Zongpan Li1,2
Xue-Qiang Wang1,2*- 1Department of Sport Rehabilitation, Shanghai University of Sport, Shanghai, China
- 2Department of Sport Rehabilitation Medicine, Shanghai Shangti Orthopaedic Hospital, Shanghai, China
Rheumatoid arthritis (RA) is a common systematic, chronic inflammatory, autoimmune, and polyarticular disease, causing a range of clinical manifestations, including joint swelling, redness, pain, stiffness, fatigue, decreased quality of life, progressive disability, cardiovascular problems, and other comorbidities. Strong evidence has shown that exercise is effective for RA treatment in various clinical domains. Exercise training for relatively longer periods (e.g., ≥ 12 weeks) can decrease disease activity of RA. However, the mechanism underlying the effectiveness of exercise in reducing RA disease activity remains unclear. This review first summarizes and highlights the effectiveness of exercise in RA treatment. Then, we integrate current evidence and propose biological mechanisms responsible for the potential effects of exercise on immune cells and immunity, inflammatory response, matrix metalloproteinases, oxidative stress, and epigenetic regulation. However, a large body of evidence was obtained from the non-RA populations. Future studies are needed to further examine the proposed biological mechanisms responsible for the effectiveness of exercise in decreasing disease activity in RA populations. Such knowledge will contribute to the basic science and strengthen the scientific basis of the prescription of exercise therapy for RA in the clinical routine.
1. Introduction
Rheumatoid arthritis (RA) is a type of systematic, chronic inflammatory, autoimmune, and polyarticular disease that causes a range of clinical manifestations, including joint swelling, redness, pain, stiffness, fatigue, decreased quality of life, progressive disability, cardiovascular problems, and other comorbidities (1–3). RA affects 0.5%–1.0% of adults, with an annual incident rate of 5–50/100,000 person-years. The prevalence of RA in women is higher than that in men and increases with age (4–7). RA ranks 42nd among 291 conditions causing disability globally, accounting for 0.49% of the total years of living with disability (8). With the growing population and aging, the overall burden of RA, estimated by disability-adjusted life years, increased from 3.3 million in 1990 to 4.8 million in 2010 (9). Aside from the high disease burden, RA has substantial economic impact. The total average medical costs for individual RA patient ranged from US$ 5720 to US$ 5822, accounting for 8%–24% of the total medial costs, 8%–21% of physician visits, and 17%–88% of in-patient stays (10). In addition, the average number of days of absences due to RA ranges from 2.7 days/year to 30 days/year (11, 12).
Current practice involves the usage of disease-modifying drugs, and biological agents can substantially improve disease activity and minimize structural damage (13, 14). However, challenges in the current practice of RA management should be considered. Some patients remain difficult to treat or can barely achieve the targeted clinical remissions or low disease activity (15). Nonpharmacological treatments, such as exercise therapy, are promising approaches for symptom control and daily function improvement and widely used for patients with RA (16). Moreover, exercise intervention can effectively improve cardiorespiratory fitness, reduce the risk of commensurate cardiovascular disease, and decrease disease activity and severity in patients with RA (17). Thus, physical exercise therapy, as a cost-effective approach, in conjunction with drug therapy has been recommended by the European Alliance of Associations for Rheumatology (EULAR) in 2018 (18).
The clinical effect of exercise on RA has been extensively studied, and the results have been well synthesized by several reviews published from 1998 to 2022 (19–29). An expert review from Metsios et al. discussed the physiological mechanisms by which exercise alleviates inflammation, psychologic health, and cardiovascular risk in patients with RA and provided detailed description on how to incorporate exercises into RA management (30). Moreover, a systematic review from Sveaas et al. reported that high evidence supporting exercises are beneficial for reducing RA disease activity (31). However, to the best of our knowledge, the possible biological mechanisms of how exercise can decrease the RA disease activity have not been comprehensively reviewed. Such information would be essential for understanding the basic science, which can promote the administration of exercises in the routine management of RA.
