Acute effects of exercise on pain symptoms, clinical inflammatory markers and inflammatory cytokines in people with rheumatoid arthritis: a systematic literature review

Abstract

Background
Exercise is advocated in the treatment of rheumatoid arthritis (RA). However, uncertainty around the acute effects of exercise on pain and inflammation may be stopping people with RA from exercising more regularly.

Objectives
To determine the acute effects of exercise on pain symptoms, clinical inflammatory markers, and inflammatory cytokines in RA.

Design
A systematic review of the literature.

Data sources and methods
Five databases were searched (PubMed, Cochrane Library, CINAHL, Scopus and SPORTDiscus); inclusion criteria were studies with acute exercise, a definite diagnosis of RA and disease characteristics assessed by clinical function (i.e., disease activity score, health assessment questionnaire and self-reported pain), clinical markers associated with inflammation (i.e., c-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)), and inflammatory cytokines (i.e., interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α)).

Results
From a total of 1544 articles, initial screening and full text assessment left 11 studies meeting the inclusion criteria. A total of 274 people were included in the studies (RA = 186; control = 88). Acute bouts of aerobic, resistance, and combined aerobic and resistance exercise did not appear to exacerbate pain symptoms in people with RA.

Conclusion
Post-exercise responses for pain, clinical inflammatory markers and inflammatory cytokines were not different between people with or without RA. Exercise prescription was variable between studies, which limited between-study comparisons. Therefore, future investigations in people with RA are warranted, which combine different exercise modes and intensities to examine acute effects on pain symptoms and inflammatory markers.

Registration
The PROSPERO international prospective register of systematic reviews – CRD42018091155.

Full text

https://doi.org/10.1177/1759720X221114104
https://doi.org/10.1177/1759720X221114104
Ther Adv Musculoskelet Dis
2022, Vol. 14: 1–16
DOI: 10.1177/
1759720X221114104
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THERAPEUTIC ADVANCES in
Musculoskeletal Disease
Introduction
Rheumatoid arthritis (RA) is the most prevalent
inflammatory arthritis, affecting approximately
1% of the UK population.1 It is characterised by
chronic systemic inflammation, resulting in
synovial tissue damage and bone destruction.2
Also, certain inflammatory cytokines (e.g., inter-
leukin 6 (IL-6) and tumour necrosis factor alpha
Acute effects of exercise on pain symptoms,
clinical inflammatory markers and
inflammatory cytokines in people with
rheumatoid arthritis: a systematic literature
review
Christopher Balchin , Ai Lyn Tan, Joshua Golding, Lesley-Anne Bissell, Oliver J. Wilson,
Jim McKenna and Antonios Stavropoulos-Kalinoglou
Abstract
Background: Exercise is advocated in the treatment of rheumatoid arthritis (RA). However,
uncertainty around the acute effects of exercise on pain and inflammation may be stopping
people with RA from exercising more regularly.
Objectives: To determine the acute effects of exercise on pain symptoms, clinical
inflammatory markers, and inflammatory cytokines in RA.
Design: A systematic review of the literature.
Data sources and methods: Five databases were searched (PubMed, Cochrane Library, CINAHL,
Scopus and SPORTDiscus); inclusion criteria were studies with acute exercise, a definite
diagnosis of RA and disease characteristics assessed by clinical function (i.e., disease activity
score, health assessment questionnaire and self-reported pain), clinical markers associated
with inflammation (i.e., c-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)), and
inflammatory cytokines (i.e., interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α)).
Results: From a total of 1544 articles, initial screening and full text assessment left 11 studies
meeting the inclusion criteria. A total of 274 people were included in the studies (RA = 186;
control = 88). Acute bouts of aerobic, resistance, and combined aerobic and resistance
exercise did not appear to exacerbate pain symptoms in people with RA.
Conclusion: Post-exercise responses for pain, clinical inflammatory markers and
inflammatory cytokines were not different between people with or without RA. Exercise
prescription was variable between studies, which limited between-study comparisons.
Therefore, future investigations in people with RA are warranted, which combine different
exercise modes and intensities to examine acute effects on pain symptoms and inflammatory
markers.
Registration: The PROSPERO international prospective register of systematic reviews –
CRD42018091155.
Keywords: acute exercise, clinical inflammatory markers, inflammatory cytokines, pain,
rheumatoid arthritis
Received: 27 January 2022; revised manuscript accepted: 29 June 2022.
Correspondence to:
Antonios Stavropoulos-
Kalinoglou
Carnegie School of Sport,
Leeds Beckett University,
Headingley Campus, 225
Fairfax Hall, Churchwood
Avenue, Leeds LS6 3QS,
UK.
A.Stavropoulos@
leedsbeckett.ac.uk
Christopher Balchin
Joshua Golding
Oliver J. Wilson
Jim McKenna
Carnegie School of Sport,
Leeds Beckett University,
Leeds, UK
Ai Lyn Tan
Lesley-Anne Bissell
Leeds Institute of
Rheumatic and
Musculoskeletal Medicine,
University of Leeds,
Chapel Allerton Hospital,
Leeds, UK
NIHR Leeds Biomedical
Research Centre, Leeds
Teaching Hospitals NHS
Trust, Leeds, UK
Joshua Golding
is now affiliated to School
of Medicine, St George’s
University of London,
London, UK
1114104TAB0010.1177/1759720X221114104Therapeutic Advances in Musculoskeletal DiseaseC Balchin, AL Tan
research-article20222022
Systematic Review

THERAPEUTIC ADVANCES in
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Volume 14
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(TNF-α)) are considered integral in the patho-
physiology of RA.3 Typical musculoskeletal man-
ifestations, including joint pain and swelling can
significantly impact physical functioning.4 RA
symptoms are commonly managed through
pharmacological interventions.5 How-ever, non-
pharmacological approaches, such as exercise, have
been effective in improving disease symptoms.6–8
Thus, European Alliance of Associations for
Rheumatology (EULAR) recommends a multidis-
ciplinary approach in RA disease management, via
co-treatment with medicine and exercise.9,10
During exercise there is a short-term (i.e., acute)
elevation of inflammatory cytokines such as
IL-6,11,12 which may coincide with post-exercise
soreness in the muscle.13 Typically levels of
inflammatory cytokines decrease within a few
hours of exercise cessation11,14 and muscle sore-
ness disappears after 24–72 h.13 Importantly exer-
cise training, which involves regular exercise over
a prolonged period,15 is safe for people with RA,
does not worsen pain, and improves disease activ-
ity and overall health.9,16–18 Despite this, people
with RA are less physically active than the general
population.19,20 Fear of acute post-exercise pain
and disease aggravation (i.e., a flare-up) may par-
tially explain this.10,21 Therefore, their concerns
regarding pain and disease activity post-exercise
need to be addressed.22 Furthermore, it is impor-
tant to clarify the precise pain and inflammatory
response following an acute bout of exercise.
Especially, as a better understanding of the acute
effects on disease characteristics would allow for
optimum exercise prescription in people with
RA23 and better management of individual fears
and expectations. Consequently, the aim of this
review was to determine the acute effects of exer-
cise on pain symptoms, clinical inflammatory
markers, and inflammatory cytokines in people
with RA.
Method
The review details were submitted and subse-
quently accepted by the PROSPERO interna-
tional prospective register of systematic reviews
on 23 May 2018 (registration number:
CRD42018091155). Five databases were
screened: PubMed, Cochrane Library, CINAHL,
Scopus and SPORTDiscus and a final search was
performed on 30 April 2021. In the PubMed
search, the keywords ‘rheumatoid arthritis’,
‘acute exercise’, ‘disease activity’ and ‘acute pain’
were each searched as subject headings and in all
fields combined with Boolean logical operators
(‘AND’ or ‘OR’) (Supplementary Data 1).
Eligibility criteria
Human only studies in people with a definite
diagnosis of RA according to ACR and EULAR
guidelines24–27 were included. All acute exercise
modalities were considered to capture relevant
articles. Disease characteristics were assessed
via clinical function (i.e., disease activity score-28
(DAS), health assessment questionnaire (HAQ)
and self-reported perceptions of pain) and clinical
inflammatory markers (i.e., c-reactive protein
(CRP) and erythrocyte sedimentation rate
(ESR)), as routinely assessed in RA disease man-
agement. In addition, inflammatory cytokines
associated with RA pathogenesis and progression
(i.e., IL-6 and TNF-α) were examined to deter-
mine the post-exercise responses. Importantly, all
outcomes were assessed within 72 h following an
acute bout of exercise to capture post-exercise
changes. Also included were studies which
involved varied training status and habitual physi-
cal activity levels. Only published articles were
accepted, therefore abstracts and conference pro-
ceedings were not considered. Studies were
excluded with people less than 18 years of age and
in a language other than English. Furthermore,
studies where participants had been diagnosed
with various types of inflammatory arthritis or
other connective diseases, but not in combination
with RA were excluded. Due to the limited num-
ber of randomised controlled trials (RCTs) inves-
tigating acute exercise in people with RA,
observational studies including cross-sectional
studies were included within the analyses.
Study inclusion and data extraction process
Two reviewers (C.B. and L-A.B.) were responsi-
ble for independently screening the titles and
abstracts. Subsequently, relevant articles were
assessed based on their full-texts regarding inclu-
sion and exclusion criteria. In the case of disa-
greement between the reviewers, a third reviewer
(A.S-K.) was consulted to resolve any disputes.
Furthermore, the reference lists of included arti-
cles were searched, and citation tracking was per-
formed to ensure all relevant articles were
captured. Data extraction was independently
completed by the two reviewers for articles meet-
ing the predefined inclusion criteria; the data
extraction sheet included: study information,
study population, intervention, and outcome

