**2.1 Disability**

Despite advances in the pharmaceutical treatment of RA, disability remains a feature of the disease. In a recent report from the British Society for Rheumatology Biologics Register (Lunt et al., 2010), the median (interquartile range) Health Assessment Questionnaire (HAQ) scores for large samples of patients receiving anti-tumor necrosis factor (anti-TNF) treatment (n=12,672) or standard disease modifying anti-rheumatic drugs (DMARD's; n=3,522) were 2.1 (1.8-2.5) and 1.6 (0.9-2.1), respectively; which are levels indicative of moderate to severe disability. Such widespread disability, as well as causing enormous suffering and reduction of Quality of Life (QoL) on a personal level, also has huge social and economic costs (Verstappen et al., 2004; Yelin, 1996). For example, within 10 years of RA diagnosis a prevalence of 35% for work disability is currently reported for both US and European populations (Allaire et al., 2008; Eberhardt et al., 2007).

Resistance Training for Patients with Rheumatoid Arthritis: Effects on Disability,

(see Kotler, 2000 for a review).

**2.3 Obesity**

the disease.

Rheumatoid Cachexia, and Osteoporosis; and Recommendations for Prescription 289

The degree and prevalence of cachexia typically present in RA patients is alarming since it represents in excess of a third of the maximal loss of body cell mass or LBM that is compatible with survival (i.e. 40%; Walsmith & Roubenoff, 2002). Additionally, as in other catabolic diseases, muscle loss as well as causing weakness and disability is associated with osteoporosis, low aerobic capacity, impaired immune and pulmonary function, glucose intolerance, depression, loss of independence, compromised QoL, and increased mortality

Muscle depletion associated with RA, however, is generally undiagnosed (and consequently, untreated) as a concomitant increase in fat mass (FM) masks the decrease in muscle mass when bodyweight is measured. Thus, for a given body mass index (BMI), Stavropoulos-Kalinoglou et al. (2007) found that RA patients had on average 4.3% more body fat than matched, healthy controls. Alternatively, for a given body fat percentage (%BF), RA patients have a BMI almost 2kg/m2 lower than members of the general population. Consequently, these authors have proposed that the BMI cut-offs for defining "overweight" and "obesity" in RA patients should be reduced to 23kg/m2 and 28kg/m2, respectively (Stavropoulos-Kalinoglou et al., 2007). This recommendation is supported by comparisons of BMI and %BF values reported for RA patients. Mean BMI's usually reported for RA patients (25.2-29.1 kg/m2) (Gordon et al., 2002; Marcora et al., 2005a, 2005b; Saravana & Gillot, 2004; Stavropoulos-Kalinoglou et al., 2007) are consistent with that of the entire adult UK population (27.1 kg/m2) (Craig et al., 2009), suggesting that RA patients, like the overall population, are generally merely overweight. However, when body composition is assessed (Elkan et al., 2009; Lemmey et al., 2009; Marcora et al., 2005a, 2005b; Stavropoulos-Kalinoglou et al., 2007, 2009; Westhovens et al., 1997) RA patients are revealed to be significantly fatter than the overall population, with a mean %BF of around 40% and a prevalence of obesity (using the criteria of 38%BF or more for women, and 27%BF or more for men; Baumgartner et al., 1999) of approximately 80% (Lemmey et al., 2009; Marcora et al., 2005a, 2005b; Stavropoulos-Kalinoglou et al., 2009). Using a stricter criteria, Elkan et al. (2009a) found that 33% of female and >50% of male RA patients had a FM index above the 90th percentile for the whole population. As with muscle loss, this high prevalence of obesity is evident in recently diagnosed RA patients (Marcora et al., 2006), again indicating that the body composition perturbations characteristic of rheumatoid cachexia occur early in

Disturbingly, as well as favouring accumulation of higher total fat, RA appears to preferentially predispose to central obesity (Elkan et al., 2009b; Giles et al., 2010; Inaba et al., 2007; Westhovens et al., 1997). In the general population, obesity, and in particular central obesity, is a well established, independent risk factor for CVD and many of the classical CVD risk factors (e.g. Mahabadi et al., 2009; Rosito et al., 2008). Similarly in RA patients, central obesity is linked with hypertension, elevated fasting glucose levels, and metabolic syndrome (Giles et al., 2010), and arterial thickening and stiffening (Inaba et al., 2007). As there is an increased risk of CVD in RA patients, with rates of both CVD events and mortality increased approximately 50% relative to non-RA controls (Avina-Zubieta et al., 2008; Naranjo et al., 2008), one would assume that loss of fat, particularly trunk fat, would

be highly beneficial for the CV health of this population.

