Rheumatol Int (2009) 30:147–158 DOI 10.1007/s00296-009-1090-5 REVIEW ARTICLE A systematic review of the eVects of dynamic exercise in rheumatoid arthritis Andrew P. Cairns · Joseph G. McVeigh Received: 20 March 2009 / Accepted: 7 August 2009 / Published online: 22 August 2009  Springer-Verlag 2009 Abstract Exercise is commonly used in the management of patients with rheumatoid arthritis (RA); however, there is little consensus in the literature to support its use. This systemic review aimed to determine the eVects of dynamic exercise on patients with RA. A systematic search of Medline (1949–2007), Cinahl (1982–2007), Embase (1974–2007) and Cochrane library was performed for randomised-controlled trials using the keywords “rheumatoid arthritis” and “exercise” or “training” or “sport”. The methodological quality of studies was assessed using a ten-point scale. Eighteen papers relating to 12 diVerent studies met inclusion criteria. The mean methodological quality score was 6.9/10. Studies using aerobic training, strength training and combinations of both were included. Patients with early, stable, and active RA were studied. A number of studies reported improvement in muscle strength, physical function and aerobic capacity with dynamic exercise. Some studies also reported improvements in disease activity measures, and small improvements in hip bone mineral density. One study reported signiWcantly less progression of small joint radiographic damage of the feet in the dynamic exercise group. However, one study also reported worse large joint radiographic damage in patients using dynamic exercise who had pre-existing large joint damage, though this was a A. P. Cairns (&) Department of Rheumatology, Musgrave Park Hospital, Belfast BT9 7JB, Northern Ireland, UK e-mail: andrew.cairns@belfasttrust.hscni.net J. G. McVeigh Health and Rehabilitation Sciences Research Institute, School of Health Sciences, University of Ulster, Jordanstown BT37 0QB, Northern Ireland, UK retrospective analysis. No studies reported worse outcomes for function, disease activity or aerobic capacity with dynamic exercise. Cardiovascular outcomes were not reported in any study, and no data were presented to assess the eVect of exercise on patients with signiWcant underlying cardiovascular disease. This systematic review suggests that the majority of patients with RA should be encouraged to undertake aerobic and/or strength training exercise. Exercise programmes should be carefully tailored to the individual, particularly for patients with underlying large joint damage or pre-existing cardiovascular disease. Keywords Rheumatoid arthritis · Exercise · Rehabilitation · Systematic review Introduction Rheumatoid arthritis (RA) is a chronic, systemic, inXammatory disorder of unknown aetiology that primarily involves joints. Patients with RA suVer increased morbidity and mortality from cardiovascular disease, largely due to accelerated atherosclerosis [1, 2]. This is not all due to traditional cardiovascular risk factors. The vascular eVects of chronic systemic inXammation are thought to play a signiWcant role [3, 4]. Traditionally, patients with active RA were advised to rest from active exercise, particularly during exacerbations [5]. In the last two decades, there has been increasing use of active exercise in patients with RA, with a number of studies looking at the eVect of exercise on outcome measures as diverse as Wtness, muscle strength, bone density, functional scores, disease activity and joint damage [6]. However, this remains a controversial area in rheumatology, with some clinicians discouraging active exercise for patients with 123 148 RA, particularly during times of disease Xare. While the beneWts of exercise for healthy individuals in terms of cardiovascular health are clear, there has been little study of the cardiovascular beneWts of exercise for patients with RA, who already have excess cardiovascular risk, and who have lower baseline levels of activity. A Cochrane review of dynamic exercise therapy for treating RA concluded that dynamic exercise is eVective at increasing aerobic capacity and muscle strength [6]. No detrimental eVects on disease activity and pain were observed at this time; however, the eVects on functional ability and radiological progression were unclear, further there was no examination of the eVect of exercise on cardiovascular outcomes. This Cochrane review [6] published in 2000 included only six studies. In the years since this review was carried out, there have been a number of studies looking at the eVect of diVerent types of exercise on a number of outcome measures in RA. The aim of this review, therefore, was to determine the eVectiveness of dynamic exercise in improving outcomes for patients with RA. Methods A systematic search of Medline (1949–2007) for randomised-controlled trials using keywords “rheumatoid arthritis” and “exercise” or “training” or “sport” limited to human subjects and English language was performed in July 2007. Similar searches were also performed using the Cinahl (1982–2007), Embase (1974–2007) and Cochrane library. Abstracts were scanned and all potentially relevant papers requested for analysis. Existing reviews in the area were also scanned searching for additional references. Inclusion criteria All randomised-controlled trials of adult patients with a conWrmed diagnosis of RA where the intervention included any form of dynamic physical exercise were examined. Primary outcome measures included radiographic damage, swollen and tender joint counts, laboratory measures of inXammation, bone density, functional scores, measures of Wtness