Rheumatology 2008;47:239–248 Advance Access publication 28 November 2007 doi:10.1093/rheumatology/kem260 Review Rheumatoid arthritis, cardiovascular disease and physical exercise: a systematic review G. S. Metsios1–3, A. Stavropoulos-Kalinoglou1–3, J. J. C. S. Veldhuijzen van Zanten2,4, G. J. Treharne2,5, V. F. Panoulas2, K. M. J. Douglas2, Y. Koutedakis1,3 and G. D. Kitas2 KEY WORDS: Rheumatoid arthritis, Cardiovascular disease, Dynamic exercise, Aerobic exercise, Physical activity. facilitates management and improvements of outcome in all four of these categories. It helps maintain a healthy life-style, reduce CVD risk factors including obesity [19], dyslipidaemia [20, 21], hypertension [22], diabetes mellitus [23] and possibly even inflammation [24]; it is also effective for preventing acute coronary syndromes [25–32]. Moreover, exercise helps the management of established CVD: both aerobic exercise [33, 34] and resistance training [35] improve myocardial contractility and quality of life in patients with chronic heart failure and produce significant functional benefits in people with intermittent claudication [36]. More importantly, cardiac exercise rehabilitation programmes are an important part in the management of patients after an acute coronary syndrome (ACS) [37] and lead to significantly improved quality of life and reduced mortality rates [38–40]. Interestingly, there is evidence that patients with RA are rarely offered the opportunity to participate in cardiac rehabilitation programmes even after an ACS [3]. This may be, at least in part, because of the specific considerations required when prescribing exercise to such patients. These include: (i) whether the individual is physically able to perform, and psychologically likely to adhere to exercise regimens designed for cardiovascular improvements; (ii) whether RA health professionals are sufficiently aware of the evidence regarding exercise in RA patients and educate their patients accordingly; and (iii) whether existing exercise programmes and facilities can be adapted to cater for the extra needs that people with some degree of physical disability may have. In the present review, we describe briefly the settings and types of exercise used for cardiovascular improvement in the general population. We then present systematic reviews of aerobic exercise interventions in RA and of the factors that may influence adherence to exercise in this disease. Finally, we give suggestions for exercise interventions suitable for improving the cardiovascular profile of people with RA and propose areas for future research in the field. Introduction Rheumatoid arthritis (RA) associates with increased morbidity and mortality from cardiovascular disease (CVD) [1], most of which is due to greater prevalence [2] and worse outcome [3] of ischaemic heart disease, largely attributed to accelerated atherosclerosis. The exact processes leading to this phenomenon remain undetermined. Much attention has been paid to the potential role of high-grade systemic inflammation [4] and its vascular and metabolic effects [5]. Sometimes this takes the focus away from the indisputable fact that classical modifiable CVD risk factors— such as hypertension [6, 7], dyslipidaemia [8], insulin resistance/ metabolic syndrome [9], obesity [10], physical inactivity [11] and smoking [12]—are highly prevalent but under-investigated and suboptimally managed in this group of patients [13]. Even though these risk factors are not sufficient to explain the entire magnitude of CVD morbidity and mortality in RA [2], they represent an easily identifiable target for intervention, using both pharmacological [14–16] and behavioural approaches [17, 18]. Exercise is one of the most important behavioural interventions that can have a major beneficial impact on the likelihood to develop, suffer symptomatically or die from CVD. In the context of CVD, people, including those who have RA, could be divided schematically into four categories: those who have neither CVD nor any significant risk factor burden for it; those who have risk factors but no clinical evidence of CVD; those who have clinically apparent vascular and cardiac disease but have not suffered a lifethreatening acute cardiovascular event such as a myocardial infarction (MI); and those who have survived an acute cardiovascular event. There is overwhelming evidence that, in the general population and several at risk subpopulations, exercise provides significant physical and psychosocial benefits, and 1 University of Wolverhampton, School of Sport, Performing Arts and Leisure, Walsall, 2Department of Rheumatology, Dudley Group of Hospitals NHS Trust, Russells Hall Hospital, Dudley, West Midlands, UK, 3Research Institute in Physical Performance and Rehabilitation, Centre for Research and Technology Thessaly, Trikala, Greece, 4School of Sport and Exercise Sciences and 5School of Psychology, University of Birmingham, UK. Methods After taking into consideration an evidence-based tool for literature searching specifically for RA [41], six databases [Medline, Cochrane Library, Cumulative Index to Nursing & Allied Health Literature (CINAHL) research database, Google Scholar, Excerpta Medica database (EMBASE) and Physiotherapy Submitted 6 May 2007; revised version accepted 28 August 2007. Correspondence to: G. S. Metsios, University of Wolverhampton, Walsall, West Midlands. E-mail: gm@wlv.ac.uk 239 ß The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org Downloaded from https://academic.oup.com/rheumatology/article/47/3/239/1774371 by guest on 04 June 2022 This systematic review investigates the effectiveness of exercise interventions in improving disease-related characteristics in patients with rheumatoid arthritis (RA). It also provides suggestions for exercise programmes suitable for improving the cardiovascular profile of RA patients and proposes areas for future research in the field. Six databases (Medline, Cochrane Library, CINAHL, Google Scholar, EMBASE and PEDro) were searched to identify publications from 1974 to December 2006 regarding RA and exercise interventions. The quality of the studies included was determined by using the Jadad scale. Initial searches identified 1342 articles from which 40 met the inclusion criteria. No studies were found investigating exercise interventions in relation to cardiovascular disease in RA. There is strong evidence suggesting that exercise from low to high intensity of various modes is effective in improving disease-related characteristics and functional ability in RA patients. Future studies are required to investigate the effects of exercise in improving the cardiovascular status of this patient population. 240 G. S. Metsios et al. Exercise for the prevention and management of cardiovascular disease The increasing incidence and prevalence of CVD, together with its socioeconomic impact, have raised the need for early and effective prevention strategies (e.g. comprehensive screening and education) regarding relevant lifestyle modifications. Exercise has been identified as one of the most important behavioural strategies for CVD prevention. Specific guidelines have been developed about the required amount and intensity of daily and weekly physical activity [43], and its importance is emphasized by several campaigns promoting an active lifestyle, including those by the British Heart Foundation. Any physical activity is better than no, or little, physical activity. The overall physiological adaptations that occur as a result of exercise [44] provide protection against CVD mortality, even in the presence of well-established CVD risk factors [45, 46]. CVD mortality is lower in highly fit than in moderately fit individuals [47], while physical inactivity is an independent risk factor for the development of CVD [48, 49]. Even though cardiorespiratory fitness may have a familial component [50], it can be increased significantly by exercise training, regardless of age, gender, race and initial fitness levels [51]. The required activity levels can be accrued through formal training programmes or leisure-time physical activities [52]. Moreover, supervised exercise programmes are more effective compared with non-supervised exercise [53, 54], most likely due to greater adherence. Great controversy still exists about the optimum amount of exercise for eliciting the greatest cardiovascular benefit. Different exercise intensity [55, 56] and duration [57], as well as various combinations of them [58], may have different impacts on the magnitude of cardiorespiratory fitness improvement. Most authors agree that there is a dose–response relation between the amount of exercise, all-cause and cardiovascular mortality [55, 57, 59]. The greatest potential for reduced mortality is in sedentary individuals (such as many RA patients), in whom even slight increases in daily physical activity are beneficial [59, 60]; for more active individuals, higher levels of intensity should be pursued [59]. Depending primarily on the starting levels of physical activity, cardiovascular fitness has been reported to increase by 8–51% following an exercise intervention [57, 59, 61–63]. Moderate-intensity exercise of long duration appears to elicit the most benefit on CVD risk and mortality [55, 56, 58–60]. Current guidelines by the American College of Sports Medicine (ACSM) suggest that an individual should engage in exercise at least three times a week, at an intensity of 60–80% of maximum oxygen uptake (VO2max), for at least 20–30 min, in order to experience significant improvements in cardiorespiratory fitness and optimum cardiovascular benefits [43]. In terms of caloric expenditure, this can be translated to 1000–2000 kcal/week [64]. These calories can be expended in either continuous exercise or accumulated from several short bouts of exercise during a day [64–66]. Aerobic exercise is the most appropriate, but this can be supplemented by low-to-moderate intensity resistance training [65, 67]. The exercise regimen should be reconsidered regularly, usually every 4–6 weeks, based on the principles of exercise periodization [68] so that participants continue to improve their performance. Exercise in RA RA manifestations include pain, stiffness, structural joint damage, bone density loss and muscle weakness [69]. As a result, a large proportion of patients exhibit decreased range of movement of the affected joints and general functional limitation in performing daily physical tasks: this may significantly compromise their fitness levels compared with people of the same age and sex [70]. RA patients’ fear for disease aggravation and an indefensible traditional approach of rheumatology health professionals to recommend exercise restriction may account for the inactive lifestyle of this population [70, 71]. It is now established that welldesigned physical exercise programmes promote prolonged improvements [72–74] without inducing harmful effects on disease activity and joint damage [71, 75–77]. Thus far, the main objectives of exercise therapy in RA have been to maintain functional ability and improvement of physical capacity [78]. Exercise programmes with the specific purpose of improving cardiovascular fitness and reduced CVD mortality have attracted only minimal attention in this population. Resistance training Conventional resistance exercise programmes consisting of low-impact isometric and range-of-motion exercises have been repeatedly utilized in RA. The application of low-to-moderate intensity strength exercise in RA patients increased physical capacity [79, 80] without exacerbating pain or disease activity [81]. However, high-intensity resistance exercise programmes represent a more effective means for increasing muscular strength compared with low-intensity training and range-of-motion exercises, without any evidence of aggravation of joint symptoms [82]. Highintensity exercise has even been reported to decelerate joint damage in individuals with RA compared with non-exercising RA patients [83, 84], although this remains controversial [85, 86]. Some patients with extensive structural damage may have to refrain from activities that include significant loading of the damaged joints [87]. Well-constructed progressive resistance exercise is an effective and safe intervention for stimulating muscle growth in patients with RA and may even reverse rheumatoid cachexia [88]. This metabolic abnormality, which affects nearly two-thirds of all individuals with RA, is characterized by involuntary loss of muscle mass and progressive increase of fat mass in the presence of stable or even slightly decreased weight [89]. The exact underlying mechanisms are not entirely clear [90]: possible Downloaded from https://academic.oup.com/rheumatology/article/47/3/239/1774371 by guest on 04 June 2022 Evidence Database (PEDro)] were searched to identify publications from 1974 to December 2006 in English regarding RA and exercise interventions. The Medical Subject Heading (MeSH) terms ‘physical activity’, ‘training’ and ‘exercise’ were employed in combination with ‘rheumatoid arthritis’. Initial searches identified 1342 articles (Supplementary Fig. S1, available at Rheumatology Online). Full articles were retrieved for assessment if the information in the abstract fulfilled both of the following criteria: (i) studying any aerobic or aerobic combined with resistance exercise intervention; and (ii) involving RA patients. Studies incorporating only participants with various types of inflammatory arthritis, degenerative arthritis or other inflammatory or connective tissue diseases were excluded. If the title and abstract did not provide sufficient information for this process, then the full-text manuscript was examined. Conference proceedings were not included in the review. The quality of the identified randomized controlled trials (RCTs) was assessed using standardized procedures as previously described [42]. Due to the limited number of RCTs for certain types of exercise (e.g. dance), crosssectional and non-randomized longitudinal studies are also presented in the tables. However, the main conclusions and recommendations in this review are based on the results of RCTs. For adherence to exercise in RA, keyword searches of Medline were carried out using the terms ‘exercise’ and all root variations on ‘adherence’ (e.g. ‘nonadherent’) and ‘compliance’ (e.g. ‘complying’) in combination with ‘rheumatoid arthritis’ (Supplementary Table S1, available at Rheumatology Online). Half of the identified studies were interventions with a focus on exercise component, and the majority contained only limited information on the role of adherence/compliance. Exercise and rheumatoid arthritis contributing factors not only include the overproduction of inflammatory cytokines such as TNF-a [89] but also physical inactivity [91, 92]. Non-RCTs investigating the effects of resistance training in RA differ widely in training regimens, methodological approaches and outcomes, making any conclusions difficult. The effectiveness of strength training lies on the quality and quantity of its application. Indeed, incorrect application of exercise frequency and intensity may not induce improvements in muscular strength; according to the ACSM [93], a successful muscular strength training programme for older populations or individuals with sedentary lifestyles should incorporate at least two sessions per week, involve 8–10 exercises for different muscle groups and allow completion of one set of 10–15 repetitions per exercise. RCTs complying to these recommendations have revealed significant increases in functional ability [74, 84, 94] and muscular strength [75], without exacerbating existing joint damage [73, 95] in patients with RA. 241 appears to consistently induce beneficial effects in aerobic capacity, functional ability and muscle strength. Dance. The effects of dance exercise have been investigated in many non-randomized trials (Table 3), which suggest improvements in aerobic capacity, walking ability, muscular strength [115–117] and psychological parameters, such as anxiety and depression [115, 118]. The only randomized trial involving dance as an intervention in