2. Clinical effect of exercise for patients with rheumatoid arthritis
To summarize the evidence regarding the clinical effect of exercise on RA, we conducted a literature search using the keywords (exercise, physical activity, clinical effect, and rheumatoid arthritis) in PubMed and Google scholar to identify related individual studies and review articles. As there are overlaps between the individual studies and review articles and some reviews have a specific focus (e.g., a certain type of exercise or clinical domain) (24, 29, 32, 33), we chose to review the individual original studies and provide an overall summary of the clinical effect of exercise for patients with RA (Table 1). A total of 30 related studies published between 1985 and 2019 were identified and reviewed, of which 27 were randomized controlled trials (RCTs (34–42, 44–59, 61, 62), 2 were non-RCTs (17, 60), and 1 was before-after trial (43).
Table 1 Characteristics of Included Studies.
Exercise interventions are effective in improving physical ability (17, 34–45, 47–49, 51–61), alleviating pain (35–42, 45, 46, 48, 50, 56, 57, 62), and improving aerobic function (17, 34, 36, 37, 44, 46, 54, 58–60, 62) in patients with RA. In addition, exercise can be effective in improving quality of life (38, 42–44, 49, 56), mental health or sleep status (40, 41, 48, 54, 60), and fatigue (17, 40, 48) and does not aggravate disease activity (17, 35–39, 43, 44, 46–49, 52–54, 57–61) or severity of some conditions, including swollen joints (36, 37, 46, 55, 57, 59, 61, 62) and joint stiffness (40, 50, 55, 57, 59, 61). Exercise training for relatively longer periods can decrease disease activity or clinical severity (i.e., 12–96 weeks) (17, 35–37, 39, 40, 52, 53, 57, 58). The duration of an effective exercise ranges from 2 weeks to 96 weeks, suggesting even short-term exercises can be clinically beneficial for patients with RA. For safety considerations, most exercise protocols utilize moderate intensities for strengthening (i.e., 50%–70% one repetition maximum: 1 RM) and aerobic training (i.e., 50%–70% maximum heart rate: HRmax or peak oxygen uptake: VO2 max). However, several studies have shown that high-intensity strengthening (i.e., 1 RM ≥ 70%) and aerobic (i.e., HRmax or VO2 max ≥ 70%) exercises are effective for patients with RA, and no exercise-related adverse events have been reported (17, 34, 45, 47, 54, 59, 62). Hence, exercises with moderate-to-high intensities are clinically effective and safe for patients with RA. Exercise therapies seem effective and safe for patients with various stages of RA (i.e., duration 0.5–50 years). More importantly, exercises can effectively promote clinical remission in patients with relatively early RA stages (i.e., duration ≤ 5 years (39, 51–53). Hence, exercise therapies are safe and cost-effective approaches and provide a “window of opportunity” for the early management of RA in first-line treatment (63).
In summary, exercise is effective in alleviating pain, improving physical ability, aerobic function, quality of life, mental health, and sleep status and reducing fatigue in patients with RA. Exercise training for relatively longer periods is effective in reducing disease activity.
3. Biological mechanism of exercise for rheumatoid arthritis
Exercise enables a range of biological responses, including the immune systems (64), inflammation (65), matrix metalloproteinase (MMP) (66), oxidative stress (67), and epigenetic adaptation (68). Exercise may reduce the RA disease activity from the following biological aspects: immune cells and immunity, inflammatory response and inflammatory factors, MMP, oxidative stress, and epigenetic expression (Figure 1).
Figure 1 Clinical effects and possible biological mechanisms of exercise for rheumatoid arthritis.
3.1. Immune cells and immunity
RA is known as a chronic autoimmune disease, with a maladaptive tissue repair process elicited by multiple types of immune cells and malfunction of signaling networks (69). Exercise can profoundly affect the immune system, and causes regulation of immune functions (64), which may reduce the RA disease activity. A single bout of brief dynamic exercise (several minutes) causes an increase in the leukocyte count to 2 to 3 times, whereas prolonged exercise (0.5–3 hours) may increase the count of leukocytes up to fivefold (70, 71). Although the increase of leukocyte count is a common indicator of infection/inflammation, the increase can be returned to the pre-exercise level within 6–24 hours after cessation of the exercise (64). Particularly after endurance exercises, the lymphocyte count in blood would be falling 30–50% below pre-exercise level, reaching the clinically low level (i.e., < 1.0 x 109/L) (64, 70, 71). In addition, the neutrophils and lymphocytes can be predominantly mobilized by exercise (70, 71), and the exercise-mobilized cells have increased effector/cytotoxic functions (64).
