Rheumatoid cachexia: metabolic abnormalities, mechanisms and interventions.

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-1beta 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.

The relationship between growth hormone kinetics and sarcopenia in postmenopausal women: the role of fat mass and leptin.

Sarcopenia, the decline in body cell mass (BCM) and especially in muscle mass with age, is an important age-related cause of frailty and loss of independence in the elderly. Because the decline in BCM with age parallels a decline in GH secretion from young adulthood to old age, loss of GH secretion has been considered an important contributory cause of sarcopenia in the elderly. To test this hypothesis in a group of healthy postmenopausal women (n = 15; mean +/- SD age, 66.9 +/- 7.8 yr), 24-h GH concentrations and secretory kinetics were correlated with BCM (measured by whole body counting of 40K) and percent body fat (measured by dual energy x-ray absorptiometry or neutron inelastic scattering). Serum leptin levels were determined as a measure of adipocyte mass. Contrary to prediction, GH secretion was lower in women with higher BCM (r = 0.50; P < 0.05), whereas their mean fat mass was higher (r = 0.51, P < 0.05). These data indicate that sarcopenia in postmenopausal women is not associated with reduced GH secretion and is inversely correlated with fat mass. Serum leptin levels were inversely associated with GH secretion (r = -0.67; P < 0.006). Although a causal relationship has not been demonstrated, these data suggest that leptin could modulate GH secretion through its action on the aging hypothalamic-pituitary axis, or that GH regulates leptin secretion.

Effects of progressive resistance training on immune response in aging and chronic inflammation.

The effects of 12 wk of progressive resistance strength training on in vivo and in vitro immune parameters were evaluated in a controlled study of eight subjects with rheumatoid arthritis (RA), eight healthy young (22-30 yr), and eight healthy elderly (65-80 yr) individuals. Six healthy elderly (65-80 yr) nontraining control subjects were also evaluated to account for seasonal and psychosocial effects. Training subjects exercised at 80% of their one-repetition maximum and performed eight repetitions per set, three sets per session on a twice weekly basis. Peripheral blood mononuclear cell (PBMC) subpopulations, cytokine and prostaglandin (PG) E2 production, proliferative response, and delayed type hypersensitivity (DTH) skin response were measured before and after 12 wk of training. Training did not induce changes in PBMC subsets, interleukin (IL)-1 beta, tumor necrosis factor-alpha (TNF), IL-6, IL-2, or PGE2 production, lymphocyte proliferation, or DTH response in any of the training groups, compared with control subjects. These data suggest that 12 wk of high-intensity progressive resistance strength training does not affect immune function in young or elderly healthy individuals or subjects with RA.

Protein metabolism in rheumatoid arthritis and aging. Effects of muscle strength training and tumor necrosis factor alpha.

OBJECTIVE: To determine the effects of rheumatoid arthritis (RA) on whole-body protein metabolism. METHODS: We examined protein metabolism and its hormonal and cytokine mediators before and 12 weeks after progressive resistance muscle strength training in 8 healthy young (mean +/- SD age 25 +/- 2 years) and 8 healthy elderly (70 +/- 5 years) men and women, and in 8 adults with RA (42 +/- 13 years). An additional 6 healthy elderly subjects (69 +/- 3 years) served as a swimming-only control group. RESULTS: Subjects with RA had higher rates of protein breakdown than did young or elderly healthy subjects (79.9 +/- 17.2 versus 60.3 +/- 5.8 and 63.7 +/- 12.4 mumoles/gm total body potassium/hour, respectively, P < 0.05), while there was no effect of age per se. Patients treated with methotrexate had normal rates of protein breakdown (P < 0.01 versus RA without methotrexate; P not significant versus healthy young subjects). Increased protein catabolism in RA was no longer evident after strength training. In multiple regression analysis, levels of tumor necrosis factor alpha (TNF alpha) (r = 0.47, P = 0.01) and growth hormone (r = -0.51, P = 0.006) were associated with protein breakdown, and plasma glucagon levels were inversely correlated with protein synthesis (r = -0.45, P = 0.02). Growth hormone (r = -0.56, P = 0.002) and glucagon (r = 0.45, P = 0.04, levels were associated with protein oxidation. CONCLUSION: Adults with RA have increased whole-body protein breakdown, which correlates with growth hormone, glucagon, and TNF alpha production.

