Update on the epidemiology, risk factors and disease outcomes of osteoarthritis

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Update on the epidemiology, risk factors and disease outcomes of osteoarthritis Terence W. O'Neill a, Paul S. McCabe b, John McBeth a, * a Arthritis Research UK Centre for Epidemiology, The University of Manchester, Manchester, UK & NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK b Royal Oldham Hospital, Pennine Acute NHS Trust, Rochdale Rd, Oldham OL1 2JH, UK

a b s t r a c t Keywords: Osteoarthritis Epidemiology Risk factors Outcomes

Osteoarthritis (OA) is the most frequent form of arthritis and a leading cause of pain and disability worldwide. OA can affect any synovial joint, although the hip, knee, hand, foot and spine are the most commonly affected sites. Knowledge about the occurrence and risk factors for OA is important to define the clinical and public health burden of the disease to understand mechanisms of disease occurrence and may also help to inform the development of population-wide prevention strategies. In this article, we review the occurrence and risk factors for OA and also consider patientreported outcome measures that have been used for the assessment of the disease. © 2018 Elsevier Ltd. All rights reserved.

Introduction Osteoarthritis (OA) is the most common form of arthritis worldwide and a major cause of disability in middle-age and older adults [1]. The most frequently affected joints are the hip, knee, hand, foot and spine, although OA can affect any joint. It is estimated that symptomatic OA affects one in eight men and women in the US (27e31 million) [1,2], and worldwide, it is estimated that 250 million people have knee OA [3]. OA is an important cause of disability, with hip and knee OA accounting for 17 million years lived with disability or 2.2% of all-cause years lived with disability [3,4].

* Corresponding author. E-mail address: [email protected] (J. McBeth). https://doi.org/10.1016/j.berh.2018.10.007 1521-6942/© 2018 Elsevier Ltd. All rights reserved.

Please cite this article as: O'Neill TW et al., Update on the epidemiology, risk factors and disease outcomes of osteoarthritis, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/ j.berh.2018.10.007

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OA is linked to substantive economic costs estimated in developed countries to be between 1% and 2.5% of GDP [5,6]. The bulk (85%) of the direct costs of OA treatment are due to the costs of joint replacement surgery [7]. In the UK, there were over 185,000 primary hip and knee replacements performed in 2016, with the number set to increase substantially related in part to the ageing population [8,9]. Although cartilage loss remains the signature pathological feature of OA, it is currently recognised that OA is a disease of the whole joint, with pathological changes in the bone, the soft tissues including synovium, menisci and ligaments. OA may be characterised as primary if there is no identifiable underlying cause and secondary if there is an underlying cause or significant triggering event such as prior trauma. The main symptoms of OA include pain, stiffness and loss of function. There is, however, discordance between the presence of symptoms and radiographic change, and many people with radiographic OA (up to 50%) do not have associated symptoms [10]. The reason for this apparent discordance is unclear, although it is likely in part because plain radiography is an insensitive indicator of the structural and nociceptive changes that occur in OA. OA can be classified on the basis of radiographic criteria alone or combination criteria including symptoms and radiographic changes (symptomatic OA). The most widely used radiographic criteria are the Kellgren-Lawrence method, which characterises disease as one of the five grades (0e4) based on the presence of joint space narrowing, osteophytes and sclerosis of the subchondral bone [11]. There are, however, limitations related in part to inconsistencies in scoring and also the reliance on the presence of osteophytes, and other criteria have been developed on the basis of scoring of individual radiographic features of the disease [12]. Prevalence Most of the published data on prevalence derive from population-based radiographic surveys. Plain radiographs are insensitive to early disease, and therefore, these studies tend to underestimate disease occurrence. In a survey of individuals with neither radiographic signs nor symptoms of OA, by magnetic resonance imaging, a more sensitive indicator of joint damage, abnormalities thought to be associated with knee OA were detected in 89% of cases [13]. Estimates of the occurrence of OA vary in part according to the definition used to categorise disease and also characteristics of the study population including age [14]. In the Framingham study, the prevalence of radiographic knee OA (age 63e94 years) was estimated as 33%, with the prevalence slightly greater in women than in men (34% vs 31%). The prevalence of symptomatic knee OA in the same study was 9.5% and significantly greater in women than in men (11.4% vs 6.8%) [15]. Focusing on knee symptoms, data from the UK suggest that one in four people aged 55 years and older report a significant episode of knee pain in the past year, with half of those (12.5%) reporting some associated disability [16]. In Framingham study, the prevalence of both symptomatic and radiographic OA increased with age, although there was a less marked increase in men. Among women, the prevalence of symptomatic knee OA increased from 7.6% in those aged less than 70 years, increasing to 15.8% in those aged 80 years and older. Data from a large Dutch survey, which included a wider age range, confirm an increase in the prevalence of radiographic knee OA, with age beginning at approximately 45 years in both men and women, with a greater apparent increase with age in women than in men [17]. There is also some evidence from the Framingham study of a trend for a 20-year period towards an increase in the prevalence of symptomatic, although, interestingly, without any increase in the prevalence of radiographic knee OA [18]. There is a relative paucity of data concerning the prevalence of hip OA. Using data from the Framingham study, the age-standardised prevalence of radiographic hip OA in men and women over the age of 50 years was 19.6% and of symptomatic hip OA was 4.2%. In this study, the prevalence of radiographic OA was greater in men than in women (24.7% vs 13.6%), while the prevalence of symptomatic hip OA was broadly similar (5.2% vs 3.0%) [19]. Data from other studies, however, suggest parity in the radiographic prevalence of the disease in men and women [14]. The hand is the peripheral joint site most frequently affected by OA. Using data from the Framingham study (mean age 58.9 years), the age-standardised prevalence of radiographic OA was slightly higher in women (44.2%) than in men (37.7%). The gender effect was more marked for Please cite this article as: O'Neill TW et al., Update on the epidemiology, risk factors and disease outcomes of osteoarthritis, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/ j.berh.2018.10.007

