Rheumatoid cachexia: a complication of rheumatoid arthritis moves into the 21st century

Rheumatoid cachexia, loss of muscle mass and strength and concomitant increase in fat mass, is very common in patients with rheumatoid arthritis (RA). Despite great advances in the treatment of RA, it appears that rheumatoid cachexia persists even after joint inflammation improves. Rheumatoid cachexia may be an important risk factor for cardiovascular disease and excess mortality in RA. In this issue of Arthritis Research & Therapy, Elkan and colleagues demonstrate a link between rheumatoid cachexia and metabolic syndrome, further reinforcing the need for therapy directed beyond inflammation and at the metabolic consequences of RA

Cachexia as a major underestimated and unmet medical need: facts and numbers

Cachexia is a serious, however underestimated and underrecognised medical consequence of malignant cancer, chronic heart failure (CHF), chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), cystic fibrosis, rheumatoid arthritis, Alzheimer's disease, infectious diseases, and many other chronic illnesses. The prevalence of cachexia is high, ranging from 5% to 15% in CHF or COPD to 60% to 80% in advanced cancer. By population prevalence, the most frequent cachexia subtypes are in order: COPD cachexia, cardiac cachexia (in CHF), cancer cachexia, and CKD cachexia. In industrialized countries (North America, Europe, Japan), the overall prevalence of cachexia (due to any disease) is growing and currently about 1%, i.e., about nine million patients. The relative prevalence of cachexia is somewhat less in Asia, but is a growing problem there as well. In absolute terms, cachexia is, in Asia (due to the larger population), as least as big a problem as in the Western world. Cachexia is also a big medical problem in South America and Africa, but data are scarce. A consensus statement recently proposed to diagnose cachexia in chronic diseases when there is weight loss exceeding 5% within the previous 3–12 months combined with symptoms characteristic for cachexia (e.g., fatigue), loss of skeletal muscle and biochemical abnormalities (e.g., anemia or inflammation). Treatment approaches using anabolics, anti-catabolic therapies, appetite stimulants, and nutritional interventions are under development. A more thorough understanding of the pathophysiology of cachexia development and progression is needed that likely will lead to combination therapies being developed. These efforts are greatly needed as presence of cachexia is always associated with high-mortality and poor-symptom status and dismal quality of life. It is thought that in cancer, more than 30% of patients die due to cachexia and more than 50% of patients with cancer die with cachexia being present. In other chronic illnesses, one can estimate that up to 30% of patients die with some degree of cachexia being present. Mortality rates of patients with cachexia range from 10% to 15% per year (COPD), to 20% to 30% per year (CHF, CKD) to 80% in cancer

Plasma Leptin Levels and Incidence of Heart Failure, Cardiovascular Disease, and Total Mortality in Elderly Individuals

OBJECTIVE: Obesity predisposes individuals to congestive heart failure (CHF) and cardiovascular disease (CVD). Leptin regulates energy homeostasis, is elevated in obesity, and influences ventricular and vascular remodeling. We tested the hypothesis that leptin levels are associated with greater risk of CHF, CVD, and mortality in elderly individuals. RESEARCH DESIGN AND METHODS: We evaluated 818 elderly (mean age 79 years, 62% women) Framingham Study participants attending a routine examination at which plasma leptin was assayed. RESULTS: Leptin levels were higher in women and strongly correlated with BMI (P < 0.0001). On follow-up (mean 8.0 years), 129 (of 775 free of CHF) participants developed CHF, 187 (of 532 free of CVD) experienced a first CVD event, and 391 individuals died. In multivariable Cox regression models adjusting for established risk factors, log-leptin was positively associated with incidence of CHF and CVD (hazard ratio [HR] per SD increment 1.26 [95% CI 1.03–1.55] and 1.28 [1.09–1.50], respectively). Additional adjustment for BMI nullified the association with CHF (0.97 [0.75–1.24]) but only modestly attenuated the relation to CVD incidence (1.23 [1.00–1.51], P = 0.052). We observed a nonlinear, U-shaped relation between log-leptin and mortality (P = 0.005 for quadratic term) with greater risk of death evident at both low and high leptin levels. CONCLUSIONS: In our moderate-sized community-based elderly sample, higher circulating leptin levels were associated with a greater risk of CHF and CVD, but leptin did not provide incremental prognostic information beyond BMI. Additional investigations are warranted to elucidate the U-shaped relation of leptin to mortality.National Institutes of Health's National Heart, Lung, and Blood Institute (N01-HC25195, N01-HV28178, K24-HL04334, R01-DK080739

Systemic inflammation, body composition, and physical performance in old community-dwellers

