**2. Exercise in rheumatoid arthritis treatment**

The primary goals of RA treatment are to suppress inflammation and limit or prevent joint damage, while relieving pain and improving the patients' quality of life (Kowh et al. 2002). There is currently no cure for rheumatoid arthritis and treatment strategies involve a combination of drugs as well as non-pharmacologic treatments such as exercise and physical therapy (Smolen et al. 2010). As soon as the diagnosis for RA is established, prescribed medications include disease-modifying antirheumatic drugs (DMARDs), nonsteroidal anti-inammatory drugs, glucocorticoids, and TNF‑α inhibitors (Deighton et al. 2009; Bijlsma 2010).

Although drug treatment helps improve disease outcome, exercise is still a vital part of rheumatoid arthritis treatment. For the general adult population, the American College of Sports Medicine and the Heart Association recommends at least 30 minutes of moderateintensity exercise five days a week (Haskell et al. 2007). The benefits of regular exercise for healthy adults are well accepted, and include reducing the risk of coronary artery disease and improving cardiovascular health (Muller-Riemenschneider et al. 2011), reducing adiposity (Brukner and Brown 2005), and increasing muscle strength (Brentano and Martins Kruel 2011; Peterson and Gordon 2011). Randomized clinical trials have reported that the

activates an anti-rheumatologic response which includes an inhibition of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) in healthy and diabetic patients (Lundberg and Nader 2008). There is also evidence regarding the potential beneficial effects of exercise in preventing or suppressing the destructive consequences of inflammation in joint tissues (Ferretti et al. 2005; Ferretti et al. 2006). Clearly, the mechanical loading component of the exercise stimulus might be one of the mechanisms by which exercise exerts a protective anti-inflammatory effect at the local tissue level by preventing the expression of pro-inflammatory molecules. For example, studies have shown that moderate mechanical loading *in vitro* and *in vivo* upregulate production of anti-inflammatory cytokines interleukin (IL)-4 and IL-10, and suppress expression of IL-1β (Millward-Sadler

This will be followed by a discussion of how anti-inflammatory cytokines may work in concert with the anti-catabolic nature of physiologic biomechanical signals to mediate the protective effects of exercise. Elevated levels of pro-inflammatory cytokines such as IL-1β and TNF-α stimulate production of proteolytic enzymes matrix metalloproteinases (MMPs) and A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) which mediate the cartilage destruction process in RA (Sun 2010). Studies have demonstrated physiological loading suppresses MMP and ADAMTS expression in both inflamed and noninflamed joints to exert protective effects on the synovium and articular cartilage (Ferretti et al. 2005; Ferretti et al. 2006; Leong et al. 2010). The most recent progress on these mechanotransduction pathways which regulate the loading-induced anti-inflammatory and anti-catabolic responses will be presented, as well as possible crosstalk between these two

The chapter will conclude with perspectives on how identification of the signaling pathways activated by exercise will lead to the discovery of new treatment targets and development of novel treatment strategies which may have significant clinical potential in treating

The primary goals of RA treatment are to suppress inflammation and limit or prevent joint damage, while relieving pain and improving the patients' quality of life (Kowh et al. 2002). There is currently no cure for rheumatoid arthritis and treatment strategies involve a combination of drugs as well as non-pharmacologic treatments such as exercise and physical therapy (Smolen et al. 2010). As soon as the diagnosis for RA is established, prescribed medications include disease-modifying antirheumatic drugs (DMARDs), nonsteroidal anti-inammatory drugs, glucocorticoids, and TNF‑α inhibitors (Deighton et al.

Although drug treatment helps improve disease outcome, exercise is still a vital part of rheumatoid arthritis treatment. For the general adult population, the American College of Sports Medicine and the Heart Association recommends at least 30 minutes of moderateintensity exercise five days a week (Haskell et al. 2007). The benefits of regular exercise for healthy adults are well accepted, and include reducing the risk of coronary artery disease and improving cardiovascular health (Muller-Riemenschneider et al. 2011), reducing adiposity (Brukner and Brown 2005), and increasing muscle strength (Brentano and Martins Kruel 2011; Peterson and Gordon 2011). Randomized clinical trials have reported that the

and Salter 2004; Ferretti et al. 2005).

pathways.

rheumatoid arthritis.

2009; Bijlsma 2010).

