Rheumatoid cachexia: metabolic abnormalities, mechanisms and interventions

L. C. Rall and R. Roubenoff1,2

Marshfield Clinic Research Foundation, Epidemiology Research Center, Marshfield, WI, 1 Millennium Pharmaceuticals, Inc., Cambridge and 2 Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA

Correspondence to: L. C. Rall, Epidemiology Research Center, ML-2, Marshfield Clinic Research Foundation, 1000 N. Oak Avenue, Marshfield, WI 54449, USA. E-mail: rall.laura{at}mcrf.mfldclin.edu


    Abstract
 Top
 Abstract
 Introduction
 Rheumatoid cachexia
 Mechanisms
 Summary
 References
 
We have previously identified the phrase ‘rheumatoid cachexia’ to describe the loss of body cell mass (BCM) that may occur among patients with rheumatoid arthritis (RA). Specifically, rheumatoid cachexia is characterized by altered energy and protein metabolism (reduced total energy expenditure, increased resting energy expenditure and increased whole-body protein catabolism) and increased inflammatory cytokine production (interleukin-1ß and tumour necrosis factor-{alpha}). Patients with rheumatoid cachexia consistently have a diet that appears adequate in protein and calories (based on US Dietary Reference Intakes), but with reduced physical activity. These phenomena are similar to some of the metabolic abnormalities that occur with normal ageing, but the aetiology appears to be different in RA. This review will focus on describing the metabolic abnormalities observed in rheumatoid cachexia, identifying potential mechanisms for loss of BCM and discussing strategies for intervention.

KEY WORDS: Rheumatoid arthritis, Cachexia, Protein metabolism, Muscle, Body cell mass, Interleukin-1ß, Tumour necrosis factor-{alpha}, Exercise


    Introduction
 Top
 Abstract
 Introduction
 Rheumatoid cachexia
 Mechanisms
 Summary
 References
 
Rheumatoid cachexia was first described by Sir James Paget over a century ago [1]. However, this ‘bad condition’ (literal translation from Greek) has not been recognized as a common problem among patients with rheumatoid arthritis (RA) until relatively recently. While cachexia generally connotes a state of advanced malnutrition and wasting, we now know that this term refers, more specifically, to a loss of body cell mass (BCM) [2]. Furthermore, the reason why loss of BCM is so important is that, in all situations in which it has been studied—starvation, critical illness and normal ageing—loss of greater than 40% of baseline BCM is associated with death [3–5]. Even with as little as 5% loss of BCM there are demonstrable changes in morbidity, including loss of muscle strength, altered energy metabolism, and increased susceptibility to infections [6]. To put these numbers in perspective, the average loss of BCM among patients with RA is between 13 and 15% [7, 8], approximately one-third of the maximum survivable loss of BCM. Thus, rheumatoid cachexia should be viewed as an important contributor to increased morbidity and premature mortality in RA. Although patients do not die of RA per se, people with RA do have a 2- to 5-fold higher mortality rate, with the same causes of death as in the general population except for an increased risk of infections [9–11]. Understanding the metabolic abnormalities and mechanisms involved in the development of rheumatoid cachexia may help to identify potential new therapeutic targets.


    Rheumatoid cachexia
 Top
 Abstract
 Introduction
 Rheumatoid cachexia
 Mechanisms
 Summary
 References
 
Definition
BCM is the most metabolically active component of the human body, accounting for 95% of all metabolic activity. The amount of BCM determines energy expenditure, protein requirements and the metabolic response to physiological stress [12]. BCM consists primarily of muscle mass, with visceral mass (serum proteins, erythrocytes, granulocytes, lymphocytes, liver, kidneys, pancreas, heart) and immune cell mass contributing lesser amounts. Fat mass, extracellular water, connective tissue (cartilage, fibrous tissues, skeletal tissues) and bone account for the remaining components. These structural proteins are not readily exchangeable with other body pools of protein, so changes that occur in BCM during disease cannot be counteracted by mobilization of extracellular connective tissue.

The aetiology and consequences of loss of BCM can be variable. Frank wasting involves loss of body weight (fat mass) and BCM, and is typically due to inadequate dietary intake. Cachexia, however, refers to loss of BCM without loss of weight; in fact, loss of BCM is often accompanied by increased fat mass and stable body weight. In patients with RA, these changes predispose to a condition termed ‘rheumatoid cachectic obesity’, which, though seemingly contradictory, appears to be a common metabolic consequence of RA, affecting nearly two-thirds of all patients with RA [7, 8].

