Impaired physical function and disability are common features in patients with rheumatoid arthritis (RA) (40). The development of powerful disease-modifying antirheumatic drugs has made it possible to improve control of disease activity and to reduce progression of joint damage and deformity, so that many patients are able to maintain an active life in the community. However, even in stable disease with minimal joint symptoms, most patients experience limitations of physical function, often leading to work disability (31).
Escalante and del Rincón's (5) hierarchical regression model of disability in RA accounted for 59% of the variance in RA disability by disease activity, joint inflammation, joint damage and pain, psychosocial factors, and demographics. However, their model did not assess the influence of muscle on disability in RA. Recently, Giles et al. (9) demonstrated a strong association between body composition in RA (low muscle mass and high percent body fat) and disability. The prevalence of muscle wasting, i.e., rheumatoid cachexia, is higher in patients with RA than in the general population (26,34), possibly because of the catabolic effect of proinflammatory cytokines (e.g., tumor necrosis factor) and the down-regulation of anabolic factors for muscle (e.g., insulin-like growth factor I) (19,20,34).
In addition, exercise training, which restores muscle mass, has been shown to substantially improve physical function and to reduce disability in patients with RA without increasing disease activity (4,20,21). Thus, encouragement to exercise has become part of routine rheumatology care, and more patients, especially those with milder, well-controlled disease, attend public gyms.
Extensive research has been conducted on the factors that determine muscle force production and muscle function in the healthy population and the adverse changes that occur in aging and disuse (25,37). A similar comprehensive assessment of the physiological characteristics of skeletal muscle in patients with RA is absent, which is surprising in view of the recent developments in RA treatment. Consequently, it is not known whether the catabolic effect of RA results in alterations in skeletal muscle properties; for example, muscle-specific force and architecture, which may then contribute to the reduced physical function in patients with RA.
Thus, the present study sought to investigate the properties of skeletal muscle in community-based patients with RA with controlled disease. Skeletal muscle-specific force, i.e., maximal isometric force per cross-sectional area of the muscle, concentric force, contractile properties, activation capacity, and architectural characteristics of the muscle are assessed. These results are presented alongside measures of body composition and physical function.
Twenty-three patients with a diagnosis of RA according to the American Rheumatism Association's 1987 revised criteria (2) were recruited from the rheumatology outpatient clinics of the local National Health Service Trust. These included a subset of patients who were found to be cachectic and were included in a separate analysis (22). Inclusion criteria were disease duration of at least 3 yr and stable disease activity (i.e., no flare or change in medication for the last 3 months). Exclusion criteria were the presence of any other catabolic disease, high-dose steroid therapy (i.e., >10 mg of prednisolone daily) or a recent steroid injection, and joint replacement or current pain or swelling in the right or left knee joints. The recruited RA patients were age- and sex-matched with 23 healthy volunteers. We initially recruited 25 patients but had to exclude 2: one participant did not attend for the assessment, and the other was tested but no matching healthy control was found. This led to a final number of 23 pairs. Written informed consent was given by all participants. The study was approved by the North Wales Health Authority Research Ethics Committee and was conducted in compliance with the Declaration of Helsinki.
Involvement in the study necessitated two appointments for participants: the first for body composition measurements, physical function tests, and questionnaires; and the second for assessment of muscle size, strength, and activation.
The RA patients completed the modified Rheumatoid Arthritis Disease Activity Index (18), a patient questionnaire assessing global disease activity during the past 6 months and current disease activity in terms of swollen and tender joints, arthritis pain, general health, and duration of morning stiffness, which scores from 0 = no disease activity to 10 = active disease. Antecubital venous blood was analyzed for erythrocyte sedimentation rate, a measure of systemic inflammation, in the Haematology Department of Gwynedd Hospital.
Body composition was assessed by whole-body dual-energy x-ray absorptiometry (DXA) and bioelectrical impedance spectroscopy. In brief, on presentation at the laboratory, body mass was measured on a calibrated balance scale (Seca, Hamburg, Germany) in a standard way, with patients only in their underwear, barefoot, fasted, and voided (6). Whole-body DXA was then performed using a pencil-beam scanner (QDR1500; Hologic, Bedford, MA) to determine total and regional (left and right arm, left and right leg, trunk, and head) lean and fat masses. The combined lean mass of arms and legs, called appendicular lean mass (ALM), is a proxy measure of total body skeletal muscle mass (16). The bioelectrical impedance spectroscopy measure (Hydra 4200; Xitron Technologies, San Diego, CA) was used to ensure euhydration (8,21).
