Tumor necrosis factor-alpha production is associated with less body cell mass in women with rheumatoid arthritis.

OBJECTIVE: To examine the relationship between inflammatory cytokine production and body cell mass (BCM) in women with stable, medically well-controlled rheumatoid arthritis (RA). METHODS: Case-control study of 20 women with RA and 20 healthy women matched for age, race, and body mass index (kg/m2). Tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta), and IL-6 production were measured by specific, non-cross-reacting ELISA of peripheral blood mononuclear cells (PBMC) cultured with and without 100 ng/ml of endotoxin. Total BCM was assessed by the reference method of whole-body counting of naturally occurring radioactive potassium-40. RESULTS: Patients with RA were cachectic, with 14% less BCM (p < 0.001) and higher TNF-alpha production (p < 0.05) than controls. TNF-alpha production was inversely associated with BCM both without (r = -0.51, p = 0.03) and with (r = -0.57, p = 0.01) endotoxin stimulation in patients but not in controls. In multivariate linear regression models, these inverse associations remained significant after adjustment for age and physical activity. No association was found for IL-1beta or IL-6 production in these models. CONCLUSION: Women with stable, medically well-controlled RA have lower than normal BCM that is inversely associated with elevated TNF-alpha production.

A randomized controlled trial of resistance exercise training to improve glycemic control in older adults with type 2 diabetes.

OBJECTIVE: To determine the efficacy of high-intensity progressive resistance training (PRT) on glycemic control in older adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed a 16-week randomized controlled trial in 62 Latino older adults (40 women and 22 men; mean +/- SE age 66 +/- 8 years) with type 2 diabetes randomly assigned to supervised PRT or a control group. Glycemic control, metabolic syndrome abnormalities, body composition, and muscle glycogen stores were determined before and after the intervention. RESULTS: Sixteen weeks of PRT (three times per week) resulted in reduced plasma glycosylated hemoglobin levels (from 8.7 +/- 0.3 to 7.6 +/- 0.2%), increased muscle glycogen stores (from 60.3 +/- 3.9 to 79.1 +/- 5.0 mmol glucose/kg muscle), and reduced the dose of prescribed diabetes medication in 72% of exercisers compared with the control group, P = 0.004-0.05. Control subjects showed no change in glycosylated hemoglobin, a reduction in muscle glycogen (from 61.4 +/- 7.7 to 47.2 +/- 6.7 mmol glucose/kg muscle), and a 42% increase in diabetes medications. PRT subjects versus control subjects also increased lean mass (+1.2 +/- 0.2 vs. -0.1 +/- 0.1 kg), reduced systolic blood pressure (-9.7 +/- 1.6 vs. +7.7 +/- 1.9 mmHg), and decreased trunk fat mass (-0.7 +/- 0.1 vs. +0.8 +/- 0.1 kg; P = 0.01-0.05). CONCLUSIONS: PRT as an adjunct to standard of care is feasible and effective in improving glycemic control and some of the abnormalities associated with the metabolic syndrome among high-risk older adults with type 2 diabetes.

Cachexia in rheumatoid arthritis is not explained by decreased growth hormone secretion.

OBJECTIVE: Patients with rheumatoid arthritis (RA) lose body cell mass (BCM) by unknown mechanisms. Since the loss of BCM in normal aging individuals parallels the characteristic age-related decline in growth hormone (GH) secretion, this study was carried out to determine whether further decreased GH secretion plays a role in the pathogenesis of this loss of BCM in RA patients, termed "rheumatoid cachexia." METHODS: GH secretory kinetics were determined by deconvolution analysis in 16 patients with RA and 17 healthy controls matched for age (mean +/- SD 45.4 +/- 13.2 years and 47.1 +/- 14.6 years, respectively), sex, race, and body mass index. Blood samples were obtained every 20 minutes for 24 hours. Body composition was ascertained using total-body potassium (TBK) as a measure of BCM and dual x-ray absorptiometry to determine fat mass. RESULTS: BCM was reduced in patients with RA compared with healthy controls (mean +/- SD gm TBK 79.5 +/- 9.5 versus 94.9 +/- 11.9; P < 0.0005), but there was no difference in fat mass. GH kinetic parameters in patients with RA did not differ from those in controls. CONCLUSION: These findings suggest that GH kinetics are unaltered in RA patients compared with healthy subjects; thus, GH deficiency does not account for rheumatoid cachexia.

Low physical activity reduces total energy expenditure in women with rheumatoid arthritis: implications for dietary intake recommendations.

BACKGROUND: Rheumatoid arthritis (RA) causes cachexia, a metabolic response characterized by loss of muscle mass and elevated resting energy expenditure (REE). However, energy expenditure in physical activity in subjects with RA is lower than that in healthy subjects. It is not known which effect predominates in regulating total energy expenditure (TEE), and thus whether the dietary energy requirements of subjects with RA are higher or lower than those of healthy subjects. OBJECTIVE: Our objective was to determine TEE in women with RA by using the reference method of doubly labeled water ((2)H(2)(18)O). DESIGN: In this case-control study, we examined 20 women with RA and 20 healthy women who were matched for age and body mass index. RESULTS: The patients with RA were cachectic (their body cell mass was 14% lower than that of the controls, P < 0.001), but REE was not elevated, reflecting good disease control. Mean (+/- SD) TEE was 1344 kJ/d lower in the patients than in the controls (9133 +/- 1335 compared with 10 477 +/- 1992 kJ/d; P < 0.02). The energy expenditure in physical activity of the patients was 1034 kJ/d lower than that of the controls (P < 0.04), which accounted for 77% of the difference in TEE between the 2 groups. The physical activity level (TEE/REE) of the patients also tended to be lower than that of the controls (1.70 +/- 0.24 compared with 1.89 +/- 0.36; P < 0.07). CONCLUSION: A low physical activity level is the main determinant of lower-than-normal TEE, and thus energy requirements, in women with RA.

Cachexia in rheumatoid arthritis.

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-alpha and interleukin-1beta. Tumor necrosis factor-alpha is probably the central mediator of muscle wasting in rheumatoid arthritis, and is known to act synergistically with interleukin-1beta to promote cachexia. In general, tumor necrosis factor-alpha and interleukin-1beta 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-alpha 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.