Osteoarthritis and Cartilage 22 (2014) 1953e1957
Review
Osteoarthritis Year in Review 2014: clinical G.A. Hawker y z *, I. Stanaitis y y Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, Canada z Departments of Medicine and Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
a r t i c l e i n f o
s u m m a r y
Article history: Received 22 May 2014 Accepted 12 June 2014
A systematic search was conducted for the time period April 1 2013 to March 30 2014 using PubMed to identify major osteoarthritis (OA) clinical research themes of the past year. Articles within each theme were selected for inclusion in this review based on study quality and relevance. Two major themes emerged, which relate to the current understanding of OA as a heterogeneous condition with multiple pathogenic mechanisms and clinical manifestations. Theme 1 stems from the role of systemic inflammation in OA pathogenesis, and the concept of ‘metabolic OA’. Over the past year, research has examined the effect of OA on incidence and progression of other ‘metabolic syndrome’-related conditions, especially cardiovascular disease (CVD) and diabetes and the impact of multi-morbidity on the clinical management of OA. Theme 2 focuses on the concept of personalized medicine as it relates to the treatment of OA. It is hypothesized that the modest efficacy of available OA treatments is a result of inclusion of heterogeneous groups of OA patients in clinical trials. Prognostic studies in the past year have been helpful in identifying ‘OA phenotypes’ that are more or less likely to respond to treatments e e.g., the presence of synovitis on imaging, central pain sensitization on quantitative sensory testing (QST), or coping efficacy by self-reported patient questionnaire. Their findings are being increasingly used to target interventions to these identified ‘OA responder’ subgroups with the hopes that treatment effect will be amplified. © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Keywords: Osteoarthritis Multi-morbidity Inflammation Treatment
Introduction It is now generally understood that osteoarthritis (OA), is a heterogeneous condition that develops as a result of the effects of local (joint level) factors, e.g., abnormal gait biomechanics, and systemic factors, e.g., aging, genetics, and systemic inflammation related to obesity. Adipose tissue produces inflammatory adipokines that have the potential to influence all synovial joint tissues, which has given rise to the term ‘metabolic OA’1,2. Given shared risk factors e aging and obesity e there is also growing appreciation of the fact that most people living with OA are also living other chronic conditions, including hypertension3,4, dyslipidemia5, diabetes6, and cardiovascular disease (CVD)7. It is estimated that 90% of individuals aged 65þ years with OA have at least one other chronic condition8. This is concerning as comorbidity in OA has been linked significantly and independently to under-use of effective
* Address correspondence and reprint requests to: G.A. Hawker, Department of Medicine, University of Toronto, 190 Elizabeth Street, Suite RFE 3-805, Toronto, Canada, M5G 2C4. Tel: 1-416-946-8071; Fax: 1-416-323-7513. E-mail addresses: [email protected], [email protected] (G.A. Hawker).
therapies9e13. Without effective treatment, people with OA tend to give up activities, like exercise, that exacerbate their symptoms10,14. This has led researchers over the past year to hypothesize that, by limiting physical activity, painful OA may increase the risk for CVD and all-cause death. Indeed, in 2011 Nuesch et al.15 reported in a cohort aged 35þ years with hip and knee OA recruited 1994e1995 from 40 English general practices (n ¼ 2703), and after controlling for confounders, that baseline walking disability predicted increased all-cause death (1.48, 1.17e1.86), especially from CVD causes. Given the high prevalence of OA in the population, confirmation of these relationships is important. Recognition that OA it not so much a single entity but the final common pathway of a variety of conditions with distinct causes (genetic, developmental, metabolic, traumatic), but with similar biologic, morphologic and clinical outcomes, has led to a paradigm shift in how we think about treatment for this condition. The failure of clinical trials to date to identify highly efficacious therapies in OA may be due to true lack of such therapies or the conduct of trials in heterogeneous groups of OA patients e that is, in groups of patients that include both potential ‘responders’ and ‘non-responders’16. Stratification of patients into subgroups based on their likelihood of response to the treatment of interest has potential to improve the
http://dx.doi.org/10.1016/j.joca.2014.06.018 1063-4584/© 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
1954
G.A. Hawker, I. Stanaitis / Osteoarthritis and Cartilage 22 (2014) 1953e1957
effectiveness of both available and future OA therapies. This has spurred interest in identifying predictors of response to available and new OA therapies which may inform patientephysician decision making about treatment options. With this background, this review sought to highlight studies published over the prior year, since the 2013 meeting of the Osteoarthritis Research Society International (OARSI), pertaining to advances in the epidemiology and treatment of OA. Methods The primary literature search was conducted using PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) with the search terms “osteoarthritis [ti] AND treatment [All Fields]” and the following limits activated: humans, English language, all adult 19þ years, published between April 1 2013 and March 31 2014. This search identified 113 articles. A secondary literature search was then conducted with the search terms “osteoarthritis [ti] AND epidemiology”, with the same limits; these searches identified a total of 122 articles. The titles of all articles were reviewed in order to refine the topic area and to identify major OA clinical research themes of the past year. Studies selected for inclusion in the review presentation were those deemed by the author to be of high quality with