Associated loss of fat-free mass and bone mineral density in chronic obstructive pulmonary disease

We hypothesized that in patients with chronic obstructive pulmonary disease, loss of fat-free mass (FFM) and loss of bone mineral density (BMD) were related to (1) each other and may be clinically inapparent, (2) urinary markers of cellular and bone collagen protein breakdown, and (3) severity of lung disease. Eight-one patients and 38 healthy subjects underwent dual-energy X-ray absorptiometry to determine body composition and BMD. Urinary protein breakdown markers, inflammatory mediators, and their soluble receptors were determined. Thirty-three patients had a low fat-free mass index (kg/m(2)), 17 of whom had a normal body mass index. Thirty-two percent of patients (13% of healthy subjects) had osteoporosis at the hip or lumbar spine. The marker of cellular protein breakdown was elevated in patients and related to lung disease severity and body composition. The marker of bone collagen breakdown was greater in patients with osteoporosis. Inflammatory mediators were elevated in patients. Loss of FFM and loss of BMD were related, occurred commonly, and could be subclinical in patients with chronic obstructive pulmonary disease. Loss of both was greatest with severe lung disease. Increased excretion of cellular and bone collagen protein breakdown products in those with low FFM and BMD indicates a protein catabolic state in these patients.     

Hidden depletion of fat-free mass and bone mineral density in adults with cystic fibrosis

BACKGROUND: Weight loss is associated with reduced survival in patients with cystic fibrosis (CF). OBJECTIVE: We hypothesized that some adult patients with a normal body mass index (BMI) have evidence of hidden fat-free mass (FFM) and bone mineral density (BMD) depletion that is linked to more severe disease. DESIGN: Fat mass (FM), FFM, and BMD were determined by dual-energy x-ray absorptiometry (DXA) and by bioelectric impedance in 56 adults in clinically stable condition and 20 age-matched healthy subjects. FM index and FFM index (FFMI) [kilograms per meter squared] of the right arm, leg, and trunk (ratio to height squared) were calculated. Lung function, including the maximum inspiratory pressure (MIP) and sustained MIP (SMIP), physical activity, serum C-reactive protein (CRP) and the number of exacerbations in the previous year were recorded. RESULTS: Patients had a lower total FFM than healthy subjects (p < 0.01), while FM was similar. Of the 56 patients, 30 patients had a normal BMI, of which 12 patients had a low FFM (hidden loss) by DXA. The right arm, leg, and trunk FFMI and BMD at hip sites were less in these patients than in those with a normal BMI and normal FFM (all p < 0.01). This group had a lower FEV(1), SMIP, more frequent exacerbations, and greater circulating CRP (all p < 0.05). CONCLUSIONS: In adults with CF, apparent or hidden loss of FFM, rather than weight loss, was related to overall disease severity. Hidden depletion of FFM was associated with increased loss of BMD and systemic inflammatory activity.     

Adverse alterations in bone metabolism are associated with lung infection in adults with cystic fibrosis

Low bone density, fractures, and kyphosis complicate the lives of adults with cystic fibrosis (CF), and inflammatory cytokines (interleukin [IL]-1beta, IL-6, and tumor necrosis factor [TNF]-alpha) that may alter bone metabolism have been previously found to be increased in the lungs and serum of CF patients. The objective of this prospective study was to determine the impact of lung infection on bone physiology in 17 adult CF patients. Serum osteocalcin, a marker of bone formation; urine N-telopeptides of type I collagen and free deoxypyridinoline, both of which are markers of bone breakdown; serum cytokines (TNF-alpha, IL-1beta, and IL-6); and general inflammatory markers (serum C-reactive protein [CRP] and chondrex) were measured at the beginning and end of treatment for an acute exacerbation of lung infection and again 3 wk later. After treatment with conventional antibiotics, decreases in N-telopeptides (147.3 +/- 77.5 [mean +/- SEM] versus 95.5 +/- 57.3 bone collagen equivalents (BCE)/mmol creatinine, p = 0.0014), deoxypyridinoline (8.42 +/- 2.8 versus 6.8 +/- 3.0 mmol/mmol creatinine, p = 0.08), IL-1beta (1.43 +/- 1.13 versus 0.65 +/- 0.63 pg/ml, p = 0.03), IL-6 (9.5 +/- 6.5 versus 4.7 +/- 3.2 pg/ml, p = 0. 012), CRP (43.1 +/- 29.3 versus 23.4 +/- 25.3 mg/ml, p = 0.04), and chondrex (151.7 +/- 111.7 versus 101.4 +/- 67.3 ng/ml, p = 0.014), and increases in osteocalcin levels (14.5 +/- 5.4 versus 22.5 +/- 8. 7 ng/ml, p = 0.010) were observed. Three weeks later, the changes in N-telopeptides and osteocalcin persisted. These data indicate that pulmonary infection, through the elaboration of inflammatory cytokines, may be linked to increased bone resorption and diminished bone formation. These results provide insights into the impact of systemic inflammation on bone health, and suggest novel mechanisms for bone disease in CF.     