RA patients revealed that despite no significant changes in bone mineral density and disease activity, functional capacity and physical activity were significantly improved [119]. Aerobic training Patients with RA are less active, and therefore less physically fit, compared with healthy individuals of the same age [70, 96]. The most frequently used mode of aerobic exercise training in studies involving RA patients is cycling, followed by aquatic exercise, aerobic dance and walking/running. Cycling. Cycling is a non-weight-bearing aerobic activity where participants utilize large muscle groups of the lower extremity. It can be performed both in clinical settings as well as outdoors, either individually or in groups [97]. Indoor cycles can be modified to accommodate the needs of almost every RA patient [98] and can be effective even when the patients are minimally supervised [99]. An overview of the studies using cycling is provided in Table 1. Although individual studies vary in exercise frequency and overall duration of the intervention, cycling Walking and running. Walking has been used as an intervention for improving patients’ disease status [108, 121, 122], for the assessment of functional ability via gait analyses [123–125] or walking tests [126], and as a method to predict maximal oxygen uptake [127]. Walking or jogging has been included in training programmes without specifying the exact intensity, duration and frequency, but no RCTs based on walking or running as the main mode of exercise have been conducted TABLE 1. Interventional training regimens in patients with rheumatoid arthritis—cycling programmes Cycling programmes EG CG Main outcomes Ekblom et al. [100, 101] Author [reference] 34 RA DS ¼ 25–40 min Intensity ¼ 50–70% of HRmax Frequency ¼ 5 d/wk, twice daily PD ¼ 5 wk and 6 months Rehabilitation programme Acute increase in aerobic capacity, walk test No change in pain perception Long term ¼ increase in aerobic capacity, muscle strength 2 Harkcom et al. [102] 17 RA DS ¼ 15, 25 or 35 min Intensity ¼ 70% of HRmax Frequency ¼ 3 d/wk PD ¼ 12 wk Routine activities Acute increase in aerobic capacity, exercise tolerance Decrease in disease activity 2 Karper and Evans [103] 1 RA DS ¼ 20–30 min Intensity ¼ 50–70 Watts Frequency ¼ 3 d/wk PD ¼ 14 wk Improvement of physiological and psychological status Case study Lyngberg et al. [104] 18 RA DS ¼ 15–45 min Intensity ¼ 50–70% of HRmax Frequency ¼ 2 d/wk PD ¼ 8 wk Routine activities Acute decrease in disease activity Strength and aerobic status not reported No randomization Baslund et al. [105] 18 RA EG ¼ 8 CG ¼ 8 DS ¼ 15–30 min Intensity ¼ 80% of HRmax Frequency ¼ 4–5 d/wk PD ¼ 8 wk Current physical activities Increase in aerobic capacity No changes on the immune system (blood mononuclear cells, proliferative response, natural killer cell activity) 2 Lyngberg et al. [94] 24 RA EG ¼ 12 CG ¼ 12 DS ¼ 45 min Intensity ¼ 50–70% of HRmax Frequency ¼ 2 d/wk PD ¼ 3 months Current activities Increase in functional capacity and strength No significant differences were observed in ESR, number of tender joints and morning stiffness 2 n Quality d/wk, day/week; RA, rheumatoid arthritis; EG, intervention for experimental group; CG, intervention for control group; DS, duration of session in minutes; PD, programme duration; HRmax, maximal heart rate in beats per minute; ESR, erythrocyte sedimentation rate; n, number of participants. Downloaded from https://academic.oup.com/rheumatology/article/47/3/239/1774371 by guest on 04 June 2022 Aquatic. Different types of water-based exercises such as aqua-aerobics and deep-water running have been applied in people with RA (Table 2). The in-water environment is thought to provide the ideal means for exercising in this population, as weight-bearing is minimized due to buoyancy [106]. This is extended by the general belief of patients that this type of exercise improves their functional ability [107]. Most of the available evidence suggests that aquatic exercise does improve aerobic capacity [108–110], muscular strength [85, 111] and psychological status [109]. The RCT with the larger number of RA patients combining both warm water immersion and exercise revealed significant improvements, as assessed by the Arthritis Impact Measurement Scales 2. However, this study did not include a laboratory-based evaluation of physical activity [109]. G. S. Metsios et al. 242 TABLE 2. Interventional training regimens in patients with rheumatoid arthritis—aquatic programmes Aquatic programmes Author [reference] EG n CG 8 RA Water exercise Stenstrom et al. [85] 60 RA DS ¼ 30–40 min Frequency ¼ 1 d/wk PD ¼ 4 yrs Hansen et al. [86] 75 RA EG ¼ 45 CG ¼ 15 Minor and Hewett [113] Results Quality Increase in maximal quadriceps strength Increase in aerobic capacity No randomization Medical treatment Increase in activity level, grip strength No changes functional/psychological status. Controls had significantly more admittances for acute hospital care No randomization DS ¼ 45–90 min Frequency ¼ 3 d/wk PD ¼ 2 yrs Normal treatment No effect of training on disease activity and damage progression 2 42 RA EG ¼ 20 CG ¼ 22 DS ¼ NS Intensity ¼ NS Frequency ¼ 3 d/wk PD ¼ 12 wk Received no attention apart from the testing Improved aerobic capacity and exercise tolerance No randomization Rintala et al. [114] 34 RA EG ¼ 18 CG ¼ 16 DS ¼ 45–60 min Intensity ¼ individualized Frequency ¼ 2 d/wk