Accompanying the loss of BCM that occurs in rheumatoid cachexia, other features are noticeably absent; specifically, there are no impairments in renal or hepatic function, there is no malabsorption, and there is only limited corticosteroid use among patients with RA. These aspects create an ideal model in which to study hypercytokinaemic cachexia.

Lessons from ageing: sarcopenia
Sarcopenia (literally, lack of flesh) refers to the loss of muscle mass that occurs with advancing age [13]. Although it happens to almost everyone to a certain extent, the rate of sarcopenia and severity of the sequelae vary depending on health status, physical activity and perhaps diet [14]. Sarcopenia is distinct from cachexia caused by inflammatory disease and from muscle wasting caused by starvation or advanced chronic disease [15]. However, sarcopenia has been referred to as the backdrop against which the drama of disease is played out: ‘normal’ age-related protein loss creates a state whereby the body is less able to withstand the protein catabolism that occurs with illness [16]. Thus, in the case of rheumatoid cachexia, RA amplifies a condition that is already present in healthy people with age, although it remains unclear whether the circuit is the same as in normal ageing but simply with a greater voltage, or whether there are additional pathways recruited that are specific to RA. Furthermore, given that we have not found tumour necrosis factor (TNF)-{alpha} to be increased in the elderly [17], while it is in RA, we would suggest that RA compounds and accelerates sarcopenia, whereas sarcopenia per se may work primarily through interleukin (IL)-6 and IL-1ß/IL-1 receptor antagonist.


    Mechanisms
 Top
 Abstract
 Introduction
 Rheumatoid cachexia
 Mechanisms
 Summary
 References
 
Role of sarcoactive cytokines
The inflammatory cytokines TNF-{alpha} and IL-1ß are thought to be centrally involved in the pathogenesis of RA. Both of these cytokines are produced primarily by monocytes and macrophages, but they are also produced by a variety of other cells, including B lymphocytes, T lymphocytes and skeletal muscle [18–21]. Concentrations of TNF-{alpha} and IL-1ß are high in patients with active RA [22, 23]; these compounds act by stimulating the release of tissue-destroying matrix metalloproteinases, as well as by inhibiting the production of endogenous inhibitors of these metalloproteinases, the net result being joint damage [24].

Not only are TNF-{alpha} and IL-1ß centrally involved in joint damage in RA, but these cytokines also exert a powerful influence on whole-body protein and energy metabolism. The so-called sarcoactive (‘muscle-active’) cytokines include, in addition to TNF-{alpha} and IL-1ß, also, IL-6, interferon-gamma (IFN-{gamma}), transforming growth factor-beta (TGF-ß1) and the transcription factor MyoD, mentioned in this context because of the integral role that MyoD has with TNF-{alpha} and TGF-ß1.

Over 20 years ago, researchers first demonstrated that circulating inflammatory cytokines such as TNF-{alpha} and IL-1ß are released into the plasma by leucocytes, and can stimulate protein degradation and whole-body protein wasting [25]. Although the specific mechanism by which TNF-{alpha} and IL-1ß exert their catabolic effect is not known, we have shown that subjects with RA have higher rates of whole-body protein breakdown compared with young and elderly healthy subjects, and, furthermore, that protein breakdown rates are directly associated with TNF-{alpha} production by peripheral blood mononuclear cells [26].

Studies have also shown that skeletal muscle protein loss is dependent upon the combined signaling activities of TNF-{alpha} and IFN-{gamma}, and that nuclear factor kappa B (NF-{kappa}B) activity is required for these cytokines to induce muscle damage [27]. Specifically, TNF-induced activation of NF-{kappa}B has been shown to inhibit skeletal muscle differentiation by suppressing MyoD mRNA at the post-transcriptional level [27]. MyoD regulates skeletal muscle differentiation and is essential for the repair of damaged tissue [27]. Work is currently under way in our laboratory to examine transcript (mRNA) levels of a panel of sarcoactive cytokines, including TNF-{alpha}, IL-1ß, IL-6, IL-15, IFN-{gamma}, TGF-ß1 and MyoD [28, 29]. Recent additional work has suggested that protein kinase B and Smad3 proteins may also play a role in mediating the action of these sarcoactive cytokines by affecting the protection and vulnerability of cells against TGF-ß1-induced apoptosis [30].

