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Updates in OA 2011 Post Grad

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My very first talk on Osteoarthritis! Whew! Updates presented during the UP PGH Post Graduate Course in 2011

Updates in OA 2011 Post Grad

  1. 1. UPDATES INOSTEOARTHRITISSIDNEY ERWIN T. MANAHAN, MD, FPCP, FPRAInternal Medicine – Rheumatology28 October 2011
  2. 2. Disclosures• Received honoraria from Pfizer, Roche & Ajanta Pharma• Speakers Bureau for Pfizer• Presently and previously involved in clinical drug trials conducted locally for Roche, Wyeth, Parexel and Novartis
  3. 3. Outline • What causes OA? Processes • What are the implications on treatment? • What’s new about drugs we Old Drugs are presently using in OA therapy? • What new drugs are in the New Drugs pipeline?
  4. 4. OA Pathogenesis: Traditional Change in CARTILAGE Properties CARTILAGE Fibrillations LOSS OF CARTILAGE Subchondral Bone Remodelling Osteophytosis
  5. 5. Changing Concepts in Pathogenesis • Inadequate flow to osteocytes • Bone Marrow Like Oedema Lesions • Evacuation of non-viable bone • Micro-channels in sunchondral • Subchondral bone collapse • Subchondral bone cysts BONE ISCHEMIA BMLOL SYNOVITIS MECHANICAL • Ligamental strain • Elaboration of cytokines • Muscle spasm • Low grade chronic inflammation • BursitisPunzi L, et al. New Horizons in OA. Swiss Med Weekly 2010.
  6. 6. OA Pathogenesis: Updated
  7. 7. Cytokine Signals in OA Catablolic Inhibitory Anabolic Cytokines Cytokines Cytokines IL-1ß IL-4 IGF1 TNF-alpha IL-10 TGFß IL-6(?) IL-11 FGFs IL-17 IL-13 BMPs IL-18 IFN In KNEE OA, • High levels of TNF-alpha  SIX-FOLD INCREASE in JSN Progression • High levels of IL-10  FOUR-FOLD INCREASE in JSN Progression In HAND OA • SNP for gene encoding IL-1ß  associated with Erosive Hand OAPunzi L, et al. New Horizons in OA. Swiss Med Weekly 2010.
  8. 8. New Targets in OA STRATEGIES CLINICAL TRIALS PROTEINASES MMP Inhibitor (PG-116800) • Ineffective in modifying matrix • Induced numerous rheumatic s/sx SIGNALLING PATHWAYS Anakinra (IL-1Ra) (through anti-cytokine • Animal studies  modified disease progression therapies) • 12-week OLS  modified disease progression • RCT  no statistical difference vs placebo CHRONDROCYTE APOPTOSIS (vis iNOS or Capsace inhibitors)Punzi L, et al. New Horizons in OA. Swiss Med Weekly 2010. Caron JP, et al. Arthritis Rheum. 1996;39:1535–44. ZhangX, et al. J Orthop Res. 2004;22:742–50 Chevalier X, et al. Arthritis Rheum. 2009;61:344–52.
  9. 9. OPG/ RANK/ RANKL as Target in OA • 20 Patients with severe Knee OA for joint replacement • 3 months on NSAID vs control CONCLUSION • NSAID treatment inhibited resorptive signals in chondrocytes and RANKL expressionMoreno-Rubio J, et al. Arth & Rheum 2010; 62:478-88.
  10. 10. NSAIDs: Beyond COX Inhibition • Severe Knee OA for Joint Replacement • 10 on Celecoxib 200mg/d • 10 on Aceclofenac 200 mg/d • 10 on Placebo • 3 months of treatment CONCLUSIONS • CBX & ACF improved pain and function and reduced PGE2, COX expression • CBX & ACF have different anti- inflammatory profilesAlvarez-Soria MA, et al. Arth & Rheum 2006; 65:998-1005.
