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  • Review Article
  • Published:

Early-stage symptomatic osteoarthritis of the knee — time for action

Nature Reviews Rheumatology volume 17, pages 621–632 (2021)Cite this article

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Abstract

Osteoarthritis (OA) remains the most challenging arthritic disorder, with a high burden of disease and no available disease-modifying treatments. Symptomatic early-stage OA of the knee (the focus of this Review) urgently needs to be identified and defined, as efficient early-stage case finding and diagnosis in primary care would enable health-care providers to proactively and substantially reduce the burden of disease through proper management including structured education, exercise and weight management (when needed) and addressing lifestyle-related risk factors for disease progression. Efforts to define patient populations with symptomatic early-stage knee OA on the basis of validated classification criteria are ongoing. Such criteria, as well as the identification of molecular and imaging biomarkers of disease risk and/or progression, would enable well-designed clinical studies, facilitate interventional trials, and aid the discovery and validation of cellular and molecular targets for novel therapies. Treatment strategies, relevant outcomes and ethical issues also need to be considered in the context of the cost-effective management of symptomatic early-stage knee OA. To move forwards, a multidisciplinary and sustained international effort involving all major stakeholders is required.

Key points

  • Early-stage knee osteoarthritis (OA) could present a ‘window of opportunity’ in which to arrest the disease process at the early stages and restore joint homeostasis.

  • The initiating cellular and molecular cascade of events in early disease need to be studied in more detail and connected to triggering events and the patient profile.

  • The goal of classification criteria for early-stage knee OA is to enable discrimination of patient populations with early-stage symptomatic knee OA, who are at increased risk of structural progression, from patients with knee symptoms due to other reasons.

  • Final classification criteria for early-stage knee OA should be validated by a multidisciplinary panel of experts in the field with involvement of all relevant stakeholders.

  • Early diagnosis in clinical practice enables proper disease management and reduction of the burden of disease.

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Fig. 1: The natural course of knee osteoarthritis.
Fig. 2: Comparison of newly proposed classification criteria for early-stage knee OA and the ACR classification criteria for knee OA.
Fig. 3: Development of validated classification criteria for rheumatic diseases.
Fig. 4: Cellular and molecular events of early OA.
Fig. 5: The potential for overdiagnosis and overtreatment of OA.

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References

  1. Hunter, D. J., March, L. & Chew, M. Osteoarthritis in 2020 and beyond: a Lancet Commission. Lancet https://doi.org/10.1016/S0140-6736(20)32230-3 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Safiri, S. et al. Global, regional and national burden of osteoarthritis 1990-2017: a systematic analysis of the Global Burden of Disease Study 2017. Ann. Rheum. Dis. 79, 819–828 (2020).

    Article  PubMed  Google Scholar 

  3. Vanlauwe, J. et al. Five-year outcome of characterized chondrocyte implantation versus microfracture for symptomatic cartilage defects of the knee: early treatment matters. Am. J. Sports Med. 39, 2566–2574 (2011).

    Article  PubMed  Google Scholar 

  4. Neogi, D. S. et al. Role of nonoperative treatment in managing degenerative tears of the medial meniscus posterior root. J. Orthop. Traumatol. 14, 193–199 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ikuta, F. et al. Effect of physical therapy on early knee osteoarthritis with medial meniscal posterior tear assessed by MRI T2 mapping and 3D-to-2D registration technique: a prospective intervention study. Mod. Rheumatol. 30, 738–747 (2020).

    Article  PubMed  Google Scholar 

  6. Caneiro, J. P. et al. Three steps to changing the narrative about knee osteoarthritis care: a call to action. Br. J. Sports Med. 54, 256–258 (2020).

    Article  CAS  PubMed  Google Scholar 

  7. Gomez-Isla, T. & Frosch, M. P. The challenge of defining alzheimer disease based on biomarkers in the absence of symptoms. JAMA Neurol. 76, 1143–1144 (2019).

    Article  Google Scholar 

  8. Langa, K. M. & Burke, J. F. Preclinical Alzheimer disease — early diagnosis or overdiagnosis? JAMA Intern. Med. 179, 1161–1162 (2019).

    Article  PubMed  Google Scholar 

  9. Jack, C. R. et al. Prevalence of biologically vs clinically defined Alzheimer spectrum entities using the National Institute on Aging–Alzheimer’s Association research framework. JAMA Neurol. 76, 1174–1183 (2019).