and muscle strength, and measures of cardiovascular outcomes. Studies presenting data from mixed groups of patients with diVerent arthropathies were excluded. The analysis is qualitative rather than quantitative because of the wide variation in study subjects, interventions, and outcome measures used. Methodological quality Each study was assessed for methodological quality using 10 criteria (see below and Table 1). These criteria were 123 Rheumatol Int (2009) 30:147–158 modiWed from the Delphi list [7], with reference to similar criteria published by Van den Ende et al. [6], Van Tulder et al. [8], and the Pedro scale [9]. The quality criteria relating to blinding of patient and blinding of care provider were not suitable for intervention involving dynamic physical exercise and were not included in this list. Each criterion was scored yes, no, or unclear with no weighting of results giving a maximum quality score of 10/10. For the purpose of this review, drop out rates of 25% or less were deemed satisfactory. Studies fulWlling seven or more criteria are deemed high quality. Those with less than four out of 10 are deemed low quality: 1. 2. 3. 4. 5. 6. 7. 8. Adequate randomisation. Allocation concealment. Groups similar at baseline. Eligibility criteria speciWed. SuYcient description of intervention. Blinding of outcome assessor. Co-interventions avoided or similar between groups. Presentation of point estimates and measures of variability for primary outcome measures. 9. Drop out rate described and acceptable. 10. Intention to treat analysis. Results Selection of included trials The search strategy yielded 62 potentially relevant papers, from which a total of 46 studies were identiWed. Of these, 18 relevant papers that met inclusion criteria were included in this review. These papers relate to 12 separate studies. All trials were prospective randomised studies, though one paper reports a retrospective subgroup analysis [10]. Study characteristics and outcomes are directly compared in Table 2. Excluded papers Excluded papers and reasons for exclusion are listed in Table 3. Intervention A number of diVerent exercise interventions were used in these studies, including aerobic Wtness training, strength exercises, or combinations of both. With the exception of Bilberg et al.’s study [11], which used moderately intense pool exercise, all exercises were performed on dry land. Rheumatol Int (2009) 30:147–158 149 Table 1 Methodological quality of studies Study Adequate Allocation Groups Eligibility Description Blinding CoPresentation Drop ITT randomisation concealment similar criteria of intervention of outcome intervention of point out analysis at baseline speciWed assessor avoided estimates rate and measures of variability Bilberg et al. [11] Y Y Y Y Y Y Y Y Y N de Jong et al. [12] Y Y N Y Y Y Y Y Y Y de Jong et al. [13] Y Y N Y Y Y Y Y Y Y de Jong et al. [14] Y Y N Y Y Y Y Y Y Y Hakkinen et al. [15] Y U Y Y Y U N Y Y N Hakkinen et al. [16] Y U Y Y Y U N Y Y N Hakkinen et al. [17] Y U Y Y Y U N Y Y N Hakkinen et al. [18, 19] Y U Y Y Y U N Y Y N Harckom et al. [20] Y U N Y Y U Y Y Y U Komatireddy et al.[21] U U Y Y Y Y U Y Y N Lyngberg et al. [22] Y Y Y Y Y Y Y Y Y Y McMeekin et al. [23] U Y Y Y Y Y Y Y Y Y Melikoglu et al. [24] U U Y Y Y Y U Y Y U Munneke et al. [10] Y Y N Y Y Y Y Y Y Y Van den Ende et al.[25] U U Y Y Y N Y Y Y Y Van den Ende et al. [26] Y Y N Y Y Y U Y Y Y U U Y Y Y Y U Y N Y Westby et al. [27] Aerobic exercises The studies by Harckom et al. [20] and Melikoglu et al. [24] used largely aerobic interventions. Harckom et al. [20] studied 20 women with RA aged 27–68 years, of ARA functional class II for 12 weeks. Four intervention groups (3 exercise, 1 control) were used. Exercises were performed on a bicycle ergometer 3 times a week for 12 weeks. Five bouts of exercise per session were performed, each separated by a 1-min rest. The protocols diVered in the initial length of total exercise time, the rate of progression, and the Wnal total duration of activity achieved. The control group continued with routine daily activities. Outcome measures were aerobic capacity (VO2 max), grip strength, 50 foot walk time, muscle strength (knee Xexors and extensors), functional status index, and joint counts (combined tender/swollen score). Melikoglu et al. [24] performed a prospective randomised study of short-term (2 weeks) dynamic exercise therapy versus range of motion (ROM) controls in 40 female patients with non-active rheumatoid disease, functional class I or II, and on stable medication. The intervention was dynamic exercise on a treadmill to achieve 60% of age predicted maximum heart rate. Both groups exercised for Wve sessions per week, 20 min per session, for a total of 2 weeks. An additional healthy (non-RA) control group was also studied but is not included in this analysis. Primary outcome measures were levels of serum insulin-like growth factor (IGF-1), and serum insulin-like binding protein 3 (IGFBP-3). Pain VAS, HAQ, morning stiVness duration, RAI, ESR, and CRP were also recorded. Strength training The studies by Hakkinen et al. [15–19] and McMeekin et al. [23] used primarily strength training interventions. Hakkinen et al. published Wve related papers on the eVect of dynamic strength training on 70 patients (44 female) with early RA [15–19]. None of the patients had commenced treatment with disease modifying drugs or corticosteroids at the beginning of the study. Mean duration of symptoms was 10.5 months at the start of the study. The exercise group performed home dynamic strength training twice weekly for 12 months with rubber bands and dumbbells