What an earlier recognition of osteoarthritis can do for OA prevention

Osteoarthritis (OA) is a serious disease. It causes substantial, persistent morbidity (pain, fatigue, sleep disturbance, depression & disability), and has an enormous burden on people's day-to-day functioning and quality of life. There are no licensed drugs with proven disease-modifying activity. Available therapies aim to reduce pain and improve function and quality of life, but effects are modest and sometimes associated with side effects. When these therapies fail to control OA symptoms, guidelines recommend joint replacement. However, joint replacement is not a cure for OA and as many as 20–30% of hip or knee replacement recipients report little or no improvement in their OA symptoms and/or dissatisfaction with their surgical results 1 year after joint replacement1Hawker G.A. Conner-Spady B.L. Bohm E. Dunbar M.J. Jones C.A. Ravi B. et al.Patients' preoperative expectations of total knee arthroplasty and satisfaction with outcomes at one year: a prospective cohort study.Arthritis Rheum. 2021; 73: 223-231https://doi.org/10.1002/art.41510Crossref Scopus (12) Google Scholar. This argues for a greater attention to, and implementation of, OA prevention measures, the earlier the better (Fig. 1). Given the global burden of OA, early identification of the disease in order to prevent progression to long-term disability is critical. However, efforts to change the course of OA have met with little if any success. There are many reasons for this failure, one of them being that we have typically targeted patients in later stages of the disease. Intervening earlier in the disease process may stand a better chance of changing the course of the disease and prevent the downstream consequences of chronic pain, depression, joint destruction, disability, and development of co-morbidities. The importance of identifying and treating early-stage disease is now embraced in other chronic conditions such as diabetes, cardiovascular disease, Alzheimer's disease, and rheumatoid arthritis (RA). Why should our approach for managing OA be different? Like these other conditions, the disease process in OA represents a continuum from the presence of recognized risk factors and preclinical phase, through the earliest symptoms and signs of the clinical condition, to established disease and end-stage advanced disease (Fig. 1). In the context of prevention, the first three phases of the continuum provide opportunities for primary, secondary and tertiary prevention. The focus of this commentary is the development and validation of classification criteria to identify people with early-stage symptomatic knee OA. The setting is assumed to be primary care/community practice, which may limit the choice of selection instruments. OA is a highly heterogeneous disease, with no single clinical, laboratory, pathological or radiologic feature serving as a ‘gold standard’ for the diagnosis and/or classification of the disease. As a result, we rely on standardized criteria to enable diagnosis and treatment in routine clinical care and classification of participants in clinical research. The current American College of Rheumatology, ACR, classification criteria for clinical OA of the knee were developed to distinguish OA from RA and incorporate the presence of signs of structural change, e.g., bony enlargement2Altman R. Asch E. Bloch D. Bole G. Borenstein D. Brandt K. et al.Development of criteria for the classification and reporting of osteoarthritis: classification of osteoarthritis of the knee.Arthritis Rheum. 1986; 29: 1039-1049https://doi.org/10.1002/art.1780290816Crossref PubMed Scopus (5247) Google Scholar, which earlier identification of OA would hope to prevent. Thus, new criteria are needed. How do classification and diagnostic criteria differ? Classification criteria are intended to create homogeneous cohorts of patients who share key features of the condition for clinical research. Validated criteria are critical to the interpretation of study findings and comparisons of results between studies. Classification criteria seek high specificity, which may be at the expense of lower sensitivity. Consequently, few individuals are incorrectly labeled as having a disease (false positives), but a proportion of those with the disease may be missed (false negatives). Meeting classification criteria is, in general, not equivalent to carrying a given diagnosis. In clinical practice, physicians generally take into consideration clinical features beyond those encompassed in classification criteria, including locally relevant differential diagnoses, to make a diagnosis in a particular patient. Diagnosis of symptomatic early-stage knee OA provides the