Energy expenditure profile
Early studies from our research group suggested that resting energy expenditure (REE) was elevated in patients with RA [7, 8]. Resting energy expenditure is only one component of total daily energy expenditure (TEE), however, the others being the energy expenditure of physical activity (EEPA) and the thermic effect of food (TEF), such that:

Therefore, although REE may be elevated in RA, the net effect on TEE also depends on EEPA. We have recently examined this issue in women with RA and in age- and body mass index-matched controls, and found that TEE is actually significantly lower in patients with RA than in controls because of lower EEPA [31]. In fact, the magnitude of the difference in EEPA was quite large in this study: 1034 kJ/day (approximately a 10% difference between RA and controls). Clearly, low EEPA predominates in determining TEE in patients with RA. Furthermore, in the 14 years since we first showed that cachexia is common in RA [32], improvements in disease treatment have made overt hypermetabolism (elevated REE) less common. The implication of what is now known about energy metabolism in RA is that patients need to be cautioned to maintain a diet that is adequate—and not excessive—in terms of protein and calories in an attempt to maintain muscle but prevent fat gain.

Whole-body protein turnover
We have consistently demonstrated that a loss of BCM is common in patients with RA [7, 8, 31–33]. By definition, catabolism (negative protein balance) must occur in order for cachexia to develop, and, consistent with this, we have also found that adults with RA have increased whole-body protein breakdown rates (measured by 13C-leucine infusion) [26]. Furthermore, we observed a direct relationship between peripheral blood mononuclear cell production of TNF-{alpha} and leucine flux—an indicator of whole-body protein breakdown in the fasting state—where higher TNF-{alpha} production was associated with higher rates of whole-body protein breakdown (catabolism) [26]. Studies are underway in our laboratory to examine the skeletal muscle fractional synthetic rate in patients with RA [28].

Physical activity
We have demonstrated that patients with RA have low physical activity [8]. Many factors contribute to reduced physical activity among patients with RA, including joint pain and stiffness, metabolic changes leading to loss of muscle mass and strength, and simple disuse, perhaps related to general cautiousness with regard to physical activity.

Hormones
Growth hormone (GH) and insulin-like growth factor-I (IGF-I)
The loss of BCM mass that occurs in RA is similar to that which occurs in healthy ageing. In the case of healthy ageing, an association has been shown between this loss of lean mass and declining activity of the GH–IGF-I axis. This raises the question of whether GH is reduced in patients with RA, and whether a reduction in GH may contribute to some of the body composition changes observed in these patients. Evidence exists for abnormalities of various other hormones in RA [34–36]. However, a recent study measuring GH secretory kinetics by deconvolution analysis after 24-h blood sampling found no differences between patients with RA and healthy control subjects after adjusting for differences in fat mass between the two groups, as fat is known to suppress GH secretion [37]. Patients with RA did, however, have significantly reduced BCM. These findings suggest that persistent GH deficiency does not appear to be the cause of rheumatoid cachexia. However, it should be noted that a trend towards lower serum IGF-I levels was found; these results have been supported by others, who observed significant reductions in circulating IGF-I [38]. It is thus possible that reduced IGF-I could contribute to rheumatoid cachexia.

Insulin
Insulin acts to inhibit muscle protein degradation, thus making it a potent anabolic hormone. Several researchers have documented insulin resistance in inflammatory arthritis [39, 40], although its effect on protein metabolism remains unknown. We have hypothesized that the metabolic milieu created by a state of insulin resistance may be permissive to cytokine-driven muscle loss [41], although this hypothesis remains to be investigated. The aetiology of reduced peripheral insulin action in RA is not known, but TNF-{alpha} has been shown to interfere with insulin receptor signalling and may be a contributing factor [42, 43].

Interventions
Although the precise mechanisms whereby rheumatoid cachexia develops are still continuing to unfold, it is already clear that the functional consequences of this condition are to increase morbidity and mortality in patients with RA. Because of this, attempts must be made to try to slow and/or reverse the loss of BCM in RA and improve functional status. There are essentially three methods for doing so: exercise interventions, dietary interventions and pharmacological interventions.

Exercise
Over two decades ago the traditional concept of rest for managing joint symptoms of RA began to be challenged. Two early studies demonstrated that high-intensity strength training is feasible and safe in selected patients with well-controlled RA [33, 44]. Furthermore, there were significant improvements in strength, pain and fatigue without exacerbating disease activity or joint pain in these subjects [33]. There were no adverse effects on a host of immune system parameters either, as may sometimes occur after an acute bout of exercise [45]. Subsequently, additional studies have confirmed the early findings and have shown that regular progressive resistance strength training improves muscle strength and physical functioning in patients with RA [46–49], even over the long term [50]. Strength training should be considered an important cornerstone of the non-pharmacological treatment of RA and should be routinely prescribed and maintained in order to achieve maximal benefit [51].

