Equine intra-articular therapy (Proceedings)

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Equine intra-articular therapy (Proceedings)

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Nov 01, 2009
123Next Therapeutic goals • Eliminate lameness (pain) • Disease modification • Chondroprotection What are we treating? • Inflammation • Mechanical stress • Synovial fluid changes • Cartilage pathology – breakdown • Degenerative changes Target areas for treatment • Synovium • Synovial fluid • Articular Cartilage • Sub-chondral Bone Challenges of medical management • Specific joint involved • Stage of lesions • Current and intended use of the horse • Age of the horse • Treatment cost • Response to therapy • Regulations What we use • Steroids      o Methylprednisolone acetate      o Triamcinolone      o Betamethasone • Sodium hyaluronate • Polysulfated glycosaminoglycans• Interleukin-1 Receptor Antagonist • Autologous Stem Cell Corticosteroids • Effects on Inflammation      o Inhibition of prostaglandin synthesis      o Phospholipase A2 inhibition • Disease-modifying effects      o Inhibition of NF-κβ      o Decrease cytokine production      o Decrease IL-I, TNF α      o Inhibit MMP production      o Decrease fibrin deposition • Effects of IA Corticosteroids on target Areas      o Synovium/Synovial Fluid           • Reduce synovitis                - Reduced synovial effusion (MPA) (Van Pelt RW. JAVMA 143:738-748, 1963)                - Decrease synovial membrane permeability (Eymontt et al. J Rheum 9:198-203 1982)                - Decreased total protein, increased viscosity, increased HA concentration (MPA) (Chunekamrai S et al. AJVR 50:1733-1741 1989)           • Inhibit interleukin-1 synthesis by synovial lining cells           • May improve cartilage nutrition by controlling severity of synovitis                - Enable return of normal synovial fluid properties                - Improve fluid exchange within the joint           • Increase proteoglycan concentrations (Roneus B et al. Zentralbl Veterinarmed; 40:10-16 1993)           • Increase in HA concentrations (Tulamo RM. AJVR; 52:1940-1944 1991)      o Cartilage           • Reduce matrix metalloproteinase activity in osteoarthritic cartilage in vitro (Richardson DW et al. Inflamm Res; 52:39-49 2003)                - Dose dependent           • Inhibit synthesis of metalloproteinase activators like plasminogen activator or plasmin           • Reduced cartilage damage in OA models in horses (Frisbie DD et al. EVJ 29:349-359 1997)           • Deleterious effects of steroids on cartilage:                - Inhibition of proteoglycan synthesis (Trotter et al. AJVR 52:83-87 1991)                - Dose dependent (Todhunter RJ et al J Rheum 23:1207-1213, 1996)           • Depresses total protein and collagen synthesis at high doses (Todhunter RJ et al J Rheum 23:1207-1213, 1996)           • Decrease in Safranin-O staining                - Estimate of matrix GAG content (Trotter et al. AJVR 52:83-87 1991)           • Decreased chondrocyte metabolism (Chunekamrai S et al. AJVR 50:1733-1741 1989)           • Chondrocyte necrosis and hypocellularity (MPA) (Chunekamrai S et al. AJVR 50:1733-1741 1989)           • Decreases in cartilage proteoglycan can be prolonged (Chunekamrai S et al. AJVR 50:1733-1741 1989; Trotter et al. AJVR 52:83-87 1991)      o Bone           • Most effects on bone are associated with systemic administration                - Adrenal suppression           • Decreases osteophyte formation and fibrillation (Williams JM et al; Arthritis Rheum 28:1267-1273 1985) • Associated Complications of Steroid Use      o Steroid Arthropathy           • Defined as acceleration of degenerative changes within joint associated with steroid use                - Loss of joint space                - Instability of the joint                - Osteonecrosis                - Peri-articular osteophytosis           • Low incidence                - <1% in humans (Hollander JL. MD Med J; 19:62-66)                - May be progression of degenerative joint disease/osteoarthritis irrespective of steroid use                - Especially in cases where exercise is continued      