for upper and lower extremities, abdominal and back muscles. The exercise group is also encouraged to engage in recreational physical activities such as walking, cycling, skiing and swimming two to three times a week. The control group performs ROM and stretching exercises. Recreational activities are allowed except for strength training of any kind. Training diaries are kept by both groups. Hakkinen et al.’s Wrst paper reports results after 1 year [15]. Outcome measures are strength, bone mineral density at hip and lumbar spine by Lunar DEXA, disease activity score (DAS28), pain VAS and functional capacity (HAQ). Hakkinen et al.’s second paper reports results after 123 150 123 Table 2 Study characteristics and outcomes Study Participants Intervention Primary outcomes Positive outcomes for exercise group Bilberg et al. [11] 47 stable RA Moderately intense pool exercises VO2 max, physical SF-36 Index of muscle function, chair test, muscle endurance 9 de Jong et al. [12] 300 stable RA RAPIT: cycling, circuits, game MACTAR, HAQ, Large joint Larsen MACTAR score, VO2 max, muscle strength, HADS score 9 Duration: 2 years RAPIT: cycling, circuits, game Bone density Hip bone density 9 Larsen score (hands & feet) Larsen score (feet) 9 Muscle strength, bone density, DAS28, HAQ Muscle strength, ESR, HAQ, DAS28, 6 Muscle strength, bone density, DAS28, HAQ, Larsen (hands/feet) Hip bone density, HAQ, pain VAS 6 Duration: 2 years Home dynamic strength training Valpar 9 None 6 Muscle strength, DAS28 6 Duration: 2 years (5-year follow-up) Muscle strength, bone density, DAS28, HAQ, Larsen (hands/feet) Cycling VO2 max, muscle strength, VO2 max, joint count 5 Muscle strength, VO2 max, functional status, joint counts Self-reported joint count, night pain, sit-to-stand time, anaerobic threshold 6 Joint counts, walk times, muscle strength, VO2 max, ESR Left ankle strength Muscle strength, HAQ, pain VAS, TUG Peak muscle torque, TUG, pain, HAQ 9 IGF-1 level 6 Duration: 12 weeks de Jong et al. [13] 281 stable RA Quality score/10 Duration: 2 years de Jong et al. [14] 281 stable RA RAPIT: cycling, circuits, game Duration: 2 years Hakkinen et al. [15] 70 early RA Home dynamic strength training Duration: 12 months Hakkinen et al. [16] Hakkinen et al. [17] 70 early RA 70 early RA Home dynamic strength training Duration: 2 years Hakkinen et al. [18, 19] 70 early RA Harckom et al. [20] 20 stable RA Home dynamic strength training Duration: 12 weeks Komatireddy et al.[21] 49 stable RA Circuits Duration: 12 weeks Lyngberg et al. [22] McMeekin et al. [23] 24 elderly fragile RA on steroids 36 stable RA Cycling and dynamic strength training Duration: 3 months Concentric quad/hamstring training Duration: 6 weeks joint counts, functional status 10 40 stable RA Treadmill Duration: 2 weeks IGF-1, IGFBP-3, pain VAS, HAQ, RAI, ESR, CRP Munneke et al. [10] 281 stable RA RAPIT: cycling, circuits, game Large joint radiographic change None. * More progression of large joint Larsen score in patients with pre-existing damage in exercise group 9 VO2 max, muscle strength, VO2 max, joint mobility, 7 Duration: 2 years (retrospective subgroup analysis) Van den Ende et al. [25] 100 stable RA 4 groups: High intensity exercises/cycling; low intensity group exercise; low intensity individual exercise, home ROM Duration: 12 weeks HAQ, joint counts, pain VAS, ESR/CRP muscle strength, swollen joint count Rheumatol Int (2009) 30:147–158 Melikoglu et al. [24] Duration: 12 months Fitness by questionnaire Aerobic dance & low load strengthening exercise 30 stable RA Westby et al. [27] Duration: 30 days Swollen/tender joint count, ESR, bone density, HAQ, Wtness estimation 6 8 Muscle strength Swollen joint count 64 active RA inpatients Van den Ende et al. [26] Isometric/isokinetic exercises and cycling Positive outcomes for exercise group Participants Study Table 2 continued Intervention Primary outcomes Quality score/10 Rheumatol Int (2009) 30:147–158 151 continuing the strength programme for 2 years [16]. Outcome measures reported are strength, bone mineral density at hip and lumbar spine (Lunar DEXA); disease activity (DAS28), pain VAS, functional capacity (HAQ), and also the radiographic Larsen joint score of small joints. Hakkinen et al.’s third paper reports a separate outcome measure (physical function as assessed by the Valpar 9 work sample test) after 2 years in the same group [17]. Hakkinen et al.’s 2004 papers report 5-year follow-up data following the initial 2-year exercise programme [18, 19]. Both papers report muscle strength, radiological damage (Larsen small joint score of hands and feet), function (HAQ), and disease activity (DAS28). Bone mineral density (by DEXA) is reported in the Annals of Rheumatic Disease paper only [19]. McMeekin et al. performed a prospective randomised 6-week study of knee extensor and Xexor muscle training in 36 patients with RA (30 female), with a mean age 50.6 years [23]. The intervention was concentric quadriceps and hamstring training. Sessions were performed every 3 days for a total of 6 weeks, completing 14 sessions in total. Outcome measures were pain VAS, HAQ, timed up and go test (TUG), and peak torque of knee extensor and Xexor muscle activity. Aerobic/strength combinations The following studies used exercise programmes with signiWcant aerobic and strength training aspects: Bilberg et al. [11], the RAPIT programme studies by de Jong et al. [12–14] and Munneke et al. [10], Komatireddy et al. [21], Lyngberg et al. [22], Van den Ende et al. [16, 25], and Westby et al. [27]. Bilberg et al. studied 47 (42 women, 5 men) patients with RA aged 20–65 [11]. Disease duration was 1–5 