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symptomatic OA (15.9% vs. 8.2%) and also erosive OA (9.9% vs 3.3%) [20]. With regard to OA at other joint sites, the prevalence of hand OA increases with age in both men and women [17,20]. Incidence Using data from the Fallon Community Health Plan, a health maintenance organisation in Central Massachusetts, among adults aged 20e89 years, the age- and sex-standardised incidence of knee OA was 240/100,000 person years, hip OA was 88/100,000 person years and hand OA was 100/100,000 person years [21]. Incidence increased with age, however, with a levelling off or decline at older ages (>80 years) and with rates greater in women than in men, especially after the age of 50 years [21]. Data from Chingford suggest an annual cumulative incidence of 2.3% of radiographic knee OA in women, whereas in the Framingham study, the cumulative incidence of hand OA for a 9-year period was 34.6% for women and 33.7% for men [20,22]. Lifetime risk Using data from the Johnston County OA project, it is has been estimated that 40% of adults from the age of 45 years will develop symptomatic hand OA by the age of 85 years for those who live up to that age; this is similar to the corresponding risk of symptomatic knee OA (45%), which is greater than that for hip OA (25%) [23e25]. Using data based on self-report, however, from the US National Health Interview Survey, the lifetime risk of symptomatic knee OA from the age of 25 years was significantly lower at 14% [26]. Influence of race and ethnicity There are ethnic differences in the occurrence of OA. European and American data do not appear to differ markedly in the occurrence of disease for hand, knee and hip OA [27]. Chinese men and women have a lower prevalence of both radiographic and symptomatic hand OA and radiographic hip OA than Caucasians [28,29]. The prevalence of radiographic knee OA, however, is similar in Chinese and Caucasian men, whereas prevalence of both radiographic and symptomatic knee OA appears to be greater in Chinese women than in others. In both men and women, Chinese subjects had more frequent lateral knee OA than Caucasians [30,31]. Data from within the US suggest that both radiographic and symptomatic knee OA are more common in African-Americans than in Caucasians, although this may vary with gender e with some, however, not all studies suggesting an excess in women than in men [32e34]. There appears also to be some difference in the expression of the disease; African-Americans appear to have more severe tibiofemoral knee OA, a greater prevalence and severity of osteophytes joint space narrowing and sclerosis [35]. Pain and functional limitations are more common also in African-Americans than in Caucasians with knee OA, although these differences could be explained by clinical factors including body mass index (BMI) and depressive symptoms [36]. Radiographic hand OA is less common in African-Americans than in Caucasian Americans [37e39]. Hand OA is also less common among South African blacks [40]. At the hip, there do not appear to be important differences in occurrence in US Caucasians and African-Americans, although there is some evidence that the frequency of specific radiographic features may vary among men, for example, African-Americans were more likely than Caucasians to have superior or medial joint space narrowing and lateral osteophytes [41]. Secular change With the demographic change to a more elderly population, the number of people with OA is set to increase. Such demographic change is likely to be compounded by the increase in the prevalence of obesity, which is a major risk factor for the disease. Data from Canada suggest that the numbers of people with OA will increase from 4.4 million in 2010 to 10.4 million in 2040 [42]. More recent data from Sweden suggest an increase in clinically diagnosed OA (any site) from 26.6% in 2012 to 29.5% in 2032 among those aged 45 years and older [43]. Please cite this article as: O'Neill TW et al., Update on the epidemiology, risk factors and disease outcomes of osteoarthritis, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/ j.berh.2018.10.007

