What predicts obesity in patients with rheumatoid arthritis? An investigation of the interactions between lifestyle and inflammation.

OBJECTIVE: To assess whether physical activity, diet or inflammation is a more important determinant of body mass index (BMI) and body fat (BF) in patients with rheumatoid arthritis (RA). METHODS: A total of 150 RA patients (102 female) were assessed for BMI and BF. Their habitual physical activity was assessed with the international physical activity questionnaire (IPAQ) and their energy intake with a 3-day food diary. Pro-inflammatory cytokines (interleukins, IL-1 and IL-6, and tumor necrosis factor-alpha), erythrocyte sedimentation rate, C-reactive protein, disease activity score-28 and physical function (Health Assessment Questionnaire-HAQ) were also measured. RESULTS: BMI correlated inversely with IPAQ (r=-0.511, P=0.000) and positively with energy intake (r=0.331, P=0.016) and HAQ (r=0.133, P=0.042). BF correlated inversely with IPAQ (r=-0.575, P=0.000) and positively with HAQ (r=0.201, P=0.037). Normal weight patients were more physically active compared with those who were either overweight (P=0.006) or obese (P=0.000). Underweight patients consumed significantly fewer calories compared with other patients (P<0.05 in all cases). Cytokines or HAQ did not differ between weight groups. IPAQ was the sole predictor of obesity, whereas energy intake was the sole predictor of underweight. CONCLUSIONS: Inflammation does not seem to influence BMI and BF in RA. As in the general population, high levels of habitual physical activity associate with low BMI and BF in RA. Energy intake is a major determinant of being underweight in those who consume fewer calories. Further research is needed to investigate the suitability of exercise and diet modalities, and their effects on the body composition of RA patients.

Cardiovascular risk factors and not disease activity, severity or therapy associate with renal dysfunction in patients with rheumatoid arthritis.

OBJECTIVES: The present study aimed to evaluate the prevalence and associations of renal dysfunction in patients with rheumatoid arthritis (RA). It specifically addressed the hypotheses that renal dysfunction in these patients may associate with the presence of insulin resistance, dyslipidaemia, uric acid levels and/or current levels of systemic inflammation. METHODS: Renal function was assessed by estimated glomerular filtration rate (GFR) using the modification of diet in renal disease equation in 400 consecutive RA patients for this cross-sectional, single-centre study. Risk factors for renal dysfunction were recorded/measured in all participants. Correlations between GFR and other variables were analysed by Pearson or Spearman test as appropriate. Linear regression was used to test the independence of the associations between GFR and other variables. RESULTS: In this RA patient cohort, 67.75% of patients had a reduced GFR of less than 90 ml/minute per 1.73 m(2) and 12.75% had a GFR of less than 60 ml/minute per 1.73 m(2). Multivariable analysis revealed significant associations between GFR and age (beta = -0.370, p<0.001), female sex (beta = -0.181, p=0.002), total cholesterol (beta = -0.112, p=0.022), serum uric acid (SUA) (beta = -0.425, p<0.001) and the presence of extra-articular disease, apart from sicca and/or nodules (beta = -0.084, p=0.040). CONCLUSIONS: Renal dysfunction in RA is quite common and associates with classic cardiovascular risk factors such as advanced age and dyslipidaemia, levels of SUA and the presence of extra-articular disease. Renal dysfunction was not related to other RA-related factors including disease activity and duration, disability and past or present use of nephrotoxic medications.

Transforming growth factor-beta1 869T/C, but not interleukin-6 -174G/C, polymorphism associates with hypertension in rheumatoid arthritis.