years, and drug therapy was stable. The intervention was pool exercise twice weekly for 12 weeks. The control group continued normal activities. Outcomes were assessed at 3 months. Primary outcomes were aerobic capacity and physical SF-36. Secondary outcome measures were the chair test, shoulder endurance test, index of muscle function (IMF), and hand grip force. de Jong et al. published four papers from the multicentre RA patients in training (RAPIT) programme [10, 12–14]. This was a 2-year prospective study comparing an intensive exercise programme (RAPIT) with usual care physiotherapy (UC). Three hundred patients with RA (237 women) aged 20–70 were enrolled. All patients were on stable medication, functional class I–III and with no signiWcant cardiopulmonary disease. The RAPIT programme consisted of supervised bi-weekly group exercise of 1.25 h per session. Each session had three parts: bicycle training (20 min), exercise circuit (20 min), sport or game (20 min). Primary 123 152 Table 3 Excluded studies Rheumatol Int (2009) 30:147–158 Study Reason for exclusion Baslund et al. [28] Study group with mixed types of inXammatory arthritis Bearne et al. [29] Control group of healthy subjects Bell et al. [30] Details of intervention not given Brighton et al. [31] Non-dynamic hand exercises only Brus et al. [32] Intervention is education; outcome is compliance with treatment Buljina et al. [33] Non-dynamic hand exercises only Daltroy et al. [34] Pooled data of patients with RA and SLE Ekdahl et al. [35] Baseline and Wnal data not presented numerically Eversden et al. [36] Not dynamic exercise (hydrotherapy) Hakkinen et al. [37] Mixed groups with RA and psoriatic arthritis Hakkinen et al. [38] Healthy control group Hakkinen et al. [39] Mixed groups with RA and psoriatic arthritis Hall et al. [40] Not dynamic exercise (hydrotherapy) Hansen et al. [41] Exercise programme not clearly described Lineker et al. [42] Details of intervention not given (follow-up study of Bell et al. [30]) Lyngberg et al. [43] Numerical values, estimates of variability and p values not given for outcome measures Marcora et al. [44] Not randomised Minor et al. [45] Mixed RA/osteoarthritis groups Minor, Hewett [46] Not randomised MoVet et al. [47] Observational study (no control group) Nordemar [49] Nordemar et al. [48] Not randomised Noreau et al. [50] Not randomised Neuberger et al. [51] Observational study (no control group) Stenstrom et al. [52] Not randomised Stenstrom et al. [53] Intervention compared is cognitive therapy Stenstrom et al. [54] Study group with mixed types of inXammatory arthritis van den Berg et al. [55] Internet study; primary outcome measure is physical activity outcome measures [12] were divided into measures of eVectiveness: functional ability as assessed by the MACTAR and HAQ scores, and safety: Larsen large joints score of radiographic damage. Secondary outcome measures were physical capacity and emotional status (eVectiveness) and disease activity score (DAS4) (safety). Outcomes were assessed after 24 months. The primary outcome measure reported in the paper published in Arthritis and Rheumatism [13] was bone mineral density at the hip and spine (by DEXA) at 2 years. The primary outcome measure in the paper published in the Annals of Rheumatic Disease [14] was radiological joint damage of the hands and feet. Munneke et al. published a retrospective subgroup analysis of the RAPIT programme with the primary outcome measure of the Larsen large joint radiographic score [10]. Komatireddy et al. performed a prospective randomised 12-week study of circuit-based training at home [21]. The control group had no exercise intervention. Forty-nine patients with RA (37 women) were studied. The mean age 123 was 60.5, and patients were functional class II or III. 38 patients were receiving NSAIDs, 28 oral steroids, 48 DMARDs, and 17 combination DMARDs. Home circuit training using resistive exercises and 12–15 reps per set was performed. EYcacy of the exercise programme was assessed by evaluation of changes in muscle strength, cardiopulmonary function (VO2 max, anaerobic threshold), functional ability (50 foot walk, sit-to-stand test, HAQ, arthritis impact measurement scales—AIMS), self-reported health status (pain and fatigue VAS and self-reported joint counts) and disease activity status (physician’s global assessment and tender/swollen joint counts). Lyngberg et al. performed a prospective randomised study of progressive interval training over 3 months in elderly patients with RA on oral steroids [22]. Twenty-four elderly patients who had been treated with low-dose oral steroids for at least 2 years were studied. The mean age was 66.5 years, and mean disease duration 12 years. Patients studied had “slight or moderate” disease activity. Patients with signiWcant heart disease were excluded. The interventions Rheumatol Int (2009) 30:147–158 were aerobic training on an ergometer, dynamic strength training exercises, and stretching exercises. Exercises were performed for 45 min, twice a week. Outcomes (swollen/ tender joint counts, 30 m walk time, grip strength, stair climbing, muscle strength, aerobic capacity, and ESR) were assessed after 2 weeks. In 1996, Van den Ende et al. reported a prospective randomised-controlled study comparing four diVerent exercise programmes in patients with stable RA, all lasting 12 weeks [25]. One hundred patients with RA (63 female), of mean age 52 years, and mean disease duration 10 years, were studied. Four intervention groups, each with 25 patients, are described: high intensity exercise programme (HIE), low intensity group exercise (LIE-gr), low