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Rheumatology Advance Access published online on April 30, 2008
Rheumatology, doi:10.1093/rheumatology/ken146
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Review

Rheumatoid cachexia: a clinical perspective

G. D. Summers1, C. M. Deighton1, M. J. Rennie2 and A. H. Booth1

1Department of Rheumatology, Derby Hospitals NHS Foundation Trust and 2University of Nottingham, Graduate Entry Medical School, Derby City Hospital, Derby, UK.

Correspondence to: G. D. Summers, Department of Rheumatology, Derby Hospitals NHS Foundation Trust, Derbyshire Royal Infirmary, London Road, Derby DE1 2QY, UK. E-mail: greg.summers{at}derbyhospitals.nhs.uk


   Abstract
Top
 Abstract
Introduction
 Body weight and body...
 Measurement of body composition...
 Evidence for rheumatoid cachexia
 Consequences of rheumatoid...
 Therapy for rheumatoid cachexia
 Summary and conclusions
 Reference
 
Rheumatoid cachexia is under-recognized in clinical practice. The loss of lean body tissue, which characterizes cachexia, is often compensated for by gain in body fat—so called ‘cachectic obesity’—so that 85% or more RA patients have a normal BMI. Severe cachexia with loss of weight leads to increased morbidity and premature mortality but loss of muscle bulk with a normal BMI also associates with poor clinical outcomes. Increasing BMI, even into the obese range, is associated with less joint damage and reduced mortality. Measurement of body composition using DXA and other techniques is feasible but the results must be interpreted with care. Newer techniques such as whole-body MRI will help define with more confidence the mass and distribution of fat and muscle and help elucidate the relationships between body composition and outcomes. Cachexia shows little response to diet alone but progressive resistance training and anti-TNF therapies show promise in tackling this potentially disabling extra-articular feature of RA.

KEY WORDS: Rheumatoid arthritis, Rheumatoid cachexia, Body composition measurement, Body mass index


   Introduction
Top
 Abstract
 Introduction
Body weight and body...
 Measurement of body composition...
 Evidence for rheumatoid cachexia
 Consequences of rheumatoid...
 Therapy for rheumatoid cachexia
 Summary and conclusions
 Reference
 
How often do you see an RA patient with cachexia? For many rheumatologists the answer would be ‘not very often’ as the term conjures up an image of someone who is gaunt and emaciated with severe systemic disease. Whereas extreme cases of cachexia are occasionally seen in RA, the condition is almost certainly under-recognized in clinical practice.

What is cachexia and how might we be missing the diagnosis in our patients? Three weight-losing syndromes have been defined, which are associated with different disease states [1, 2]. These are cachexia, starvation and sarcopenia [1]. In cachexia, lean body mass (LBM) is lost whilst fat mass tends to be maintained or even increased so that body weight, at least in the early stages, can remain stable [1, 2]. Cachexia, which occurs in the context of a chronic inflammatory response in diseases such as rheumatoid arthritis, cancer, AIDS, cardiac failure, tuberculosis, inflammatory bowel disease and chronic lung disease [1], is always associated with a poor prognosis [1, 3–6] and cannot be treated with protein–energy repletion alone [1]. Starvation is characterized by pure energy deficiency, which, at least in the earlier stages, leads to increased fat mobilization and catabolism with relative conservation of muscle. Malabsorption may give rise to a similar phenomenon [1, 7]. The term sarcopenia is usually reserved to describe age-related skeletal muscle (SM) loss or isolated loss of muscle in the context of dieting, physical immobility or growth hormone deficiency [1, 8].

Accelerated loss of LBM in inflammatory arthritis has been recognized for more than 100 yrs. Sir James Paget (1873) observed ‘... wasting occurs, in greater or lesser degree, in all muscles near joints that are inflamed ... It is, I repeat, not a mere wasting from disuse: it is far more rapid than that ...’ [9]. This peri-articular muscle wasting adjacent to an inflamed joint parallels the finding of peri-articular osteoporosis. Similarly, just as generalized loss of bone density is characteristic of RA [10, 11], so also may be the generalized loss of muscle bulk. The syndrome of cachexia can be seen to encompass other tissues and cells in the body including the bone, blood and immune system [12, 13].