OBJECTIVES: Part of the deleterious effects of systemic inflammation on the cardiovascular system of patients with RA may be exerted via increased propensity to hypertension. IL-6 and TGF-beta1 are important regulators of the inflammatory response. In some, but not all, studies, IL6 -174G/C (rs1800795) and TGFB1 869T/C (rs1982073) gene polymorphisms have been associated with hypertension in the general population. The present study addressed their potential association with hypertension in RA patients. METHODS: TGFB1 869T/C and IL6 -174G/C were identified in 400 RA patients and 422 local, non-RA controls using real-time PCR and melting curve analysis. Binary logistic and linear regression models were used to identify the independence of the effects of the polymorphisms on hypertension. RESULTS: Genotypic and allelic frequencies of the two polymorphisms were similar in RA and controls. Within the RA group, there was no significant association between IL6 -174G/C and hypertension, but TGF 869T-allele carriers had significantly increased prevalence of hypertension compared with CC homozygotes (70.2 vs 55.2%; P = 0.023). This association remained significant after adjustment for other hypertension risk factors and medication (odds ratio = 1.96; 95% CI 1.02, 3.77; P = 0.044), and was more pronounced in patients with increased systemic inflammation. CONCLUSIONS: This study suggests an association of TGFB1 869T/C, but not of IL6 -174G/C, with hypertension in RA patients. If this finding is confirmed in prospective studies, this polymorphism could be used as a screening tool for RA patients with higher risk of developing hypertension and lead to increased surveillance and earlier treatment.

Associations of obesity with modifiable risk factors for the development of cardiovascular disease in patients with rheumatoid arthritis.

OBJECTIVES: To assess the association of body mass index (BMI) with modifiable cardiovascular disease (CVD) risk factors in patients with rheumatoid arthritis (RA). METHODS: BMI, disease activity, selected CVD risk factors and CVD medication were assessed in 378 (276 women) patients with RA. Patients exceeding accepted thresholds in >or=3 CVD risk factors were classified as having the metabolic syndrome (MetS). RESULTS: BMI independently associated with hypertension (OR = 1.28 (95% CI = 1.22 to 1.34); p = 0.001), high-density lipoprotein (OR = 1.10 (95% CI = 1.06 to 1.15); p = 0.025), insulin resistance (OR = 1.13 (95% CI = 1.08 to 1.18); p = 0.000) and MetS (OR = 1.15 (95% CI = 1.08 to 1.21); p = 0.000). In multivariable analyses, BMI had the strongest associations with CVD risk factors (F(1-354) = 8.663, p = 0.000), and this was followed by lipid-lowering treatment (F(1-354) = 7.651, p = 0.000), age (F(1-354) = 7.541, p = 0.000), antihypertensive treatment (F(1-354) = 4.997, p = 0.000) and gender (F(1-354) = 4.707, p = 0.000). Prevalence of hypertension (p = 0.004), insulin resistance (p = 0.005) and MetS (p = 0.000) was significantly different between patients with RA who were normal, overweight and obese, and BMI differed significantly according to the number of risk factors present (p = 0.000). CONCLUSIONS: Increasing BMI associates with increased CVD risk independently of many confounders. RA-specific BMI cut-off points better identify patients with RA at increased CVD risk. Weight-loss regimens should be developed and applied in order to reduce CVD in patients with RA.

Rheumatoid cachexia and cardiovascular disease.

OBJECTIVE: It has been frequently stated that rheumatoid cachexia (RC) associates with increased cardiovascular risk; however, no studies to date have investigated this. The aim of this study was to investigate the association of RC with multiple novel and classical cardiovascular disease (CVD) risk factors and the presence of established CVD in rheumatoid arthritis (RA). METHODS: A total of 34 RA patients with RC (RA+RC) were identified from a database of 400 RA patients using published RC criteria and compared to the remaining patients (RA-RC) who did not fulfil RC criteria. All patients were assessed for fat and fat-free mass, albumin (indicator of catabolism), disease activity/severity, novel and classical risk CVD factors and established CVD. RESULTS: Fat-free mass (kg) and albumin (g/L) were significantly decreased in RA+RC vs. RA-RC patients: 37.3(33.9-41.6) vs. 45.9(41.2-55.5), p<0.001 and 39.6 + or - 6.7 vs. 42.4 + or - 4.9, p=0.001). Percent body fat was not significantly different. No significant differences were detected in either the classical or novel CVD risk factors, 10-year CVD risk or the prevalence of established CVD. CONCLUSIONS: RC does not appear to be associated with worse CVD profile in RA patients, but this needs to be confirmed in prospective studies.

The inter-operator variability in measuring waist circumference and its potential impact on the diagnosis of the metabolic syndrome.