intensity individual exercise (LIE-ind), and a home exercise programme (HE). The following outcome measures were recorded at baseline, after the 12-week exercise programme and after another 12 weeks: aerobic capacity (VO2 max), muscle strength, joint mobility (EPM-ROM score), functional ability (HAQ, Dutch-AIMS, timed 50 feet walk test, timed 10 Xight up and down stair test), disease activity (0–20 swollen joint count, modiWed RAI 0–69, ESR, CRP), and patient VAS scores for pain, morning stiVness, and tiredness. In 2000, Van den Ende et al. reported a prospective randomised-controlled study comparing intensive and conservative exercise programmes in patients admitted to hospital because of active rheumatoid disease [26]. This is a very diVerent patient group to most of the other studies where patients had relatively inactive disease. Sixty-four patients, of mean age 60 years, were studied. Mean disease duration was 8 years. Active disease was deWned by six or more swollen joints and at least two of: morning stiVness greater than 45 min, tender joint count greater than nine, ESR greater than 28. Patients were excluded if they had serious cardiorespiratory disease, knee arthroplasty, or were unable to walk 15 m indoors. All patients had conservative ROM exercises at low pace and isometric exercises of large joints without resistance, four times a week. In addition, the intensive group also had isometric and isokinetic training of knee Xexors and extensors. Intensive group patients also had isometric training of shoulder girdle muscles and performed cycling three times a week for 15 min to 60% of maximum heart rate. The mean admission length was 30 days. Patients were assessed at baseline, 3, 6, 12, and 24 weeks by an assessor blinded to study group. The primary outcome measure was the swollen joint count. Secondary outcome measures were tender joint count, ESR, DAS, patient pain VAS, knee extensor and Xexor strength (isokinetic dynamometer), joint mobility (EPM-ROM scale), HAQ, timed 50 feet walk test, and grip strength (Martin vigorimeter). 153 Westby et al. performed a prospective randomised 12-month study comparing weight bearing, aerobic exercise with usual care in women with RA on low-dose oral steroids [27]. Thirty women with RA were studied, with a mean age of 56.2 years, functional class I or II, mean disease duration 156 months, and mean oral prednisolone dose of 5 mg/day. Patients were excluded if they had a known history of osteoporotic fractures, signiWcant cardiovascular disease, planned or recent surgery, previous high-dose steroid use, or methotrexate use. The intervention was an aerobic, weight bearing exercise programme three times a week lasting 45–60 min, for 12 months. The following outcome measures were assessed by a single rheumatologist, blinded to study group, at baseline and at 12 months: 70 joint swollen and tender joint count, ESR, bone density at lumbar spine and hip (Lunar DEXA), HAQ, activity level (Caltrac accelerometer), and an aerobic Wtness estimation (though this was by a self-completed questionnaire). This study had a relatively high drop out rate (21% exercise group, 38% control group). Compliance with the exercise programme was only 71% among the completers. Methodological quality Methodological quality of the included studies was independently evaluated by the two authors; disagreements were resolved by consensus, scores ranged between Wve and ten, with a mean score of 6.9. Half of the papers (9/18) had quality scores of seven or more and were deemed of high quality. According to inclusion criteria, only randomised studies were included in the review, although four papers did not describe clearly the method of randomisation in detail. Allocation concealment was either unclear or not done in eight of the papers. There were signiWcant diVerences in the groups at baseline in six papers. All included papers speciWed inclusion criteria and described the intervention in suYcient detail. In one study [25], assessments were carried out by an assessor not blinded to allocation groups. In Wve other papers, blinding of outcome assessor was not clear. Co-interventions were avoided or similar between groups in 10 papers. Co-interventions were signiWcantly diVerent between groups in four papers, and this was unclear in another four papers. All papers presented point estimates and measures of variability for primary outcome measures. The drop out rate was described and acceptable in all but one paper [27]. Only eight papers included an intention to treat analysis. EVectiveness of interventions A summary of key outcome results is presented in Table 2. 123 154 Aerobic exercises Harkcom et al. reported an increase in VO2 max for the exercise groups compared with controls [20]. However, this only reached statistical signiWcance when the three exercise groups were combined together for analysis (p < 0.01). Percentage increases in VO2 max were 47.2, 12.8, and 32.9% in the three exercise groups, compared with 0.5% in the control group. There was an improvement in the active joint count of 39.5% in the three combined active groups compared with 16.3% in the control group (p < 0.01). No signiWcant diVerences were seen in grip strength, muscle strength or functional status index. The small group sizes (4, 3, 4, and 6) make meaningful interpretation diYcult. Melikoglu et al. reported a signiWcant increase in the mean serum IGF-1 level in the exercise group (+25.0%) compared with the control group (¡16.8%, p < 0.001) [24]. This study also reported a signiWcant improvement in the RAI in the exercise group (¡27.2%) compared with controls (¡9.3%, p < 