o Post-Injection Flare            • Acute inflammatory response                - Synovial effusion                - Increased WBC           • Heat, pain, swelling, lameness           • 8-24 hours post-injection           • 2% incidence in people (Hollander JL MD Med J 19:62-66, 1970)                - Low incidence in horses (Pool RR et al Proc AAEP 26:397-415 1980)                - Up to 13 days post-injection           • Vehicle related                - Less prevalent with branched chain esters      o Potentiation of infection           • Signs not obvious immediately following injection                - Clinical signs masked for up to 3 days (Tulamo RM et al EVJ 21:332-337, 1989)           • Infections following steroid injections can be devastating                - Severe joint pathology           • Incidence unknown in horse                - Less than 1% in humans (Charalambous CP et al Clin Rheum 22(6):386-90, 2003)                - 12% in knee      o Laminitis and IA Steroids           • Triamcinolone acetonide                - Most often implicated                - Evidence of direct correlation is tenuous                     • Retrospective analysis                          o 0/201 horses treated with 40-80 mg doses                          o 4/205 developed laminitis                          o All 4 had prior history of laminitis                - Alters glucose metabolism = hyperglycemia (French et al. J vet Pharm Therap 23:287-292, 2000)                     • Given IV or IM                          o Effects persist                          o 3-4 days at low dose (0.05 mg/kg)                          o 8 days at high dose (0.2 mg/kg)                     • Laminitis associated with altered glucose metabolism (Pass et al. EVJ suppl 26:133-138, 1998) • Doseage Guidelines (whole-body dose)      o Triamcinolone < 18 mg      o Methylprednisolone acetate < 200 mg      o Betamethasone < 30 mg • Potency per Unit Dose      o Flumethasone (most potent)      o Isoflupredone      o Betamethasone      o Triamcinolone      o Methylprednisolone (least potent) • Duration of Action      o Short-acting Corticosteroids           • Hydrocortisone, Flumethasone      o Longer-acting Corticosteroids           • Triamcinolone, Betamethasone, Methylprednisolone acetate      o Water solubility is irrelevant      o Rate of hydrolysis of ester is critical • Triamcinolone acetonide      o Medium length intra-articular half-life (1-5 days)      o 6-12 mg/joint      o 18 mg total body dose      o Has shown the most positive effects of the steroids studied           • In vitro (Richardson DW et al. Inflamm Res; 52:39-49 2003)                - Inhibit synthesis of MMP and other proteinases      • In OCF model (Frisbie DD et al. EVJ 29:349-359 1997)                - Minimized development of OA • Methylprednisolone acetate (Depo-Medrol)      o Dose dependent balance between combating inflammation, yet maintaining healthy joint environment      o 10 - 40 mg / joint      o Long acting (intra-articular half-life 1 month)      o 120 mg total body dose • Betamethasone (Betavet)      o Potent      o Medium to long duration of action      o 16 mg/joint (Foland JW et al. Vet Surg 23:369-376 1994)           • In exercised and non-exercised horse no deleterious affects on cartilage in OCF model           • Can affect proteoglycan synthesis at low doses (Frean SP et al J Vet Pharm and Ther; 25:289-298 2002)      o 30 mg total body dose • Steroid Application      o Choose wisely      o Low dose           • Most affects are in high-dose models      o Rest after use           • 24 hours in human patients prolongs response (Chakravarty K et al Br J Rheumatol 33:464-468 1994)           • Impact of exercise on compromised joint      o Limit repeated doses           • More effects observed in studies with repeated doses • Where are we now in regards to steroid use?      o Low doses of corticosteroids have chondroprotective properties without marked deleterious effects on chondrocytes      o Still have much to learn           • Dose?           • Frequency of administration?           • Enhance efficacy if combined with HA or growth factor therapy? 123Next