The effect of progressive resistance training in rheumatoid arthritis. Increased strength without changes in energy balance or body composition.

OBJECTIVE: To demonstrate the feasibility of high-intensity progressive resistance training in rheumatoid arthritis (RA) patients compared with healthy control subjects. METHODS: Eight subjects with RA, 8 healthy young subjects, and 8 healthy elderly subjects underwent 12 weeks of high-intensity progressive resistance training, while 6 elderly subjects performed warm-up exercises only. Fitness, body composition, energy expenditure, function, disease activity, pain, and fatigue were measured at baseline and followup. RESULTS: All 3 training groups demonstrated similar improvements in strength compared with the change among control subjects (RA group 57% [P < 0.0005], young exercise group 44% [P < 0.01], elderly exercise group 36% [P < 0.05]). Subjects with RA had no change in the number of painful or swollen joints but had significant reductions in self-reported pain score (21% [P < 0.05]) and fatigue score (38% [P = 0.06]), improved 50-foot walking times (mean +/- SD 10.4 +/- 2.2 seconds versus 8.3 +/- 1.5 seconds [P < 0.005]), and improved balance and gait scores (48.9 +/- 3.8 versus 50.4+/- 2.0 [P = 0.07]). CONCLUSION: High-intensity strength training is feasible and safe in selected patients with well-controlled RA and leads to significant improvements in strength, pain, and fatigue without exacerbating disease activity or joint pain.

Assessment of the safety of high-dose, short-term supplementation with vitamin E in healthy older adults.

The effect of daily supplementation of 800 mg dl alpha-tocopheryl acetate for 30 d on general health, nutrient status, hepatic and renal function, intermediary metabolism, hematological status, plasma nutrients and antioxidant status, thyroid hormones, and urinary creatinine concentrations was studied in 32 healthy elderly (> 60 y) people who participated in a double-blind, placebo-controlled, residential trial. The subjects reported no side effects due to the supplements. Supplementation had no effect on body weight, plasma total protein, albumin, glucose, total cholesterol and triglycerides, conjugated and unconjugated bilirubin, alkaline phosphatase, indicators of hepatic and renal function, hematologic status, thyroid hormones, or serum and urinary creatinine concentrations and creatinine clearance. Supplementation did cause a significant increase in serum vitamin E, and a small (5%) but significant (P < 0.05) increase in plasma zinc in the vitamin E-supplemented group. Thus, short-term supplementation with 800 mg vitamin E/d has no adverse effect on healthy older adults.

Vitamin B6 and immune competence.

Animal and human studies suggest that vitamin B6 deficiency affects both humoral and cell-mediated immune responses. Lymphocyte differentiation and maturation are altered by deficiency, delayed-type hypersensitivity responses are reduced, and antibody production may be indirectly impaired. Although repletion of the vitamin restores these functions, megadoses do not produce benefits beyond those observed with moderate supplementation. Additional human studies indicate that vitamin B6 status may influence tumor growth and disease processes. Deficiency of the vitamin has been associated with immunological changes observed in the elderly, persons infected with human immunodeficiency virus (HIV), and those with uremia or rheumatoid arthritis. Future research efforts should focus on establishing the mechanism underlying the effects of vitamin B6 on immunity and should attempt to establish safe intake levels that optimize immune response.

Humoral mediation of changing body composition during aging and chronic inflammation.

A decline in lean body mass and an accompanying increase in fat mass are known to occur during aging. The consequences of these changes in body composition may include decreased strength and physical activity, altered energy metabolism, and impaired resistance to infection. The mechanisms behind these age-related events remain unknown, but they may include changes in some of the hormonal and cytokine mediators that seem to regulate body composition. The common inflammatory condition rheumatoid arthritis could provide a useful model of these phenomena dissociated from chronological aging. This article reviews changes in neuroendocrine and immune modulators of metabolism and their consequences during aging and chronic inflammation.