Growing evidence has shown that exercise and habitual physical activity enhance the immune function of adaptive and innate cells in healthy adults (70, 72). Several studies have examined the effect of exercise on immune response in patients with RA. One study investigated the effect of an 8-week bicycle exercise on immune response in patients with RA and observed temporary increase in lymphoproliferative response during the acute phase of the exercise and no significant changes in the levels of blood mononuclear cell populations in the post-exercise resting state (73). Another study assessed immune responses to exercise in patients with RA and found no changes in lymphocyte proliferation and natural killer cells, suggesting that exercise does not enhance primary cell functions in RA (74). A more recent study that examined the effects of exercise training on immune function in stable patients with RA showed that the neutrophil migration toward chemokines (CXCL-8) was promoted and the frequency of proinflammatory monocytes (CD14+/CD16+) in the circulation was reduced after exercise (75). As RA is characterized by the dysfunctions of peripheral blood neutrophil migration and increased frequency of proinflammatory monocytes (69, 76), exercise may reduce RA disease activity by improving innate immune functions from the two above-mentioned aspects.
3.2. Inflammatory response and inflammatory factors
Once immune cells detect an infection or tissue injury, inflammation is triggered by the innate immune system (69). Certain inflammatory cytokines (e.g., interleukin: IL-6; and tumor necrosis factor alpha: TNF-α) are related to the pathogenesis and progression of RA (77). Clinically, inflammatory markers (i.e., c-reactive protein: CRP) and erythrocyte sedimentation rate (ESR) are routinely used in detecting and monitoring inflammation. In addition, ESR has been commonly used as a component in the calculation of disease activity (e.g., DA28-ESR) (78, 79). Evidence from RCTs has shown that exercise can effectively decrease inflammation/disease activity (i.e., exercise-induced decrease in ERS) in patients with RA (52, 57, 58). However, the biological mechanism of such effects remains unclear.
Although IL-6 is commonly viewed as a proinflammatory cytokine, accumulating evidence has shown that the muscle-derived IL-6, known as a type of myokine, has anti-inflammatory functions (80). Different from the signaling pathway of the expression of IL-6 in macrophages during sepsis (i.e., dependent upon the activation of NF-κB), the contraction of the skeletal muscle causes an increased cytosolic Ca2+ and increased activation of p38 MAPK/calcineurin, which facilitates the production of IL-6 but not of TNF (81). IL-6 is the first cytokine released into the blood during exercise (82). In general, inflammatory cytokine level decreases within a few hours after an exercise (83, 84). However, evidence of the acute effect of exercise on inflammatory response in patients with RA is inconsistent (85). Two observational studies examined the acute effect of a single-session exercise on inflammatory cytokine (e.g., IL-6) in patients with RA; one of the studies found no significant change in IL-6 (86), whereas the other observed IL-6 level sharply increased in the first one hour, then gradually decreased, and returned to pre-exercise level in 24 hours (87). Future studies are needed to clarify the role of muscle-derived IL-6 in the inflammatory response during exercise, and its potential anti-inflammatory function in RA populations.
3.3. Matrix metalloproteinase
Matrix metalloproteinase (MMP) constitutes a large group of zinc-dependent proteases that degrade the components of the extracellular matrix, including collagen, gelatin, casein, and elastin. Exercise may regulate MMP level by affecting their tissue inhibitor of metalloproteinase (TIMPs), transforming growth factor-β (TGF- β), or RNA expression of MMPs (88–90). Evidence shows that physical exercise training is effective in reducing MMP level in healthy men (91), sedentary women (92), individuals with metabolic syndrome (93), patients with coronary artery disease (94), patients with diabetes (95, 96), patients with multiple sclerosis (97), and female patients with postmenopausal osteoporosis (98). Overall, physical exercise can effectively reduce MMP level in different populations.
