Arthritis & Rheumatism (Arthritis Care & Research)

Vol. 61, No. 12, December 15, 2009, pp 1726 –1734

DOI 10.1002/art.24891
© 2009, American College of Rheumatology
ORIGINAL ARTICLE

Effects of High-Intensity Resistance Training in

Patients With Rheumatoid Arthritis: A
Randomized Controlled Trial
ANDREW B. LEMMEY,1 SAMUELE M. MARCORA,1 KATHRYN CHESTER,1 SALLY WILSON,1
FRANCESCO CASANOVA,1 AND PETER J. MADDISON2

Objective. To confirm, in a randomized controlled trial (RCT), the efficacy of high-intensity progressive resistance
training (PRT) in restoring muscle mass and function in patients with rheumatoid arthritis (RA). Additionally, to
investigate the role of the insulin-like growth factor (IGF) system in exercise-induced muscle hypertrophy in the context
of RA.
Methods. Twenty-eight patients with established, controlled RA were randomized to either 24 weeks of twice-weekly
PRT (n ⴝ 13) or a range of movement home exercise control group (n ⴝ 15). Dual x-ray absorptiometry–assessed body
composition (including lean body mass [LBM], appendicular lean mass [ALM], and fat mass); objective physical function;
disease activity; and muscle IGFs were assessed at weeks 0 and 24.
Results. Analyses of variance revealed that PRT increased LBM and ALM (P < 0.01); reduced trunk fat mass by 2.5 kg
(not significant); and improved training-specific strength by 119%, chair stands by 30%, knee extensor strength by 25%,
arm curls by 23%, and walk time by 17% (for objective function tests, P values ranged from 0.027 to 0.001 versus controls).
In contrast, body composition and physical function remained unchanged in control patients. Changes in LBM and
regional lean mass were associated with changes in objective function (P values ranged from 0.126 to <0.0001).
Coinciding with muscle hypertrophy, previously diminished muscle levels of IGF-1 and IGF binding protein 3 both
increased following PRT (P < 0.05).
Conclusion. In an RCT, 24 weeks of PRT proved safe and effective in restoring lean mass and function in patients with
RA. Muscle hypertrophy coincided with significant elevations of attenuated muscle IGF levels, revealing a possible
contributory mechanism for rheumatoid cachexia. PRT should feature in disease management.

INTRODUCTION rheumatoid cachexia (2), and increased adiposity are as-

Rheumatoid arthritis (RA) is characterized by, and a major
cause of disability. Recently, Giles et al (1) showed that
disability in patients with RA is linked to adverse changes
in body composition, with mean Health Assessment Ques-
tionnaire (HAQ) scores being inversely related to appen-
dicular lean mass (ALM; a surrogate measure of skeletal
muscle mass), and directly related to appendicular fat
mass. Unfortunately, both reduced muscle mass, termed
Supported by the Arthritis Research Campaign (UK)
(grant L0563).
1
Andrew B. Lemmey, PhD, Samuele M. Marcora, PhD,
Kathryn Chester, MPhil, Sally Wilson, MSc, Francesco
Casanova, MSc: Bangor University, Bangor, UK; 2Peter J.
Maddison, MD: Bangor University and Gwynedd Hospital,
Bangor, UK.
Address correspondence to Andrew B. Lemmey, PhD,
SSHES, Bangor University, George Building, Bangor, Gwyn-
edd, UK, LL57 2PZ. E-mail: a.b.lemmey@bangor.ac.uk.
Submitted for publication April 7, 2007; accepted in re-
vised form August 19, 2009.
sociated with RA (3). In fact, according to the definitions
proposed by Baumgartner et al (4), 67% of our whole-body
dual x-ray absorptiometry (DXA)–assessed patients with
RA are muscle wasted, and 80% are obese (5–7).
Relative to age- and sex-matched healthy sedentary con-
trols, the loss in lean body mass (LBM) that we observe
averages ⬃15% (Lemmey et al: unpublished observations);
a magnitude in accordance with the 14 –16% reductions in
body cell mass identified by Roubenoff et al for patients
with RA (8,9). This degree and prevalence of rheumatoid
cachexia is alarming because, in addition to diminished
function and increased disability, muscle loss is associ-
ated with impaired immune and pulmonary function, os-
teoporosis, glucose intolerance, and increased mortality
(10). Consequently, interventions that can increase muscle
mass in cachectic individuals have the potential to im-
prove physical performance and decrease morbidity and
mortality (11).
In a nonrandomized pilot study (5), we showed that 12
weeks of high-intensity progressive resistance training