Measuring body composition in chronic heart failure: a comparison of methods

AIMS: Fat-free mass (FFM) is increasingly recognized as a systemic marker of disease severity in chronic organ failure and is an important target for physiologic and pharmacologic interventions to improve functional status. The aim of this study was therefore to evaluate two clinical methods to assess FFM in patients with chronic heart failure (CHF) using deuterium dilution (DEU) as reference and bromide dilution to assess the ratio between intracellular (ICW) and extracellular water (ECW) as potential confounder. METHODS: Body composition was measured with dual-energy X-ray absorptiometry (DXA), bioelectrical impedance analysis (BIA) and DEU in 22 stable patients from our heart failure outpatient clinic and 24 healthy age matched controls. RESULTS: FFM values measured by DXA and DEU in patients (r = 0.92, SEE: 3.1 kg) and controls (r = 0.99, SEE: 1.3 kg) were strongly related. In both patients and controls, the inter method difference increased with higher values of FFM (DXA overestimating DEU). The ICW/ECW ratio was within the normal range and comparable between the groups. In patients, a highly significant correlation coefficient was found (r = 0.93, SEE 2.1 p = 0.01) between total body water (DEU) and height squared/resistance (Ht2/R). On multiple regression next to Ht2/R, body weight was an independent predictor of FFM(DEU) (r = 0.95, SEE 2.5 kg, p<0.001; TBWdeu = 0.528 Ht2/R + (0.182 weight) + 8.277). CONCLUSION: DXA and DEU are appropriate and interchangeable laboratory methods for assessment of FFM in clinically stable heart failure patients, however, overestimation of FFM(DXA) should be considered. BIA is a suitable clinical alternative for diagnostic purposes.     

Two year randomized controlled trial of etidronate in rheumatoid arthritis: changes in serum aminoterminal telopeptides correlate with radiographic progression of disease

OBJECTIVE: To investigate the effect of intermittent cyclical etidronate treatment on radiographic progression, bone collagen markers, and clinical disease activity in patients with rheumatoid arthritis (RA). METHODS: Forty patients with RA of less than 5 years' duration were randomized to receive intermittent cyclical etidronate therapy in conjunction with antirheumatic therapy or antirheumatic therapy alone (without etidronate) in a 2 year open-label protocol. Radiographs of hands and feet and serum samples for determination of aminoterminal propeptide (PINP), crosslinked C-telopeptide (ICTP), and aminoterminal telopeptides (NTx) of type I collagen were obtained at baseline and at 24 months. RESULTS: There was significant and similar worsening of the radiologic scores in both treatment groups. Both PINP, a marker of bone formation, and ICTP, an indicator of collagen degradation, declined in the etidronate group compared to the control group (p = 0.001 and p = 0.042, respectively). The groups did not differ for the change in serum NTx, a specific systemic marker of osteoclastic bone resorption. However, the change in serum NTx correlated significantly with the increase in erosion score in the total study population and in the control group (r = 0.41, p = 0.01 and r = 0.48, p = 0.034, respectively). CONCLUSION: Etidronate therapy did not prevent radiologic progression in patients with RA, but the decline in serum PINP and ICTP concentrations suggests a favorable effect on general bone metabolism. Correlation between the change in serum NTx and worsening of the erosion score provides biochemical evidence that osteoclast is the principal cell type responsible for focal bone resorption in RA.     

