Cachexia in rheumatoid arthritis

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Abstract

Rheumatoid arthritis is a debilitating, chronic, systemic, autoimmune disease of unknown etiology that causes destruction of joint cartilage and bone. It generally occurs between the fourth and sixth decades of life, and affects two to three times more women than men. It is characterized by joint stiffness, pain, and swelling, and is accompanied by a loss of body cell mass. This loss of cell mass, known as rheumatoid cachexia, predominates in skeletal muscle, but also occurs in the viscera and immune system. Thus, rheumatoid cachexia leads to muscle weakness and a loss of functional capacity, and is believed to accelerate morbidity and mortality in rheumatoid arthritis. Currently there is no established mechanism for rheumatoid cachexia, but it is accompanied by elevated resting energy expenditure, accelerated whole-body protein catabolism, and excess production of the inflammatory cytokines, tumor necrosis factor-α and interleukin-1β. Tumor necrosis factor-α is probably the central mediator of muscle wasting in rheumatoid arthritis, and is known to act synergistically with interleukin-1β to promote cachexia. In general, tumor necrosis factor-α and interleukin-1β are thought to alter the balance between protein degradation and protein synthesis in rheumatoid arthritis to cause muscle wasting. The precise mechanism by which they do this is not known. Reduced peripheral insulin action and low habitual physical activity are important consequences of rheumatoid arthritis, and have also been implicated as mediators of rheumatoid cachexia. Insulin inhibits muscle protein degradation. Consequently, reduced peripheral insulin action in rheumatoid arthritis is thought to be permissive to cytokine-driven muscle loss. The cause of reduced peripheral insulin action in rheumatoid arthritis is not known, but tumor necrosis factor-α has been shown to interfere with insulin receptor signaling and is probably an important contributor. Low habitual physical activity has consistently been observed in rheumatoid arthritis and is an important consequence of, and contributor to, muscle wasting. In addition, low physical activity predisposes to fat gain and is believed to precipitate a negative reinforcing cycle of muscle loss, reduced physical function, and fat gain in rheumatoid arthritis, which leads to ‘cachectic obesity’. To date, there is no standard treatment for rheumatoid cachexia. However, physical exercise is currently believed to be the most important and clinically relevant countermeasure against rheumatoid cachexia. In general, a combination of skeletal muscle strength training and aerobic exercise is recommended, but must be prescribed with the patient’s disease status, overall health, and safety in mind. Future studies should investigate the safety, efficacy, and required dose of anti-cytokine therapy for the treatment of rheumatoid cachexia. In this review, we outline the current definition of rheumatoid cachexia, and discuss the etiology, pathogenesis, and treatment of rheumatoid cachexia.

Introduction

Rheumatoid arthritis is a chronic, systemic, autoimmune disease of unknown etiology that causes destruction of joint cartilage and bone. It affects ∼1% of the population and predominates among women, affecting two to three times more women than men [1], [2]. Rheumatoid arthritis generally occurs between the fourth and sixth decades of life and is characterized by joint stiffness, pain, and swelling. The synovium of the joint is the crucial site in the onset of joint deterioration and is characterized by a predominance of proliferating T-lymphocytes (CD4+ more so than CD8+), pronounced immunoglobin production, and increased inflammatory cytokine production [3].

The inflammatory cytokines tumor necrosis factor-α and interleukin-1β are believed to play central roles in the pathogenesis of rheumatoid arthritis. Both tumor necrosis factor-α and interleukin-1β are primarily produced by monocytes and macrophages, but are also produced by a host of other cells, including B-lymphocytes, T-lymphocytes, and skeletal muscle [4], [5], [6], [7], [8], [9], [10]. Synovial and serum concentrations of tumor necrosis factor-α and interleukin-1β are high in patients with active rheumatoid arthritis [11], [12], and both cytokines are potent stimulators of synovial fibroblasts, chondrocytes, and osteoclasts, all of which release tissue-destroying matrix metalloproteinases [13]. In addition, tumor necrosis factor-α and interleukin-1β inhibit the production of endogenous inhibitors of matrix metalloproteinases [13]. Thus, tumor necrosis factor-α and interleukin-1β activate tissue-destroying matrix metalloproteinases and inhibit endogenous inhibitors of matrix metalloproteinases. These dual actions are thought to lead to joint damage in rheumatoid arthritis.

Although rheumatoid arthritis is not intrinsically fatal, life expectancy is reduced by an average of 3 to 18 years [14], and 80% of patients with rheumatoid arthritis are disabled after 20 years with the disease [15]. Deaths from infection occur 20 times more frequently in patients with rheumatoid arthritis [16], and all-cause mortality is two to five times higher in rheumatoid arthritis than in the general population [16], [17]. The most frequent causes of death in rheumatoid arthritis, cardiovascular disease and cancer, mirror the leading causes of death in the general population, suggesting, in effect, that patients with rheumatoid arthritis are physiologically ‘older’ than their healthy counterparts.

