Chapter 80 - Medical treatment of joint disease Flashcards
Figure 80-1. Schematic representation of inhibition
of the inflammatory cascade by nonsteroidal antiinflammatory
drugs (NSAIDs) and corticosteroids.
Figure 80-2. Schematic representation of effects associated with the administration of nonsteroidal antiinflammatory drugs (NSAIDs). MMP, Matrix metalloproteinase.
Figure 80-3. Schematic representation of the cyclooxygenase isoenzymes and target tissues. PGH2, Prostaglandin H2.
What are the two main goals of medical treatment for osteoarthritis in horses?
Reducing pain (lameness) and minimizing progression of joint deterioration.
What factors influence the optimization of a treatment plan for OA?
Accurate diagnosis, stage of disease, severity, available treatment modalities, and rehabilitation time.
What is the primary action of nonsteroidal anti-inflammatory drugs (NSAIDs) in treating joint disease?
Inhibiting the arachidonic acid cascade.
Which specific prostaglandin series is involved in pain and inflammation in damaged joints?
Prostaglandin E (PGE) series.
Why is long-term use of NSAIDs limited in treating joint disease?
Due to renal and gastrointestinal side effects.
What is a significant concern regarding the inhibition of PGE production?
Potential long-term unfavorable effects on cartilage metabolism.
What discovery in the early 1990s advanced the understanding of NSAIDs for OA treatment?
Identification of cyclooxygenase (COX) isoenzymes COX-1 and COX-2.
What role does COX-1 play in the body?
Associated with housekeeping functions and normal physiological functions of the gastrointestinal and renal systems.
How is COX-2 primarily involved in the body?
Associated with inflammatory events driven by macrophages and synovial cells.
What adverse effects are linked to NSAIDs that preferentially inhibit COX-1?
Damage to the gastroduodenal mucosa.
What has research indicated about topical NSAID applications?
They can be clinically beneficial and may reduce systemic side effects.
Which NSAID remains popular for musculoskeletal pain in horses, and why?
Phenylbutazone; due to its cost, ease of administration, and relatively few side effects in short-term use.
What were the findings when comparing phenylbutazone and diclofenac cream in horses with OA?
Phenylbutazone was associated with significantly more pathologic changes.
What effect does phenylbutazone have on μ-opioid receptor (MOR) expression in equine synovial membrane?
It attenuates the upregulation of MOR expression following synovitis.
What is the significance of firocoxib in the treatment of equine OA?
It is a selective COX-2 inhibitor approved for use in horses, effective in controlling inflammation associated with OA.
What concerns arise from stacking NSAIDs like phenylbutazone with flunixin meglumine?
Potential secondary side effects from combining NSAIDs.
How did lameness scores change during a study of firocoxib administration?
Scores improved rapidly within the first 7 days and continued to improve more slowly through 14 days.
What does ongoing research need to focus on regarding NSAIDs?
Determining appropriate dosages and durations of prescription.
How does the pharmacokinetics of firocoxib impact its clinical use?
A loading dose has been shown to maintain a constant drug concentration.
What is the current status of NSAIDs in treating joint inflammation associated with OA in horses?
Continued use is likely, with selective COX-2 inhibitors being utilized more frequently.
What enzyme do corticosteroids inhibit in the arachidonic acid cascade?
Phospholipase A2.
What is a selective action of corticosteroids aside from their effects on the arachidonic acid cascade?
They are selective COX-2 inhibitors.
What three corticosteroid preparations are currently available for equine clinicians?
Methylprednisolone acetate (MPA), triamcinolone acetonide (TA), and compounded betamethasone.
Which corticosteroid preparation showed the most beneficial effects in studies?
Triamcinolone acetonide (TA).
What detrimental effects were noted with methylprednisolone acetate (MPA)?
Detrimental effects on articular cartilage.
What does the lack of measured effects from compounded betamethasone suggest?
It has a less potent effect on joint tissues compared to TA and MPA.
In what context is the use of corticosteroids particularly recommended?
In high-motion joints.
What concerns arise regarding corticosteroids and catastrophic racetrack injuries?
Their ability to mask pain and potentially exacerbate injuries.