Increased urinary N-telopeptide cross-linked type 1 collagen predicts bone loss in patients with inflammatory bowel disease

OBJECTIVE: Reduced bone mineral density (BMD) is common in patients with inflammatory bowel disease (IBD), but the factors associated with its longitudinal rate of change have not been established. We prospectively assessed the rate of change in BMD, and its association with biochemical markers of bone turnover. METHODS: Twenty-two patients with Crohn's disease and 14 ulcerative colitis patients age 37.1 +/- 11.6 yr were followed for 2 yr. Lumbar spine (L2-L4) and femoral neck BMD were measured by dual x-ray absorptiometry at baseline and 24 months. Bone-specific alkaline phosphatase, osteocalcin, urinary N-telopeptide crosslinked type 1 collagen (NTx), parathyroid hormone, and 25-hydroxyvitamin-D were determined at baseline. RESULTS: At baseline, 59% of Crohn's patients and 43% of ulcerative colitis patients were osteoporotic, with spine or femoral neck BMD T-score < -2.5. Spine BMD, and spine and femoral neck T-scores were lower and disease duration was longer in nine patients with ileal resection compared with nonoperated patients (0.84 +/- 0.15 g/cm2 vs 0.96 +/- 0.11 g/cm2, -3.0 +/- 1.5 vs -1.7 +/- 1.3, -3.2 +/- 1.5 vs -2.2 +/- 1.0, respectively; all p < 0.05). At 24 months, 13/36 (36%) and 14/36 (39%) patients experienced spinal and femoral neck bone loss, respectively, with mean annual percent BMD changes of -2.0% and -1.5%, respectively. NTx, a bone resorption marker, inversely correlated with spinal BMD rate of change (r = -0.4, p < 0.05). Using quartiles analysis, patients with the highest NTx (Q4) experienced the greatest decrease in spine BMD compared with patients with the lowest NTx (Q1). CONCLUSIONS: Spine and femoral neck bone loss continues over time in more than one-third of IBD patients. Increased NTx level predicts spinal bone loss in IBD patients.     

Increased levels of serum pentraxin 3, a novel cardiovascular biomarker,in patients with inflammatory rheumatic disease

Objective

Pentraxin 3 (PTX3), a key component of innate immunity, is a strong marker of disease severity in coronary artery disease (CAD). The aim of this study was to compare levels of serum PTX3 in CAD patients with and without inflammatory rheumatic disease (IRD) and in healthy controls.

Methods

We examined 69 patients with IRD (CAD/IRD group) and 53 patients without IRD (CAD/non‐IRD) referred to coronary artery bypass grafting, and 30 healthy controls.

Results

The mean ± SD serum PTX3 level in the CAD/IRD group was 1.96 ± 0.98 ng/ml; this was statistically significantly higher than that of the CAD/non‐IRD (1.41 ± 0.74 ng/ml) and healthy control (1.21 ± 0.59 ng/ml) groups. In contrast to most other IRDs, serum PTX3 levels were relatively low in patients with systemic lupus erythematosus (SLE) and other systemic connective tissue diseases. In sex‐ and age‐adjusted analysis, IRD, acute coronary syndromes, and low alcohol intake were associated with higher serum PTX3 levels.

Conclusion

CAD patients with IRD had higher mean serum PTX3 levels than patients without IRD and healthy controls. In addition, acute coronary syndromes and low alcohol intake independently predicted higher serum PTX3 levels. Higher serum PTX3 levels in IRD may be related to the higher cardiovascular risk of IRD patients. Circulating PTX3 could likely be used as a biomarker for severity of cardiovascular disease in IRDs; its importance, however, might be limited in SLE and related disorders.     

Vitamin K status in patients with Crohn's disease and relationship to bone turnover

BACKGROUND: There is a high prevalence of osteopenia among patients with Crohn's disease (CD). There is some evidence that a deficiency of certain bone-active nutrients (including vitamins K and D) may have a partial role in this bone loss. AIMS: To compare the intake and the status of vitamin K in CD patients, currently in remission, with age- and sex-matched controls, and furthermore to investigate the relationship between vitamin K status and bone turnover in these patients. SUBJECTS: CD patients (n = 44; mean age: 36.9 yr) and matched controls (n = 44) were recruited from the Cork University Hospital and Cork City area, respectively. METHODS: Bloods were analyzed for the total and undercarboxylated (Glu)-osteocalcin and urine analyzed for cross-linked N-telopeptides of type I collagen (NTx). Vitamin K(1) intake was estimated by food frequency questionnaire. RESULTS: Vitamin K(1) intake in CD patients tended to be lower than that of controls (mean (SD), 117 (82) vs 148 (80) mug/d, respectively; p= 0.059). Glu and NTx concentrations in CD patients were higher than controls (mean (SD), 5.1 (3.1) vs 3.9 (2.1) ng/ml, respectively; p= 0.03 for Glu; and 49 (41) vs 25.8 (19.5) nM BCE/mM creatinine, respectively; p= 0.001 for NTx). In CD patients, Glu was significantly correlated with NTx (r= 0.488; p < 0.001), even after controlling for age, gender, vitamin D status, calcium intake, and corticosteroid use. CONCLUSION: Vitamin K status of CD patients was lower than that of the healthy controls. Furthermore, the rate of bone resorption in the CD was inversely correlated with vitamin K status, suggesting that it might be another etiological factor for CD-related osteopenia.     

