The Effects of Exercise Training on Functional Capacity and Quality of Life in Patients with Rheumatoid Arthritis: A Systematic Review

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation. The purpose of this systematic review is to evaluate the effectiveness of exercise training on functional capacity and quality of life (QoL) in patients with RA. We performed a search in four databases, selecting clinical trials that included community or outpatient exercise training programs in patients with RA. The primary outcome was functional capacity assessed by peak VO2 or the 6 min walking test, and the secondary outcome was QoL assessed by questionnaires. Seven studies were finally included, identifying a total number of 448 patients. The results of the present systematic review show a statistically significant increase in peak VO2 after exercise training in four out of seven studies. In fact, the improvement was significantly higher in two out of these four studies compared to the controls. Six out of seven studies provided data on the patients’ QoL, with five of them managing to show statistically significant improvement after exercise training, especially in pain, fatigue, vitality, and symptoms of anxiety and depression. This systematic review demonstrates the beneficial effects of exercise training on functional capacity and QoL in patients with RA.

Full text

Citation: Athanasiou, A.; Papazachou,
O.; Rovina, N.; Nanas, S.; Dimopoulos,
S.; Kourek, C. The Effects of Exercise
Training on Functional Capacity and
Quality of Life in Patients with
Rheumatoid Arthritis: A Systematic
Review. J. Cardiovasc. Dev. Dis. 2024,
11, 161. https://doi.org/10.3390/
jcdd11060161
Academic Editor: Elena Cavarretta
Received: 4 April 2024
Revised: 18 May 2024
Accepted: 21 May 2024
Published: 22 May 2024
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Journal of
Cardiovascular
Development and Disease
Systematic Review
The Effects of Exercise Training on Functional Capacity and
Quality of Life in Patients with Rheumatoid Arthritis:
A Systematic Review
Amalia Athanasiou 1, †, Ourania Papazachou 1,2, Nikoletta Rovina 3, Serafim Nanas 1, Stavros Dimopoulos 1,4
and Christos Kourek 1, 5,*,†
1Clinical Ergospirometry, Exercise & Rehabilitation Laboratory, 1st Critical Care Medicine Department,
Evangelismos Hospital, National and Kapodistrian University of Athens, 10676 Athens, Greece;
ama.athanasiou@gmail.com (A.A.); ranpapaza@yahoo.gr (O.P.); sernanas@gmail.com (S.N.);
stdimop@gmail.com (S.D.)
2Department of Cardiology, “Helena Venizelou” Hospital, 10676 Athens, Greece
31st Department of Respiratory Medicine, Sotiria Chest Hospital, School of Medicine,
National and Kapodistrian University of Athens, 11527 Athens, Greece; nikrovina@med.uoa.gr
4Cardiac Surgery Intensive Care Unit, Onassis Cardiac Surgery Center, 17674 Athens, Greece
5Department of Cardiology, 417 Army Share Fund Hospital of Athens (NIMTS), 11521 Athens, Greece
*Correspondence: chris.kourek.92@gmail.com
†These authors contributed equally to this work.
Abstract: Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation.
The purpose of this systematic review is to evaluate the effectiveness of exercise training on functional
capacity and quality of life (QoL) in patients with RA. We performed a search in four databases,
selecting clinical trials that included community or outpatient exercise training programs in patients
with RA. The primary outcome was functional capacity assessed by peak VO
2
or the 6 min walking
test, and the secondary outcome was QoL assessed by questionnaires. Seven studies were finally
included, identifying a total number of 448 patients. The results of the present systematic review
show a statistically significant increase in peak VO
2
after exercise training in four out of seven studies.
In fact, the improvement was significantly higher in two out of these four studies compared to the
controls. Six out of seven studies provided data on the patients’ QoL, with five of them managing to
show statistically significant improvement after exercise training, especially in pain, fatigue, vitality,
and symptoms of anxiety and depression. This systematic review demonstrates the beneficial effects
of exercise training on functional capacity and QoL in patients with RA.
Keywords: rheumatoid arthritis; peak VO2; quality of life; aerobic exercise; anaerobic exercise
1. Introduction
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder charac-
terized by inflammatory arthritis and extra-articular involvement [
1
]. In particular, some
symptoms of rheumatoid arthritis are the presence of pain, tenderness, and redness and
swelling in certain joints, usually in the fingers, wrists, or metatarsals, while there is often
symmetry in the joint involvement [
2
]. It is a fairly common disease worldwide and it is
estimated to affect approximately 0.24% to 1% of the population. In Europe and North
America, its prevalence is 0.5 to 1.0% [
3
]. In addition, it affects at least twice as many
women as men, and although the onset of the disease can occur at any age, the greatest
risk of its occurrence is at the age of 50 [
4
]. Patients with RA frequently present exercise
intolerance [5], increased cardiovascular risk [5], and decreased quality of life (QoL) [6].
Exercise has a significant role in preventing or improving vascular endothelial func-
tion [
7
]. Endothelial nitric oxide synthase (eNOS) plays an essential role in the regulation of
endothelial function and acts as a principal regulator of vascular tone and homeostasis [
8
,
9
].
J. Cardiovasc. Dev. Dis. 2024,11, 161. https://doi.org/10.3390/jcdd11060161 https://www.mdpi.com/journal/jcdd