Rheumatoid cachexia has been described and analysed in a series of studies and reviews by Roubenoff and colleagues over the past 15 years including a review in this journal in 2004 [2, 5, 12–29]. They describe evidence of cachexia in two-thirds of RA patients with muscle wasting and often compensatory increase in fat mass; the so-called cachectic obesity; with loss of weight or BMI being uncommon [27]. They have provided evidence for a state of cytokine (primarily TNF-{alpha})-driven hypermetabolism causing an increased level of muscle protein degradation. More recent contributions to the field have been made by groups in North Wales [30–32] and Dudley, UK [33–37].

The purpose of this current review is to look at cachexia from the clinical point of view—How common is it? How do we recognize and measure it? Is it important? What treatments are available to alleviate it? It sets out to complement and update the material presented in the 2004 review in this journal, which focused on physiological mechanisms [13].


   Body weight and body composition
Top
 Abstract
 Introduction
 Body weight and body...
Measurement of body composition...
 Evidence for rheumatoid cachexia
 Consequences of rheumatoid...
 Therapy for rheumatoid cachexia
 Summary and conclusions
 Reference
 
Although it is known that people lose weight during acute or chronic systemic illness, there is surprisingly little documentation of weight changes in RA. Clinically, body weight or BMI (body weight in kilograms divided by height in metres squared) are used to assess the nutritional status of a patient. When BMI is plotted against all-cause mortality for a general population, there is a J-shaped relationship with excess mortality in those who are underweight and overweight [38]. The ideal range for BMI, associated with the lowest mortality, is 18.5–25 kg/m2 [38]. A BMI of around 12 may be the lower limit for survival [39].

Cross-sectional comparisons of patients with RA and healthy controls often show no difference in BMI between the groups [40]. In studies from Minnesota, Birmingham (USA) and Scotland [40–42] ~13% of RA patients had a low BMI, whereas in German and Texan cohorts only 1 and 5%, respectively were underweight [43, 44]. Being underweight has been associated with more active disease [45] and increased collagen breakdown products in the synovium and urine consistent with increased joint damage [46]. Low BMI is an independent predictor of poor radiological outcome [47, 48], more powerful for this purpose than the presence of the shared epitope [48], erosions at baseline [48] or a range of other extra-articular features [47]. Loss of body weight since disease onset is also associated with a greater level of disability [41]. The protective effect of increasing BMI also extends throughout the whole weight range with seropositive patients of normal weight having significantly more joint damage than obese patients [44].

Despite the usefulness of body weight or BMI in predicting survival and disease activity in RA, they do not reflect the changes in body composition that occur with age and disease. Ageing produces a reduction in LBM and an increase in fat mass [5]. SM comprises 45% of body weight in the young adult and 27% body weight in the elderly [5, 49–51]. Diseases such as RA characterized by an increase in protein turnover have a greater impact in the elderly, putting greater demands upon the already reduced LBM [5].

In RA, analysis of body composition is important in order to understand the effect of the disease on the individual as significant changes in the tissues are not captured by body weight or BMI [2]. Understanding the changes in body tissue compartments and their aetiology is clearly necessary in order to design appropriate treatment programmes.

A key concept in the understanding of the consequences of cachexia is body cell mass (BCM) [52]. BCM reflects the cellular components of the body which are involved in biochemical processes and energy metabolism [53] and is literally the ‘living’ core of the body [54]. Nutritional status, physical activity level and disease states such as RA alter BCM that in turn can serve as a biomarker for these processes [53]. SM, which makes up the majority of BCM, is the most labile portion and this directly predicts strength and functional status [2, 55, 56]. BCM accounts for 95% of body metabolic activity and loss of BCM is a very powerful predictor of outcome in starvation, critical illness and normal ageing [5]. In all clinical situations, loss of >40% of baseline BCM is associated with death [2, 5, 7, 27, 28].


