects of PPS and hypothesized that it may be beneficial in the treatment of joint diseases via improved perfusion into the subchondral bone.84 Due From these vascular effects, it has been proposed that PPS may delay the 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 the partial thrombin time which haspersisted for up to 24 hours has been observed.87 Thus, some have recommended that doses of 3 mg/kg or more should not be administered to horses within 24 hours. hours of strenuous activity or when physical injury may pose a risk. The mechanisms of action of PPS related to joint disease are thought to be twofold, as it has been shown to promote HA synthesis in OA joints and to inhibit induction. of articular cartilage matrix degeneration via inhibition of MMPs and modulation of cytokine receptors, although further research exists.85,86 The first in vivo study in horses used the OFM model to compare 3 mg/kg PPS IM to an equivalent volume of saline solution. Results showed minor DMOAD effects, including a reduction in articular cartilage fibrillation, an increase in markers of chondroitin sulfate (CS) synthesis in both arthritic and non-arthritic joints of the same individual, and a tendency toward improvement in cartilage histological scores.88 Based on the remote effect on CS synthesis. , systemic upregulation of aggrecan synthesis may occur.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 In a separate study, PPS produced more favorable results.89 Interestingly, a second study using the OFM model of osteoarthritis showed DMOAD effects. beneficial effects of IV PPS administered in combination with N-acetylglucosamine (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 osteoarthritis showed that 3 mg /kg of IM PPS improved lameness scores more quickly. and maintained this improvement longer compared to 500 mg PSGAG IM.159 Clinical reports indicate that 3 mg/kg administered IM once weekly for 4 weeks is anecdotally beneficial. Repeat evaluation confirms that, compared to IM PSGAG, Pentosan polysulfate is the only systemically administered DMOAD available to the equine veterinarian. Biological Therapies Biological therapy has become common in the treatment of equine joint diseases. Commercially available options include autologous conditioned serum (ACS), platelet-rich plasma (PRP), and stem cells. Various attributes are prescribed for each, and equine veterinarians tend to use the biological therapy they are most comfortable with based on their 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 aims to increase the production of anti-inflammatory cytokines, but cannot be achieved without also allowing the production of pro-inflammatory cytokines. What is very important, as has been demonstrated in the horse, is the relationship between the production of anti-inflammatory cytokines and the production of pro-inflammatory cytokines.92 IRAP, as the ACS products came to be called, refers to the interleukin 1 receptor antagonist protein and is the target molecule. of positive regulation in ACS treatment. 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 commercial ACS kit. compared to the base serum. 92 This highlights the fact that IRAP is not the only protein in the SCA, but rather it is a “soup” of biologically active molecules. There is evidence supporting the positive role of ACS in the treatment of joint diseases. Results from a human study comparing ACS to HA and saline showed significantly superior results when ACS was used to treat knee osteoarthritis compared to the other two in 376 patients. It also showed that joints treated with ACS had a lower incidence of adverse events (23%) compared to those treated with saline (28%) and HA (23%).93 In a another study, certain clinical parameters of osteoarthritis decreased up to one year after ACS. treatment, and IL-1β concentrations were lower in synovial fluid for up to 10 days.94 There is one in vivo equine study evaluating ACS in induced equine osteoarthritis. It demonstrated improvement in lameness, synovial membrane parameters and cartilage fibrillation, indicating DMOAD and SMOAD effects.95 Interestingly, IRAP concentrations increased and remained elevated throughout the period study, probably indicating a prolonged beneficial effect stimulated endogenous production. The clinical use of SCA in horses to treat joint diseases is, however, anecdotal, but according to a survey of 791 equine practitioners, the most common indication for use is in joints that do not respond to steroids. PRP has multiple recognized uses in medicine today and optimization for a specific application will likely be the subject of future research. In equine practice, it is often used for the treatment of musculoskeletal conditions related to tendon, ligament and joint injuries. Not all PRP products are created equal and variability may be seen in platelet concentration, platelet activators, and white blood cell (WBC) concentration. For musculoskeletal conditions, platelet concentrations 2 to 6 times those in serum have been shown to produce positive results, but concentrations greater than 6 times suggest negative effects.96 Additionally, platelet activation may be important in