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Multimodal approach to intraarticular drug delivery in knee osteoarthritis

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Abstract

The expectations from any future disease-modifying treatment for knee osteoarthritis (KOA) are extremely high as it has to impact the joint as a whole leading to favorable alterations of diverse tissues and functions. In this light, targeting the knee only from the inside may not be biologically justified for the management of a whole joint disease such as KOA. Our hypothesis to test is whether any injectable therapeutic intervention alone can lead to disease modification of KOA which is viewed in the complexity of the modern concept of osteoarthritis (OA) as a whole joint disease. Therefore, we aimed at analyzing the intraarticular route to the KOA patient in an attempt to unveil its “biological” constraints. A comprehensive search through databases was carried out using specific keywords to add objectivity to the main messages. The literature analysis has shown that “cutting-edge” intraarticular therapies may offer a key to non-invasive symptomatic relief. Changing the course of KOA, however, may necessitate a multimodal approach towards the knee joint including a combination of intraarticular injections with interventions on multiple levels. Importantly, our understanding of OA has evolved redefining the concept of the disease, being in interaction with the human body as a whole. Any future conservative disease-modifying treatment of KOA should aim at a multimodal, holistic approach towards the knee joint including but not limited only to intraarticular injections. A combination with other interventions should be further researched.

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References

  1. Hunter DJ, Bierma-Zeinstra S (2019) Osteoarthritis. Lancet 393:1745–1759. https://doi.org/10.1016/S0140-6736(19)30417-9

    Article  CAS  PubMed  Google Scholar 

  2. Felson DT, Neogi T (2018) Emerging treatment models in rheumatology: challenges for osteoarthritis trials. Arthr Rheumatol 70(8):1175–1181. https://doi.org/10.1002/art.40515

    Article  Google Scholar 

  3. Cao P, Li Y, Tang Y, Ding C, Hunter DJ (2020) Pharmacotherapy for knee osteoarthritis: current and emerging therapies. Expert Opin Pharmacother 21(7):797–809. https://doi.org/10.1080/14656566.2020.1732924

    Article  CAS  PubMed  Google Scholar 

  4. Hoy DG, Smith E, Cross M, Sanchez-Riera L, Blyth FM, Buchbinder R, Woolf AD, Driscoll T, Brooks P, March LM (2015) Reflecting on the global burden of musculoskeletal conditions: lessons learnt from the global burden of disease 2010 study and the next steps forward. Ann Rheum Dis 74(1):4–7. https://doi.org/10.1136/annrheumdis-2014-205393

    Article  PubMed  Google Scholar 

  5. Georgiev T, Angelov AK (2019) Modifiable risk factors in knee osteoarthritis: treatment implications. Rheumatol Int 39(7):1145–1157. https://doi.org/10.1007/s00296-019-04290-z

    Article  PubMed  Google Scholar 

  6. Poole AR (2012) Osteoarthritis as a whole joint disease. HSS J 8(1):4–6. https://doi.org/10.1007/s11420-011-9248-6

    Article  PubMed  PubMed Central  Google Scholar 

  7. Martel-Pelletier J, Barr A, Cicuttini F, Conaghan PG, Cooper C, Goldring MB et al (2016) Osteoarthritis. Nat Rev Dis Primers 2:12. https://doi.org/10.1038/nrdp.2016.72

    Article  Google Scholar 

  8. Rai MF, Pham CT (2018) Intra-articular drug delivery systems for joint diseases. Curr Opin Pharmacol 40:67–73. https://doi.org/10.1016/j.coph.2018.03.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gasparyan AY, Ayvazyan L, Mukanova U, Yessirkepov M, Kitas GD (2019) Scientific hypotheses: writing, promoting, and predicting implications. J Korean Med Sci 34(45):e300. https://doi.org/10.3346/jkms.2019.34.e300

    Article  PubMed  PubMed Central  Google Scholar 

  10. Lespasio MJ, Piuzzi NS, Husni ME, Muschler GF, Guarino A, Mont MA (2017) Knee Osteoarthritis: a Primer. Perm J 21:16–183. https://doi.org/10.7812/TPP/16-183

    Article  PubMed  PubMed Central  Google Scholar 

  11. Berkoff DJ, Miller LE, Block JE (2012) Clinical utility of ultrasound guidance for intra-articular knee injections: a review. Clin Interv Aging 7:89–95. https://doi.org/10.2147/CIA.S29265