OBJECTIVE: The International Diabetes Federation (IDF) has proposed ethnicity specific cut-off values for waist circumference, as an essential criterion for the diagnosis of the metabolic syndrome (MetS). However, before introducing waist circumference measurement as part of the clinical examination, or an obligatory criterion for MetS, it is important to ensure that the measurement is reliable and reproducible. STUDY DESIGN: The inter- and intra-operator variability in measuring waist circumference was assessed in a preliminary study of 10 health professionals and the inter-operator variability in clinical practice was assessed in a study of 102 patients. Repeated measures analysis of variance (ANOVA) was used to assess the significance of the inter- and intra-operator variability. RESULTS: Intra-operator variability was not found to be significant in the preliminary study (F = 0.15, p = 0.764). However, the inter-operator variability was significant in both studies (preliminary: F = 4.16, p<0.001, clinical practice study: F = 14.06, p<0.001). In clinical practice, this could lead to disagreement among operators regarding the presence of central obesity in 9% of the patients. After giving written instructions on how to measure waist circumference, the coefficient of variation was not significantly altered (p = 0.202) but the inter-operator variability lost significance (F = 2.34, p = 0.11), suggesting a reduction in systematic error. CONCLUSIONS: Measuring waist circumference is subject to significant inter-operator variability and could potentially lead to misclassifying patients as having the MetS, or not. Better training of health professionals on how to measure waist circumference properly is needed in order to ensure that patients are not misclassified and that international comparisons of the prevalence of the MetS are reliable.

Hypertension in rheumatoid arthritis.

RA associates with an increased burden of cardiovascular disease, which is at least partially attributed to classical risk factors such as hypertension (HT) and dyslipidaemia. HT is highly prevalent, and seems to be under-diagnosed and under-treated among patients with RA. In this review, we discuss the mechanisms that may lead to increased blood pressure in such patients, paying particular attention to commonly used drugs for the treatment of RA. We also suggest screening strategies and management algorithms for HT, specific to the RA population, although it is clear that these need to be formally assessed in prospective randomized controlled trials designed specifically for the purpose, which, unfortunately, are currently lacking.

New resting energy expenditure prediction equations for patients with rheumatoid arthritis.

OBJECTIVES: Resting energy expenditure (REE), one of the main components of total energy expenditure, can be measured via indirect calorimetry and/or predicted from equations. The latter may be misleading in RA, as they do not take into account the metabolic alterations occurring in RA. The objectives of this study are to evaluate the accuracy of widely used REE-predictive equations in RA patients against measured REE and to develop RA-specific equations. METHODS: We assessed REE (via indirect calorimetry and several predictive equations), fat-free mass (FFM; via bioelectrical impedance) and disease activity (CRP) in RA patients and healthy controls. Data from 60 RA patients (experimental group) were used to assess the accuracy of existing REE equations and to develop new equations. The new equations were validated in an independent cross-validation group of 22 RA patients. These two groups were merged and two final equations were developed. RESULTS: All equations significantly under-predicted measured REE (from 15% to 18.2%, all at P < 0.001) in the RA experimental group, but not in the control group. After both equations demonstrated a high validity in the cross-validation group, the new final REE prediction equations developed from the total RA sample (n = 82) were: Model 1: REE (kcal/day) = 126.1 x FFM(0.638) x CRP(0.045) (R(2) = 0.70) and Model 2: REE (kcal/day) = 598.8 x weight(0.47) x age(-0.29) x CRP(0.066) (R(2) = 0.62). CONCLUSION: The new equations provide an accurate prediction of REE in RA patients and could be used for clinical monitoring of resting metabolism of these patients without the requirement for specialized personnel.

Lymphotoxin 252A>G polymorphism is common and associates with myocardial infarction in patients with rheumatoid arthritis.