Physical function and quality of life
Physical function was assessed objectively with the 30-s chair sit-to-stand and 8-ft up-and-go lower-body function tests derived from the "Senior Fitness Test" by Rikli and Jones (33). In addition, the participants performed a 50-ft walk and a single-leg balance test (23). Subjective physical function was ascertained by the modified Health Assessment Questionnaire (mHAQ, scores 0-3), which includes questions on the individual's difficulty in performing various activities of daily living (31), and the 36-question Short-Form Health Survey (SF-36), which provides a subjective evaluation of an individual's health status through questions on physical function, emotional health, and quality of life (14), with physical component summary scores of 22-59 and mental component summary scores of 11-62. Habitual physical activity was assessed by a questionnaire developed by Saltin and Grimby (35), which has previously been used in RA and aging populations (21,36). In this questionnaire, scores from 1 "being sedentary" to 4 "being involved in heavy physical activity" are given separately for occupational and recreational activities, providing a total score between 2 and 8.
Muscle strength and EMG.
After familiarization with the test procedures on the first laboratory visit, muscle strength and EMG were assessed during their second visit. For these, the participants sat upright on a Humac Norm isokinetic dynamometer (CSMI Medical Solutions, Stoughton, MA), with their right leg strapped to the dynamometer arm above the ankle with additional straps secured to prevent extraneous movement at the hips and shoulders. The hip angle was fixed at 90°. To assess maximal isometric knee extension and flexion torque (N·m), the knee joint angle was fixed at 70° from full leg extension, the optimum angle for force production by the quadriceps muscles (28).
After a set protocol of warm-up contractions, participants performed three rapid maximal voluntary isometric contractions (MVC) of the knee extensors. When voluntary torque peaked, participants were asked to maintain their effort for 2-3 s. Participants then performed three rapid maximal isometric knee flexions. Feedback was provided to the participants through a real-time display of the muscle torque on a computer screen. There was at least a 1-min rest between each MVC to minimize fatigue, and verbal encouragement was given during each effort.
The contraction with the highest torque was used for analysis. The vastus lateralis (VL) muscle force was then calculated as representative of the quadriceps muscle group using established methods (32), which takes into account torque, patellar tendon moment arm length, and antagonist cocontraction torque estimated from EMG activity. Self-adhesive Ag/AgCl electrodes, 10 mm in diameter (Ambu, Ballerup, Denmark), placed over the VL and the long head of the biceps femoris (BF), recorded the root mean square of the raw EMG signal during the MVC.
BF antagonist cocontraction torque was calculated as follows:
BF torque=(BF EMG during knee extension/BF EMG during knee flexion)×knee flexion torque (30).
Quadriceps force was calculated as follows:
quadriceps force=(BF torque+knee extension torque)/estimated patellar tendon moment arm length (32).
The relative contribution of the VL to quadriceps force was assumed from previous data by Narici et al. (28).
Voluntary muscle activation capacity and contractile properties.
To detect deficits in muscle fiber recruitment, three additional MVC of the knee extensors were performed by participants with superimposed and postcontraction supramaximal double twitches. The twitches were applied percutaneously from a DSV Digitimer Stimulator (Digitimer Ltd., Hertfordshire, UK) over the proximal (anode) and distal (cathode) regions of the quadriceps muscles using rubber stimulation pads (38 × 89 mm and 76 × 127 mm; Versastim; Conmed, Utica, NY) (38). The strongest voluntary contraction was used for analysis. Voluntary activation capacity of the quadriceps muscle group was calculated as follows:
voluntary activation (%)=(1−(superimposed doublet torque/post-MVC doublet torque)) × 100 (1,12).
A series of four supramaximal resting twitches was performed to assess contractile properties including peak torque, time to peak torque, and half-relaxation time (calculated from the mean of the second, third, and fourth twitches) (38).
Muscle volume, architecture, physiological cross-sectional area, and muscle-specific force.
