**2.5 Treatments for rheumatoid cachexia**

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 Consistent with these findings, are the findings of an unpublished randomised controlled trial we conducted (Elamanchi et al., manuscript in preparation), in which nandrolone decanoate (ND), an anabolic steroid, was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 assessed.

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.