    Article  PubMed Central  Google Scholar 

  10. Lard, L. R. et al. Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: comparison of two cohorts who received different treatment strategies. Am. J. Med. 111, 446–451 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Goekoop-Ruiterman, Y. D. et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum. 52, 3381–3390 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Verschueren, P. et al. Effectiveness of methotrexate with step-down glucocorticoid remission induction (COBRA Slim) versus other intensive treatment strategies for early rheumatoid arthritis in a treat-to-target approach: 1-year results of CareRA, a randomised pragmatic open-label superiority trial. Ann. Rheum. Dis. 76, 511–520 (2017).

    Article  PubMed  Google Scholar 

  13. Haroon, M., Gallagher, P. & FitzGerald, O. Diagnostic delay of more than 6 months contributes to poor radiographic and functional outcome in psoriatic arthritis. Ann. Rheum. Dis. 74, 1045–1050 (2015).

    Article  CAS  PubMed  Google Scholar 

  14. Van Nies, J. et al. What is the evidence for the presence of a therapeutic window of opportunity in rheumatoid arthritis? A systematic literature review. Ann. Rheum. Dis. 73, 861–870 (2014).

    Article  PubMed  Google Scholar 

  15. Roos, E. M. & Dahlberg, L. Positive effects of moderate exercise on glycosaminoglycan content in knee cartilage: a four-month, randomized, controlled trial in patients at risk of osteoarthritis. Arthritis Rheum. 52, 3507–3514 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Di Martino, A. et al. Surgical treatment of early knee osteoarthritis with a cell-free osteochondral scaffold: results at 24 months of follow-up. Injury 46, S33–S38 (2015).

    Article  PubMed  Google Scholar 

  17. GLA:D®. Good Life with osteoArthritis in Denmark (GLA:D®). Univ. Southern Denmark https://www.glaid.dk/english.html (2012).

  18. Smith, T. O., Higson, E., Pearson, M. & Mansfield, M. Is there an increased risk of falls and fractures in people with early diagnosed hip and knee osteoarthritis? Data from the Osteoarthritis Initiative. Int. J. Rheum. Dis. 21, 1193–1201 (2018).

    Article  PubMed  Google Scholar 

  19. Hawker, G. et al. Understanding the pain experience in hip and knee osteoarthritis–an OARSI/OMERACT initiative. Osteoarthritis Cartilage 16, 415–422 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Driban, J. B. et al. Defining and evaluating a novel outcome measure representing end-stage knee osteoarthritis: data from the Osteoarthritis Initiative. Clin. Rheumatol. 35, 2523–2530 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Felson, D. et al. Progression of osteoarthritis as a state of inertia. Ann. Rheum.Dis. 72, 924–929 (2013).

    Article  PubMed  Google Scholar 

  22. Driban, J. B. et al. Risk factors can classify individuals who develop accelerated knee osteoarthritis: data from the osteoarthritis initiative. J. Orthop. Res. 36, 876–880 (2018).

    CAS  PubMed  Google Scholar 

  23. Losina, E. et al. Cost-effectiveness of total knee arthroplasty in the United States: patient risk and hospital volume. Arch. Intern. Med. 169, 1113–1121 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Schiphof, D. et al. The clinical and radiographic course of early knee and hip osteoarthritis over 10 years in CHECK (Cohort Hip and Cohort Knee). Osteoarthritis Cartilage 27, 1491–1500 (2019).

    Article  CAS  PubMed  Google Scholar 

  25. Singh, J. A., Yu, S., Chen, L. & Cleveland, J. D. Rates of total joint replacement in the United States: future projections to 2020–2040 using the National Inpatient Sample. J. Rheumatol. 46, 1134–1140 (2019).

    Article  PubMed  Google Scholar 

  26. Runciman, W. B. et al. CareTrack: assessing the appropriateness of health care delivery in Australia. Med. J. Aust. 197, 100–105 (2012).

    Article  PubMed  Google Scholar 

  27. Roos, E. M. & Arden, N. K. Strategies for the prevention of knee osteoarthritis. Nat. Rev. Rheumatol. 12, 92 (2016).

    Article  CAS  PubMed  Google Scholar 

  28. Mahmoudian, A., Van Assche, D., Herzog, W. & Luyten, F. P. Towards secondary prevention of early knee osteoarthritis. RMD Open 4, e000468 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Aggarwal, R. et al. Distinctions between diagnostic and classification criteria? Arthritis Care Res. 67, 891–897 (2015).

    Article  Google Scholar 

  30. Madry, H. et al. Early osteoarthritis of the knee. Knee Surg. Sports Traumatol. Arthrosc. 24, 1753–1762 (2016).

    Article  PubMed  Google Scholar 

  31. Hayashi, D., Roemer, F. W., Jarraya, M. & Guermazi, A. Imaging in osteoarthritis. Radiol. Clin. 55, 1085–1102 (2017).