However, evidence regarding the effectiveness of exercise on MMP reduction in patients with RA is limited. Wang et al. obtained knee synovial tissues from patients with RA who underwent total knee replacement to examine whether mechanical stretching regulates MMP secretion; they found that mechanical stretching induced significant reduction in the messenger RNA expression levels of MMP-1 and MMP-13 (88). To the best of our knowledge, no in vivo study has explored the effectiveness of exercise in reducing MMP level in patients with RA. MMP-3 is produced in the joints, and it aggravates inflammation by activating a range of pro-MMPs and cleaving extracellular matrix components (99). Elevated serum MMP-3 level is positively associated with inflammatory mediators and the disease activity of RA (100–103) and is a crucial outcome for early RA (101–103). Thus, MMP-3 has been regarded as a reliable marker for disease activity, predictability of disease outcome, radiological monitoring, and therapeutic response for RA (104). Hence, it is important for future studies to examine the exercise-induced change in MMP-3 in RA patients and its potential role in explaining the biological mechanism of exercise-induced reduction in RA disease activity.
3.4. Oxidative stress
In RA, particularly at the early stage, oxidative stress may initiate and perpetuate the local and systemic inflammation process (105). Oxidative stress has detrimental effects on the structures and functions of cellular proteins and proteoglycans, via different processes (i.e., oxidation and nitrosylation) (106). The accumulated oxidized cellular components and damaged products may aggravate the synovial inflammation; and the damaged contents caused by oxidative stress can also be released into the extracellular spaces and increase cellular death (106).
Oxidative stress is characterized as elevated intracellular levels of reactive oxygen species (ROS), which can be indirectly measured by lipid peroxidation (e.g., malondialdehyde: MDA), protein oxidation or nitration (e.g., protein carbonyl), or DNA/RNA damage (e.g., 8-hydroxydeoxyguanosine: 8-oxo-dG) (107). Exercise-induced metabolic challenges result in elevated generation of ROS, and such exercise-related changes in the redox milieu are modulated by several factors of mitochondrial biogenesis (e.g., PGC-1α, mitogen-activated protein kinase, and SIRT1) (108). Evidence from animal and human studies suggests that exercise can effectively reduce oxidative stress and improve antioxidant defense. Findings from animal studies have shown that high-intensity aerobic exercise can effectively reduce oxidative stress (reduces MDA concentration) and improve antioxidant defenses (increases GPx) in rats (109, 110). Similar results have been obtained by studies on the effectiveness of physical exercise on oxidative stress (reduced rate and concentration of MDA; decreased 8-oxo-dG) and antioxidant defense system (increased GPx) in humans with or without diseases (111–114).
However, inconsistent results can be seen in RA populations. Wadley et al. reported that a single bout of moderate-intensity exercise increased the oxidative stress (increased protein carbonyls and nitric oxide metabolites) in RA patients, while the following 3-month exercise significantly decreased the RA disease activity, but without significant change in oxidative stress (115). In contrast, Tuna et al. found that the 30-minute aerobic exercise caused a significant reduction in MDA concentration immediately and 24 hours after the exercise in the RA group (116). It is important for future studies to further examine the effect of exercise on oxidative stress and antioxidant defenses in RA populations, and the related biological and molecular mechanisms of exercise, oxidative stress, and the resultant reduction in RA disease activity.
3.5. Epigenetic mechanism
A range of aberrantly expressed noncoding RNAs (miRNA, lncRNA, and circRNA) were observed in RA. For instance, the expression levels of miRNA146a/b and H19 (lncRNA) are upregulated (117–119), but the miRNA-150-5p expression is downregulated in RA (120). Regular exercise induces genome-wide epigenetic modifications in skeletal muscles and adipose tissues in the human body, which are linked with altered expression of mRNA (121, 122). Such exercise-induced alteration in DNA methylation and mRNA expression are believed to improve the metabolic phenotypes and decrease the risk of disease (68).
