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Biologics Treatments for Osteoarthritis
- 1. Biologic treatments for OA Translating basic sciences to clinical application Adult Reconstruction - Adolescent and Young Adult Hip Service Washington University Orthopedics School of Medicine, St Louis, MO Dr. Cecilia Pascual-Garrido
- 2. • 27 Millions adults US • By 2030 • The demand for THA will increase 174% • Nearly, 67 million people (25%) will have OA in the US Osteoarthritis Arthritis Rheum. 2009 Dec;60(12):3546-53. doi: 10.1002/art.24984. Insurer and out-of-pocket costs of osteoarthritis in the US: evidence from national survey data. Kotlarz H1, Gunnarsson CL, Fang H, Rizzo JA.
- 3. Bulletin of World Health Organization 2013 Prevalence and costs of Osteoarthritis OA Increase Medical Care Expenditure: $185 billion/yearly (women: 2/3) Insurer Expenditure: $149 billion/yearly Out of Pocket: $36 billion/yearly Arthritis Rheum. 2009 Dec;60(12):3546-53. doi: 10.1002/art.24984. Insurer and out-of-pocket costs of osteoarthritis in the US: evidence from national survey data. Kotlarz H1, Gunnarsson CL, Fang H, Rizzo JA.
- 4. Imaging modalities: late diagnosis
- 6. OA: articular joint failure Ryd et al. Pre Osteoarthritic: Definition and Diagnosis of an Elusive Clinical Entity. Cartilage 2015
- 7. e between biology, mechanics, and structure: A systems-based approach to developing osteoarthritis prevention strate Chu CR1,2, Andriacchi TP1,2,3. Slot machine system metaphor FAI DDH ACL RA Obesity Age
- 8. FAI: pre-OAHip at risk
- 9. Dysplasia: pre-OA The acetabular rim syndrome 25 years ago….. “The precursor of OA on the hip” 1991 Hip at risk
- 10. Clinical and radiographic predictors of intra-articular hip disease in arthroscopy. Nepple JJ, Carlisle JC, Nunley RM, Clohisy JC. • Chondral lesions were present in 70% of the cohort (n:338) • Morphological abnormalities such as Cam deformity and DDH were an associated risk for chondromalacia grade 3-4 Patterns of Intraarticular Cartilage Wear in the Pre-Arthritic Hip: A Diagnostic Contemporary Intraoperative Tool Pascual-Garrido, Easmobhana, Grammatopoulos, Li, Rowlands, Beaule and Clohisy . AAHKS 2017 • Chondral lesions were present in 90% if the hips(n:1358) • Highest percent of lesions in patients with DDH and FAI cam • Specific pattern of wear according to hip morphology Redefining the Natural History of Osteoarthritis in Patients With Hip Dysplasia and Impingement. Wyles CC, Heidenreich MJ, Jeng J, Larson DR, Trousdale RT, Sierra RJ. • OA occurs earlier in life in patients with DDH and FAI compared to those with normal morphology Structural Abnormality in the hip: Pre-OA/OA
- 11. Knee at risk ray Analysis of Macroscopically Normal Articular Cartilage from Knees Undergoing Partial Medial Meniscectomy: Potential Prediction of the Risk for Developing O Rai MF, Sandell LJ, Zhang B, Wright RW, Brophy RH. PLoS One. 2016 May 12;11(5):e0155373. doi: 10.1371/journal.pone.0155373. eCollection 2016.
- 12. Young Adult Hip Contemporary Approach Patient-Reported Outcomes of Periacetabular Osteotomy from the Prospective ANCHOR Cohort Study. Clohisy JC, Ackerman J, Baca G, Baty J, Beaulé PE, Kim YJ, Millis MB, Podeszwa DA, Schoenecker PL, Sierra RJ, Sink EL, Sucato DJ, Trousdale RT, Zaltz I. Innovations in Joint Preservation Procedures for the Dysplastic Hip "The Periacetabular Osteotomy". Pascual-Garrido C, Harris MD, Clohisy JC. Young Adult Hip with OA: Arthroplasty What is the prognosis of revision total hip arthroplasty in patients 55 years and younger? Adelani MA, Crook K, Barrack RL, Maloney WJ, Clohisy JC. Total hip arthroplasty in patients 50 years or less: do we improve activity profiles? Kuhn M1, Harris-Hayes M, Steger-May K, Pashos G, Clohisy JC.
- 14. Biologic treatments Any substance derived from animal products or other biological sources and used to treat or prevent disease
- 15. Biologics: remedy of all disease?
- 16. Biologic treatments Biological Therapies for Cartilage Lesions in the Hip: A New Horizon. Chahla J, LaPrade RF, Mardones R, Huard J, Philippon MJ, Nho S, Mei-Dan O, Pascual-Garrido C. Orthopedics. 2016 Jul 1;39(4):e715-23. doi: 10.3928/01477447-20160623-01. Epub 2016 Jun 30. Review. PMID: 27359284
- 18. PRP BMAC Stem CellsNot FDA Approved Biologic Options for Articular Cartilage Wear (Platelet-Rich Plasma, Stem Cells, Bone Marrow Aspirate Concentrate). Kraeutler MJ, Chahla J, LaPrade RF, Pascual-Garrido C. Clin Sports Med. 2017 Jul;36(3):457-468. doi: 10.1016/j.csm.2017.02.004. Epub 2017 Apr 1. Review.