Arterial stiffness and osteoporosis in chronic obstructive pulmonary disease

RATIONALE: Chronic obstructive pulmonary disease (COPD) is associated with an increased risk of cardiovascular events and osteoporosis. Increased arterial stiffness is an independent predictor of cardiovascular disease. OBJECTIVES: We tested the hypothesis that patients with COPD would have increased arterial stiffness, which would be associated with osteoporosis and systemic inflammation. METHODS: We studied 75 clinically stable patients with a range of severity of airway obstruction and 42 healthy smoker or ex-smoker control subjects, free of cardiovascular disease. All subjects underwent spirometry, measurement of aortic pulse wave velocity (PWV) and augmentation index, dual-energy X-ray absorptiometry, and blood sampling for inflammatory mediators. MEASUREMENTS AND MAIN RESULTS: Mean (SD) aortic PWV was greater in patients, 11.4 (2.7) m/s, than in control subjects, 8.95 (1.7) m/s, p < 0.0001. Inflammatory mediators and augmentation index were also greater in patients. Patients with osteoporosis at the hip had a greater aortic PWV, 13.1 (1.8) m/s, than those without, 11.2 (2.7) m/s, p < 0.05. In patients, aortic PWV was related to age (r = 0.63, p < 0.0001) and log(10) IL-6 (r = 0.31, p < 0.01), and inversely to FEV(1) (r = -0.34, p < 0.01). The strongest predictors of aortic PWV in all subjects were age (p < 0.0001), percent predicted FEV(1) (p < 0.05), mean arterial pressure (p < 0.05), and log(10) IL-6 (p < 0.05). CONCLUSIONS: Increased arterial stiffness was related to the severity of airflow obstruction and may be a factor in the excess risk for cardiovascular disease in COPD. The increased aortic PWV in patients with osteoporosis and the association with systemic inflammation suggest that age-related bone and vascular changes occur prematurely in COPD.     

Raised serum hyaluronate levels in scleroderma: an effect of growth factor induced activation of connective tissue cells?

The circulating levels of hyaluronate were determined in 36 patients with scleroderma and in 36 control subjects matched for age and sex. The mean serum hyaluronate concentration in patients with progressive systemic sclerosis (n = 25) was 131 +/- 67 (SD) microgram/l and significantly greater (p less than 0.001) than that of the controls (mean level 49 +/- 21 (SD) microgram/l). Hyaluronate levels in patients with localised scleroderma (n = 4) were 141 +/- 47 (SEM) microgram/l and in patients with scleroderma-associated overlap syndromes (n = 7) 202 +/- 54 (SEM) microgram/l. The increase in serum hyaluronate probably reflected an enhanced synthesis or outflow of hyaluronate from the connective tissue, or both; it could not be explained by affection of the liver, which is the catabolic site of hyaluronate. The hyaluronate values were not related to certain serological indicators of inflammatory activity or to the extent of the skin lesions or the severity of internal organ manifestations. A positive correlation was noted between circulating platelet counts and hyaluronate levels (p less than 0.001). Plasma beta-thromboglobulin was measured in 15 of the patients with systemic sclerosis and found to correlate positively with platelet counts. Raised levels of beta-thromboglobulin were associated with the highest hyaluronate values. Platelet-derived growth factor, which stimulates connective tissue cells and is stored in the alpha-granules of platelets together with beta-thromboglobulin, was shown to enhance hyaluronate synthesis in fibroblast cultures. The results suggest an involvement in scleroderma of connective tissue activating substances released from platelets.     