potential to affect the management of OA in clinical practice. Results Theme 1: the interplay between OA & other chronic conditions OA and risk for serious cardiovascular outcomes Two studies examined the risk for CVD in people with OA. Rahman et al.17 compared time to a composite CVD outcome (hospital admission for myocardial infarction, ischemic heart disease, congestive heart failure or stroke) in 12,745 adults 20 years with OA (cases) and no prior CVD history with up to three non-OA matched controls (sex, age, year of ‘diagnosis’). Using health administrative data, OA cases were those with at least two visits to a health professional in 2 years separated by at least 1 day or 1 discharge from hospital with ICD-9 code of 715 or ICD-10 codes of M15eM19. From a published abstract, the sensitivity & specificity of this OA diagnosis algorithm were 60e70%18. Over a mean followup 13 years, the authors identified 7995 hospitalizations for CVD events. Controlling for covariates (neighborhood income quintile, body mass index (BMI), imputed using population data for age and sex, chronic obstructive pulmonary disease (COPD), hypertension, hyperlipidemia, diabetes, and Charlson score) in the final multivariable Cox proportional hazards model, OA diagnosis was found to be an independent predictor of CVD among: older men (Relative Risk (RR) 1.15, 1.04e1.27); younger women (RR 1.26, 1.13e1.42); older women (RR 1.17, 1.07e1.26); but not younger men (RR 1.08, 0.97e1.19). A second study utilized data from an established population cohort with moderate to severe hip and knee OA to examine the relationship between baseline walking disability (Health Assessment Questionnaire (HAQ) walking disability score 0e3) and risk for a composite CVD outcome (hospitalization for angina, acute myocardial infarction (AMI), coronary revascularization (coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI)), congestive heart failure (CHF), stroke or transient ischemic attack (TIA))19. Over median 9.2 years, 38% of 2156 OA participants experienced the CVD outcome. Controlling for socio-demographics, CVD risk factors (BMI, smoking, diabetes, hypertension, non-steroidal anti-inflammatory drug (NSAID) use) and additional health problems, walking disability was a significant independent predictor of CVD events with an adjusted Hazard Ratio (HR) per unit
increase in HAQ walking of 1.17 (1.08e1.27). Further adjustment for post-baseline receipt of a primary, elective hip or knee joint arthroplasty (TJA) did not attenuate this effect and found that TJA was protective of CVD events (adjusted HR ¼ 0.66, 0.52e0.85, P < 0.001). Interestingly, the effect of a HAQ walking score of 2 vs 0 on risk for CVD events was roughly equivalent to that associated with a baseline diagnosis of diabetes. Vascular abnormalities and OA It has also been hypothesized is that circulatory disturbances associated with CVD may impact the synovial membrane and subchondral bone and contribute to cartilage destruction and OA20,21. Using data from the Rotterdam study, Hoeven et al.22 examined the relationship between atherosclerosis (carotid intima media thickness and carotid plaque) with both the presence and progression of knee, hip & hand OA (Kellgren-Lawrence (KL) grade on X-ray) controlling for confounders (age, BMI, lipid levels, smoking, diabetes, and hypertension). They documented independent associations between these vascular abnormalities and OA of knee and hand joint in women but not men, but found no association with hip OA. The authors propose that their findings are consistent with the greater perceived influence of systemic inflammation in knee vs hip OA23,24. Metabolic syndrome and OA Jungmann et al.25 evaluated the association of metabolic risk factors (abdominal circumference, hypertension, fat consumption, and diabetes) with severity and 2-year progression of early degenerative cartilage changes in the knee, evaluated using T2 relaxation times and magnetic resonance imaging (MRI), in 403 OsteoArthritis Initiative (OAI) participants. In cross-sectional analyses, the authors found that metabolic risk factors were significantly associated with higher T2 relaxation times, suggesting increased cartilage degeneration may be caused by modifiable metabolic disorders. No longitudinal relationships were found. Diabetes and OA Nieves-Plaza et al.26 asked: Is diabetes a risk factor for OA? In their study, the prevalence of hip, knee, hand OA (defined using American College of Rheumatology classification criteria) was compared in Hispanics with vs without diabetes, and before and after controlling for self-reported confounders (smoking, exercise, socio-demographics, comorbidities, insulin use). In their fully adjusted model, the likelihood that subjects met criteria for OA was significantly higher among those with vs without diabetes (adjusted Odds Ratio (OR) 2.18, 1.12e4.24). Further, within their diabetes cases, the risk of OA was five times greater in women than men, and higher in those that were not using insulin. Given that Insulin-like growth factor 1 (IGF-1) is known to be reduced in OA, the latter finding is provocative, suggesting that growth factors may preserve cartilage. OA in the setting of other conditions The impact of comorbidity on the treatment of OA has also been evaluated in several studies over the past year. The 2014 OARSI nonsurgical knee OA treatment guidelines27 evaluated the evidence supporting use of available therapies in four distinct knee OA patient subgroups e those with and without concomitant joint complaints and with and without other chronic conditions (Fig. 1). The guidelines highlight the paucity of evidence supporting the use of therapies in the largest group of patients with knee OA, those with comorbid conditions and multiple joint complaints, emphasizing the need more clinical trials in people with OA in setting of other common chronic conditions.
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Fig. 1. Appropriate treatments summary. From: McAlindon TE, Bannuru RR, Sullivan MC, Arden NK, Berenbaum F, Bierma-Zeinstra SM, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage 2014;22:363e88.
