**3.1 Effects on function**

290 Rheumatoid Arthritis – Treatment

Another feature of RA is secondary osteoporosis. RA patients have greater incidence of osteoporosis and osteoporotic fractures than matched non-RA controls (e.g. Frank & Gottwalt, 2009; Huusko et al., 2001; Sinigaglia et al., 2006); with this increase attributed to the disease itself (systemic inflammation), treatment with high dose oral glucocorticoids, and sedentary lifestyle (Cantley et al., 2009; Frank & Gottwalt, 2009; Huusko et al., 2001; Sinigaglia et al., 2006; ). Interestingly, after high-dose steroid therapy, the reduced bone mineral density (BMD) in RA patients has been found to be most strongly associated with low strength (quadriceps and handgrip) and poor physical function (Huusko et al., 2001;

Clearly, interventions capable of reversing cachexia in RA patients (i.e. increasing muscle mass and decreasing FM, especially trunk FM) have the potential to improve physical function and thus decrease disability, prolong independence, improve QoL, reduce comorbidities, and perhaps increase life expectancy. Such an intervention would also significantly reduce the huge economic impact of RA (half of which results from production losses caused by functional impairment (McIntosh, 1996)). Several anabolic agents, such as recombinant human GH and anabolic steroids, have been proposed for increasing muscle mass in sarcopenic/cachectic states (e.g. Bross et al., 1999; Johansen et al., 1999, 2006; Macdonald et al., 2007). However, GH therapy is expensive and may cause carpal tunnel syndrome and insulin resistance, whilst anabolic steroids are associated with side effects such as liver disorders, masculinisation in women, and prostate cancer and testicular atrophy in men (Bhasin, 2003; Johansen et al., 1999; Korkia & Stimson, 1997; Macdonald et al., 2007). Furthermore, when used alone, despite increasing lean mass, these drugs often fail to improve physical function (Bross et al., 1999; Johansen et al., 2006; Macdonald et al., 2007; Rodriguez-Arnao et al., 1999). Consistent with these findings, are the findings of an unpublished randomised controlled trial we conducted (Elamanchi et al., manuscript in preparation), in which nandrolone decanoate (ND), an anabolic steroid, was administered (i.m. injection, 100mg/wk) for 6 months to 20 male RA patients with stable disease Despite inducing substantial increases in mean ALM (≈1.5kg), administration of ND failed to improve any of the objective measures of physical function

As rheumatoid cachexia has been attributed to cytokine (principally TNF-α) driven muscle catabolism by Roubenoff group ( Rall & Roubenoff, 2004; Rall et al., 1996a; Roubenoff et al., 1994, 2002), it was anticipated that treatment with anti-TNF drugs could restore a healthier body composition to RA patients. However, Marcora et al. (2006) found that treatment of recently diagnosed RA patients for 6 months with etanercept (anti-TNF agent) had no effect on body composition relative to treatment with methotrexate ("standard DMARD"). This lack of effect of anti-TNF's on LBM in RA patients has subsequently been confirmed by Metsios et al. (2007). Of concern was their additional observation of increased trunk fat in established RA patients following 3 months on anti-TNF's. These findings are further supported by a recent report (Engvall et al., 2010), which observed increased FM in recentonset RA patients treated with anti-TNF's for 21 months relative to DMARD treated patients

(mean±sd; +3.4±1.4kg, p<0.05), and no changes in LBM for either treatment.

**2.4 Osteoporosis** 

Madsen et al., 1998, 2001).

assessed.

**2.5 Treatments for rheumatoid cachexia** 

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 of Komatireddy et al. (1997).

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 measures of efficacy.

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


repetition maximum. **Ψ RCT** = randomised controlled trial, ROM = range of movement exercises, NC = normal care, RA = non-randomised rheumatoid arthritis patients, HC = healthy controls. ↑ = improved strength/function, ↔ = no change. ↑LM = increased total lean mass, ↓FM = decreased total/trunk fat mass, ↑LM\* = increased quadriceps LM, ↓FM\* = decreased quadriceps subcutaneous fat, ↑ fibre x-sect area = increase in vastus lateralis fibre cross-sectional area. ↓ = decreased disease activity. \_ = not assessed +/or reported. Table 1. Summary of interventions and effects of resistance training programs  Resistance Training for Patients with Rheumatoid Arthritis: Effects on Disability,

very low training intensity (Komatireddy et al., 1997).

al., 2009); LBM, ALM (

**3.2 Effects on rheumatoid cachexia (body composition)** 

Rheumatoid Cachexia, and Osteoporosis; and Recommendations for Prescription 293

women, 2 men; age 55.6±8.3 years; disease duration 74±76 months) whose objectively measured physical function at baseline was poor relative to population norms, were able to achieve or exceed these performance norms following 24 weeks of high-intensity PRT. Restoration of normal levels of strength and function in RA patients following PRT has also been observed in the studies of Hakkinen et al. (2003, 2005) which featured healthy, age- and sex-matched control subjects, and in our uncontrolled pilot study (Marcora et al., 2005). In a point that will be pursued later, it should be noted that the only investigation that did not report significant increases in strength in RA patients following resistance training utilised a