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Risk factors The majority of studies investigating risk factors for the development of OA have focussed on either the knee or hip joint, with relatively few studies addressing risk factors for the development of OA at other common sites including the spine, hand and foot. Cross-study comparisons of risk factors are complicated because of differences in the populations studied, categorisation of individual risk factors and also the method used to define OA [44]. Risk factors for OA can be broadly categorised as either systemic, including age, gender, genetics and ethnicity, or mechanical, including joint structure/ alignment, trauma, physical activity and also occupation. However, the distinction maybe arbitrary, as some factors, for example, increased BMI may increase the risk of developing OA by both local and systemic mechanisms. Systemic factors A range of systemic risk factors for the development of OA have been reported. The impact of age, gender and ethnicity on the occurrence of OA has been considered earlier. Both genetic and environmental risk factors including BMI, smoking and nutrition have been associated with OA. Genetics OA has a significant genetic component. Twin studies have shown that contribution of genetic factors to OA is approximately 40% for hand OA in women, 65% for knee OA, 70% for hip OA and 70% for spine OA [45,46]. The heritable component of OA is approximately 50%, and this is polygenic [45e47]. There is significant genetic heterogeneity according to the skeletal site involved and also evidence of racial variation, which complicates genetic studies [48e51]. Approximately 30 loci have been associated with the risk of developing hip or knee OA, although, cumulatively, these explain only ~25% of the heritability of OA at these sites, and further research is required [47,48,51]. Body mass index Being overweight (BMI 25e30 kg/m2) or obese (BMI>30 kg/m2) is a strong risk factor for the development of knee OA, with a recent meta-analysis reporting an odds ratio (OR) of developing knee OA of 1.98 (95% CI 1.57e2.20) and, if obese, OR of 2.66 (95% CI 2.15e3.28), thus suggesting an increased risk as weight increases [52]. Similarly, weight loss has been reported to be associated with a reduction in the risk of developing knee OA. The Framingham study reported that a reduction in BMI of 2 or more units decreased the odds of developing knee OA significantly (OR 0.46; 95% CI, 0.24 to 0.86) [53]. For the hip, the association between increased BMI and OA is less clear, with some studies reporting no association [54], whilst others report a significant, yet weaker, association than that for the knee [55], and in others, only for bilateral disease [56]. It is likely that increased BMI is a risk factor for knee OA in part because of its effect on mechanical loading of the knee. However, increased BMI has also been shown to be moderately associated with the development of OA of the hand, a nonweight-bearing area, thus suggesting that increased BMI may also increase the risk of developing OA through systemic factors, potentially including systemic inflammation as a mediator [57]. Lifestyle Smoking tobacco appears to associated with a reduction in the risk of developing knee OA, and a recent meta-analysis reported that the relative risk of developing knee OA for ever smokers was 0.80 (95% CI 0.73e0.88), with a more marked effect in men than in women (RR ¼ 0.69; 95% CI 0.58e0.80) [58]. In another meta-analysis, the odds of developing OA at any site was reduced (OR ¼ 0.87; 95% CI 0.80e0.94) [59]. The mechanism by which smoking is linked to a reduced risk of OA is unclear, although it may in part be mediated by smokers generally having lower BMI than nonsmokers [58e60]. The relationship between alcohol consumption and OA remains uncertain. One study reported that beer consumption appears to increase the risk of developing OA of the knee and hip, but wine consumption was associated with a reduced risk, although no definitive data are available yet [61]. Please cite this article as: O'Neill TW et al., Update on the epidemiology, risk factors and disease outcomes of osteoarthritis, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/ j.berh.2018.10.007