J. Cardiovasc. Dev. Dis. 2024,11, 161 2 of 15
Exercise affects vascular reactivity in the coronary and skeletal muscle circulations through
upregulation of nitric oxide (NO) release and endothelium-dependent hyperpolarization-
mediated responses resulting from increases in blood flow and thus shear stress [
10
]. In
recent years, evidence has accumulated confirming that NO release by endothelial cells can
be chronically increased (e.g., by estrogen, exercise) and decreased (e.g., by oxidative stress)
by aging and during vascular diseases (e.g., diabetes and hypertension) [
11
]. It has been
shown that aerobic exercise, as well as its combination with resistance exercise, improves
maximal oxygen uptake (peak VO
2
), vascular endothelial function, or QoL in patients with
cardiovascular comorbidities [
12
–
15
] and autoimmune rheumatic diseases [
16
]. Physical
activity or moderate intensity exercise have profound anti-inflammatory effects in patients
with chronic diseases or RA [
17
,
18
]. As far as the possible underlying molecular mecha-
nisms are concerned, recent studies have investigated the possible role in heart failure (HF)
of sirtuins, a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacety-
lases, among which sirtuin 1 (Sirt1) is the best characterized member [
19
,
20
].
Sirtuin 1
is involved in biological processes strongly related to HF, including oxidative stress and
cellular senescence. It also plays a crucial role in angiotensin II-induced vascular remodel-
ing and inflammatory response by modulating the expression of certain cytokines [
19
,
20
].
It is not surprising, therefore, that exercise is recognized as an activator of Sirt1. High
frequency of training induces systemic vascular adaptations and increases the effect of
aerobic exercise on endothelial function compared to a low training frequency [
13
]. In
addition, high-intensity interval training increases endothelial function to a greater extent
than moderate-intensity training [
13
]. Nevertheless, the impact of exercise training on
functional capacity in patients with RA has not been extensively studied in the literature.
The aim of the present systematic review is to evaluate and compare the effect of
combined exercise training programs on functional capacity and QoL in patients with RA.
2. Materials and Methods
2.1. Search Strategy
A search for clinical trials or randomized controlled trials (RCTs) was performed in
Pubmed, Cochrane, PEDro, and Embase databases between 28 June 2023 and 10 July 2023.
Articles that resulted from the search were selected based on specific criteria: English
language and clinical studies or RCTs. Specific terms including (“Exercise” OR “Exercise
Training” OR “Rehabilitation” OR “Breathing Exercise”) AND (“Rheumatoid Arthritis”
OR “Arthritis” OR “Rheumatic Disease” OR “Rheumatics”) were used for the search. This
review was performed in accordance with the PRISMA (Preferred Reporting Items for
Systematic Reviews and Meta-Analyses) guidelines. Duplicates were removed from the
initial number of studies, and the rest were evaluated twice. The search and evaluation
of studies were performed by the principal investigator and verified and assessed for
validity and accuracy by an independent investigator. Final evaluation and approval were
performed by a third independent researcher. The data used for each study included
demographic characteristics of the intervention and control group, details on training
protocols, key endpoints, and results.
2.2. Study Selection Criteria
The inclusion criteria were as follows: (1) clinical trials or randomized clinical trials that
included an interventional and a control group; (2) patients with RA, under stable treatment
and without hospitalizations in the last three months; (3) aged
≥
18 years;
(4) aerobic
or resistance exercise training or combined exercise protocols; (5) duration of exercise
train
ing ≥2 w
eeks; and (6) studies that included results of exercise training on peak VO
2
or the 6 min walking test and/or QoL.
The exclusion criteria were as follows: (1) systematic reviews, guidelines, abstracts, and
meta-analyses; (2) patients with comorbidities of increased severity and symptoms, such as
moderate to severe HF (New York Heart Association (NYHA) class III–IV), moderate to
severe chronic obstructive pulmonary disease (COPD), asthma, and vasculitis; (3) studies

J. Cardiovasc. Dev. Dis. 2024,11, 161 3 of 15
using a different intervention than exercise; and (4) studies investigating the acute effect
of exercise.
2.3. Quality Assessment
A quality assessment was performed using the Physiotherapy Evidence Database
(PEDro Scale). This scale consists of a checklist of 11 yes/no questions related to internal
validity and statistical information provided. Each study receives 1 unit for each criterion it
meets. The maximum score is 10/10 (criterion 1 regarding eligibility criteria is not included
in the final score, as it refers to external validity). High-quality studies are those with a
score of 6–10/10, moderate 4–5/10, and low ≤3/10.
2.4. Outcome Measures
The primary outcome was functional capacity assessed by peak VO
2
or the 6 min walk-
ing test, while the secondary outcome was the assessment of QoL through questionnaires
(e.g., Short-Form Health Survey 36 (SF-36)). Both outcomes were evaluated at baseline and
post-intervention.
3. Results
3.1. Search Results
The results of the research and screening are illustrated in the PRISMA flowchart.
(Figure 1). The initial search strategy identified 5083 articles from PubMed, Cochrane, PE-
Dro, and Embase databases. The removal of duplicate publications excluded 28
12 arti
cles.
Subsequently, from the screening of 2271 studies, 2141 were excluded after title or abstract
assessment. Ninety-four studies were assessed for eligibility, of which 87 were excluded
due to exclusion criteria. Therefore, seven studies met the inclusion criteria and were finally
included in the review [21–27].
J. Cardiovasc. Dev. Dis. 2024, 11, 161 3 of 17
The exclusion criteria were as follows: (1) systematic reviews, guidelines, abstracts,
and meta-analyses; (2) patients with comorbidities of increased severity and symptoms,
such as moderate to severe HF (New York Heart Association (NYHA) class III–IV),
moderate to severe chronic obstructive pulmonary disease (COPD), asthma, and
vasculitis; (3) studies using a different intervention than exercise; and (4) studies
investigating the acute effect of exercise.
2.3. Quality Assessment
A quality assessment was performed using the Physiotherapy Evidence Database
(PEDro Scale). This scale consists of a checklist of 11 yes/no questions related to internal
validity and statistical information provided. Each study receives 1 unit for each criterion
it meets. The maximum score is 10/10 (criterion 1 regarding eligibility criteria is not
included in the final score, as it refers to external validity). High-quality studies are those
with a score of 6–10/10, moderate 4–5/10, and low ≤ 3/10.
2.4. Outcome Measures
The primary outcome was functional capacity assessed by peak VO
2
or the 6 min
walking test, while the secondary outcome was the assessment of QoL through
questionnaires (e.g., Short-Form Health Survey 36 (SF-36)). Both outcomes were evaluated
at baseline and post-intervention.
3. Results
3.1. Search Results
The results of the research and screening are illustrated in the PRISMA flowchart.
(Figure 1). The initial search strategy identified 5083 articles from PubMed, Cochrane,
PEDro, and Embase databases. The removal of duplicate publications excluded 2812
articles. Subsequently, from the screening of 2271 studies, 2141 were excluded after title
or abstract assessment. Ninety-four studies were assessed for eligibility, of which 87 were
excluded due to exclusion criteria. Therefore, seven studies met the inclusion criteria and
were finally included in the review [21–27].
Figure 1. PRISMA flowchart including the screening results of the systematic review.
Figure 1. PRISMA flowchart including the screening results of the systematic review.
3.2. Assessment of the Methodological Quality of the Studies
The methodological quality of the studies (RCTs and clinical trials) was assessed using
the PEDro scale. The scores on the PEDro scale ranged from 4 to 7 (Table 1). None of the