C Balchin, AL Tan et al.
journals.sagepub.com/home/tab 3
measures. Data were presented as mean ± stand-
ard deviation (SD), unless otherwise stated. This
review is reported within the PRISMA guidelines
(Supplementary Tables 1 and 1b).28
Risk of bias assessment
Studies were independently graded by the two
reviewers according to the National Institutes of
Health (NIH) quality assessment tool for obser-
vational cohort and cross-sectional studies, the
NIH quality assessment tool for before-after
(pre–post) studies with no control group29 and
the tool for the assessment of study quality and
reporting in exercise (TESTEX) scale for RCTs.30
Any disagreements between the reviewers, a third
reviewer (A.S-K.) was used as an arbitrator.
Results
A total of 1554 studies were identified after initial
searches (PubMed: 392, Cochrane: 242, Scopus:
774, CINAHL: 100 and SPORTDiscus: 46).
After removal of duplicates 1059 articles were
left. Following review of titles and abstracts, 1024
papers were excluded. Full-text review was then
carried out for the remaining 35 potentially rele-
vant papers, yielding 10 articles that met the
inclusion criteria. Manual searches of the refer-
ence lists from the included articles identified a
further study, resulting in a total of 11 studies
(Figure 1). Six of these studies were classified as
observational while the remaining five were
RCTs. The study information (e.g., authors),
study population (e.g., descriptive characteris-
tics), intervention (e.g., acute exercise protocol)
and outcome measures (e.g., pain and inflamma-
tory markers) are described in Table 1.
Study quality assessment
The NIH quality assessment tool for observa-
tional cohort and cross-sectional studies rated
four studies as good and one study was rated as
fair (mean score: 7) (Table 2), while one study
was rated as fair (total score: 6) using the NIH
quality assessment tool for before-after (pre-post)
studies with no control group (Table 3). Table 4
describes the outcome of the TESTEX scale for
the five relevant studies (mean score: 7). All qual-
ity assessment tools were adapted to meet the
specific needs of this review, certain criterions
Figure 1. PRISMA 2020 flow diagram for systematic reviews. (Identification) articles were identified through
database searching and duplicates were removed; (Screening) titles and abstract of remaining articles were
screened, full-text retrieval and assessment for eligible articles, citation searching for articles, and reasons provided
for excluded articles; (Included) full-text articles included for systematic review. N, number.

THERAPEUTIC ADVANCES in
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Table 1. Data extraction table including study information, study population, intervention, and outcome measures.
Author Study design Sample size RA age/CON
age (years;
mean)
Exercise protocol Primary outcomes Pain and
inflammatory
marker outcomes
Significance
in primary
outcomes
Significance in pain
and inflammatory
marker outcomes
Aerobic exercise
Knudsen
et al.31
Observational ERA = 10
LRA = 10
CON = 14
NR 20-min cycling
at submaximal
intensity (70–80%
max pulse),
progressively
higher work
rates attained by
increasing load
(0.5, 0.7, 0.9, 1.1,
and 1.3 kg) every
4-min
IL-6 IL-6 Yes: CON IL-6
significantly
increased
post-exercise
(immediately
post: p = 0.0006;
1-h post:
p = 0.002; 3-h
post-exercise:
p = 0.027)
No changes in
IL-6 immediately,
1- or 3-h post-
exercise in people
with RA (all
p > 0.05)
No in RA groups
Melton-
Rogers
et al.32
Observational RA = 8 RA = 35.9 VO2peak assessed
during dry land
cycle ergometry
and running in
water
Peak ventilatory and
cardiorespiratory
responses
VAS pain Yes: VE (p = 0.01)
and VT (p < 0.001)
higher during
cycling, while
RER (p = 0.02)
higher during
water running
No
Resistance exercise
Lofgren
et al.33
Observational RA = 46
CON = 20
RA = 61
CON = 60
Right leg knee
extension
contraction,
maintained until
unable to sustain
30% of MVC
Pressure pain
sensitivity
PPTs,
segmental and
plurisegmental
EIH
Yes: RA
significantly
higher sensitivity
to pressure pain
(p < 0.001) and
suprathreshold
pressure pain
(p = 0.001;
p = 0.002) during
exercise
Yes: Segmental
EIH (RA: p < 0.001;
CON: p = 0.016) and
plurisegmental
EIH (RA: p < 0.001;
CON: p < 0.001)
significantly
increased during
contraction
(Continued)

