Neuromuscular electrical stimulation and volitional exercise for individuals with rheumatoid arthritis: a multiple-patient case report.

More than 50% of patients with rheumatoid arthritis (RA) are affected by rheumatoid cachexia. (1) Rheumatoid cachexia is characterized by altered energy and metabolic abnormalities that result in the loss of body cell mass despite a relatively small loss of body weight. (2,3) Many factors may contribute to the loss of body cell mass in rheumatoid cachexia, including a catabolic cytokine profile characteristic of the disease activity (increased production of interleukin-[beta] and tumor necrosis factor [alpha] by peripheral blood mononuclear cells), dietary intake that is inadequate to meet increased energy needs, medication effects (particularly those of chronic corticosteroid use), and a decline in activity due to pain. (4-6) Rheumatoid cachexia predominates in skeletal muscle and not only leads to muscle atrophy, muscle weakness, fatigue, and disability, but also is associated with increased risk of infection and premature death. (2,7,8)

The interventions proposed to slow or reverse the loss of body cell mass in RA are essentially exercise, diet, and medication. (2) Physical exercise currently is believed to be the most important and clinically relevant countermeasure against rheumatoid cachcxia. (7) Although muscle strengthening and endurance exercises clearly improve strength (force-producing capacity) and physical function in patients with RA, (9-15) it is not as clear whether exercises reverse the muscle atrophy and restore the lean muscle mass that has been lost due to the catabolic effects of the disease process. (10,16,17)

Rail et al (10) were unable to demonstrate significant changes in lean body mass--despite significant improvement in muscular strength, pain, and performance on a 15.24-m (50-ft) walking test--in a select group of patients with RA who had undergone an intense, 12-week progressive resistance training program. Marcora et al (16) demonstrated a significant increase in lean muscle mass, muscle strength, and measures of physical function in response to a 12-week progressive resistance training program in a group of patients with RA and mild disabilities. In the study by Marcora et al, (16) the changes in lean muscle mass were correlated with changes in strength and measures of physical function. Hakkinen et al (18) have recently reported significant increases in endurance, muscle strength, electromyographic activity, and muscle mass in women with RA following 21 weeks of combined strength and endurance training.

Studies that demonstrated improvements in lean muscle mass due to exercise (16,18) have used exercise programs with higher training intensity and volume than the studies that did not show a benefit. (10) For example, the progressive resistance training programs used by Rail et al (10) and Marcora et al (16) were identical with one exception. Marcora et al combined a higher number of resistance exercises per training session and higher training frequency, which resulted in more than twice the number of weight lifts per week (576 weight lifts per week versus 240). Although the patients with RA in the more intense exercise programs tolerated the activities without exacerbation of their joint disease, (16,18) the patients in these studies were only mildly disabled as defined by the RA functional classification from the American College of Rheumatology. (19) It is not known how patients with different levels of disability or involvement of major weight-bearing joints would respond to intense exercise programs. Furthermore, some patients may not have the time to commit to an intense exercise regimen. Therefore, alternative treatments that promote increases in lean muscle mass for patients with RA need to be explored.

There is evidence to suggest that electrically stimulated muscle contractions may be a viable treatment option for muscle atrophy and weakness. Cabric et al (20) reported increased muscle hypertrophy and increased muscle cell nuclear size and mitochondrial fraction following 19 sessions of neuromuscular electrical stimulation (NMES) to the gastrocnemius muscles of 6 subjects who were healthy. In a group of subjects who had knee ligament surgery, Wigerstad-Lossing et al (21) reported less whole muscle atrophy and increased muscle fiber area in the quadriceps femoris muscles of 13 subjects who received a 6-week program of NMES combined with volitional muscle contractions compared with 10 subjects who received only a program of volitional muscle contractions. Patients with respiratory disease (22) and congestive heart failure (23) cannot tolerate intense volitional exercise programs, yet NMES has been shown to increase muscular strength and physical function in those patients. Therefore, patients with RA who cannot tolerate a volitional exercise program intense enough to improve strength and lean muscle mass may obtain improvements in these areas following treatment with NMES.

To date, no studies that investigated NMES use in patients with RA have been reported. According to the conclusions of the Ottawa Panel, (24) there is no evidence about the use of electrical stimulation of muscle in patients with RA. The purposes of this multiple-patient case report are: (1) to describe the use of NMES to the quadriceps femoris muscles in conjunction with an exercise program; (2) to report on patient tolerance and changes in muscle mass, quadriceps femoris muscle strength, and physical function; and (3) to explore how changes in muscle mass relate to changes in quadriceps femoris muscle strength, measures of physical function, and patient adherence.

Description of Cases

Patients

The patients were diagnosed by their physician as having RA and met the American College of Rheumatology criteria for RA. (19) All patients had a physician's referral to participate in a NMES strengthening program for the quadriceps femoris muscles. Their medication regimen was stable for at least 1 month prior to treatment.

Because we were interested in exploring the effects of NMES on muscle hypertrophy, muscle function, and functional outcome measures, and because there are no established guidelines for safe use of NMES in patients with RA, we excluded patients with the following: history of a neurological disorder that may affect muscle function, prior quadriceps tendon or patellar tendon rupture, a previous adverse reaction associated with electrical stimulation treatment, unstable hypertension, current use of a statin, and an inability to independently operate the home NMES device. We did not include patients with passive knee flexion range of motion less than 70 degrees because they would not have been able to perform the quadriceps femoris torque testing procedure. Pregnant patients were excluded to eliminate risk of ionizing radiation exposure to the unborn fetus during computed tomography (CT) imaging. All patients signed an informed consent document approved by the University of Pittsburgh Institutional Review Board.