Diet
Our research has suggested that dietary intake appears to be adequate in terms of energy and protein intake among patients with RA, and that inadequate intake does not contribute significantly to rheumatoid cachexia. We have consistently demonstrated that dietary intake is not different between patients with RA and healthy controls [8, 26, 31, 52], with mean protein intakes (mean ± S.D.) between 0.7 ± 0.1 [52] and 1.3 ± 0.19 g/kg per day [26], and mean energy intake ranging from 25.5 ± 10 [8] to 31 ± 3.8 kcal/kg per day [26]. Of note, in the study in which protein intake was estimated to be 0.7 g/kg per day [52], both patients with RA and controls under-reported dietary energy intake compared with TEE measured by doubly-labelled water, which implies that protein intake was likely to have been underestimated as well.

The recommended protein intake, based on the Dietary Reference Intakes (DRI), is 0.8 g/kg per day for adults, while the estimated energy requirement is defined as the average dietary energy intake that is predicted to maintain energy balance in a healthy adult of a defined age, gender, weight, height and level of physical activity, consistent with good health [53]. Clearly, patients with RA do not fall under the definition of ‘healthy adult’, so while the DRI may not apply directly in our studies, the concept of energy required for maintaining a healthy weight still applies. Furthermore, given that TEE is actually reduced among patients with RA compared with healthy control subjects, leading to a propensity to fat accretion over time, clinicians should not recommend increased dietary energy intake to patients with RA despite their risk of elevated REE [31]. Future studies are needed to determine optimal protein intakes for overcoming the catabolic process in RA, particularly when combined with an exercise intervention. It is entirely possible that increased amounts of nitrogen are required in order to attain maximal anabolic benefit.

With regard to alteration or supplementation of various dietary components, a complete discussion is beyond the scope of this article. Many dietary modifications for RA have been suggested in the past, ranging from fasting or vegetarianism to supplementation with various fatty acids or protein supplements [54]. The goal of these interventions, however, has focused more on disease management (joint symptoms and pain) than on metabolic abnormalities. For the time being at least, none of these various diets has proven to be particularly effective in either respect. Furthermore, it should be noted that a possible adverse effect of following a vegetarian diet in terms of further loss of lean mass has been observed [55], so patients should be cautioned in this regard.

Cytokine antagonists
In order to prevent the inflammatory and destructive changes of RA that have been attributed primarily to TNF-{alpha}, a number of agents have been developed aimed at inhibiting TNF-{alpha} production. The US Food and Drug Administration recently approved three TNF-{alpha} antagonists for the treatment of RA, one of which is a soluble receptor and the others are monoclonal antibodies [56]. While these agents have been shown to be effective in the treatment of signs and symptoms of RA [56], concerns about their safety have been raised. Although there are some risks involved (i.e. reactivation of granulomatous diseases, increased incidence of non-Hodgkin's lymphoma, and exacerbation of advanced heart failure), with careful monitoring it appears that these agents can be safely used in most instances. There have been no studies to date, to our knowledge, examining the effect of these agents on body composition in RA and future studies are warranted. One could speculate that by blocking the action of TNF-{alpha}—the primary cytokine that has been implicated in rheumatoid cachexia—BCM might be preserved in RA.


    Summary
 Top
 Abstract
 Introduction
 Rheumatoid cachexia
 Mechanisms
 Summary
 References
 
Rheumatoid arthritis is a chronic, systemic, inflammatory condition that is characterized, in part, by increased production of the inflammatory cytokines TNF-{alpha} and IL-1ß. TNF-{alpha} seems to be a key mediator in the disease process, and IL-1ß takes on a more permissive role, acting to shift whole-body protein metabolism towards net catabolism, elevate resting energy expenditure and increase joint pain and stiffness.

Of note, it seems that the metabolic abnormalities in RA (net whole-body protein catabolism and hypermetabolism) are primarily a problem during active disease. Still, even when disease is well controlled and metabolic abnormalities are minimized, the metabolic consequences—loss of BCM and the functional sequelae—are not corrected without additional, direct intervention.

For the time being, increasing physical activity and maintaining a diet adequate in protein and energy remain the cornerstones of good clinical management of the metabolic consequences of RA. It is important to point out that at present there is little scientific evidence to define optimal interventions for the specific treatment of rheumatoid cachexia, and further research is needed. In the meantime, although lifestyle factors alone certainly cannot be relied upon to treat the disease itself, these simple modifications may help to maintain functional status in patients with RA.

RR is an employee of Millennium Pharmaceuticals. LCR has declared no conflicts of interest.


    References
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 Abstract
 Introduction
 Rheumatoid cachexia
 Mechanisms
 Summary
 References
 

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Submitted 10 May 2004; revised version accepted 18 June 2004.



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