1726
Resistance Training in RA
(PRT; 3 days/week) significantly increased LBM and ALM,
decreased percent body fat, and substantially improved
objective functional capacity in cachectic patients with
RA. Similarly, Hakkinen et al (12) subsequently found that
combined strength and aerobic training increased thigh
muscle mass and decreased thigh fat mass in female pa-
tients with RA. However, these body composition results
are at odds with the earlier investigation of Rall et al (13),
in which PRT failed to augment LBM in patients with RA.
Therefore, the efficacy of PRT in restoring muscle mass in
patients with RA requires confirmation.
Also awaiting clarification are the mechanisms by which
exercise-induced improvements are made, and further in-
sights into the pathology of rheumatoid cachexia are also
needed. It is likely that the insulin-like growth factor (IGF)
system plays a key role in these processes, because IGF-1
produced locally in the muscle (mIGF-1) is thought to
regulate adult skeletal muscle maintenance and its hyper-
trophic adaptation to increased loading (14). In support of
this, significantly reduced mIGF-1 levels have been iden-
tified in conditions characterized by muscle wasting
(15–18). Furthermore, the success of exercise training in
restoring muscle mass in these conditions appears to be
dependent on whether mIGF-1 levels respond to the exer-
cise stimulus (15,18,19).
Consequently, in the current randomized controlled
study we aimed to confirm our preliminary observations
(i.e., that PRT reverses debilitating cachexia and improves
function in patients with RA), and to investigate the role
of the local IGF system in exercise-induced hypertrophy of
skeletal muscle in patients with RA.
PATIENTS AND METHODS
Study design and ethics. This was a randomized, con-
trolled intervention trial conducted July 2004 –January
2007. Approval was received from the North West Wales
National Health Service Trust Research Ethics Committee.
Subject recruitment and eligibility. Sample size was
determined by power calculations for the primary out-
come variable: ALM. This calculation, based on the mean
ALM change (0.93 kg) for PRT subjects in our pilot study
(4), assumed normal distribution, 2 groups, equal variance,
no change in the control group, a common SD for each
group (i.e., the SD for our pilot study PRT group, 0.46 kg)
(4), ␣ ⫽ 0.05, and power ⫽ 0.80, resulted in a requirement
of 5 subjects per group. To account for potential dropouts,
we aimed to recruit 18 subjects per group (i.e., a total of 36
patients).
The progress of patients through the study is depicted in
Figure 1. Thirty-six eligible volunteer patients (Table 1)
from the Gwynedd Rheumatology Department were ran-
domized to either a high-intensity PRT group or to a home-
based, low-intensity range of movement (ROM) exercise
(control) group by stratified random allocation, with age,
sex, and estrogen status serving as the stratified variables.
Of these, 28 attended baseline assessment and commenced
training.
1727
Outcome measures. Assessments were conducted at
baseline (pretest) and immediately following (posttest) the
24-week training period. For each assessment, subjects
presented at approximately the same time of day, having
fasted and refrained from strenuous exercise for 24 hours.
Body composition. Total and regional lean and fat
masses were measured with a whole-body pencil-beam
DXA scanner (QDR1500, software version V5.72; Hologic,
Waltham, MA). Subsequently, ALM (i.e., total arms ⫹ legs
soft–lean mass), a proxy measure of total body skeletal
muscle mass (20), was determined (21); relative skeletal
muscle index was calculated (ALM [kg]/height [m2]) (7);
and percent body fat was estimated. Relative skeletal mus-
cle index and percent body fat were then used to deter-
mine whether patients were cachectic, obese, or, if both,
cachectic-obese, according to the definitions of Baumgart-
ner et al (4).
Immediately following DXA scanning, bioelectrical im-
pedance spectroscopy (Hydra 4200; Xitron Technologies,
San Diego, CA) was performed to estimate extracellular
water and total body water (TBW). Checking these is nec-
essary because DXA measures of body composition are
affected by edema. By combining DXA and bioelectrical
impedance spectroscopy data, we estimated total body
protein using the model of Fuller et al (22), i.e., LBM in
grams minus (0.2302 ⫻ total bone mineral content in
grams) minus TBW in grams.
Muscle strength, physical function, and habitual physi-
cal activity. PRT-specific strength was determined by the
total weight lifted per session (i.e., ⌺ [resistance in kg ⫻
number of sets ⫻ repetitions per set] for each exercise). To
account for the initial neural adaptations (i.e., increased
strength due to enhanced muscle fiber recruitment), base-
line measures for training-specific strength were taken af-
ter 2 weeks of PRT. Maximal voluntary isometric knee
extensor strength (KES; at a fixed joint angle of 90°) was
measured by an isokinetic dynamometer (Kin-com, Chat-
tanooga, TN). Objective physical function was addition-
ally measured by tests from the Senior Fitness Test (23): a
30-second arm curl, a 30-second chair stand, and a 50-foot
walk.
Subjective, patient-reported physical disability was as-
sessed with the Multidimensional HAQ (MDHAQ) (24).
Habitual physical activity was estimated by electronic pe-