Seven patients, 6 women and 1 man (median age=61 years, range= 39 - 80 years), met the above criteria. Table 1 describes each patient's baseline characteristics such as age, sex, ethnicity, height, weight, body mass index (BMI), disease duration, additional health problems, and medication regimen.

Tests and Measures

Patients underwent 2 pretreatment (baseline) measurement sessions that included bilateral quantification of lean muscle mass of the quadriceps femoris muscle using CT imaging, a maximum voluntary isometric quadriceps femoris muscle torque test, the timed chair rise test, and self-reported assessments of physical function (the Lower Extremity Function Scale [LEFS] and the Health Activity Questionnaire Disability Index [HAQ-DI]). Following pretreatment measurements, the patients underwent a 16-week NMES quadriceps femoris muscle strength training program combined with a lower-extremity strengthening program. After the 16-week treatment period, the pretreatment measurements were repeated.

Computed tomography imaging. Axial CT images of the mid-thigh were used to quantify changes in 3 variables: total cross-sectional area (CSA), lean muscle CSA, and adipose tissue CSA of the quadriceps femoris muscle. (25,26) Patients were imaged in the supine position with the legs extended flat on the table. A single, 10-mm-thick axial image slice was obtained at the femoral midpoint (middle of distance between the medial edge of the greater trochanter and the intercondyloid fossa). Scanning parameters of the image were 120 kVp and 200 to 250 mA.

Quadriceps femoris muscle and adipose tissue CSAs were calculated from the CT images using proprietary IDL development software. * Muscle and adipose tissue areas were calculated by multiplying the area of a given pixel as extracted from the image header. The mean attenuation coefficient values of muscle fibers within the quadriceps femoris muscle on the image were determined by averaging the CT number (pixel intensity) in Hounsfield units (HIS). Skeletal muscle and adipose tissue areas were distinguished by a bimodal image histogram resulting in distribution of CT numbers in muscle and adipose tissue. (27) The peaks are readily separable, (26) and the areas of muscle and adipose tissue in the entire image were determined by the areas under their respective peaks of the histogram. Reproducibility of this method demonstrated a coefficient of variation less than 5%. (25)

The 3 variables of interest in this study were defined as follows. Total CSA was the total area of skeletal muscle that had attenuation coefficient values ranging from 0 to 100 HU. (28) Lean muscle CSA was the portion of the total CSA that had attenuation coefficient values ranging from 35 to 100 HU, which represents the area of skeletal muscle with very low lipid content. (28) We named this variable as normal density muscle (NDM) area. Adipose tissue was the area of fat contained within the fascia plus the fat between the muscle fibers that had attenuation coefficient values ranging from -190 to -30 HU. (28)

Maximum voluntary isometric quadriceps femoris muscle torque output. A maximum voluntary isometric quadriceps femoris muscle torque test was used to determine quadriceps femoris muscle strength. (11,29) While patients were seated on a dynamometer, the test knee was positioned in 60 degrees of flexion. Patients exerted as much force as possible while extending the knee against the force arm of the dynamometer. Maximum voluntary torque values were recorded in newton-meters. The best of 3 trials was recorded as the maximum torque output. In our laboratory, we have demonstrated good intertester reliability for this test procedure (intraclass correlation coefficient [ICC] =.82) with a standard error of measurement (SEM) of 8.7 N*m.

Timed chair rise. The timed chair rise was used as a physical performance measure of function. The test consists of timing an individual while the individual rises from a chair without the use of arm support on the chair. (30) The time to complete 5 chair stands has been used to reflect lower-extremity muscle force, balance, and functional mobility. (31-33) The timed chair rise has demonstrated good test-retest reliability (ICC=.84-.92) in a sample of older adults. (34) Performance on this test has been categorized from 0 to 4, with 0 representing inability to complete the test and 4 representing the highest level of performance (score of 1: 16.7 seconds; score of 2:16.6-13.7 seconds; score of 3:13.6-11.2 seconds; score of 4: [less than or equal to] 11.1 seconds). This categorization was based on quartiles of performance of community-dwelling older adults. (35)

Lower Extremity Function Scale (LEFS). The LEFS (36) is a 20-item patient self-report survey that is intended for use in patients with pathologies affecting lower-extremity function. This scale queries patients on their ability to perform general activities of daily living, general recreational activities, specific daily physical tasks, and specific recreational or occupational related tasks. Scores on the LEFS range from 0 to 80. Higher scores represent better function. The LEFS has been shown to be reliable and valid for self-reported physical function. Internal consistency ([alpha]) was .96, the ICC for test-retest reliability was .86, and the correlation (r) between the LEFS and the physical function subscale of the 36-Item Short-Form Health Survey (8F-36) was .80. (36,37) Its minimal clinically important difference (MCID) is 9 points. (36)

Health Activity Questionnaire Disability Index (HAQ-DI). The HAQ-DI is a widely used tool. The HAQ-DI covers 20 activities of daily living, divided into 8 functional categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and community activities. Each category or domain is scored from 0 (without any difficulty) to 3 (unable to do). The Disability Index is expressed on a scale from 0 to 3 units, representing the mean of the 8 domain scores. A HAQ-DI of 0 indicates no functional disability, whereas a score of 3 indicates severe functional disability. (38) Test-retest correlations (Pearson r) demonstrating reproducibility have ranged from .87 to .99. (39) The HAQ-DI has been validated in numerous studies as a tool to quantify self-reported functional disability in RA. (40) The MCID of the HAQ-DI was 0.24 units. (41)

Adherence. Adherence was measured by the total number of NMES and volitional exercise sessions performed (supervised + home). The total number of sessions prescribed was 60:12 supervised in the clinic and 48 at home. The subjects recorded the training program performed at home in a daily diary. We defined a patient as adhering to the intervention when at least 40 of the 60 prescribed sessions were performed.