stimulating the production and release of biologically active substances. molecules. Three mechanisms of platelet activation have been proposed, including endogenous activation, calcium chloride, and thrombin. In trials comparing each method, only calcium chloride and endogenous activation were found to be non-detrimental.96,97 Second, one author proposed platelet activation via postinjection shock wave therapy. In an in vitro study in which platelets were exposed to extracorporeal shock wave therapy, growth factor concentrations were increased compared to unactivated PRP.104 It is important to note that none of the known inflammatory cytokines affect platelets. produced by the platelets were analyzed, and it is unclear whether the platelets were truly activated or simply destroyed, as no comparison with platelet lysate was studied. The appropriate concentration of leukocytes in PRP products is a topic of constant debate. Currently, studies have shown the deleterious effects of“high leukemia” PRP preparations although to date no evidence of the same effect has been published on “low” leukocyte preparations.98,99 The presence of leukocytes could increase the presence of catabolic enzymes. in vivo, although this work has not been carried out. It is also important 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 ratio of beneficial/deleterious molecules. Two systematic reviews were conducted in the human literature. The first contained 6 studies and compared IA HA or saline to various PRP preparations in a total of 653 patients with knee osteoarthritis. Overall, the results indicated a significant improvement in patients' functional outcomes, without significant effects on pain measures. 100, 101 The second review was larger and included 1,543 patients with knee osteoarthritis and a again reported significant functional improvements.101 Differences in effectiveness based on centrifugation methods or activation were not identified, but results from a single centrifugation did not appear as convincing as those using a duplicate technique. centrifugation. This is in contrast to a second study which found an increased incidence of pain and swelling after a double centrifugation technique compared to a single centrifugation technique.102 Little work has been published on the AI ​​use of PRP in horses. . One study further confirmed that no activation, or activation via calcium chloride, resulted in the least clinical reaction, the lowest intra-articular leukocyte concentration, and the best growth factor profile.97 Additionally , these authors note that "in normal joints, intra-articular PRP induces a mild to moderate inflammatory response in the synovial fluid, which lasts for approximately 1 day", and that platelets were activated by simple mixing with the synovial fluid. So, adding activators may not be necessary. A second study of what the author calls an autologous protein solution (APS) in 40 horses with naturally occurring osteoarthritis showed significant improvement in lameness 14 years after treatment.103 All reports, human and equine, suggest that case selection is likely important, and that there is a greater likelihood of beneficial outcomes in milder than in severe cases of 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 higher for ACS than for PRP. Stem CellsMesenchymal stem cells (MSCs) are cells that have the ability to replicate and differentiate into various mesenchymal tissues.105 Their use for the treatment of orthopedic diseases is quickly becoming more common. Continued use has highlighted several important considerations, including source, dose, timing of treatment, and indications for specific types of musculoskeletal diseases/injuries. Stem cells can be harvested from a number of different tissue sources in the body, but currently, bone marrow-derived cells harvested from the ilium show significantly better results in terms of cell matrix production after chondrocyte differentiation.107 When used therapeutically, doses in human studies withPositive results and anecdotal evidence in horses have used cell numbers ranging from 10 to 50 million. .2 When used to treat an AI or tendon injury, significantly better results are reported when treatment is delayed beyond resolution of the inflammatory phase of the injury.108Equine practitioners use the stem cells for a variety of different applications, although their therapeutic use in joint diseases has been studied most rigorously in cartilage resurfacing, osteoarthritis and for the treatment of intra-articular soft tissue injuries. Focal cartilage abnormalities are reported to occur in more than 50% of human knee and equine stifle arthroscopies.109-112 In an effort to regenerate functional articular cartilage using MSCs, these are either maintained over a defect using a matrix, or simply injected freely into a common compartment. The feasibility of implanting MSCs using a matrix has been demonstrated in several human clinical trials. 