dometers (Digiwalker DW 200; Yamax, Tokyo, Japan) worn
during all waking hours of the first (pretest) and last (post-
test) weeks of training. For statistical analyses, the average
number of daily steps for each of the 2 assessment weeks
was used.
Muscle biopsies and blood sampling. From patients who
consented (PRT group n ⫽ 9, control group n ⫽ 5), muscle
biopsy specimens from vastus lateralis were obtained, as
previously described (17), prior to and 3–7 days after the
intervention period. Clotted venous blood was collected
from all subjects at 0 and 24 weeks, following an overnight
fast. Muscle and serum samples were stored at ⫺70°C.
IGF system assays. Muscle IGF-1 and IGF binding pro-
tein 3(IGFBP-3), and serum IGF-1, IGF-2, IGFBP-1, and
IGFBP-3 levels were measured in triplicate by specific,
in-house radioimmunoassays using established tech-
niques (25–27). The intraassay and interassay coefficient
1728
Figure 1. Flow of participants through each stage of the trial.
GP ⫽ general practitioner.
of variations were 3% and 15%, respectively, for IGF-1,
5% and 14%, respectively, for IGF-2, 4% and 13%, respec-
tively, for IGFBP-1, and were 4% and 14%, respectively,
for IGFBP-3. To assess IGFBP-3 protease activity, serum
was analyzed by Western immunoblotting, and the per-
centage of fragmented IGFBP-3 was estimated from the
pixel densities of the 3 bands (43– 46-kd doublet and 30-kd
fragment) (28). Muscle IGF-1 and IGFBP-3 values were
expressed per total muscle protein.
Disease activity and inflammation. Disease activity was
assessed by the Disease Activity Score in 28 joints (DAS28)
(29), and systemic inflammation by the erythrocyte sedi-
mentation rate (ESR).
Exercise intervention. After baseline assessment, sub-
jects in the PRT group trained twice a week for 24 weeks
at a community gym under the supervision of exercise
physiologists (KC, SW, and FC). The PRT program con-
sisted of 3 sets of 8 repetitions with a load corresponding
to 80% of the 1-repetition maximum (1-RM; i.e., the max-
imum load lifted for each of the prescribed exercises), with
1–2 minutes of rest between sets, for each of the following
multi-stack machine exercises: leg press, chest press, leg
Lemmey et al
extension, seated rowing, leg curl, triceps extension,
standing calf raises, and bicep curl.
Training volumes and intensities such as this are con-
sidered optimal for inducing muscle hypertrophy (30). To
reduce muscle soreness, only 1 set was performed for each
exercise in the first week and only 2 sets were performed
in the second week. To further facilitate adaptation, 15
repetitions/set at 60% of 1-RM were performed in weeks
1– 4 and 12 repetitions/set at 70% of 1-RM were performed
in weeks 5 and 6, before progressing to 8 repetitions/set at
80% of 1-RM in weeks 7–24. To ensure maintenance of
relative intensities, the 1-RMs were reassessed every 4
weeks. PRT sessions were preceded by a warmup and
ended by a cool down, each comprising 10 minutes of
low-intensity ROM exercises. Following instruction, con-
trol subjects were asked to perform these ROM exercises
twice weekly at home. ROM exercise was chosen as a
control condition because this form of exercise, while
being the type most commonly prescribed for patients
with RA, features insufficient intensity to elicit muscle
hypertrophy (30). A training diary was maintained by all
patients so that compliance and any adverse effects could
be evaluated; additionally, control patients were phoned
every two weeks. Other than their directed training, sub-
jects were instructed to maintain their habitual physical
activity levels and diet during the experimental period.
Statistical analysis. Differences between groups at base-
line were examined using multiple paired t-tests for con-
tinuous variables and Fisher’s exact probability test for
categorical variables. Where no difference was confirmed,
treatment effects were assessed by multiple 2 ⫻ 2 (time ⫻
group) factor analyses of variance with repeated measures
for time. The assumptions of sphericity and normality
of distribution were verified by Mauchly’s test and the
Kolmogorov-Smirnov test, respectively. The effect size for
the time ⫻ group interaction was calculated as eta squared
Table 1. Eligibility criteria for inclusion in the study*
Criteria
Fulfills the ACR 1987 revised criteria for the diagnosis of
rheumatoid arthritis (44)
Age ⱖ18 years
Functional class I or II
Not cognitively impaired
Antiinflammatory and/or antirheumatic drug therapy has
been stable for the previous 3 months
If on corticosteroids, maintained on a dosage ⬍10 mg/day
Free of other cachectic diseases (e.g., cancer, HIV
infection)
Free of medical conditions contraindicating regular high-
intensity exercise
Not taking drugs or nutritional supplements known to be
anabolic
Not currently undertaking regular, intense physical
training
Not pregnant
* ACR ⫽ American College of Rheumatology (formerly the Ameri-
can Rheumatism Association); HIV ⫽ human immunodeficiency
virus.
Resistance Training in RA
(␩2), with thresholds for small, moderate, large, and very
large effects set at 0.01, 0.08, 0.26, and 0.50, respectively.
After pooling both groups’ data, Pearson’s correlation co-
efficient (r) was employed to assess the significance of
hypothesized relationships (e.g., changes in arm and leg
lean mass and changes in objective measures of upper- and
lower-body function, respectively). P values less than 0.05