    Article  Google Scholar 

  32. Bastick, A. N., Belo, J. N., Runhaar, J. & Bierma-Zeinstra, S. M. What are the prognostic factors for radiographic progression of knee osteoarthritis? A meta-analysis. Clin. Orthop. Relat. Res. 473, 2969–2989 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Migliore, A. et al. The challenge of the definition of early symptomatic knee osteoarthritis: a proposal of criteria and red flags from an international initiative promoted by the Italian Society for Rheumatology. Rheumatol. Int. 37, 1227–1236 (2017).

    Article  PubMed  Google Scholar 

  34. Runhaar, J., Kloppenburg, M., Boers, M., Bijlsma, H. & Bierma-Zeinstra, S. Towards developing diagnostic criteria for early knee osteoarthritis. Osteoarthritis Cartilage 28, S385–S386 (2020).

    Article  Google Scholar 

  35. Altman, R. et al. Development of criteria for the classification and reporting of osteoarthritis: classification of osteoarthritis of the knee. Arthritis Rheum. 29, 1039–1049 (1986).

    Article  CAS  PubMed  Google Scholar 

  36. Skou, S. T., Koes, B. W., Grønne, D. T., Young, J. & Roos, E. M. Comparison of three sets of clinical classification criteria for knee osteoarthritis: a cross-sectional study of 13,459 patients treated in primary care. Osteoarthritis Cartilage 28, 167–172 (2020).

    Article  CAS  PubMed  Google Scholar 

  37. Luyten, F. P., Denti, M., Filardo, G., Kon, E. & Engebretsen, L. Definition and classification of early osteoarthritis of the knee. Knee Surg. Sports Traumatol. Arthrosc. 20, 401–406 (2012).

    Article  PubMed  Google Scholar 

  38. Luyten, F. et al. Toward classification criteria for early osteoarthritis of the knee. Semin. Arthritis Rheum. 47, 457–463 (2018).

    Article  CAS  PubMed  Google Scholar 

  39. Mahmoudian, A., Lohmander, L. S., Jafari, H. & Luyten, F. P. Towards classification criteria for early-stage knee osteoarthritis: A population-based study to enrich for progressors. Semin. Arthritis Rheum. 51, 285–291 (2021).

    Article  PubMed  Google Scholar 

  40. Sasaki, E. et al. Early knee osteoarthritis prevalence is highest among middle-aged adult females with obesity based on new set of diagnostic criteria from a large sample cohort study in the Japanese general population. J. Knee Surgery Sports Traumatol. Arthrosc. 28, 984–994 (2020).

    Article  Google Scholar 

  41. Ishibashi, K. et al. Bone marrow lesion severity was associated with proximal tibial inclination in early knee osteoarthritis. Knee Surg. Sports Traumatol. Arthrosc. https://doi.org/10.1007/s00167-020-06378-7 (2021).

    Article  PubMed  Google Scholar 

  42. Ishibashi, K. et al. Detection of synovitis in early knee osteoarthritis by MRI and serum biomarkers in Japanese general population. Sci. Rep. 10, 12310 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. O’Neill, T. W., McCabe, P. S. & McBeth, J. Update on the epidemiology, risk factors and disease outcomes of osteoarthritis. Best Pract. Res. Clin. Rheumatol. 32, 312–326 (2018).

    Article  PubMed  Google Scholar 

  44. Silverwood, V. et al. Current evidence on risk factors for knee osteoarthritis in older adults: a systematic review and meta-analysis. Osteoarthritis Cartilage 23, 507–515 (2015).

    Article  CAS  PubMed  Google Scholar 

  45. Leyland, K. M. et al. Obesity and the relative risk of knee replacement surgery in patients with knee osteoarthritis: a prospective cohort study. Arthritis Rheumatol. 68, 817–825 (2016).

    Article  PubMed  Google Scholar 

  46. Piepoli, M. F. et al. Update on cardiovascular prevention in clinical practice: a position paper of the European Association of Preventive Cardiology of the European Society of Cardiology. Eur. J. Prev. Cardiol. 27, 181–205 (2020).

    Article  PubMed  Google Scholar 

  47. Kanis, J. A. et al. A decade of FRAX: how has it changed the management of osteoporosis? Aging Clin. Exp. Res. 32, 187–196 (2020).

    Article  PubMed  Google Scholar 

  48. Kraus, V. B. et al. Predictive validity of biochemical biomarkers in knee osteoarthritis: data from the FNIH OA Biomarkers Consortium. Ann. Rheum. Dis. 76, 186–195 (2017).