PD ¼ 24 sessions Normal daily activities Improved muscle strength and mobility No increases in aerobic capacity 1 Hall et al. [109] 139 RA DS ¼ 30 min Intensity ¼ NS Frequency ¼ 2 d/wk PD ¼ 3 months Seated immersion Physical (AIMS2) and psychological benefits (mood and tension) were apparent in all groups Hydrotherapy resulted in the greatest improvements 2 Sanford-Smith et al. [111] 24 RA DS ¼ 25–60 min Intensity ¼ 70% of HRmax Frequency ¼ 3 d/wk PD ¼ 10 wk ROM and isometric exercises Increase in both grip strength and exercise tolerance and decrease in ESR Trend for improved HAQ 2 Bilberg et al. [107] 46 RA EG ¼ 20 CG ¼ 26 DS ¼ 45 min Frequency ¼ 2 d/wk PD ¼ 12 wk Normal activities No changes in aerobic capacity Increased perception of physical function and muscular function 3 d/wk, day/week; n, number of participants; RA, rheumatoid arthritis; EG, intervention for experimental group; CG, intervention for control group; DS, duration of session in minutes; PD, programme duration; NS, not specified; HRmax, maximal heart rate in beats per minute; ROM, range-of-motion; AIMS2, arthritis impact measurement scales 2; ESR, erythrocyte sedimentation rate; HAQ, health assessment questionnaire. TABLE 3. Interventional training regimens in patients with rheumatoid arthritis—dancing programmes Dancing programmes Author [reference] n EG Perlman et al. [118] 43 RA DS ¼ 30–60 min Intensity ¼ 60–70% of HRmax Frequency ¼ 2 d/wk PD ¼ 16 wk Noreau et al. [115] 29 RA DS ¼ 30–60 min Intensity ¼ 50–70% of HRmax Frequency ¼ 2 d/wk PD ¼ 12 wk Noreau et al. [116] 10 RA Neuberger et al. [117] CG Results Quality Increase in performance of 50 ft walk Decrease in pain and depression No randomization Increase in performance of 50 ft walk, aerobic power, hamstring strength and mood state Decrease in pain, depression and anxiety No randomization DS ¼ 25–60 min Intensity ¼ 50–70% of HRmax Frequency ¼ 2 d/wk PD ¼ 8 wk Increase in 6 min walk distance and improved psychological state No significant changes in aerobic capacity, disease activity No randomization 25 RA Low impact aerobic dance Decreased fatigue in the patients who participated the most Increased aerobic fitness and grip strength Decreased pain and walk time No significant increases in joint count or ESR No randomization Westby et al. [119] 53 RA women EG ¼ 23 CG ¼ 30 DS ¼ 45–60 min Intensity ¼ NS Frequency ¼ 3 d/wk PD ¼ 12 months Improved functional capacity and activity level BMD did not differ significantly between groups No change in disease activity 2 Moffet et al. [120] 10 RA DS ¼ 45–60 min Intensity ¼ 50–70% of HRmax PD ¼ 8 wk Significant improvement in locomotion ability and walking ability No randomization Counselling sessions Habitual physical activities and therapy n, number of participants; RA, rheumatoid arthritis; EG, intervention for experimental group; CG, intervention for control group; DS, duration of session in minutes; PD, programme duration; NS, not specified; HRmax, maximal heart rate in beats per minute; BMD, bone mineral density; d/wk, day/week. Downloaded from https://academic.oup.com/rheumatology/article/47/3/239/1774371 by guest on 04 June 2022 Danneskiold-Samsoe et al. [112] Exercise and rheumatoid arthritis in RA. Interestingly, a case study has described a female with RA who completed a whole marathon run following a training programme [128]. Combination of aerobic and strength training. The com- Adherence to exercise in RA Consistent engagement in an exercise regimen is essential to reach improvements in fitness and physical well-being as well as psychological benefits in people with RA. We therefore carried out a systematic investigation of the evidence as to whether RA patients adhere to exercise regimens and what factors may influence this. In general, adherence/compliance has either been mentioned in relation to lack of long-term continuation of exercise after an intervention [139] or has been investigated in exercise regimes not specifically targeted at RA patients [99, 140–148]. This has made it difficult to reach any definitive conclusion [139, 149–158]. The Ottawa Panel’s meta-analysis [154] reviewing previous RCTs of exercise regimens for RA patients demonstrated that adherence/compliance was included as an outcome only in two studies [148, 159]; the first was excluded from the metaanalysis for being a head-to-head study rather than a fully controlled study (it assessed dynamic muscle training vs progressive muscle relaxation) [148]; the second was excluded for having adherence as the sole outcome with little specific detail of the content of the (hand only) exercise intervention [159]. Other studies can also be criticized for inadequate-sized samples, short follow-up, inappropriate control conditions and poor conformity with the interventions [151]. Long-term adherence may be particularly important as a 12-week RCT comparing dynamic exercise with isometric and range-of-motion exercises among RA patients found that benefits for aerobic capacity and strength were lost another 12 weeks after the intervention [129]. O’Grady et al. [153] also stated that long-term adherence would be required for sustained cardiovascular benefits in RA patients, but none of the studies they reviewed had addressed this. General patient education has been reported to be effective in increasing the time spent exercising [141, 142]; however, this is not a consistent finding [146]. It