C Balchin, AL Tan et al.
journals.sagepub.com/home/tab 5
Author Study design Sample size RA age/CON
age (years;
mean)
Exercise protocol Primary outcomes Pain and
inflammatory
marker outcomes
Significance
in primary
outcomes
Significance in pain
and inflammatory
marker outcomes
Mikkelsen
et al.34
RCT RA = 13
CON = 13
RA = 56
CON = 57
Resistance
exercise: one leg
extensions, 10
sets, 8 repetitions,
70%1RM, 30-min
Myofibrillar
protein synthesis,
gene expression,
myogenesis,
inflammatory
signaling, muscle
atrophy
IL-6, TNF-αYes: myofibrillar
protein synthesis
in RA and CON
significantly
increased
post-exercise
(p < 0.001)
No difference
in basal and
post-exercise
myofibrillar
protein synthesis
between groups
Gene expression
response similar
in RA versus CON
Yes: IL-6 and
TNF-α increased
immediately
post-exercise
(p < 0.001)
Cytokine response
not different
between RA and
CON
Pereira
Nunes Pinto
et al.35
Observational RA = 17
CON = 17
RA = 55.6
CON = 53.8
Resistance
exercise: knee
extension, knee
flexion, hip
abduction, and
hip adduction,
2 sets, first set
12 repetitions
50%1RM, second
set 8 repetitions
75%1RM, 1-min
rest between
sets, 2-min rest
between exercises,
25-min in total
COMP, IL-1β, IL-1ra,
IL-10, IL-6, TNF-α,
CRP
IL-6, TNF-α, CRP Yes: significant
differences
between pre-
and post-
exercise COMP
concentration
(p < 0.001), IL-1β
(p = 0.045), IL-1ra
(p < 0.001), IL-10
(p = 0.004) and
IL-6 (p < 0.001)
No significant
difference in pre-
and pos-texercise
TNF-α or CRP
Yes: IL-6
significantly
increased post-
exercise in both
groups (p < 0.001)
No differences in
the responses of
the two groups to
exercise for IL-6,
TNF-α or CRP (all
p > 0.05)
Combined exercise
Beals et al.36 Observational RA = 8
OA = 6
CON = 6
RA = 50.5
OA = 49.2
CON = 49.2
Right knee
extensor and
flexor muscle
performance
assessed,
thermographic
measurements
300kpm/min
on stationary
bicycle, maximal
aerobic capacity
assessment using
a stationary cycle
ergometer
Muscle strength
testing,
electromyography,
quantitative
thermography,
maximum aerobic
capacity
Joint symptoms Yes: Isotonic knee
extension and
flexion as well
as grip strength
significantly
lower in RA than
CON (all p < 0.05)
No increase in joint
symptoms or pain
(Continued)
Table 1. (Continued)

THERAPEUTIC ADVANCES in
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Author Study design Sample size RA age/CON
age (years;
mean)
Exercise protocol Primary outcomes Pain and
inflammatory
marker outcomes
Significance
in primary
outcomes
Significance in pain
and inflammatory
marker outcomes
Bearne
et al.37
RCT with
partial
crossover
RA = 15 24 isometric
MVCs at 90° knee
flexion (4 sets,
6 contractions,
1-min rest
between sets),
3 functional
exercises (e.g.,
sit-to-stand, step
up) and 3 balance
exercises (e.g.,
wobble-board)
Quadriceps
sensorimotor
function, lower
limb functional
performance and
subjective disability
IL-6, TNF-αYes: all primary
outcomes
significantly
improved after
rehabilitation
(p < 0.05)
No increase in IL-6
or TNF-α 1-h post-
exercise following
a single exercise
session
Friden
et al.38
Observational RA = 10
CON = 10
RA = 56.5
CON = 59
Isokinetic knee
flexor/extensor
strength, hand-
grip strength,
lower extremity
function timed
stands test,
isometric muscle
contraction
Muscle strength, pain
sensitivity
PPT,
suprathreshold
pressure pain,
segmental and
plurisegmental
endogenous
pain inhibitory
mechanisms
Yes: RA
significantly
weaker in knee
flexor peak
torque and hand–
grip strength
(p < 0.05),
significantly
slower in
timed standing
(p < 0.05)
No difference in
knee extensor
strength
Yes: RA higher
sensitivity to
threshold pain and
suprathreshold
pressure pain
(p < 0.05)
PPTs increased in
contracting and
resting muscle
during static
contractions in both
groups (p < 0.05)
Relative change in
PPTs between rest
and contraction did
not differ
No group
differences in time
to exhaustion
Law et al.39 Randomised
crossover
design
Study 1:
RA = 8
CON = 8
Study 1:
RA = 60
CON = 60
Aerobic exercise
session: High
(70–90% HRmax)
and low intensity
(40–50% HRmax)
treadmill walking
Resistance
exercise session:
Leg curl, leg
extension and leg
press; 3 sets of
8 repetitions at
80%1RM
COMP, knee joint
synovial inflammation
(doppler ultrasound
CF)
Knee joint pain,
CRP
No No significant
change in knee joint
pain and CRP
(Continued)
Table 1. (Continued)

C Balchin, AL Tan et al.
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Author Study design Sample size RA age/CON
age (years;
mean)
Exercise protocol Primary outcomes Pain and
inflammatory
marker outcomes
Significance
in primary
outcomes
Significance in pain
and inflammatory
marker outcomes
Other exercise modalities
Byers40 Observational RA = 30 RA = 61.8 Evening exercise
completed on 1 of
2 evenings: non–
weight bearing
ROM exercises
Morning exercise
completed on
both mornings:
ROM exercises,
flexions and
extensions of
right hand
Morning stiffness and
mobility
Subjective finger
stiffness, elastic
stiffness
Yes: mobility
was significantly
greater when
evening exercise
performed
(p < 0.001)
Yes: subjective
finger stiffness and
elastic stiffness
was significantly
less when evening
exercise performed
(p < 0.001)
Thompson
et al.41
RCT RA = 11 RA = 62 Morning
physiotherapy:
moderate to
vigorous intensity,
90-min
Cytidine deaminase CRP No significant
inter-day
differences
for cytidine
deaminase
No significant
circadian variation
of CRP
No significant inter-
day differences for
CRP
CF, color fraction; COMP, cartilage oligomeric matrix protein; CON, control; CRP, C-reactive protein; EIH, exercise-induced hypoalgesia; ERA, early rheumatoid arthritis; HRmax, heart
rate maximum; IL-6, interleukin-6; IL-10, interleukin-10; IL-1β, interleukin-1 beta; IL-1ra, interleukin-1 receptor antagonist; LRA, late rheumatoid arthritis; MVC, maximum voluntary
contraction force; NR, not reported; OA, osteoarthritis; PPT, pressure pain thresholds; RA, rheumatoid arthritis; RCT, randomised controlled trial; RER, respiratory exchange ratio; 1RM,
one-repetition maximum; ROM, range of motion; TNF-α, tumour necrosis factor alpha; VAS, visual analogue scale; VE, minute ventilation; VO2peak, peak oxygen uptake; VT, tidal volume.
Table 1. (Continued)

THERAPEUTIC ADVANCES in
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were scored NA and the total score was adjusted
accordingly.
Participant characteristics
A total of 274 people were included in the studies
[RA: n = 186, age (mean ± SD) 55 ± 9 years;
Control (CON): n = 88, age 56 ± 5 years]. Due to
very low numbers, the six osteoarthritis (OA) par-
ticipants were excluded from any further analysis
and discussion. Concerning the people with RA,
five studies assessed body mass index (BMI)
(25.2 ± 0.7 kg/m2), in six studies RA disease dura-
tion could be determined (99 ± 36 months), four
studies assessed baseline HAQ (0.9 ± 0.5), three
studies assessed baseline DAS28 (4.4 ± 2.6),
three studies assessed baseline CRP
(2.4 ± 2.5 mg/l), one study assessed baseline ESR
(38 ± 10 mm/h), four studies assessed baseline
IL-6 (12.9 ± 10.4 pg/ml), and three studies
assessed baseline TNF-α (18.3 ± 11.6 pg/ml).
Exercise modalities
Out of the 11 studies, two used aerobic exercise,
three used resistance exercise, four studies used a
combination of aerobic and resistance exercise
(i.e., combined exercise) and the final two studies
involved other exercise modalities not clearly
defined.
Table 2. NIH quality assessment tool for observational cohort and cross-sectional studies: study summary.
Author Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Q11 Q12 Q13 Q14 Total
score
Quality
rating
Beals et al.36 Y N NA Y N N Y NA Y Y Y NA NA N 6 (10) Fair
Friden et al.38 Y N NA Y N N Y Y Y Y Y NA NA N 7 (11) Good
Knudsen et al.31 Y N Y N N Y Y NA Y NA Y NA NA Y 7 (10) Good
Lofgren et al.33 Y N Y Y N N Y Y Y Y Y NA NA Y 9 (12) Good
Pereira Nunes
Pinto et al.35
Y N NA Y Y N Y NA Y Y Y NA NA N 7 (10) Good
N, No; NA, not applicable; NIH, National Institutes of Health; Q1, Question 1; Y, Yes.
Table 3. NIH quality assessment tool for before-after (pre-post) studies with no control group: study summary.
Author Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Q11 Q12 Total
score
Quality
rating
Melton-Rogers et al.32 Y N Y Y N Y Y NA NA Y NA N 6 (9) Fair
N, No; NA, Not Applicable; NIH, National Institutes of Health; Q1, Question 1; Y, Yes.
Table 4. TESTEX quality assessment tool for randomised controlled trials: study summary.
Author Study quality – 5 points Study reporting – 10 points Total
score
Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Q11 Q12
Bearne et al.37 1 1 1 NA 1 1 1 2 0 0 1 1 10 (14)
Byers40 0 0 NA 0 0 1 NA 2 1 0 NA 0 4 (12)
Law et al.39 1 0 NA NA 1 3 0 2 0 NA 1 1 9 (12)
Mikkelsen et al.34 1 0 NA NA 1 2 NA 2 1 1 NA 1 9 (11)
Thompson et al.41 0 0 NA 1 0 0 NA 2 0 0 NA 0 3 (12)
NA, not applicable; Q1, Question 1.