To estimate muscle volume (VOL), VL muscle anatomical cross-sectional area (ACSA) was measured by ultrasonography at 25%, 50%, and 75% of the muscle length using a 7.5-MHz linear probe (MyLab50; Esaote, Firenze, Italy). The ultrasound probe was then placed along the VL to gain images of the muscle architecture at rest, which, in turn, were used to calculate physiological cross-sectional area (PCSA). Previous studies have shown this to be a reliable method (32) because PCSA takes into account muscle geometry (pennation angle θ and fiber fascicle length Lf) and is at right angles to the direction of the fiber fascicles. In contrast, using ACSA alone can result in overestimation and underestimation of muscle size because ACSA changes variably along the length of the muscle with training and detraining, respectively, with the most pronounced changes occurring in the midregion of a muscle (32). Using PCSA, therefore, provides a more accurate measure of muscle size for the assessment of the stress of a muscle because it will correctly relate the force developed along the fibers (28).
Pennation angle θ was defined as the angle of insertion of the fiber fascicle into the deep aponeurosis of the VL. Lf was calculated from θ and the muscle thickness (d, measured as the distance between the two aponeuroses of the VL) by the following equation: Lf = d/sinθ (17). PCSA was calculated as VOL/Lf, and specific force was calculated by normalizing VL force to VL PCSA. The estimation of Lf with this method is associated with an error of 2%-7% (7,27). After obtaining the resting ultrasound images of muscle architecture, the ultrasound probe was held in the same position during three maximal voluntary knee extension contractions to assess the extent of changes to θ and Lf between the contracted and the relaxed VL.
Concentric torque and velocity-specific power.
Participants then performed four maximal concentric contractions of the knee extensors at velocities of 50°·s−1 and 100°·s−1 to assess maximal concentric torque and velocity-specific power, calculated as follows:
velocity-specific power = maximum torque generated at each velocity × velocity (rad).
Also assessed were the angle of maximum concentric torque and the concentric torque at 70° knee flexion.
To determine the sample size, statistical power was calculated for maximal voluntary isometric muscle force, a principal dependent variable, using the differences between young and middle-aged healthy individuals found by Onambele et al. (29). Assuming normal distribution, two groups, equal variance, common SD for each group, two-tailed test, α = 0.05, and power = 0.80, this analysis gave a requirement of 10 per group. Depending on normality of distribution of the data, we used either Student's paired t-test or Wilcoxon test to determine differences between the patients and the matched control group. All statistical analyses were performed by SPSS software version 14.0 (Chicago, IL). Values are presented as means ± SEM. Significance was accepted at the level P < 0.05, with a P of 0.05-0.10 considered a trend. Intraclass correlation coefficients were used to assess the reliability of the ultrasound measurements. The analysis of the ultrasonograms for θ, muscle depth, and VL ACSA was performed blinded on two separate occasions. Intraclass correlation coefficients were r = 0.81-0.95 on a subsample of 10 participants. Correlations between functional capacity and power produced during concentric MVC were calculated with simple regression analysis.
The 23 patients with RA were age- and sex-matched with 23 healthy controls (Table 1). All patients had stable disease, with mean Rheumatoid Arthritis Disease Activity Index score of 3.1 ± 0.3 (range = 1.0-5.4), indicating low disease activity. Erythrocyte sedimentation rate was 19.1 ± 2.5 mm·h−1 (range = 3-41 mm·h−1), representing normal levels for this age group or low-grade inflammation. Twelve patients (52%) were positive for rheumatoid factor. The average disease duration for patients was 12.9 ± 1.8 yr. Treatment for RA was as follows: 18 patients (78%) were taking methotrexate, 3 of them combined with an anti-tumor necrosis factor agent (2 with infliximab and 1 with adalimumab); 3 patients (13%) were taking sulfasalazine; 9 patients (39%) were taking nonsteroidal antiinflammatory drugs; and 6 patients (26%) were taking prednisolone (range of 1-10 mg daily, average dose of 7.3 mg).
A reduction of ALM by 1 kg (5.8%) was observed in the patient group compared with the controls, despite a tendency toward higher body mass index (by 4.4%) and body weight (by 2.5%; Table 1). Body fat was significantly higher in the patients (Table 1).
Physical activity and function.