opportunity to manage the disease at an earlier stage. Despite the often-perceived limitations in dealing effectively with knee OA, first-line tools are available to manage these patients to reduce the burden of the disease, but are under-utilized3Abbate L.M. Jeffreys A.S. Coffman C.J. Schwartz T.A. Arbeeva L. Callahan L.F. et al.Demographic and clinical factors associated with nonsurgical osteoarthritis treatment among patients in outpatient clinics.Arthritis Care Res. 2018; 70: 1141-1149https://doi.org/10.1002/acr.23466Crossref PubMed Scopus (20) Google Scholar, 4King L.K. Marshall D.A. Faris P. Woodhouse L.J. Jones C.A. Noseworthy T. et al.Use of recommended non-surgical knee osteoarthritis management in patients prior to total knee arthroplasty: a cross-sectional study.J Rheumatol. 2020; 47: 1253-1260https://doi.org/10.3899/jrheum.190467Crossref PubMed Scopus (20) Google Scholar, 5Cronström A. Nero H. Lohmander L.S. Dahlberg L.E. On the waiting list for joint replacement for knee osteoarthritis: are first-line treatment recommendations implemented?.Osteoarthritis Cartilage Open. 2020; 2: 100056Crossref Google Scholar. Published results show this management to be associated with reduced pain and analgesics consumption, less sick leave, better quality of life and function, and increased physical activity, and may delay the need for joint replacement6Roos E.M. Grønne D.T. Skou S.T. Zywiel M.G. McGlasson R. Barton C.J. et al.Immediate outcomes following the GLA:D® program in Denmark, Canada and Australia. A longitudinal analysis including 28,370 patients with symptomatic knee or hip osteoarthritis.Osteoarthritis Cartilage. 2021; 29: 502-506https://doi.org/10.1016/j.joca.2020.12.024Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 7Dahlberg 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. 2020; 15: e0229783https://doi.org/10.1371/journal.pone.0229783Crossref PubMed Scopus (16) Google Scholar, 8Bannuru R.R. Osani M.C. Vaysbrot E.E. Arden N. Bennell K. Bierma-Zeinstra S.M.W. et al.OARSI guidelines for the non-surgical management of knee, hip and polyarticular osteoarthritis.Osteoarthritis Cartilage. 2019; 27: 1578-1589https://doi.org/10.1016/j.joca.2019.06.011Abstract Full Text Full Text PDF PubMed Scopus (1023) Google Scholar, 9Skou S.T. Roos E.M. Laursen M.B. Rathleff M.S. Arendt-Nielsen L. Simonsen O. et al.A randomized, controlled trial of total knee replacement.N Engl J Med. 2015; 373: 1597-1606https://doi.org/10.1056/NEJMoa1505467Crossref PubMed Scopus (368) Google Scholar. While evidence in support of exercise and life-style modification on OA-related joint structural integrity remains limited8Bannuru R.R. Osani M.C. Vaysbrot E.E. Arden N. Bennell K. Bierma-Zeinstra S.M.W. et al.OARSI guidelines for the non-surgical management of knee, hip and polyarticular osteoarthritis.Osteoarthritis Cartilage. 2019; 27: 1578-1589https://doi.org/10.1016/j.joca.2019.06.011Abstract Full Text Full Text PDF PubMed Scopus (1023) Google Scholar,10Roos 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. 2005; 52: 3507-3514https://doi.org/10.1002/art.21415Crossref PubMed Scopus (351) Google Scholar, the outcome of this management, if implemented earlier in the course of OA, has the potential to reduce the OA burden at the population level. Defining early-stage knee OA by validated classification criteria would result in more homogenous patient populations to allow a better understanding of the mechanisms that drive the early phases of disease development, thereby revealing new prevention and treatment targets11Mahmoudian A. Lohmander L.S. Mobasheri A. Englund M. Luyten F.P. Early-stage symptomatic osteoarthritis of the knee — time for action.Nat Rev Rheumatol. 2021; (Accepted 22 July 2021, Published 31 August 2021)https://doi.org/10.1038/s41584-021-00673-4Crossref PubMed Scopus (23) Google Scholar. Intervening early in the disease process may stand the best chance to accomplish long sought-after disease modification. Assuming that only a fraction of all patients with early-stage OA will progress, further refinement of the classification criteria may be needed to identify those at highest risk of disease progression (Fig. 2). Specialist groups could identify molecular and imaging biomarkers to support further refinement of these classification criteria to enrich studies for patients at high risk for disease progression. These patients could be a preferred group for recruitment into clinical trials of OA disease modification, and consequently, for treatment with any approved such agents12Kraus V.B. Simon L.S. Katz J.N. Neogi T. Hunter D. Guermazi A. 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. 