were considered statistically significant, and P values
ranging from 0.05 to 0.10 were considered a trend. Data
were analyzed using the Statistical Package for the Social
Sciences, version 14 (SPSS, Chicago, IL), and are pre-
sented as the mean ⫾ SD.
RESULTS
Twenty-eight patients with established, stable RA com-
pleted baseline assessment and commenced either high-
intensity PRT (n ⫽ 13) or home-based ROM exercise
(control; n ⫽ 15) (Figure 1). At baseline, the groups were
not significantly different for age, sex, disease duration,
current disease activity and medication, or estrogen status
(Table 2). The subjects who provided muscle biopsy spec-
imens for investigation of local IGF responses to training
were not different from their respective groups (either
demographically or in training response; data not shown).
Compliance, training effect, and safety. Compliance to
training was good for the PRT group. Of the 48 scheduled
sessions, subjects completed on average 34.6 sessions
(range 11– 45 sessions), i.e., 73% of the sessions. The ef-
fectiveness of the PRT program was apparent from the
mean total session load lifted by each patient, which in-
creased from 4,931 kg at week 2 (training baseline) to
10,803 kg by week 24 (P ⬍ 0.0001); an increase in training-
specific strength of 119%.
Subjects in the ROM exercise control group reported
relatively good compliance for a home-based program,
with an average of 25.9 sessions (range 11– 48 sessions)
completed, i.e., 54%. No training-related injuries or other
adverse events were reported by subjects in either group.
Despite its high intensity and volume, the PRT program
did not exacerbate disease activity (mean ⫾ SD DAS28
score pretest versus posttest: 3.29 ⫾ 1.27 versus 3.12 ⫾
1.34 for the PRT group and 3.28 ⫾ 1.27 versus 3.56 ⫾ 0.71
for the control group; P ⫽ 0.471 for the interaction), or
systemic inflammation (mean ⫾ SD ESR pretest versus
posttest: 18.0 ⫾ 12.5 mm/hour versus 17.5 ⫾ 10.5 mm/
hour for the PRT group and 26.2 ⫾ 15.1 mm/hour versus
31.1 ⫾ 16.4 mm/hour for the control group; P ⫽ 0.285 for
the interaction).
Body composition. The effects of 24 weeks of exercise
training on DXA-assessed body composition are presented
in Table 3. PRT increased both total LBM (mean ⫾ SD
1,536 ⫾ 1,471 gm) and ALM (1,211 ⫾ 1,235 gm), which is
a more precise measure of muscle mass. Conversely, over
the same period the control subjects lost an average of
⬃400 gm and ⬃160 gm in LBM and ALM, respectively.
Analyses of the bioelectrical impedance spectroscopy
data confirmed that the PRT-induced increases in lean
1729
Table 2. Baseline characteristics of patients with RA in
the PRT and control groups*
PRT Control
Variable (n ⴝ 13) (n ⴝ 15) P†
Age, years 55.6 ⫾ 8.3 60.6 ⫾ 11.2 0.201
No. women/men 11/2 12/3 0.686
Disease duration, 74 ⫾ 76 125 ⫾ 101 0.146
months
DAS28 score 3.29 ⫾ 1.27 3.28 ⫾ 1.07 0.989
Postmenopausal, 9 9
no. patients
ERT, no. patients 1 0
* Values are the mean ⫾ SD unless otherwise stated. RA ⫽ rheu-
matoid arthritis; PRT ⫽ progressive resistance training; DAS28 ⫽
Disease Activity Score in 28 joints; ERT ⫽ estrogen replacement
therapy.
† For continuous variables, differences between groups were exam-
ined using multiple paired t-tests.
mass were not attributable to fluid retention, because no
changes in extracellular water were observed (mean
⫾ SD pretest versus posttest: 13.94 ⫾ 1.75 liters versus
13.97 ⫾ 1.51 liters for the PRT group and 14.61 ⫾ 1.98
liters versus 14.77 ⫾ 2.06 liters for the con-
trol group; P ⫽ 0.934 for the interaction). Consistent with
this data is an increase in mean estimated total body pro-
tein (⫹1,796 gm) following PRT, contrasting with a numer-
ical loss for the controls (⫺413 gm). Seemingly large losses
of total fat mass (⫺2,298 gm and ⫺1,326 gm for the PRT
and control groups, respectively) and trunk fat mass
(⫺2,500 gm and ⫺1,318 gm, respectively) were observed
over the intervention period, although none of these
changes approached significance. Additionally, PRT re-
duced the number of patients classified as cachectic,
obese, and cachectic-obese, whereas low-intensity ROM
training failed to modify this classification in control pa-
tients (Table 3).
Physical function. As anticipated, the anabolic effects
of our PRT program concurred with improvements in
objectively assessed physical function (Table 4). Relative
to baseline, mean performance improved by 30% for the
30-second chair stand test, 25% for KES, 23% for the
30-second arm curl test, and 17% for the 50-foot walk
following PRT. The ␩2 for these improvements indicate
large treatment effects. These PRT-induced improvements
saw our patients with established RA attain or surpass
the respective 50th percentile performance score (sex-
weighted) for healthy, age-matched individuals for the
chair stand, arm curl, and walk tests (23) (Table 4). In
contrast, no changes in performance were observed in
control patients.
The link between muscle mass and physical function is
underlined by the correlations between increases in lean
mass and improvements in performance. Therefore, change
in LBM was consistent with changes in the scores of the
50-foot walk test (r ⫽ ⫺0.613, P ⬍ 0.0001), the chair rise
test (r ⫽ 0.383, P ⬍ 0.05), the arm curl test (r ⫽ 0.292, P ⫽
0.064), and KES (r ⫽ 0.251, P ⫽ 0.09). More specifically,
change in arm lean mass correlated with change in the
1730 Lemmey et al

