Evidence for knee injection techniques in osteoarthritis

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1 Evidence for knee injection techniques in osteoarthritis Geoffrey Littlejohn Associate Professor/Emeritus Director Rheumatology Monash University and MonashHealth Melbourne

2 Knee Osteoarthritis Prevalence common increasing prevalence ageing population associated with metabolic syndrome Burden High symptoms functional impact costs

3 Knee replacements in Australia keep increasing Australian registry data $25,000 per TKR

4 Big problem Big money

5 Risk Factors for OA of the Knee Abnormal stresses Abnormal cartilage Compromised cartilage Biophysical changes Collagen network fracture Proteoglycan unraveling Biochemical changes Inhibitors reduced Proteolytic enzymes increased Cartilage breakdown Mandelbaum B, Waddell D. Orthopedics. 2005;28(2 Suppl):s207-s214. 5

6 Imbalance Between Synthesis and Degradation of Cartilage Matrix Synthesis Degradation Proinflammatory cytokines MMPs (collagenases, stromelysin, gelatinases Aggrecaneses Prostaglandins Nitric oxide (NO) Anti-inflammatory cytokines TIMPs Growth factors Collagen synthesis Proteoglycan synthesis MMPs=matrix metalloproteinase; TIMP=tissue inhibitor of metalloprotineases. 1. Moreland LW. Arthritis Res Ther. 2003;5: Pelletier JP et al. Arthritis Rheum. 2001;44:

7 Structural changes in osteoarthritis

8 Processes Pain mechanisms in OA Peripheral Synovial inflammation Bone marrow changes Mechanical instability Mechanisms Nociception Peripheral sensitization

9 Pain mechanisms in OA Processes Central sensitization Central Benefits with SNRI Duloxetine FDA approved for OA Placebo pathway

10 The Multi-Modality Approach to OA Knee Pain INTRAARTICULAR INJECTIONS OTC MEDICATIONS PRESCRIPTION MEDICATIONS EXERCISE & LIFESTYLE SURGERY Personalized medicine Jordan KM, et al. Ann Rheum Dis. 2003;62;

11 Injection therapies for OA Corticosteroids Hyaluronic acid Platelet-rich plasma Growth factors Stem cells Others Botulinum toxin-a New treatments

12 Corticosteroid injections evidence Used for 60 years Corticosteroid better than placebo Data variable Duration response 2-6 weeks Cochrane review 2009

13 ACR 2012 recommendations steroids for OA Knee consensus judgment of clinical experts from a wide range of disciplines informed by available evidence balancing the benefits and harms of both nonpharmacologic and pharmacologic modalities incorporating their preferences and values. conditionally recommended for initial management Among other strategies

14 Approach to OA of the Knee Adapted from 1. Creamer P., and Hochberg MC. Lancet. 1997;350:506, 2. ACR Subcommittee on OA Guidelines,

15 Corticosteroid injections general consensus Considered where inflammation prominent Strict aseptic technique, know landmarks Expect improvement from 2 weeks to 3 months or more better results in early OA Inject no more than 3 times per year per joint avoids excess steroid effect on cartilage

16 Injection of hyaluronic acid Viscosupplementation

17 Hyaluron contributes to Synovial Fluid viscoelastic properties Low Frequency Movement Molecules align in the direction of movement Viscous properties: lubrication and molecular barrier effect High Frequency Impact MW: 6,000,000 Daltons Entangled molecular network resists deformation and acts as a shock absorber Energy is stored as elasticity 1 7

18 Progression of OA of the Knee Kellgren-Lawrence Radiographic Criteria 1 RADIOGRAPHIC GRADE GRADE 0 GRADE 1 GRADE 2 GRADE 3 GRADE 4 CLASSIFICATION Normal Doubtful Mild Moderate Severe DESCRIPTION No features of OA Minute osteophyte; doubtful significance Definite osteophyte; normal joint space Moderate joint space reduction Joint space greatly reduced; subchondral sclerosis MOLECULAR WEIGHT (million Daltons) ELASTICITY (Pa at 2.5 Hz) VISCOSITY (Pa at 2.5 Hz) As in 21-to 45-year olds As in 18- to 27-year olds Altman RD, Gold GE. Osteoarthritis Cartilage. 2007;15(suppl A):A1-A Balazs EA, et al. 1967;10(4): Praest BM, Greiling H, Kock R. Clin Chim Acta. 1997;266(2): Mazzucco D, et al. J Orthop Res. 2002;20:

19 1 9 Viscosupplementation 1) Removal of pathologic synovial fluid 2) Replacement with products with rheologic properties similar to normal SF Objective is to: Restore viscoelastic properties of SF Reduce inflammation Decrease pain and improve mobility Promote synthesis of normal HA by synoviocytes

20 Physical Properties of Viscosupplements Healthy, young synovial fluid 1, Synvisc /Synvisc One (hylan G-F 20) YES Osteoarthritis synovial fluid 3, Hyalgan NO Euflexxa NO Neovisc Not available Not available NO Durolane 5 n/a YES Monovisc YES n/a= not applicable As in 21-to 45-year olds As in 18- to 27-year olds 1. Synvisc /Synvisc One Product Monographs. 2. Balazs EA, et al. Arthritis Rheum. 1967;10(4): Praest BM, Greiling H, Kock R. Clin Chim Acta. 1997;266(2): Mazzucco D, et al. J Orthop Res. 2002;20: Data on file. Genzyme Corp. 6. Neovisc Product Information. 2 0

21 Effect of Hylan G-F 20 on SF at 3 Months In human OA joints, Synvisc significantly increased synovial fluid HA concentration to that of healthy adult knees at 3 months (p<0.0008) Synvisc significantly increased complex shear modulus at 3 months (p<0.03) Bagga H, et al. The Journal of Rheumatology. 2006;3(5):

22 Hyaluron and potential cartilage preservation Annual percentage change in tibial cartilage volume after 2 years, as measured by MRI [n=78] Statistically Significant Cartilage Preservation within Synvisc Group Adapted from Wang et al. Poster presented at: European League Against Rheumatism (EULAR); June 16-19, 2010; Rome, Italy. 2 2

23 Hyaluron and potential cartilage preservation Cartilage defect score after 2 years Significantly Less Deterioration of Cartilage within Synvisc Group Adapted from Wang et al. Poster presented at: European League Against Rheumatism (EULAR); June 16-19, 2010; Rome, Italy. 2 3

24 2 4 Hyaluron effects on cartilage matrix External molecular barrier from synovial fluid Enhances hyaluronic acid synthesis Stimulates proteoglycan synthesis Prevents proteoglycan breakdown and loss from cartilage matrix

25 Hyaluron in Normal Synovial Fluid multiple properties Mechanical Lubrication (viscosity) Load absorption(elasticity) Anti-inflammatory properties Anti-nociceptive properties Protective effect on cartilage matrix Prevention of inflammationmediated sensitization of articular pain receptors Entrapment of nociceptive molecules Insulation of A-δ and C- fiber pain receptor endings Decreased synthesis of substance P and bradykinin 1. Moreland LW. Arthritis Res Ther. 2003;5: Marshall. Foot Ankle Clin N Am, 2003;8:

26 Over 70% of Patients Responded to Synvisc One within 8 weeks Walking Pain Response Rate N=253 Versus 53% with placebo at Week 18 (p=0.003). At week 26, significantly more (64%) of patients treated with Synvisc One responded to treatment vs. placebo (50%; p=0.028). Adapted from Chevalier et al, Ann Rheum Dis. 2010; 69:

27 Long-Lasting Pain Relief Synvisc vs standard of care [ACR 1995] over 1 Year N=255 Adapted from Raynauld JP, et al. OsteoArthritis and Cartilage. 2005; 13:

28 Synvisc Has Been Shown to Significantly Delay Time to TKR by a Median of 2.1 yrs 6-year retrospective case series 863 patients grade IV OA, VAS >60 treated with Synvisc in one orthopedic practice Adapted from Waddell et al, Journal of Managed Care Pharmacy. 2007; 2(13):

29 Cochrane assessment for Viscosupplements Effective on pain, function and patient global assessment at different post injection periods but especially at the 5 to 13 week post injection period. the magnitude of the clinical effect is different for different products, comparisons, time points, variables and trial designs