Intervention

The intervention consisted of a 16week NMES quadriceps femoris muscle strength training program combined with a volitional lower-extremity strengthening program. The volitional lower-extremity strengthening program is shown in the Appendix. We designed the intervention to be a combination of supervised and self-treatment sessions. In our experience, patients with RA often have difficulty attending 3 outpatient physical therapy intervention sessions per week. With this in mind, we combined some supervised sessions with home-based self-treatment to increase the likelihood that our patients would attain their exercise goals. The supervised sessions were used to monitor the treatments and to advise patients on treatment progression. A total of 12 supervised training sessions over the 16-week period were scheduled: 2 sessions per week for the first 2 weeks, 1 session per week for the second 2 weeks, and 1 session every 2 weeks for the remaining 12 weeks. The patients also were asked to perform the training program at least 3 days per week at home. Patients were instructed to otherwise maintain their prior levels of physical activity throughout the 16-week intervention.

Table 2 depicts each patient's adherence to supervised and home sessions. The patients were treated a median of 9 supervised sessions (range=l-12 sessions), with a median of 31 home sessions of NMES and volitional exercises (range=-048). According to our definition, 4 out of 7 patients (patients 1, 2, 3, and 6) were adherent.

NMES Quadriceps Femoris Muscle Strength Training Program

Each patient was positioned in either supine or long sitting, according to the patient's preference, and the knee was positioned in a comfortable degree of knee extension. Large (6.98 cm x 12.7 cm [2.75 in x 5 in]) self-adhesive electrodes (Dura-Stick ([dagger]) were placed over the vastus lateralis muscle proximally and the vastus medialis muscle distally. The NMES quadriceps femoris muscle strength training program was performed using the Empi 300 portable NMES unit. ([double dagger]) The stimulus parameters included a pulse rate of 75 pulses per second, a pulse duration of 250 microseconds, with a 4-second ramp-up and ramp-down time, a 6-second stimulation period at the maximum amplitude, followed by a 50-second rest period to minimize muscle fatigue. These stimulus parameters were based on stimulation protocols that were found to be effective in improving quadriceps femoris muscle strength. (42-45)

The amplitude of the stimulus was set at an intensity that was high enough to produce a full, sustained, tetanic contraction of the quadriceps femoris muscle (no fasciculations observed on visual inspection) with visual or palpable evidence of a superior glide of the patella. Once this was achieved, the stimulus intensity was increased further to maximum patient tolerance. Maximum tolerance was the maximum amount of discomfort under the electrode sites that the patient could tolerate during NMES. Patients were instructed to relax and allow the electrical stimulus to contract their muscles during treatment.

Patients initiated training with 10 electrically stimulated contractions on each leg per session, increasing this number to 30 contractions per session over the first 2 weeks of training as tolerated. Therefore, treatment time per day ranged from 10 minutes to a maximum of approximately 1 hour, depending on the number of contractions being performed, and whether patients performed the stimulation to one leg at a time or both legs simultaneously. At each supervised training session, the stimulus intensity was adjusted to the maximum patient tolerance.

To ensure safety of the NMES program at home, patients had to demonstrate to the clinician that they fully understood the operation of the Empi 300 for the NMES training that and they were able to correctly reproduce the electrode placement used in the clinic. Each patient also received an illustrated guide with detailed step-by-step instructions how to operate the stimulation unit at home. Patients were instructed to use the same electrode placement and stimulus amplitude used during the last supervised session for their home sessions.

Data Analysis

Spearman rho correlations were calculated to explore how changes in quadriceps femoris muscle and adipose tissue CSA related to changes in quadriceps femoris muscle strength and physical function and to the total number of sessions performed. We used nonparametric statistics because the data were not normally distributed.

Outcomes

CT Imaging

Table 3 shows the total CSA, the area of NDM, and the area of adipose tissue of the quadriceps femoris muscles before and after the 16 weeks of treatment. Computed tomographic imaging data is absent for patient 3 due to a technical difficulty during the imaging data backup procedure. We comment on the results based on changes in NDM area because it represents the area of skeletal muscle with very low lipid content and probably better characterizes changes in muscle atrophy. For the patients who were adherent, the median percentage of improvement in NDM area was 7.5% and ranged from 5.8% to 21%. In the most affected side, these improvements were 7%, 5.8%, and 21% for patients 1, 2, and 6, respectively. The improvements in NDM area in the least affected side for the same patients were 6.2%, 8%, and 17.6%. Patient 5 completed 18 out of 60 prescribed sessions and improved in 8.1% and 9.6% in NDM area in the most-affected and least-affected sides, respectively. Changes in NDM area for patients 4 and 7, who completed only 1 and 6 treatment sessions, ranged from 0.8% to -6%, where negative numbers represent a decrease in NDM area.

Quadriceps Femoris Muscle Extension Torque

Four patients improved quadriceps femoris muscle strength bilaterally; the median percentage of improvement was 18.5% and ranged from 5% to 22% (Tab. 4). In the most-affected side, these improvements were 22%, 20%, 20%, and 5% for patients 1, 2, 5, and 6, respectively. The improvements in the least-affected side for the same patients were 20%, 17%, 13%, and 14%. Patient 3's strength decreased in the most-affected limb by 35% and in the least-affected limb by 4%. This patient was going through an episode of low back pain and reported back pain while performing the strength test. Data for the 16-week follow-up is absent for patient 4 because she only agreed to the CT imaging during that measurement session. Patient 7's muscle strength improved in the most-affected limb by 41% and decreased in the least-affected limb by 11%.