**2. Exercise in rheumatoid arthritis treatment** 

health benefits of exercise are also obtained in patients with RA without adverse effects on disease activity (van den Ende et al. 2000; de Jong et al. 2003; Bilberg et al. 2005; Melikoglu et al. 2006; van den Berg et al. 2006; Neuberger et al. 2007; Baillet et al. 2009; Lemmey et al. 2009). Furthermore, exercise at a high intensity, but within a physiologic range, was more effective in increasing physical function when compared to low intensity exercise (van den Ende et al. 2000; Lemmey et al. 2009).

#### **2.1 Description of prescribed exercises**

Based on the beneficial effects of physical activity in RA clinical trials, exercise programs for people with RA typically involve a combination of stretching exercises, aerobic training, and strength training (Stenstrom and Minor 2003; Cairns and McVeigh 2009; Forestier et al. 2009; Hurkmans et al. 2009; Baillet et al. 2010; Metsios et al. 2010). Table 1 summarizes commonly prescribed modes of exercise and their recommended doses (Resnick 2001; Medicine et al. 2009). Exercise programs are initially prescribed and supervised by an experienced professional, who tailors the program according to the patient's disease activity and symptoms (de Jong and Vliet Vlieland 2005). Since many RA patients have severe disability and a below average physical capacity, the intensity of training is initially low and gradually increased. If pain or swelling appears during exercise, patients are advised to reduce exercise intensity and/or duration until the pain or swelling subsides.

Daily stretching is recommended to decrease joint stiffness and maintain or increase painfree range of motion (ROM). Patients with RA should begin their exercise programs with two to three daily repetitions of each stretching and ROM exercise, and eventually progress to 10 repetitions daily (Nieman 2000; Medicine et al. 2009). Range of motion exercises should be performed slowly with appropriate support, and should not be attempted in a rapid manner with bouncing movements (Resnick 2001).

Walking, cycling, rowing, swimming, water aerobics, and dance are examples of aerobic exercises prescribed to RA patients. Regular brisk walking in previously sedentary adults improved aerobic fitness and reduced cardiovascular risk in healthy adults (Murphy et al. 2002). Cycling at 70-80% predicted maximum heart rate significantly improved aerobic capacity, muscle strength, and joint mobility in RA individuals when compared to patients who only performed ROM exercises (van den Ende et al. 1996). Hydrotherapy, which combines elements of warm water immersion and exercise, was reported to improve the physical and emotional states of RA patients. Specifically, there was a reduction in joint tenderness and an improvement in knee range of motion, and emotional and physiological well-being (Hall et al. 1996). Moderately intensive pool exercise therapy in patients with RA did not improve aerobic capacity, but there were significant improvements in the muscle endurance in the lower and upper extremities (Bilberg et al. 2005). Although dance programs are not well-studied in the RA population, one study did report that female participants in a four week dance-based exercise program involving slow body movements exhibited significant improvements in locomotor ability (Moffet et al. 2000).

Loss of muscle mass and strength is a common characteristic in RA patients (Pedersen and Saltin 2006), and therefore muscle strengthening exercises are often recommended. These high-intensity training exercises include the leg press, chest press, leg extension, seated rowing, leg curl, triceps extension, standing calf raises, and bicep curl (Lemmey et al. 2009). Progressive resistance training (PRT) programs involving the large muscle groups as well as

Molecular Effects of Exercise in Rheumatoid Arthritis 315

resistance exercise also has been reported to reverse RA cachexia by restoring muscle mass

Because of RA cachexia, it was hypothesized that patients with RA were resistant to the anabolic effects of exercise (Rall et al. 1996). However, no differences in the physiological properties of muscle that determine force, including contractile properties, voluntary activation capacity, and contraction velocity, were found between cachectic RA patients and healthy controls (Matschke et al. 2010). Recent clinical trials have found that the muscle of RA patients respond in similar manner to that of muscle in healthy individuals. The strengthening effects of PRT in RA patients (Lemmey et al. 2009) are similar to those observed in healthy middle-aged subjects (Morse et al. 2007). Studies which directly compared RA patients with age-matched healthy patients reported similar findings. Following resistance and aerobic exercise training, comparable increases in strength and thigh muscle cross-section, and decreases in thigh fat thickness were found in both RA and healthy female patients (Hakkinen et al. 2005). Together, these studies demonstrate that exercise training increases muscle mass, strength, and improves physical function in a similar manner in patients with RA and in healthy individuals. In fact, the inclusion of highintensity PRT is recommended in RA treatment strategies to counteract the effects of