Ackerman et al.28 conducted a secondary analysis of data from a randomized trial evaluating the efficacy of the 6-week Stanford Arthritis Self-Management Program (ASMP), delivered in a community-based setting. Subjects were adults referred to rheumatology or orthopedic surgery for hip or knee OA. The trial found that uptake of the ASMP was low despite the absence of financial barriers to participation and flexibility of times offered. Thus, the current study examined factors limiting participation in selfmanagement based on data from recorded recruitment telephone calls. Among the most frequently reported reasons for nonparticipation was concurrent illness (OA is not the only problem) and the appropriateness of an arthritis-specific vs generic chronic disease self-management approach. Additional reasons for nonparticipation included: disinterest; limited mobility (pain, fear of falling, difficulty getting to the program); lack of endorsement of the value of the program by their primary care physician; a desire for pharmacotherapy or surgery; and a sense by the patient that they were already coping well with their OA. Cheraghi-Sohi et al.29 examined OA patients' health priority setting when living with more than one chronic condition. The authors re-analyzed four qualitative studies to examine how patients with OA prioritize OA relative to their other health problems. Key findings of their study were as follows: patients have limited time to address their health concerns; they tend to prioritize the condition(s) that are perceived as ‘more severe’ or with worse future implications; health priorities changed over time, influenced by whether or not the condition was ‘under control’, which was, in turn, influenced by the messages they received from physicians; OA was seen as a priority when it impacted mobility for independence or care-giving; and, finally, in an effort to balance health care issues, the most frequently dropped activity was exercise. Their findings are consistent with those of Wilkie et al.30 who prospectively evaluated the impact of multi-morbidity on participation restriction in a cohort of 1053 people who consulted primary
care for lower extremity OA. Those with participation restrictions at baseline were excluded. Multi-morbidity was defined based on patient self report. Participants were asked to report the presence of three common chronic health conditions (chest problems, heart problems, diabetes), two impairments most commonly associated with disability (deafness and eyesight problems) and seven other impairments (falls, memory, cough with spit, breathless with walking, dizziness, weakness in arms/legs, elevated blood pressure); a count of health conditions and impairments was calculated (0e12) and multi-morbidity was defined as a score > the median value of 2 (i.e., 3þ vs 0e2). Path analysis was used to determine the relationship between baseline multi-morbidity & incident participation restrictions at 3 years. Additional variables of interest were joint pain severity, obesity, locomotor disability, and depression. Analyses found that multi-morbidity contributed to the development of participation restrictions at 3 years through its effects on locomotor disability and depression. Theme 2: targeted treatment in OA (personalized medicine) Predictors of response to intra-articular injection of corticosteroids in knee OA Maricar et al.31 conducted a systematic review of the predictors of response to intra-articular injection of corticosteroids in subjects with knee OA. Eleven publications met their eligibility criteria and were included in their review. The studies were mainly small in size with substantial variability in the predictors of response studied, and in how these predictors were defined. Thus, the authors were unable to pool the studies. From the individual studies, they found inconsistent evidence that likelihood of response to intra-articular steroid injection in knee OA is greater if: there is evidence of inflammation (synovitis, effusion, fluid withdrawal); OA symptoms are more severe; and ultrasound is used to guide the injection. The authors conclude that larger, higher quality studies are needed.
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Treating systemic inflammation in OA e immunomodulating agents Given the role of systemic inflammation in the pathogenesis of OA, immunomodulating agents are increasing being investigated as treatment options in OA. Wenham et al.32 conducted a pilot open label study of methotrexate (MTX) in 30 knee OA patients with demonstrated synovitis (ultrasound confirmed effusion and synovial thickening) and who were intolerant of other OA therapies. The mean age of participants was 64.5 years, with a mean pain visual analog scale (VAS) score of 6.8/10. MTX was prescribed up to 20 mg/ week for 24 weeks. Thirteen of the 30 patients achieved the OARSI responder criteria, but no relationship was found between pain response and change in synovitis on ultrasound. A potential explanation for the findings posed by the authors is that ultrasound may be an insensitive measure of treatment effect on the synovium (e.g., evaluates thickness but not cellularity) and cannot assess other aspects of OA structural damage, including bone marrow lesions and bone attrition. A randomized trial is currently underway using MRI to evaluate the structural impact, if any, of treatment of OA with MTX.