Whilst the causes of disability in RA are multifactorial (Escalante & del Rincon, 1999, 2002), Giles et al. (2008) has shown that it is strongly associated with adverse changes in body composition, with HAQ scores inversely related to appendicular lean mass (ALM; a surrogate measure of muscle mass) and directly related to total and appendicular fat masses. Subsequently, Stavropoulos-Kalinoglou et al. (2009) have also shown that obesity is significantly and independently associated with disability in RA patients. Such links between body composition and physical function are not surprising as they reflect those observed in the general elderly population, whereby classification as either muscle-wasted (sarcopenic) or obese significantly exacerbates the likelihood of disability, whilst the coincidence of both conditions (sarcopenic-obesity) increases disability risk 12-fold in women and 9-fold in men (Morley et al., 2001).

#### **2.2 Rheumatoid cachexia**

Unfortunately, both reduced muscle mass and elevated adiposity, termed "rheumatoid cachexia" (Roubenoff et al., 1992), are characteristic of RA. Muscle wasting due to RA was first observed by Sir James Paget in 1873 and has been consistently reported in recent decades (see Summers et al., 2008 for a review); most prolifically and notably by Ronenn Roubenoff's group (Rall & Roubenoff, 1996, 2004; Rall et al., 1996a, 2002; Roubenoff, 2000; Roubenoff et al., 1992, 1994, 2002; Walsmith & Roubenoff, 2002; Walsmith et al., 2004). Using a definition of significant muscle loss as being below the 50th percentile for arm muscle circumference of a reference population, Roubenoff et al. (1994) found that 67% of their RA patients were cachectic. Whilst Munro and Capell (1997), employing the more stringent cut-off of the 10th percentile, concluded that 50% of their British RA sample was muscle wasted. More recently, in a series of studies, mostly featuring patients who volunteered for high intensity exercise training (Marcora et al., 2005a, 2005b; Lemmey et al., 2009; Elamanchi et al. and Lemmey et al., manuscripts in preparation), we have identified that 2/3's of our stable RA patients are muscle wasted according to the whole-body dualenergy x-ray absorptiometry (DXA) definitions of Baumgartner et al. (1998; i.e. ALM (kg) / height2 (m2) more than two standard deviations below the mean of a young reference group). Interestingly, using the same methodology we found a similar incidence of rheumatoid cachexia in treatment-naïve, recent-onset RA patients (<6 months since diagnosis), suggesting that the loss of lean body mass (LBM) occurs early in the course of the disease (Marcora et al., 2006).

The magnitude of this loss in LBM is reported by Roubenoff's group (using the potassium-40 method) to be 14-16% in RA patients with controlled disease (Rall et al., 2002; Roubenoff et al., 1994, 2002); which agrees with the ≈15% loss we observe in stable RA patients relative to age- and sex-matched healthy sedentary controls (Lemmey et al., unpublished observations). Given this magnitude of muscle loss, it is not surprising that RA patients have substantially reduced muscle strength, with values ranging from 30-80% of normal being reported (Ekblom et al., 1974; Ekdahl & Broman, 1992; Ekdahl et al., 1989; Hakkinen et al., 1995; Madsen et al., 1998; Nordesjo et al., 1983). Also consistent with expectations is the very strong relationship Stucki et al. (1998) revealed between muscle weakness and disability in RA patients. In this study, HAQ was significantly correlated with muscle strength index (MSI), disease activity, morning stiffness, pain, and joint damage. However, when analysing the effect of change in these predictors with change in HAQ, only MSI and pain remained significantly associated. Thus confirming the importance of strength's, and by extension – muscle mass's, association with disability in RA.

The degree and prevalence of cachexia typically present in RA patients is alarming since it represents in excess of a third of the maximal loss of body cell mass or LBM that is compatible with survival (i.e. 40%; Walsmith & Roubenoff, 2002). Additionally, as in other catabolic diseases, muscle loss as well as causing weakness and disability is associated with osteoporosis, low aerobic capacity, impaired immune and pulmonary function, glucose intolerance, depression, loss of independence, compromised QoL, and increased mortality (see Kotler, 2000 for a review).