   Measurement of body composition in RA
Top
 Abstract
 Introduction
 Body weight and body...
 Measurement of body composition...
Evidence for rheumatoid cachexia
 Consequences of rheumatoid...
 Therapy for rheumatoid cachexia
 Summary and conclusions
 Reference
 
Five levels of body composition have been defined [57]: atomic, molecular, cellular, tissue and whole body, and it is necessary to use a combination of these levels to understand the structure and function of the body in weight-losing syndromes. Measurements at the atomic and molecular levels can be extrapolated to provide information on the mass of clinically relevant tissues such as SM and bone as well as total body water and BCM. Other techniques rely on measuring some aspect of the physical or electrical properties of the tissues: imaging techniques will divide the body into anatomical compartments while other methods provide measurements of fat and fat-free mass (Fig. 1) [51, 53, 54, 58]. Studies into body composition in RA have used a variety of these methods including total body in vivo neutron-activation analysis [59], anthropometric measures of weight, height, triceps skin fold thickness and mid-arm circumference [18, 19, 60–63], urinary creatinine output [18], bioelectrical impedance analysis (BIA) [19, 30, 31, 33, 35–37], potassium-40 whole body counting [12, 15, 21, 26, 28] and DXA [12, 15, 21, 26, 28, 30, 64–69]. Ultrasound [70], MRI and CT are newer technologies that are just beginning to be used in the context of RA.


Figure 1
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  		FIG. 1. The diagram represents the mass of various tissues and body compartments: (a) as viewed by imaging techniques such as CT or MRI; (b) as viewed by BIA; (c) DXA scan view of body composition; (d) the components of LBM: extra-cellular fluid (ECF), BCM and ECS (extra-cellular solids) and (e) the components of body cell mass.

 
Anthropometric methods
BMI, triceps skin-fold thickness and arm circumference are easy to use bedside techniques for measuring fat and muscle mass, although they are of limited accuracy and reproducibility except in skilled hands [38, 71–73].

Imaging techniques
CT and MRI provide a good approximation to anatomical measurements of SM and fat, allowing visceral adipose tissue (VAT) to be distinguished from subcutaneous adipose tissue (SAT). They are expensive to use but approach the gold standard for measuring soft-tissue mass [74–77]. In a typical protocol for whole-body MRI, the subject lies in a 1.5 T scanner in a prone position with arms extended above the head. Forty-one cross-sectional images are acquired, using a T1-weighted spin echo sequence, and subsequently analysed to determine volume of SM, VAT and SAT [75]. Single-image slices through the mid-thigh and the mid-abdomen also provide excellent estimates of whole-body SM mass and fat mass, respectively and may provide a practical solution for clinicians and researchers [75].

‘Research’ methods
Whole body potassium counting and in vivo neutron activation for atomic analysis of the body are available in only a few centres world-wide. These techniques provide a unique window onto body composition as certain atoms are largely segregated into different tissue compartments such as bone (calcium), cells (potassium) and the protein ‘pool’ (nitrogen). The total body potassium content is taken to represent the BCM [52, 74]. This is calculated by measuring potassium-40, a naturally occurring isotope, which exists in a constant abundance of 0.0012%, using a body scintillation counter [50, 74].

BIA
BIA utilizes the differing electrical conductivity of fat and lean tissue. The passage of an electrical signal is facilitated through the hydrated fat-free tissue and extra-cellular water compared with fat because of the greater electrolyte content. The impedance to flow of the electrical current will be directly proportional to the quantity of body fat [38, 58, 78]. This method has not been validated for RA and is very sensitive to hydration status [50, 58]. It is, however, quick and easy to use and may be useful to detect longitudinal changes [74].

DXA
DXA relies on the fact that an X-ray beam passing through a complex substance (e.g. the body) is attenuated to a different extent by the different substances it passes through. Using a dual beam with different X-ray images the machine is able to partition the body into two compartments on a pixel-by-pixel basis. Dense pixels corresponding to the bone are separated from less dense soft-tissue pixels. The soft-tissue compartment is then analysed to separate fat mass from LBM [51, 74, 79]. DXA has emerged as the most clinically useful technique for measuring bone and soft-tissue mass [80, 81]. This method has also not been independently validated for RA and is also sensitive to hydration status [50, 58, 82].

Urinary creatinine excretion
Creatinine is the spontaneous breakdown product of creatine phosphate and creatine, which are mainly found in SM. In normal subjects, there is a strong correlation between 24-h urinary creatinine and total body SM mass. Ideally, the subject should consume a meat-free diet for 7 days prior to the measurement. The accuracy of urine collection and true knowledge of the muscle creatine limits this method [51, 83]. It has never been validated in RA as far as we know.