    Article  CAS  PubMed  Google Scholar 

  49. Hunter, D. J. et al. Multivariable modeling of biomarker data from the phase 1 Foundation for the NIH osteoarthritis biomarkers consortium. Arthritis Care Res. https://doi.org/10.1002/acr.24557 (2021).

    Article  Google Scholar 

  50. Espay, A. J. The final nail in the coffin of disease modification for dopaminergic therapies: the LEAP trial. JAMA Neurol. 76, 747–748 (2019).

    Article  PubMed  Google Scholar 

  51. Ratneswaran, A., Rockel, J. S. & Kapoor, M. Understanding osteoarthritis pathogenesis: a multiomics system-based approach. Curr. Opin. Rheumatol. 32, 80–91 (2020).

    Article  PubMed  Google Scholar 

  52. Coryell, P. R., Diekman, B. O. & Loeser, R. F. Mechanisms and therapeutic implications of cellular senescence in osteoarthritis. Nat. Rev. Rheumatol. 17, 47–57 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Berenbaum, F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis Cartilage 21, 16–21 (2013).

    Article  CAS  PubMed  Google Scholar 

  54. Englund, M. The role of biomechanics in the initiation and progression of OA of the knee. Best Pract. Res. Clin. Rheumatol. 24, 39–46 (2010).

    Article  PubMed  Google Scholar 

  55. Mobasheri, A. et al. The role of metabolism in the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 13, 302 (2017).

    Article  CAS  PubMed  Google Scholar 

  56. Swärd, P., Frobell, R., Englund, M., Roos, H. & Struglics, A. Cartilage and bone markers and inflammatory cytokines are increased in synovial fluid in the acute phase of knee injury (hemarthrosis)–a cross-sectional analysis. Osteoarthritis Cartilage 20, 1302–1308 (2012).

    Article  PubMed  Google Scholar 

  57. Struglics, A., Larsson, S., Kumahashi, N., Frobell, R. & Lohmander, S. Changes in synovial fluid and serum cytokines and ARGS-aggrecan, and urine CTX-II and NTX-I over five years after anterior cruciate ligament rupture: An exploratory analysis in the KANON trial. Arthritis Rheumatol. 67, 1816–1825 (2015).

    Article  CAS  PubMed  Google Scholar 

  58. Larsson, S., Struglics, A., Lohmander, L. S. & Frobell, R. Surgical reconstruction of ruptured anterior cruciate ligament prolongs trauma-induced increase of inflammatory cytokines in synovial fluid: an exploratory analysis in the KANON trial. Osteoarthritis Cartilage 25, 1443–1451 (2017).

    Article  CAS  PubMed  Google Scholar 

  59. Jeon, O. H., David, N., Campisi, J. & Elisseeff, J. H. Senescent cells and osteoarthritis: a painful connection. J. Clin. Invest. 128, 1229–1237 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Rai, M. F., Brophy, R. H. & Sandell, L. J. Osteoarthritis following meniscus and ligament injury: insights from translational studies and animal models. Curr. Opin. Rheumatol. 31, 70–79 (2019).

    Article  PubMed  Google Scholar 

  61. Kisand, K., Tamm, A., Lintrop, M. & Tamm, A. New insights into the natural course of knee osteoarthritis: early regulation of cytokines and growth factors, with emphasis on sex-dependent angiogenesis and tissue remodeling. A pilot study. Osteoarthritis Cartilage 26, 1045–1054 (2018).

    Article  CAS  PubMed  Google Scholar 

  62. Dam, E. B. et al. Identification of progressors in osteoarthritis by combining biochemical and MRI-based markers. Arthritis Res. Ther. 11, R115 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Kraus, V. B. et al. Application of biomarkers in the development of drugs intended for the treatment of osteoarthritis. Osteoarthr. Cartil. 19, 515–542 (2011).

    Article  CAS  Google Scholar 

  64. Kraus, V. B. & Hsueh, M.-F. in Genomic and Precision Medicine 429–444 (Elsevier, 2019).

  65. Emery, C. A. et al. Establishing outcome measures in early knee osteoarthritis. Nat. Rev. Rheumatol. 15, 438–448 (2019).

    Article  PubMed  Google Scholar 

  66. Styrkarsdottir, U. et al. The CRTAC1 protein in plasma associates with osteoarthritis and predicts progression to joint replacements: a large-scale proteomics scan in Iceland. Arthritis Rheumatol. https://doi.org/10.1002/art.41793 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Hosnijeh, F. S., Bierma-Zeinstra, S. & Bay-Jensen, A. Osteoarthritis year in review 2018: biomarkers (biochemical markers). Osteoarthritis Cartilage 27, 412–423 (2019).