  11. 11. NSAIDs in the Rheumatic Diseases NON SELECTIVE CARDIAC RISK • Aspirin • Ibuprofen • Indomethacin Low (<10%) High (>10%) • Naproxen Low All NSAIDs Naproxen SOMEWHAT COX2 • Diclofenac • Meloxicam GI RISK nsNSAID + PPI Inter • Nimesulide Naproxen + PPI COXIB HIGHLY COX2 High • Celecoxib COXIB + PPI Avoid all NSAIDs • EtoricoxibBurmester G, et al. Ann Rheum Dis 2010. do1 10.1136
  12. 12. Addressing CV Concerns RISK FOR RISK FOR CV RISK FOR MI DEATHS STROKE Rofecoxib Ibuprofen Ibuprofen Lumiracoxib Diclofenac Lumiracoxib Ibuprofen Lumiracoxib Diclofenac Celecoxib Etoricoxib Etoricoxib Etoricoxib Naproxen Rofecoxib Naproxen Celecoxib Celecoxib Diclofenac Rofecoxib NaproxenTrelle S, Reichenbach S, et al. BMJ 2011; 342: c7068.
  13. 13. CINODs: The New NSAID Balanced COX COX Inhibitors Inhibition with Nitric COX-1 COX-2 Oxide Donators PG INHIBITION NITRIC OXIDE More Gastric Flow Mucosal Damage More Mucus Secretion Bleeding More HCO3 Secretion THERAPEUTIC Reduced Gastric Flow Epithelial Repair ACTIVITY Less Pain Vasodilation Less Swelling Poor Renal Perfusion Better CV Function Less Inflammation Hypertension Less Platelet Aggregation Increased CV Risk Less AtherosclerosisWallace J, et al. Trends in Pharma Sci 2009;30:112-117.
  14. 14. Efficacy of Naproxcinod • 918 Knee OA Patients* • Naproxcinod >> Placebo (Pain • Naproxcinod 750 mg BID WOMAC, Function WOMAC, • Naproxcinod 375 mg BID Disease Activity Likert) • Naproxen 500 mg BID • Placebo • Naproxcinod 750 mg BID was non-inferior to Naproxen 500 • 810 Hip OA Patients mg BID at 13 and 53 weeks • Naproxcinod 750 mg BID • Naproxen 500 mg BID • BP changes Naproxen >> • Placebo Naproxcinod = Placebo • Double Blind RCT x 13 wks • *Double Blind RCT x 53 wksSchnitzer TJ, et al. Sem in Arth & Rheum 2010: 40: 285-297. Schnitzer TJ, et al. Osteoarth & Cart 2010; 18: 629-39.Baerwald C, et al. Arth & Rheum 2010: 62: 3635-44.
  15. 15. Naproxcinod and HPN • 916 OA Patients + HPN • SBP Increase >10 mm Hg • Naproxcinod 750 mg BID • Naproxen – 22% • Naproxcinod 375 mg BID • Naproxcinod 750 – 14% • Naproxen 550 mg BID • Naproxcinod 375 – 14% • Placebo • Placebo – 15.6% • Double Blind RCT x 13 wks • Increases in BP over 13 wks • Ibuprofen > Naproxen • Naproxcinod = PlaceboWhite WB, et al. Am J Cardiol 2009; 104: 840-5.
  16. 16. Naproxcinod and GI Events • 970 OA Patients • GI Symptoms Rating Score • Naproxcinod 750 mg BID • Abdominal pain and reflux were • Naproxen 500 mg BID lower in Naproxcinod • Placebo • No difference in indigestion, constipation and diarrhea • Double Blind RCT x 6 weeks • Naproxcinod was as effective as Naproxen in reducing • Incidence of Endo Ulcers WOMAC Scores • Naproxen 13.7% • Naproxcinod 9.7% (p = 0.07)Lohmander LS, et al. Ann Rheum Dis 2005; 64: 449-56.