Timed Chair Rise

In the patients who adhered to the exercise prescription, the median improvement in the timed chair rise was 24%, ranging from 19% to 53%. Patient 7, who participated in 6 treatment sessions, and patient 5, who participated in 18 sessions, improved by 11% and 32%, respectively. We do not have follow-up data on patient 4. Initially, of the patients who adhered to the exercise prescription, 3 received scores of 1 (16.7 seconds) on the timed chair rise test, indicating severe disability, and 1 received a score of 2 (16.613.7 seconds), indicating moderate disability. After the intervention, 1 of these patients had a score of 2, indicating moderate disability; 2 had a score of 3 (13.6 - 11.2 seconds), indicating mild disability; and 1 bad a score of 4 (< 11.1 seconds), indicating ability to function in the community (Tab. 4).

Self-Report Measures of Physical Function

Patient 1 had clinically important improvements in LEFS scores. The areas of initial difficulty of this patient that improved after treatment were ability to squat, lift objects, standing for 1 hour, running, making sharp turns, and hopping. Patient 2 had clinically important improvement in HAQ-DI scores (Tab. 4). The areas of initial difficulty that improved after treatment for this patient were the ability to take a tub bath and grip activities such as opening jars. For patient 5, the ceiling effects on these instruments may have hindered measures of improvement. Patient 7 worsened on both self-reported measures of function.

Association Between Quadriceps Femoris Muscle Area and Muscle Strength, Physical Function, and Number of Sessions

Table 5 shows the associations between changes in quadriceps femoris muscle area for the most-affected and least-affected lower extremities and changes in knee extension torque, timed chair rise, HAQ-DI and LEFS scores, and the total number of NMES sessions. These associations indicate that the trends observed between these variables were mainly in the expected direction. Negative coefficients between changes in muscle area and changes in HAQ-DI and timed chair rise indicate a trend toward less disability and a faster time to perform chair rises in patients who increased muscle area. Positive coefficients between LEFS and muscle area indicate that patients who increased muscle area perceived that they were functioning better. There were no trends between changes in adipose tissue and changes in function or strength. The trends between changes in knee extension torque and changes in quadriceps femoris muscle area were different for the most-affected and least-affected lower extremity, which will be discussed later. The correlation coefficients also suggest that patients who performed higher numbers of NMES and volitional exercise sessions experienced larger gains in total CSA and NDM area.

Discussion

This is the first report of the use of NMES in patients with RA. In our series of 7 patients, those who completed greater numbers of NMES and volitional exercise sessions had higher gains in muscle CSA. The improvements in lean muscle mass, which ranged from 5.8% to 21%, seen in patients who completed at least one-third of the proposed intervention sessions are comparable to the changes reported in other studies. Marcora et al (16) measured leg lean mass by dual-energy x-ray absorptiometry (DEXA). They reported that their subjects with RA had experienced a mean improvement in leg lean mass of 6%, changing from 13.3 kg before to 14.1 kg after a 12-week progressive resistance training program. (16)

Hakkinen et al (18) measured muscle mass thickness of the quadriceps femoris muscle group in women with RA using a compound ultrasonic scanner and a 5-Mhz convex transducer. In their study, the mean relative increases in muscle mass thickness of the quadriceps femoris muscle was 7.4%, changing from 4.75 cm before to 5.1 cm after 21 weeks of combined strength and endurance training. We used percentages to compare the results of these studies because each study used a different technique to measure lean muscle mass.

Because the literature on intervention trials that investigated changes in skeletal muscle composition is scarce, it seems premature at this point to state that the changes in muscle area observed in our patients were clinically relevant. Studies with larger numbers of subjects are needed to investigate whether changes in muscle area are also related to changes in physical function. Furthermore, trials on exercise in patients with RA (10,16,18) have used methods to quantify body composition that cannot be directly compared with the method used with our patients (CT imaging). When comparing our data with data from studies that used CT imaging to measure quadriceps femoris muscle area, it seems that our patients had comparable quadriceps femoris muscle CSA. Taaffe et al (46) investigated 80 postmenopausal women who were healthy, aged 50 to 57 years, and reported a mean ([+ or -]SD) quadriceps femoris muscle CSA of 46 [+ or -] 7 [cm.sup.2]. Goodpaster et al (26) investigated 2,627 men and women between 70 and 80 years of age and reported a mean quadriceps femoris muscle CSA of 52.3 [+ or -] 13.6 [cm.sup.2]. Our patients had a median age of 61 years and a median quadriceps femoris muscle CSA of 47.5 [cm.sup.2].