    Article  Google Scholar 

  68. Kraus, V. B. & Karsdal, M. A. Osteoarthritis: current molecular biomarkers and the way forward. Calcif. Tissue Int. https://doi.org/10.1007/s00223-020-00701-7 (2020).

    Article  PubMed  Google Scholar 

  69. Roemer, F. W., Eckstein, F., Hayashi, D. & Guermazi, A. The role of imaging in osteoarthritis. Best Pract. Res. Clin. Rheumatol. 28, 31–60 (2014).

    Article  PubMed  Google Scholar 

  70. Wallace, G. et al. Associations between clinical evidence of inflammation and synovitis in symptomatic knee osteoarthritis: a cross-sectional substudy. Arthritis Care Res. 69, 1340–1348 (2017).

    Article  CAS  Google Scholar 

  71. Roemer, F. W., Kwoh, C. K., Hayashi, D., Felson, D. T. & Guermazi, A. The role of radiography and MRI for eligibility assessment in DMOAD trials of knee OA. Nat. Rev. Rheumatol. 14, 372–380 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Loef, M. et al. Comparison of histological and morphometrical changes underlying subchondral bone abnormalities in inflammatory and degenerative musculoskeletal disorders: a systematic review. Osteoarthritis Cartilage 26, 992–1002 (2018).

    Article  CAS  PubMed  Google Scholar 

  73. Englund, M. et al. Incidental meniscal findings on knee MRI in middle-aged and elderly persons. N. Engl. J. Med. 359, 1108–1115 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Guermazi, A. et al. Prevalence of abnormalities in knees detected by MRI in adults without knee osteoarthritis: population based observational study (Framingham Osteoarthritis Study). BMJ 345, e5339 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Aletaha, D. & Smolen, J. S. Diagnosis and management of rheumatoid arthritis: a review. JAMA Intern. Med. 320, 1360–1372 (2018).

    Google Scholar 

  76. Drosos, A. A., Pelechas, E. & Voulgari, P. V. Treatment strategies are more important than drugs in the management of rheumatoid arthritis. Clin. Rheumatol. 39, 1363–1368 (2020).

    Article  PubMed  Google Scholar 

  77. Maly, M. R., Marriott, K. A. & Chopp-Hurley, J. N. Osteoarthritis year in review 2019: rehabilitation and outcomes. Osteoarthritis Cartilage 28, 249–266 (2020).

    Article  CAS  PubMed  Google Scholar 

  78. Lohmander, L. S. & Roos, E. M. Disease modification in OA — will we ever get there? Nat. Rev. Rheumatol. 15, 133–135 (2019).

    Article  PubMed  Google Scholar 

  79. Kraus, V. et al. Proposed study designs for approval based on a surrogate endpoint and a post-marketing confirmatory study under FDA’s accelerated approval regulations for disease modifying osteoarthritis drugs. Osteoarthritis Cartilage 27, 571–579 (2019).

    Article  CAS  PubMed  Google Scholar 

  80. Felson, D. T. & Neogi, T. Emerging treatment models in rheumatology: challenges for osteoarthritis trials. Arthritis Rheumatol. 70, 1175–1181 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Hart, D. & Spector, T. Kellgren & Lawrence grade 1 osteophytes in the knee — doubtful or definite? Osteoarthr. Cartil. 11, 149–150 (2003).

    Article  CAS  Google Scholar 

  82. Bowes, M. A. et al. Machine-learning, MRI bone shape and important clinical outcomes in osteoarthritis: data from the Osteoarthritis Initiative. Ann. Rheum. Dis. 80, 502–508 (2020).

    Article  Google Scholar 

  83. Peat, G. et al. Clinical classification criteria for knee osteoarthritis: performance in the general population and primary care. Ann. Rheum. Dis. 65, 1363–1367 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Turkiewicz, A. et al. Prevalence of knee pain and knee OA in southern Sweden and the proportion that seeks medical care. Rheumatology 54, 827–835 (2015).

    Article  CAS  PubMed  Google Scholar 

  85. Jordan, K. et al. Influences on the decision to use an osteoarthritis diagnosis in primary care: a cohort study with linked survey and electronic health record data. Osteoarthritis Cartilage 24, 786–793 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hawezi, Z. et al. Regional dGEMRIC analysis in patients at risk of osteoarthritis provides additional information about activity related changes in cartilage structure. Acta Radiol. 57, 468–474 (2016).

    Article  CAS  PubMed  Google Scholar 

  87. Bannuru, R. R. et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthr. Cartil. 27, 1578–1589 (2019).

    Article  CAS  Google Scholar 

  88. Kolasinski, S. L. et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Rheumatol. 72, 149–162 (2020).

    Article  Google Scholar 

  89. Skou, S. T. & Roos, E. M. Physical therapy for patients with knee and hip osteoarthritis: supervised, active treatment is current best practice. J. Clin. Exp. Rheumatol. 37, S112–S117 (2019).