Regular exercise, such as endurance training, can reduce basal levels of many inflammatory mediators/markers (King et al. 2003). Consequently, exercise has been recommended as an anti-inflammatory therapy in chronic inflammatory disorders such as RA (Kowh et al. 2002),

Physical inactivity, a common consequence of RA symptoms, leads to the accumulation of visceral fat and activation of inflammatory pathways (Walsh et al. 2011). Chronic inflammation can also drive the development of insulin resistance and atherosclerosis (Handschin and Spiegelman 2008). Increased physical activity has been reported to reduce inflammation in non-RA patients, as indicated by a downregulation of inflammation markers/mediators (Petersen and Pedersen 2005). In another demonstration of the antiinflammatory effects of exercise, a model of low grade inflammation was established in healthy volunteers through the administration of a low dose of E. coli endotoxin. While circulating levels of TNF-α were increased in resting individuals, this increase was blocked in subjects who exercised prior to the endotoxin administration (Starkie et al. 2003), suggesting exercise may inhibit the production of TNF-α. Together, it is possible the antiinflammatory effects of exercise are due to a decrease in visceral fat mass as well as the

With exercise, there is a release of inflammatory-related cytokines from muscle into the circulation. IL-6 is the first cytokine released during exercise. Levels of circulating IL-6 increase exponentially after exercise and then decline post-exercise (Petersen and Pedersen 2006, Walsh et al. 2011). It is unclear whether this acute elevation in IL-6 modulates inflammatory processes during physical activity. Although IL-6 is a pro-inflammatory cytokine in the rheumatic joint, recent studies suggest the transient response of IL-6 may

rheumatoid cachexia (Pedersen and Saltin 2006; Lemmey et al. 2009).

and its effects are observed on the systemic and local levels.

**2.3 Anti-inflammatory effects of exercise** 

production of anti-inflammatory factors.

**2.3.1 Systemic effects** 

(Marcora et al. 2005).

hand exercises have demonstrated improvements in physical function, increase in muscle mass, and reduction in fat mass (Hakkinen et al. 2005; Marcora et al. 2005; Lemmey et al. 2009). Early RA patients who enrolled in a two year strength training program exhibited significant improvements not only in muscle strength, but also showed reductions in systemic inflammation, pain, and disease activity (Hakkinen et al. 2001). With continued training, these gains in muscle strength can be maintained (de Jong et al. 2009).


Table 1. Exercise management guidelines for the treatment of RA (Resnick 2001; Lemmey et al. 2009; Medicine et al. 2009)

### **2.2 Beneficial effects of exercise in RA**

Many RA patients suffer from cachexia, which is characterized by a decrease in muscle mass along with an increase in fat mass. This is unlike the cachexia associated with conditions such as HIV-AIDS, cancers, chronic obstructive pulmonary disease (COPD), and old age, which is defined by significant muscle wasting alone, and is usually characterized by weight loss (Roubenoff et al. 1992). These changes in body composition may increase the risk of developing diabetes and cardiovascular disease (Roubenoff et al. 1992; Lavie et al. 2009), as well as lead to muscle weakness, decreased physical activity, pain, and fatigue, which together further adversely affect skeletal health (Hakkinen 2004). Muscle strengthening is important not only to regain normal physical function, but it is also necessary for joint stability, which may protect against the development of osteoarthritis (Sun 2010). Exercise has been demonstrated to significantly improve many of the symptoms of rheumatoid arthritis, including disability, pain, joint stiffness and fatigue (Hakkinen 2004; Marcora et al. 2005; Neill et al. 2006; Brorsson et al. 2009; Lemmey et al. 2009). Progressive resistance training was reported to increase muscle mass, improve physical function, and reduce disabilities associated with RA (Marcora et al. 2005; Lemmey et al. 2009). High intensity

hand exercises have demonstrated improvements in physical function, increase in muscle mass, and reduction in fat mass (Hakkinen et al. 2005; Marcora et al. 2005; Lemmey et al. 2009). Early RA patients who enrolled in a two year strength training program exhibited significant improvements not only in muscle strength, but also showed reductions in systemic inflammation, pain, and disease activity (Hakkinen et al. 2001). With continued

intensity/frequency/duration

Daily, before and after aerobic exercise. Hold stretch for 10-30 seconds, 3-5 repetitions

Full range of motion for all joints

At least 1 set of 2-3 reps (up to 3 sets of 10 reps) at 80% of the 1 repetition maximum (the maximum load lifted for each of

the prescribed exercises)

2-3 days/week

60-80% maximum heartrate Up to 30 minutes/session

daily

Rowing 3-5 days/week

training, these gains in muscle strength can be maintained (de Jong et al. 2009).