    Article  PubMed  PubMed Central  Google Scholar 

  12. Klocke R, Levasseur K, Kitas GD, Smith JP, Hirsch G (2018) Cartilage turnover and intra-articular corticosteroid injections in knee osteoarthritis. Rheumatol Int 38(3):455–459. https://doi.org/10.1007/s00296-018-3988-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Oo WM, Liu X, Hunter DJ (2019) Pharmacodynamics, efficacy, safety and administration of intra-articular therapies for knee osteoarthritis. Expert Opin Drug Metab Toxicol 15(12):1021–1032. https://doi.org/10.1080/17425255.2019.1691997

    Article  CAS  PubMed  Google Scholar 

  14. Balazs EA, Denlinger JL (1993) Viscosupplementation: a new concept in the treatment of osteoarthritis. J Rheumatol 20:3–9

    Google Scholar 

  15. Marshall KW (2000) Intra-articular hyaluronan therapy. Curr Opin Rheumatol 12(5):468–474. https://doi.org/10.1097/00002281-200009000-00022

    Article  CAS  PubMed  Google Scholar 

  16. Gupta RC, Lall R, Srivastava A, Sinha A (2019) Hyaluronic acid: molecular mechanisms and therapeutic trajectory. Front Vet Sci 6:192. https://doi.org/10.3389/fvets.2019.00192

    Article  PubMed  PubMed Central  Google Scholar 

  17. Soltés L, Mendichi R, Kogan G, Schiller J, Stankovska M, Arnhold J (2006) Degradative action of reactive oxygen species on hyaluronan. Biomacromol 7(3):659–668. https://doi.org/10.1021/bm050867v

    Article  CAS  Google Scholar 

  18. Chernos M, Grecov D, Kwok E, Bebe S, Babsola O, Anastassiades T et al (2017) Rheological study of hyaluronic acid derivatives. Biomed Eng Lett 7:17–24. https://doi.org/10.1007/s13534-017-0010-y

    Article  PubMed  PubMed Central  Google Scholar 

  19. Migliore A, Giovannangeli F, Granata M, Laganá B (2010) Hylan g-f 20: review of its safety and efficacy in the management of joint pain in osteoarthritis. Clin Med Insights Arthr Musculoskelet Disord 20:55–68. https://doi.org/10.1177/117954411000300001

    Article  Google Scholar 

  20. Lee JK, Choi CH, Oh KJ, Kyung HS, Yoo JH, Ha CW (2017) Safety and efficacy of bi-annual intra-articular LBSA0103 injections in patients with knee osteoarthritis. Rheumatol Int 37(11):1807–1815. https://doi.org/10.1007/s00296-017-3803-5

    Article  CAS  PubMed  Google Scholar 

  21. Bannuru RR, Natov NS, Dasi UR, Schmid CH, McAlindon TE (2011) Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis–meta-analysis. Osteoarthr Cartil 19(6):611–619. https://doi.org/10.1016/j.joca.2010.09.014

    Article  CAS  Google Scholar 

  22. Bannuru RR, Vaysbrot EE, Sullivan MC, McAlindon TE (2014) Relative efficacy of hyaluronic acid in comparison with NSAIDs for knee osteoarthritis: a systematic review and meta-analysis. Semin Arthr Rheum 43(5):593–599. https://doi.org/10.1016/j.semarthrit.2013.10.002

    Article  CAS  Google Scholar 

  23. Rutjes AW, Jüni P, da Costa BR, Trelle S, Nüesch E, Reichenbach S (2012) Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis. Ann Intern Med 157:180–191. https://doi.org/10.7326/0003-4819-157-3-201208070-00473

    Article  PubMed  Google Scholar 

  24. McAlindon TE, Bannuru R, Sullivan MC, Arden NK, Berenbaum F, Bierma-Zeinstra SM, Hawker GA, Henrotin Y, Hunter DJ, Kawaguchi H, Kwoh K (2014) OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthr Cartil 22(3):363–388. https://doi.org/10.1016/j.joca.2014.01.003

    Article  CAS  Google Scholar 

  25. Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, Towheed T, Welch V, Wells G, Tugwell P (2012) American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthr Care Res (Hoboken) 64(4):465–474. https://doi.org/10.1002/acr.21596

    Article  CAS  Google Scholar 

  26. Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, Gunther K, Hauselmann H, Herrero-Beaumont G, Kaklamanis P, Lohmander S (2003) EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis 62(12):1145–1155. https://doi.org/10.1136/ard.2003.011742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dai WL, Zhou AG, Zhang H, Zhang J (2017) Efficacy of platelet-rich plasma in the treatment of knee osteoarthritis: a meta-analysis of randomized controlled trials. Arthroscopy 33(3):659–670. https://doi.org/10.1016/j.arthro.2016.09.024