    Google Scholar 

  90. Dahlberg, L. E., Dell’Isola, A., Lohmander, L. S. & Nero, H. Improving osteoarthritis care by digital means-Effects of a digital self-management program after 24-or 48-weeks of treatment. PLoS ONE 15, e0229783 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Jönsson, T., Eek, F., Dell’Isola, A., Dahlberg, L. E. & Hansson, E. E. The Better Management of Patients with Osteoarthritis Program: outcomes after evidence-based education and exercise delivered nationwide in Sweden. PLoS ONE 14, e0222657 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Skou, S. T. & Roos, E. M. Good Life with osteoArthritis in Denmark (GLA:D™): evidence-based education and supervised neuromuscular exercise delivered by certified physiotherapists nationwide. BMC Musculoskelet. Disord. 18, 72 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Spitaels, D. et al. Barriers for guideline adherence in knee osteoarthritis care: a qualitative study from the patients’ perspective. J. Eval. Clin. Pract. 23, 165–172 (2017).

    Article  PubMed  Google Scholar 

  94. Spitaels, D. et al. Educational outreach visits to improve knee osteoarthritis management in primary care. BMC Med. Educ. 19, 66 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Swaithes, L., Paskins, Z., Dziedzic, K. & Finney, A. Factors influencing the implementation of evidence-based guidelines for osteoarthritis in primary care: A systematic review and thematic synthesis. Musculoskeletal Care 18, 101–110 (2020).

    Article  PubMed  Google Scholar 

  96. Egerton, T., Diamond, L., Buchbinder, R., Bennell, K. & Slade, S. C. A systematic review and evidence synthesis of qualitative studies to identify primary care clinicians’ barriers and enablers to the management of osteoarthritis. Osteoarthritis Cartilage 25, 625–638 (2017).

    Article  CAS  PubMed  Google Scholar 

  97. Leech, R. D., Eyles, J., Batt, M. E. & Hunter, D. J. Lower extremity osteoarthritis: optimising musculoskeletal health is a growing global concern: a narrative review. Br. J. Sports Med. 53, 806–811 (2019).

    Article  PubMed  Google Scholar 

  98. King, L. K. et al. Use of recommended non-surgical knee osteoarthritis management in patients prior to totalv knee arthroplasty: a cross-sectional study. J. Rheumatol. 47, 1253–1260 (2020).

    Article  PubMed  Google Scholar 

  99. Doust, J. A., Bell, K. J. & Glasziou, P. P. Potential consequences of changing disease classifications. Jama 323, 921–922 (2020).

    Article  PubMed  Google Scholar 

  100. Reiman, M. P. et al. Consensus recommendations on the classification, definition and diagnostic criteria of hip-related pain in young and middle-aged active adults from the International Hip-related pain research network, Zurich 2018. Br. J. Sports Med. 54, 631–641 (2020).

    Article  PubMed  Google Scholar 

  101. Khoja, S. S., Almeida, G. J. & Freburger, J. K. Recommendation rates for physical therapy, lifestyle counseling, and pain medications for managing knee osteoarthritis in ambulatory care settings: a cross-sectional analysis of the national ambulatory care survey (2007–2015). Arthritis Care Res. 72, 184–192 (2020).

    Article  Google Scholar 

  102. van der Helm-van Mil, A. & Landewé, R. B. The earlier, the better or the worse? Towards accurate management of patients with arthralgia at risk for RA. Ann. Rheum. Dis. 79, 312–315 (2020).

    Article  PubMed  Google Scholar 

  103. Spitaels, D. et al. Quality of care for knee osteoarthritis in primary care: a patient’s perspective. Arthritis Care Res. 72, 1358–1366 (2019).

    Article  Google Scholar 

  104. Hochberg, M. C. et al. Effect of intra-articular sprifermin vs placebo on femorotibial joint cartilage thickness in patients with osteoarthritis: the FORWARD randomized clinical trial. JAMA 322, 1360–1370 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Conaghan, P. G. et al. Disease-modifying effects of a novel cathepsin k inhibitor in osteoarthritis. Ann. Intern. Med. 172, 86–95 (2020).

    Article  PubMed  Google Scholar 

  106. Yazici, Y. et al. A novel Wnt pathway inhibitor, SM04690, for the treatment of moderate to severe osteoarthritis of the knee: results of a 24-week, randomized, controlled, phase 1 study. Osteoarthritis Cartilage 25, 1598–1606 (2017).