- 19. • Increased platelets above baseline
- 20. Release of GFs Biologic half-life 30 minutes to 7 hours
- 21. Am J Sports Med. 2011 Nov;39(11):2362-70. doi: 10.1177/0363546511419278. Epub 2011 Aug 19. Platelet-rich plasma releasate inhibits inflammatory processes in osteoarthritic chondrocytes. van Buul GM1, Koevoet WL, Kops N, Bos PK, Verhaar JA, Weinans H, Bernsen MR, van Osch GJ. Reduce inflammation! Chondrocyte
- 22. Platelet-Rich Plasma for the Treatment of Knee Osteoarthritis: A Review. Piuzzi NS, Chughtai M, Khlopas A, Harwin SF, Miniaci A, Mont MA, Muschler GF. J Knee Surg. 2017 Jun 23. doi: 10.1055/s-0037-1603795. [Epub ahead of print] No abstract available. Preparation protocol: LR vs LP 17 protocols available
- 24. • 105 studies • Preparation, composition and clinical indications?? • Reporting of PRP preparation protocols in clinical studies is highly inconsistent and the majority of studies did not provide sufficient information to allow the protocol to be reproduced. • Low reporting of PRP preparation and composition does not enable comparison of the PRP products being delivered to patients
- 25. PRP: what is next? • PRP preparation are highly heterogeneous both in processing methods that are used and in composition • There is no consensus on the optimal preparation method and composition of PRP for each clinical condition • A call for standardization!! A detailed, precise and stepwise description of the PRP preparation protocol is required to allow comparison among studies and enable reproducibility
- 26. Connective Tissue Progenitors Stem Cells-Progenitors Cells Bone Marrow CTPs (Stem & Progenitor Cells) Periosteum Bone Muscle Blood
- 27. CTP: 1/ 2000-40,000 cells Stem Cells Progenitor Cells
- 28. Stem Cell • Culture Expanded cells that adhere to tissue culture plastic • Cells Retain Capacity the capability of trilineage differentiation • Cells expressing specific CD markers • Cells lacking expression of specific CD markers To drive the translation of all cellular therapies for the benefit of patients worldwide. hese criteria are not met the term Stem Cell should not be use
- 30. Basic science clinical applications Bone-Marrow derived Cellular Therapies • Bone Marrow Aspiration • Bone Marrow Concentrate (BMAC)
- 31. Bone Marrow Concentrate CTP WBC Growth Factors
- 32. CTP prevalence in BMA Mean 31.2 ± 20.4 106 nucleated cells/mL Mean PCTP was 36.7 ± 31.9 CTPs/106 nucleated cells
- 33. Density separation Stem Cells: 0.001 to 0.01%
- 34. • BMAC for OA and chondral lesions • From the 11 included studies , 3 were identified for OA (R, P and CS) • Significant PROs and no major adverse events • None of the studies perform biological assay to determine CTP or CFU, growth factors or presence of stem cells • Studies were highly heterogeneous
- 37. at in excess of 80% of patients had good results or symptomat
- 38. • Articles: Clinical outcomes for intra-articular cell therapy in the human knee with a minimum 12 month follow up • Level I-II-III • Coleman methodology score to assess quality of methodology in each study • 6 studies • Significant PROs in cellular treatment group and no major adverse events • Only one study assayed the cell population using CFU • Mean mCMS was 60 (not good quality) • Studies were highly heterogeneous
- 39. • Cellular based therapies should still be considered at the proof of concept stage due to potential unknown risks, minimal support evidence. • The value and effective use of stem cell therapy in orthopedics still remain unclear • Standardization, measurements outcomes and well designed clinical trials will be necessary
- 40. Thank you
Editor's Notes
- OA is a common and debilitating disease that affects 27 million people in the US. Given an aging population, the prevalence and costs associated with OA are projected to increase. Forecasts indicate that by year 2030, 25% of population or nearly 67M people will have OA.
- You can see here how the incidence of OA increase with age in all different regions of the world. In male the most prevalent is in those patients belonging from developing countries in both male and females. As you can see here prevalence is higher in females. OA increase health care expenditure dramatically by 185 billion/year and women account for almost two thirds of these expenditures.
- An one of the reason why OA continues to raise is that this disease goes unnoticed until the disease has progressed significantly. OA, should be considered an organ failure where normal homeostasis cannot be maintained. And this graphic is a The OA is a disease that take multiple years to develop. For this reason, pre OA “must exist” representing the long term transition from normal healthy cartilage to ostearthritic cartilage.