J. Cardiovasc. Dev. Dis. 2024,11, 161 4 of 15
studies had an overall score of less than 4. One of the seven studies had an overall score
of 4
and was classified as good. The remaining seven studies had a total score of 5 to 7 and
are characterized as very good. The lowest scoring area in all the studies was participant
and therapist blindness.
3.3. Characteristics of Participants
The total number of participants was 448, with the majority of them being females
(145 vs. 50 males). Aerobic exercise was performed by 232 patients, 37 patients performed
a combination of aerobic exercise and resistance exercise, and the remaining 179 belonged
to the control group. The mean age of the participants ranged from 44 to 55 years, while
the mean time since the diagnosis of RA ranged from 2 to 35 years. The mean peak VO
2
(mL/kg/min) ranged from 21.10 to 34.2. The disease activity score was low to moderate, as
the mean value ranged from 2.9 to 4.1, while the body mass index (BMI) was high, with
a range of 26.1 kg/m
2
to 28.8 kg/m
2
. The demographics and baseline characteristics are
outlined in Table 2.
3.4. Exercise Training Protocols
The seven studies used specific exercise protocols. Six studies consisted of one in-
tervention group and one control group, while one consisted of two intervention groups
and one control group. Aerobic exercise was used as an intervention in all the studies,
while combined aerobic and resistance exercise was performed in five of them. In one
study, aerobic exercise was performed through the form of dancing, and in another study,
it was performed in water. The duration of the intervention ranged from 3 to 6 months
(3 months in five studies, 2 months in one study, and 6 months in one study), while the
frequency of exercise training was from 2 to 3 times a week. Each training session had a
duration between 35 and 90 min. The controls received usual care that varied among the
studies. Specifically, in Bilberg et al.’s [
23
] and Stavropoulos-Kalinoglou et al.’s studies [
26
],
the patients continued their daily activities, which included the home exercise program
introduced to them on admission to the clinic. In Neuberger et al.’s [
24
] study, the patients
were asked to remain at the same level of fitness as they had at the baseline measurement,
while in Azeez et al.’s study [
27
], the standard care involved advice on the benefits of
exercise in rheumatoid arthritis and outlining recommendations for physical activity in
older adults. Finally, in some studies [21,22,25], the usual care was not further explained.
The cardiopulmonary exercise testing (CPET) characteristics are highlighted in Table 2
for each study.
3.5. Effect of Exercise Training on Cardiorespiratory Fitness
The peak VO
2
improved significantly within the intervention group after exercise
training in four out of seven studies [
21
,
25
–
27
] (Table 3). In fact, the improvement was
significantly higher in two out of these four studies compared to the controls [
25
,
26
]. In
Noreu et al.’s study [
21
], the peak VO
2
was found to increase in the intervention group
by 13% (22.2
±
7.4 to 25.0
±
7.2 mL/kg/min, p
≤
0.01), while in the control group, it
remained unchanged (22.7
±
6.5 to 23.8
±
5.7 mL/kg/min, p> 0.05). In the study of
Bilberg et al. [
23
], there was no improvement in the peak VO
2
in either the intervention
or the control group after exercise training. Similar results were presented in the research
performed by Neuberger et al. [
24
], where, although there was significant improvement
within each exercise group and not within the control group, no statistically significant
difference between the intervention groups and the control group was observed (p> 0.05).
In the study of Breedland et al. [
25
], there was a significant improvement in the intervention
group (31.52
±
10.17 to 35.34
±
11.33 mL/kg/min, p
≤
002), while no improvement was
noticed in the control group (25.99
±
6.07 to 25.55
±
6.36 mL/kg/min), with a statisti-
cally significant difference between the two groups (intervention group: +12.1% versus
control group:
−
1.7%; p< 0.05). In the study of Stavropoulos-Kalinoglou et al. [
26
], the
intervention group showed a significant improvement (p< 0.002), with no improvement in

