First, I’d like to thank the organizers for inviting me to be part of the UP PGH Department of Rehabilitation Medicine’s 11th post graduate course. It is both an honor and pleasure to present to you updates in osteoarthritis - a disease we frequently encounter in practice and yet we often feel we could do little about.
When we talk of osteoarthritis, we see the response and result of joint failure. For in essence, that is what osteoarthritis is … JOINT FAILURE. And like other subspecialties, osteoarthritis is our equivalent to end stage joint disease which may result from a variety of pathologies. No discussion would be complete without mentioning loss of cartilage and osteophyte formation – which are considered the sine qua non of the disease. We have been taught that cartilage somehow loses its material properties in OA leading it to become less hydrophilic and less compliant – making it more predisposed to fibrillation or microfractures in the cartilage matrix. This would proceed to loss of articular cartilage and subsequent subchondral bone collapse and then osteophytosis. From this simple scheme, we could see that the much of the attention has really been directed at events starting in the cartilage which would then involve the rest of the joint. But new information suggests that it is not cartilage that initiates the whole process.
We know much about the mechanical derangements in osteoarthritis – something which I feel you know more about being rehab med specialist – and not only is the joint involved but also the periarticular tissues such as the bursae, ligaments and muscles. But actually there are several more process ongoing in the OA joint. It is now believed that the cascade of events actually start with the osteocytes – which function as mechanoreceptors in the cartilage and subchondral bone matrix. During normal bone loading, these osteocytes modulate cell-to-cell and ECM signalling – promoting cartilage homeostasis. In the osteoarthritis joint, however, there is inadequate flow of fluid to this osteocytes – making them undergo programmed cell death and apoptosis. This apoptosis would then attract osteoclasts which would then excavate non-viable bone. And as this process continues, subchondral bone collapse ensues. Due to the subchondral bone collapse, there is microchannels develop within the cartilage and this is appreciated on MRI as Bone Marrow Like Oedema Lesions or sometimes referred to as BME – which is seen in both early and established OA and in individuals with painful joints. Additionally BMLOL are an independent risk factors for structural deterioration in knee OA and it is within BMLOLs that sunchondral cysts develop. Aside from this, bone ischemia actually initiates a cascade of cytokine signals which would lead to chronic low grade inflammation within the joint. So from this new model, there are two deviations from our prior model of osteoarthritis. FIRST, we could see shift in OA from the cartilage to the subchondral bone as the crucial structure in pathology. It is believed that this happens as a result of its defective role as a shock absorbers, the abnormal functioning of osteocytes within it and the increased production of cytokines in proteinases. And when we talk of cytokines –there is INFLAMMATION a concept previously attributed to gout, RA and the spondyloarthropathies but not to OA.
So here we again see a diagram of events that follow mechanical loading in an osteoarthritic joint… the subchondral bone malfunctions as a shock absorber leading to osteocyte apoptosis – and in the process it elaborates IL-1 together with the synovial tissue. IL-1 actually inhibits production of proteoglycans and type 2 collagen and actually stimulates chondrocytes to elaborate proteinases such as MMP and aggrecanase that lead to cartilage breakdown and other cytokines and chemokines such as IL-6, TNF-alpha and PGE2. And with apoptosis of osteocytes, osteoclast from the adjacent bone are attracted leading to resorption of non-viable tissue and collapse of the subchondral bone. An assay of cytokines reveal that the subchondral bone actually has highest concentration of cytokines and proteinases in the OA joint.
But not all cytokines in OA are the same, there are those that promote cartilage breakdown such as IL-1, TNF, IL-6, IL-17 and IL-18. There are those that promote cartilage synthesis such as IGF-1, TGF, FGF and BMP and those that regulate interactions between these two subsets of cytokines. There are also clinical correlates to the levels of the cytokines – such as high levels of TNF and IL-10 being associated with increases in joint space narrowing in knee OA and polymorphisms in IL-1 being associated with erosive hand OA.
And these new concepts in OA, opens an opportunity to alter the process of osteoarthritis by proving potential targets of disease modifying drugs in OA achieved by either inhibiting the actions of effector proteinases or by altering the cytokine signalling pathway or by preventing apoptosis of osteocytes and chondrocytes in subchondral bone. Unfortunately, early trials were not successful. The study on a MMP inhibitor not only proved to be ineffective but it also created additional musculoskeletal complaints. An available anti IL-1Ra Anakinra which is used in RA was tried in OA and early animal studies and open label trials showed promise for the drug as it altered disease progression. But when it was tested against the rigors on a RCT, the drug showed no difference from placebo after more than a month of use.