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Summary of main findings
Regarding acute exercise, three studies reported
no significant change in post-exercise pain and
joint symptoms, when compared with base-
line.32,36,39 Byers40 concluded that morning joint
stiffness was significantly less and joint mobility
was significantly greater when evening exercises
were performed. Two studies reported significant
increases in pressure pain thresholds and exer-
cise-induced hypoalgesia during muscle contrac-
tion in both RA and CON groups.33,38 People
with RA demonstrated higher pain sensitivity, but
no significant effect was observed for group inter-
action, and relative change in pressure pain
thresholds did not differ between RA and CON
groups.33,38
Three of the included studies suggested no sig-
nificant changes in CRP and/or ESR concentra-
tion following either acute aerobic or resistance
exercise;35,39,41 with no difference in clinical
marker changes post-exercise between RA and
CON groups.35 Pereira Nunes Pinto etal.35 iden-
tified no difference in IL-6 or TNF-α response
post-exercise between RA and CON groups. Two
studies found circulating IL-6 significantly
increased post-exercise34,35 and one study found
TNF-α expression increased immediately after
exercise.34 Bearne et al.37 reported no change
from baseline in TNF-α post-exercise; while in
IL-6 there was no change from baseline in the
second session, but IL-6 significantly decreased
post-exercise in the 10th session. Whereas one
study reported no change in post-exercise IL-6 in
people with RA.31
Aerobic exercise
Knudsen et al.31 examined the effect of exercise
on circulating IL-6 in people with untreated early
RA (ERA) (disease duration < 6 months), long-
term erosive RA (LRA) and healthy controls.
Following cycle ergometer exercise, the authors
reported no IL-6 changes from baseline to imme-
diately post-, 1-h post- or 3-h post-exercise in
ERA or LRA (all p > 0.05), while IL-6 signifi-
cantly increased in the CON group at all time-
points post-exercise (all p < 0.05). However, IL-6
was significantly elevated in the people with RA at
baseline and post-exercise compared with CON
group (p < 0.001). Melton-Rogers et al.32 exam-
ined peak ventilatory and cardiovascular responses
during dry-land cycling versus running in water
with a flotation device in people with RA. No dif-
ference was observed in joint pain between
treatments (p = 0.46), and neither mode exacer-
bated joint pain during exercise.
Resistance exercise
Lofgren etal.33 investigated pressure pain thresh-
olds and exercise-induced hypoalgesia following
right leg isometric knee extension muscle contrac-
tions. Pressure pain thresholds significantly
increased at contracting quadriceps in both groups
(RA pre-exercise: 1.0 kPa versus during exercise:
1.3 kPa, p < 0.001; CON pre-exercise: 0.9 kPa ver-
sus during exercise: 1.1 kPa, p < 0.016). There was
a significant effect for the factor time (p < 0.001),
but there was no significant effect for group or sig-
nificant time x group interaction. The worst thigh
pain reported during contraction using a visual
analogue scale (VAS):0–100 was significantly
higher in RA versus CON (RA median: 22, 25th–
75th percentiles: 2–52; CON median: 0, 25th–
75th percentiles: 0–26; p = 0.003). Therefore, the
higher pain sensitivity reported by the RA group
suggests increased sensitivity to pain during exer-
cise, but normal activation of segmental and
plurisegmental exercise-induced hypoalgesia.
Mikkelsen et al.34 used a case match design for
RA and healthy controls, based on gender, BMI
and physical activity levels. RA was well con-
trolled, as demonstrated by low disease activity
(DAS28: 2.6 ± 1.0). Basal CRP was significantly
higher in people with RA than CON (RA:
2.3 ± 0.5 mg/l versus CON: 1.1 ± 0.3 mg/l;
p = 0.038); while baseline IL-6 was higher in peo-
ple with RA, but this was not significant (RA
IL-6: 2.9 ± 0.7 pg/ml versus CON: 1.7 ± 0.3 pg/
ml; p = 0.065). IL-6 immediately increased post-
exercise in both groups (p < 0.001). In addition,
basal mRNA expression of TNF-α was higher in
people with RA than CON (RA: 1.2 ± 0.3 pg/ml
versus CON: 0.6 ± 0.1 pg/ml; p = 0.008). TNF-α
increased in response to exercise in both groups
(p < 0.001), although post-exercise TNF-α in RA
remained above CON (p = 0.036). Indeed,
cytokine responses were not different between
RA and CON groups. Furthermore, cytokine
changes were not associated with post-exercise
differences in acute anabolic response of signal-
ling pathways or muscle protein synthesis.
Pereira Nunes Pinto et al.35 examined the acute
effects of resistance exercise on females with or
without RA. The control group consisted of peo-
ple without RA who were matched according to
age and BMI. There was no difference between

