Cachexia in rheumatoid arthritis
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.
References (56)
- et al.
Long-term outcome of treating rheumatoid arthritis: results after 20 years
Lancet
(1987) - et al.
Muscle protein breakdown and the critical role of the ubiquitin–proteasome pathway in normal and disease states
J Nutr
(1999) - et al.
George Clowes’ classic paper and the search for ‘muscle proteolysis factor’
Nutrition
(1996) Nervous mimicry of organic diseases
Lancet
(1873)- et al.
Catabolic effects of high-dose corticosteroids persist despite therapeutic benefit in rheumatoid arthritis
Am J Clin Nutr
(1990) - et al.
Impaired glucose handling in active rheumatoid arthritis: relationship to the secretion of insulin and counter-regulatory hormones
Metabolism
(1987) - et al.
Impaired glucose handling in active rheumatoid arthritis: effects of corticosteroids and antirheumatic treatment
Metabolism
(1987) - et al.
Evidence for peripheral impaired glucose handling in patients with connective tissue diseases
Metabolism
(1991) - et al.
Epidemiology and prevention of musculoskeletal disorders
Rheumatoid arthritis: epidemiology, etiology, rheumatoid factor, pathology, pathogenesis
Humoral mediation of changing body composition during aging and chronic inflammation
Nutr Rev
Cytokine pathways and joint inflammation in rheumatoid arthritis
N Engl J Med
Cytokines in rheumatoid arthritis
J Invest Med
The expression of tumor necrosis factor-α by human muscle
J Clin Invest
Resistance exercise decreases skeletal muscle tumor necrosis factor-α in frail elderly humans
FASEB J
Cytokines and chemokines are both expressed by human myoblasts: possible relevance for the immune pathogenesis of muscle inflammation
Int Immunol
Increased interleukin-1β in human skeletal muscle after exercise
Am J Physiol
Cytokine production in muscle tissue of patients with idiopathic inflammatory myopathies
Arthritis Rheum
Detection of tumor necrosis factor-α but not tumor necrosis factor-β in rheumatoid arthritis synovial fluid and serum
Arthritis Rheum
Peripheral blood and synovial fluid monocyte expression of interleukin-1α and 1β during active rheumatoid arthritis
J Rheumatol
The effects of cytokines on metalloproteinase inhibitors (TIMP) and collagenase production by human chondrocytes and TIMP production by synovial cells and endothelial cells
Clin Exp Immunol
Taking mortality in rheumatoid arthritis seriously—predictive markers, socioeconomic status and comorbidity
J Rheumatol
Mortality in rheumatoid arthritis
Br J Rheumatol
The mortality of rheumatoid arthritis
Arthritis Rheum
Rheumatoid cachexia: cytokine-driven hypermetabolism accompanying reduced body cell mass in chronic inflammation
J Clin Invest
Tumor necrosis factor-α production is associated with less body cell mass in rheumatoid arthritis
Arthritis Rheum
Rheumatoid cachexia: depletion of lean body mass in rheumatoid arthritis. Possible association with tumor necrosis factor-α
J Rheumatol
A cross-sectional study of muscle strength and mass in 45 to 78 year-old men and women
J Appl Physiol
Cited by (225)
Peripheral Volumetric Muscle Area and Total Body Volume in Postmenopausal Women With Rheumatoid Arthritis
2021, Journal of Clinical DensitometryAssessment of nutritional deficiency manifestations in patients with rheumatic diseases
2021, Egyptian RheumatologistEffect of basal metabolic rate on rheumatoid arthritis: a Mendelian randomization study
2024, Postgraduate Medical JournalEffects of Aerobic and Resistive Exercise on Muscle Measurements and Body Composition in Female Patients with Rheumatoid Arthritis
2023, American Journal of Physical Medicine and RehabilitationFrom amino-acid to disease: the effects of oxidation on actin-myosin interactions in muscle
2023, Journal of Muscle Research and Cell Motility