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Nutrition A large number of nutritional factors or deficiency states have been reported to be possibly associated with the development of OA-based observational data. These include vitamin D deficiency [62e64], vitamin C [65], vitamin K [66,67] and selenium amongst others. Experimental trials of replacing micronutrients including vitamin A [68], D [69], E [70] and K [71] and selenium [68], however, have been disappointing, with no significant evidence of benefit in those with established OA. Current evidence is insufficient therefore to make specific recommendation regarding dietary modification to prevent or treat OA, although a healthy balanced diet that maintains a normal BMI may reduce the risk of incident OA, OA severity and OA progression [72]. Sex hormones, reproduction and bone density The role of gender in the epidemiology of OA has been considered previously. In addition to the gender differences, sex hormone status may also alter the risk of developing OA. In females, menarche at a younger age is associated with an increased risk of undergoing a total knee or hip replacement (RR for menarche #11 years versus 12 years, hip 1.09; 95% CI 1.03e1.16, knee 1.15 (95% CI 1.08 to 1.22)) [73], for which severe OA is by far the most frequent indication, thus potentially suggesting that oestrogen exposure at a younger age increases the risk of severe OA. The age at menopause does not appear to alter the risk of hip or knee replacement [74,75], although there is some evidence to suggest an increased risk of developing hand OA around the time of the menopause [76]. Parity also increases the risk of incident knee OA [77], and in the Million Women study, each additional birth was associated with a 2% (95% CI 1e4%) increase in the relative risk of hip replacement and 8% (95% CI 6e10%) for knee replacement [74], although the mechanism by which increasing parity is associated with a greater likelihood of incident OA and joint replacement is uncertain and may include both hormonal and biomechanical factors. The role of exogenous sex hormone supplementation in the pathogenesis of OA is less clear. The use of the oestrogen-containing oral contraceptive pill (OCP) is associated with altered ligamental laxity at the knee [78] and has also been reported to reduce the risk of anterior cruciate ligament injuries [79] and therefore plausibly may also effect the risk of developing OA. However, studies assessing the association between OCP use and risk of total knee replacement have yielded conflicting results [74,75]. Studies assessing the effect of post-menopausal hormone replacement therapy (HRT) report often conflicting results, with some reporting that HRT is associated with a reduced the risk of OA at the knee, hip or spine [80e82], whilst other studies have not identified any protective effect [83e87]. In the million women study, current users of HRT had significantly increased incidence of both hip (RR ¼ 1.38; 95%CI 1.30e1.46) and knee replacements (RR ¼ 1.58; 95% CI 1.48e1.69) [74]. The available evidence does not support the use of HRT for the primary prevention of OA. The effect of testosterone levels on the risk of males developing OA has not been reported previously. However, testosterone levels are associated with other known OA risk factors including muscle weakness and increased BMI and also decrease with age [88], and the potential role of testosterone in the aetiopathogenesis of OA warrants further investigation. Increased bone mineral density (BMD) has been positively associated with OA of the hip, knee, hand and spine in multiple cross-sectional studies [89e93]. More recent longitudinal studies have confirmed prospectively the link between high BMD and incident knee [94e97] and hip OA [98], although the relationship between BMD and OA progression remains unclear. In the Multicenter Osteoarthritis Study, the OR of incident knee OA for a 30-month follow-up duration was 2.3 (95% CI 1.2e4.5) for those in the highest quartile of femoral neck BMD compared to those in the lowest quartile [97]. The mechanism by which high BMD may increase the risk of OA is not fully understood, although it is likely to include local biomechanical factors and genetics mediators of bone tone turnover (reviewed in Ref. [99]). Mechanical factors Local joint factors may result in altered biomechanics within the joint, thus leading to abnormal loading, altered tissue composition and mechanical changes leading to the development of OA. Please cite this article as: O'Neill TW et al., Update on the epidemiology, risk factors and disease outcomes of osteoarthritis, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/ j.berh.2018.10.007