IS contributed to the collection and assembly of data, analysis and interpretation of data, drafting and revision of the article, as well as final approval of the submitted article. Role of funding source There was no funding source for this publication. Funding bodies had no role in the design of the literature review, identification of the articles, or writing of the manuscript. Competing interest statement GAH holds the F.M. Hill Chair in Academic Women's Medicine at Women's College Hospital. IS reports no competing interests. Acknowledgments None. References
Pain sensitization and prediction of pain outcomes after joint replacement Approximately 20% of patients experience severe chronic pain after knee replacement33. Wylde and colleagues hypothesized34 that non-response to knee replacement may be greater in those patients with vs without pain sensitization? If so, targeted treatment of pain sensitization prior to surgery may reduce adverse pain outcomes. Using quantitative sensory testing (QST), they examined the relationship between pre-operative pain thresholds and the presence of persistent pain (Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scale score) 1 year after total knee replacement (TKR) in 51 OA patients. Among their study subjects, 15 (29%) met their criteria for ‘persistent pain’. Those with lower pre-operative pressure pain thresholds at the forearm (indicating greater widespread pain sensitization) reported more severe pain in the replaced knee 1 year after surgery. Larger studies are now underway to confirm these findings. Conclusions The past year has seen an enhanced focus by OA clinical researchers on understanding the influence of systemic inflammation on OA phenotype, management, and outcomes, and on elucidating the characteristics of subgroups of patients with OA who are more or less likely to respond to specific therapies (i.e., personalizing management approach). Results from these studies highlight the high prevalence of comorbidities among people living with symptomatic OA and the interplay of these conditions with OA on chronic disease management and outcomes. This body of research indicates an urgent need for clinical trials of interventions in OA that take into consideration the heterogeneity of OA as a condition. Specifically, careful characterization of OA patients e at the joint and systemic levels e and consideration of the potential interactions between treatments and these OA characteristics are needed. Finally, given the high prevalence of other common ageand obesity-related conditions in people living with OA, additional research is warranted to promote evidence-based practice for the treatment of OA in the setting of other common chronic conditions. Author contributions GAH contributed to the conception and design, collection and assembly of data, analysis and interpretation of data, drafting and revision of the article, as well as final approval of the submitted article.
1. Conde J, Scotece M, Gomez R, Lopez V, Gomez-Reino JJ, Gualillo O. Adipokines and osteoarthritis: novel molecules involved in the pathogenesis and progression of disease. Arthritis 2011;2011:203901. 2. Garnero P, Rousseau JC, Delmas PD. Molecular basis and clinical use of biochemical markers of bone, cartilage, and synovium in joint diseases. Arthritis Rheum 2000;43:953e68. 3. Tu K, Chen Z, Lipscombe LL. Prevalence and incidence of hypertension from 1995 to 2005: a population-based study. CMAJ 2008;178:1429e35. 4. Tu JV, Nardi L, Fang J, Liu J, Khalid L, Johansen H. National trends in rates of death and hospital admissions related to acute myocardial infarction, heart failure and stroke, 1994e2004. CMAJ 2009;180:E118e25. 5. Vinluan CM, Zreikat HH, Levy JR, Cheang KI. Comparison of different metabolic syndrome definitions and risks of incident cardiovascular events in the elderly. Metabolism 2012;61: 302e9. 6. Lipscombe LL, Hux JE. Trends in diabetes prevalence, incidence, and mortality in Ontario, Canada 1995e2005: a population-based study. Lancet 2007;369:750e6. 7. Lee DS, Chiu M, Manuel DG, Tu K, Wang X, Austin PC, et al. Trends in risk factors for cardiovascular disease in Canada: temporal, socio-demographic and geographic factors. CMAJ 2009;181:E55e66. 8. Centers for Medicare and Medicaid Services. Chronic Conditions among Medicare Beneficiaries, Chartbook. 2012 edn. 2012. Baltimore, MD. 9. Caporali R, Cimmino MA, Sarzi-Puttini P, Scarpa R, Parazzini F, Zaninelli A, et al. Comorbid conditions in the AMICA study patients: effects on the quality of life and drug prescriptions by general practitioners and specialists. Semin Arthritis Rheum 2005;35:31e7. 10. Sale JEM, Gignac M, Hawker G. How “bad” does the pain have to be? A qualitative study examining adherence to pain medication in older adults with osteoarthritis. Arthritis Rheum 2006;55:272e8. 11. Fisher J, Ballantyne PJ, Hawker G. Older adults living with osteoarthritis: examining the relationship of age and gender to medication use. Can J Aging 2012;31:323e33. 12. Fisher J, Ballantyne PJ, Cairney J, Hawker G. The use of nonsteroidal anti-inflammatory drugs (NSAIDS) in osteoarthritis: using multilevel models to examine changes over time [abstract]. Arthritis Rheum 2008;58:S279.