What recommendation did the International Federation of Horse Racing Authorities make regarding corticosteroid withdrawal?
A 14-day withdrawal period.
What was the role of corticosteroids in the study linking them to musculoskeletal injuries?
A positive association was identified but not a specific causal role.
What combination of substances was found to be most toxic to bovine articular chondrocytes?
Methylprednisolone acetate (MPA) combined with lidocaine.
How did the administration of mepivacaine affect the efficacy of TA?
It did not alter the potency or duration of action of TA.
What is a controversial aspect regarding the rest period following IA corticosteroid treatment?
Whether a rest period is necessary for better drug penetration and effectiveness.
What concerns are there regarding corticosteroids’ effects on chondrocyte metabolism?
They may transiently decrease anabolic metabolism, but the concern is considered overstated.
What has been noted about the effects of MPA on joint tissues?
Changes induced by MPA can last for more than 21 days.
What does clinical impression suggest about confinement after corticosteroid injection?
Confinement for 7 to 10 days can prolong the duration of action.
What association has been suggested between corticosteroids and laminitis?
A corticosteroid-induced laminitis association has not been directly proven.
What are the suggested maximum total body doses of TA to avoid laminitis?
18 mg for TA, 200 mg for MPA, and 30 mg for compounded betamethasone.
What did studies reveal about the incidence of laminitis following TA injections?
Very low incidence rates of 0.5% and 0.15% were reported.
Why is it difficult to establish a consistent model of laminitis following corticosteroid injection?
Due to variability in clinical reports and anecdotal suggestions.
What total body dose of TA does the author typically use in healthy athletic horses?
20 to 40 mg.
What should be considered regarding the frequency of corticosteroid treatment?
Higher total body doses should not be repeated frequently, especially in unfit horses.
What potential effects did the study on IA corticosteroids show regarding inflammatory cytokines?
A therapy attenuated the effects of IL-1 and TNF-α on cartilage.
Which matrix metalloproteinases’ expression was decreased by corticosteroids?
MMP-1, MMP-3, and MMP-13 mRNA.
What finding suggests that corticosteroids might impede cartilage degradation?
Decreased expression of MMPs during inflammation.
What type of joint is triamcinolone acetonide particularly recommended for?
High-motion joints.
How can the effectiveness of corticosteroid injections be influenced post-treatment?
By the exercise or rest period that follows administration. box stall or paddock for 7 to 10 days, with a slow return to full work in the subsequent week can prolong the duration of action following injection,
what are the maximal dosages of triam, methy and beta?
It has been suggested that the total body dose of TA should not exceed 18 mg, MPA should not exceed 200 mg, and compounded betamethasone should not exceed 30 mg.
What are the two components that make up the disaccharide hyaluronan?
D-glucuronic acid and N-acetyl-D-glucosamine.
Who produces HA for incorporation into synovial fluid?
Synoviocytes.
What cells are responsible for producing HA that is incorporated into the extracellular matrix?
Chondrocytes.
How do the concentration and molecular weight of HA affect its function?
They are important for its normal function and lubricating properties.
What happens to the lubricating properties of HA during disease?
They are believed to decrease, leaving the joint unprotected.
What anti-inflammatory activities has exogenous HA been documented to have?
Inhibition of chemotaxis, phagocytosis, and lymphocyte activity.
What type of free radicals does HA scavenge?
Oxygen-derived free radicals.
What is the half-life of exogenous HA when administered intraarticularly?
In the magnitude of hours.
What is the hypothesized effect of exogenous HA administration on synoviocytes?
It may increase the synthesis of high-molecular-weight hyaluronate.
What correlation has been established regarding HA and articular cartilage erosion?
A direct correlation between lubricating properties of HA and cartilage erosion.
What is the normal molecular weight range for HA found in synovial fluid?
0.5 to 3.0 million Daltons.
What concentration range is normal for HA in synovial fluid?
0.33 to 1.5 g/L.
What molecular mass is believed to have little effect when it comes to HA?
Less than 500 kDa.
What was the dosage of HA administered in the randomized controlled trial involving knee OA?