    Article  CAS  PubMed  Google Scholar 

  107. Zhu, Z. et al. Investigational drugs for the treatment of osteoarthritis, an update on recent developments. Expert Opin. Invest. Drugs 27, 881–900 (2018).

    Article  CAS  Google Scholar 

  108. Di Matteo, B. et al. Minimally manipulated mesenchymal stem cells for the treatment of knee osteoarthritis: a systematic review of clinical evidence. Stem Cells Int. 2019, 1735242 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Wang, A.-T., Feng, Y., Jia, H.-H., Zhao, M. & Yu, H. Application of mesenchymal stem cell therapy for the treatment of osteoarthritis of the knee: A concise review. World J. Stem Cell 11, 222 (2019).

    Article  Google Scholar 

  110. Evans, C. H., Ghivizzani, S. C. & Robbins, P. D. Gene delivery to joints by intra-articular injection. Hum. Gene Ther. 29, 2–14 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Nakamura, A., Ali, S. A. & Kapoor, M. Antisense oligonucleotide-based therapies for the treatment of osteoarthritis: Opportunities and roadblocks. Bone 138, 115461 (2020).

    Article  CAS  PubMed  Google Scholar 

  112. Mobasheri, A., Choi, H. & Martín-Vasallo, P. Over-production of therapeutic growth factors for articular cartilage regeneration by protein production platforms and protein packaging cell lines. Biology 9, 330 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  113. Uzieliene, I., Kalvaityte, U., Bernotiene, E. & Mobasheri, A. Non-viral gene therapy for osteoarthritis. Front. Bioeng. Biotechnol. https://doi.org/10.3389/fbioe.2020.618399 (2020).

    Article  PubMed  Google Scholar 

  114. Mendes, L. et al. Advancing osteochondral tissue engineering: bone morphogenetic protein, transforming growth factor, and fibroblast growth factor signaling drive ordered differentiation of periosteal cells resulting in stable cartilage and bone formation in vivo. Stem Cell Res. Ther. 9, 42 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Beard, D. J. et al. Considerations and methods for placebo controls in surgical trials (ASPIRE guidelines). Lancet 395, 828–838 (2020).

    Article  CAS  PubMed  Google Scholar 

  116. Caneiro, J. et al. Infographic. Roadmap to managing a person with musculoskeletal pain irrespective of body region. Br. J. Sports Med. 54, 554 (2020).

    Article  CAS  PubMed  Google Scholar 

  117. Landewé, R. B. Overdiagnosis and overtreatment in rheumatology: a little caution is in order. Ann. Rheum. Dis. 77, 1394–1396 (2018).

    Article  PubMed  Google Scholar 

  118. Leyland, K. et al. The natural history of radiographic knee osteoarthritis: A fourteen-year population-based cohort study. Arthritis Rheum. 64, 2243–2251 (2012).

    Article  CAS  PubMed  Google Scholar 

  119. Dell’Isola, A. & Steultjens, M. Classification of patients with knee osteoarthritis in clinical phenotypes: Data from the osteoarthritis initiative. PLoS ONE 13, e0191045 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Burgers, L. E., Raza, K. & van der Helm-van, A. H. Window of opportunity in rheumatoid arthritis–definitions and supporting evidence: from old to new perspectives. RMD Open 5, e000870 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Aletaha, D. et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 62, 2569–2581 (2010).

    Article  PubMed  Google Scholar 

  122. Landewé, R. B. Response to: ‘Early identification of rheumatoid arthritis; the risk of overtreatment in perspective’ by Landewé. Ann. Rheum. Dis. 78, e108–e108 (2019).

    Article  PubMed  Google Scholar 

  123. Funovits, J. et al. The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: methodological report phase I. Ann. Rheum. Dis. 69, 1589–1595 (2010).

    Article  PubMed  Google Scholar 

  124. Neogi, T. et al. The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: phase 2 methodological report. Arthritis Rheum. 62, 2582–2591 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Fransen, J. et al. Items for developing revised classification criteria in systemic sclerosis: results of a consensus exercise. Arthritis Care Res. 64, 351–357 (2012).

    Article  Google Scholar 

  126. Johnson, S. R. et al. Systemic Sclerosis Classification Criteria: Developing methods for multi-criteria decision analysis with 1000Minds. J. Clin. Epidemiol. 67, 706 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Van Den Hoogen, F. et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum. 65, 2737–2747 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Johnson, S. R. et al. Validation of potential classification criteria for systemic sclerosis. Arthritis Care Res. 64, 358–367 (2012).

    Article  Google Scholar 

  129. Aringer, M., Dörner, T., Leuchten, N. & Johnson, S. Toward new criteria for systemic lupus erythematosus — a standpoint. Lupus 25, 805–811 (2016).