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13. Fisher J, Ballantyne PJ, Hawker G. Arthritis-related drug use in a population based cohort: are there differences by gender and age? [abstract]. Arthritis Rheum 2007;56:S86. 14. Hawker GA, Gignac MA, Badley E, Davis AM, French MR, Li Y, et al. A longitudinal study to explain the pain-depression link in older adults with osteoarthritis. Arthritis Care Res (Hoboken) 2011;63:1382e90. 15. Nuesch E, Dieppe P, Reichenbach S, Williams S, Iff S, Juni P. All cause and disease specific mortality in patients with knee or hip osteoarthritis: population based cohort study. BMJ 2011;342:d1165. 16. Karsdal MA, Christiansen C, Ladel C, Henriksen K, Kraus VB, Bay-Jensen AC. Osteoarthritis e a case for personalized health care? Osteoarthritis Cartilage 2014;22:7e16. 17. Rahman MM, Kopec JA, Anis AH, Cibere J, Goldsmith CH. Risk of cardiovascular disease in patients with osteoarthritis: a prospective longitudinal study. Arthritis Care Res (Hoboken) 2013;65:1951e8. 18. Rahman MM, Aghanjanian J, Kopec JA, Cibere J. Validation of osteoarthritis diagnosis in administrative data using a clinically and radiologically defined population-based cohort of osteoarthritis [abstract]. Osteoarthritis Cartilage 2008;16: S150. 19. Hawker GA, Croxford R, Bierman AS, Harvey PJ, Ravi B, Stanaitis I, et al. All-cause mortality and serious cardiovascular events in people with hip and knee osteoarthritis: a population based cohort study. PLoS One 2014;9:e91286. 20. Conaghan PG, Vanharanta H, Dieppe PA. Is progressive osteoarthritis an atheromatous vascular disease? Ann Rheum Dis 2005;64:1539e41. 21. Katz JD, Agrawal S, Velasquez M. Getting to the heart of the matter: osteoarthritis takes its place as part of the metabolic syndrome. Curr Opin Rheumatol 2010;22:512e9. 22. Hoeven TA, Kavousi M, Clockaerts S, Kerkhof HJ, van Meurs JB, Franco O, et al. Association of atherosclerosis with presence and progression of osteoarthritis: the Rotterdam Study. Ann Rheum Dis 2013;72:646e51. 23. Cerhan JR, Wallace RB, el-Khoury GY, Moore TE, Long CR. Decreased survival with increasing prevalence of full-body, radiographically defined osteoarthritis in women. Am J Epidemiol 1995;141:225e34. 24. Jonsson H, Helgadottir GP, Aspelund T, Eiriksdottir G, Sigurdsson S, Ingvarsson T, et al. Hand osteoarthritis in older women is associated with carotid and coronary atherosclerosis: the AGES Reykjavik study. Ann Rheum Dis 2009;68: 1696e700.
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25. Jungmann PM, Kraus MS, Alizai H, Nardo L, Baum T, Nevitt MC, et al. Association of metabolic risk factors with cartilage degradation assessed by T2 relaxation time at the knee: data from the osteoarthritis initiative. Arthritis Care Res (Hoboken) 2013;65:1942e50. 26. Nieves-Plaza M, Castro-Santana LE, Font YM, Mayor AM, Vila LM. Association of hand or knee osteoarthritis with diabetes mellitus in a population of Hispanics from Puerto Rico. J Clin Rheumatol 2013;19:1e6. 27. McAlindon TE, Bannuru RR, Sullivan MC, Arden NK, Berenbaum F, Bierma-Zeinstra SM, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage 2014;22:363e88. 28. Ackerman IN, Buchbinder R, Osborne RH. Factors limiting participation in arthritis self-management programmes: an exploration of barriers and patient preferences within a randomized controlled trial. Rheumatology (Oxford) 2013;52: 472e9. 29. Cheraghi-Sohi S, Bower P, Kennedy A, Morden A, Rogers A, Richardson J, et al. Patient priorities in osteoarthritis and comorbid conditions: a secondary analysis of qualitative data. Arthritis Care Res (Hoboken) 2013;65:920e7. 30. Wilkie R, Blagojevic-Bucknall M, Jordan KP, Lacey R, McBeth J. Reasons why multimorbidity increases the risk of participation restriction in older adults with lower extremity osteoarthritis: a prospective cohort study in primary care. Arthritis Care Res (Hoboken) 2013;65:910e9. 31. Maricar N, Callaghan MJ, Felson DT, O'Neill TW. Predictors of response to intra-articular steroid injections in knee osteoarthritis e a systematic review. Rheumatology (Oxford) 2013;52:1022e32. 32. Wenham CY, Grainger AJ, Hensor EM, Caperon AR, Ash ZR, Conaghan PG. Methotrexate for pain relief in knee osteoarthritis: an open-label study. Rheumatology (Oxford) 2013;52: 888e92. 33. Beswick AD, Wylde V, Gooberman-Hill R, Blom A, Dieppe P. What proportion of patients report long-term pain after total hip or knee replacement for osteoarthritis? A systematic review of prospective studies in unselected patients. BMJ Open 2012;2:e000435. 34. Wylde V, Palmer S, Learmonth ID, Dieppe P. The association between pre-operative pain sensitisation and chronic pain after knee replacement: an exploratory study. Osteoarthritis Cartilage 2013;21:1253e6.
