Equine intra-articular therapy (Proceedings)

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?

Sodium hyaluronate

• Hyaluronic Acid

     o HA = hyaluronan = hyaluronic acid

     o Long unbranched nonsulfated glycosaminoglycan

     o Synthesized by

          • Type B synoviocytes

          • Chondrocytes

               - Component of extra-cellular matrix

     o Functions within the joint:

          • Viscoelasticity of joint fluid

          • Boundary lubrication

          • Modulates chemotactic response

• Sodium Hyaluronan (HA)

     o Linear polydisaccharide

     o Original concept - viscosupplementation

     o Most effective in treatment of acute synovitis

     o Mechanisms remain unclear

          • Anti-inflammatory effects

               - Suppression of cytokines and proteinases (Takahashi K et al. Osteoarthritis Cartilage; 7:182-190 1999)

          • Stimulation of endogenous HA production

     o Mechanisms of action

          • Steric hindrance

          • Scavenge free radicals

          • Reduction of bradykinin and prostaglandin

          • Increase in endogenous HA synthesis via cAMP levels

     o HA Choices

          • Does size matter?

               - Hylartin V (3.5,000,000 Da)

               - Legend (1,000,000 Da)

               - Hyvisc (1,000,000 Da)

               - Hyalovet (400,000 Da)

               - Synacid (150,000 Da)

          • Conflicting evidence

               - Differences between in vivo and in vitro work

               - Difference between studies using OA models

          • Recommendation is to use products between 500,000 and 2,000,000 Da MW

     o Combination Treatment

          • With steroids:

               - Synergistic beneficial effect

               - More long-lasting clinical effect (Rydell NW et al. Acta Vet Scand 11:139-155 1970)

               - Combination helps prevent changes associated with steroids (Roneus B et al Zentralbl Veterinar med A 40:10-16 1993)

Polysulfated glycosaminoglycan (Adequan)

• Semi synthetic preparation of bovine trachea

     o Composed primarily of chondroitin sulfate

• Stimulation of production of HA (synoviocytes)

• ±Increase synthesis of proteoglycans and collagen by chondrocytes

• Inhibit degradative enzymes

     o nMMP

     o Plasminogen activators

     o Lysosomal elastase

     o Cathepsin

• Adverse Effects of PSGAG

     o Increases activated partial thromboplastin, prothrombin, and activated clotting times in dogs at 5 and 25 mg/kg (Beale et al., 1990)

     o Thrombocytopenia (human)

     o IA use: Increased minimum inhibitory concentration of antibiotics effective in vitro against S. aureus (Gustafson et al., 1989)

Interleukin-1 receptor antagonist (IRAP)

• Autologous Conditioned Serum

     o Interleukin-1 Receptor Antagonist

          • Competes with Interleukin-1 for binding

          • Prevents activation of receptor

          • Experimental evidence for decreasing joint inflammation is strong

     o Increase IRAP in serum by incubation with chromium beads

          • Stimulate monocytes (human)

               - ↑ IRAP_____140x

               - ↑ IL-4, IL-10___2x

               - IL-1β, TNF-α__0x

          • Improved lameness

          • Decreased synovial membrane hyperplasia

          • Better for acute synovitis

• Levels of IRAP???? Cost!

• Carpal chip model of OA

     o IL-1 Ra level increased after processing:

          • 234 pg/ml v. 45 pg/ml

     o Improved histologic score

     o Synovial fluid IL-1 Ra increased over time

          • Stimulates endogenous production of IL-1 Ra

Autologous stem cells

• Cell-based Therapies

• Direct injection of cells

     o Nucleated cell fraction from adipose tissue (VetStem)

     o Cultured bone marrow mesenchymal stem cells

• VetStem

     o Joint Injection

          • 56.7% (34/60) returned to full work at prior level and 26.7% (16/60) returned to full work at a reduced level

          • 50/60 back in work