OBJECTIVE: Cardiovascular disease (CVD) is more prevalent and more likely to lead to death in patients with rheumatoid arthritis (RA). Single nucleotide polymorphisms of the genes for lymphotoxin-A (LT-A) and its regulatory protein galectin-2 (LGALS2) have been implicated as genetic risk factors for acute cardiovascular events in the general population: we hypothesised that their risk alleles/genotypes (a) may be more frequent among patients with RA compared with non-RA controls (thus explaining some of the increased CVD in RA), and (b) may be more frequent among patients with RA with prevalent CVD compared with patients with RA without CVD. METHODS: Genomic DNA samples were collected from 388 patients with RA and 399 local population controls without RA. LT-A gene intron 1 252A>G and LGALS2 intron 1 3279C>T single nucleotide polymorphisms were identified using real-time polymerase chain reaction and melting curve analysis. RESULTS: LT-A 252GG homozygotes were significantly more prevalent among patients with RA compared with controls (19.8% vs 11.8%, p = 0.002; OR(GG/GA,AA) = 1.85, 95% CI 1.25 to 2.75, p = 0.002). Patients with RA possessing LT-A 252 GG were significantly more likely to have had a myocardial infarction compared with those with LT-A 252 AA or GA (13% vs 5.5%, p = 0.02; adjusted OR(GG/GA,AA) = 3.03, 95% CI 1.2 to 7.68, p = 0.002). The frequency of LGALS2 polymorphisms was similar between RA and controls and was not associated with CVD among patients with RA. CONCLUSIONS: The LT-A 252GG genotype occurs more frequently among patients with RA than the general population. In RA, this genotype appears to associate with increased likelihood of suffering an myocardial infarction.

Long-term exposure to medium-dose glucocorticoid therapy associates with hypertension in patients with rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) associates with increased cardiovascular morbidity and mortality that is due to both traditional and novel cardiovascular risk factors. Hypertension (HT), one of the most common risk factors for cardiovascular disease, is highly prevalent in RA. The effects of long-term glucocorticoid (GC) therapy on blood pressure have not been established yet. This study examined whether GC exposure associates with HT in patients with RA. METHODS: Four hundred consecutive RA patients with detailed clinical and laboratory assessments were categorized into three groups according to GC exposure: no or limited exposure (N/L-E); a low-dose (< 7.5 mg) long-term exposure (LD/LT-E); and medium-dose (> or = 7.5 mg) long-term exposure (MD/LT-E). The association of GC exposure with HT was evaluated using logistic regression analysis. RESULTS: HT was more prevalent in the MD/LT-E group (84.7%) than the LD/LT-E or N/L-E groups (70.7 and 67.3%, respectively, P = 0.028). Logistic regression revealed increased odds for HT when comparing MD/LT-E with N/L-E, after adjustment for HT risk factors [odds ratio (OR) = 2.57, 95% CI 1.01-6.56, P = 0.049] and RA disease characteristics (OR = 3.64, 95% CI: 1.36-9.77, P = 0.01). CONCLUSIONS: MD/LT GC exposure associates with a very high prevalence of HT. This appears to be independent of other risk factors for HT or of channelling bias due to disease severity, even though the latter cannot be excluded given the cross-sectional nature of our study. RA patients in this GC exposure group should be particularly targeted for early identification and aggressive management of HT.

Rheumatoid arthritis, cardiovascular disease and physical exercise: a systematic review.

This systematic review investigates the effectiveness of exercise interventions in improving disease-related characteristics in patients with rheumatoid arthritis (RA). It also provides suggestions for exercise programmes suitable for improving the cardiovascular profile of RA patients and proposes areas for future research in the field. Six databases (Medline, Cochrane Library, CINAHL, Google Scholar, EMBASE and PEDro) were searched to identify publications from 1974 to December 2006 regarding RA and exercise interventions. The quality of the studies included was determined by using the Jadad scale. Initial searches identified 1342 articles from which 40 met the inclusion criteria. No studies were found investigating exercise interventions in relation to cardiovascular disease in RA. There is strong evidence suggesting that exercise from low to high intensity of various modes is effective in improving disease-related characteristics and functional ability in RA patients. Future studies are required to investigate the effects of exercise in improving the cardiovascular status of this patient population.

Serum uric acid is independently associated with hypertension in patients with rheumatoid arthritis.