### **2.3 Obesity**

288 Rheumatoid Arthritis – Treatment

Whilst the causes of disability in RA are multifactorial (Escalante & del Rincon, 1999, 2002), Giles et al. (2008) has shown that it is strongly associated with adverse changes in body composition, with HAQ scores inversely related to appendicular lean mass (ALM; a surrogate measure of muscle mass) and directly related to total and appendicular fat masses. Subsequently, Stavropoulos-Kalinoglou et al. (2009) have also shown that obesity is significantly and independently associated with disability in RA patients. Such links between body composition and physical function are not surprising as they reflect those observed in the general elderly population, whereby classification as either muscle-wasted (sarcopenic) or obese significantly exacerbates the likelihood of disability, whilst the coincidence of both conditions (sarcopenic-obesity) increases disability risk 12-fold in women

Unfortunately, both reduced muscle mass and elevated adiposity, termed "rheumatoid cachexia" (Roubenoff et al., 1992), are characteristic of RA. Muscle wasting due to RA was first observed by Sir James Paget in 1873 and has been consistently reported in recent decades (see Summers et al., 2008 for a review); most prolifically and notably by Ronenn Roubenoff's group (Rall & Roubenoff, 1996, 2004; Rall et al., 1996a, 2002; Roubenoff, 2000; Roubenoff et al., 1992, 1994, 2002; Walsmith & Roubenoff, 2002; Walsmith et al., 2004). Using a definition of significant muscle loss as being below the 50th percentile for arm muscle circumference of a reference population, Roubenoff et al. (1994) found that 67% of their RA patients were cachectic. Whilst Munro and Capell (1997), employing the more stringent cut-off of the 10th percentile, concluded that 50% of their British RA sample was muscle wasted. More recently, in a series of studies, mostly featuring patients who volunteered for high intensity exercise training (Marcora et al., 2005a, 2005b; Lemmey et al., 2009; Elamanchi et al. and Lemmey et al., manuscripts in preparation), we have identified that 2/3's of our stable RA patients are muscle wasted according to the whole-body dualenergy x-ray absorptiometry (DXA) definitions of Baumgartner et al. (1998; i.e. ALM (kg) / height2 (m2) more than two standard deviations below the mean of a young reference group). Interestingly, using the same methodology we found a similar incidence of rheumatoid cachexia in treatment-naïve, recent-onset RA patients (<6 months since diagnosis), suggesting that the loss of lean body mass (LBM) occurs early in the course of

The magnitude of this loss in LBM is reported by Roubenoff's group (using the potassium-40 method) to be 14-16% in RA patients with controlled disease (Rall et al., 2002; Roubenoff et al., 1994, 2002); which agrees with the ≈15% loss we observe in stable RA patients relative to age- and sex-matched healthy sedentary controls (Lemmey et al., unpublished observations). Given this magnitude of muscle loss, it is not surprising that RA patients have substantially reduced muscle strength, with values ranging from 30-80% of normal being reported (Ekblom et al., 1974; Ekdahl & Broman, 1992; Ekdahl et al., 1989; Hakkinen et al., 1995; Madsen et al., 1998; Nordesjo et al., 1983). Also consistent with expectations is the very strong relationship Stucki et al. (1998) revealed between muscle weakness and disability in RA patients. In this study, HAQ was significantly correlated with muscle strength index (MSI), disease activity, morning stiffness, pain, and joint damage. However, when analysing the effect of change in these predictors with change in HAQ, only MSI and pain remained significantly associated. Thus confirming the importance of strength's, and

by extension – muscle mass's, association with disability in RA.

and 9-fold in men (Morley et al., 2001).

**2.2 Rheumatoid cachexia** 

the disease (Marcora et al., 2006).

Muscle depletion associated with RA, however, is generally undiagnosed (and consequently, untreated) as a concomitant increase in fat mass (FM) masks the decrease in muscle mass when bodyweight is measured. Thus, for a given body mass index (BMI), Stavropoulos-Kalinoglou et al. (2007) found that RA patients had on average 4.3% more body fat than matched, healthy controls. Alternatively, for a given body fat percentage (%BF), RA patients have a BMI almost 2kg/m2 lower than members of the general population. Consequently, these authors have proposed that the BMI cut-offs for defining "overweight" and "obesity" in RA patients should be reduced to 23kg/m2 and 28kg/m2, respectively (Stavropoulos-Kalinoglou et al., 2007). This recommendation is supported by comparisons of BMI and %BF values reported for RA patients. Mean BMI's usually reported for RA patients (25.2-29.1 kg/m2) (Gordon et al., 2002; Marcora et al., 2005a, 2005b; Saravana & Gillot, 2004; Stavropoulos-Kalinoglou et al., 2007) are consistent with that of the entire adult UK population (27.1 kg/m2) (Craig et al., 2009), suggesting that RA patients, like the overall population, are generally merely overweight. However, when body composition is assessed (Elkan et al., 2009; Lemmey et al., 2009; Marcora et al., 2005a, 2005b; Stavropoulos-Kalinoglou et al., 2007, 2009; Westhovens et al., 1997) RA patients are revealed to be significantly fatter than the overall population, with a mean %BF of around 40% and a prevalence of obesity (using the criteria of 38%BF or more for women, and 27%BF or more for men; Baumgartner et al., 1999) of approximately 80% (Lemmey et al., 2009; Marcora et al., 2005a, 2005b; Stavropoulos-Kalinoglou et al., 2009). Using a stricter criteria, Elkan et al. (2009a) found that 33% of female and >50% of male RA patients had a FM index above the 90th percentile for the whole population. As with muscle loss, this high prevalence of obesity is evident in recently diagnosed RA patients (Marcora et al., 2006), again indicating that the body composition perturbations characteristic of rheumatoid cachexia occur early in the disease.