Increased carotid intima-media thickness and serum inflammatory markers in obstructive sleep apnea

Increased carotid intima-media thickness (IMT) and increased serum levels of inflammatory markers, such as C-reactive protein (CRP), interleukin (IL)-6, and IL-18, are associated with an increased risk of cardiovascular and cerebrovascular diseases. The aim of this study was to evaluate whether carotid IMT, a useful marker for early atherosclerosis, is associated with these inflammatory markers in patients with obstructive sleep apnea (OSA). Carotid IMT was investigated with ultrasonography in 36 patients with OSA and 16 obese control subjects. Serum levels of CRP, IL-6, and IL-18 were measured at 5:00 A.M. Carotid IMT (p < 0.001) and serum levels of CRP (p < 0.003), IL-6 (p < 0.005), and IL-18 (p < 0.03) of patients with OSA were significantly higher than those of obese control subjects. Carotid IMT was significantly correlated with serum levels of CRP (r = 0.61, p = 0.0001), IL-6 (r = 0.41, p = 0.01), and IL-18 (r = 0.45, p = 0.005), duration of OSA-related hypoxia (r = 0.60, p = 0.0001), and severity of OSA (r = 0.50, p = 0.002). In addition, the primary factor influencing carotid IMT was duration of hypoxia during total sleep time (p = 0.036). These results suggest that OSA-related hypoxia and systemic inflammation might be associated with the progression of atherosclerosis and thus might increase the risks of cardiovascular and cerebrovascular morbidity in patients with OSA.     

Breath condensate pH in children with cystic fibrosis and asthma: a new noninvasive marker of airway inflammation?

STUDY OBJECTIVES: The noninvasive assessment and monitoring of airway inflammation could be important in respiratory disease. The pH of exhaled breath condensate (EBC) is a promising marker. Although pH has been measured in the EBC of adults with inflammatory airway diseases, no study has measured this in children. DESIGN: This study aimed to assess whether there is a change in pH in the EBC of children with cystic fibrosis (CF) and asthma, and to try to determine whether pH could be used as a marker of airway inflammation. Furthermore, the relationships among EBC pH, severity of disease, and oxidative stress were studied. PATIENTS AND METHODS: We studied 20 children with CF (mean [+/- SEM] age, 7 +/- 3 years), 20 children with asthma (mean age, 7 +/- 2 years), and 15 age-matched healthy children (mean age, 7 +/- 2 years). The pH of EBC was measured using a pH meter. MEASUREMENTS AND RESULTS: Lower pH values were observed in the EBC of children with CF and asthma compared to control subjects (mean pH, 7.23 +/- 0.03 and 7.42 +/- 0.01 vs 7.85 +/- 0.02, respectively). Furthermore, relationships among EBC pH, severity of asthma, and the presence of an infective exacerbation of CF was found. There was a negative correlation between exhaled pH and exhaled leukotriene B(4) concentrations (r = -0.5; p < 0.005). CONCLUSION: We conclude that the measurement of EBC pH may be useful in the evaluation of airway inflammation in children with asthma and CF.     

Iron deficiency in cystic fibrosis: relationship to lung disease severity and chronic Pseudomonas aeruginosa infection.

BACKGROUND: Iron deficiency (ID) is common in patients with cystic fibrosis (CF) and may be related to GI factors and chronic inflammation. Pseudomonas aeruginosa (PA) infection is predominantly responsible for chronic lung suppuration in patients with CF, but its survival is critically dependent on the availability of extracellular iron, which it obtains via highly efficient mechanisms. OBJECTIVE: To determine whether ID in CF patients is directly related to the severity of suppurative lung disease. DESIGN: We determined the iron status of 30 randomly selected adult CF patients (13 women) and assessed the relationship to lung disease severity and GI factors by determining their daily sputum volume, FEV(1) percent predicted, C-reactive protein (CRP) level, erythrocyte sedimentation rate, and degree of pancreatic supplementation. Additionally, we measured the sputum concentrations of iron and ferritin in a randomly selected subgroup of 13 of the 30 subjects. SETTING: Adult CF Service in a tertiary-care center. RESULTS: Seventy-four percent of subjects experienced ID (ie, serum iron levels < or = 12 micromol/L and/or transferrin saturation levels < or = 16%). There was no relationship found with the degree of pancreatic supplementation. The daily sputum volume was strongly associated with low serum iron levels, transferrin saturation, ferritin/CRP ratio, and FEV(1) percent predicted (p < 0.05). Serum iron levels and transferrin saturation were negatively related to CRP (r = -0.8 and r = -0.7, respectively; p < 0.01) and erythrocyte sedimentation rate (r = -0.5 and r = -0.4, respectively; p < 0.05). FEV(1) percent predicted was positively related to serum iron level (r = 0.5; p < 0.01), transferrin saturation (r = 0.4; p < 0.05), and ferritin/CRP ratio (r = 0.7; p < 0.05). Sputum iron concentration (median, 63 micromol/L; range, 17 to 134 micromol/L) and ferritin concentration (median, 5,038 microg/L; range, 894 to 6,982 microg/L) exceeded plasma levels and negatively correlated with FEV(1) percent predicted (r = -0.6 and r = -0.5, respectively; p < or = 0.05). CONCLUSION: In our CF patients, ID was directly related to the increased severity of suppurative lung disease but not to the degree of pancreatic insufficiency. Iron loss into the airway may contribute to ID and may facilitate PA infection.     