    Article  PubMed  Google Scholar 

  28. Gasparyan AY, Ayvazyan L, Pretorius E, Kitas GD (2014) Platelets in rheumatic diseases: friend or foe? Curr Pharm Des 20(4):552–566. https://doi.org/10.2174/138161282004140213143843

    Article  CAS  PubMed  Google Scholar 

  29. Huang G, Hua S, Yang T, Ma J, Yu W, Chen X (2018) Platelet-rich plasma shows beneficial effects for patients with knee osteoarthritis by suppressing inflammatory factors. Exp Ther Med 15(3):3096–3102. https://doi.org/10.3892/etm.2018.5794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Han Y, Huang H, Pan J, Lin J, Zeng L, Liang G, Yang W, Liu J (2019) Meta-analysis comparing platelet-rich plasma vs hyaluronic acid injection in patients with knee osteoarthritis. Pain Med 20(7):1418–1429. https://doi.org/10.1093/pm/pnz011

    Article  PubMed  PubMed Central  Google Scholar 

  31. Dong Y, Zhang B, Yang Q, Zhu J, Sun X (2020) The effects of platelet-rich plasma injection in knee and hip osteoarthritis: a meta-analysis of randomized controlled trials. Clin Rheumatol. https://doi.org/10.1007/s10067-020-05185-2

    Article  PubMed  PubMed Central  Google Scholar 

  32. Rajan PV, Ng MK, Klika A, Kamath AF, Muschler GF, Higuera CA, Piuzzi NS (2020) The cost-effectiveness of platelet-rich plasma injections for knee osteoarthritis: a markov decision analysis. J Bone Joint Surg Am. https://doi.org/10.2106/JBJS.19.01446

    Article  PubMed  Google Scholar 

  33. Chahla J, Cinque ME, Piuzzi NS, Mannava S, Geeslin AG, Murray IR, Dornan GJ, Muschler GF, LaPrade RF (2017) A call for standardization in platelet-rich plasma preparation protocols and composition reporting: a systematic review of the clinical orthopaedic literature. J Bone Joint Surg Am 99(20):1769–1779. https://doi.org/10.2106/jbjs.16.01374

    Article  PubMed  Google Scholar 

  34. Xing D, Wang Q, Yang Z, Hou Y, Zhang W, Chen Y, Lin J (2018) Mesenchymal stem cells injections for knee osteoarthritis: a systematic overview. Rheumatol Int 38(8):1399–1411. https://doi.org/10.1007/s00296-017-3906-z

    Article  CAS  PubMed  Google Scholar 

  35. Peister A, Mellad JA, Larson BL, Hall BM, Gibson LF, Prockop DJ (2004) Adult stem cells from bone marrow (MSCs) isolated from different strains of inbred mice vary in surface epitopes, rates of proliferation, and differentiation potential. Blood 103(5):1662–1668. https://doi.org/10.1182/blood-2003-09-3070

    Article  CAS  PubMed  Google Scholar 

  36. Hocking AM, Gibran NS (2010) Mesenchymal stem cells: paracrine signaling and differentiation during cutaneous wound repair. Exp Cell Res 316(14):2213–2219. https://doi.org/10.1016/j.yexcr.2010.05.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. de Girolamo L, Kon E, Filardo G, Marmotti AG, Soler F, Peretti GM et al (2016) Regenerative approaches for the treatment of early OA. Knee Surg Sports Traumatol Arthrosc 24(6):1826–1835. https://doi.org/10.1007/s00167-016-4125-y

    Article  PubMed  Google Scholar 

  38. Filardo G, Madry H, Jelic M, Roffi A, Cucchiarini M, Kon E (2013) Mesenchymal stem cells for the treatment of cartilage lesions: from preclinical findings to clinical application in orthopedics. Knee Surg Sports Traumatol Arthrosc 21(8):1717–1729. https://doi.org/10.1007/s00167-012-2329-3

    Article  PubMed  Google Scholar 

  39. Caplan AI (2017) Mesenchymal stem cells: time to change the name! Stem Cells Transl Med 6(6):1445–1451. https://doi.org/10.1002/sctm.17-0051

    Article  PubMed  PubMed Central  Google Scholar 

  40. Izadpanah R, Trygg C, Patel B, Kriedt C, Dufour J, Gimble JM, Bunnell BA (2006) Biologic properties of mesenchymal stem cells derived from bone marrow and adipose tissue. J Cell Biochem 99(5):1285–1297. https://doi.org/10.1002/jcb.20904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sekiya EJ, Forte A, Kühn TI, Janz F, Bydlowski SP, Alves A (2012) Establishing a stem cell culture laboratory for clinical trials. Rev Bras Hematol Hemoter 34(3):236–241. https://doi.org/10.5581/1516-8484.20120057

