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

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

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

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

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

Loss of oxidative defense and potential blockade of satellite cell maturation in the skeletal muscle of patients with cancer but not in the healthy elderly

Purpose: Muscle wasting in old age or cancer may result from failure of myofibre regeneration and /or accelerated apoptosis both of which may be up-regulated by oxidative stress or inflammation. The aim of this study was to determine from the transcriptome in human skeletal muscle whether there is evidence for oxidative stress and its relationship with satellite cell differentiation or apoptosis in the muscle of patients with cancer (weight-stable: CWS or weight-losing: CWL) or healthy elderly (HE) when compared with healthy middle aged controls (HMAC) . Design: 28 patients with resectable upper GI/pancreatic cancer (CWS: 14 and CWL14), 17 HE and 22 HMAC underwent biopsy of the quadriceps muscle. Markers of muscle regeneration, inflammation, oxidative stress and apoptosis were measured by qPCR. Results: The expression of transcription factors responsible for muscle regeneration (Pax3, Pax7 and MyoD) were increased in the skeletal muscle of CWS and HE when compared with HMAC (P<0.001). In contrast, the expression of myogenic differentiation markers (MyoG and Myh2) was reduced in CWS and CWL but increased in HE when compared with HMAC (P<0.0001). The expression of the pro-apoptotic gene Bax was significantly increased in CWS, CWL and HE compared with HMAC (P<0.0001). Pro-inflammatory cytokine expression was variable with increased expression of TNF in CWS and HE, increased Il-6 in CWS and increased Il-1 in CWL when compared with HMAC. Expression of the oxidative defense genes SOD2, GCLM, and NRF2 was decreased in CWS and CWL but increased in HE when compared with HMA (P<0.0001). Conclusion: There is evidence for blockade of satellite cell maturation, upregulation of apoptosis and reduced oxidative defense in the skeletal muscle of cancer patients. In contrast, in muscle from healthy elderly the potential for myotube differentiation and oxidative defense is maintained

Biomarkers of Sarcopenia in Clinical Trials—Recommendations from the International Working Group on Sarcopenia

Sarcopenia, the age-related skeletal muscle decline, is associated with relevant clinical and socioeconomic negative outcomes in older persons. The study of this phenomenon and the development of preventive/therapeutic strategies represent public health priorities. The present document reports the results of a recent meeting of the International Working Group on Sarcopenia (a task force consisting of geriatricians and scientists from academia and industry) held on June 7–8, 2011 in Toulouse (France). The meeting was specifically focused at gaining knowledge on the currently available biomarkers (functional, biological, or imaging-related) that could be utilized in clinical trials of sarcopenia and considered the most reliable and promising to evaluate age-related modifications of skeletal muscle. Specific recommendations about the assessment of aging skeletal muscle in older people and the optimal methodological design of studies on sarcopenia were also discussed and finalized. Although the study of skeletal muscle decline is still in a very preliminary phase, the potential great benefits derived from a better understanding and treatment of this condition should encourage research on sarcopenia. However, the reasonable uncertainties (derived from exploring a novel field and the exponential acceleration of scientific progress) require the adoption of a cautious and comprehensive approach to the subject

Tai Chi for treating knee osteoarthritis: Designing a long-term follow up randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Knee Osteoarthritis (KOA) is a major cause of pain and functional impairment among elders. Currently, there are neither feasible preventive intervention strategies nor effective medical remedies for the management of KOA. Tai Chi, an ancient Chinese mind-body exercise that is reported to enhance muscle function, balance and flexibility, and to reduce pain, depression and anxiety, may safely and effectively be used to treat KOA. However, current evidence is inconclusive. Our study examines the effects of a 12-week Tai Chi program compared with an attention control (wellness education and stretching) on pain, functional capacity, psychosocial variables, joint proprioception and health status in elderly people with KOA. The study will be completed by July 2009.</p> <p>Methods/Design</p> <p>Forty eligible patients, age > 55 yr, BMI ≤ 40 kg/m²with tibiofemoral osteoarthritis (American College of Rheumatology criteria) are identified and randomly allocated to either Tai Chi (10 modified forms from classical Yang style Tai Chi) or attention control (wellness education and stretching). The 60-minute intervention sessions take place twice weekly for 12 weeks. The study is conducted at an urban tertiary medical center in Boston, Massachusetts. The primary outcome measure is the Western Ontario and McMaster Universities (WOMAC) pain subscale at 12 weeks. Secondary outcomes include weekly WOMAC pain, function and stiffness scores, patient and physician global assessments, lower-extremity function, knee proprioception, depression, self-efficacy, social support, health-related quality of life, adherence and occurrence of adverse events after 12, 24 and 48 weeks.</p> <p>Discussion</p> <p>In this article, we present the challenges of designing a randomized controlled trial with long-term follow up. The challenges encountered in this design are: strategies for recruitment, avoidance of selection bias, the actual practice of Tai Chi, and the maximization of adherence/follow-up while conducting the clinical trial for the evaluation of the effectiveness of Tai Chi on KOA.</p> <p>Trial registration</p> <p>ClinicalTrials.gov identifier: NCT00362453</p

Causal Modeling Using Network Ensemble Simulations of Genetic and Gene Expression Data Predicts Genes Involved in Rheumatoid Arthritis

Tumor necrosis factor α (TNF-α) is a key regulator of inflammation and rheumatoid arthritis (RA). TNF-α blocker therapies can be very effective for a substantial number of patients, but fail to work in one third of patients who show no or minimal response. It is therefore necessary to discover new molecular intervention points involved in TNF-α blocker treatment of rheumatoid arthritis patients. We describe a data analysis strategy for predicting gene expression measures that are critical for rheumatoid arthritis using a combination of comprehensive genotyping, whole blood gene expression profiles and the component clinical measures of the arthritis Disease Activity Score 28 (DAS28) score. Two separate network ensembles, each comprised of 1024 networks, were built from molecular measures from subjects before and 14 weeks after treatment with TNF-α blocker. The network ensemble built from pre-treated data captures TNF-α dependent mechanistic information, while the ensemble built from data collected under TNF-α blocker treatment captures TNF-α independent mechanisms. In silico simulations of targeted, personalized perturbations of gene expression measures from both network ensembles identify transcripts in three broad categories. Firstly, 22 transcripts are identified to have new roles in modulating the DAS28 score; secondly, there are 6 transcripts that could be alternative targets to TNF-α blocker therapies, including CD86 - a component of the signaling axis targeted by Abatacept (CTLA4-Ig), and finally, 59 transcripts that are predicted to modulate the count of tender or swollen joints but not sufficiently enough to have a significant impact on DAS28