Review
Osteoarthritis Year in Review 2014: clinical G.A. Hawker y z *, I. Stanaitis y y Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, Canada z Departments of Medicine and Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
a r t i c l e i n f o
s u m m a r y
Article history: Received 22 May 2014 Accepted 12 June 2014
A systematic search was conducted for the time period April 1 2013 to March 30 2014 using PubMed to identify major osteoarthritis (OA) clinical research themes of the past year. Articles within each theme were selected for inclusion in this review based on study quality and relevance. Two major themes emerged, which relate to the current understanding of OA as a heterogeneous condition with multiple pathogenic mechanisms and clinical manifestations. Theme 1 stems from the role of systemic inflammation in OA pathogenesis, and the concept of ‘metabolic OA’. Over the past year, research has examined the effect of OA on incidence and progression of other ‘metabolic syndrome’-related conditions, especially cardiovascular disease (CVD) and diabetes and the impact of multi-morbidity on the clinical management of OA. Theme 2 focuses on the concept of personalized medicine as it relates to the treatment of OA. It is hypothesized that the modest efficacy of available OA treatments is a result of inclusion of heterogeneous groups of OA patients in clinical trials. Prognostic studies in the past year have been helpful in identifying ‘OA phenotypes’ that are more or less likely to respond to treatments e e.g., the presence of synovitis on imaging, central pain sensitization on quantitative sensory testing (QST), or coping efficacy by self-reported patient questionnaire. Their findings are being increasingly used to target interventions to these identified ‘OA responder’ subgroups with the hopes that treatment effect will be amplified. © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Keywords: Osteoarthritis Multi-morbidity Inflammation Treatment
Introduction It is now generally understood that osteoarthritis (OA), is a heterogeneous condition that develops as a result of the effects of local (joint level) factors, e.g., abnormal gait biomechanics, and systemic factors, e.g., aging, genetics, and systemic inflammation related to obesity. Adipose tissue produces inflammatory adipokines that have the potential to influence all synovial joint tissues, which has given rise to the term ‘metabolic OA’1,2. Given shared risk factors e aging and obesity e there is also growing appreciation of the fact that most people living with OA are also living other chronic conditions, including hypertension3,4, dyslipidemia5, diabetes6, and cardiovascular disease (CVD)7. It is estimated that 90% of individuals aged 65þ years with OA have at least one other chronic condition8. This is concerning as comorbidity in OA has been linked significantly and independently to under-use of effective
* Address correspondence and reprint requests to: G.A. Hawker, Department of Medicine, University of Toronto, 190 Elizabeth Street, Suite RFE 3-805, Toronto, Canada, M5G 2C4. Tel: 1-416-946-8071; Fax: 1-416-323-7513. E-mail addresses: [email protected], [email protected] (G.A. Hawker).
therapies9e13. Without effective treatment, people with OA tend to give up activities, like exercise, that exacerbate their symptoms10,14. This has led researchers over the past year to hypothesize that, by limiting physical activity, painful OA may increase the risk for CVD and all-cause death. Indeed, in 2011 Nuesch et al.15 reported in a cohort aged 35þ years with hip and knee OA recruited 1994e1995 from 40 English general practices (n ¼ 2703), and after controlling for confounders, that baseline walking disability predicted increased all-cause death (1.48, 1.17e1.86), especially from CVD causes. Given the high prevalence of OA in the population, confirmation of these relationships is important. Recognition that OA it not so much a single entity but the final common pathway of a variety of conditions with distinct causes (genetic, developmental, metabolic, traumatic), but with similar biologic, morphologic and clinical outcomes, has led to a paradigm shift in how we think about treatment for this condition. The failure of clinical trials to date to identify highly efficacious therapies in OA may be due to true lack of such therapies or the conduct of trials in heterogeneous groups of OA patients e that is, in groups of patients that include both potential ‘responders’ and ‘non-responders’16. Stratification of patients into subgroups based on their likelihood of response to the treatment of interest has potential to improve the
http://dx.doi.org/10.1016/j.joca.2014.06.018 1063-4584/© 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
1954
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effectiveness of both available and future OA therapies. This has spurred interest in identifying predictors of response to available and new OA therapies which may inform patientephysician decision making about treatment options. With this background, this review sought to highlight studies published over the prior year, since the 2013 meeting of the Osteoarthritis Research Society International (OARSI), pertaining to advances in the epidemiology and treatment of OA. Methods The primary literature search was conducted using PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) with the search terms “osteoarthritis [ti] AND treatment [All Fields]” and the following limits activated: humans, English language, all adult 19þ years, published between April 1 2013 and March 31 2014. This search identified 113 articles. A secondary literature search was then conducted with the search terms “osteoarthritis [ti] AND epidemiology”, with the same limits; these searches identified a total of 122 articles. The titles of all articles were reviewed in order to refine the topic area and to identify major OA clinical research themes of the past year. Studies selected for inclusion in the review presentation were those deemed by the author to be of high quality with potential to affect the management