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RA and CON groups in basal CRP (RA: 0.05 ±
0.04 mg/l; CON: 0.03 ± 0.03 mg/l; p = 0.118);
while CRP concentration was not altered post-
exercise with no difference between RA and CON
groups (p = 0.294). Similarly, there were no dif-
ferences in circulating IL-6 or TNF-α post-exer-
cise between groups (p = 0.665; p = 0.565
respectively). IL-6 concentration significantly
increased immediately, 1- and 2-h-post-exercise
in both groups (RA immediately post: 44.1 ±
37.6 mg/l, 1-h-post: 43.8 ± 33.9 mg/l, 2-h-post:
27.5 ± 32.5 mg/l; CON immediately post: 38.6 ±
28.2 mg/l, 1-h-post: 37.1 ± 26.4 mg/l, 2-h-post:
17.7 ± 15.0 mg/l; all p ⩽ 0.01), returning to base-
line 24-h after the exercise session. However, in
both groups there were no significant changes in
pre- and post-exercise CRP and TNF-α concentra-
tion (p = 0.617; p = 0.096 respectively). Therefore,
the response of circulating clinical markers to an
acute bout of resistance exercise was not different
between females with or without RA.
Combined exercise
Beals et al.36 performed a cross-sectional study
which involved assessments of muscle strength
and maximal aerobic capacity. Baseline joint stiff-
ness was significantly higher in the RA group
(37.0 ± 8.5) when compared with the sedentary
CON group (0.3 ± 0.3; p < 0.001), but there were
no reported increases in joint symptoms or pain
among people with RA following a single com-
bined exercise session. Bearne etal.37 randomised
people with RA to a rehabilitation or a CON
group. The rehabilitation group participated in
two exercise sessions a week for five weeks and
each session involved maximum voluntary con-
tractions and functional exercises. Acute changes
in pro-inflammatory cytokines were assessed
immediately before and after the second and tenth
(i.e., last) exercise session. There was no signifi-
cant change in IL-6 or TNF-α post-exercise in the
second session when compared with baseline.
However, following a progressive exercise training
programme there was a significant reduction in
post-exercise IL-6 concentration in the last ses-
sion (p < 0.05). In contrast, TNF-α remained
unchanged post-exercise in the final session.
In the Friden etal.38 study, pressure pain thresh-
olds significantly increased during quadricep con-
traction in both RA group and healthy controls
(RA rest: 311.8 ± 266.8, contraction: 368.5 ±
322.4 kPa, p = 0.013; CON rest: 416.1 ± 228.9,
contraction: 465.6 ± 251.0 kPa, p = 0.028). The
RA group had an increased sensitivity to thresh-
old and suprathreshold pressure pain versus CON,
but the relative change in pressure pain thresh-
olds between rest and contraction did not differ
between groups (quadriceps mean % change
RA: 23%; CON: 20%; p > 0.05). The time until
muscle exhaustion at 30% maximum voluntary
contraction was also not significantly different
between groups (p > 0.05). Based on the relative
change in pressure pain thresholds, the RA group
had normal functioning of exercise-induced
endogenous pain inhibition.
Law et al.39 included people with RA who per-
formed a randomised cross-over-designed trial
with a 1-week washout between exercise sessions.
Their results indicated circulating post-exercise
CRP concentration was higher in RA versus CON
group (RA: 14.3 ± 2.1 mg/l; CON: 1.3 ± 1.9 mg/l;
p < 0.01); however, there were no significant
interactions with either exercise bout or timepoint
and no worsening of systemic disease activity
post-exercise. The CON group reported no pain
during either form of exercise when measured on
a 0–10 pain intensity scale, while the RA group
reported some knee pain during the aerobic
(0.5 ± 0.7) and resistance exercise sessions
(2.2 ± 3.0), but not of clinical significance. There
were no significant changes in CRP or knee joint
pain in the 24-h period following either mode of
exercise for the RA group.
Other exercise modalities
Byers40 investigated the effects of exercise on
morning stiffness and mobility in people with RA.
Range of motion exercises were performed on
both mornings, but only one of the two evenings.
Elastic stiffness and subjective ratings of stiffness
were significantly less, and mobility was signifi-
cantly greater when evening exercises were per-
formed alongside morning exercises (all p < 0.001).
Evening exercise was effective for all people with
RA, with 21 people reporting less elastic stiffness
when evening exercise was performed (p < 0.05).
Thompson etal.41 randomly allocated people with
RA to 24-h bedrest or normal ward activities on
the first day, crossing to the other regimen for the
second day. There were no significant inter-day
differences for CRP (p < 0.05). Therefore, CRP
concentration was not different to baseline.
Subsequently they concluded CRP was unaffected
by joint motion and exercise.

C Balchin, AL Tan et al.
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Discussion
The aim of this systematic review was to deter-
mine the effects of an acute bout of exercise on
pain symptoms, clinical inflammatory markers
(i.e., CRP and ESR) and inflammatory cytokines
(i.e., IL-6 and TNF-α) in RA. The major findings
are that when people with RA perform an acute
bout of exercise it does not appear to exacerbate
pain symptoms during or post-exercise. In addi-
tion, exercise does not unfavourably alter clinical
inflammatory markers and the inflammatory
cytokine response, when compared with healthy
controls.
Pain is a major feature of RA and common mis-
conceptions by people with RA are that exercise
may increase pain and lead to further joint dam-
age.22 Nevertheless, the present review of the
available evidence suggests that an acute bout of
exercise does not exacerbate pain symptoms in
people with RA, regardless of exercise mode and
intensity. While chronic pain and inflammation in
RA are linked,42 our findings suggest pain symp-
toms are unchanged following exercise in people
with RA. This coincided with some changes in
inflammatory cytokines that are typical of the
post-exercise response in people without RA.
Therefore, other pathways could be associated
with pain response post-exercise such as periph-
eral43 and central mechanisms (i.e., central sensi-
tisation),33,44 which might play a role in pain
processing for people with RA. Nonetheless, peo-
ple with RA demonstrate a post-exercise pain
response consistent with healthy controls.45
Consequently, individual fears of acute pain flare-
ups following an acute bout of exercise can be
better managed to secure more widespread adop-
tion-adherence to regular exercise. Although the
different modes of exercise showed no differences
in pain symptoms between people with or without
RA, few of these modes of exercise are widely
adopted. This suggests generic, rather than
RA-specific issues affecting popularity and imple-
mentation of regular exercise are at play.
The present review found that moderate inten-
sity exercise did not significantly affect CRP con-
centration in people with RA, which is consistent
with non-RA populations.46–48 However, CRP
has previously increased in sedentary overweight
people (p < 0.05) following intensive or pro-
longed exercise,49 which might explain our find-
ings. TNF-α is a key cytokine that causes
inflammation in RA50 and there is a perceived
risk that elevated TNF-α concentration follow-
ing exercise could amplify the pro-inflammatory
response. Of the studies included in this review,
two reported no change in TNF-α post-
exercise,35,37 as consistent with previous research
in healthy adults;51–53 whereas one study found
TNF-α expression increased immediately after
exercise in both RA and CON groups.34 There-
fore, future research is required to precisely con-
firm the TNF-α response post-exercise in RA.
Nevertheless, the findings suggest that the rela-
tive change in circulating TNF-α in people with
RA in response to exercise, and across varied
exercise modes, was not different to healthy
individuals.
IL-6 plays a prominent role in RA pathogenesis54
and is commonly known for its pro-inflammatory
functions. During exercise IL-6 stimulates the
circulation of anti-inflammatory cytokines such
as interleukin-10, which inhibits production of
pro-inflammatory cytokines such as TNF-α.55,56
Furthermore, exercise-associated increases in cir-
culating IL-6 are thought to play an important
role in energy production through enhancing glu-
cose uptake and lipolysis.57,58 Therefore, elevated
IL-6 post-exercise in people with RA might not
be considered the unfavourable inflammatory
response that was previously believed.59 In the
four studies that examined IL-6, two reported a
significant increase in response to exercise,34,35
which agrees with previous findings in healthy
adults.60,61 However, one study found IL-6 sig-
nificantly decreased from baseline immediately
after the final exercise session,37 while another
study reported no IL-6 change post-exercise.31
Although Knudsen etal.31 suggested that people
with RA performed less strenuous exercise com-
pared to the control group. Consequently, the
findings in the present review are inconsistent and
further investigations are necessary to determine
the precise impact of different modes of exercise
on IL-6 response in RA.
Furthermore, in four studies the frequency, inten-
sity, type and time of the exercise (FITT) as
advocated by the American College of Sports
Medicine (ACSM)62 was not clear. The study by
Byers40 included people with RA who only com-
pleted range of motion exercises, while Thompson
etal.41 did not detail the morning physiotherapy.
In both cases, the exercise characteristics are
inadequately reported with no clear exercise pre-
scription (i.e., FITT). Despite some studies fully
reporting the exercise characteristics, the specific