Background Chronic inflammation, changes in body composition, and declining physical function are hallmarks of the ageing process. The aim of the present study was to provide a preliminary characterisation of the relationship among these age-related phenomena via multivariate modelling. Methods Thirty-five old adults (OAs) and 17 young adults (YAs) were enrolled. The volume of skeletal muscle, subcutaneous adipose tissue (SAT), and intermuscular adipose tissue (IMAT) of the thigh was quantified by three-dimensional magnetic resonance imaging. Muscle strength was measured by knee extension strength testing. In OAs, physical performance was further assessed via the Short Physical Performance Battery (SPPB). Multi-block partial least squares-discriminant analysis (PLS-DA) was employed to explore the relationship among inflammatory profiles and functional and imaging parameters. Double cross-validation procedures were used to validate the predictive ability of the PLS-DA model. Results The optimal complexity of the PLS-DA model was found to be two latent variables. The proportion of correct classification was 92.3% in calibration (94.1% in YAs and 91.4% in OAs), 84.6% in internal validation (95.3% in YAs and 78.5% in OAs), and 82.6% in external validation (94% in YAs and 76.9% in OAs). Relative to YAs, OAs were characterised by smaller muscle volume, greater IMAT volume, lower muscle strength, and higher levels of myeloperoxidase, P-selectin, soluble intercellular adhesion molecule 1, and vascular cell adhesion molecule 1. Compared with OAs with SPPB &gt;8, those scoring 8 were characterised by smaller muscle volume, greater SAT volume, lower muscle strength, and higher levels of interleukin 1 beta, 6, 10, 12, 13, tumour necrosis factor alpha, and granulocyte-macrophage colony-stimulating factor. Conclusions Multi-block PLS-DA identified distinct patterns of relationships among circulating cytokines and functional and imaging parameters in persons of different ages and varying levels of physical performance. The longitudinal implementation of such an innovative strategy could allow for the tracking of health status over time, the early detection of deviations in health trajectories, and the monitoring of response to treatments

The impact of obesity on skeletal muscle architecture in untrained young vs. old women.

It is unknown whether loading of the lower limbs through additional storage of fat mass as evident in obesity would promote muscular adaptations similar to those seen with resistance exercise. It is also unclear whether ageing modulates any such adjustments. This study aimed to examine the relationships between adiposity, ageing and skeletal muscle size and architecture. A total of 100 untrained healthy women were categorised by age into young (Y) (mean ± SD: 26.7 ± 9.4 years) vs. old (O) (65.1 ± 7.2 years) and body mass index (BMI) classification (underweight, normal weight, overweight and obese). Participants were assessed for body fat using dual energy x-ray absorptiometry, and for gastrocnemius medialis (GM) muscle architecture (skeletal muscle fascicle pennation angle and length) and size [GM muscle volume and physiological cross-sectional area (PCSA)] using B-mode ultrasonography. GM fascicle pennation angle (FPA) in the obese Y females was 25% greater than underweight (P = 0.001) and 25% greater than normal weight (P = 0.001) individuals, while O females had 32 and 22% greater FPA than their underweight (P = 0.008) and normal weight (P = 0.003) counterparts. Furthermore, FPA correlated with body mass in both Y and O females (Y r = 0.303; P 0.05). Both GM muscle volume (P = 0.003) and PCSA (P = 0.004) exhibited significant age × BMI interactions. In addition, muscle volume and PCSA correlated with BMI, body mass and fat mass. Interestingly, ageing reduced both the degree of association in these correlations (P < 0.05) and the slope of the regressions (P < 0.05). Our findings partly support our hypotheses in that obesity-associated changes in GM PCSA and volume differed between the young and old. The younger GM muscle adapted to the loading induced by high levels of body mass, adiposity and BMI by increasing its volume and increasing its pennation angle, ultimately enabling it to produce higher maximum torque. Such an adaptation to increased loading did not occur in the older GM muscle. Nonetheless, the older GM muscle FPA increased to a similar extent to that seen in young GM muscle, an effect which partly explains the relatively enhanced absolute maximum torque observed in obese older females

Inflammation causes tissue-specific depletion of vitamin B(6)

Previously we observed strong and consistent associations between vitamin B(6 )status and several indicators of inflammation in patients with rheumatoid arthritis. Clinical indicators, including the disability score, the length of morning stiffness, and the degree of pain, and biochemical markers, including the erythrocyte sedimentation rate and C-reactive protein levels, were found to be inversely correlated with circulating vitamin B(6 )levels. Such strong associations imply that impaired vitamin B(6 )status in these patients results from inflammation. In the present study we examined whether inflammation directly alters vitamin B(6 )tissue contents and its excretion in vivo. A cross-sectional case-controlled human clinical trial was performed in parallel with experiments in an animal model of inflammation. Plasma and erythrocyte and pyridoxal 5'-phosphate concentrations, urinary 4-pyridoxic acid excretion, and the activity coefficient of erythrocyte aspartate aminotransferase were compared between patients and healthy subjects. Adjuvant arthritis was induced in rats for investigating hepatic and muscle contents as well as the urinary excretion of vitamin B(6 )during acute and chronic inflammation. Patients with rheumatoid arthritis had low plasma pyridoxal 5'-phosphate compared with healthy control subjects, but normal erythrocyte pyridoxal 5'-phosphate and urinary 4-pyridoxic acid excretion. Adjuvant arthritis in rats did not affect 4-pyridoxic acid excretion or muscle storage of pyridoxal 5'-phosphate, but it resulted in significantly lower pyridoxal 5'-phosphate levels in circulation and in liver during inflammation. Inflammation induced a tissue-specific depletion of vitamin B(6). The low plasma pyridoxal 5'-phosphate levels seen in inflammation are unlikely to be due to insufficient intake or excessive vitamin B(6 )excretion. Possible causes of decreased levels of vitamin B(6 )are discussed