The effects of resistance training on body composition in RA are less well reported (Table 1). In 1976, Nordemar et al. observed increased cross-sectional area of type I and especially type II fibres in 10 RA patients following 6 weeks of cycling, walking and quadriceps strength training. Similarly, Hakkinen et al. (1994) observed increases in quadriceps muscle crosssectional area in RA patients following 6 months PRT. However, when Rall et al. (1996b) reported no changes in whole-body composition (DXA assessed) in 8 RA subjects following 12 weeks PRT (despite significant improvements in strength), the conclusion was that RA patients are resistant to the anabolic effects of exercise. This concern has subsequently been refuted by methodologically more robust trials. Initially, we (Marcora et al., 2005a) reported significant increases in (DXA assessed) LBM, ALM and estimated total body protein (TBP), and reductions in %BF, with a trend toward reduced trunk fat (-0.75kg) following 12 weeks of high-intensity PRT. Subsequently, these effects were confirmed by our RCT (Lemmey et

and total and especially trunk FM (-2.5kg, i.e. 18%) were substantially reduced following 24 weeks of PRT. Additionally, Hakkinen et al. (2005) have reported quadriceps femoris hypertrophy (p<0.001) and reduced quadriceps subcutaneous fat thickness (p<0.001) in

Whilst aerobic exercise training, by increasing daily energy expenditure, has been shown to be an effective adjunct to restricted energy intake for weight loss in young adults, its efficacy in middle aged and elderly individuals is questionable. This is because sedentary individuals of this aged are usually so deconditioned that they are unable to perform exercise of sufficient intensity and duration to significantly elevate daily energy expenditure (Evans, 1999). In contrast, in elderly men and women an elevation of approximately 15% in resting metabolic rate (RMR) has been observed following 12 weeks PRT as a consequence of increased LBM (Campbell et al., 1994). An increase in RMR of this magnitude is very

In our PRT studies (Lemmey et al., 2009; Marcora et al., 2005a), the elicited increases in muscle mass were significantly associated with improvements in objectively assessed physical function (i.e. 30 sec arm curl, 30 sec sit-to-stand, 50' walk, hand-grip strength, and knee extensor strength; tests taken from the Senior Fitness Test (Rikli & Jones, 2001), and designed to reflect the ability to perform ADL's). Interestingly, the increased muscle mass and reduced fat mass in the PRT subjects in our RCT (Lemmey et al., 2009) caused a reclassification of the body types of many of these patients. Wherein, whereas at baseline, 9 (out of 13) were classified as cachectic, 10 as obese, and 5 as both (i.e. "cachectic-obese"),

female RA patients following 21 weeks of combined PRT and aerobic training.

relevant as RMR typically accounts for 60-75% of 24 hr energy expenditure.

≈1.2kg), and TBP were all significantly increased (p's=0.002-0.006)

† = exercise group or, if multiple exercise groups, the highest intensity exercise group. PRT = progressive resistance training, RT = resistance training, isom = isometric strength exercises, aerobic = aerobic training e.g. cycling, walking, swimming etc, balance = balance training. ‡ = % 1-

† = exercise group or, if multiple exercise groups, the highest intensity exercise group. PRT = progressive resistance training, RT = resistance training, isom = isometric strength exercises, aerobic = aerobic training e.g. cycling, walking, swimming etc, balance = balance training. ‡ = % 1-

**Ψ RCT** = randomised controlled trial, ROM = range of movement exercises, NC = normal care, RA = non-randomised

decreased total/trunk fat mass, ↑LM\* = increased quadriceps LM, ↓FM\* = decreased quadriceps subcutaneous fat, ↑ fibre x-sect area = increase

in vastus lateralis fibre cross-sectional area. ↓ = decreased disease activity. \_ = not assessed +/or reported.

y of interventions and effects of resistance trainin

g

pro

grams

↔ = no change. ↑LM = increased total lean mass, ↓FM =

repetition maximum.

Table 1. Summar

rheumatoid arthritis patients, HC = healthy controls. ↑ = improved strength/function,

women, 2 men; age 55.6±8.3 years; disease duration 74±76 months) whose objectively measured physical function at baseline was poor relative to population norms, were able to achieve or exceed these performance norms following 24 weeks of high-intensity PRT. Restoration of normal levels of strength and function in RA patients following PRT has also been observed in the studies of Hakkinen et al. (2003, 2005) which featured healthy, age- and sex-matched control subjects, and in our uncontrolled pilot study (Marcora et al., 2005). In a point that will be pursued later, it should be noted that the only investigation that did not report significant increases in strength in RA patients following resistance training utilised a very low training intensity (Komatireddy et al., 1997).