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exercise prescription (e.g., aerobic or resistance
exercise; high or low intensity) was variable,
which also limits study comparisons. Sub-
sequently, different exercise parameters make it
difficult to accurately assess the impact of exercise
in people with RA and as highlighted in a recent
review the optimal intensity, frequency, mode
and exercise duration for RA has yet to be deter-
mined.63 Therefore, further research with clearly
defined FITT, which examines how different
exercise prescription (e.g., high versus low inten-
sity exercise) impacts acutely on RA disease char-
acteristics is required.
It is also important to acknowledge the variability
in pain assessments. Two studies measured pain
sensitivity using standardised pressure pain
thresholds,33,38 a pain VAS was used by Melton-
Rogers et al.32 and Lofgren et al.33 while Law
etal.39 assessed knee joint pain using an adapted
Pain Intensity Scale.64 Although subjective pain
scales have been validated,65,66 they demonstrate
substantial heterogeneity across the scientific lit-
erature and direct comparisons cannot be made
across different assessment tools. Patient-reported
outcomes such as pain symptoms are essential in
monitoring RA67 and further work is necessary to
obtain a better insight into post-exercise pain
response using consistent methods.
Furthermore, one study did not include a com-
parator control group;32 therefore, it is not pos-
sible to directly compare outcome measures in
RA and other populations. In addition, the peo-
ple with RA in Melton-Rogers et al.32 were
younger (age: 35.9 ± 3.0 years) than the mean
age of all people with RA in the present review
(age: 55 ± 9 years). This might explain why joint
pain (or the lack of it) did not impair exercise
performance in their study.32 Notably, two stud-
ies did not assess outcome parameters post-
exercise, as pain sensitivity was examined during
the exercise protocol.33,38 Therefore, neither
allows assessment of post-exercise pain sensitiv-
ity differences or differences between people
with or without RA. A recent systematic review
by Hall et al.68 suggested that in people with
knee OA, pressure pain threshold improved
post-acute exercise and they also experience
hypoalgesia following exercise similar to that of
healthy individuals. Although these results are
only generalisable to people with knee OA, acute
exercise did not appear to worsen pain symp-
toms, which supports the findings in the present
review.
This review has important limitations. First, dif-
ferences in follow-up time for outcome variables
(immediately post-exercise to 24-h post-exercise),
patient demographics, participant inclusion–
exclusion criteria, RA disease activity (low versus
high disease activity), disease duration and sam-
ple sizes all limit study comparability. It is impor-
tant to acknowledge that baseline values for
inflammation (i.e., CRP and TNF-α) were
low and disease activity (i.e., DAS28) was rela-
tively well controlled among RA participants.
Subsequently, this may have contributed towards
a lack of exercise-induced change in the included
studies. In addition, the small sample sizes in the
included studies may partially explain the lack of
reported change in outcome variables. There
were also three studies that provided no informa-
tion on disease duration36,40,41 and in one study
where disease duration was reported to be more
than 10 years,35 the impact of acute exercise on
outcome measures may be limited.
Indeed the high heterogeneity in study character-
istics may impact on the findings presented in this
review and thus, caution is advised when inter-
preting the results as a firm conclusion cannot be
drawn. Furthermore, six studies provided no
information on RA medication,31–33,35,40,41 while
two studies did not fully report medication for all
people with RA.36,39 In one study the medication
of the 15 randomised people with RA was
unclear.37 Consequently, incomplete reporting of
medication may have misrepresented potential
interactions between medication and exercise
response.45 Medication therapy is recommended
for all people with RA69 with likely variability in
the prescribed medication across the included
studies. Consequently, the potential bias in the
outcome measures cannot be excluded.
We have also highlighted important variations in
exercise prescription. Due to the limited number
of RCTs, observational studies have been
included in this review. This affects the review
quality; cross-sectional designs do not allow
assessments of causality. Due to high heterogene-
ity in outcome measures, we have been unable to
pool study results and perform quantitative analy-
ses. To ensure inclusion in subsequent reviews,
future research designs should standardise out-
come measures.
Moreover, there are limitations with the bias
assessments, as weaknesses were found regarding
description of study population31,33,35,36,38 and

C Balchin, AL Tan et al.
journals.sagepub.com/home/tab 13
sample size32 when using the NIH assessment
tool. Weaknesses were also found in the methods
of randomisation for studies assessed using the
TESTEX tool.34,37,39–41
Future research
The present review has highlighted important
gaps still exist in this area of research. Indeed, a
more consistent approach to assessing RA-related
outcomes is warranted in future investigations.
Furthermore, a prospective randomised crossover
trial should look to combine different exercise
doses (e.g., aerobic exercise versus resistance exer-
cise, higher exercise intensities versus moderate
exercise intensities) to precisely determine
the acute effects of exercise on pain symptoms,
inflammatory markers and inflammatory cytokines
among people with RA. Also, the vast majority of
existing research has been carried out on people
with established RA (i.e., more than two years
since diagnosis), as is evident in this review (mean
disease duration: 99 months). There is limited evi-
dence on the acute effects of exercise in people
with early RA (i.e., less than two years since diag-
nosis) and this is despite recommendations to
include exercise in the early stages of treatment.
Subsequently, future investigations into the acute
effects of exercise should consider people with
early RA as the target population.
Conclusion
Previous research shows that regular exercise can
improve pain symptoms, clinical inflammatory
markers and inflammatory cytokines in people
with RA. Nevertheless, evidence suggests people
with RA do not meet the physical activity guide-
lines, which could be attributed to concerns that
acute exercise exacerbates pain and disease activ-
ity. The current review has demonstrated that
acute exercise does not appear to worsen pain
symptoms. Also, post-exercise responses for pain
symptoms, clinical inflammatory markers and
inflammatory cytokines were not different in peo-
ple with or without RA, which is an important
message for people with RA and health profes-
sionals. Perception of acute joint pain is consid-
ered a prominent barrier to exercise, and our
findings could help people with RA better man-
age those fears. Nevertheless, we have identified
an inconsistency of exercise prescription to assess
the acute effects of exercise. We recommend
future research combine different exercise modes,
durations and intensities to examine the acute
effects of exercise on subjective pain symptoms
(i.e., VAS pain), clinical inflammatory markers
(i.e., CRP) and inflammatory cytokines (i.e., IL-6
and TNF-α).
Declartions
Ethics approval and consent to participate
Ethical approval was granted by Leeds Beckett
University Ethics Committee (application ID:
48219).
Consent for publication
Not applicable.
Author contributions
Christopher Balchin: Conceptualisation; Data
curation; Formal analysis; Investigation;
Methodology; Writing – original draft; Writing –
review & editing.
Ai Lyn Tan: Investigation; Methodology;
Supervision; Writing – original draft; Writing –
review & editing.
Joshua Golding: Data curation; Formal analy-
sis; Investigation; Methodology; Writing – review
& editing.
Lesley-Anne Bissell: Data curation; Formal
analysis; Investigation; Methodology; Writing –
review & editing.
Oliver J. Wilson: Conceptualisation; Investi-
gation; Supervision; Writing – original draft;
Writing – review & editing.
Jim McKenna: Investigation; Supervision;
Writing – original draft; Writing – review &
editing.
Antonios Stavropoulos-Kalinoglou: Concep-
tuali sation; Data curation; Formal analysis;
Investigation; Methodology; Supervision; Writing
– original draft; Writing – review & editing.
Acknowledgements
C.B. thanks the co-authors, the Carnegie School
of Sport at Leeds Beckett University and the
Leeds Teaching Hospitals NHS Trust for their
assistance and support in completing this system-
atic review.
Funding
The authors disclosed receipt of the following
financial support for the research, authorship,
and/or publication of this article: C.B. was sup-
ported by an internal PhD bursary from Leeds
Beckett University.