The underlying cause of this accelerated mortality in rheumatoid arthritis is unclear, and was observed in the pre-steroid, pre-immunosuppression era, suggesting that the chronic systemic inflammation of rheumatoid arthritis and not the immunosuppressive treatment, plays an important role. In addition to the joint, bone, and system-wide inflammatory damage that occurs in rheumatoid arthritis, nearly two-thirds of all patients experience a muscle wasting condition known as rheumatoid cachexia. Unlike cancer and AIDS cachexia, which is often a proximal cause of death, rheumatoid cachexia is not directly fatal, but is known to compromise muscle strength and functional capacity, and is believed to be an important contributor to comorbidity and reduced life expectancy in rheumatoid arthritis. This is because muscle is the primary store of body protein, and depletion of body protein impairs adaptation to metabolic stress and the ability of patients to cope with secondary infection and concurrent illness.

Currently, there is no established mechanism for rheumatoid cachexia. However, it is refractory to nutrition therapy, and develops in the absence of clinically evident malabsorption and liver and renal dysfunction, and is accompanied by excess production of the inflammatory cytokines tumor necrosis factor-α and interleukin-1β [18], [19]. Tumor necrosis factor-α is believed to be the central mediator of muscle wasting in rheumatoid arthritis, and is known to act synergistically with interleukin-1β to exert a powerful influence on muscle protein turnover [20], [21]. In general it is thought that excess production of tumor necrosis factor-α and interleukin-1β alters the balance between muscle protein breakdown and muscle protein synthesis in rheumatoid arthritis, resulting in net muscle protein degradation and muscle wasting. The precise mechanism by which tumor necrosis factor-α and interleukin-1β cause muscle wasting in rheumatoid arthritis has yet to be elucidated, but may involve other cytokines, as well as sarcoactive (muscle active) transcription factors and hormones. In addition to excess tumor necrosis factor-α and interleukin-1β production, reduced peripheral insulin action and low habitual physical activity are believed to play important roles in the development of rheumatoid cachexia.

In this review, we will outline the current definition of rheumatoid cachexia, and will describe our current understanding of the etiology and pathogenesis of rheumatoid cachexia. Lastly, we will discuss the measures that can be taken to counteract rheumatoid cachexia.

Section snippets

Definition of rheumatoid cachexia

Rheumatoid cachexia was first described by Sir James Paget in 1873 [22], and is the term used to describe the loss of body cell mass, predominantly in skeletal muscle, that occurs in nearly two-thirds of all patients with rheumatoid arthritis [18], [23]. A hallmark of rheumatoid cachexia is elevated resting energy expenditure in active rheumatoid arthritis [18]. At the simplest level, the human body can be divided into fat-free mass and fat mass. Fat-free mass consists of body cell mass,

Mechanisms of rheumatoid cachexia

Although the precise cause of rheumatoid cachexia has yet to be elucidated, there are several potential mechanisms that have been investigated. The etiology is likely multifactorial, and involves excess inflammatory cytokine production, namely excess tumor necrosis factor-α and interleukin-1β production; reduced peripheral insulin action; and low habitual physical activity. Importantly, rheumatoid cachexia occurs in the absence of clinically evident malabsorption, and in the absence of liver

Countermeasures against rheumatoid cachexia

Rheumatoid cachexia currently has no standard treatment. However, countermeasures against rheumatoid cachexia may best be aimed at its etiologic factors, namely excess tumor necrosis factor-α and interleukin-1β production and low habitual physical activity. To date, the most effective therapeutic intervention for rheumatoid cachexia is physical exercise. A combination of aerobic exercise and progressive skeletal muscle strength training with weights is generally believed to be the most

Summary

Rheumatoid cachexia is an important metabolic consequence of rheumatoid arthritis and leads to muscle weakness, disability, and loss of independence. In addition, it is believed to be an important contributor to comorbidity and reduced life expectancy in rheumatoid arthritis. The etiology of rheumatoid cachexia is multifactorial, and involves excess tumor necrosis factor-α and interleukin-1β production; reduced peripheral insulin action; and low habitual physical activity. In addition to

Acknowledgements

Supported by a Clinical Science Grant from the Arthritis Foundation, USDA Cooperative Agreement 58-1950-9-001, and National Research Service Award #T32 AG00209-09. The contents of this publication do not necessarily reflect the views or policies of the US Department of Agriculture, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

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