20 to 25 mg of HA once a week for three treatments.
What was the outcome of the HA treatment in the knee OA trial?
Reduced pain by up to 50% for 6 months post-treatment.
What issue does the study raise about high molecular weight HA products?
It questions their cost/benefit ratio compared to mid-molecular weight products.
What is the purpose of viscosupplementation?
To restore the elasticity and viscosity of synovial fluid.
What advantage does cross-linked HA have over other forms?
Longer retention time and increased resistance to free radicals.
What is Hylan G-F 20, and what are its reported benefits?
A cross-linked HA with effectiveness shown in clinical studies as a nonsteroidal medication.
What was the outcome of the study on hylan in horses?
It failed to show beneficial effects, possibly due to differences in disease models.
What dosing frequency has been suggested based on human clinical studies?
At least three doses, administered 1 week apart.
What dosage of conventional HA was found effective in the equine fracture model?
20 mg per joint.
In what conditions might HA be more effective?
In mild synovitis or capsulitis, rather than severe conditions.
What outcomes were observed in a study of IV HA in Quarter Horses?
Horses treated with HA raced longer, had better performance metrics, and earned more money.
What is the significance of the molecular weight of HA in its therapeutic effects?
Higher molecular weight is generally more effective, though exact correlations can vary.
What are some unanswered questions regarding the mechanism of action for IV HA?
The specific mechanisms and long-term effects are not well understood.
What are some examples of polysulfated polysaccharides (PSPs)
Polysulfated glycosaminoglycan (PSGAG; Adequan), GAG peptide complex (Rumalon), and pentosan polysulfate (Cartrophen Vet; Pentequin).
What are chondroprotective effects, and how are PSPs related to them?
Chondroprotective effects refer to the ability to protect, retard, or reverse cartilage damage, which PSPs exhibit, although they are more specifically categorized as DMOAoaDs for their slow-acting effects on osteoarthritis.
From what source is PSGAG primarily manufactured?
PSGAG is manufactured from bovine lung and trachea extracts containing chondroitin sulfate.
Which key enzymes and cytokines have PSGAGs been shown to inhibit in some studies?
IL-1, matrix metalloproteinases (MMPs), and prostaglandin E2 (PGE2).
What forms of PSGAG administration are mentioned in the text, and which is suggested to be more effective?
Intramuscular (IM) and intra-articular (IA) administration; IA administration appears to be more effective, particularly for acute synovitis and hemarthrosis.
What were the findings of studies administering IA PSGAGs weekly in horses with induced osteochondral lesions?
IA PSGAGs significantly improved lameness, reduced radiographic progression of OA, and improved joint capsule parameters compared to untreated ponies.
What was observed regarding PSGAG’s effectiveness when administered IM compared to shock wave therapy?
Shock wave therapy showed more impressive improvements than IM PSGAGs in treating joint conditions.
How did the combination of PSGAG and triamcinolone acetonide (TA) perform compared to using each alone?
The combination was found to be less effective than using PSGAG or TA alone.
For what conditions did practitioners find PSGAGs to be more effective than hyaluronic acid (HA)?
PSGAGs were deemed more effective for subacute osteoarthritis (OA) but less effective for idiopathic joint effusion and acute synovitis.
What unique characteristic does pentosan polysulfate (PPS) have compared to PSGAG?
PPS is derived from beech wood hemicellulose, unlike PSGAG, which is sourced from animal extracts.
Why is amikacin recommended when administering IA PSGAGs?
Amikacin is recommended because it lowers the risk of bacterial infection, which is increased with IA administration of PSGAGs.
What type of joint therapy is PPS suggested to be beneficial for?
PPS could be useful for systemic treatment of mild or early-stage OA, especially in cases with multiple joint involvement.
How did an oral HA product perform when tested for PGE2 levels in a model of equine OA?
Oral HA led to a significant reduction in PGE2 levels in OA joints compared to placebo-treated horses.
What potential benefits of extracorporeal shock wave therapy (ESWT) in treating osteoarthritis (OA) in horses have been suggested by clinical studies?