This has lead researches to study other avenues of OA treatment such as the OPG/ RANK and RANKL pathway which is involved in osteoporosis pathogenesis. If you remember our previous slides of molecular pathogenesis, following bone ischemia, osteoclasts are attracted to non-viable bone which it then resorbs. This involves activation of your OPG/ RANK and RANKL pathways. A small study in 20 OA patients who were scheduled for knee replacement had them received Celecoxibvs placebo for 3 months prior to surgery. And at the time of surgery cartilage biopsies were obtained for molecular studies. The first two diagrams show that CElecoxib did not affect the expression of OPG but significantly reduced the expression of RANK Ligand. And when cultures of chondrocytes were stimulated with IL-1 which we had discussed as a major player in OA pathogenesis, those chondrocytes given the NSAID did nothing to the expression of OPG but suppressed the expression of RANKL. So the conclusion was that Celecoxib has suppressed the expression of resorptive signals in the chondrocytes mainly by its action on RANKL.
A similar study performed in 30 patients with severe OA scheduled for knee replacement had them randomized to either paracetamol, aceclofenac or celecoxib for 3 months and cartilage biopsies were once again obtained at the time of surgery. Patients in both aceclofenac and celecoxib arms reported comparable improvements in pain and function. However, on assay of the tissue for cytokines, Significantly lower levels of both TNF and IL-1 were found in those patients treated with CElecoxib. Leading the trialists to conclude that although both NSAIDs had effects on symptoms and levels of inflammation, these two drugs have different anti-inflammatory profiles in terms of their impact on the elaboration of cytokines. I did not anymore include the trial comparing the administration of indomethacin and celecoxib in animal models but their conclusion was there were also significant differences in levels of cytokine inhibition between the two drugs.
So it appears we need not look to far in terms of new drugs that already target these new pathways we discovered in OA as some of these old drugs may already be addressing these processes. However, with NSAIDs our real concern is their long term safety more that their efficacy. In fact in 2010, an expert panel from the European countries advised that the choice of NSAID to be given should be based on risk stratification of patients based on their CV and GI status. Those patients with age >65, concomitantly using steroids, aspirin and anticoagulants and previous or present GI events should be classified as being low, intermediate or high risk depending on the presence of these risk factors. And low and high CV risk depending on their 10 year annual risk for CV Events. Those low risk for both CV and GI can receive any of the NSAIDs and COXIBs, while those at high risk for GI should receive COXIBS or an NSAID used concomitantly with PPI while those at high risk for CV AE should be given Naproxen with PPI. Those who would unfortunately be at high risk for both GI and CV events should avoid all NSAIDs if possible. This table shows the dichotomy we place between non-selective NSAIDs and COX2 inhibitors, those at high risk for CV should go for ns NSAIDs while those who are at high risk for GI should receive COXIBS. But then again, does that still hold true up to now?
A recent network meta-analysis looked into the results of 31 large RCTs that compared the use of NSAIDs with other NSAIDs, paracetamol or placebo for different arthritis conditions mainly OA and RA. 7 NSAIDs were compared in terms of their risk for MI, stroke and CV-related deaths – and these were of celecoxib, diclofenac, etoricoxib, ibuprofen, lumiracoxib, naproxen, and rofecoxib. Celecoxib had the most number of trials in the meta while etoricoxib and ibuprofen had the most number of study participants. Only trials with arms involving at least 100 patients years of NSAID exposure were included. In the results, the highest risk was associated with rofecoxib followed by lumiracoxib and ibuprofen. The highest risk for stroke was seen in those who received ibuprofen, diclofenac and lumiracoxib and the highest risk for CV-related deaths were seen in ibuprofen, lumiracoxib and diclofenac. From these results we could see that Naproxen consistently ranks among those with lowest risk for CV events – justifying it’s use in those with high CV risk. But surprisingly two nsNSAIDs were also included as those with high risk for CV events – ibuprofen and diclofenac – which are probably the most well advertised NSAIDs and most widely available. So I guess, that the dichotomy no longer holds true. And instead of a class effect, we may need to look at the individual safety profiles of these drugs.
And while the debate of NSAIDs and COXIBs are still ongoing we are now being introduced to a new class of NSAIDs referred to as CINODs. We know that NSAIDs act via COX inhibition leading to its anti-inflammatory and analgesic effects and it is also via the same mechanisms that problems with GI tract and CV systems occur. We see that there is a predisposition to mucosal injury and bleeding as a results of COX1 inhibition and poor renal perfusion, hypertension and increased CV risk from both COX-1 and COX-2 inhibition. Nitric oxide has been found to exert an opposite effect on both GI and CV systems – it actually stimulates mucus and bicarbonate production in the stomach leading to improved gastric blood flow and epithelial repair and since it is a vasodilator it also improves CV functions and produces less platelet aggregation. So they produced CINODs as a new class of NSAIDs claimed to be the holy grail in terms of NSAID safety.