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Joint structure and malalignment Joint structural abnormalities may increase the risk of developing OA. Variation in femoral head shape has been reported to significantly increase the risk of incident hip OA (OR 1.62; 95% CI 1.08e2.45) [100] with similar observations reported for the knee [101]. Joint malalignment is also a significant risk factor for incident OA; in a multicentre osteoarthritis trial, varus knee alignment was associated with increased odds of incident radiographic tibiofemoral OA (adjusted OR 1.49; 95% CI 1.06 to 2.10) and also progression of medial tibiofemoral OA (adjusted OR 3.59; 95% CI 2.62 to 4.92) [102],with a similar trend observed in other populations for radiographic, although not clinical, knee OA [103]. Developmental abnormalities such as developmental dysplasia of the hip are also thought to be a significant risk factor for the development of OA, and this may present at a younger age [104,105]. Trauma Trauma to a joint, including surgery, may result in the onset of OA, usually termed post-traumatic OA (PTOA) and is typically considered a distinct clinical entity. The mechanism of the development of PTOA may be due to acute hyperloading of the joint tissues during the injury, thus leading to irreparable tissue injury. Following trauma, there may also be long-term structural changes in the joint, thereby leading to altered biomechanics in a similar manner as that of developmental abnormalities, although often there will be a combination of both mechanisms [106]. Trauma leading to PTOA is estimated to be responsible for approximately 12% of all symptomatic OA in the US [107]. The contribution of trauma as a risk factor to the burden of OA varies remarkably by the joint, for instance, in the ankle, trauma is estimated to the inciting factor in the development of OA in 70e90% of cases compared to only 2e10% of the hip and knee OA, thus likely reflecting the frequency of traumatic OA and nontraumatic OA in specific joints [107e109]. Physical activity The relationship between exercise and incident knee OA has been evaluated in multiple cohort studies including those assessing the general population and specific groups such as recreational runners, none of which reported an increased risk of incident OA in those undertaking moderate physical activity [83,110e115]. In contrast, self-reported ‘heavy physical activity’ has been reported to increase the risk of developing knee OA in the Framingham study, with those who engage in heavy physical activity for greater than 4 hours per day having an increased odds of developing knee OA (OR 7.0; 95% CI 2.4e20) compared to controls who participated in no heavy physical activity [111]. For the hip, data from Swedish caseecontrol studies have identified an increased risk of developing hip OA (RR: men 4.5, women 2.3) in those who recalled the highest levels of sports participation up to the age of 50 years compared to low activity groups [116,117]. In general, evidence suggests that moderate levels of physical activity are unlikely to significantly increase the risk of developing OA of the hip or knee. Muscle strength It is widely recognised that patients with symptomatic knee and hip OA have reduced muscle strength in neighbouring muscle groups such as the quadriceps or hip abductors (22e24), and this is present even in early disease [118,119]. Traditionally, this has been thought to be a secondary phenomenon with OA-related joint symptoms resulting in reduced activity levels, relative muscle atrophy and consequent weakness. More recent studies, however, suggest that muscle weakness predates the onset of knee OA [120e124], and weakness of knee extensors significantly increased the odds of developing symptomatic OA (OR 1.65; 95% CI 1.23e2.21) [125]. The role of muscle weakness in the progression of knee OA is less clear [126]. Muscle weakness therefore may be an important modifiable risk factor for the development of OA, although further research is required to confirm the role of exercise in the primary prevention of incident knee OA and to evaluate the contribution of muscle weakness to OA at other sites. Occupation Occupational activity may also be associated with the development of OA. In professional sport persons such as football (soccer) players and weight lifters, an increased risk of developing knee OA has Please cite this article as: O'Neill TW et al., Update on the epidemiology, risk factors and disease outcomes of osteoarthritis, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/ j.berh.2018.10.007