Ultrasound
Muscle and subcutaneous fat thickness can be measured with an ultrasound scanner. A convenient area is the right quadriceps femoris muscle at the mid-portion between the greater trochanter and the lateral joint line of the knee [70]. Ultrasound maybe especially useful in the obese in whom anthropometric measures are inaccurate [38]. Ultrasound mapping of muscle and fat thickness at different body regions and quantifying changes in topographical fat patterns are useful adjuncts to body composition assessment [38].

Estimating the mass of fat or muscle from the various measurements relies on many assumptions that have been validated to varying degrees against other techniques, in some cases cadaveric dissection [76]. Sometimes a combination of techniques is used in the same study, for example, the estimation of BCM by potassium-40 and fat mass by DXA [12, 15, 21, 26]. Employing a combination of independent measurements avoids transferring errors in one compartment to another compartment. Comparison between the different studies in cachexia is not straightforward as BCM- and DXA-derived LBM cannot be directly equated although SM comprises the major component of both [84]. BCM, LBM (by DXA) and fat-free mass (by BIA) all tend to be used as surrogate measures of muscle mass in studies on cachexia. In future, whole-body MRI, functional MRI and PET scanning will make increasing contributions to the understanding of body composition [85].


   Evidence for rheumatoid cachexia
Top
 Abstract
 Introduction
 Body weight and body...
 Measurement of body composition...
 Evidence for rheumatoid cachexia
Consequences of rheumatoid...
 Therapy for rheumatoid cachexia
 Summary and conclusions
 Reference
 
Thirty-four studies between 1979 and the present have been identified in which body composition has been measured in adult RA using a variety of techniques [12, 15, 18, 19, 21, 26, 30–33, 35–37, 41, 45, 59–70, 86–92]. In three of the studies [15, 26, 92], additional data were published separately on the same group of patients [16, 28, 93]. One study was published in abstract form [33]. Over 1000 individuals with RA have been studied with different age ranges, proportion of patients taking steroids and different levels of disability. Three studies [45, 61, 63] used all or mostly OA controls, which may have skewed their data in view of the known association between OA and obesity [94]. Seventeen studies allow comparison of muscle and fat mass with healthy control subjects or reference standards [12, 18, 19, 21, 26, 41, 59, 60, 64, 65, 67, 70, 86–88, 90, 92] (Table 1). In 15 reports, the BMI was similar in subjects and healthy controls [12, 18, 19, 21, 26, 60, 64, 65, 67, 70, 86–88, 90, 92].


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  		TABLE 1. Studies from 1979 to 2007 in which body composition in RA patients has been compared with healthy controls

 
Thirteen studies document loss of LBM or BCM in comparison with control subjects or reference standards [12, 18, 19, 21, 26, 41, 59, 60, 64, 65, 67, 86, 90]. Conversely, four studies: Kalla et al. [88] using anthropometric variables to estimate muscle mass, Madsen et al. [87] using DXA, Engelhart et al. [92] using potassium-40 and Hakkinen et al. [70] using ultrasound, found no difference in weight, BMI, percentage of fat, lean tissue mass or BCM between RA patients and controls. Comparison of the study populations between reports that demonstrate evidence of cachexia and those which do not reveals no obvious differences in rheumatoid disease severity such as mean ESR, number of patients taking prednisolone, mean prednisolone dose, disease duration or number of swollen joints. Comparing studies using the same measuring techniques does not allow any further conclusions to be drawn: in the four studies that measure BCM by the potassium-40 technique, the three reports from Roubenoff's group show a highly significant reduction in BCM of 14% (26), 15% (21) and 16% (12). The study of Engelhart et al. [92] reports a non-significant 2.7% reduction in BCM in RA patients, although the control group was not part of the original study protocol. In three of the four studies measuring LBM by DXA, percentage reductions in LBM are reported to be 5.6% (in a study involving identical twins) [86], 0% [86, 87] and 12% [64]. The remaining study records a significant reduction in LBM Z-score (S.D. units) of 1.46 for females and 2.61 for males [65].