    Article  PubMed  PubMed Central  Google Scholar 

  42. Lopa S, Moretti M, de Girolamo L (2012) The role of MSCs for nonsurgical treatment of OA. In: Farr J, Gomoll A (eds) Cartilage restoration. Springer, Cham. https://doi.org/10.1007/978-3-319-77152-6

    Chapter  Google Scholar 

  43. Orozco L, Munar A, Soler R, Alberca M, Soler F, Huguet M, Sentís J, Sánchez A, García-Sancho J (2013) Treatment of knee osteoarthritis with autologous mesenchymal stem cells: a pilot study. Transplantation 95(12):1535–1541. https://doi.org/10.1097/TP.0b013e318291a2da

    Article  CAS  PubMed  Google Scholar 

  44. Davatchi F, Abdollahi BS, Mohyeddin M, Shahram F, Nikbin B (2011) Mesenchymal stem cell therapy for knee osteoarthritis. Preliminary report of four patients. Int J Rheum Dis 14(2):211–215. https://doi.org/10.1111/j.1756-185X.2011.01599.x

    Article  PubMed  Google Scholar 

  45. Kim SH, Ha CW, Park YB, Nam E, Lee JE, Lee HJ (2019) Intra-articular injection of mesenchymal stem cells for clinical outcomes and cartilage repair in osteoarthritis of the knee: a meta-analysis of randomized controlled trials. Arch Orthop Trauma Surg 139(7):971–980. https://doi.org/10.1007/s00402-019-03140-8

    Article  PubMed  Google Scholar 

  46. Jones IA, Togashi R, Wilson ML, Heckmann N, Vangsness CT Jr (2019) Intra-articular treatment options for knee osteoarthritis. Nat Rev Rheumatol 15(2):77–90. https://doi.org/10.1038/s41584-018-0123-4

    Article  PubMed  PubMed Central  Google Scholar 

  47. Evans CH, Ghivizzani SC, Robbins PD (2018) Gene delivery to joints by intra-articular injection. Hum Gene Ther 29(1):2–14. https://doi.org/10.1089/hum.2017.181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Liu-Bryan R, Terkeltaub R (2015) Emerging regulators of the inflammatory process in osteoarthritis. Nat Rev Rheumatol 11(1):35–44. https://doi.org/10.1038/nrrheum.2014.162

    Article  CAS  PubMed  Google Scholar 

  49. Ko JH, Kang YM, Yang JH, Kim JS, Lee WJ, Kim SH, Yang IH, Moon SH (2019) Regulation of MMP and TIMP expression in synovial fibroblasts from knee osteoarthritis with flexion contracture using adenovirus-mediated relaxin gene therapy. Knee 26(2):317–329. https://doi.org/10.1016/j.knee.2019.01.010

    Article  PubMed  Google Scholar 

  50. Zhao L, Huang J, Fan Y, Li J, You T, He S, Xiao G, Chen D (2019) Exploration of CRISPR/Cas9-based gene editing as therapy for osteoarthritis. Ann Rheum Dis 78(5):676–682. https://doi.org/10.1136/annrheumdis-2018-214724

    Article  CAS  PubMed  Google Scholar 

  51. Bellavia D, Veronesi F, Carina V, Costa V, Raimondi L, De Luca A, Alessandro R, Fini M, Giavaresi G (2018) Gene therapy for chondral and osteochondral regeneration: is the future now? Cell Mol Life Sci 75(4):649–667. https://doi.org/10.1007/s00018-017-2637-3

    Article  CAS  PubMed  Google Scholar 

  52. Blom AB, Brockbank SM, van Lent PL, van Beuningen HM, Geurts J, Takahashi N, van der Kraan PM, van de Loo FA, Schreurs BW, Clements K, Newham P (2009) Involvement of the Wnt signaling pathway in experimental and human osteoarthritis: prominent role of Wnt-induced signaling protein 1. Arthr Rheum 60(2):501–512. https://doi.org/10.1002/art.24247

    Article  CAS  Google Scholar 

  53. Yazici Y, McAlindon TE, Gibofsky A, Lane NE, Clauw DJ, Jones MH et al (2018) Results from a 52-week randomized, double-blind, placebo-controlled, phase 2 study of a novel, intra-articular wnt pathway inhibitor (SM04690) for the treatment of knee osteoarthritis [abstract]. Osteoarthr Cartil 26:S293–S294. https://doi.org/10.1016/j.joca.2018.02.589