seems that increased adherence to exercise associates with lower baseline functional disability and disease activity [160] as well as the baseline levels of physical activity and fatigue [99]. Social factors, such as support of friends, significantly contribute to increased adherence to exercise regimens [145]. This suggests that appropriate regimens should be chosen for patients with more severe disease; dance sessions, for example, have high attendance [120], which is potentially due to the relatively low demands of this mode of exercise together with its social component. Indeed, tailoring exercise regimens has been suggested to improve adherence [144, 153]. In summary, adherence to exercise has not been adequately studied in RA. High-quality evidence is rare, and appears to suggest that well-controlled disease, better functional ability and strong social structure may facilitate adherence to exercise by patients with RA. Rigorous investigations are required to test whether tailoring exercise regimens around these considerations improves long-term adherence and goes on to improve cardiovascular outcomes for these patients. RA, cardiovascular disease and exercise Suggestions for future practice and research We propose the systematic introduction of exercise training as part of the routine multidisciplinary care of patients with RA, with the specific aim of reducing cardiovascular risk and preventing or managing CVD. This will require further research, adaptation of existing knowledge and resources where available, as well as development of new services. Education on the cardiovascular aspects of rheumatoid disease and the role of exercise in preventing CVD and managing RA itself is a major area for future research and clinical practice development; this needs to be targeted both to patients and to healthcare professionals, aiming to achieve not just improved knowledge but mainly sustained lifestyle changes. This may require a combination of approaches, including behavioural approaches, involving several healthcare professionals [161]. It can link in with the further research required into ways of optimising long-term adherence to an active lifestyle and exercise regimes in this population. The short- and longer-term effects of different exercise regimens on important metabolic factors and on vascular function need to be specifically investigated in the RA population. These have never been researched in any populations characterized by ‘high grade’ systemic inflammation, where their regulation may be under overwhelming pressure from inflammatory networks [4] rendering them less susceptible to beneficial change through exercise. Ultimately, long-term RCTs are needed to show whether structured exercise programmes can be adhered to in the long term, provide sustained cardiovascular benefits and reduce CVD mortality in RA. In the meantime, a pragmatic approach can be taken, building upon existing infrastructure, knowledge and expertise. Rheumatology clinical nurse specialists [162], liaising with their cardiology counterparts and local cardiac rehabilitation services, can incorporate the important role of exercise in their RA patient education programmes. Equipment and expertise available in cardiac rehabilitation centres and community fitness clubs can be adopted to provide exercise opportunities and classes for people with variable (and changing) degrees of physical disability, such as those with RA. Exercise can then be ‘prescribed’ on the basis of a person’s exact needs. In Fig. 1, we propose a general schema of the factors that need to be considered in any patient with RA, and their possible operationalization, with regard to the main objectives of their personalized exercise regimen. This includes two main categories of factors: (i) cardiovascular status and objectives; and (ii) overall and specific physical ability to exercise, related to RA status. We suggest as general principles that: (i) exercise is part of the general management of the RA patient and can be facilitated by other interventions (e.g. pharmacological, educational, behavioural); (ii) its main targets are first the attainment and maintenance of optimal (for the individual patient) function of the musculoskeletal system, which can then facilitate exercises focused on cardiorespiratory fitness; and (iii) exercise is tailored to the individual (although it can be delivered in a group environment), taking into account their baseline fitness and physical ability as well as their personal preferences and objectives, so that ideally a concordance of objectives can be achieved between the patients and the therapist [162]. Cardiovascular status. We suggest a schematic division into those in whom exercise is aimed at reducing/managing CVD risk and those in whom it is incorporated in the management of existing CVD (before or after an acute coronary syndrome). Downloaded from https://academic.oup.com/rheumatology/article/47/3/239/1774371 by guest on 04 June 2022 bination of intensive aerobic and strength training has been the most widely used exercise regimen in recent research in RA and produces an effective physical stimulus to achieve desirable physiological adaptations (Table 4). An RCT by van den Ende and colleagues [129] has highlighted that combining intense aerobic and resistance training can lead to significant enhancement in both cardiorespiratory capacity and muscular strength. Other RCTs support the beneficial effects of this type of exercise in patients with recent-onset [95], active [129] or inactive RA [130]. As a result of these findings, the American College of Rheumatology updated the treatment guidelines to introduce dynamic exercise as an effective means for the management of RA [131]. 