30 Guidelines for Viscosupplements Osteoarthritis Research Society International (OARSI) (2008) 1 - Injections of IA hyaluronate may be useful in patients with knee or hip OA. They are characterised by delayed onset, but prolonged duration, of symptomatic benefit when compared to IA injections of corticosteroids. American Academy of Orthopaedic Surgeons (AAOS) 2 - Viscosupplementation may have a role in the treatment of knee pain due to osteoarthritis during the initial 12 weeks in the hands of physicians technically proficient in arthrocentesis. American College of Rheumatology (ACR) 2012 conditionally recommended early and in context IA injection of HA is recommended in 8/9 existing guidelines as a useful therapeutic modality for treating patients with OA knee as a viscosupplement or pharmaceutical Zhang W et al. Osteoarthritis Cartilage. 2008;16(2): AAOS Clinical Guideline on Osteoarthritis of the KneeSupport Document

31 Viscosupplementation general consensus Considerations Considered as an effective therapy for patients with mild-to-moderate knee OA Use concomitantly with physical therapy and medical therapeutics, with a high likelihood of increased efficaciousness 1 Benefit lasts longer than steroid Limitations Magnitude of the clinical effect remains controversial and appears different according to the formulations differ widely in molecular weight, origin (animal or bacterial), and residence time in the joint 2 1. Langworthy, MJ et al. The Physician and Sportsmedicine. ISSN June 2010;38(2). 2. Mathieu, P. Clin Orthop Relat Res. 2009;467:

32 Platelet-rich plasma [PRP] I/A injections for sports injuries tendon, cartilage PRP contains factors potentially promoting cartilage healing/regeneration vascular endothelial growth factor, transforming growth factor-β, platelet-derived growth factor Smelter and Hochberg 2013 Curr Opinion Rheumatol

33 Platelet-rich plasma [PRP] 100 patients with knee OA 3 injections 3 weeks apart assessed 6 and 12 months after last injection well tolerated At 6 months Statistically significant improvement IKDC subjective and objective scores European quality of life VAS At 12 months IKDC scores worsened European quality of life VAS stayed same At 24 months Continued worsening of both scores Kon 2010 Knee Surg Sports Traumatol Arthrosc

34 Platelet-rich plasma [PRP] 14 patients with knee OA injections 4 weeks apart At 6 months pain significantly better at various times US assessed cartilage thickness not different from baseline Sampson 2010 Am J Phys Med Rehabil

35 Platelet-rich plasma [PRP] 150 patients with knee OA 50 PRP 50 low MW hyaluronic acid 50 high MW hyaluronic acid At 2 months PRP improvement same as low MW hyaluronic acid PRP improvement better than high MW hyaluronic acid Kon 2011 Arthroscopy

36 Platelet-rich plasma [PRP] 120 patients with knee OA 60 PRP 60 hyaluronic acid weekly for 3 weeks At 3 and 6 months significant improvements in WOMAC and pain scores both time points both groups not designed as equivalence or non-inferiority Spackova 2012 Am J Phys Med Rehabil

37 Platelet-rich plasma [PRP] What does this mean? Pain improves uncontrolled studies No evidence about cartilage Need bigger saline-controlled trials Smelter and Hochberg 2013 Curr Opinion Rheumatol

38 Growth factors Bone morphogenic protein-7 member of transforming growth factor Β superfamily reparative effects on cartilage Animal studies I/A injection decreased cartilage degradation Human studies Phase 1, 12 week study: non-significant trend less pain in treatment group Hunter Nat Rev Rheum :17

39 Growth factors Fibroblast growth factor-18 I/A injection shows cartilage repair in animals Phase 1 trials in humans Hunter Nat Rev Rheum :17

40 Growth factors What does this mean? unclear Need bigger saline-controlled trials Smelter and Hochberg 2013 Curr Opinion Rheumatol

41 Botulinum toxin- A Small studies show decrease in joint pain 37 and 60 patients no long-term data Currently large RCT comparing to saline enrolling