Range of motion

Class of Exercise Type of exercise Recommended

Cycling

Dance

Swimming Water aerobics

Weight machines Elastic bands

Table 1. Exercise management guidelines for the treatment of RA (Resnick 2001; Lemmey et

Many RA patients suffer from cachexia, which is characterized by a decrease in muscle mass along with an increase in fat mass. This is unlike the cachexia associated with conditions such as HIV-AIDS, cancers, chronic obstructive pulmonary disease (COPD), and old age, which is defined by significant muscle wasting alone, and is usually characterized by weight loss (Roubenoff et al. 1992). These changes in body composition may increase the risk of developing diabetes and cardiovascular disease (Roubenoff et al. 1992; Lavie et al. 2009), as well as lead to muscle weakness, decreased physical activity, pain, and fatigue, which together further adversely affect skeletal health (Hakkinen 2004). Muscle strengthening is important not only to regain normal physical function, but it is also necessary for joint stability, which may protect against the development of osteoarthritis (Sun 2010). Exercise has been demonstrated to significantly improve many of the symptoms of rheumatoid arthritis, including disability, pain, joint stiffness and fatigue (Hakkinen 2004; Marcora et al. 2005; Neill et al. 2006; Brorsson et al. 2009; Lemmey et al. 2009). Progressive resistance training was reported to increase muscle mass, improve physical function, and reduce disabilities associated with RA (Marcora et al. 2005; Lemmey et al. 2009). High intensity

Flexibility Stretching

Aerobic Walking

Strength Free weights

al. 2009; Medicine et al. 2009)

**2.2 Beneficial effects of exercise in RA** 

resistance exercise also has been reported to reverse RA cachexia by restoring muscle mass (Marcora et al. 2005).

Because of RA cachexia, it was hypothesized that patients with RA were resistant to the anabolic effects of exercise (Rall et al. 1996). However, no differences in the physiological properties of muscle that determine force, including contractile properties, voluntary activation capacity, and contraction velocity, were found between cachectic RA patients and healthy controls (Matschke et al. 2010). Recent clinical trials have found that the muscle of RA patients respond in similar manner to that of muscle in healthy individuals. The strengthening effects of PRT in RA patients (Lemmey et al. 2009) are similar to those observed in healthy middle-aged subjects (Morse et al. 2007). Studies which directly compared RA patients with age-matched healthy patients reported similar findings. Following resistance and aerobic exercise training, comparable increases in strength and thigh muscle cross-section, and decreases in thigh fat thickness were found in both RA and healthy female patients (Hakkinen et al. 2005). Together, these studies demonstrate that exercise training increases muscle mass, strength, and improves physical function in a similar manner in patients with RA and in healthy individuals. In fact, the inclusion of highintensity PRT is recommended in RA treatment strategies to counteract the effects of rheumatoid cachexia (Pedersen and Saltin 2006; Lemmey et al. 2009).

#### **2.3 Anti-inflammatory effects of exercise**

Regular exercise, such as endurance training, can reduce basal levels of many inflammatory mediators/markers (King et al. 2003). Consequently, exercise has been recommended as an anti-inflammatory therapy in chronic inflammatory disorders such as RA (Kowh et al. 2002), and its effects are observed on the systemic and local levels.

#### **2.3.1 Systemic effects**

Physical inactivity, a common consequence of RA symptoms, leads to the accumulation of visceral fat and activation of inflammatory pathways (Walsh et al. 2011). Chronic inflammation can also drive the development of insulin resistance and atherosclerosis (Handschin and Spiegelman 2008). Increased physical activity has been reported to reduce inflammation in non-RA patients, as indicated by a downregulation of inflammation markers/mediators (Petersen and Pedersen 2005). In another demonstration of the antiinflammatory effects of exercise, a model of low grade inflammation was established in healthy volunteers through the administration of a low dose of E. coli endotoxin. While circulating levels of TNF-α were increased in resting individuals, this increase was blocked in subjects who exercised prior to the endotoxin administration (Starkie et al. 2003), suggesting exercise may inhibit the production of TNF-α. Together, it is possible the antiinflammatory effects of exercise are due to a decrease in visceral fat mass as well as the production of anti-inflammatory factors.