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been reported [127]. Similarly, in baseball pitchers, elbow disease is more frequent [128], thus suggesting that repetitive loading of the joint may be associated with the onset of OA. Similar patterns have been seen in more routine occupations with jobs that require repetitive kneeling and squatting, such as miners and carpenters, being associated with an increased odds of developing knee OA (OR 1.4e6.0) with similar, although less, strong association also reported for hip OA [129]. Comparable observations have been reported in the hands of mill workers whose work required repetitive pinch grip and in whom there was a higher prevalence of distal interphalangeal joint OA [130]. The effect of more contemporary specific occupational roles on the risk of developing OA requires further research. Measurement of osteoarthritis outcomes: patient-reported outcome measures (PROMs) Patient-reported outcome measures (PROMs) are amongst the most commonly used and convenient methods to assess OA outcomes. They include recommended core outcome sets of pain, function and quality of life [131,132]. OA PROMs are specifically designed for ease of completion and allow for regular measurement. These qualities of well-constructed and validated PROMs not only enable clinicians and patients to monitor disease progression with time but also allow the detection of changes in disease in response to treatment. This section outlines the most commonly used OA PROMs and highlights their recent advances including the development of the Musculoskeletal Health Questionnaire [133], a PROM that can be used across musculoskeletal conditions including OA, and initiatives to develop patient-reported and passively monitored composite outcome measures. The Western Ontario and McMaster Universities osteoarthritis index (WOMAC) PROM description: The WOMAC [134] is a self-complete or interviewer-administered diseasespecific, tri-dimensional questionnaire for assessing health status and health outcomes in OA of the knee and/or hip. The questionnaire covers the dimensions of pain (five items: during walking, using stairs, in bed, sitting or lying and standing upright), stiffness (two items: after first waking and later in the day) and physical function (activities of daily living [ADLs]) (17 items including using stairs, rising from sitting, standing, bending and walking) for the past 48 hours. Scoring and psychometric properties: WOMAC item response options are ‘None’ (score 0), ‘Mild’ (1), ‘Moderate’ (2), ‘Severe’ (3) and ‘Extreme’ (4). Individual scale scores for pain range from 0 to 20, stiffness 0 to 8 and physical function 0 to 68, with a total score derived by summing all three scale scores. Higher scores indicate worse pain, more stiffness and more functional limitations. In patients with knee and hip OA, the content (the extent to which a PROM represents all facets of a dimension) and construct (the degree to which the PROM measures what it claims, or purports, to be measuring) validity for all three WOMAC dimensions are excellent [135]. The internal consistency (the extent to which items that propose to measure the same general dimension produce similar scores) and testeretest reliability (the degree to which PROM results are consistent with time) is less clear and the measurement properties of the stiffness subscale for both patient groups have not been demonstrated [135]. Recent developments: WOMAC scores varied significantly by age, sex and BMI in an unselected general population sample [136]. These values can be used to assess the pain, stiffness and function of patients with OA pre- and post-treatment when compared to general population norms [136]. Clinically important difference post-operative scores have been reported after adjusting for the confounding effects of age, sex and BMI and preoperative WOMAC scores [137]. WOMAC scores have been used to predict capability scores, a broad measure of wellbeing that is increasingly being used in health economic analyses to make decisions about the effectiveness of individual interventions [138]. Knee injury and Osteoarthritis Outcome Score (KOOS) and hip disability and Osteoarthritis Outcome Score (HOOS) PROM description: Although widely used in clinical trials [139e141], the WOMAC is a diseasespecific instrument developed for the elderly to assess OA-induced pain, stiffness and functional limitation. The Knee injury and Osteoarthritis Outcome Score (KOOS) [142]and the Hip disability and Please cite this article as: O'Neill TW et al., Update on the epidemiology, risk factors and disease outcomes of osteoarthritis, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/ j.berh.2018.10.007