0.05), and in the pain VAS in the exercise group (¡10.7%) compared with controls (+3.8%). No signiWcant diVerences were seen in IGFBP-3 levels, morning stiVness, or inXammatory markers. Further study of the eVect of exercise on key cytokines such as TNF alpha would be of interest. Strength training Hakkinen et al. reported signiWcant improvements in knee extension, trunk Xexion and grip strength at 1 and 2 years with persisting improvement in knee extension and trunk extension at 5 years in the exercise group [15–19]. SigniWcant diVerences between the exercise and control groups were seen for ESR (¡59.6 vs. ¡23.3%, p = 0.015), HAQ (¡65.3 vs. ¡43.7%, p = 0.01), and DAS28 (¡48.9 vs. ¡40.0%, p = 0.019) at 1 year, in favour of the exercise group. At 2 years, there was persistent signiWcant diVerence in HAQ and pain VAS, in favour of the exercise group. At 5 years, the DAS28 remained signiWcantly better in the exercise group (¡47.7 vs. ¡38.8%, p = 0.012), though HAQ and pain VAS were no longer diVerent suggesting that exercise programmes need to be continued to maintain many of the beneWcial eVects. There was a small but statistically signiWcant diVerence in hip bone mineral density at 1 year in favour of the exercise group (+1.1 vs. ¡2.85%, p = 0.024). At 5 years, the bone density was reasonably well maintained, but statistical signiWcance was lost (+2.12 vs. ¡0.45%, p > 0.05). Spinal bone density did not show any signiWcant diVerence at any stage. Bone density by DEXA is relatively insensitive to change, and further study of the eVect of exercise on bone turnover markers and ultimately fracture rates would be of 123 Rheumatol Int (2009) 30:147–158 interest. There was no statistical diVerence in Valpar 9 scores at 2 years, or in Larsen scores at 5 years. McMeekin et al. reported signiWcant improvements in the timed up and go test (TUG) (¡11.1 vs. ¡3.2%, p = 0.005), pain VAS (¡4.9 vs. ¡44.2%, p = 0.031), and HAQ (¡30.0 vs. +14.3%, p = 0.036) all in favour of the strength training intervention [23]. She also reports signiWcant improvements in knee Xexor and extensor torque in the exercise group compared with the controls. Aerobic/strength combinations Bilberg et al. reported no signiWcant diVerences in aerobic capacity or the physical component of the SF-36 with moderately intensive pool-based exercises [11]. The IMF, however, did show signiWcant improvement in the exercise group compared with controls (¡59.3 vs. ¡4.3%, p = 0.006), and the chair test was also signiWcantly improved in the intervention group (+15 vs. ¡4.3%, p = 0.005). There were also some signiWcant diVerences in favour of the intervention for a number of muscle endurance outcomes, though the beneWts were less marked than in some of the more intensive programmes in this review. Outcomes from the RAPIT study are reported in four papers [10, 12–14]. The mean diVerence in change in function as measured by the MACTAR score was signiWcantly diVerent and in favour of the exercise group at 12, 18 and 24 months (RAPIT 6.8% improvement vs. usual care 1.3% improvement, p = 0.017 at 24 months). There was no signiWcant diVerence in function as measured by the HAQ score. The authors comment that the MACTAR score may be more relevant here because of its assessment of endurance and ability to perform repetitive complex tasks. The RAPIT group had signiWcantly more improvement in aerobic capacity (mean change +8.2 vs. ¡6.7 W, p < 0.001) and muscle strength (mean change 26.1 vs. 9.6 N, p < 0.001) at 2 years compared with the control group, in keeping with outcomes from other studies in this review. The mean diVerence in emotional status as measured by the HADS score was also signiWcantly diVerent and in favour of the RAPIT group at 12 and 24 months (¡10 vs. +0.9%, p = 0.007 at 2 years). Disease activity as measured by DAS4 (RAI and number of swollen joints) decreased in both groups throughout the study with no signiWcant diVerence between the groups. There was no diVerence between the groups in terms of ESR or general health. In the 2 years of the study, the median radiographic damage of large joints did not increase in either group. However, it was noted that the mean diVerence in change of the large joint Larsen score between the groups showed a nonsigniWcant trend towards more damage in the RAPIT group. Patients with more baseline damage showed slightly more Rheumatol Int (2009) 30:147–158 progression in damage, and this was more obvious in the RAPIT group. This trend was felt to be diYcult to interpret by the authors and a retrospective subgroup analysis of the progression of large joint radiologic damage was undertaken [10]. In this paper, linear regression analysis was used to test which predeWned variables at baseline (age, disease duration, disease activity, physical capacity, functional ability, joint damage) modiWed the eVect of high intensity exercise on the progression of radiologic damage of large joints over 24 months. Baseline radiographic joint damage was the only variable associated with the eVect of the RAPIT programme on large joint damage progression. In patients with pre-existing extensive damage of large joints (Larsen score >5, n = 59), 85% of the RAPIT group had progression of damage compared with 48% of the usual care group (p < 0.05). There was no signiWcant diVerence in patients without pre-existing extensive large joint damage (Larsen score < 5, n = 218). In the subgroup with extensive baseline damage, a signiWcantly higher percentage of shoulders and subtalar joints deteriorated in the RAPIT group compared with the usual care group when joints were analysed individually (no signiWcant