Influence of exercise on the metabolic profile caused by 28 days of bed rest with energy deficit and amino acid supplementation in healthy men

Objective:&nbsp;Muscle loss and metabolic changes occur with disuse [i.e. bed rest (BR)]. We hypothesized that BR would lead to a metabolically unhealthy profile defined by: increased circulating tumor necrosis factor (TNF)-&alpha;, decreased circulating insulin-like-growth-factor (IGF)-1, decreased HDL-cholesterol, and decreased muscle density (MD; measured by mid-thigh computerized tomography).&nbsp; Methods:&nbsp;We investigated the metabolic profile after 28 days of BR with 8&plusmn;6% energy deficit in male individuals (30-55 years) randomized to resistance exercise with amino acid supplementation (RT, n=24) or amino acid supplementation alone (EAA, n=7). Upper and lower body exercises were performed in the horizontal position. Blood samples were taken at baseline, after 28 days of BR and 14 days of recovery.&nbsp; Results:&nbsp;We found a shift toward a metabolically unfavourable profile after BR [compared to baseline (BLN)] in both groups as shown by decreased HDL-cholesterol levels (EAA: BLN: 39&plusmn;4 vs. BR: 32&plusmn;2 mg/dL, RT: BLN: 39&plusmn;1 vs. BR: 32&plusmn;1 mg/dL; p&lt;0.001) and Low MD (EAA: BLN: 27&plusmn;4 vs. BR: 22&plusmn;3 cm2, RT: BLN: 28&plusmn;2 vs. BR: 23&plusmn;2 cm2; p&lt;0.001). A healthier metabolic profile was maintained with exercise, including NormalMD (EAA: BLN: 124&plusmn;6 vs. BR: 110&plusmn;5 cm2, RT: BLN: 132&plusmn;3 vs. BR: 131&plusmn;4 cm2; p&lt;0.001, time-by-group); although, exercise did not completely alleviate the unfavourable metabolic changes seen with BR. Interestingly, both groups had increased plasma IGF-1 levels (EAA: BLN:168&plusmn;22 vs. BR 213&plusmn;20 ng/mL, RT: BLN:180&plusmn;10 vs. BR: 219&plusmn;13 ng/mL; p&lt;0.001) and neither group showed TNF&alpha; changes (p&gt;0.05).&nbsp; Conclusions:&nbsp;We conclude that RT can be incorporated to potentially offset the metabolic complications of BR

Strength training improves muscle quality and insulin sensitivity in Hispanic older adults with type 2 diabetes

Hispanics are at increased risk of morbidity and mortality due to their high prevalence of diabetes and poor glycemic control. Strength training is the most effective lifestyle intervention to increase muscle mass but limited data is available in older adults with diabetes. We determined the influence of strength training on muscle quality (strength per unit of muscle mass), skeletal muscle fiber hypertrophy, and metabolic control including insulin resistance (Homeostasis Model Assessment –HOMA-IR), C-Reactive Protein (CRP), adiponectin and Free Fatty Acid (FFA) levels in Hispanic older adults. Sixty-two community-dwelling Hispanics (>55 y) with type 2 diabetes were randomized to 16 weeks of strength training plus standard care (ST group) or standard care alone (CON group). Skeletal muscle biopsies and biochemical measures were taken at baseline and 16 weeks. The ST group show improved muscle quality (mean±SE: 28±3) vs CON (-4±2, p<0.001) and increased type I (860±252µm(2)) and type II fiber cross-sectional area (720±285µm(2)) compared to CON (type I: -164±290µm(2), p=0.04; and type II: -130±336µm(2), p=0.04). This was accompanied by reduced insulin resistance [ST: median (interquartile range) -0.7(3.6) vs CON: 0.8(3.8), p=0.05]; FFA (ST: -84±30µmol/L vs CON: 149±48µmol/L, p=0.02); and CRP [ST: -1.3(2.9)mg/L vs CON: 0.4(2.3)mg/L, p=0.05]. Serum adiponectin increased with ST [1.0(1.8)µg/mL] compared to CON [-1.2(2.2)µg/mL, p<0.001]. Strength training improved muscle quality and whole-body insulin sensitivity. Decreased inflammation and increased adiponectin levels were related with improved metabolic control. Further studies are needed to understand the mechanisms associated with these findings. However, these data show that strength training is an exercise modality to consider as an adjunct of standard of care in high risk populations with type 2 diabetes