Table 3. Effects of 24 weeks of high-intensity PRT on body composition in patients

with RA*

PRT group Control group

Variable (n ⴝ 13) (n ⴝ 15) P† ␩2‡

Lean body mass

Pretest 37.25 ⫾ 3.95 40.42 ⫾ 8.92
Posttest 38.79 ⫾ 4.17 40.02 ⫾ 8.68 0.006§ 0.26
Appendicular lean mass
Pretest 14.29 ⫾ 1.78 15.65 ⫾ 4.07
Posttest 15.48 ⫾ 2.24 15.49 ⫾ 3.98 0.002§ 0.33
Total body protein
Pretest 6.40 ⫾ 2.02 7.66 ⫾ 3.56
Posttest 8.20 ⫾ 1.84 7.25 ⫾ 3.93 0.004§ 0.28
Total fat mass
Pretest 27.83 ⫾ 11.95 31.26 ⫾ 8.74
Posttest 25.53 ⫾ 10.75 29.93 ⫾ 10.43 0.657
Trunk fat mass
Pretest 14.00 ⫾ 6.46 16.11 ⫾ 5.70
Posttest 11.50 ⫾ 5.23 14.79 ⫾ 6.09 0.489
Cachectic, no.¶
Pretest 9 7
Posttest 4 7
Obese, no.#
Pretest 10 12
Posttest 7 12
Cachectic-obese, no.**
Pretest 5 5
Posttest 2 5

* Values are the mean ⫾ SD in kilograms unless otherwise stated. PRT ⫽ progressive resistance training;
RA ⫽ rheumatoid arthritis.
† For group ⫻ time interaction.
‡ Effect size, with thresholds for small, moderate, large, and very large effects set at 0.01, 0.08, 0.26, and
0.50, respectively.
§ Significant.
¶ Relative skeletal muscle index ⱕ5.45 kg/m2 and ⱕ7.26 kg/m2 for women and men, respectively (4).
# Percent body fat ⱖ38% and ⱖ27% for women and men, respectively (4).
** Coincidence of both cachexia and obesity.