With exercise, there is a release of inflammatory-related cytokines from muscle into the circulation. IL-6 is the first cytokine released during exercise. Levels of circulating IL-6 increase exponentially after exercise and then decline post-exercise (Petersen and Pedersen 2006, Walsh et al. 2011). It is unclear whether this acute elevation in IL-6 modulates inflammatory processes during physical activity. Although IL-6 is a pro-inflammatory cytokine in the rheumatic joint, recent studies suggest the transient response of IL-6 may

Molecular Effects of Exercise in Rheumatoid Arthritis 317

sustained arthritis with denser synovial infiltrates as well as enhanced cartilage damage. Adding exogenous IL-10 further enlarged the suppressive effect of endogenous IL-10. However, these findings require further investigation in human clinical trials of RA patients.

Considering cartilage destruction is a hallmark of RA, the role of exercise in maintaining cartilage matrix integrity is of great importance (Table 2) (Maini and Feldmann 2004). Articular cartilage functions as a nearly frictionless bearing surface while uniformly transferring loads on underlying bone and preventing high stress concentrations. Cartilage consists of one cell type, the chondrocyte, embedded in an extracellular matrix of mainly type II collagen and proteoglycans (Milner 2008). Physiologic loading of the cartilage tissue is required to maintain tissue homeostasis, while non-physiologic loading (disuse and overuse) promotes its degradation (Sun 2010). Intensive dynamic and weightbearing exercises were originally considered detrimental for patients with RA due to concerns of exacerbating disease, (van den Ende et al. 1996), but studies have shown such exercise does not cause an increase in the rate of damage to either large (de Jong et al. 2003) or small joints (de Jong et al. 2004). There were no significant differences in the rate of damage of large joints 18 months following the end of a high-intensity program between RA patients who discontinued exercise and those who were still exercising (de Jong et al. 2009). Furthermore, levels of cartilage oligomeric matrix protein (COMP), a measure of cartilage damage were unchanged after 3 months of exercise in RA patients, suggesting exercise did not cause significant damage to the cartilage matrix (de Jong et al. 2008). Exercise may also enhance joint lubrication, further acting to promote the health of the RA joint. During joint movement, synovial fluid is squeezed out from between the two surfaces of the joint, resulting in fluid film lubrication (Isenberg et al. 2004). Lubricin, a mucinous glycoprotein secreted by synovial fibroblasts, is the factor responsible for lubrication (Jay et al. 2001), and reduced levels of this protein found in RA patients may increase joint friction and promote cartilage degradation (Jay et al. 2004; Elsaid et al. 2007). However, whether exercise increases lubricin expression in patients with RA has not yet been determined. Exercise also promotes adequate strength of the muscles and surrounding joint soft tissues, providing optimal joint stability, alignment and attenuation

After vigorous exercise in patients with moderate disease activity, a reduction in the number of diseased joints is observed (Minor et al. 1989; van den Ende et al. 1996). Animal studies have demonstrated physiologic loading of joints exerts beneficial effects by suppressing the activity of proteolytic enzymes in healthy and arthritic rats. Passive joint motion prevented cartilage destruction due to inactivity and downregulated MMPs 1 and 3 (Leong et al. 2010; Leong et al. 2011). In antigen-induced rabbits, passive motion prevented proteoglycan loss and suppressed expression of MMP-1 (Ferretti et al. 2005;

Although the beneficial effects of exercise for rheumatoid arthritis patients are well documented, the mechanisms are still largely unclear. As detailed previously, the effects of

**3. Mechanisms of exercise in rheumatoid arthritis treatment** 

**2.4 Anti-catabolic effects of exercise on cartilage** 

of impact and compressive forces (Sun 2010).

Ferretti et al. 2006).

play a metabolic, rather than an immunological role (Walsh et al. 2011). Following the increase of IL-6 in response to exercise in healthy individuals, IL-10 and IL-1 receptor antagonist (IL-1ra) are released into the circulation (Petersen and Pedersen 2006). Notably, an infusion of IL-6 enhanced plasma levels of IL-1ra and IL-10, (Steensberg et al. 2003). This suggests that the anti-inflammatory effect of exercise can be attributed, at least in part, to the induction of IL-6 and the creation of an anti-inflammatory environment (Table 2). Of note, no changes in serum IL-6 were detected in RA patients after exercise, but this might be attributable to a less strenuous exercise regimen when compared to healthy individuals (Knudsen et al. 2008). It is also possible that the anti-inflammatory effect of exercise is blunted in patients with RA, but this requires further study.


Table 2. Anti-inflammatory and anti-catabolic effects of exercise