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Osteoarthritis Outcome Score (HOOS) [143] PROMs were developed to extend the WOMAC for use in a younger and more active patient groups with knee/hip injuries or knee/hip OA. The development of these PROMs reflects the increasingly younger and more active demographics of people undergoing surgery [144]. In addition to evaluating pain, symptoms and quality of life, the KOOS/HOOS capture a broader range of patient-relevant functional ability using subscales that include leisure activities as well as ADLs [145]. The scales cover five domains: Pain (KOOS nine items; HOOS 10 items), other Symptoms (seven; five items), ADL function (17 items for both scales), Sport and Recreation Function (five items) and Quality of Life (four items) for the past 7 days. Scoring and psychometric properties: Response options are scored from No Problems (score 0) to Extreme Problems (score 4), with scale scores being the total of the individual items. Scores are transformed to a 0e100 scale, with 0 indicating extreme knee problems and 100 indicating no knee problems. The total score should not be calculated. The psychometric properties of the KOOS and HOOS are generally desirable with all scales having excellent content and construct validity and internal consistency [146,147]. Test-retest reliability is adequate for pain, symptoms and ADLs but poor for sport and recreation and quality of life [146,147]. Recent developments: Similar to WOMAC scores, in an unselected population, KOOS scores vary significantly by age, sex and BMI [136]. The HOOS and KOOS have recently been developed in short forms (HOOS JR and the KOOS JR) that have sound psychometric properties [148] and are responsive with time to treatment [149]. A cross-cultural study assessed the performance of the physical function short forms of KOOS and HOOS in participants consulting for total hip or knee replacement surgery in nine countries (Czech Republic, Sweden, the United Kingdom, Australia, Canada, France, the Netherlands, the United States of America and Germany). Both measures demonstrated high internal consistency across countries and correlated highly with the WOMAC function subscale (Spearman correlation coefficients KOOS 0.75e0.91 and HOOS 0.76e0.90) [150]. However, the ability of both scales to identify patients achieving a meaningful post-surgical clinical outcome was dependent on the methods used to estimate the minimal clinically important difference and the minimal detectable change [151]. Measure of intermittent and constant osteoarthritis pain (ICOAP e knee and hip versions) PROM description: The ICOAP is a multidimensional OA -specific measure designed to comprehensively evaluate pain in people with hip or knee OA. The ICOAP measures pain intensity; frequency and impact on mood, sleep and quality of life, independent of the effect of pain on physical function [152]. It is intended for use alongside a measure of physical disability. Scoring and psychometric properties: The ICOAP has 11-items: five items measure constant pain and six items measure intermittent pain or ‘pain that comes and goes’ in the past week [152]. Two supplementary questions assess unpredictability of intermittent pain when present. All items have five levels of response. For items asking about intensity, response options range from ‘not at all’ to ‘extremely’. For items about frequency, response options range from ‘never’ to ‘very often’. For the supplementary items asking about predictability of pain, the response options range from ‘never’ to ‘very often’. Both ICOAP scales have excellent content validity and internal consistency [153]. The ICOAP is responsive to changes in OA pain in patients receiving duloxetine [154]and joint replacement surgery [155]. Recent developments: The cross-cultural validity of the ICOAP has been demonstrated [150]. Musculoskeletal Health Questionnaire (MSK-HQ) PROM description: The MSK-HQ is a recently developed 14-item questionnaire that measures symptoms including pain, fatigue and sleep; physical activity levels and symptom impact on ADLs in people with musculoskeletal conditions [133]. The MSK-HQ is intended to be used across musculoskeletal conditions and was developed in consultation with multiple stakeholders including physiotherapists, orthopaedic and rheumatology patients, general practitioners, physiotherapists, orthopaedists, rheumatologists and pain specialists. Scoring and psychometric properties: The MSK-HQ has 14 items, each scored from 0 (biggest impact) to 4 (least impact). The psychometric properties of the MSK-HQ were tested in four validation cohorts of 210 community physiotherapy patients and 360 secondary care patients (150 hip, 150 knee and 60 shoulder) [33]. Please cite this article as: O'Neill TW et al., Update on the epidemiology, risk factors and disease outcomes of osteoarthritis, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/ j.berh.2018.10.007