Table 4. Effects of 24 weeks of high-intensity PRT on objectively assessed physical function in patients
with RA*

PRT group Control group Healthy

Variable (n ⴝ 13) (n ⴝ 15) P† ␩2‡ controls§

30-second arm curl test, reps

Pretest 16.1 ⫾ 4.9 14.5 ⫾ 4.1
Posttest 19.8 ⫾ 4.6 15.5 ⫾ 4.2 0.027¶ 0.27 16.5
30-second chair test, reps
Pretest 12.5 ⫾ 4.0 11.8 ⫾ 3.1
Posttest 16.3 ⫾ 4.0 11.9 ⫾ 4.2 0.001¶ 0.45 15.2
50-foot walk test, seconds
Pretest 9.33 ⫾ 2.40 10.03 ⫾ 3.78
Posttest 7.77 ⫾ 1.40 9.89 ⫾ 4.28 0.013¶ 0.28 8.0
KES, newtons
Pretest 323 ⫾ 79 308 ⫾ 131
Posttest 404 ⫾ 122 329 ⫾ 123 0.006¶ 0.34

* Values are the mean ⫾ SD unless otherwise stated. PRT ⫽ progressive resistance training; RA ⫽ rheumatoid arthritis; KES ⫽
knee extensor strength.
† For group ⫻ time interaction (2 ⫻ 2).
‡ Effect size, with thresholds for small, moderate, large, and very large effects set at 0.01, 0.08, 0.26, and 0.50, respectively.
§ 50th percentile performance level (weighted for sex, i.e., 23 women, 5 men) for healthy 60 – 64-year-olds for tests selected from
the Senior Fitness Test (26).
¶ Significant.
Resistance Training in RA 1731

Table 5. Effects of 24 weeks of high-intensity PRT on mIGF-1, mIGFBP-3, sIGF-1,

sIGF-2, sIGFBP-1, sIGFBP-3, and sIGFBP-3 fragmentation levels in patients with RA*

Variable PRT group Control group P† ␩2‡

mIGF-1, ng/mg total protein§

Pretest 1.048 ⫾ 0.274 1.306 ⫾ 0.524
Posttest 1.474 ⫾ 0.398 0.938 ⫾ 0.379 0.016¶ 0.39
mIGFBP-3, ng/mg total protein§
Pretest 22.74 ⫾ 7.50 34.18 ⫾ 13.49
Posttest 39.32 ⫾ 18.27 30.88 ⫾ 12.12 0.039¶ 0.31
sIGF-1, ng/ml#
Pretest 127 ⫾ 50 130 ⫾ 43
Posttest 130 ⫾ 30 126 ⫾ 39 0.819
sIGF-2, ng/ml#
Pretest 1,263 ⫾ 430 1,167 ⫾ 332
Posttest 1,097 ⫾ 205 1,097 ⫾ 268 0.708
sIGFBP-1, ng/ml#
Pretest 22.57 ⫾ 12.31 36.98 ⫾ 21.62
Posttest 21.48 ⫾ 10.49 31.64 ⫾ 24.62 0.498
sIGFBP-3, ng/ml#
Pretest 4,275 ⫾ 864 3,992 ⫾ 874
Posttest 4,366 ⫾ 532 4,055 ⫾ 863 0.321
sIGFBP-3 fragmentation, %#
Pretest 36.42 ⫾ 9.23 40.15 ⫾ 18.03
Posttest 38.23 ⫾ 12.66 36.96 ⫾ 13.56 0.411

* Values are the mean ⫾ SD unless otherwise stated. PRT ⫽ progressive resistance training; mIGF-1 ⫽
muscle insulin-like growth factor 1; mIGFBP-3 ⫽ mIGF binding protein 3; sIGF-1 ⫽ serum IGF 1;
sIGFBP-1 ⫽ sIGF binding protein 1; RA ⫽ rheumatoid arthritis.
† For group ⫻ time interaction.
‡ Effect size, with thresholds for small, moderate, large, and very large effects set at 0.01, 0.08, 0.26, and
0.50, respectively.
§ For the PRT group n ⫽ 9; for the control group n ⫽ 5.
¶ Significant.
# For the PRT group n ⫽ 13; for the control group n ⫽ 15.