J. Cardiovasc. Dev. Dis. 2024,11, 161 5 of 15
the control group. Moreover, a statistically significant difference was observed between
the groups (p= 0.002). In the research of Rintala et al. [
22
], both groups improved their
peak VO
2
(intervention group from 27.9
±
7.1 to 29.5
±
7.0 mL/kg/min and control group
from 25.7
±
5.1 to 27.1
±
5.8 mL/kg/min; p< 0.05); however, there was no statistically
significant difference between them (p= 0.204). Finally, in the study of Azeez et al. [
27
],
the intervention group showed a statistically significant improvement [23.2 (16–88) to 27.6
(14–75) mL/kg/min, p= 0.002), while the control group showed no difference [26.1 (14–83)
to 27.6 (18–65) mL/kg/min, p= 0.313). However, no statistically significant difference was
observed between the two groups.
3.6. Effect of Exercise Training on Quality of Life
Six out of seven studies provided data on the patients’ QoL before and after exercise
training [
21
,
23
–
27
] (Table 3). Five of them managed to show statistically significant
improvement in QoL after exercise training [
21
,
23
,
24
,
26
,
27
]. Specifically, Noreu et al. [
21
]
presented a statistically significant improvement in pain (4.37
±
2.15 to 3.47
±
1.85),
mobility (0.46
±
1.26 169 to 1.25
±
2.08), household activities (1.01
±
1.03 to
0.77 ±0.89
),
depression (2.05
±
1.56 to 1.18
±
1.29), and anxiety (4.22
±
1.50 to 3.07
±
1.74) on the
Abnormal Involuntary Movement Scale (AIMS) questionnaire, and tension (7.32
±
6.35
to 4.11
±
4.41), vigor (16.47
±
4.26 to 20.37
±
4.28), depression (8.74
±
7.65 to
4.74 ±5.96
),
fatigue (7.89
±
5.86 to 5.68
±
4.77), and total score (22.4
±
27.7 to
2.6 ±23.1
) on the POMS
questionnaire within the intervention group (p< 0.05), while in the control group, all
these parameters remained unchanged, except for the depression score (
11.50 ±12.64
to
6.70
±
6.62) of the Profile of Mood States (POMS) questionnaire. In the clinical trial of
Bilberg et al. [
23
], the intervention group showed a statistically significant improvement
in functionality (56.0
±
20.9 to 64.7
±
20.0, p= 0.001), physical pain (
40.7 ±21.0
to
50.8 ±23.4
,p< 0.05), vitality (41.5
±
23.9 to 51.8
±
22.6, p= 0.01), physical condition
(
33.0 ±9.6
to 37.1
±
10.5, p= 0.01), and mental health (68.4
±
23.5 to 77.5
±
17.6,
p= 0.01
) after a follow-up at 6 months, according to the SF-36 questionnaire. However,
only vitality improved significantly in the intervention group compared to the controls
(p= 0.021). In addition, physical health (2.6
±
1.5 to 2.1
±
1.4, p= 0.01) and the Health
Assessment Questionnaire (HAQ) score (0.9
±
0.5 to 0.7
±
0.5, p= 0.05) of the Arthritis
Impact Measurement Scales 2 (AIMS2) questionnaire improved statistically significantly
only in the intervention group. This improvement in the HAQ score was statistically
higher in the intervention group compared to the control group (p= 0.045). In the
research by Neuberger et al. [
24
], according to the POMS, McGill Pain, and the Center for
Epidemiologic Studies Depression Scale (CES-D) questionnaires, there was a reduction
in symptoms of fatigue, pain, and depression within the intervention groups, as well
as between the intervention groups and controls (p< 0.04). Overall symptoms such as
fatigue (1.53
±
0.98 to 1.35
±
1.08), pain (4.67
±
2.14 to 4.05
±
2.24), and depression
(
0.59 ±0.67
to 0.49
±
0.62) decreased significantly after exercise training. In the research
by Stavropoulos-Kalinoglou et al. [
26
], there was a statistically significant difference in
the Disease Activity Score (DAS28) (3.5
±
1.2 to 2.7
±
0.7, p< 0.05) and HAQ (1.4
±
0.8 to
0.9
±
0.6, p< 0.001) within the intervention group, while the control group did not show
improvement in the parameters above. The DAS28 and HAQ score improvement was
significantly higher in the intervention group than the controls (p= 0.008 and p= 0.003,
respectively). Finally, Azeez et al. [
27
] showed improvements in the HAQ (0.5 (0.0–2.4)
to 0.25 (0.0–2.5), p= 0.05) and the Global Fatigue Index (GFI) score (13.2 (6.4–34.1) to
10.9 (6.5–37.5), p= 0.047) within the intervention group, but only the GFI score was
significantly better compared to the controls.
On the contrary, Breedland et al. [
25
] failed to show significant differences between
the intervention and control groups according to the Dutch version of the Arthritis Im-
pact Measurement Scales-2 (Dutch-AIMS2) and the Arthritis Self-Efficacy Scale (ASES)
questionnaires.

J. Cardiovasc. Dev. Dis. 2024,11, 161 6 of 15
Table 1. Quality assessment of the included studies using the physiotherapy evidence database.
Criteria Noreu et al. [21] Rintala et al. [22] Bilberg et al. [23] Neuberger et al. [24] Breedland et al. [25] Stavropoulos-Kalinoglou et al. [26] Azeez et al. [27]
Criterion 1: Eligibility criteria √ √ √ √ √ √ √
Criterion 2: Random allocation √ √ √ √ √ √
Criterion 3: Concealed allocation √
Criterion 4: Baseline compararability √ √ √ √ √ √ √
Criterion 5: Blinded subjects
Criterion 6: Blinded therapists
Criterion 7: Blinded assesors √ √ √
Criterion 8: Adequate follow-up √ √ √ √ √
Criterion 9: Intention-to-treat analysis √ √
Criterion 10: Between-group comparisons √ √ √ √ √ √ √
Criterion 11: Point estimates and variability √ √ √ √ √ √ √
Total score 4/10 5/10 6/10 6/10 7/10 5/10 5/10
Criterion 1 (eligibility criteria) is not included in the sum of the total score.
Table 2. Main baseline characteristics among patients with rheumatoid arthritis of each study included in the systematic review.
Studies Groups Females/Males
(n)
Year after
Diagnosis Age (Years) BMI
(kg/m2)Peak VO2
(mL/kg/min) DAS-28 CPET Characteristics for
All Patients (Test/Protocol)
Medication (%)
Noreau et al. [21]
I (n = 19) 12/7 8.1 ±8.2 49.3 ±13.0 NA 22.2 ±7.4 NA
Maximal cycle ergometer
test/Bruce protocol
•Articular injections (11)
•Cortisone (21)
•NSAID (74)
•Remittive agents (68)
C (n = 10) 8/2 11.0 ±5.1 49.4 ±11.9 NA 22.7 ±6.5 NA •Articular injections (30)
•Cortisone (20)
•NSAID (70)
•Remittive agents (60)
Rintala et al. [22]
I (n = 18) 15/3 <5 (6 patients),
≥5 (12 patients)
<50 (9 patients),
≥50 (9 patients) NA 27.9 ±7.1 NA
Submaximal cycle
ergometer test/Bruce
protocol
•Gold therapy (47)
•NSAID (100)
•Sulfasalazine (32)
•Gold therapy + sulfasalazine (6)
•Methotrexate (6)
•D-penicillamine (3)
•Sulfasalazine + prednisone (3)
•Prednisone (3)
•for the total sample
C (n = 16) 14/2 <5 (6 patients),
≥5 (10 patients) <50 (8 patients),
≥50 (8 patients) NA 25.7 ±5.1 NA