Fat mass was compared with control or reference values in 15 studies [12, 18, 19, 21, 26, 41, 64, 65, 67, 70, 86–88, 90, 92], in two of which [18, 19] a reduction in fat mass in RA patients was observed by anthropometry. Westhovens et al. [65] showed a higher percentage of fat at all body sites except for the legs in the rheumatoid group compared with controls. In 11 reports, there was a non-significant increase in fat mass in RA [12, 21, 26, 41, 64, 70, 86–88, 90, 92]. Stavropoulos-Kalinoglou et al. [37] observed that for a given BMI, RA patients exhibited an average 4.3% increase in body fat compared with healthy controls.

Two studies, [65] and [89], examined the fat distribution ratio using DXA to calculate the fat mass of the arms and legs separately to produce a trunk:peripheral fat ratio. Both these studies show significant shift of fat to the trunk in RA patients compared with healthy controls.

The burden of evidence, therefore, points towards a reduction in muscle mass in most RA patients. Further research is required in order to resolve if the lack of finding of cachexia in some populations is real or due to technical factors.

How common is rheumatoid cachexia?
The frequency of occurrence of rheumatoid cachexia depends upon what degree of reduction of muscle mass is considered to be significant. Using the 50th percentile of the reference population as the ideal for arm muscle area or circumference, Roubenoff and co-workers [19] found that 67% of patients had values below this level, and could therefore be diagnosed as having rheumatoid cachexia. Taking 80% of this ideal as a cut-off, cachexia was diagnosed in 14% of the patients by Helliwell and co workers [45] and 28.8% of the patients by Fukuda and colleagues [91]. Using the more stringent 10th centile of the reference population as a cut-off, Munro and Capell [41] found that 50% of the RA population was below this level whereas Hernandez-Beriain and colleagues [90] found that 24% of RA patients fell beneath it. Thirty per cent of patients studied by Roubenoff and colleagues [19] were below the 5th percentile of arm muscle area compared with only 8% of those studied by Hernandez-Beriain and co-workers [90].

Morley et al. [4] have taken a more stringent approach to the diagnosis of cachexia and have proposed the following diagnostic criteria: unintentional weight loss ≥5%, BMI below the normal range, low serum albumin, fat-free mass in the lowest 10% and evidence of cytokine excess. They have estimated that 10% of the people with RA have cachexia in comparison with other diseases such as AIDS 35%, cancer 30%, chronic obstructive pulmonary disease 20%, renal failure 40% and heart failure 20%.

Rheumatoid cachexia and disease activity
It has already been noted that reduction in BMI is a marker for severe rheumatoid disease. However, in the presence of normal BMI, analysis of body composition can give us valuable insights into disease activity and outcome.

Significant correlations have been found between depletion of LBM and the number of swollen joints [19, 61], ESR [41, 61, 90], CRP [41] and the presence of extra-articular disease [90].

Strong correlations have been found between the degree of depletion of muscle mass or BCM and the impact of RA as measured by American College of Rheumatology (ACR) functional class [21, 90], the Steinbrocker disease stage [90, 91] and the HAQ score [61].


   Consequences of rheumatoid cachexia
Top
 Abstract
 Introduction
 Body weight and body...
 Measurement of body composition...
 Evidence for rheumatoid cachexia
 Consequences of rheumatoid...
Therapy for rheumatoid cachexia
 Summary and conclusions
 Reference
 
Life expectancy in RA is reduced by an average of 3–18 yrs [95] with an increase in all-cause mortality of 2- to 5-fold compared with the general population [96]. Most of the excess deaths are attributable to infection, coronary heart disease and respiratory disease [97]. The underlying cause of accelerated mortality, particularly from cardiovascular disease, may be partly related to metabolic and vascular effects of chronic systemic inflammation but also to rheumatoid cachexia: the 15% reduction in BCM described by Roubenoff and colleagues [12, 21, 26] represents over one-third of the maximum survivable loss of BCM [5]. Patients with RA are at increased risk of infection not only as a result of immunosuppressive treatment but also due to increased disease activity [96]. Roubenoff and Rall [5] have suggested that this is related to the reduced cellular mass of the immune system as a component of BCM. Reduced respiratory and diaphragmatic muscle mass and function resulting in impairment of the cough reflex may be an additional factor [5].