    Article  CAS  PubMed  Google Scholar 

  130. Petri, M. et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 64, 2677–2686 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Taylor, W. J. et al. Study for updated gout classification criteria: identification of features to classify gout. Arthritis Care Res. 67, 1304–1315 (2015).

    Article  Google Scholar 

  132. De Lautour, H. et al. Development of preliminary remission criteria for gout using Delphi and 1000Minds consensus exercises. Arthritis Care Res. 68, 667–672 (2016).

    Article  Google Scholar 

  133. Neogi, T. et al. 2015 gout classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheumatol. 67, 2557–2568 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Wallace, Z. S. et al. The 2019 American College of Rheumatology/European League against rheumatism classification criteria for IgG4-related disease. Arthritis Rheumatol. 79, 77–87 (2020).

    CAS  Google Scholar 

  135. Shiboski, C. H. et al. 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren’s syndrome: a consensus and data-driven methodology involving three international patient cohorts. Ann. Rheum. Dis. 69, 35–45 (2017).

    Google Scholar 

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Acknowledgements

The authors acknowledge funding from Greta and Johan Kock Foundations, Sweden. A.Mo. is also affiliated with the Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania; Departments of Orthopedics, Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Utrecht, Netherlands; Department of Joint Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; and the World Health Organization Collaborating Center for Public Health Aspects of Musculoskeletal Health and Ageing, Université de Liège, Liège, Belgium.

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Authors and Affiliations

  1. Department of Development & Regeneration, KU Leuven, Leuven, Belgium

    Armaghan Mahmoudian & Frank P. Luyten

  2. Department of Clinical Sciences Lund, Orthopaedics, Lund University, Lund, Sweden

    Armaghan Mahmoudian, L. Stefan Lohmander & Martin Englund

  3. Research Unit of Medical Imaging, Physics and Technology, Faculty of Medicine, University of Oulu, Oulu, Finland

    Ali Mobasheri

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Contributions

A.Ma., L.S.L., A.Mo. and F.P.L. researched data for the article. All of the authors made substantial contributions to discussions of the content, writing the article and reviewing and/or editing of the manuscript before submission.

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Correspondence to Frank P. Luyten.

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Competing interests

L.S.L declares that he serves as member of an AstraZeneca Data and Safety Monitoring Board, has acted as a consultant for the planning of phase II and III clinical trials for Paradigm Biopharmaceuticals Australia & Ireland, is a member of an expert group for assessing research proposals on musculoskeletal pain for Pfizer/Lilly USA, acts as a consultant for the scientific evaluation and publication of outcomes of an eHealth app for hip and knee osteoarthritis (Arthro Therapeutics Sweden), and was a member of an expert group for National Guidelines Osteoarthritis Care 2020 for the National Board of Health and Welfare Sweden. A.Mo. declares that he has acted as a consultant for Abbvie, AlphaSights, Artialis SA, Atheneum Partners, Flexion Therapeutics, Galapagos, GSK Consumer Healthcare, Guidepoint Global, Image Analysis Group, Kolon TissueGene, Novartis, Pacira Biosciences Inc, Pfizer Consumer Healthcare, Servier, Sterifarma, and Science Branding Communications; has received research funding from the European Commission (FP7, IMI, Marie Skłodowska-Curie, ES Struktūrinės Paramos), Versus Arthritis (Arthritis Research UK) and initiated research contracts with Merck KGaA and Kolon TissueGene; he has received speaker payments from Achē Laboratórios Farmacêuticos, the American College of Rheumatology, Bioiberica SA, the Korean Society for Osteoarthritis and Cartilage Repair, Laboratoires Expanscience, the Spanish Society of Rheumatology, Sanofi, the Heilongjiang Rheumatology Association and the Zhujiang Hospital of Southern Medical University; he currently serves as President of the Osteoarthritis Research Society International (OARSI), a member of the Advisory Board of Research Square and he is a member of the Scientific Advisory Board of Kolon TissueGene; however, none of the organizations listed above was involved in the conceptualization, design, data collection, analysis, decision to publish, or preparation of this manuscript. M.E. declares that he has received an honorarium for serving on a 1-day advisery board for Pfizer; he also serves as an Executive Board Member (Treasurer) for OARSI. A.Ma. and F.P.L. declare no competing interests.

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Mahmoudian, A., Lohmander, L.S., Mobasheri, A. et al. Early-stage symptomatic osteoarthritis of the knee — time for action. Nat Rev Rheumatol 17, 621–632 (2021). https://doi.org/10.1038/s41584-021-00673-4

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