42 Mesenchymal stem cells Active area 11 current trials 2 case series, I small RCT Smelter and Hochberg 2013 Curr Opinion Rheumatol

43 Mesenchymal stem cells 25 patients with 1o OA knee Arthroscopic debridement Adipose synovium collected Cells extracted Injected several hours later, with platelet-rich plasma 3mls PRP given every 7 days x 3 times Non-blinded control group arthroscopy+ PRP Koh Y-G, Choi Y-J, Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis, Knee (2012), doi: /j.knee

44 Mesenchymal stem cells Koh Y-G, Choi Y-J, Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis, Knee (2012), doi: /j.knee

45 Mesenchymal stem cells Footballers being used 'as stem cell lab rats 'BY: GREG BEARUP From: The Australian May 04, 2013 AFL and NRL footballers are being used as "lab rats" by biomedical companies to promote radical stem cell therapy, a treatment scientists say has not been proven to work, or even to be safe.the therapy is being aggressively pitched to footballers.

46 Orthokine /regenokine injections Hawks set the pace in injection science Date September 25, 2012 Read later Samantha Lane Sports Writer 'We've done probably 120 patients now and we're getting a 95 per cent response rate, which is unheard of. Dr Paul Marks, Melbourne Read more: Targets Interleukin 1? Not FDA approved Trials in OA knee lacking New York Times July

47 Available on the net Regenexx Advanced Stem Cell and Platelet Procedures for Knee Injury and Knee Osteoarthritis Regenexx Stem Cell Procedures are breakthrough, nonsurgical stem-cell treatments for people suffering from knee pain due to common injuries to the knee meniscus, ACL or MCL, cartilage, or who are experiencing degenerative conditions, such as osteoarthritis. Traditional options for patients suffering from these conditions include arthroscopic knee surgery to repair ligament tears, or total knee joint replacement. With both surgeries, months of rehab are required, and the patient must be aware of and prepared to take on the risks. As an alternative, the Regenexx-SD (same-day) procedure may help alleviate knee pain and the conditions that cause it with a simple office injection procedure.

48 Allogeneic stem cells mesoblast The exceptional results of preclinical cartilage trials have shown that a single injection of Mesoblast s allogeneic cell product, RepliCart, into knee joints damaged by osteoarthritis can prevent further deterioration and regenerate and regrow cartilage tissue lining the damaged joint. Mesoblast s clinical trials are ongoing.

49 Mesenchymal stem cells Kartogenin I/A promotes differentiation of human mesenchymal stem cells cartilage nodules mouse models encouraging potential to use endogenous stem cells Marini and Forlino NEMJ :2522

50 Mesenchymal stem cells What does this mean? unclear but promising Need bigger saline-controlled trials Smelter and Hochberg 2013 Curr Opinion Rheumatol

51 Other targets in osteoarthritis Hunter Nat Rev Rheum :17

52 Metalloproteinase inhibition Animal models good results Significant side-effects in humans arthralgia

53 Cytokine inhibition Interleukin-1 stimulates matrix metalloproteinases, reduces aggrecan, other matrix constituents DBRCT of I/A IL1-inhibitor no clinical benefit at 3 and 12 months Tumor necrosis factor DBRCT of S/C TNFi no clinical benefit

54 Cytokine inhibition Nerve growth factor Tanezumab [monoclonal a/b to NGF] effective Monthly S/C Cases of rapidly progressive OA risk profile now established program now restarted 697 patients with OA knee Brown J Pain :790

55 Other new treatments: bone Zolendronate Decreases bone-marrow lesions and pain Strontium ranelate Decreases joint space narrowing compared to placebo Decreases pain

56 Placebo response high in knee OA In trials large effect size Placebo 0.54 No placebo control 0.03 for injections greater if multiple Wang et al Ann Rheum Dis 2008;67: doi: /ard

57 Early detection of Osteoarthritis Currently symptom-driven approach radiographic OA = gross cartilage loss target high at-risk groups ACL/meniscal injury» years until OA Future Biomarkers Genetics Serum markers Imaging

58 Summary Corticosteroids useful for inflammation Hyaluronic acid useful for symptom control, possible structure effect Platelet-rich plasma need more studies Stem cell treatments need more studies