scores of the arm curl test (r ⫽ 0.321, P ⬍ 0.05), whereas
change in leg lean mass correlated with change in the
scores of the 50-foot walk (r ⫽ ⫺0.634, P ⬍ 0.0001) and
chair rise (r ⫽ 0.364, P ⬍ 0.05) tests, and was weakly
associated with KES change (r ⫽ 0.224, P ⫽ 0.126).
The marked improvements in objectively measured
physical function following PRT are not reflected in pa-
tients’ perceived function, as MDHAQ scores were un-
changed (mean ⫾ SD pretest versus posttest: 0.914 ⫾ 0.680
versus 0.817 ⫾ 0.691 for the PRT group and 0.575 ⫾ 0.619
versus 0.575 ⫾ 0.590 for the control group; P ⫽ 0.513 for
the interaction). Habitual physical activity was unchanged
in both groups (mean ⫾ SD pretest versus posttest: 7,975 ⫾
2,827 steps/day versus 8,207 ⫾ 2,762 steps/day for the
PRT group and 6,057 ⫾ 2,605 steps/day versus 5,601 ⫾
2,320 steps/day for the control group; P ⫽ 0.537 for the
interaction). Similarly, no changes in diet were reported
by subjects in either group.
IGF system. The IGF data are presented in Table 5.
Increases in muscle IGF-1 and IGFBP-3 levels (41% and
73%, respectively) were observed following 24 weeks of
PRT. In contrast, mIGF-1 levels decreased (by 28%) and
mIGFBP-3 levels remained stable for the control group. For
both muscle IGF proteins, the interactions were significant
and the ␩2 indicated large treatment effects. Overall (n ⫽
14), changes in mIGF-1 were significantly correlated to
changes in mIGFBP-3 (r ⫽ 0.584, P ⬍ 0.05). No effects on
systemic IGF-1, IGF-2, IGFBP-1, IGFBP-3, or IGFBP-3 frag-
mentation levels were detected.
DISCUSSION
In this randomized controlled trial, we have confirmed our
pilot study findings (5) that PRT significantly increases
muscle mass and restores physical function in patients
with RA. In addition, we have identified a probable mech-
anism for muscle anabolism in RA.
The results of Rall et al (13) suggested that patients with
RA, perhaps due to their hypermetabolic state, were resis-
tant to the anabolic effects of exercise. However, subse-
quent studies (5,12), and especially the current investiga-
tion, which features a more robust methodologic design,
refute this. Our pilot study (5) and the current trial have
both observed marked increases in LBM, ALM, and total
body protein following high-intensity PRT, and Hakkinen
et al (12) demonstrated increases in quadriceps femoris
thickness (P ⬍ 0.001) in female patients with RA following
21 weeks of PRT combined with aerobic training. Simi-
larly, these studies consistently show reductions in fat
following training. In the study by Hakkinen et al (12),
quadriceps femoris subcutaneous fat thickness decreased
(P ⬍ 0.001); in our pilot study (4), percent body fat was
reduced (P ⬍ 0.05) and there was a trend for trunk fat mass
to decrease (⫺752 gm; P ⫽ 0.084); and in the current study,
1732
physiologically significant reductions in fat mass (2.3 kg)
and trunk fat mass (2.5 kg, i.e., 18%) were observed. This
repeated suggestion that PRT reduces trunk fat mass is of
clinical interest because RA predisposes to central obesity
(31) and, consequently, insulin resistance, dyslipidemia,
hypertension, and the metabolic syndrome (32).
One difference between the studies that achieved exer-
cise training–induced improvements in body composition
in patients with RA (refs. 5, 12, and the current study) and
that of Rall et al (13), which did not, is volume of training.
Whereas in the earlier investigation (13) subjects on aver-
age completed only 21 training sessions (2 sessions/week
for 12 weeks with 87% compliance), at least 30 sessions
were completed, on average, in the other trials. Addition-
ally, the training implemented by Rall and colleagues in-
volved performing only 5 exercises per session (13),
whereas our program featured 8 different exercises (ref. 5,
and the current study).
In terms of the magnitude of training effect, the body
composition changes we observed correspond to those
typically seen for healthy middle-aged or older subjects
following 3–12 months of high-intensity PRT (33,34). A
more direct comparison is provided by Hakkinen et al (12),
who found almost identical increases in thigh muscle and
comparable reductions in thigh fat in female patients with
RA and age-matched, healthy women following comple-
tion of the same training program. Therefore, it is now
clear that patients with RA are not resistant to the anabolic
effects of exercise, and that for patients with RA, as for
healthy individuals, an appropriate combination of PRT
intensity and volume is required to produce beneficial
changes in body composition (35).
Predictably, the increases in muscle mass elicited by our
PRT intervention were associated with improvements in
strength and objectively assessed function. Although these
correlations are mostly moderate, indicating that other
factors also contribute to the improvements in physical
function induced by PRT in patients with RA (36,37), this
association between muscle hypertrophy and enhanced
physical performance replicates the findings from our pi-
lot study (5). Interestingly, given that muscle mass is
thought to decline in the general population at approxi-
mately 6% per decade after the age of 50 years and strength
by approximately 12–14% per decade over the same pe-
riod (38), there is reasonable agreement from the mean
gains we observed in ALM (8.4%) and KES (25%) follow-
ing 24 weeks of PRT that these training effects are equiv-