  17. 17. Evidence on SYSADOAs Product GRADE Quality of Evidence Comment Recommendation Glucosamine SO4 STRONG Moderate Advantageous Chondroitin SO4 STRONG Moderate Advantageous Hyaluronic Acid STRONG Moderate Advantageous Risedronate STRONG High Not advantageous Strontium Ranelate Weak Very Low Advantageous GRADE Recommendation • STRONG – We recommend (should) • WEAK – We suggest (might) Quality of Evidence • HIGH – Further research is unlikely to change the estimate of effect • MODERATE – Further research may change the estimate of effect • LOW – Further research is likely to change the estimate of effectBruyere O, et al. BMC Musculoskeletal Dso 2008; 9: 165.
  18. 18. Recommendations on Nutraceuticals PRA 2008 OARSI 2008The use of pharmaceutical grade Treatment with glucosamineglucosamine sulfate is and/or chondroitin sulfaterecommended for its smallbenefit on pain reduction & may provide symptomaticimprovement of function in benefit. If no response ispatients with knee OA. apparent within 6 months,LoE: High treatment should be discontinued.Chondroitin sulfate is notrecommended for knee OA.LoE: High LoE: 1a SoR: 63%
  19. 19. Latest Data on Glucosamine CONCLUSION • Glucosamine, Chondroitin or the Combination do NOT reduce joint pain or impact on JSNWandel S, et al. BMJ 2010; 341: c4675.
  20. 20. Latest Data on Chondroitin • 69 Knee OA Patients with evidence of synovitis • Placebo controlled RCT - CS 800 mg/d vs Placebo for 6 months then Open label study – CS 800 mg/d for 6 months • Less cartilage loss at 6 months persisting to 12 months; reduced BML at 12 months; No difference in clinical symptoms.Wildi LM, et al. Ann Rheum Dis 2011; 70: 982-89.
  21. 21. ASU (Piascledine) • Avocado oils 100 mg + • Meta-analysis of RCTs from Soybean oils 200 mg systematic searches that explicit state hip/knee OA • Inhibits IL-1, IL-6, IL-8, PGE- patients randomized to 2 and MMP-13 ASU or placebo • Piascledine 300 mg od vs • Stimulates TGF-B, PAI-1, aggrecan and matrix placebo component synethesis, and TIMP • Reduction in pain and Lequesne index (ES)Altinel L, et al. Tohoku J Exp Med 2007. 211:181. Appelboom T, et al. Scand J Rheumatol 2001. 30:242Henrotin YE,et al. J Rheumatol 2003: 30: 1825. Henrotin YE, et al. Clin Rheumatol 1998: 17: 31. Christensen R, ET AL.Osteoarthritis Cartilage 2007: doi:10.1016/j.joca2007.10.003
  22. 22. Avocado-soy unsaponifiable Blotman, Mahue, Appelboom Lequesne, COMBINED 1997 1997 , 2001 2001ITT pop 163 164 174 163 664OA hip, % 88 31 0 100 41QS 5 5 3 5 4.5Tx dur, mos 3 6 3 12 6Age, yrs 64.1 64.1 64.9 63.2 64.1Females, % 66 72 81 37 64Mean BMI 25.5 26.8 28.8 25.9 26.8Mean KL 2.0 2.1 2.0 2.0 2.0Mean pain 53.2 56.1 53.9 50.2 53.4Mean 8.7 9.6 9.4 9.5 9.3Lequesne
  23. 23. ASU impact on pain reduction ES 0.40 ( 0.25 to 0.55) ES 0.99 ( 0.54 to 1.44) ES - 0.44 (-1.05 to -0.17)
  24. 24. ASU impact on function ES 0.46 ( 0.27 to 0.64) ES 0.65 ( 0.10 to 1.21) ES 0.17 (-0.57 to -0.92)
  25. 25. ASU Impact on self-reported response OR 2.20 (1.60 to 3.02) ES 2.60 ( 1.01 to 6.70) ES 1.72 (0.40 to 6.17)
  26. 26. Summary• Changes in Pathogenesis of Osteoarthritis • Focus on subchondral bone • Role of cytokines/ chemokines• Implications on potential targets for therapy• New information about NSAIDs – safety and CINODs• Reviewed latest evidence on SYSADOAs • Introduced ASU
  27. 27. Philrheumajr.blogspot.comTHANK YOU!

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