113, 114 Most experimental studies using this technique in horses have been relatively unsuccessful and have gained little in popularity, because the cells must have previously been harvested and expanded before definitive diagnosis of cartilage erosion at arthroscopy. One study, however, showed the superiority of autologous cells over allogeneic cells, based on the fact that more radiographic pathology was observed in allogeneically treated defects compared to those treated with autologous cells. It is also interesting to note that MSCs could have a propensity for bone formation when combined with a PRP/fibrin matrix on cartilage defects.115 The combination of these results seems to indicate that direct injection could currently be a superior technique to direct implantation of the matrix. When MSCs are injected freely 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 via two randomized trials, in which multiple doses Blood or bone marrow-derived stem cells were combined with HA and injected into the knee of patients after arthroscopic debridement. In the first study, imaging and biopsy results showed significant improvement compared to HA alone, but functional scores were not significantly improved.119 The second, on the other hand, showed both imaging evidence and functional evidence of improvement for 1 to 2 years after the last injection.118 Evidence in an equine model of focal cartilage defect in the stifle showed enhanced aggrecan staining (indicating better repair) 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 of bone marrow-derived AI MSCs in rabbits with severed anterior cruciate ligaments, results revealed significantly less cartilage degeneration, osteophyte formation, and subchondral sclerosis compared to control animals. .120 In horses, however, results confirmed safety but were not as compelling for the use of MSCs in a choking model of OA. The author reports that the timing of the injection (14 days after surgery) could have been inappropriate and could explain the results. It is also important to note, as thisaddresses clinical concerns, that a combination of studies using allogeneic or bone marrow-derived cells report reaction (push) rates of no more than 9% in the horse.121-123 Intra-articular soft tissue injuries can provide the most compelling evidence for the use of AI MSCs. In 2003, a study in which goat stifles were destabilized via ACL transection and complete medial meniscectomy showed that 6 million IA MSCs produced not only protective effects on articular cartilage, but also 50 to 70 years of regeneration. % of initial meniscal volume.124 The authors called this a “neomeniscal” and commented that the decrease in osteoarthritis scores in joints treated with MSC was likely due to partial restabilization of the joint. by the newly formed tissue. Subsequent studies in human and rabbit models supported this early work and showed superior tissue quality with faster tissue regeneration following meniscectomy.125 With positive evidence in other species, research was subsequently conducted on horses with clinical lameness localized to the stifle. Initial pilot data on 15 cases of meniscal injuries showed that 67% of horses with meniscal injuries that received AI MSCs were able to return to their previous level of work. This led to the expansion of the project, including more cases and follow-up of up to 36 months, and the results confirmed once again that arthroscopic meniscal debridement combined with the administration of HA plus IA MSC allowed 76% of horses return to work, including 43%. their previous level of performance.121 It is important to note that all individuals included in this study were refractory to previous medical management. Overall, autologous bone marrow-derived and culture-expanded MSCs are used most commonly in equine orthopedic AI research. There are again multiple applications for MSCs in the equine patient, including cartilage injuries, osteoarthritis, and intra-articular soft tissue injuries. A period of at least 4 weeks between surgery/injury and MSC treatment appears appropriate. Focal articular cartilage defects may improve with arthroscopic debridement and implantation of MSC plus HA, there is little evidence supporting effectiveness in cases of equine osteoarthritis, and in cases of meniscal lesions, improvement long term can be achieved. Oral Joint Supplements in Equines Joint Diseases Due to the enormous cost associated with the treatment and prevention of osteoarthritis, much research and development has gone into producing easy-to-administer oral supplements. It is estimated that nearly 50% of horse owners purchase and administer oral dietary supplements. The equine veterinarian must therefore become familiar with the myriad of options.126 The majority aim at supplementation of articular cartilage building blocks or attenuation of the inflammatory cascade. responsible for the progression of osteoarthritis. The majority of joint supplements contain glucosamine (GU) and chondroitin sulfate (CS). Both are components of articular cartilage and are thought to counteract degradation via enzymatic inhibition and provision of cartilage precursors.127-140 Commercial products are often made from bovine tracheal tissue and sea mussel Perna canaliculus. In vitro evidence on equine cartilage explants showed a minor reduction in cartilage matrix degradation (GAG), but only at higher doses. He is.