THERAPEUTIC ADVANCES in
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Competing interests
The authors declared no potential conflicts of
interest with respect to the research, authorship,
and/or publication of this article.
Availability of data and materials
All data relevant to the study are included in the
article or uploaded as supplementary material.
The data will be shared on reasonable request to
the corresponding author and following ethical or
other needed approval.
ORCID iD
Christopher Balchin https://orcid.org/0000-
0001-8221-3955
Supplemental material
Supplemental material for this article is available
online.
References
1. Humphreys JH, Verstappen SM, Hyrich KL,
etal. The incidence of rheumatoid arthritis in
the UK: comparisons using the 2010 ACR/
EULAR classification criteria and the 1987 ACR
classification criteria. Results from the Norfolk
Arthritis Register. Ann Rheum Dis 2013; 72:
1315–1320.
2. Choy E and Panayi G. Cytokine pathways and
joint inflammation in rheumatoid arthrtis. N Engl
J Med 2001; 344: 907–916.
3. McInnes IB and Schett G. Cytokines in the
pathogenesis of rheumatoid arthritis. Nat Rev
Immunol 2007; 7: 429–442.
4. Lee DM and Weinblatt ME. Rheumatoid
arthritis. Lancet 2001; 358: 903–911.
5. Tak PP and Kalden JR. Advances in
rheumatology: new targeted therapeutics. Arthritis
Res Ther 2011; 13(Suppl. 1): S5.
6. van den Ende CH, Breedveld FC, le Cessie S,
etal. Effect of intensive exercise on patients with
active rheumatoid arthritis: a randomised clinical
trial. Ann Rheum Dis 2000; 59: 615–621.
7. Hakkinen A, Sokka T, Kotaniemi A, etal. A
randomized two-year study of the effects of
dynamic strength training on muscle strength,
disease activity, functional capacity, and bone
mineral density in early rheumatoid arthritis.
Arthritis Rheum 2001; 44: 515–522.
8. Lemmey AB, Marcora SM, Chester K, etal.
Effects of high-intensity resistance training in
patients with rheumatoid arthritis: a randomized
controlled trial. Arthritis Rheum 2009; 61:
1726–1734.
9. Metsios GS, Stavropoulos-Kalinoglou A
and Kitas GD. The role of exercise in the
management of rheumatoid arthritis. Expert Rev
Clin Immunol 2015; 11: 1121–1130.
10. Combe B, Landewe R, Daien CI, etal. 2016
update of the EULAR recommendations for the
management of early arthritis. Ann Rheum Dis
2017; 76: 948–959.
11. Febbraio MA and Pedersen BK. Muscle-derived
interleukin-6: mechanisms for activation and
possible biological roles. FASEB J 2002; 16:
1335–1347.
12. Pedersen BK, Steensberg A and Schjerling P.
Muscle-derived interleukin-6: possible biological
effects. J Physiol 2001; 536: 329–337.
13. Vickers AJ. Time course of muscle soreness
following different types of exercise. BMC
Musculoskelet Disord 2001; 2: 5.
14. Ostrowski K, Rohde T, Asp S, etal. Pro- and
anti-inflammatory cytokine balance in stenous
exercise in humans. J Physiol 1999; 515: 287–291.
15. Pescatello LS, Riebe D and Thompson PD.
ACSM’s guidelines for exercise testing and
prescription. 9th ed. Philadelphia, PA: Lippincott
Williams & Wilkins, 2014.
16. Baillet A, Zeboulon N, Gossec L, etal. Efficacy of
cardiorespiratory aerobic exercise in rheumatoid
arthritis: meta-analysis of randomized controlled
trials. Arthritis Care Res 2010; 62: 984–992.
17. Cooney JK, Law RJ, Matschke V, etal. Benefits
of exercise in rheumatoid arthritis. J Aging Res
2011; 2011: 681640.
18. Lemmey AB. Efficacy of progressive resistance
training for patients with rheumatoid arthritis and
recommendations regarding its prescription. Int J
Clin Rheumatol 2011; 6: 189–205.
19. Tierney M, Fraser A and Kennedy N. Physical
activity in rheumatoid arthritis: a systematic
review. J Phys Act Health 2012; 9: 1036–1048.
20. Qvarfordt M, Andersson ML and Larsson I.
Factors influencing physical activity in patients
with early rheumatoid arthritis: a mixed-
methods study. SAGE Open Med 2019; 7:
2050312119874995.
21. Baslund B, Lyngberg K, Andersen V, etal. Effect
of 8 wk of bicycle training on the immune system
of patients with rheumatoid arthritis. J Appl
Physiol 1993; 75: 1691–1695.
22. Law RJ, Breslin A, Oliver EJ, etal. Perceptions
of the effects of exercise on joint health in

C Balchin, AL Tan et al.
journals.sagepub.com/home/tab 15
rheumatoid arthritis patients. Rheumatology 2010;
49: 2444–2451.
23. Veldhuijzen van Zanten JJ, Rouse PC, Hale ED,
etal. Perceived barriers, facilitators and benefits
for regular physical activity and exercise in
patients with rheumatoid arthritis: a review of the
literature. Sports Med 2015; 45: 1401–1412.
24. Steinbrocker O, Traeger CH and Batterman RC.
Therapeutic criteria in rheumatoid arthritis. J Am
Med Assoc 1949; 140: 659–662.
25. Ropes MW. 1958 REVISION of diagnostic
criteria for rheumatoid arthritis. Arthritis Rheum
1959; 2: 16–20.
26. Arnett FC, Edworthy SM, Bloch DA, etal. The
American Rheumatism Association 1987 revised
criteria for the classification of rheumatoid
arthritis. Arthritis Rheum 1988; 31: 315–324.
27. Aletaha D, Neogi T, Silman AJ, etal. 2010
rheumatoid arthritis classification criteria: an
American College of Rheumatology/European
League Against Rheumatism collaborative
initiative. Ann Rheum Dis 2010; 69: 1580–1588.
28. Page MJ, McKenzie JE, Bossuyt PM, etal. The
PRISMA 2020 statement: an updated guideline
for reporting systematic reviews. BMJ 2021; 372:
n71.
29. Tawfik GM, Dila KAS, Mohamed MYF, etal.
A step by step guide for conducting a systematic
review and meta-analysis with simulation data.
Trop Med Health 2019; 47: 46.
30. Smart NA, Waldron M, Ismail H, etal.
Validation of a new tool for the assessment of
study quality and reporting in exercise training
studies: TESTEX. Int J Evid Based Healthc 2015;
13: 9–18.
31. Knudsen LS, Christensen IJ, Lottenburger T,
etal. Pre-analytical and biological variability in
circulating interleukin 6 in healthy subjects and
patients with rheumatoid arthritis. Biomarkers
2008; 13: 59–78.
32. Melton-Rogers S, Hunter G, Walter J, etal.
Cardiorespiratory responses of patients with
rheumatoid arthritis during bicycle riding and
running in water. Phys Ther 1996; 76: 1058–1065.
33. Lofgren M, Opava CH, Demmelmaier I, etal.
Pain sensitivity at rest and during muscle
contraction in persons with rheumatoid arthritis:
a substudy within the Physical Activity in
Rheumatoid Arthritis 2010 study. Arthritis Res
Ther 2018; 20: 48.
34. Mikkelsen UR, Dideriksen K, Andersen MB,
etal. Preserved skeletal muscle protein anabolic
response to acute exercise and protein intake
in well-treated rheumatoid arthritis patients.
Arthritis Res Ther 2015; 17: 271.
35. Pereira Nunes Pinto AC, Natour J, de Moura
Castro CH, etal. Acute effect of a resistance
exercise session on markers of cartilage
breakdown and inflammation in women with
rheumatoid arthritis. Int J Rheum Dis 2017; 20:
1704–1713.
36. Beals CA, Lampman RM, Banwell BF, etal.
Measurement of exercise tolerance in patients
with rheumatoid arthritis and osteoarthritis.
J Rheumatol 1985; 12: 458–461.
37. Bearne LM, Scott DL and Hurley MV.
Exercise can reverse quadriceps sensorimotor
dysfunction that is associated with rheumatoid
arthritis without exacerbating disease activity.
Rheumatology 2002; 41: 157–166.
38. Friden C, Thoors U, Glenmark B, etal. Higher
pain sensitivity and lower muscle strength in
postmenopausal women with early rheumatoid
arthritis compared with age-matched healthy
women – a pilot study. Disabil Rehabil 2013; 35:
1350–1356.
39. Law RJ, Saynor ZL, Gabbitas J, etal. The effects
of aerobic and resistance exercise on markers of
large joint health in stable rheumatoid arthritis
patients: a pilot study. Musculoskeletal Care 2015;
13: 222–235.
40. Byers PH. Effect of exercise on morning stiffness
and mobility in patients with rheumatoid arthritis.
Res Nurs Health 1985; 8: 275–281.
41. Thompson PW, James IT, Wheatcroft S, etal.
Circadian rhythm of serum cytidine deaminase in
patients with rheumatoid arthritis during rest and
exercise. Ann Rheum Dis 1989; 48: 502–504.
42. Lee YC. Effect and treatment of chronic pain in
inflammatory arthritis. Curr Rheumatol Rep 2013;
15: 300.
43. Boyden SD, Hossain IN, Wohlfahrt A, etal.
Non-inflammatory causes of pain in patients with
rheumatoid arthritis. Curr Rheumatol Rep 2016;
18: 30.
44. Leffler AS, Kosek E, Lerndal T, etal.
Somatosensory perception and function of diffuse
noxious inhibitory controls (DNIC) in patients
suffering from rheumatoid arthritis. Eur J Pain
2002; 6: 161–176.
45. Meeus M, Hermans L, Ickmans K, etal.
Endogenous pain modulation in response to
exercise in patients with rheumatoid arthritis,
patients with chronic fatigue syndrome and
comorbid fibromyalgia, and healthy controls: a
double-blind randomized controlled trial. Pain
Pract 2015; 15: 98–106.