Our multiple-patient case report could not determine whether NMES combined with exercises is better than NMES alone, which has to be determined in a randomized trial. We believe that both the NMES and the volitional exercises used by the patients in this report may have contributed in some degree to the changes in quadriceps femoris muscle strength. Several studies have shown that improvement in muscle strength can be achieved by volitional exercises (9-11) as well as by NMES treatment. (21-23) On the other hand, we believe that the changes in quadriceps femoris lean muscle mass observed in this report were more likely due to the NMES program than to the volitional exercises because our volitional exercise program was not of high intensity like the studies that have shown increases in lean muscle mass. (16,18) Studies involving patients with RA that used volitional exercise programs of moderate intensity have shown significant improvements in muscle strength without showing increases in lean muscle mass. (10,17)

The only 2 studies reporting a significant increase in lean muscle administered a high-intensity training program with strengthening exercises that included high resistance and high number of repetitions. (16,18) For example, in the 21-week program of Hakkinen et al, (18) the lower-extremity exercises included 2 exercises for the leg extensor muscles and 1 knee flexion or leg adduction/ abduction exercise, or both. During the first 7 weeks of training, the subjects trained with loads of 50% to 70% of their 1-repetition maximum, 10 to 15 repetitions per set and 3 to 4 sets of each exercise. By the final 7 weeks, the subjects were using 2 different load ranges for the leg extensors. The subjects completed 3 to 6 repetitions per set with loads of 70% to 80% of the 1-repetition maximum and 8 to 12 repetitions per set with loads of 50% to 60% of the 1-repetition maximum. The number of sets varied between 4 and 6.is In the study by Marcora et al, (16) the 12-week exercise program included 4 exercises for the lower extremities: leg press, leg extension, leg curl, and standing calf raise. The exercises were repeated 3 times per week, and each resistance exercise had 3 sets of 8 repetitions with a load corresponding to 80% of the 1-repetition maximum.

Neuromuscular electrical stimulation may be helpful to reverse the muscle atrophy experienced by patients with RA because it may predominantly affect type II muscle fibers. The cytokine-driven muscle atrophy observed in chronic inflammatory conditions appears to affect primarily type II muscle fibers. (47,48) Volitional muscle contractions appear to utilize type I muscle fibers more readily and to a greater extent than type II fibers, and type II fibers most likely are only approaching their maximum force production capabilities during near-maximal voluntary contractions. (49-51) Volitional exercises may need to be performed at near-maximum intensities to provide enough tension through the atrophied type II fibers to induce hypertrophy of these fibers. Such a high level of intensity may not be tolerated by all subsets of patients with RA.

There is evidence to suggest that electrically stimulated muscle contractions may more readily affect type II muscle fibers than volitional exercise. (20,21,52) In a recent review of the literature, Gregory and Bickel (53) presented physiologic, metabolic, and mechanical data that suggest that motor fiber recruitment via cutaneous electrical stimulation is most likely nonselective, spatially fixed, and temporally synchronous. The implication is that both type I and II fibers can be readily recruited with NMES. Although this pattern of motor recruitment is not representative of a reversal of motor recruitment order compared with volitional muscle activation, it is still different from the size of the principal order of recruitment observed in volitional activation. Gregory and Bicke1 (53) noted that a nonselective activation pattern also can explain clinical advantages with NMES in that all fibers of the muscle can be activated at relatively low contraction force levels. In patients who may not be able to perform volitional contractions intensely enough to activate type II fibers, NMES may help activate these fibers at lower, more tolerable contraction intensities.

Due to our small number of patients, the results of the associations reported in Table 5 should be interpreted with caution. For the most part, the trends in our report appear to agree with the only previous study that investigated the associations between body composition and physical function in patients with RA.16 Marcora et al (16) reported that change in leg lean mass correlated moderately with change in serf-reported function measured by the Advanced Activities of Daily Living Scale. They also reported a strong association between change in leg lean mass and the 30-second maximal sit-to-stand test. The association between knee extensor strength and leg lean mass was not reported.

In our report, the inconsistent trends between changes in knee extension torque and changes in quadriceps femoris muscle area for the most-affected and least-affected lower extremity were not expected. For the least-affected side, the patients who increased total CSA and NDM area had higher increases in extension torque; however, for the most-affected side, these patients had less of an increase in extension torque. We visually inspected the scatter plots for these data and observed that this negative trend was influenced by patients 6 and 7. Patient 6, who had a large improvement in NDM area (21%), improved only 9 N*m in quadriceps femoris muscle strength. Patient 7, who had a decrease of 3% in NDM area, improved 44 N*m in quadriceps femoris muscle strength. Studies with larger number of subjects should further investigate these associations.

One of our aims was to assess whether the NMES treatment would be well tolerated by patients with RA. One patient in our series did not tolerate the NMES treatment (patient 4). The patient complained of mild nausea, and her blood pressure rose during the electrical stimulation. The patient reported that the electrical stimulation was not painful but made her feel too anxious to endure it. Overall, she received 10 minutes of electrical stimulation with an intensity of 38 mA. This patient agreed to return for the 16-week follow-up to receive the CT imaging so that her change in muscle area could be compared with the changes of other patients. This patient's characteristics differed from those of the other patients on several aspects: she had a higher BMI and a shorter duration of disease, and she was the only patient with a history of depression. Future studies should investigate whether these factors are associated with adherence and outcome in patients with RA who receive NMES and exercise.

Two patients (patients 5 and 7) did not complete at least one third of the proposed treatment. The lack of adherence of these patients did not seem related to the use of NMES. Patient 5 did not complete participation because she had an RA flare-up. Both the patient and her physician attributed the flare-up to unexpected increase in physical activity on her job. The flare-up was treated with steroidal medication. After the flare-up was treated, the patient had to travel and was unable to return and complete the training program. Patient 7 lived 112 km (70 miles) away from our clinic, and she realized, after signing the consent form and starting treatment, that she could not commit to the regular supervised visits. She agreed to come back for the 16-week measurement session. These 2 patients denied that they were bothered by the electrical stimulation. One patient (patient 3) stopped the NMES and exercises at week 14 due to a flare-up of a chronic low back condition. This patient has had low back problems with frequent intervals. Even though the flare-up did not seem related to the performance of exercises, we advised the patient to stop the intervention at that time. Although still complaining of some back pain, the patient agreed to participate in the 16-week measurement session.