Naproxcinod or the complex of Naproxen and NO is the first CINOD that had complete phase III drug trials. And based on two large RCTs involving patients with knee and hip OA – Naproxcinod 750 mg BID was found to be non-inferior to Naproxen 500 mg BID in terms of efficacy with effects on BP similar to that of placebo.
Another trial looking into the effect of Naproxcinod on BP showed that there were fewer increases in BP among those receiving Naproxcinod with number comparable to those receiving placebo.
Unfortunately, when they looked into GI safety the results were not as convincing. When they looked into 970 patients who were given either Naproxcinod, Naproxen or placebo for 6 weeks – there appeared to be fewer endoscopic ulcers and erosions among those receiving Naproxcinod however the difference was not clinically significant. Fortunately, in terms of the GI Symptoms Rating Scale – fewer patients reported pain and reflux symptoms among those receiving Naproxcinod. So we could still say that there is a lower tendency for GI events in those receiving Naproxcinod compared to Naproxen From literature, the US FDA has yet to approve Naproxcinod as it still lacks long term studies on safety – as the longest trial for 53 weeks was only published in 2010.
The quest for a safe NSAID still remains elusive that’s why many clinicians still look to nutraceuticals as part of their treatment for osteoarthritis. Based on an evaluation of the evidence in 2008 for different Sysadoas. There is benefit in using G, C and HA in the treatment of OA and no evidence of the use of risedronate for OA. But before we start prescribing let us clarify the difference between strength of the recommendation and the quality of evidence. When we talk of GRADE recommendation or SoR – we indicate the after careful considerate of the trade offs between benefit and harm, burden and possible costs – there is sufficient reason to support the use or the intervention might be considered but values. and when we talk of the level of evidence we talk about how future studies may actually change the estimate of the treatment effect.
The two most commonly used nutraceuticals are actually glucosamine and chondroitin – both the Phil Rheuma Association and the OA Research Initiative came up with guidelines in 2008 but you could see the difference in their recommendations. While the OARSI suggest the use of glucosamine and chondroitin the PRA would only recommend glucosamine but not chondroitin. I’m not about to discuss which of the two is correct but do look that in both groups the level of evidence is quite high meaning RCTs were the basis for these recommendations but it is only the OARSI that indicates that the SoR is
A recent metaanalysis on the efficacy of Chondroitin, Glucosamine or the Combination looked into their efficacy in reducing pain and improving function. And 10 trials involving 3803 patients were included looking into Glucosamine SO4, chondroitin sulphate or the combination of GHCl and CHCl. You could see from this diagram the cumulative effect of Glucosamine was -0.4 cm reduction in VAS, Chondroitin was -0.3 cm while the combination was -0.5 cm reduction in VAS. All of which produced small if not modest shifts in your 10 cm VAS. And none of these estimates actually produced a significant change compared to placebo. And when you looked into the level of joint space narrowing, were all minute with confidence intervals overlapping zero. Thus it came as no surprise that the conclusion was that all three preparations did not impact siginificantly as far as pain reduction and joint space narrowing were concerned. And was even harsh in saying that health authorities and health insurers should not cover the cost of these preparations.
But as some of you might have known, over the last couple of months there have been renewed interests in chondroitin and this was brought about by this study published in early 2011. 69 knee oa patients received either placebo or CS 800 mg OD for 6 months then all were given CS for another 6 months. The results on MRI measurements showed that there was less cartilage loss beginning on the 6th month of treatment and that there were fewers BMEs after 12 months of use of CS. And not surprisingly, there was no significant difference between symptoms of patients randomized to the two groups. In fact, it was consistent with the meta I previously presented to you. So the renewed interest is actually because of the potential for disease modification as shown by the MRI study.
And finally, there is a new nutraceutical which will be introduced later this year in the Phils… This product had been available in france for quite some time now and it is only recently that they showed interest in promoting their product in our country. It consists of 100 mg Avocado oils and 200 mg Soybean Oils – this is referred to as ASU in literature or Avoicado soybean unsaponifiables. Based on animal and human chondrocyte cultures, ASU shows anti-catabolic effects as it is able to inhibit the following cytokines and an pro-anabolic effect via these actions. A meta-analysis was done in 2007 looking into the 4 RCT done so far comparing Piascledine to Placebo. In all trials patients were initially given NSAIDs and after an a wash out phase, patients were monitored in terms of likelihood to re-initiate NSAIDs due to pain or worsening function as measured by your Lequesne Index.
Updates in OA 2011 Post Grad
UPDATES INOSTEOARTHRITISSIDNEY ERWIN T. MANAHAN, MD, FPCP, FPRAInternal Medicine – Rheumatology28 October 2011
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
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?
OA Pathogenesis: Traditional Change in CARTILAGE Properties CARTILAGE Fibrillations LOSS OF CARTILAGE Subchondral Bone Remodelling Osteophytosis
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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%
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.
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.
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
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)
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)
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)
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