THERAPEUTIC ADVANCES in
Musculoskeletal Disease
Volume 14
16 journals.sagepub.com/home/tab
46. Pedersen BK and Hoffman-Goetz L. Exercise
and the immune system: regulation, integration,
and adaptation. Physiol Rev 2000; 80: 1055–
1081.
47. Markovitch D, Tyrrell RM and Thompson D.
Acute moderate-intensity exercise in middle-aged
men has neither an anti- nor proinflammatory
effect. J Appl Physiol 2008; 105: 260–265.
48. Brown WM, Davison GW, McClean CM,
etal. A systematic review of the acute effects of
exercise on immune and inflammatory indices in
untrained adults. Sports Med Open 2015; 1: 35.
49. Mendham AE, Donges CE, Liberts EA, etal.
Effects of mode and intensity on the acute
exercise-induced IL-6 and CRP responses in a
sedentary, overweight population. Eur J Appl
Physiol 2011; 111: 1035–1045.
50. Vasanthi P, Nalini G and Rajasekhar G. Role
of tumor necrosis factor-alpha in rheumatoid
arthritis: a review. Int J Rheum Dis 2007; 10:
270–274.
51. Starkie R, Ostrowski SR, Jauffred S, etal.
Exercise and IL-6 infusion inhibit endotoxin-
induced TNF-alpha production in humans.
FASEB J 2003; 17: 884–886.
52. Benatti FB and Pedersen BK. Exercise as an
anti-inflammatory therapy for rheumatic diseases
– myokine regulation. Nat Rev Rheumatol 2015;
11: 86–97.
53. Windsor MT, Bailey TG, Perissiou M, etal.
Cytokine responses to acute exercise in healthy
older adults: the effect of cardiorespiratory
fitness. Front Physiol 2018; 9: 203.
54. Yoshida Y and Tanaka T. Interleukin 6 and
rheumatoid arthritis. Biomed Res Int 2014; 2014:
698313.
55. Steensberg A, Fischer CP, Keller C, etal. IL-6
enhances plasma IL-1ra, IL-10, and cortisol in
humans. Am J Physiol Endocrinol Metab 2003;
285: E433–E437.
56. Pedersen BK. Anti-inflammatory effects of
exercise: role in diabetes and cardiovascular
disease. Eur J Clin Invest 2017; 47: 600–611.
57. Lehrskov LL and Christensen RH. The role of
interleukin-6 in glucose homeostasis and lipid
metabolism. Semin Immunopathol 2019; 41:
491–499.
58. Petersen AM and Pedersen BK. The anti-
inflammatory effect of exercise. J Appl Physiol
2005; 98: 1154–1162.
59. Metsios GS, Moe RH and Kitas GD. Exercise
and inflammation. Best Pract Res Clin Rheumatol
2020; 34: 101504.
60. Pedersen BK and Febbraio MA. Muscle as
an endocrine organ: focus on muscle-derived
interleukin-6. Physiol Rev 2008; 88: 1379–1406.
61. Pedersen BK. Muscle as a secretory organ. Compr
Physiol 2013; 3: 1337–1362.
62. Riebe D, Ehrman JK, Liguori G, etal. ACSM’s
guidelines for exercise testing and prescription. 10th
ed. Philadelphia, PA: Lippincott Williams &
Wilkins, 2017.
63. Hu H, Xu A, Gao C, etal. The effect of physical
exercise on rheumatoid arthritis: an overview of
systematic reviews and meta-analysis. J Adv Nurs
2021; 77: 506–522.
64. Cook DB, O’Connor PJ, Eubanks SA, etal.
Naturally occurring muscle pain during exercise:
assessment and experimental evidence. Med Sci
Sports Exerc 1997; 29: 999–1012.
65. Burckhardt CS and Jones KD. Adult measures
of pain: the McGill Pain Questionnaire (MPQ),
Rheumatoid Arthritis Pain Scale (RAPS), Short-
Form McGill Pain Questionnaire (SF-MPQ),
Verbal Descriptive Scale (VDS), Visual
Analog Scale (VAS), and West Haven-Yale
Multidisciplinary Pain Inventory (WHYMPI).
Arthritis Care Res 2003; 49: S96–S104.
66. Sokka T. Assessment of pain in rheumatic
diseases. Clin Exp Rheumatol 2005; 23: S77–S84.
67. Kalyoncu U, Dougados M, Daurès J-P, etal.
Reporting of patient-reported outcomes in
recent trials in rheumatoid arthritis: a systematic
literature review. Ann Rheum Dis 2009; 68:
183–190.
68. Hall M, Dobson F, Plinsinga M, etal. Effect of
exercise on pain processing and motor output
in people with knee osteoarthritis: a systematic
review and meta-analysis. Osteoarthritis Cartilage
2020; 28: 1501–1513.
69. Singh JA, Saag KG, Bridges SL Jr, etal. 2015
American College of Rheumatology guideline for
the treatment of rheumatoid arthritis. Arthritis
Rheumatol 2016; 68: 1–26.
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