Cross sectional evaluation of biochemical markers of bone, cartilage, and synovial tissue metabolism in patients with knee osteoarthritis: relations with disease activity and joint damage

OBJECTIVE: To analyse the relations between the urinary levels of type II collagen C-telopeptide (CTX-II) and glucosyl-galactosyl pyridinoline (Glc-Gal-PYD)-two newly developed biochemical markers of type II collagen and synovial tissue destruction respectively-disease activity and the severity of joint destruction in patients with knee osteoarthritis (OA). The clinical performance of these two new markers was compared with that of a panel of other established biochemical markers of connective tissue metabolism. METHODS: The following biochemical markers were measured in a group of 67 patients with knee OA (mean age 64 years, median disease duration eight years ) and in 67 healthy controls: for bone, serum osteocalcin, serum and urinary C-telopeptide of type I collagen (CTX-I); for cartilage, urinary CTX-II, serum cartilage oligomeric matrix protein (COMP), and serum human cartilage glycoprotein 39 (YKL-40); for synovium, urinary Glc-Gal-PYD, serum type III collagen N-propeptide (PIIINP), serum hyaluronic acid (HA); and for inflammation, serum C reactive protein. Biochemical markers were correlated with pain and physical function (WOMAC index) and with quantitative radiographic evaluation of the joint space using the posteroanterior view of the knees flexed at 30 degrees. RESULTS: All bone turnover markers were decreased in patients with knee OA compared with controls (-36%, -38%, and -52%, p<0.0001 for serum osteocalcin, serum CTX-I and urinary CTX-I, respectively). Serum COMP (+16%, p=0.0004), urinary CTX-II (+25%, p=0.0009), urinary Glc-Gal-PYD (+18%, p=0.028), serum PIIINP (+33%, p<0.0001), and serum HA (+ 233%, p<0.0001) were increased. By univariate analyses, increased urinary Glc-Gal-PYD (r=0.41, p=0.002) and decreased serum osteocalcin (r=-0.30, p=0.025) were associated with a higher total WOMAC index. Increased urinary CTX-II (r=-0.40, p=0.0002) and Glc-Gal-PYD (r=-0.30, p=0.0046) and serum PIIINP (r=-0.29, p=0.0034) were the only markers which correlated with joint surface area. By multivariate analyses, urinary Glc-Gal-PYD and CTX-II were the most important predictors of the WOMAC index and joint damage, respectively. CONCLUSION: Knee OA appears to be characterised by a systemic decrease of bone turnover and increased cartilage and synovial tissue turnover. CTX-II, Glc-Gal-PYD, and PIIINP may be useful markers of disease severity in patients with knee OA.     

Antibodies to viral citrullinated peptide in rheumatoid arthritis

OBJECTIVE: To analyze the frequency of anti-viral citrullinated peptide (anti-VCP) antibodies in sera from patients with rheumatoid arthritis (RA) by an Epstein-Barr virus (EBV)-derived peptide in which arginine is replaced with citrulline.METHODS: Anti-VCP antibodies were determined in 627 serum samples, 300 from patients with RA and 327 from controls, including connective tissue diseases, chronic arthritides, and healthy donors. Among patients with RA, a possible correlation with systemic involvement, disease severity, and disease activity was investigated; in 94 RA patients antibodies to cyclic citrullinated protein (anti-CCP) were also measured. RESULTS: Anti-VCP antibodies were found in 45% of RA sera versus less than 5% of controls; anti-VCP levels correlated with anti-CCP levels (p < 0.0001), rheumatoid factor (p = 0.02), and erythrocyte sedimentation rate (p = 0.0058). No correlation was found with extraarticular manifestations of the disease or with disease severity. CONCLUSION: Anti-VCP antibodies are helpful in discriminating RA from other chronic arthritides or connective tissue disorders. The level of positivity is positively correlated with the anti-CCP level, suggesting that VCP can be considered a novel substrate to detect anti-citrullinated peptide/protein antibodies (ACPA). The reactivity of RA-specific antibodies with a viral citrullinated antigen raises questions on the role of EBV in the induction of ACPA.     