Evidence has shown the effectiveness of exercise in the regulation of noncoding RNAs (123–125). Four studies reported that physical exercise downgraded the expression of miRNA146 in trained males (126), active males (127), amateur basketball players (128), and patients with chronic kidney diseases (129). Findings from an animal study suggested that a 4-week moderate endurance exercise reduced the expression of H19 in the hearts of rats with myocardial infarction (123). Van Craenenbroeck et al. reported that miRNA150 expression was upregulated after 10 minutes of endurance aerobic exercise in people with chronic kidney diseases (129). Despite these findings from non-RA populations, the effectiveness of exercise in regulating noncoding RNA expression in patients with RA remains unexplored.
Noncoding RNAs, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), play crucial roles in the regulation of inflammation, autoimmunity, and activation, differentiation, and polarization of immune cells (130). Epigenetic disorders can activate rheumatoid arthritis synovial fibroblasts (RASFs) (131), which promote inflammation and joint destruction in RA (132). In non-inflammatory joints of healthy individuals, normal SFs are differentiated from mesenchymal stromal/stem cells under normal genetic regulation. However, aberrant epigenetic alterations would promote the activation of SFs in inflammatory joints of patients with RA (131). A recent study from Haque et al. reported that in response to cytokine stimulation, the guanylate binding protein 5 (GBP-5) from RASFs is a potential target to restore cellular homeostasis, inflammation, and tissue destruction in RA (133).
In summary, future studies are needed to examine the effect of exercise on noncoding RNA expression in RA populations. It is also important to explore the potential role of epigenetic regulation in the biological mechanism of exercise for the reduction of RA disease activity.
4. Conclusions
The clinical effectiveness of exercise for RA treatment has been extensively studied. Substantial evidence has shown that exercise therapies of different types, durations, and intensities can be clinically effective for RA. More importantly, exercise for relatively longer periods can decrease the RA disease activity. This review discusses the possible biological mechanism of exercise for reducing RA disease activity from the following aspects: 1) immunity; 2) inflammatory response; 3) MMP; 4) oxidative stress; and 5) epigenetic mechanism. However, the related evidence is mainly based on evidence from non-RA populations. This may highlight the urgency for future studies to further examine the proposed biological mechanisms in RA populations.
5. Future directions
Based on current evidence, the following directions regarding the exercise for reducing RA disease activity are proposed for further investigation in RA populations: 1) exercise may cause neutrophil migration toward chemokines (e.g., CXCL-8) and reduce the frequency of proinflammatory monocytes (e.g., CD14+/CD16+) in the circulation; 2) exercise may promote the production of muscle-derived myokine (IL-6), which may have anti-inflammatory functions; 3) exercise may induce reduction in the messenger RNA expression of MMPs(e.g., MMP-3); 4) exercise may reduce oxidative stress (reducesMDA concentration) and improve antioxidant defenses(increases GPx level); and 5) exercise may downregulate the expression of miRNA146 and H19 but upregulate miRNA150expression, which may relate to the production of protectiveproteins (e.g., GBP-5) for decreasing RA disease activity.
Author contributions
ZL and X-QW carried out the literature search, reviewed all the included articles, and drafted and edited the manuscript. All authors contributed to the article and approved the submitted version.
Funding
This work was supported by grants from the Shanghai Key Lab of Human Performance (Shanghai University of Sport) (11DZ2261100); the Shanghai Frontiers Science Research Base of Exercise and Metabolic Health; the Talent Development Fund of Shanghai Municipal (2021081); and the Shanghai Clinical Research Center for Rehabilitation Medicine (21MC1930200).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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Keywords: exercise, clinical effect, biological mechanism, rheumatoid arthritis, review
Citation: Li Z and Wang X-Q (2023) Clinical effect and biological mechanism of exercise for rheumatoid arthritis: A mini review. Front. Immunol. 13:1089621. doi: 10.3389/fimmu.2022.1089621
Received: 04 November 2022; Accepted: 16 December 2022;
Published: 06 January 2023.
Edited by:
Tsutomu Takeuchi, Keio University School of Medicine, JapanReviewed by:
Brian J. Andonian, Duke University, United StatesCopyright © 2023 Li and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Xue-Qiang Wang, wangxueqiang@sus.edu.cn