Because 4 out of 7 patients adhered to the intervention, the adherence rate of our patients does not seem different from that reported in the literature. Prior studies (54,55) reported rates of nonadherence to treatment among people with RA to be between 36% and 60%. Although it appears that the NMES was reasonably tolerated by the patients in our report, perhaps the NMES treatment could be better tolerated if the NMES dose maximizes gains in lean muscle and minimizes patient intolerance could be determined.

One of the reasons we performed this study was to explore the feasibility of an alternate modality to reverse muscle atrophy and enhance strength and functional status in subjects with RA. Some patients with RA referred for physical therapy may not be able to go through an intense exercise program. Other patients may have time constraints that prohibit a commitment to an intense facility-based exercise regimen. Our results indicate that treatment with NMES may be a reasonable option for such patients.

The studies that have shown increases in lean muscle mass enrolled only patients who were mildly disabled. (16, 18) It is not known how patients with different levels of disability or involvement of major weight-bearing joints would respond to intense exercise programs. Perhaps there are specific patients who will not tolerate intense exercises and for whom an alternative treatment, such as the use of NMES, may help to increase lean muscle mass. In this multiple-patient case report, we specifically included patients with mild to moderate disability. Further studies are need to compare the treatments using NMES with high-intensity exercise programs in patients with a broader spectrum of disabilities.

Due to the inherent characteristic of a descriptive study with a small number of patients, this multiple-patient case report has several limitations. It is possible that factors such as level of physical activity, initial level of disability, psychosocial factors, use of medication, diet, and comorbidities, which we did not control or record, may have affected the outcomes of our patients. We cannot determine from our multiple-patient case report whether NMES combined with exercises is superior to exercise alone or to NMES alone in improving quadriceps femoris muscle strength, lean muscle mass, and overall function.

The lack of a control group raises the possibility that the changes observed on the outcome measures have occurred spontaneously rather than as a result of the intervention. Because prior studies have shown no changes in lean muscle mass unless a highly intense strength training program was used, (10,16-18) we believe that changes in lean muscle mass in patients with RA do not happen spontaneously. Furthermore, we have measured lean muscle mass by CT imaging, which is regarded as an imaging technique that provides accurate estimates of fat and skeletal muscle in vivo. (25,56,57) Consequently, the changes in lean muscle mass observed in our patients probably were due to true changes and not due to measurement error. Therefore, NMES seems to be a viable treatment option to address muscle atrophy and weakness in patients with RA.

Dr Piva, Dr Goodnite, Dr Goodpaster, Dr Chester Wasko, and Dr Fitzgerald provided concept/idea/project design. Dr Piva, Dr Goodnite, Mr Woollard, and Dr Fitzgerald provided writing. Dr Goodnite, Dr Azuma, and Mr Woollard provided data collection. Dr Piva, Dr Azuma, Mr Woollard, and Dr Fitzgerald provided data analysis. Dr Goodnite and Dr Fitzgerald provided project management. Dr Fitzgerald provided fund procurement. Dr Chester Wasko provided patients. Dr Goodpaster and Dr Fitzgerald provided facilities/equipment. Dr Azuma, Dr Goodpaster, and Dr Chester Wasko provided consultation (including review of manuscript before submission).

Appendix.

Volitional Lower-Extremity Strengthening Program

Stationary Cycling: With the seat height of the stationary bicycle adjusted so that the knee could be fully extended on the downstroke of the cycling movement, the patient was instructed to cycle at a self-selected, comfortable speed with low resistance for 5 minutes.

Isometric Quadriceps Femoris Muscle Contractions: In a long-sitting position with the knees extended, the patient was instructed to isometrically contract the quadriceps femoris muscles bilaterally for 3-5 seconds as vigorously as possible without reproducing pain. Exercise was progressed from 10 contractions to 30 contractions as tolerated.

Seated Knee Extension Isometrics: Seated on a leg extension exercise device with the knee comfortably positioned between 90o and 60o of flexion, the patient pushed against the force pad of the extension device as vigorously as possible without producing pain. The patient was instructed to hold the contraction for 5 seconds. The patient performed 4 sets of 6 contractions, with 30 seconds of rest between sets.

Supine Straight Leg Raises: In a supine position and the contralateral limb knee flexed so that the foot was resting comfortably in a foot-flat position, the patient raised the exercise limb with the knee in full extension to the height of the contralateral flexed knee, then lowered the limb back to the initial position. The exercise was progressed by applying cuff weights to the ankles as tolerated. Exercise was performed on each limb.

Standing Calf Raises: Standing with both feet flat on the floor, the patient raised up on the toes as high as possible, holding for 1-2 seconds, then returned to the foot-flat position.

Wall Slides: Positioned against a wall with feet approximately shoulder-width apart, the patient squatted down until the knees were bent at approximately 50o and then returned to a standing position.

Step-downs: Standing on a step with one foot, the patient bent the knee of the foot placed on the step until the heel of the opposite foot slightly touched the floor in front. The patient then re-straightened the knee on the step. The exercise was initiated on a 5.08-cm (2-in) step and the height of the step was progressed as tolerated during the next treatment session. The exercise was performed bilaterally.

Sit-to-Stand: Sitting on a chair with both feet flat on the floor and the hips flexed to 90[degrees], the patient stood up for 5 seconds and then sat back down in the chair. The patient was permitted to use the armrests for assistance; however, the exercise should be progressed to standing without upper-extremity assistance.