As expected, objective physical function was reduced in the RA group relative to the matched healthy controls, that is, sit-to-stand by 10.5% (number of repetitions 12.6 ± 0.7 vs 14.0 ± 0.5, P = 0.09), 8-ft up-and-go by 17.3% (6.1 ± 0.3 vs 5.2 ± 0.2 s, P < 0.01), 50-ft walk by 25.3% (9.3 ± 0.5 vs 7.5 ± 0.3 s, P < 0.001), and one-leg standing balance by 27.0% (49.0 ± 5.0 vs 67.1 ± 4.9 s, P = 0.01; Fig. 1), as were the subjective measures of self-assessed physical function: mHAQ (0.64 ± 0.07 vs 0.11 ± 0.06, P < 0.001) and SF-36 physical component summary score (38.2 ± 1.9 vs 51.3 ± 1.1, P < 0.001). Similarly, patients scored lower on psychological quality of life factors with a mean SF-36 mental component summary score of 39.8 ± 1.5 compared with 44.2 ± 0.9 for the controls (P < 0.05). Both the RA and the control groups reported low habitual physical activity levels, although the healthy controls tended to be even more sedentary than the patients (Table 1).
Muscle-specific force and architecture.
Muscle physiology data are presented in Table 2. Compared with the healthy controls, the patients with RA had a smaller PCSA (by 13.9%, P < 0.05). Patients had a nonsignificant reduction of 6.0% in VL force compared with their controls (P = 0.35). Overall, specific force, calculated by normalizing VL force to VL PCSA, was not different between the groups (P = 0.40; Table 2).
In the RA group, resting θ was 12.5% less (P = 0.01) than that in the controls, whereas Lf tended to be longer by 12.1% (P = 0.06; Table 2). At maximal contraction, θ increased by 24.6% in the patient group and by 16.2% in the control group, and Lf decreased by 19.1% in the patients and 19.0% in the controls with no differences between the groups (P = 0.78 and P = 0.16, respectively).
Muscle contractile properties and voluntary activation capacity.
During electrical stimulation of the quadriceps at rest, peak torque, time to peak torque, and half-relaxation time were similar in the RA and the control groups (P = 0.68-0.99). In addition, no difference was found in voluntary muscle activation capacity between the groups (P = 0.86; Table 2).
Concentric torque and velocity-specific power.
RA and control groups were not different regarding their maximum concentric torque at 50°·s−1 and 100°·s−1 (P = 0.61 and P = 0.99, respectively) and velocity-specific power (P = 0.61 and P = 0.99, respectively; Table 2). Similarly, there was no difference in the angle of maximum torque and power at both speeds (P = 0.50 and P = 0.28, respectively; Table 2) and in the concentric torques measured at 70° of knee flexion (87.1 ± 7.1 vs 93.0 ± 7.8 N·m, P = 0.45 at 50°·s−1, and 65.3 ± 4.9 vs 69.5 ± 5.9 N·m, P = 0.43 at 100°·s−1; Fig. 2).
The present study demonstrates that in patients with stable RA, the physiological properties of skeletal muscle, including specific force, contractile properties, activation and concentric force, and power, are not compromised and thus not a likely contributor to reduced physical function in RA. This is important and encouraging information for rheumatology health professionals and sports scientists involved in designing exercise training for RA patients, and the results are a step forward in piecing together the jigsaw of interactions between muscle function and disability in RA.
In common with most RA patients, our patient cohort had impaired physical function, with the degree of impairment comparable to our previous findings (20,21). We could also confirm the typical aberrant body composition of RA patients with a tendency to reduced ALM (by 1 kg) and increased body fat (41.1% in RA vs 35.9% in non-RA), consistent with the findings of our previous studies (20,21) and those of others: Giles et al. (10) found ALM to be significantly reduced by 1.4 kg in men with RA compared with non-RA controls (n = 72 in each group) and a nonsignificant ALM reduction of 0.3 kg in women with RA compared with non-RA (n = 117 in each group) with concomitant significantly higher body fat percentage (42.1% in RA vs 38.7% in non-RA).