Disturbingly, as well as favouring accumulation of higher total fat, RA appears to preferentially predispose to central obesity (Elkan et al., 2009b; Giles et al., 2010; Inaba et al., 2007; Westhovens et al., 1997). In the general population, obesity, and in particular central obesity, is a well established, independent risk factor for CVD and many of the classical CVD risk factors (e.g. Mahabadi et al., 2009; Rosito et al., 2008). Similarly in RA patients, central obesity is linked with hypertension, elevated fasting glucose levels, and metabolic syndrome (Giles et al., 2010), and arterial thickening and stiffening (Inaba et al., 2007). As there is an increased risk of CVD in RA patients, with rates of both CVD events and mortality increased approximately 50% relative to non-RA controls (Avina-Zubieta et al., 2008; Naranjo et al., 2008), one would assume that loss of fat, particularly trunk fat, would be highly beneficial for the CV health of this population.

Resistance Training for Patients with Rheumatoid Arthritis: Effects on Disability,

**3. Efficacy of progressive resistance training** 

review).

**3.1 Effects on function** 

of Komatireddy et al. (1997).

as measures of efficacy.

Rheumatoid Cachexia, and Osteoporosis; and Recommendations for Prescription 291

The most, perhaps the only, effective, safe and economical intervention known to increase both muscle and bone mass and also improve strength and physical function in subjects of various ages is progressive resistance training (PRT) (see Kraemer et al., 1996 for a

The efficacy of resistance training for improving strength in RA patients (Table 1) was first demonstrated by Machover and Sopecky in 1966. In this pioneering study, 11 male RA patients performed maximal isometric contractions of the quadriceps 3 times a day, 5 days/week for 7 weeks, for an average strength gain of 23%. Since then, significant improvements in strength in RA patients have been elicited by a variety of resistance training regimes (Table 1). The only exception identified being the home-based intervention

Consistent with the increases in strength are reports of improvements in physical function assessed objectively (e.g. walk tests, stair climbing, bench stepping, balance/coordination, hand-grip strength, timed up and go, vertical jump, 30-sec arm curl test, chair test, aerobic capacity; Ekdahl et al., 1990; Hakkinen et al., 1994, 1999, 2003, 2004a, 2005; Hoenig et al., 1993; Komatireddy et al., 1997; Lemmey et al., 2009; Lyngberg et al., 1994; Marcora et al., 2005a; McMeeken et al., 1999; Nordemar et al., 1976, 1981; Rall et al., 1996b; van den Ende et al., 1996, 2000) and subjectively (e.g. 100-point truth-value scale, study generated questionnaire, self reported fatigue, HAQ, McMaster Toronto Arthritis (MACTAR) Patient Preference Disability Questionnaire; Ekdahl et al., 1990; Hakkinen et al., 1994, 2001, 2004a; Komatireddy et al., 1997; Lyngberg et al., 1994; Marcora et al., 2005a; McMeeken et al., 1999; van den Ende et al., 2000) (Table 1). Although it is notable that improvements in physical function are usually not observed when it is subjectively assessed by the HAQ (de Jong et al., 2003; Hakkinen et al., 1999, 2003, 2004b, 2005; Lemmey et al., 2009; van den Ende et al., 1996). The general inability of HAQ scores to reflect objectively assessed improvements in physical function is probably due to the insensitivity of this instrument in detecting performance gains in mildly disabled patients i.e. the type of patient likely to feature in exercise intervention studies. This lack of sensitivity is evident in findings from the Rheumatoid Arthritis Patients in Training (RAPIT) program (de Jong et al., 2003) which showed improvements in patients' self-reported physical function following high intensity exercise training when assessment was by the MACTAR Questionnaire, but not when the HAQ was used. The unsuitability of the HAQ for detecting improvements in function following exercise therapy has been highlighted by van den Ende et al. (1997), who advocate objective measures related to performing activities of daily living (ADL's)

As concluded by the 2 Cochrane Reviews conducted to date (Hurkmans et al., 2009; van den Ende et al., 2000), the efficacy of resistance training programs in improving strength and physical function in RA patients is clear. In fact, with appropriate training it is not unreasonable to expect that patients with established, controlled RA can achieve levels of physical function at least as good as sedentary, healthy individuals of the same age and sex. In the RCT conducted by our group (Lemmey et al., 2009), patients with established RA (11