J. Cardiovasc. Dev. Dis. 2024,11, 161 7 of 15
Table 2. Cont.
Studies Groups Females/Males
(n)
Year after
Diagnosis Age (Years) BMI
(kg/m2)Peak VO2
(mL/kg/min) DAS-28 CPET Characteristics for
All Patients (Test/Protocol)
Medication (%)
Bilberg et al. [23]
I (n = 20) NA 31 ±15.8 * 49 (32–62) NA 34.0 ±10.9 4.1 ±1.5 Submaximal cycle
ergometer
test/Astrand–Rhyming
protocol
•Analgesic (65)
•DMARD (90)
•Oral steroids (15)
C (n = 23) NA 35 ±17.1 * 46 (21–65) NA 34.2 ±6.7 4.0 ±1.3 •Analgesic (43)
•DMARD (87)
•Oral steroids (17)
Neuberger et al. [24]I1 (n = 68) NA 8 (0.5–50)
for total sample 55.5 (40–70)
for total sample
NA 22.50 ±9.15 NA Submaximal cycle
ergometer
test/Astrand–Rhyming
protocol
NSAID or DMARD as standard therapy for total sample
I2 (n = 79) NA 23.32 ±7.19 NA
C (n = 73) NA 21.10 ±8.15 NA
Breedland et al. [25]
I (n = 19) 12/7 9.7 ±14.0 45 ±11.9 NA 31.52 ±10.17 2.9 ±1.1 Submaximal cycle
ergometer
test/Astrand–Rhyming
protocol
•DMARD (21)
•NSAID + DMARD (68)
•Biological + DMARD (11)
C (n = 15) 12/13 5.9 ±7.2 51.8 ±9.4 NA 25.99 ±6.07 3.1 ±0.9
•NSAID (7)
•DMARD (27)
•NSAID + DMARD (60)
•No medication (7)
Stavropoulos-
Kalinoglou et al. [26]
I (n = 18) 14/4 5.5 (3.0–9.7) 55.0 ±9.8 28.7 ±5.1 24.8 ±7.6 3.2 ±1.2 Maximal treadmill
test/Ramp test protocol DMARD as standard therapy for total sample
C (n = 18) 14/4 7.0 (5.0–10.0) 52.8 ±10.1 28.8 ±5.3 22.4 ±5.7 3.2 ±1.1
Azeez et al. [27]
I (n = 28) 24/4 2 (2–21) 58.5 (34–73) 26.1 (18–47) 24.3 (16–31.8) 2.37
(0.49–3.7)
Submaximal treadmill
test/Modified Bruce
protocol
•DMARD (86)
•Biologic (61)
•DMARD and biologic (54)
•Anti-hypertensive (29)
•No treatment (7)
C (n = 24) 20/4 9 (1–43) 63 (36–74) 26.3 (21–46) 25.9 (14–31.8) 2.69
(0.49–5.3)
•Steroid (8)
•DMARD (79)
•Biologic (33)
•DMARD and biologic (29)
•Anti-hypertensive (38)
•No treatment (17)
I, intervention group; C, control group; PeakVO
2
, peak oxygen consumption; BMI, body mass index; DAS-28, disease activity score 28; CPET, cardiopulmonary exercise testing; NSAID,
non-steroidal anti-inflammatory drugs; DMARD, disease-modifying antirheumatic drugs; NA, not available. * RA duration is measured in months. There were no differences between
baseline parameters such as gender, age, years after diagnosis, peak VO2, and DAS-28 between the 2 groups in each study (p> 0.05).