In accordance with the results on muscle mass and physical function, force production tended to be reduced in the RA group in the current study. We then assessed other factors intrinsic to muscle that influence physical function and established that muscle-specific force was preserved. In muscle physiology research, specific force (force per unit muscle) is the main determinant of the quality of a muscle. The unit of muscle can be given as volume, ACSA, or as PCSA, which takes into account the length of the fiber fascicles and their direction as determined by the pennation angle θ. PCSA has been shown to be a better predictor of intrinsic muscle force than ACSA or volume (28) because muscle force is dependent on the number of sarcomeres in parallel (more sarcomeres leads to a larger angle of insertion of fibers into the deep aponeurosis of the muscle and thus greater force) and on the number of sarcomeres in series (more sarcomeres leads to longer fiber fascicles and thus to increased velocity of contraction) (25). In our study, PCSA was significantly reduced in RA patients and was accompanied by minor changes in θ and Lf. Force normalized to PCSA (and ACSA and volume), however, did not reveal any change in specific force. The alterations in muscle architecture were small in absolute values and, therefore, probably not enough to have any functional consequence. This was further confirmed by the finding that the trend to a longer Lf did not lead to a change in contraction velocity measured with resting twitches, concentric torque, or velocity-specific power. Another explanation could be that the resting muscle architecture is less predictive of muscle function than the architecture of the contracted muscle, which, in our study, was not significantly different between patient and control groups, i.e., the minor changes that we found in resting θ were not present in the contracted muscle.
In the current study, the significant reduction of PCSA in the patient group compared with the control group corresponded to the lower muscle mass on DXA, whereas ACSA and VOL were not different between the groups. Unlike DXA or magnetic resonance imaging, ultrasound cannot account for intramuscular fat. In the elderly, intramuscular fat and connective tissue are increased compared with young people (15). Thus, ACSA and volume measures alone might represent an overestimation of muscle content.
Our results are in contrast to findings in aging and disuse, where a disproportionate loss in muscle strength and, in consequence, lower specific force is a typical feature, and these are associated with reductions in Lf and θ (25). This suggests that the process of muscle loss in aging and disuse is different from the muscle loss that results from a chronic inflammatory condition like RA. The fact that Lf in our study tended to be longer rather than shorter in the patient group might represent an adaptation, possibly because of the alterations in tendon compliance, which warrant further investigation.
In keeping with the preserved specific force, we did not find any differences in other factors that affect muscle force and function, namely, activation capacity, antagonist cocontraction, and contractile properties. Muscle activation capacity is typically reduced in old age (24) and after prolonged disuse (37). Studies on knee osteoarthritis and joint replacement and after traumatic knee joint damage (13,39) have also found reductions in activation capacity. The observation that, in our study, activation capacity was not different between RA patients and matched healthy controls suggests that our patients' efforts were not inhibited by guarding, pain, or fatigue and that they had not lost the capacity to contract their muscles through disuse. In contrast, Bearne et al. (3) found muscle activation to be 8% lower in an RA compared with a control group. This disparity in results might be explained by their selecting patients with confirmed knee involvement and by the differences in age between their patient and control groups (patients were, on average, 6 yr older). In contrast, our patients did not have obvious knee involvement because those with knee pain or swelling were excluded, our patients had a low mHAQ score, and our groups were age-matched.
The statistical comparison of pairs matched for age and sex was important because of the wide age range of the participants and helped to exclude age-related differences in force production and other parameters. Similarly, we aimed to align the pairs for their habitual physical activity to avoid disparate effects of disuse between groups. If anything, the controls were even more sedentary than the patients in our study.
Despite the preserved specific force and the ability to recruit muscle fibers of our RA patients, their functional capacity was still significantly impaired. To fully understand the role of muscle in RA disability, further research is required, in particular, on tendon stiffness and characteristics at the cellular level such as myosin heavy chain distribution and intramuscular protein metabolism. To minimize extrinsic influences on muscle such as joint deformity or presence of a joint effusion that might lead to malalignment and thereby altered mechanics of the joints, we only included patients with stable disease and excluded those with knee swelling or pain. However, assessing physiological muscle characteristics in active RA pretreatment or in persistently active RA in patients who have not responded well to disease-modifying antirheumatic drugs would also be relevant, albeit difficult in view of the confounding factors of joint pain, swelling, fatigue, and disuse that accompany active RA.
In conclusion, this study highlights the fact that physiological muscle properties are preserved in patients with stable RA and thereby suggests that rheumatoid muscle has the potential to respond to physical training in a similar way that healthy muscle does. This is in accordance with the success that high-intensity exercise training studies have shown in increasing muscle quantity and strength in RA patients (11,20,21) and in the near-identical training responses (of strength, muscle mass, and fat mass) of RA patients and age-matched healthy controls performing the same training (11). With the properties of rheumatoid muscle being apt to respond to exercise training, the results of our study therefore promote the inclusion of exercise in the rehabilitation program for RA patients.
This work was supported by a grant from the North West Wales National Health Service Trust.
The authors thank Dr. Jeremy Jones for reviewing the manuscript.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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