Improvements in clinical lameness, decreased synovial fluid protein, and reduced GAG release into the bloodstream
What mechanisms were proposed for ESWT’s effects in reducing OA progression in rabbit models?
Decreased chondrocyte apoptosis and a reduction in nitrous oxide (NO) levels in synovial fluid.
What specific experimental approach was used to evaluate ESWT’s effects on OA in equine models?
An osteochondral fragment was created to induce OA, with treatments initiated 14 days later.
How was the administration of shock waves scheduled in the study using ESWT for equine OA?
2000 shock waves at energy level E4 were applied on day 14, and 1500 shock waves at E6 on day 28.
In the ESWT study, which joint area was the primary target for energy delivery, and how much energy was focused on the site of fragmentation?
The middle carpal joint capsule attachment was the primary target, with approximately 20% of energy directed at the fragmentation area.
What specific improvements were observed in ESWT-treated horses compared to controls?
Significant improvements in lameness, lower synovial fluid protein levels, and reduced GAG release.
Which bisphosphonate (BP) is FDA-approved for treating navicular disease in horses, and what age restriction applies?
Clodronate (OSPHOS) is approved for horses over four years of age.
What primary concerns exist regarding the use of BPs in treating OA in horses?
Inconsistent pharmacological effects, uncertain dosing regimens, and potentially harmful routes like intra-articular administration.
What adverse effects are associated with BPs in equine treatments?
Acute side effects include colic-like symptoms and renal toxicity.
What promising effects have studies shown for the use of IA stanozolol in OA treatment models?
Reduced osteophyte formation, less subchondral bone reaction, and cartilage regeneration.
What limitation is highlighted in the study of IA stanozolol for joint health?
Long-term joint health effects and cartilage regeneration stimulation remain unclear.
What type of polymer-based materials are currently researched for mimicking articular cartilage properties?
Hydrogels, especially gelatin methacrylamide (gelMA) hydrogels, are investigated.
Which ECM components are added to gelMA hydrogels to improve their chondrogenic potential?
HA (hyaluronic acid) and CS (chondroitin sulfate).
What are the benefits of IL-1 and TNF inhibition in treating OA, according to recent findings?
Clinically beneficial effects, especially in reducing inflammation and slowing disease progression.
What advantage does autologous conditioned serum (ACS) offer in equine OA treatment?
It increases IL-1Ra levels and shows beneficial symptoms and disease-modifying effects.
What findings suggest that IRAP II may be more effective than IRAP in ACS treatment?
IRAP II sera contain significantly higher levels of IL-1Ra and other cytokines.
What is a primary reason for the clinical preference for PRP over ACS in joint treatments?
PRP requires less preparation time and is more convenient for in-stall use.
How does platelet activation with CaCl₂ affect PRP’s inflammatory response in normal horses?
Activation with CaCl₂ resulted in lower WBC release, reducing the inflammatory response.
What component concentrations are high in the “autologous protein solution” (APS) used for joint disease treatment?
WBCs, platelets, and various proteins are concentrated.
What significant outcome was observed with APS treatment in client-owned horses with natural OA?
Reduced lameness within 14 days and high client satisfaction at 12 and 52 weeks.
What makes MSCs valuable in joint disease treatment according to early studies?
They localize to and assist in the repair of damaged joint tissues like cartilage and menisci.
What findings regarding MSCs suggest potential limitations in OA treatment?
MSCs alone may not counteract OA progression due to enzymatic degradation and joint debris.
What specific challenge in MSC treatment outcomes does the equine study highlight?
The effectiveness of MSC treatment may depend on the severity of joint fibrillation.
What outcome was reported in a prospective multicenter trial for MSC-treated horses with joint damage?
A 76% return-to-work rate with 43% achieving full performance.
What were the observed benefits of MSCs in rabbits with induced OA from ACL transection?
Reduced osteophyte formation, less cartilage degeneration, and reduced subchondral sclerosis.
Why might IA injection of allogeneic MSCs require additional investigation?
Studies report a stronger inflammatory response with allogeneic cells compared to autologous cells.
What general concern affects medical management in equine joint disease, as mentioned in the text?
The reliance on human treatment data and lack of specific equine research challenges therapeutic decision-making.