diVerences were noted for elbows, hips, knees or ankles). The authors propose that biomechanical instability may be particularly prevalent in these joints in RA, but these Wndings should be interpreted with caution, as this study was not powered to assess radiological damage. In terms of bone loss, there were only small changes in bone mineral density at the spine and hip over the 2 years in both groups [13]. There was a non-signiWcant trend to less bone loss at the hip in the RAPIT group versus usual care (¡1.1 vs. ¡1.9%, p = 0.06), and no diVerence between the groups for bone density in the spine (+0.9 vs. +0.9%, p = 0.697). However, when analysed by mixed-eVect ANOVA, the mean between-group diVerence in change of hip BMD over the 2 years was statistically signiWcant (p = 0.026) in favour of the RAPIT group. The change in hip bone mineral density was signiWcantly and independently associated with changes in both muscle strength and aerobic Wtness. de Jong et al. reported the outcomes of small joint damage (Larsen score hands and feet) from the RAPIT study in 2004 [14]. The usual care group had slightly more baseline radiological damage than the RAPIT group. There was no signiWcant diVerence in radiological progression of hands between the groups (12.2 vs. 13.0% increase—RAPIT vs. usual care); however, there was signiWcantly less progression in feet in the RAPIT group (6.5%) compared with the usual care group (11.5%), p = 0.047. Multivariate subgroup analysis demonstrated that a higher rate of joint damage was independently predicted by higher baseline damage (unstandardised regression 155 coeYcient (standard error) 0.04 (0.02), p < 0.005), more frequent use of glucocorticoids (0.17 (0.09), p < 0.05), and a decrease in aerobic Wtness (¡0.01 (0.02), p < 0.05). Further long-term study, powered to detect bony changes, using high-resolution ultrasound or MRI scanning would be of interest. Komaitreddy et al. reported the outcome of a 12-week study of resistive circuit training exercises in patients with RA [21]. Of note, in pre-study screening, the authors identiWed two cases of asymptomatic ischaemic heart disease, underlining the importance of coronary artery disease in this population. SigniWcant improvements in the exercise group compared with the control group were reported for self-reported joint count (¡13.9 vs. +36.2%, p = 0.02), sitto-stand time (¡23.4 vs. ¡3.9%, p = 0.02), night time pain (¡20.6 vs. +8.1%, p = 0.05), and time to anaerobic threshold (¡35.1 vs. +10.1%, p = 0.02). No signiWcant betweengroup diVerences were noted for morning stiVness, hours before fatigue, isokinetic strength, grip strength, selfreported pain and fatigue, physicians joint count, 50 foot walk time, AIMS, HAQ, treadmill time, peak heart rate, time to anaerobic threshold, or VO2 max. Lyngberg et al. report outcomes of progressive interval training over 3 months in “elderly fragile patients” with RA on low-dose oral steroids [22]. There were no signiWcant diVerences between groups for swollen/tender joints, ESR, morning stiVness, grip strength, 30 m walk time or VO2 max. There was a small statistical diVerence in favour of the exercise group for left ankle plantar Xexion torque (¡7.1 vs. ¡53.6%, p = 0.04) though the clinical signiWcance of this is unclear. No signiWcant diVerences for muscle torque of right ankle or either knee were noted; however, the study was limited by low numbers, short duration and relatively low intensity intervention. The study did note a doubling of the work capacity of the trained patients but this was not recorded for the control group. In Van den Ende et al.’s Wrst paper, the outcomes of four diVerent exercise programmes (1. high intensity exercise, 2. low intensity exercise in a group, 3. low intensity individual exercise, and 4. home exercise) on 100 stable patients with RA from an outpatient population over 12 weeks are presented [25]. The high intensity exercise group (group 1) had signiWcantly more improvement in aerobic capacity (p < 0.001), muscle strength (p = 0.02), range of movement (EPMROM) (p < 0.001) and the walk test (p < 0.001) at 12 weeks than the other three exercise groups. The swollen joint count improved by 32.7% in group 1, when the swollen joint count either worsened or did not change in the other groups (p < 0.001). It should be noted, however, that the baseline swollen joint count was higher in this group (5.2) than in the others (3.0, 4.4, and 3.6, respectively), with 123 156 a wide standard deviation (3.2), so this Wnding should be interpreted with caution. The exercise programmes lasted 12 weeks. The assessments were also completed after 24 weeks. All signiWcant diVerences between groups were lost at 24 weeks with the exception of muscle strength (p < 0.001), underlining the importance of continuing regular exercises. There were no signiWcant between-group diVerences at any time for HAQ, Dutch-AIMS, RAI, pain VAS, global disease activity VAS or ESR. Of note, the assessments in this study were performed by a single observer not blinded to treatment group. In Van den Ende et al.’s second paper, the outcomes of a dynamic intensive exercise regimen on hospital inpatients with very active rheumatoid disease (baseline DAS 7.0) are presented [26]. Medical treatment was similar in both groups, and both groups had a gradual decline in disease activity throughout the 24-week study. No signiWcant diVerences in disease activity were observed between the groups. At 24 weeks, signiWcantly more patients in the intensive group met modiWed ACR response criteria than in the conservative group (12 vs. 3, p = 0.04). Joint mobility, the 50 foot walk