alent to the reversal of 14 –20 years of sarcopenia. That
PRT should have such a positive effect on function and
disability in patients with RA is to be expected given the
recent finding that both ALM and appendicular fat mass
exert significant effects on HAQ score (1).
In common with most exercise intervention studies re-
quiring volunteer subjects, the current study suffers from
having a relatively biased sample, i.e., our patient cohort is
less disabled than would be anticipated if outpatients were
randomly selected. Despite this restriction, the incidence
of significant muscle loss (cachexia) among subjects at
baseline approached 60%, the incidence of obesity was
79%, and the incidence of cachectic-obesity (i.e., the co-
incidence of both conditions) was ⬃36%. In the general
Lemmey et al
elderly population, classification as either muscle wasted
(sarcopenic) or obese significantly increases the likelihood
of disability (39), and the coincidence of both (sarcopenic-
obesity) independently increases the risk of disability in
women 12 fold. It is notable that in the current study,
PRT removed most of the subjects previously classified
as cachectic and cachectic-obese from these high-risk
categories.
The inability of PRT to change MDHAQ scores in the
current study is consistent with results from other exercise
intervention studies (12,36,40), and is likely to be due to
the low disability of our patients and the relative insensi-
tivity of this instrument to detect improvements in mildly
disabled patients. Although the level of disability for our
patients with RA was comparatively mild, it should be
noted that, consistent with their reduced muscle mass and
increased adiposity, performance of objective function
tests by the PRT patients at baseline and the controls
throughout was inferior to that of age- and sex-matched,
sedentary, healthy individuals. Notably, performance of
these tests, which were developed to assess the physical
capacity of elderly people to perform activities of daily
living (23), was normalized in patients with established
RA by 24 weeks of PRT. Because in the current study
habitual physical activity, diet, and disease activity re-
mained unchanged, none of these factors can account for
the improvements in body composition or function follow-
ing PRT.
Despite the devastating consequences that impaired
physical function has on patients with RA, society, and the
economy, little research has been devoted to the metabolic
changes that cause the muscle loss underlying much of
this decrement (2,8). This is regrettable because insights
into the mechanisms of rheumatoid cachexia and its re-
versal should lead to improvements in patient treatment
and outcome. To further this understanding, in the current
study we tested our hypothesis that PRT exerts its anabolic
effects in patients with RA, as it does in healthy individ-
uals, primarily through an increase in mIGF-1 activity (14).
Our data appear to support this proposed mechanism. The
mIGF-1 levels in the 14 patients with RA from whom
biopsy samples were taken were reduced relative to levels
we observed previously in healthy, sedentary controls of
a similar age (mean ⫾ SD 2.78 ⫾ 1.76 ng/mg total protein)
(17). This is consistent with the diminished mIGF-1 levels
identified in subjects with chronic renal failure (17,19),
chronic heart failure (16), chronic obstructive pulmonary
disease (COPD) (18), and advanced aging (15); all of which
are conditions characterized by muscle wasting. In turn,
mIGF-1 and mIGFBP-3 levels in our patients with RA in-
creased significantly in response to PRT. Although these
results should be interpreted conservatively due to the low
and uneven biopsy sample sizes, the effect size is large and
this finding of augmented mIGF-1 levels with accompany-
ing muscle hypertrophy has also been seen in frail, elderly
subjects following PRT (15) and in patients with COPD
after high-intensity training (18). Similarly, an increase in
mIGFBP-3 accompanying training-induced hypertrophy
has been described in patients with hemodialysis (41). In
contrast, 12 weeks of high-intensity interval cycling that
failed to increase muscle mass in patients with hemodial-
Resistance Training in RA
ysis also failed to raise mIGF-1 or IGFBP-3 levels (19).
Unlike muscle IGFs, and consistent with previous results
in older adults (42,43), including patients with RA (12),
there was no effect of PRT on any of the measured com-
ponents of the systemic IGF system in our patients.
To summarize, our results confirm that PRT is a safe and
effective means of restoring muscle mass and functional
capacity in patients with established, stable RA. Conse-
quently, we advocate that, for appropriate patients, PRT
programs similar to ours be included in disease manage-
ment. We also provided a mechanistic insight into muscle
anabolism in RA that could affect clinical and pharmaceu-
tical approaches to treatment.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors ap-
proved the final version to be submitted for publication. Dr. Lem-
mey had full access to all of the data in the study and takes
responsibility for the integrity of the data and the accuracy of the
data analysis.
Study conception and design. Lemmey, Marcora, Maddison.
Acquisition of data. Chester, Wilson, Casanova.
Analysis and interpretation of data. Lemmey, Marcora, Maddison,
Chester, Wilson, Casanova.
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