243 G. S. Metsios et al. 244 TABLE 4. Interventional training regimens involving the combination of dynamic aerobic and strength exercises in patients with rheumatoid arthritis Programme Author [reference] n EG 10 RA DS ¼ 23 h/wk Aerobic ¼ 50–70% of VO2max Strength ¼ NS PD ¼ 7 months Nordemar et al. [83] 46 RA EG ¼ 23 CG ¼ 23 DS ¼ 30–60 min Intensity ¼ varied according to the patient PD ¼ 4–8 yrs Stenstrom [133] 42 RA van den Ende et al. [129] CG Results Quality Small increase in muscle fibre size Decrease in pain Increase in muscular strength No changes in VO2max No randomization Pharmaceutical therapy EG less progression of joint damage than CG Increase in walking ability and quadriceps torque No changes in oxygen consumption and heart rate 1 DS ¼ NS Intensity ¼ NS Frequency ¼ 5 d/wk PD ¼ 12 wk Same as EEG group with different instructions Better self-efficacy, functional capacity, less pain, lowered Ritchie index and increased mobility in the EEG group 2 100 RA 3 EG each n ¼ 25 CG ¼ 25 DS ¼ 60 min Intensity ¼ 70–85% of HRmax Frequency ¼ 3 d/wk PD ¼ 12 wk ROM home exercises Intensive dynamic training is more effective than all other groups in increasing aerobic fitness, joint mobility and strength 2 Komatireddy et al. [134] 49 RA EG ¼ 25 CG ¼ 24 Circuit training DS ¼ 20–27 min Strength ¼ NS Frequency ¼ 3 d/wk PD ¼ 12 wk Habitual activities Increase in functional capacity No significant change in aerobic fitness 2 Hakkinen et al. [74] 65 RA EG ¼ 32 CG ¼ 33 DS ¼ 45 min Aerobic ¼ NS Strength ¼ 50–70% of MVC Frequency ¼ 2 d/wk PD ¼ 12 months Recreational physical activities and ROM exercises Increases of EG in all muscle groups examined greater than that in CG No effect in disease activity No changes in BMD between groups 2 van den Ende et al. [130] 64 RA EG ¼ 34 CG ¼ 30 DS ¼ NS Aerobic ¼ 60% of HRmax Strength ¼ 70% of MVC Frequency ¼ 3–5 d/wk PD ¼ 24 wk ROM and isometric exercises EG: physical and muscular strength improvement, decrease in disease activity CG: decrease in disease activity, muscular strength improvement (less than EG) 3 Hakkinen et al. [135] 70 RA EG ¼ 35 CG ¼ 35 DS ¼ 30–45 min Aerobic ¼ NS Strength ¼ 50–70% of MVC Frequency ¼ 2 d/wk PD ¼ 24 month ROM and stretching exercises Increased strength, HAQ, walking speed more pronounced in EG BMD increased in EG and decreased in CG 3 de Jong et al. [73] 309 RA EG ¼ 151 CG ¼ 158 DS ¼ 90 min Frequency ¼ 2 d/wk Aerobic ¼ 70–90% of HRmax Strength ¼ NS PD ¼ 2 yrs Habitual physical activity Significant improvement in functional ability in EG No radiological damage in any group 3 Hakkinen et al. [136] 70 RA EG ¼ 35 CG ¼ 35 DS ¼ NS Frequency ¼ 2 d/wk Aerobic ¼ NS Strength ¼ 50–70% of MVC PD ¼ 24 months ROM and stretching exercises Improvement in strength, HAQ and overall function capacity 3 Hakkinen et al. [137] 23 RA DS ¼ 45–60 min Frequency ¼ 3 d/wk Aerobic ¼ progressive load Strength ¼ progressive load PD ¼ 21 wk The same intervention in healthy individuals Significant muscular strength, walking speed, vertical jump and aerobic capacity No randomization de Jong et al. [138] RAPIT programme 309 RA EG ¼ 151 CG ¼ 158 DS ¼ 90 min Frequency ¼ 2 d/wk Aerobic ¼ 70–90% of predicted HRmax Strength ¼ NS PD ¼ 2 yrs Habitual physical activity Exercise results in slowing down in the loss of BMD at the hip 3 de Jong et al. [84] RAPIT programme 309 RA EG ¼ 151 CG ¼ 158 DS ¼ 90 min Frequency ¼ 2 d/wk Aerobic ¼ 70–90% of predicted HRmax Strength ¼ NS PD ¼ 2 yrs Habitual physical activity No progression of hand and feet damage is not increased 3 Hakkinen et al. [75] 70 RA EG ¼ 35 CG ¼ 35 DS ¼ 45 min Frequency ¼ 2 d/wk Aerobic ¼ NS Strength ¼ 50–70% of MVC PD ¼ 2 yrs follow-up after 5 years ROM and stretching exercises Strength gains during the 2-yr training programme were maintained More favourable development of BMD in EG group Radiological damage remained low 3 (continued) Downloaded from https://academic.oup.com/rheumatology/article/47/3/239/1774371 by guest on 04 June 2022 Nordemar et al. [132] Exercise and rheumatoid arthritis 245 TABLE 4. Continued Programme Author [reference] EG n CG Results Munneke et al. [87] RAPIT programme 309 RA EG ¼ 151 CG ¼ 158 DS ¼ 90 min Habitual physical activity Dynamic training accelerates Frequency ¼ 2 d/wk joint damage progression in Aerobic ¼ 70–90% of HRmax patients with pre-existing Strength ¼ NS extensive damage PD ¼ 2 yrs Hakkinen et al. [126] 23 RA 12 healthy matched controls DS ¼ 30–45 min Frequency ¼ 2–3 d/wk Aerobic ¼ NS Strength ¼ 50–70% of MVC PD ¼ 21 wk The same as EG group Significant increases in VO2max, muscle strength and EMG activity in both groups Quality 3 No randomization Cardiovascular status Reducing/managing CVD Risk Little risk Higher risk Existing CVD Pre-acute event Post-acute event Baseline cardiorespiratory fitness Available infrastructure Little inflammation Little damage Personal preferences RA patient Little inflammation Much damage Good physical ability Active inflammation Little damage Active inflammation Much damage Limited physical ability Rheumatoid arthritis status FIG. 1. Major