N-terminal pro-brain natriuretic peptide in systemic lupus erythematosus: relationship with inflammation, augmentation index, and coronary calcification

OBJECTIVE: Cardiovascular mortality is increased in systemic lupus erythematosus (SLE). Increased plasma concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) are associated with cardiovascular morbidity and mortality in the general population. We examined the hypothesis that NT-proBNP concentrations are higher in patients with SLE, and are related to inflammation, augmentation index, coronary atherosclerosis, and cardiovascular risk factors. MEHODS: Serum concentrations of NT-proBNP were measured in 113 patients with SLE and in 80 control subjects. Coronary calcification and augmentation index were measured by electron beam computed tomography and noninvasive pulse wave analysis, respectively. RESULTS: Patients with SLE had higher concentrations of NT-proBNP [median 38.6 (interquartile range 2.5-126.9) pg/ml] than controls [11.7 (1.6-47.9) pg/ml] (p = 0.002). Augmentation index was higher in patients with SLE [25.0% (20.5%-31.5%)] than controls [20.5% (12.0%-29.0%)] (p = 0.04). In patients with SLE, NT-proBNP concentrations were associated with disease damage (rho = 0.31, p < 0.001) and duration (rho = 0.21, p = 0.02) but not with disease activity, C-reactive protein, erythrocyte sedimentation rate, tumor necrosis factor-alpha, interleukin 6, coronary calcium score, or augmentation index (all p > or = 0.18). CONCLUSION: Patients with SLE have increased concentrations of NT-proBNP, but this is not explained by atherosclerotic burden, augmentation index, or inflammatory state.     

Regulation of protein metabolism in middle-aged, premenopausal women: roles of adiposity and estradiol

The age-related loss of fat-free mass (FFM) is accelerated in women during the middle-age years and continues at an increased rate throughout the postmenopausal period. Because protein is the primary structural component of fat-free tissue, changes in FFM are largely due to alterations in protein metabolism. Knowledge of the hormonal and physiological correlates of protein metabolism in middle-aged women, therefore, has important implications for understanding the mechanisms underlying changes in FFM. We measured leucine kinetics (expressed relative to FFM: micromol/kg FFM/h) in 46 middle-aged, premenopausal women (mean +/- SD, 47 +/- 3 yr) after an overnight fast (i.e. basal) and during euglycemic hyperinsulinemia (40 mU/m2/min) using a 5.5-h infusion of [1-13C]leucine. Additionally, we measured insulin-stimulated glucose disposal by euglycemic hyperinsulinemic clamp, body composition by dual energy x-ray absorptiometry, abdominal fat distribution by computed tomography, and hormone levels by RIA as possible correlates of protein metabolism. Under basal conditions, stepwise regression analysis showed that leucine appearance (i.e. protein breakdown) was related to percent body fat and serum estradiol (r2 = 40%; P < 0.01), and leucine oxidation was related to serum estradiol and percent body fat (r2 = 26%; P < 0.05). Under euglycemic hyperinsulinemic conditions, no variables correlated with the percent change in leucine appearance. The percent change in leucine oxidation was related to intraabdominal adipose tissue area and glucose disposal rate (r2 = 48%; P < 0.01). Correlates and r2 values for nonoxidative leucine disposal (i.e. protein synthesis) under basal and euglycemic hyperinsulinemic conditions were similar to those observed for leucine appearance. From these results, we conclude that adiposity and/or serum estradiol may contribute to the regulation of protein metabolism and FFM in middle-aged, premenopausal women.     

