**1. Introduction**

310 Rheumatoid Arthritis – Treatment

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Rheumatoid arthritis (RA) is an autoimmune disorder that affects approximately 1% of adults in the United States (Alamanos and Drosos 2005). Clinically, RA is manifested by pain and swelling of joints, disability, and diminished overall patient well-being (Scott et al. 2010). The etiology of RA remains enigmatic, but a range of genetic and environmental factors closely associated with RA have been identified over the past two decades. It is now known that the pathogenic process of RA involves the initiation and establishment of autoimmunity, followed by an inflammatory response, angiogenesis to maintain the chronic inflammatory state, and tissue degradation of the joint (Scott et al. 2010).

Despite the advances in the pharmacological therapies of RA over the past years, most patients (85-90%) do not achieve full remission, with up to 15% showing little clinical improvement in outcomes (Geborek et al. 2002; van der Woude et al. 2009). Accumulating studies have demonstrated the effectiveness of non-drug treatment modalities, e.g. exercise and physical activity, as an adjunct to drug therapy in patients with RA (Stenstrom and Minor 2003; Lundberg and Nader 2008). As a result, physical training is now a standard part of treatment for RA patients.

This chapter will first review results from randomized clinical trials which investigated the effects of exercise on RA disease activity. In RA patients, exercise was demonstrated to improve physical performance, cardiorespiratory fitness and muscle strength without worsening joint inflammation (Ekblom et al. 1975). Subsequent clinical studies have not only shown that exercise leads to meaningful effects on physical performance and fitness, but exercise can also reduce RA disease activity, measured by the number of swollen or tender joints (Stenstrom and Minor 2003). At the systemic level, there are several reports indicating a reduction in circulating levels of inflammatory biomarkers following long-term physical exercise (Dekker et al. 2007; Olson et al. 2007). These beneficial effects of exercise have been observed following different types of physical activity, after short-term and long-term (>2 years) exercise programs, at different phases of the disease course, and even in patients with high disease activity (van den Ende et al. 2000; Stenstrom and Minor 2003).

Next, by focusing on the effects of exercise, delivered in the form of physiologically relevant mechanical loading, this review will provide updated insights into exercise at both the systemic and local (e.g. cartilage and synovium) levels. Studies indicate that exercise

Molecular Effects of Exercise in Rheumatoid Arthritis 313

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

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

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

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

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

exercise intensity and/or duration until the pain or swelling subsides.

exhibited significant improvements in locomotor ability (Moffet et al. 2000).

manner with bouncing movements (Resnick 2001).

Ende et al. 2000; Lemmey et al. 2009).

**2.1 Description of prescribed exercises** 

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 and Salter 2004; Ferretti et al. 2005).

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 pathways.

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 rheumatoid arthritis.