considerations in designing individualized exercise training in patients with rheumatoid arthritis. Exercise for the latter has already been discussed in previous sections (but will need to be adopted according to the individual patient’s physical constraints, as discussed subsequently). For the former, the ACSM has developed a risk stratification algorithm, in order to optimize the safety of participation in exercise programmes. This is based on consideration of the following specific risk factors: total cholesterol >6.5 mmol/l; smoking; family history of CVD; sedentary lifestyle; diabetes mellitus (blood glucose >6.7 mmol/l); systolic blood pressure >140 mmHg and overweight or obesity with BMI >25 kg/m2: individuals with less than three of these components are considered at low risk for developing CVD-related complications while exercising, whereas those with three or more of these components are at higher risk [43]. The thresholds for some of these risk factors may need to be altered for the RA population: for example, total cholesterol may be spuriously low during periods of active RA [8] and BMI thresholds for overweight reduced to 23 kg/m2, as recently described [10]. Based on this, exercise of appropriate mode, intensity, duration and frequency can be designed to provide adequate workload for cardiovascular benefits [68]. There is a wide range of options, but current ACSM guidance for optimum cardiovascular benefits and enhanced cardiorespiratory capacity includes regular participation (>3 times weekly) at sufficient intensities (60–80% of VO2max) and time (at least 20–30 min) [43]. Thus, determining the current level of fitness (usually by a graded exercise test, during which the workload is increased at regular intervals until self-reported exhaustion) prior to starting an exercise intervention, will help to establish the appropriate workload for each individual and to refine their personalized exercise programme. Physical ability to exercise. We have schematically divided patients into those with good overall physical ability (mostly those with little current inflammation and little accumulated permanent joint damage); and those with limited physical ability (usually patients with a lot of joint inflammation, a lot of structural joint damage or both). This can help refine the overall multidisciplinary approach, incorporating specific exercise regimens, to their treatment. In the former, pharmacological therapy would be aimed at maintaining good disease control; some range of motion exercises and resistance training could be utilized to maintain a good level of musculoskeletal system mobility and function; and the main focus should be aerobic training aiming at optimizing cardiovascular fitness, to the degree determined by their current levels of fitness and allowed by their cardiovascular risk stratification. Patients in the group with limited physical ability to exercise due to the impact of RA have been subdivided into three subgroups: In those with a lot of current inflammation, but little structural damage, we propose aggressive pharmacological therapy to quickly reduce active inflammation and prevent muscle loss, due Downloaded from https://academic.oup.com/rheumatology/article/47/3/239/1774371 by guest on 04 June 2022 n, number of participants; RA, rheumatoid arthritis; EG, intervention for experimental group; CG, intervention for control group; DS, duration of session in minutes; PD, programme duration; NS, not specified; HRmax, maximal heart rate in beats per minute; ROM, range-of-motion; MVC, maximal voluntary contraction; BMD, ¼bone mineral density; VO2max, maximal oxygen uptake; HAQ, health assessment questionnaire; EMG, Electromyography; d|wk, day|week. G. S. Metsios et al. 246 Conclusions. Surprisingly little has been investigated and published on the role of exercise as a means to control risk and manage CVD in individuals with RA. Focused research is required to identify the optimal regimens, timing and environment for exercise, as well as educational and behavioural interventions that will facilitate long-term adherence to an active lifestyle and/or structured exercise. In the meantime, a pragmatic approach is proposed, incorporating combined range of motion, strength and aerobic training, provided in a patient-specific context as part of the multidisciplinary care of the individual with RA. Rheumatology key messages
Exercise is effective in reversing joint damage in RA patients.
RA-specific considerations should be taken into account when developing exercise programmes aiming to reduce CVD-risk of this population. Acknowledgements Funding: G.S.M. was supported by grants received from the Greek State Scholarships Foundation (IKY). This study was funded by the Dudley Group of Hospitals R&D directorate cardiovascular programme grant and a Wolverhampton University equipment grant. The Department of Rheumatology, Dudley Group of Hospitals, has an infrastructure support grant from the Arthritis Research Campaign (number: 17682). Disclosure statement: The authors have declared no conflicts of interest. Supplementary data Supplementary data are available at Rheumatology Online. References 1 Kitas GD, Erb N. Tackling ischaemic heart disease in rheumatoid arthritis. Rheumatology 2003;42:607–13. 2 del Rincon ID, Williams K, Stern MP, Freeman GL, Escalante A. 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