J. Cardiovasc. Dev. Dis. 2024,11, 161 8 of 15
Table 3. Population, intervention, comparison, outcomes, and study (PICOS) design of each study included in the systematic review.
Studies Interventions by Group Frequency Session Duration Intervention Duration Outcomes Main Results
Noreu et al. [21]
I: Warm-up (10 min),
Exercise (15–30 min): aerobic exercise in the format of
aerobic dancing, without jumps or sudden movements.
3 weeks: 50% of HRR max.
9 weeks: 70% of HRR max.
Cool-down (10 min)
Counseling
C: usual care
Twice per wk
Once per wk 35–50 min 12 wk Peak VO2
QoL (AIMS, POMS)
Peak VO2
-↑in peak VO2in the I group (from 22.2 ±7.5 to
25.0 ±7.2 mL/kg/min, p≤0.01). In the C group, there was not a
significant difference (from 22.7 ±6.5 to 23.8 ±5.7 mL/kg/min,
p> 0.05).
QoL
AIMS
-
Significant
↓
in pain, mobility, household activities, depression, and
anxiety within the I group (p< 0.05), but no difference in any of
these variables within the C group (p> 0.05).
POMS
- Significant ↓in tension, fatigue, depression, and total score, and
significant ↑in vigor within the I group (p< 0.01), but only in
depression within the C group (p< 0.05).
Rintala et al. [22]
I: Water exercise program in a pool.
Warm-up (12 min)
Exercise: arm, trunk, and leg movements, such as rotation
of the upper body, abduction and adduction of arm and
legs, and flexion and extension of arms; some included
the use of fins and balls (35 min).
Cool-down included stretching, floating, and breathing
exercises.
C: usual care
2 times/wk
45–60 min
Increased
gradually 12 wk Peak VO2
Peak VO2
- In the I group, increase from 27.9 + 7.1 to 29.5 ±7.0 mL/kg/min,
and in the C group, from 25.7 + 5.1 to 27.1 ±5.8 mL/kg/min).
- No statistically significant difference between groups (p> 0.05).
Bilberg et al. [23]
I: exercises for aerobic capacity, of moderate aerobic
intensity, dynamic (eccentric and concentric), static
muscle strength, and muscle endurance in the upper
and lower extremities, flexibility, coordination, and
relaxation.
C: usual care
2 times/wk 45 min 12 wk Peak VO2
QoL (SF-36, AIMS2)
Peak VO2
- No significant difference within the I group
(from 34.0 ±10.9 to 33.8 ±10.0 mL/kg/min, p> 0.05) and the C
group (from 34.2 ±6.7 to 32.4 ±7.3 mL/kg/min, p> 0.05).
- No statistically significant difference between groups (p> 0.05).
QoL
SF-36
- Significant improvement in physical functioning, bodily pain,
vitality, and physical component within I group (p< 0.01).
- Significant improvement in bodily pain within C group (p< 0.05).
-
Significant improvement only in vitality in the I group compared to
the C group (p= 0.021).
AIMS2
- Significant improvement in physical and HAQ score within the I
group (p< 0.05).
- No difference within the C group (p> 0.05).
-
Significant improvement in HAQ score in the I group compared to
the C group (p= 0.045).

J. Cardiovasc. Dev. Dis. 2024,11, 161 9 of 15
Table 3. Cont.
Studies Interventions by Group Frequency Session Duration Intervention Duration Outcomes Main Results
Neuberger et al. [24]
I 1: Gym-based warm-up, low-impact aerobic exercise,
strengthening exercises, and cool-down, 60% and 80%
MHR. Weeks 1–3: 20, 10, 20, and 10 min; weeks 2–3: 15, 20,
15, and 10 min; weeks 4–6: 10, 25, 20, and 5 min; and
weeks 7–12: 10, 30, 15, and 5 min.
I 2: The same program, but home- based from a videotape.
C: usual care
3 times/wk 60 min 12 wk Peak VO2
QoL (POMS, MAF,
CES-D)
Peak VO2
- Significant difference within the I1 group (from 22.50 to
25.09 mL/kg/min, p< 0.05) and I2 group (from 23.32 to
24.58 mL/kg/min, p< 0.05), but not within the control group
(p> 0.05).
- No statistically significant difference between the exercise and
control groups (p> 0.05).
QoL
-
Overall symptoms (latent variable for pain, fatigue, and depression)
decreased significantly (p< 0.04) within the I1 and I2 groups
compared to the C group, as well as between the I and C groups.
Breedland et al. [25]
I: Muscle exercise circuit at 40–60% of 1 RM for 3 sets ×
20 reps with increased load 5%/wk.
Bicycle training, 10–20 min, at 60% HRmax.
Other activities included badminton, table tennis,
bowling, uni-hockey, circuit training, and aqua jogging.
C: usual care
2 times/wk 90 min 8 wk
Peak VO2
DAS28
QoL (Dutch-AIMS2,
ASES)
Peak VO2
-↑in the I group (from 31.52 ±10.17 to 35.34 ±11.33 mL/kg/min,
p< 0.01), while no significant change in the C group
(from 25.99 ±6.07 to 25.55 ±6.36 mL/kg/min, p= 0.24).
- There was a statistically significant increase in the I group
compared to the C group (+12.1% versus −1.7%, p= 0.002).
DAS28
No significant differences in DAS28 scores between groups.
QoL
Dutch-AIMS2
- Significant improvement in physical health within the I group
(p= 0.05); no significant changes were found within the C group
(p> 0.05).
- No statistically significant differences between groups (p> 0.05).
ASES
- No statistically significant differences within and between groups
(p> 0.05).
Stavropoulos-
Kalinoglou et al. [
26
]
I: First 3 months aerobic exercise. Three circuits of 3–4
exercises (walk on treadmill, cycle, row, or hand
ergometer) at 70% VO2max for 3–4 min, with 1 min
resting interval.
After 3 months, resistance training was added to the
schedule above. Three sets of 4 resistance exercises (leg
press, chest press, shoulder press, pull-ups) for 12–15 reps.
C: usual care
3 times/wk 50–60 min 6 months
Peak VO2
DAS28
QoL (HAQ)
At 3 and at 6 months
Peak VO2
- Peak VO2significantly improved within the I group from
24.8 ±7.6 mL/min/kg by >10% and 17% within 3 and 6 months
(p< 0.001), while there was not an improvement within the C
group (p> 0.05).
- There was a significant increase in the I group compared to the C
group (3 months: p= 0.023; 6 months: p= 0.002).
DAS28
-↓
DAS28 within the I group (from 3.5
±
1.2 to 2.9
±
0.8 at 3 months
and 2.7 ±0.7 at 6 months; p< 0.05), but no significant reduction
within the C group (from 3.1 ±1.2 to 3.1 ±0.6 at 3 months and
3.2 ±0.9 at 6 months; p> 0.05).
-
Statistically significant improvement in the I group compared to the
controls (p= 0.008).
QoL (HAQ)
- Significant improvement in the I group (from 1.4 ±0.8 to 1.0 ±0.6
at 3 months and 0.9 ±0.6 at 6 months; p< 0.001), but not in the C
group (from 1.3 ±0.7 to 1.6 ±0.5 at 3 months and 1.5 ±0.6 at 6
months; p> 0.05).
- Significant improvement in the I group compared to the C group
(p= 0.003).