The last 5 exercises (supine straight leg raises, standing calf raises, wail slides, step-downs, and sit-to-stand) were progressed from 10 repetitions to 3 sets of 10 repetitions with 30 seconds rest between sets.

The home component of the volitional lower-extremity strengthening program consisted of at least 3 of the above exercises as indicated by the therapist plus 4 strengthening exercises for the hip muscles. The strengthening exercises for the hip were performed with the patient standing with an elastic band secured to the ankle and with the opposite end secured to a door jam. The hip exercises were progressed from 10 repetitions to 3 sets of 10 repetitions, with 30 seconds of rest between sets, and also were progressed by increasing the resistance of the elastic band:

(1) facing away from the door, the patient flexed the hip, keeping the knee straight.

(2) facing the door, the patient extended the hip, keeping the knee straight.

(3) standing sideways from the door such that the leg with the elastic band was more distant from the door, the patient abducted the hip.

(4) standing sideways from the door such that the leg with the elastic band was closer to the door, the patient adducted the hip.

The authors thank Empi for providing the portable stimulator units for the treatment of the patients in this multiple-patient case report.

The study was approved by the University of Pittsburgh Institutional Review Board, IRB protocol number 0410089.

This article was submitted April 25, 2006, and was accepted March 29, 2007.

DOI: 10.2522/ptj.20060123

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* Research Systems Inc (RSI), now ITT Visual Information Solutions, 4990 Pearl East Circle, Boulder, CO 80301.

([dagger]) Chattanooga Group Inc, 4717 Adams Rd, Hixson, TN 37343.

([double dagger]) Empi, 599 Cardigan Rd, St Paul, MN 55126-4099.

SR Piva, PT, PhD, OCS, FAAOMPT, is Assistant Professor, Department of Physical Therapy, School of Health and Rehabilitation Sciences, University of Pittsburgh, 6035 Forbes Tower, Pittsburgh, PA 15260 (USA). Address all correspondence to Dr Piva at: [e-mail].

EA Goodnite, PT, MS, DPT, is Physical Therapist, Keesler Air Force Base Medical Center, Biloxi Miss.

K Azuma, MD, is Postdoctoral Fellow, Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh.

JD Woollard, PT, MS, is Doctoral Candidate, Department of Physical Therapy, School of Health and Rehabilitation Sciences, University of Pittsburgh

BH Goodpaster, PhD, is Assistant Professor, Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh.

M Chester Wasko, MD, is Associate Professor, Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh.

GK Fitzgerald, PT, PhD, OCS, is Associate Professor, Department of Physical Therapy, School of Health and Rehabilitation Sciences, University of Pittsburgh.

[Piva SR, Goodnite EA, Azuma K, et al. Neuromuscular electrical stimulation and volitional exercise for individuals with rheumatoid arthritis: a multiple-patient case report. Phys Ther. 2007;87:10641077.]

Table 1.
Baseline Demographic, History Characteristics, and Medications Used by
the Patients to Treat Rheumatoid Arthritis (RA) or Related Symptoms (a)

Patient   Age   Sex   Ethnicity    Height   Weight   BMI
No.       (y)                      (cm)              (kg/[m.sup.2])
                                            (kg)

1         69    F     White        163      84       31.6

2         61    F     White        168      70       24.8

3         76    F     African      150      63       28.0
                        American

4         54    F     White        160      94       36.7

5         61    F     White        163      80       30.1

6         80    M     White        180      93       28.7

7         39    F     White        160      80       31.3

Patient   Age at     Disease    Additional Health
No.       Onset of   Duration   Problems
          RA (y)     (y)

1         64         5          None

2         39         22         Hypothyroidism
                                Gastritis

3         63         13         None
                                New episode of back pain
                                  during intervention
                                  period

4         52         2          Asthma
                                Depression

5         31         30         None

6         64         16         Gastritis

7         32         7          Gastritis

Patient   RA-Related Medication
No.
          Baseline        16-Week

1         Methotrexate    No change
          Remicade (b)

2         Celecoxib       No change
          Enbrel (c)
          Methotrexate
          Plaquenil (d)
          Prednisone

3         Aspirin         Aspirin
          Enbrel (c)      Enbrel (c)
                          Acetaminophen
                          Diclofenac

4         Celecoxib       N/A
          Methotrexate
          Enbrel (c)
          Prednisone

5         Valdecoxib      Valdecoxib
          Humira (e)      Humira (e)
                          Prednisone

6         Arava (d)       No change
          Methotrexate
          Prednisone

7         Aspirin         Aspirin
          Ibuprophen      Humira (e)
          Humira (e)      Medrol (f)

(a) BMI=body mass index, F=female, M=male, N/A=not available.

(b) Centocor Inc, 200 Great Valley Pkwy, Malvern, PA 19355.

(c) Amgen Inc, One Amgen Center Dr, Thousand Oaks, CA 91320-1799.

(d) Sanofi Aventis, 55 Corporate Dr, Bridgewater, NJ 08807.

(e) Abbott Laboratories, Pharmaceutical Product Division, North
Chicago, IL 60064.

(f) Pharmacia & Upjohn, A Division of Pfizer, 235 E 42nd St, New
York, NY 10017-5755.

Table 2.
Adherence to Supervised and Home Intervention, Total Number of
Sessions, and Intensity of Neuromuscular Electrical Stimulation
(NMES) During First and Last Sessions

Patient   No. of Supervised     No. of Home NMES    Total
No.       NMES and Volitional   and Volitional      No. of
          Exercise Sessions     Exercise Sessions   Sessions

1         12                    34                  46
2         11                    33                  44
3          9                    31                  40
4          1                     0                   1
5          7                    11                  18
6         12                    48                  60
7          3                     3                   6

Patient   NMES Intensity
No.       During Sessions
          (First-Last Session)

1         44 mA-59 mA
2         43 mA-70 mA
3         60 mA-90 mA
4         38 mA-N/A (a)
5         55 mA-80 mA
6         77 mA-87 mA
7         28 mA-37 mA

(a) N/A=not available.