2019; 27: 571-579https://doi.org/10.1016/j.joca.2018.11.002Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar,13Lohmander L.S. Roos E.M. Disease modification in OA - will we ever get there.Nat Rev Rheumatol. 2019; 15: 133-135https://doi.org/10.1038/s41584-019-0174-1Crossref PubMed Scopus (7) Google Scholar. To develop early OA classification criteria we need to1.Identify currently available clinical, laboratory, pathological and radiologic features that increase or decrease the likelihood that the person has early-stage symptomatic knee OA, and the relative weights of these factors2.Identify the currently available clinical, laboratory, pathological and radiologic features that increase or decrease the likelihood that the patient with early-stage symptomatic knee OA will progress to advanced OA3.Assess the measurement properties of above features, ideally in cohorts of real-world knee pain patients - early stage knee OA and non-OA knee pain patients; these cohorts need to be identified Further questions critical to the generation of classification criteria and that need to be resolved are4.In lieu of a gold standard for early-stage OA, what do we mean by “early-stage” with respect to symptoms, function and joint structure?5.What do we want to predict (prevent)? Over what time period? In which population? A definition of early-stage knee OA could include as an example frequency and characteristics of pain: Predictable sharp or other pain with trigger (usually activity) that eventually limits high impact activities but has no other major effects. With respect to structural changes, this would strongly depend on the chosen modality; in primary care using plain X-ray imaging it could be showing no or only minimal structural changes (Kellgren & Lawrence grade I). While the creation of new classification criteria may aid in defining the overall population of those with early-stage OA, the criteria can also enable our understanding of prognosis, useful in both clinical practice and research. One score threshold can define those with early-stage OA, while a different threshold may be required to define a subset with high likelihood of disease progression (Fig. 2). A criterion of progression needs to include symptoms (the illness) and joint structure (the disease)14Emery C.A. Whittaker J.L. Mahmoudian A. Lohmander L.S. Roos E.M. Bennell K.L. et al.Establishing outcome measures in early knee osteoarthritis.Nat Rev Rheumatol. 2019; 15: 438-448https://doi.org/10.1038/s41584-019-0237-3Crossref PubMed Scopus (57) Google Scholar. Risk factors for OA such as age, overweight-obesity, family history, prior knee injury can be included as well. Importantly, what is a relevant “progression” of both the illness and the disease needs to carefully defined. In clinical practice, patients may want to know about changes over 10 years or even longer, while in clinical trials, we are interested in changes over much shorter times of 2–5 years. Additional knee pain clinical cohorts may be required to validate the criteria. What is our measurement goal? Ideally, the developed criteria should be easy to use anywhere in the world and in most clinical contexts, e.g., primary care. However, there will most likely be additional criteria used to identify subgroups within the individuals who meet the criteria for early stage OA that identify, for example, fast progressors, that might be used in clinical trials and cohort studies and incorporate more sophisticated and costly measures. The concept of early-stage OA expands the disease definition for OA. With this follows the risk of overdiagnosis and overtreatment15Glasziou P. Moynihan R. Richards T. Godlee F. Too much medicine; too little care.BMJ. 2013; 347: f4247https://doi.org/10.1136/bmj.f4247Crossref PubMed Scopus (90) Google Scholar. However, the setting considered here focuses on persons that seek health-care because of knee symptoms. The majority of these patients can be managed with existing first-line treatments. Identifying and possibly treating those at risk but without symptoms raises broader concerns of overdiagnosis, overtreatment and cost. Early-stage knee OA classification criteria are required to advance OA prevention and therapeutics and will be required in the future for clinical decision making. Coordinated efforts by a broad consortium of methodologists and clinical OA experts will be needed to accomplish this goal. Fortunately, the OARSI community is rich in both and ready to take on this important challenge. GH and SL both contributed to article conception, drafting article and final approval of article submitted. GH declares no conflict of interest. SL declares consult honoraria from Arthro Therapeutics AB, Pfizer, Paradigm, and from DSMB membership AstraZeneca. GH declares no funding. SL declares no funding.