J. Cardiovasc. Dev. Dis. 2024,11, 161 10 of 15
Table 3. Cont.
Studies Interventions by Group Frequency Session Duration Intervention Duration Outcomes Main Results
Azeez et al. [27]
I: Personalized exercise program. Cardiovascular
exercises, such as walking,
cycling, or swimming, depended on the patient’s
preferences. Strength exercises
for the upper body (biceps curls, triceps extensions,
and shoulder press). Exercises for the lower body (leg
squat). Resistance bands and balls were used for grip
strength.
C: usual care
NA NA 3 months Peak VO2
DAS28
QoL (HAQ, GFI)
Peak VO2
- Significant increase within the I group (from 23.2 (16–88) to
27.6 (14–75) mL/kg/min, p= 0.002), but no difference in the C
group (from 26.1 (14–83) to 27.6 (18–65) mL/kg/min, p= 0.313).
DAS28
No difference in DAS28 within and between groups (p> 0.05).
QoL
HAQ
- Significant improvement in HAQ within the I group (from
0.5 (0.0–2.4) to 0.25 (0.0–2.5), p= 0.05) and within the C group
(from 1.1 (0–3.0) to 0.8 (0.0–2.9), p= 0.026).
- No difference between groups (p> 0.05).
GFI (global fatigue index)
-
Significant improvement within the I group (from 13.2 (6.4–34.1) to
10.9 (6.5–37.5), p= 0.047), but no difference within the C group
(p= 0.96).
- Significant improvement in the I group compared to the C group
(p= 0.047).
HRR max, maximal heart rate reserve; MHR, maximum heart rate; QoL, quality of life; wk, weeks; min, minutes; 1 RM, one-repetition maximum; AIMS, Abnormal Involuntary
Movement Scale (questionnaire); AIMS2, Arthritis Impact Measurement Scales 2 (questionnaire); Dutch-AIMS2, Arthritis Impact Measurement Scales Dutch version (questionnaire);
POMS, Profile of Mood States (questionnaire); SF-36, 36-Item Short-Form Survey (questionnaire); HAQ, The Health Assessment Questionnaire; GFI, Global Fatigue Index (questionnaire).
↑means increase and ↓means decrease.

J. Cardiovasc. Dev. Dis. 2024,11, 161 11 of 15
4. Discussion
In the present systematic review, we showed that various modalities of aerobic exer-
cise, as well as its combination with resistance training, resulted in the improvement of
exercise capacity, as reflected through peak VO
2
and QoL, as assessed via questionnaires
(SF-36, AIMS, GFI, HAQ) in patients with RA. The new insight of our systematic review
is the assessment of exercise training effects on functional capacity, specifically on peak
VO2. Peak VO2is considered as the principal outcome variable of cardiopulmonary ex-
ercise testing, which is the gold standard method for assessing cardiovascular functional
capacity [28–30].
The vascular endothelium plays an important role in the cardiovascular system in
maintaining blood circulation, regulating vascular tone, and promoting microvascular
permeability, angiogenesis, and inflammatory response [
3
]. Endothelial dysfunction is an
early onset in the pathogenesis of cardiovascular diseases [
31
]. Patients with RA usually
present low maximal aerobic capacity and, therefore, low endurance, rapid fatigue, and
reduced QoL [
3
,
32
,
33
]. On the other hand, exercise training induces a repeated increase
in shear stress, which leads in an increase of the bioavailability of nitric oxide (NO) and
a favorable effect on the oxidative balance [
34
]. Nitric oxide regulates central biological
processes in almost all tissues, cells, and organs of the body [
35
]. Additionally, it can induce
systemic molecular pathways, linked to angiogenesis and chronic anti-inflammatory action
with subsequent improvement of endothelial function [
35
]. All the above beneficial effects
of exercise at the microcellular level correspond with improvement of functional capacity
and QoL in patients with cardiovascular disease or other comorbidities [
36
–
40
]. Therefore,
systematic exercise could induce beneficial effects in patients with RA, including the
increase of peak VO
2
, as well as the improvement of the vascular endothelial function,
physical condition, body strength, mental health, and, finally, their QoL [41].
This systematic review consists of five RCTs and two clinical trials. Four of these stud-
ies found a statistically significant increase in peak VO
2
within the intervention group, but
not in the controls [
21
,
25
–
27
], and this increase was significantly higher in the intervention
group compared to the controls in two of these four studies [
25
,
26
]. The remaining studies
did not manage to show a statistically significant difference between the groups [
21
–
24
,
27
].
One of the main reasons that improvement was not achieved in these studies was the small
number of participants, which may have lowered the power of the analyses. Moreover,
a higher baseline peak VO
2
of patients with RA before exercise training, lack of random-
ization in clinical trials in peak VO
2
between the two groups, and/or a lower intensity of
exercise protocols may be other reasons that led to non-significant differences in functional
capacity between the groups. Instead, the combination of aerobic and resistance training
with higher intensity resulted in statistically significant improvement in peak VO2.
An equally significant aspect of rehabilitation in patients with RA is the QoL, which is
directly affected by the symptoms of the disease. In order to improve the QoL in patients
with RA, it is necessary to increase their functional capacity and reduce their symptoms,
fatigue, and pain. Regular physical exercise seems to contribute significantly to this aim, as
it particularly modifies the metabolic potential, the morphology, and the physiology of the
skeletal muscles, thus producing a number of beneficial effects on exercise tolerance and the
QoL of patients with RA [
21
,
23
,
24
,
26
,
27
]. In our systematic review, there was improvement
in the QoL in most studies [
21
,
23
,
24
,
26
,
27
]. Many questionnaires have been widely used
in the assessment of the QoL in various clinical syndromes. In RA, investigators used the
AIMS, AIMS2, Dutch AIMS2, ASES, SF-36, POMS, MAF, HAQ, GFI, McGill, and CES-D
tools, as well as the activity of the disease (DAS28) in order to assess QoL. All these tools
have proven to be reliable in different studies and are also being used to assess other clinical
syndromes except for RA.
Acute exercise is another significant aspect that has been shown to offer several benefi-
cial effects for individuals with RA. Specifically, Pereira Nunes Pinto AC et al. [
42
] showed
that a 25 min single resistance exercise session including knee extension, knee flexion,
hip abduction, and hip adduction, with one set of 12 repetitions at 50% of one repetition