Table 3.
Data of the Initial and Final Measurement Sessions From the
Computerized Tomographic Imaging of the Quadriceps Femoris
Muscles (a)

Patient   Total CSA ([cm.sup.2])

No.       Most-Affected       Least-Affected
          Side                Side

          Initial   16-Week   Initial   16-Week

1         42.8      45.7      44.2      46.3
2         38.3      39.4      39.5      39.6
3         N/A       N/A       N/A       N/A
4         50.7      51.9      52.2      51.5
5         38.5      38.9      34.6      35.0
6         51.7      57.2      54.9      60.5
7         51.5      49.4      50.9      47.9

Patient   NDM ([cm.sup.2])

No.       Most-Affected       Least-Affected
          Side                Side

          Initial   16-Week   Initial   16-Week

1         32.8      35.1      33.9      36.0
2         30.8      32.6      32.0      34.6
3         N/A       N/A       N/A       N/A
4         43.6      43.9      45.2      43.2
5         31.3      33.9      27.5      30.1
6         41.2      49.8      44.4      52.2
7         45.3      44.0      44.5      41.4

Patient   Adipose Tissue (Subfascial +
          Intermuscular) ([cm.sup.2])

No.       Most-Affected       Least-Affected
          Side                Side

          Initial   16-Week   Initial   16-Week

1         2.0       2.4       1.7       2.1
2         0.6       0.6       0.1       0.3
3         N/A       N/A       N/A       N/A
4         1.3       1.3       1.9       1.9
5         1.0       1.1       1.5       0.9
6         1.5       1.0       1.3       1.0
7         1.4       1.3       0.7       0.8

(a) CSA=cross-sectional area, NDM=normal density muscle,
N/A-not available.

Table 4.
Data From Initial and Final Measurement Sessions on Extension Torque,
Time to Perform the Chair Rise Test, Health Assessment Questionnaire
Disability Index (HAQ-DI), and Lower Extremity Function Scale (LEFS)

Patient   Extension Torque (N-m)              Timed Chair Rise
No.                                           (s)
          Most-Affected      Least-Affected
          Side               Side

          Initial  16-       Initial   16-    Initial   16-
                   Week                Week             Week

1         106      129       98        118    15.4      12.5
2         117      140       122       143    17.4      12.6
3         101      66         89        85    17.2      13.8
4         155      N/A (c)   191       N/A    17.1      N/A
5          45       54        38        43    15.1      10.2
6         175      184       176       201    18.1       8.5
7         107      151       195       173     8.5       7.6

Patient   HAQ-DI (0-3) (a)   LEFS (0-80) (b)
No.
          Initial   16-      Initial   16-
                    Week               Week

1         0.13      0.13     51        59

2         0.88      0.50     48        45
3         1.88      2.00     24        23
4         1.00      N/A      32        N/A
5         0.88      1.00     59        59
6         0.00      0.00     77        80
7         0.00      0.38     77        54

(a) Lower score indicates less disability.

(b) Higher score indicates better function.

(c) N/A = not available.

Table 5.
Associations Between Changes in Quadriceps Femoris Muscle Area for
the Most-Affected and Least-Affected Lower Extremities and Changes
in Knee Extension Torque, Timed Chair Rise, Health Activity
Questionnaire Disability Index (HAQ-DI) and Lower Extremity Function
Scale (LEFS) Scores, and the Total Number of Neuromuscular Electrical
Stimulation (NMES) Sessions (Supervised + Home Sessions) (a)

                      Change in Total CSA    Change in NDM
                      ([cm.sup.2])           ([cm.sup.2])

                      Most       Least       Most        Least
                      Affected   Affected    Affected    Affected
Change in extension
    torque
  Spearman rho         -.60        .70        -.90 (b)      .70
  P                     .29        .19         .04          .19
  N                       5          5           5            5
Change in timed
    chair rise
  Spearman rho         -.70       -.60        -.70         -.90 (b)
  P                     .19        .28         .19         -.04
  N                       5          5           5            5
Change in HAQ-DI
  Spearman rho         -.67       -.36        -.21         -.36
  P                     .22        .55         .74          .55
  N                       5          5           5            5
Change in LEFS
  Spearman rho          .80        .90         .70          .40
  P                     .10        .04         .18          .51
  N                       5          5           5            5
Total no. of NMES
    sessions
  Spearman rho          .66        .89 (b)     .77          .71
  P                     .16        .20         .07          .11
  N                       6                      6            6

                      Change in Adipose
                      Tissue ([cm.sup.2])

                      Most       Least
                      Affected   Affected
Change in extension
    torque
  Spearman rho          .30        .10
  P                     .62        .87
  N                       5          5
Change in timed
    chair rise
  Spearman rho          .40        .30
  P                     .51        .66
  N                       5          5
Change in HAQ-DI
  Spearman rho         -.10       -.46
  P                     .87        .43
  N                       5          5
Change in LEFS
  Spearman rho          .40        .20
  P                     .51        .75
  N                       5          5
Total no. of NMES
    sessions
  Spearman rho          .03        .14
  P                     .96        .79
  N                       6          6

(a) CSA=cross-sectional area, NDM=normal density muscle.

(b) Correlation is significant at the .05 level (2-tailed).