Therapeutic goals

• Eliminate lameness (pain)
• Disease modification
• Chondroprotection

What are we treating?

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?