J. Cardiovasc. Dev. Dis. 2024,11, 161 12 of 15
maximum (1 RM) and one set of eight repetitions at 75% of 1 RM decreased interleukin
1-beta (IL-1
β
) and increased anti-inflammatory cytokines IL-1 receptor antagonist (IL-1ra)
and IL-10, IL-6, and cartilage oligomeric matrix protein (COMP) immediately after and 1 h
after the exercise session. No changes were observed in tumor necrosis factor alpha (TNF-
α
)
and C-reactive protein (CRP). However, women with and without RA had similar changes
in response to acute exercise in levels of inflammation biomarkers. In another study by
Osailan A et al. [
43
], patients with RA underwent a treadmill exercise test. The authors
investigated the heart rate recovery (HRR) and showed that HRR, which reflects parasym-
pathetic activation, was associated with overall cardiovascular risk, arthritis-related burden,
and wellbeing in RA. Ba˘glan Yentur S et al. [
44
] investigated the variation of brain-derived
neurotrophic factor (BDNF) levels after acute exercise in patients with RA. The importance
of BDNF is that it may promote neuronal survival, axonal guidance, and activity-dependent
synaptic plasticity, and it may be associated with depression [
45
,
46
]. Moreover, BDNF plays
a negative regulatory role in resolving neuroinflammation, and high inflammation reduces
BDNF expression [
47
]. The authors found that a single bout of exercise may effectively
decrease serum BDNF levels in patients with RA without, however, a possible explanation
for this finding. Finally, Coelho-Oliveira AC et al. [
48
] investigated the effect of acute
whole-body vibration exercise under the hands, on handgrip strength, range of motion,
and electromyography signals of women with RA, and demonstrated that it promotes neu-
romuscular modifications during the handgrip of women with stable RA. On the contrary,
a recent systematic literature review that investigated the acute effects of exercise on pain
symptoms, clinical inflammatory markers, and inflammatory cytokines in RA concluded
that post-exercise responses for pain, clinical inflammatory markers and inflammatory
cytokines were not different between people with or without RA [49].
5. Clinical Perspectives
It is evident that more RCTs, including larger sample sizes and exercise training
programs that combine both aerobic and resistance exercise, are required. There is also a
need to create protocols with alternative forms of exercise for these patients who cannot
tolerate aerobic exercise. Moreover, it is necessary to implement strict inclusion criteria
and guidelines in order to ensure correct extraction of the results. Moderate- to high-
intensity exercise, in combination with optimal medication, should be used as the main
intervention in future studies in order to create personalized exercise programs with the
appropriate type, intensity, and frequency of exercise training. In addition, it is important
to estimate the reduction of the annual cost of hospitalizations in patients with RA of
moderate–severe disease activity due to the benefits of exercise training to their daily
life and the improvement of their symptoms. As a result, future research is required to
formulate rehabilitation programs that improve physical condition, strength, functionality,
and QoL of patients with RA.
6. Study Limitations
This systematic review has some limitations. Due to limited data in the literature, we
could not find many clinical trials or RCTs that met our inclusion criteria. Specifically, we
could not find studies including the comparison of two different modalities of exercise in
RA. Furthermore, there was heterogeneity among the sample sizes of each study in terms
of gender, age, and severity of the disease. Intervention was different in each study, with
varying modalities of exercise training, duration of the program and the training session,
intensity, and lack of follow-up after the intervention. Another limitation of our study was
the fact that we did not include studies regarding the acute effects of exercise in RA. The
reason was that the study design of our systematic review aimed to assess the effects of
regular exercise training in RA, and not the effects of a single exercise bout.

J. Cardiovasc. Dev. Dis. 2024,11, 161 13 of 15
7. Conclusions
This systematic review demonstrates the beneficial effects of exercise training on
functional capacity and QoL in patients with RA, with an increase in peak VO
2
and an
improvement in QoL questionnaire scores after a structured exercise training program.
Moreover, the reduction in pain, fatigue, and depression symptoms provided greater
confidence and mobility in their daily life. Further RCTs are required in order to create
individualized training protocols and find the appropriate intensity, duration, and
combination of exercise modalities to achieve the maximum improvement in functional
capacity and QoL.
Author Contributions: Conceptualization, A.A. and C.K.; methodology, A.A.; validation, O.P., N.R.
and S.D.; investigation, A.A.; data curation, A.A. and C.K.; writing—original draft preparation, A.A.
and C.K.; writing—review and editing, O.P., N.R., S.N. and S.D.; supervision, C.K. All authors have
read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Data Availability Statement: No new data were created.
Conflicts of Interest: The authors declare no conflicts of interest.
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