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The MSK-HQ was acceptable to patients, with complete data available for 537/570 patients (94.2%). Across the Hip, Physiotherapy and Shoulder cohorts, there was approximately 3% missing data increasing to 14.7% in the knee cohort. The convergent validity (the degree to which two measures of constructs that theoretically should be related are in fact related) and test-retest repeatability were high [133]. Composite outcome measures The relationship between the core OA domains of pain, function and quality of life is complex. All three domains fluctuate through time and are intimately related to each other. For example, in knee OA, increased levels of activity may exacerbate knee pain, while, conversely, certain forms of exercise are recognised as having a beneficial effect on knee OA symptoms [156]. Characterising and capturing the inter-relationships between outcome domains and other important predictors of outcome may be important. A recent study demonstrated that among patients receiving tanezumab for knee OA [157], a composite measure comprising the WOMAC pain score together with the use of rescue medication had a modest but non-significant improvement in responsiveness when compared to WOMAC pain alone. Importantly, however, the modest improvement in responsiveness was associated with a 20e40% reduction in the required sample size to detect the improvement. Measuring changing symptoms through time is challenging by using current methods, which are typically based on intermittent capture of data using questionnaires at fixed, spaced, time points, for example, asking a patient to summarise pain for a large time period (such as ‘in the last week’, or ‘generally this month’). Data collection tools that capture more granular data have the potential to increase the power to detect changes and changes across multiple inter-related domains. A pilot study has reported the first-ever use of smartwatch technology to collect pain, function and other data at multiple times per day for 3 months [156]. These developments will give patients and clinicians a clearer understanding of the changes in core OA outcomes and will also allow the integration of passively monitored data (for example, physical activity levels) that would reduce patient reporting burden. Whether these composite outcome measures have improved responsiveness to detect change with time and in response to treatment remains to be investigated. Summary OA is the most frequent form of arthritis and a leading cause of pain and disability. The prevalence of OA increases with age, and the number of people affected is set to increase because of increasing life expectancy. There is important variation in the frequency of OA in different racial and ethnic groups, which may provide clues to the pathogenesis of the disease. Genetic and environmental factors including obesity and trauma are important determinants of disease. The use of validated PROMs is important in clinical and research practice and enables clinicians and patients to monitor disease progression with time and also detect changes in disease in response to treatment.

Key points  Osteoarthritis (OA) is the most common form of arthritis worldwide and a major cause of disability in middle-age and older adults  With the demographic change to a more elderly population, the number of people with OA is set to increase  Genetic and environmental factors including body mass index, smoking and nutrition increase the risk of OA  Heavy but not moderate physical activity increases the risk of knee and hip OA

Please cite this article as: O'Neill TW et al., Update on the epidemiology, risk factors and disease outcomes of osteoarthritis, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/ j.berh.2018.10.007

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Research agenda  The mechanism by which high BMD may increase the risk of OA is not fully understood, and local biomechanical factors and genetic mediators of bone tone turnover should be investigated  The effect of contemporary specific occupational roles on the risk of developing OA requires further research  Patient-reported outcome measures that characterise and capture the inter-relationships between the core outcome domains of pain, function and quality of life should be developed

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Please cite this article as: O'Neill TW et al., Update on the epidemiology, risk factors and disease outcomes of osteoarthritis, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/ j.berh.2018.10.007