The effects of atorvastatin (10 mg) on systemic inflammation in heart failure

In observational studies, statins are associated with lower mortality in patients with heart failure (HF), including those with nonischemic HF. Such benefits could be related to anti-inflammatory effects; however, the effects of statins on systemic inflammation in HF are not well-established. We conducted a 16-week, single-center, randomized, double-blind, placebo-controlled, crossover clinical trial of the effects of atorvastatin 10 mg/day on concentrations of systemic inflammatory markers in 22 patients with HF (including 20 with nonischemic HF) with New York Heart Association class II or III symptoms and left ventricular ejection fraction of <40%. The absolute and percentage of changes in inflammatory marker levels were evaluated using analysis of variance. Statin treatment reduced the concentrations of soluble tumor necrosis factor receptor-1 by 132 pg/ml (p = 0.04) and 8% (p = 0.056), C-reactive protein by 1.6 mg/L (p = 0.006) and 37% (p = 0.0002), and, after adjustment for treatment order, endothelin-1 by 0.21 pg/ml (p = 0.007) and 17% (p = 0.01). In post hoc analyses, the reduction in tumor necrosis factor receptor-1 levels was highest among patients with elevated levels at baseline (at or higher than the median of 1,055 pg/ml, p interaction = 0.001), among whom statin therapy reduced the levels by 306 pg/ml (p <0.001) and 22% (p <0.001). Statin treatment did not significantly affect the levels of other inflammatory markers, including interleukin-6 and brain natriuretic peptide. In conclusion, short-term atorvastatin therapy reduced the levels of several important inflammatory markers in patients with HF.     

Peripheral muscle weakness and exercise capacity in children with cystic fibrosis

Exercise intolerance in cystic fibrosis (CF) is attributed to diminished nutritional and pulmonary function. We studied the pathophysiology of such intolerance in relation to muscle force and fat-free mass (FFM), in 15 children with moderately severe symptoms of CF (FEV1 < 80% predicted and/or weight for age < -1 SD of reference median), 13 children with mild symptoms of CF (FEV1 and weight above these thresholds), and 13 healthy controls. Cycle maximal workload (Wmax) and V O2max were assessed. Maximal peripheral muscle force was measured, and FFM was calculated from skinfolds. Patients with mild CF, as compared with matched controls, had lower values of Wmax per kilogram of FFM (3.9 +/- 0.5 versus 4.6 +/- 0.3 W/kg [mean +/- SD], respectively; difference = 0.7 [95% CI = 0.4 to 1.1]), and diminished maximal muscle force (2.7 +/- 0.4 kN versus 3.1 +/- 0.7 kN; difference = 0.44 [95% CI = 0.03 to 0.87]), but similar V O2max. Patients with moderate CF had lower FFM, muscle force, and exercise tolerance than did the other groups. Oxygen cost of work was elevated in both groups of CF patients. Muscle force showed a strong positive correlation with Wmax in patients and controls, with disproportionately lower regression slopes in the CF patients. In children with CF, muscle force is decreased and associated with diminished maximal work load, even in the absence of diminished pulmonary or nutritional status.     

Intravenous clodronate in the treatment of reflex sympathetic dystrophy syndrome. A randomized, double blind, placebo controlled study

OBJECTIVE: To evaluate the efficacy of intravenous (i.v.) clodronate in patients with reflex sympathetic dystrophy syndrome (RSDS) and to assess the urinary excretion of type I collagen crosslinked N-telopeptide (NTx) before and after the treatment. METHODS: Thirty-two patients with RSDS were randomized to receive either i.v. clodronate 300 mg daily for 10 consecutive days or placebo. Forty days later, the placebo treated patients received the clodronate treatment. Outcome measures included as a primary endpoint the visual analog scale of pain (VAS, range 0-100); secondary endpoints were a clinical global assessment (CGA, range 0-3) and an efficacy verbal score (EVS, range 0-3). Clinical and biochemical assessments were performed before the treatment, 40 (T40), 90 (T90), and 180 (T180) days later. RESULTS: At T40 the 15 patients randomized to clodronate treatment showed significant decreases of VAS and CGA (p = 0.002, p = 0.001, respectively). Compared with the placebo group (17 patients), significant differences were found in all clinical variables (VAS: p = 0.001; CGA: p = 0.001; EVS: p<0.0001). A further clinical improvement was observed throughout the study. Pooling the results of all 32 patients after clodronate treatment, at T180 the overall percentage decrease of VAS was 93.2+/-15.6%, with 30 patients significantly improved or asymptomatic. Significant inverse correlations between baseline NTx values and decreases of VAS were found at T90 (p = 0.03) and T180 (p = 0.01). No adverse events related to treatment occurred. CONCLUSION: A 10 day i.v. clodronate course is better than placebo and effective in the treatment of RSDS. NTx seems to be a predictive factor for clodronate efficacy.