of OA in clinical practice. Results Theme 1: the interplay between OA & other chronic conditions OA and risk for serious cardiovascular outcomes Two studies examined the risk for CVD in people with OA. Rahman et al.17 compared time to a composite CVD outcome (hospital admission for myocardial infarction, ischemic heart disease, congestive heart failure or stroke) in 12,745 adults 20 years with OA (cases) and no prior CVD history with up to three non-OA matched controls (sex, age, year of ‘diagnosis’). Using health administrative data, OA cases were those with at least two visits to a health professional in 2 years separated by at least 1 day or 1 discharge from hospital with ICD-9 code of 715 or ICD-10 codes of M15eM19. From a published abstract, the sensitivity & specificity of this OA diagnosis algorithm were 60e70%18. Over a mean followup 13 years, the authors identified 7995 hospitalizations for CVD events. Controlling for covariates (neighborhood income quintile, body mass index (BMI), imputed using population data for age and sex, chronic obstructive pulmonary disease (COPD), hypertension, hyperlipidemia, diabetes, and Charlson score) in the final multivariable Cox proportional hazards model, OA diagnosis was found to be an independent predictor of CVD among: older men (Relative Risk (RR) 1.15, 1.04e1.27); younger women (RR 1.26, 1.13e1.42); older women (RR 1.17, 1.07e1.26); but not younger men (RR 1.08, 0.97e1.19). A second study utilized data from an established population cohort with moderate to severe hip and knee OA to examine the relationship between baseline walking disability (Health Assessment Questionnaire (HAQ) walking disability score 0e3) and risk for a composite CVD outcome (hospitalization for angina, acute myocardial infarction (AMI), coronary revascularization (coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI)), congestive heart failure (CHF), stroke or transient ischemic attack (TIA))19. Over median 9.2 years, 38% of 2156 OA participants experienced the CVD outcome. Controlling for socio-demographics, CVD risk factors (BMI, smoking, diabetes, hypertension, non-steroidal anti-inflammatory drug (NSAID) use) and additional health problems, walking disability was a significant independent predictor of CVD events with an adjusted Hazard Ratio (HR) per unit
increase in HAQ walking of 1.17 (1.08e1.27). Further adjustment for post-baseline receipt of a primary, elective hip or knee joint arthroplasty (TJA) did not attenuate this effect and found that TJA was protective of CVD events (adjusted HR ¼ 0.66, 0.52e0.85, P < 0.001). Interestingly, the effect of a HAQ walking score of 2 vs 0 on risk for CVD events was roughly equivalent to that associated with a baseline diagnosis of diabetes. Vascular abnormalities and OA It has also been hypothesized is that circulatory disturbances associated with CVD may impact the synovial membrane and subchondral bone and contribute to cartilage destruction and OA20,21. Using data from the Rotterdam study, Hoeven et al.22 examined the relationship between atherosclerosis (carotid intima media thickness and carotid plaque) with both the presence and progression of knee, hip & hand OA (Kellgren-Lawrence (KL) grade on X-ray) controlling for confounders (age, BMI, lipid levels, smoking, diabetes, and hypertension). They documented independent associations between these vascular abnormalities and OA of knee and hand joint in women but not men, but found no association with hip OA. The authors propose that their findings are consistent with the greater perceived influence of systemic inflammation in knee vs hip OA23,24. Metabolic syndrome and OA Jungmann et al.25 evaluated the association of metabolic risk factors (abdominal circumference, hypertension, fat consumption, and diabetes) with severity and 2-year progression of early degenerative cartilage changes in the knee, evaluated using T2 relaxation times and magnetic resonance imaging (MRI), in 403 OsteoArthritis Initiative (OAI) participants. In cross-sectional analyses, the authors found that metabolic risk factors were significantly associated with higher T2 relaxation times, suggesting increased cartilage degeneration may be caused by modifiable metabolic disorders. No longitudinal relationships were found. Diabetes and OA Nieves-Plaza et al.26 asked: Is diabetes a risk factor for OA? In their study, the prevalence of hip, knee, hand OA (defined using American College of Rheumatology classification criteria) was compared in Hispanics with vs without diabetes, and before and after controlling for self-reported confounders (smoking, exercise, socio-demographics, comorbidities, insulin use). In their fully adjusted model, the likelihood that subjects met criteria for OA was significantly higher among those with vs without diabetes (adjusted Odds Ratio (OR) 2.18, 1.12e4.24). Further, within their diabetes cases, the risk of OA was five times greater in women than men, and higher in those that were not using insulin. Given that Insulin-like growth factor 1 (IGF-1) is known to be reduced in OA, the latter finding is provocative, suggesting that growth factors may preserve cartilage. OA in the setting of other conditions The impact of comorbidity on the treatment of OA has also been evaluated in several studies over the past year. The 2014 OARSI nonsurgical knee OA treatment guidelines27 evaluated the evidence supporting use of available therapies in four distinct knee OA patient subgroups e those with and without concomitant joint complaints and with and without other chronic conditions (Fig. 1). The guidelines highlight the paucity of evidence supporting the use of therapies in the largest group of patients with knee OA, those with comorbid conditions and multiple joint complaints, emphasizing the need more clinical trials in people with OA in setting of other common chronic conditions.
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Fig. 1. Appropriate treatments summary. From: McAlindon TE, Bannuru RR, Sullivan MC, Arden NK, Berenbaum F, Bierma-Zeinstra SM, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage 2014;22:363e88.