    Article  Google Scholar 

  54. Yazici Y, Mcalindon T, Gibofsky A, Lane N, Lattermann C, Skrepnik N, Swearingen C, Difrancesco A, Tambiah J, Hochberg M (2019) THU0458 Efficacy and safety from a phase 2B trial of SM04690, a novel intra-articular wnt pathway inhibitor for the treatment of osteoarthritis of the knee. Ann Rheum Dis 78:519. https://doi.org/10.1136/annrheumdis-2019-eular.5045

    Article  Google Scholar 

  55. Shkhyan R, Van Handel B, Bogdanov J, Lee S, Yu Y, Scheinberg M, Banks NW, Limfat S, Chernostrik A, Franciozi CE, Alam MP (2018) Drug-induced modulation of gp130 signalling prevents articular cartilage degeneration and promotes repair. Ann Rheum Dis 77(5):760–769. https://doi.org/10.1136/annrheumdis-2017-212037

    Article  CAS  PubMed  Google Scholar 

  56. Cheng C, Shan W, Huang W, Ding Z, Cui G, Liu F, Lu W, Xu J, He W, Yin Z (2019) ACY-1215 exhibits anti-inflammatory and chondroprotective effects in human osteoarthritis chondrocytes via inhibition of STAT3 and NF-κB signaling pathways. Biomed Pharmacother 109:2464–2471. https://doi.org/10.1016/j.biopha.2018.11.017

    Article  CAS  PubMed  Google Scholar 

  57. Bourne RB, Chesworth BM, Davis AM, Mahomed NN, Charron KD (2010) Patient satisfaction after total knee arthroplasty: who is satisfied and who is not? Clin Orthop Relat Res 468(1):57–63. https://doi.org/10.1007/s11999-009-1119-9

    Article  PubMed  Google Scholar 

  58. Pinsornsak P, Naratrikun K, Chumchuen S (2014) The effect of infrapatellar fat pad excision on complications after minimally invasive TKA: a randomized controlled trial. Clin Orthop Relat Res 472(2):695–701. https://doi.org/10.1007/s11999-013-3321-z

    Article  PubMed  Google Scholar 

  59. Kooner SS, Clark M (2017) The effect of synovectomy in total knee arthroplasty for primary osteoarthritis: a meta-analysis. J Knee Surg 30(4):289–296. https://doi.org/10.1055/s-0036-1584560

    Article  PubMed  Google Scholar 

  60. Papalia R, Campi S, Vorini F et al (2020) The role of physical activity and rehabilitation following hip and knee arthroplasty in the elderly. J Clin Med 9(5):1401. https://doi.org/10.3390/jcm9051401

    Article  PubMed Central  Google Scholar 

  61. Visser MA, Howard KJ, Ellis HB (2019) The influence of major depressive disorder at both the preoperative and postoperative evaluations for total knee arthroplasty outcomes. Pain Med 20(4):826–833. https://doi.org/10.1093/pm/pny107

    Article  PubMed  Google Scholar 

  62. West MA, Wischmeyer PE, Grocott MPW (2017) Prehabilitation and nutritional support to improve perioperative outcomes. Curr Anesthesiol Rep 7(4):340–349. https://doi.org/10.1007/s40140-017-0245-2

    Article  PubMed  PubMed Central  Google Scholar 

  63. Bonasia DE, Palazzolo A, Cottino U, Saccia F, Mazzola C, Rosso F, Rossi R (2019) Modifiable and nonmodifiable predictive factors associated with the outcomes of total knee arthroplasty. Joints 7(1):13–18. https://doi.org/10.1055/s-0039-1678563

    Article  PubMed  PubMed Central  Google Scholar 

  64. Benlidayi IC, Gokcen N, Basaran S (2018) Comparative short-term effectiveness of ibuprofen gel and cream phonophoresis in patients with knee osteoarthritis. Rheumatol Int 38:1927–1932. https://doi.org/10.1007/s00296-018-4099-9

    Article  CAS  Google Scholar 

  65. Gasparyan AY, Ayvazyan L, Blackmore H, Kitas GD (2011) Writing a narrative biomedical review: considerations for authors, peer reviewers, and editors. Rheumatol Int 31(11):1409–1417. https://doi.org/10.1007/s00296-011-1999-3

    Article  PubMed  Google Scholar 

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Georgiev, T. Multimodal approach to intraarticular drug delivery in knee osteoarthritis. Rheumatol Int 40, 1763–1769 (2020). https://doi.org/10.1007/s00296-020-04681-7

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