There is strong evidence that a lower BMI is associated with an increase in all-cause mortality [43] and cardiovascular mortality [40] in RA. This paradoxical effect of BMI on survival in RA is partly mediated by systemic inflammation, with a 15% increase in mortality for each 10 unit increase in ESR [43], and partly due to the increase in comorbidities in leaner patients. It is likely that many of these comorbidities are linked to RA or its treatment [98]. This finding of increasing cardiovascular mortality with reduction in BMI in RA reverses the trend in the general population, in which obesity is clearly linked to an increase in cardiovascular mortality. Kalantar and co-workers [99] have noted that this ‘reverse epidemiology’ of cardiovascular risk is common to many wasting diseases including chronic kidney disease, heart failure, chronic lung disease, AIDS, cancer and the elderly. They hypothesize that the survival paradox results from a time differential between the two competing risk factors; ‘over nutrition, the long term killer but short term protector versus under nutrition, the short term killer’. Conversely strong positive associations have been found between BMI and adverse cardiovascular risk factors, such as hypercholesterolaemia and diastolic hypertension in RA [100]. The tendency towards central obesity [65, 89] exacerbated by prednisolone [65] may prove to be a better predictor than BMI of cardiovascular risk in RA, as has been demonstrated in the general population [65, 101]. Increased arterial thickening and stiffening were independently associated with a higher trunk-to-peripheral fat ratio [89] but not with BMI [102] in rheumatoid patients. Further studies of body composition using MRI to differentiate between visceral and subcutaneous adipose tissue are required to elucidate if and in what way, rheumatoid cachexia is related to metabolic syndrome and cardiovascular risk.

There may be a direct link between muscle depletion and osteoporosis in RA as LBM is correlated with bone mineral density of the spine and hip and is a strong independent predictor of bone mass [67, 68].


   Therapy for rheumatoid cachexia
Top
 Abstract
 Introduction
 Body weight and body...
 Measurement of body composition...
 Evidence for rheumatoid cachexia
 Consequences of rheumatoid...
 Therapy for rheumatoid cachexia
Summary and conclusions
 Reference
 
Diet
Although most patients with RA do not have deficiency in protein or energy intake [19, 21, 26, 45], their reduced energy expenditure on physical activity means that they are more likely to be in positive energy balance and store fat as a result [3]. In common with other types of cachexia, there is evidence that muscle tissue exhibits ‘anabolic resistance’—a general failure of muscle protein synthesis to increase adequately in response to food [1, 103]. Overfeeding in patients with RA is therefore not advisable as this could induce an increase in fat mass, with possible consequences for cardiovascular and metabolic health [13].

Marcora et al. [32] investigated dietary treatment of rheumatoid cachexia using a nutritional supplement of β-hydroxy-β-methylbutyrate, glutamine and arginine, providing 7.19 g/day nitrogen and 180 kcal/day, compared with a nitrogen and calorie equivalent mixture of ‘non-essential’ amino acids (alanine, glutamic acid, glycine and serine) used as placebo. Both interventions increased muscle mass to a similar extent over a 12-week period (by 2–3%) indicating that rheumatoid cachexia may to some extent respond to nitrogen supplementation.

Weight reduction can have a salutary effect on body composition in the overweight rheumatoid: reduced dietary energy and increased protein intake together with moderate cardiovascular training was effective in reducing fat mass by 9% with only a 3% loss of BCM [92, 93].

Physical training
Patients with RA tend to refrain from physical activity due to joint pain and fear of aggravating their disease [21, 26, 34, 104]. Nevertheless, intensive physical training is well tolerated and patients consistently report improvement in pain and fatigue as well as increases in muscle strength and aerobic capacity with no adverse effect on disease activity [105–119].

An early study of twice-weekly progressive resistance training (PRT) in RA subjects compared with healthy controls showed no change in body weight, body composition, resting energy expenditure or protein metabolism after a 12-week programme [15]. This raised the possibility that systemic inflammation reduces the ability of SM cells to respond to the anabolic effects of exercise, although two recent studies contradict this interpretation. In a more intensive, thrice weekly, 12-week programme of PRT, Marcora et al. [30] found that exercising RA subjects had a significant increase in lean mass of the arms and legs compared with non-exercising RA controls. In a third study, RA subjects and healthy controls who underwent a 21-week PRT programme, achieved similar increases in muscle mass and reduction in fat mass [70]. These observations suggest that exercise can overcome the anabolic block characteristic of RA and possibly reduce the increased muscle breakdown so that muscle mass can increase.