test and HAQ improved in both groups without signiWcant diVerences between groups. Measures of muscle strength were signiWcantly better in the intensive group than the conservative group at 24 weeks (isokinetic extension +36.8 vs. +0%, p < 0.05; isometric extension +51.2 vs. +4.2%, p < 0.05). This study suggests that a short-term programme of intensive exercises is well tolerated by inpatients with active disease, resulting in signiWcant improvements in muscle strength without worsening of disease activity. However, this study did not assess longterm structural changes. Westby et al. present results of a 12-month weight bearing aerobic exercise programme on disease activity, physical function and bone mineral density in women with RA taking low-dose prednisolone [27]. There were no signiWcant diVerences in disease activity, physical function or bone density between the groups at the end of the study. There was a signiWcant improvement in Wtness estimation (though this was by questionnaire) in the exercise group (+87.1 vs. ¡12.1%, p = 0.001). Limitations A number of the studies included in this review had relatively small numbers of patients. Power calculations to determine sample size are only presented for the RAPIT study group of papers [12–14], and for the two studies by Van den Ende et al. [25, 26] increasing the risk of statistical type two error in the other studies. Many of the papers included in this review present a large number of outcome variables. In only a small number of papers is any statistical 123 Rheumatol Int (2009) 30:147–158 allowance made for this in the analysis [16, 24, 25] increasing the risk of statistical type one error in the other studies. The search strategy used in this review deliberately excluded studies that were not randomised-controlled trials. Also some studies were excluded because patients with diVerent arthropathies were analysed together. No quality assessment criteria speciWc to exercise intervention in RA have been validated though the quality assessment score used in this review is a modiWcation of the Delphi list [7], and similar to that used in the Cochrane review [6]. It was not possible to perform a quantitative review of the outcomes of these studies because of the widely diVerent patient characteristics, study design and outcome measures used in the diVerent studies. Summary The aim of this review was to evaluate the eVect of dynamic exercise on patients with RA. With the above caveats, improved outcomes with dynamic exercise in terms of muscle strength, physical function and aerobic capacity were reported in a number of studies. No studies reported worse outcomes for function, disease activity or aerobic capacity with dynamic exercise. Some studies also reported improvements in disease activity measures [15, 19, 20, 25], and small improvements in hip bone mineral density [13, 16]. One study reported signiWcantly less progression of small joint radiographic damage of the feet in the dynamic exercise group [14]. However, one study also reported worse large joint radiographic damage in patients using dynamic exercise who had pre-existing large joint damage [10], though this was a retrospective analysis. This is the only paper in this review to report a signiWcantly worse outcome in any group performing dynamic exercise. This was seen only in shoulder and subtalar joints when joints were analysed individually. The reasons for this are not clear. This does deserve recognition, and the use of caution in recommending high impact exercise to some patients, particularly those with high levels of baseline joint damage. Further study to address this issue using more sensitive imaging techniques is clearly required. Perhaps the most surprising aspect of this review is that no studies addressed the eVect of dynamic exercise on cardiovascular outcomes in terms of coronary artery disease or stroke, or major risk factors for these such as hypertension, dyslipidaemia, obesity or diabetes. Because excess cardiovascular mortality is the main cause of reduced life expectancy in RA, interventions to reduce cardiovascular disease or its risk factors are of vital importance [1–3]. It should also be noted that all of these studies excluded patients with signiWcant pre-existing cardiovascular or other serious disease. Rheumatol Int (2009) 30:147–158 Because these studies were of very diVerent designs, it is not possible to be deWnite about which forms of exercise should be encouraged. However, when diVerent intensities of exercise were compared [25], more beneWts were seen with high intensity exercise compared with low intensity. Less intensive pool exercises did not result in any improvements in aerobic capacity [11]. Improvements in aerobic capacity were reported by a number of the aerobic and combined exercise programmes [12–14, 20, 25], but not by the pure strength training programmes [16–19, 25]. Conversely, the strength training programmes report signiWcant increases in muscle strength but not in aerobic capacity. It seems sensible, therefore, to suggest combined training programmes to address both aerobic Wtness as well as strength training. It may be prudent to avoid sports and games involving twisting and rapid joint loading or unloading activities as described in the RAPIT programme [12–14] for patients with pre-existing large joint damage, pending further study. Exercise programmes should be individualised as much as possible taking into account individual patient and joint factors. References 1. Naz SM, Symmons DP (2007) Mortality in established rheumatoid arthritis. 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