- As you can see here joint health depends upon the interplay over time between three broad categories of factors: biology, mechanics and structure and these factors do not generate or prevent disease in isolation. Rather a continuously shifting balance of these factores over time ultimately determines whether joint health is maintained or whether joint shifts into high risk pre OA state. In a system with no risk factors has a high probability of maintaining a healthy joint or homeostasis if you cranck activity over time since the biological, mechanical and structural components of the system consistently fall into a nice envelope. BUT when there are risk factors in the system, that could be: FAI, DDH, ACL etc this homeostasis envelope will not be able to be maintained with the joint is loaded with activity The slot machine metaphor emphasizes the randomness of the system as well as its responsiveness to factors that are known to increase the OA risk.
- Already Ganz in 1991, suggested that the acetabular rim syndrome was a syndrome secondary to dysplasia and was the precursor or OA in the hip
- Sierra study: they identified 755 who had received a THR and had a contralateral hip without any radiographic evidence of hip disease and followed up on them during 10 years. They included 122 patients ( DDH-FAI-and normal hips). Degeneration occured earlier in patients with morphological abnormalities including FAI and DDH
- Steoroids should be incorporated in clinical practice only as a short term relief therapy
- PRP and BMAC fall under the category of minimally manipulated tissue as an autologous blood product is easier to use utilize clinically without extensive testing in preclinical or clinical data.
- Based on different relative density, sediment rate, and size blood components can be separated by centrifuge force is applied.
- The rationale behind PRP, is that platelets is that a group of bioactive molecules that platelet release ultimate promote healing of the damaged tissue and modulates inflammation. 95% of GFs are secreted within 1 hour after activation Biological half-life depends on growth factors 30 minutes to 7.6 hours Therefore, some authors have proposed serial, PRP injections to increase the benefits of its application Multiple injections increase the risk for adverse effects
- The first spin involves a soft spin obtaining the three layers: plasma, BC and the RBC. A second hard spin is then applied
- LP significantly better for OA than HA. LR no difference compared to HA
- They compare 51 studies with prospective or retrospective data where they used PRP for the treatment of different muskulosletal conditions. There was a high variability in processing characteristics, including anticoagulant, spinning, centrifuge machines. Most of the studies did not report on a second spin. The activation method to induce platelet degranulation and release of GF was reported in 43 studies,
- Stem cells and progenitors cells are present in adult tissue and are critical to tissue health, maintenance and response to injury.
- Stem cells give rise to progenitors cells and are distinguished from progenitors cells with their capacity of self renewal. In contrast, progenitors cells proliferate and expand in numbers. CTP have been identified as the heterogeneous group of stem cells and progenitor cells present in native tissue and can be activated to proliferate and genere progeny that can differentiate into 1 or more connective tissue..The amount of stem cells and progenitor cells that a tissue have varies and can be estimated in culture through the CTP. Since there are no specific markers for CTP, so as a result the concentration, biological potential of CTP in given cell population can be only estimated using in vitro CFU assay. As you can see here, the osteogenic capacity is different for each CTP as shown by different intensity of color in the assay. Stem cells is not a CTP: The
- Distribution of average cost of stem cell therapies marketed to consumers. The red one is over 7000, orange between 6000 and 7000, yellow is 4000 and 5000 and pale is less than 3000
- In this review. We considered for inclusion articles where clinical outcomes were reported for intra articular cell therapy in the human knee with a minimum of 12 month Coleman methodology is based on part A that evaluates the study size, mean follow up, number of different surgical procedures, type of study and description of surgical procedures, post operative rehab and MRI and histo. Part B evaluates outcomes criteria, procedure for assessing clinical outcomes, subject selection. Maximum score is 100 in which indicates that a study largely avoids chances, biases and confounding factors. We were able to include 6 studies (3 for focal chondral and 3 for OA), The use of stem cell therapy in the USA has expanded rapidly in the USA. However, despite extensive marketing and use of cells based therapies, most of the evidence surrounding usa is low quality. Despite as these therapies, often masked as proven therapies, still require higher quality clinical studies to prove their efficacy as better to understand their biological functions
- They hype cycle is a graphical representation to represent adoption of new technology. The maturation of new technology goes through different five phases. The technology triggers. This is when new technology kicks in. Normally is a proof of concept where stories and media are interested. Then the peak of inflated expectations: Early publicity produces a number of success stories. Then the trough of disillusionment, here interest wanes and implementation fail to deliver. The development will continue only if the surviving providers improve their product. The slope of enlightenment is when the enterprise starts to become more understood. Finally the plateau of productivity where the product is more define.
- So basically, PRP is a volume of plasma with a platelet concentrations above whole blood baseline values. The concentration is 1-3x compared to 150,000/ul and we normally say we need a concentration of 1 million platelets per ml
- In 2006 it came out the first paper of PRP in orthopedics came out and it was on elbow tendinitis.
- Leucocytes poor and leukocytes rich.
- This is a RCT where they included 111 patients and treated them with either three txt groups. As you can see, there was no statement in terms of LP-LR. All three treatment improved patients pain with significant better improvements for the PRP.
- Centrifugation characteristics stratified by body region. From a total of 105 studies that evaluated the use of PRP in muskuloeskeletal conditions, only 29 described the centrifugation and preparation technique.
- we perform a systematic review on the outcome of BMAC in the treatment of OA and chondral lesions