Although short-term exercise programmes appear not to produce any adverse effects on rheumatoid disease activity, there is a need for long-term safety data including an assessment of the effect of exercise on radiological progression.

Anti-cytokine therapy
The success of anti-TNF therapy in the management of patients with RA has put beyond doubt the premise that TNF-{alpha} has a central role in the pathogenesis of joint inflammation and destruction in RA [120–122]. Anti-TNF therapy in patients with RA often results in dramatic improvements in quality of life with measurable changes in functional abilities [122]. Rheumatoid cachexia is thought to have the same pathogenesis as joint inflammation and to be caused directly by cytokine (primarily TNF-{alpha})-driven hypermetabolism with an elevated rate of muscle protein loss [16, 123]. It would be anticipated therefore that TNF blockers would result in significant improvements in body composition. This hypothesis was tested by Marcora et al. [31] who recruited 26 patients with RA from an early synovitis clinic and randomized them to MTX or etanercept. After 24 weeks of treatment there were no changes in indices of body composition. Secondary analysis of the six patients in each group who gained weight during follow-up showed a significant effect of etanercept on the composition of the weight gained: 44% of the weight gained in the etanercept group was fat-free mass compared with only 14% in the MTX group, suggesting that etanercept may be able to restore the normal anabolic response to feeding in cachexia independent of a generic reduction in systemic inflammation. More recently, Metsios et al. [35] studied 20 established RA patients receiving anti-TNF therapy according to NICE criteria. Using BIA to assess fat-free mass, there was no change over a 3-month period despite significant improvements in disease activity and physical function.

It may be that adjunctive anabolic therapy, such as PRT or nitrogen supplementation, is needed to reverse rheumatoid cachexia. It is possible that anti-TNF therapy is superior to MTX in the long term and that changes in muscle mass are slower to occur than anticipated.


   Summary and conclusions
Top
 Abstract
 Introduction
 Body weight and body...
 Measurement of body composition...
 Evidence for rheumatoid cachexia
 Consequences of rheumatoid...
 Therapy for rheumatoid cachexia
 Summary and conclusions
Reference
 
RA is a chronic inflammatory autoimmune disease resulting in joint inflammation, increased risk of cardiovascular disease and osteoporosis, with high circulating levels of cytokines and acute-phase proteins. This can produce a loss of muscle mass with maintenance of fat mass but ultimately leads to weight loss in the more severely affected patient. The cachectic state may give rise to a vicious cycle of decreasing exercise, increased fatigue and weakness and an increase in fat mass (rheumatoid cachectic obesity) with implications for comorbidity and mortality. However, in common with other cachectic conditions, there seems to be a direct association between survival and increasing body weight. The implications of this paradoxical relationship require further investigation. Although cachexia occurs in a significant minority of patients associating with more active and severe disease, it tends to be low on the list of priorities for the treating clinician. There are a variety of methods for estimating the impact of cachexia on the body but significant problems exist with clinical interpretation of the data. DXA scanning is the most readily available method for clinical purposes but increasing use of limited MRI examinations is likely to further elucidate the clinical relevance of body composition measurements in RA. It is probably too early to recommend routine estimation of muscle and fat mass but there is good evidence that BMI measurement should form part of our routine clinical assessment. The mechanisms of rheumatoid cachexia have yet to be fully elucidated but probably include cytokine-driven hypermetabolism (particularly by TNF-{alpha}) during active disease. Protein catabolism occurs in SM even in the face of adequate protein intake but there is some evidence that specific dietary interventions may help. High-intensity resistance training can also improve muscle mass and function. Although conventional disease-modifying drugs do not appear to reverse cachexia, anti-TNF therapy holds promise for treating this hitherto largely ignored but important extra-articular manifestation of RA.

Formula


   Acknowledgments
 
Disclosure statement: C.M.D. has declared that his department has received unrestricted grants for an audit clerk and research nurse from Wyeth and Schering-Plough. All other authors have declared no conflicts of interest.


   Reference
Top
 Abstract
 Introduction
 Body weight and body...
 Measurement of body composition...
 Evidence for rheumatoid cachexia
 Consequences of rheumatoid...
 Therapy for rheumatoid cachexia
 Summary and conclusions
 Reference
 

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Submitted 30 November 2007; revised version accepted 18 March 2008.
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