Ackerman et al.28 conducted a secondary analysis of data from a randomized trial evaluating the efficacy of the 6-week Stanford Arthritis Self-Management Program (ASMP), delivered in a community-based setting. Subjects were adults referred to rheumatology or orthopedic surgery for hip or knee OA. The trial found that uptake of the ASMP was low despite the absence of financial barriers to participation and flexibility of times offered. Thus, the current study examined factors limiting participation in selfmanagement based on data from recorded recruitment telephone calls. Among the most frequently reported reasons for nonparticipation was concurrent illness (OA is not the only problem) and the appropriateness of an arthritis-specific vs generic chronic disease self-management approach. Additional reasons for nonparticipation included: disinterest; limited mobility (pain, fear of falling, difficulty getting to the program); lack of endorsement of the value of the program by their primary care physician; a desire for pharmacotherapy or surgery; and a sense by the patient that they were already coping well with their OA. Cheraghi-Sohi et al.29 examined OA patients' health priority setting when living with more than one chronic condition. The authors re-analyzed four qualitative studies to examine how patients with OA prioritize OA relative to their other health problems. Key findings of their study were as follows: patients have limited time to address their health concerns; they tend to prioritize the condition(s) that are perceived as ‘more severe’ or with worse future implications; health priorities changed over time, influenced by whether or not the condition was ‘under control’, which was, in turn, influenced by the messages they received from physicians; OA was seen as a priority when it impacted mobility for independence or care-giving; and, finally, in an effort to balance health care issues, the most frequently dropped activity was exercise. Their findings are consistent with those of Wilkie et al.30 who prospectively evaluated the impact of multi-morbidity on participation restriction in a cohort of 1053 people who consulted primary
care for lower extremity OA. Those with participation restrictions at baseline were excluded. Multi-morbidity was defined based on patient self report. Participants were asked to report the presence of three common chronic health conditions (chest problems, heart problems, diabetes), two impairments most commonly associated with disability (deafness and eyesight problems) and seven other impairments (falls, memory, cough with spit, breathless with walking, dizziness, weakness in arms/legs, elevated blood pressure); a count of health conditions and impairments was calculated (0e12) and multi-morbidity was defined as a score > the median value of 2 (i.e., 3þ vs 0e2). Path analysis was used to determine the relationship between baseline multi-morbidity & incident participation restrictions at 3 years. Additional variables of interest were joint pain severity, obesity, locomotor disability, and depression. Analyses found that multi-morbidity contributed to the development of participation restrictions at 3 years through its effects on locomotor disability and depression. Theme 2: targeted treatment in OA (personalized medicine) Predictors of response to intra-articular injection of corticosteroids in knee OA Maricar et al.31 conducted a systematic review of the predictors of response to intra-articular injection of corticosteroids in subjects with knee OA. Eleven publications met their eligibility criteria and were included in their review. The studies were mainly small in size with substantial variability in the predictors of response studied, and in how these predictors were defined. Thus, the authors were unable to pool the studies. From the individual studies, they found inconsistent evidence that likelihood of response to intra-articular steroid injection in knee OA is greater if: there is evidence of inflammation (synovitis, effusion, fluid withdrawal); OA symptoms are more severe; and ultrasound is used to guide the injection. The authors conclude that larger, higher quality studies are needed.
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Treating systemic inflammation in OA e immunomodulating agents Given the role of systemic inflammation in the pathogenesis of OA, immunomodulating agents are increasing being investigated as treatment options in OA. Wenham et al.32 conducted a pilot open label study of methotrexate (MTX) in 30 knee OA patients with demonstrated synovitis (ultrasound confirmed effusion and synovial thickening) and who were intolerant of other OA therapies. The mean age of participants was 64.5 years, with a mean pain visual analog scale (VAS) score of 6.8/10. MTX was prescribed up to 20 mg/ week for 24 weeks. Thirteen of the 30 patients achieved the OARSI responder criteria, but no relationship was found between pain response and change in synovitis on ultrasound. A potential explanation for the findings posed by the authors is that ultrasound may be an insensitive measure of treatment effect on the synovium (e.g., evaluates thickness but not cellularity) and cannot assess other aspects of OA structural damage, including bone marrow lesions and bone attrition. A randomized trial is currently underway using MRI to evaluate the structural impact, if any, of treatment of OA with MTX.
IS contributed to the collection and assembly of data, analysis and interpretation of data, drafting and revision of the article, as well as final approval of the submitted article. Role of funding source There was no funding source for this publication. Funding bodies had no role in the design of the literature review, identification of the articles, or writing of the manuscript. Competing interest statement GAH holds the F.M. Hill Chair in Academic Women's Medicine at Women's College Hospital. IS reports no competing interests. Acknowledgments None. References
Pain sensitization and prediction of pain outcomes after joint replacement Approximately 20% of patients experience severe chronic pain after knee replacement33. Wylde and colleagues hypothesized34 that non-response to knee replacement may be greater in those patients with vs without pain sensitization? If so, targeted treatment of pain sensitization prior to surgery may reduce adverse pain outcomes. Using quantitative sensory testing (QST), they examined the relationship between pre-operative pain thresholds and the presence of persistent pain (Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scale score) 1 year after total knee replacement (TKR) in 51 OA patients. Among their study subjects, 15 (29%) met their criteria for ‘persistent pain’. Those with lower pre-operative pressure pain thresholds at the forearm (indicating greater widespread pain sensitization) reported more severe pain in the replaced knee 1 year after surgery. Larger studies are now underway to confirm these findings. Conclusions The past year has seen an enhanced focus by OA clinical researchers on understanding the influence of systemic inflammation on OA phenotype, management, and outcomes, and on elucidating the characteristics of subgroups of patients with OA who are more or less likely to respond to specific therapies (i.e., personalizing management approach). Results from these studies highlight the high prevalence of comorbidities among people living with symptomatic OA and the interplay of these conditions with OA on chronic disease management and outcomes. This body of research indicates an urgent need for clinical trials of interventions in OA that take into consideration the heterogeneity of OA as a condition. Specifically, careful characterization of OA patients e at the joint and systemic levels e and consideration of the potential interactions between treatments and these OA characteristics are needed. Finally, given the high prevalence of other common ageand obesity-related conditions in people living with OA, additional research is warranted to promote evidence-based practice for the treatment of OA in the setting of other common chronic conditions. Author contributions GAH contributed to the conception and design, collection and assembly of data, analysis and interpretation of data, drafting and revision of the article, as well as final approval of the submitted article.
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