Hypertension (HT) is highly prevalent in rheumatoid arthritis (RA). Serum uric acid (SUA) has been associated with HT in the general population. The mutual exclusion of gout and RA, and the systemic inflammatory component of RA may alter this association in this patient population. We explored a potential association between SUA levels and HT in RA and evaluated whether this association is independent of HT risk factors, RA characteristics and relevant drugs. A total of 400 consecutive RA patients were assessed. SUA and complete biochemical profile were measured. Demographic, HT-related factors, RA characteristics and drugs were assessed as potential covariates. Results were analysed using binary logistic models to test the independence of the association between SUA and HT. SUA levels were higher in hypertensive compared to normotensive RA patients (5.44+/-1.6 mg dl(-1) (323.57+/-95.17 micromol l(-1)) vs 4.56+/-1.1 mg dl(-1) (271.23+/-65.43 micromol l(-1)), P<0.001). When adjusted for HT risk factors, renal function, RA characteristics, non-steroidal anti-inflammatory drugs, oral prednisolone, cyclosporine, leflunomide and low-dose aspirin, the odds of being a hypertensive RA patient per 1 mg dl(-1)(59.48 micromol l(-1)) SUA increase were significantly increased: OR=1.59 (95% CI: 1.21-2.1, P=0.001). This was also significant for the subgroup of patients who were not on diuretics (OR=1.5, 95% CI: 1.1-2.05; P=0.011). This cross-sectional study suggests that SUA levels are independently associated with HT in RA patients. Prospective longitudinal studies are needed to confirm and further explore the causes and implications of this association.

Blockade of tumour necrosis factor-alpha in rheumatoid arthritis: effects on components of rheumatoid cachexia.

OBJECTIVES: Rheumatoid arthritis (RA) is accompanied by increased resting energy expenditure (REE) and decreased fat-free mass (FFM). This is referred to as rheumatoid cachexia and is attributed to high levels of tumour necrosis factor-alpha (TNF-alpha). This study aimed to investigate the effects of anti-TNF-alpha therapy on REE, body composition, physical activity and protein intake in RA patients. METHODS: Twenty RA patients [50% female; age: (mean +/- s.d.) 61.1 +/- 6.8 yrs; body mass index (BMI): 28.3 +/- 3.7 kg/m2] and 12 age-sex-BMI-matched healthy controls were assessed. REE (indirect calorimetry), body composition (bioelectrical impedance), the International Physical Activity Questionnaire (IPAQ), diet, Health Assessment Questionnaire (HAQ), disease activity [disease activity score 28 (DAS28), erythrocyte sedimentation rate (ESR), C-reactive protein] and serum TNF-alpha were measured before (Baseline) as well as 2 weeks (Time-1) and 12 weeks (Time-2) after initiation of anti-TNF-alpha treatment. Controls were only assessed at Baseline. RESULTS: RA patients had significantly higher REE than controls at Baseline (1799.4 +/- 292.0 vs 1502.9 +/- 114.5 kcal/day, P = 0.002). Within the RA group, REE increased significantly between Time-1 and Time-2 (P = 0.001) but not between Baseline and Time-2. Sustained significant increases were observed in IPAQ (P = 0.001) and protein intake (P = 0.001). There were no significant changes in FFM or body fat. ESR (P = 0.002), DAS28 (P < 0.001), HAQ (P < 0.001) and TNF-alpha (P = 0.024) improved significantly. Physical activity (P = 0.001) and protein intake (P = 0.024) were significant between-subject factors for the elevation of REE. CONCLUSIONS: After 12 weeks of anti-TNF-alpha therapy, there were significant improvements in disease activity and physical function, as well as physical activity and protein intake, but no significant changes in REE or FFM. There is a need for longer-term studies in this field.

Prevalence and associations of hypertension and its control in patients with rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) associates with excessive cardiovascular morbidity and mortality. Hypertension (HT) contributes significantly to the development of cardiovascular disease (CVD). Little is known about the factors that influence blood pressure (BP) in patients with RA. In this study, we assessed the prevalence of HT in a secondary care cohort of RA patients, and aimed to identify factors associated with its presence and inadequate control. METHODS: A total of 400 consecutive RA patients were studied. HT was defined as systolic BP >/=140 mmHg and/or diastolic BP >/=90 mmHg or current use of antihypertensive drugs. The association of HT with several demographic and RA-related factors, comorbidities and drugs was evaluated using logistic regression. RESULTS: HT was present in 282 (70.5%) patients. Of those, 171 (60.6%) received anti-hypertensive therapy, but 111 (39.4%) remained undiagnosed. Of those treated, only 37/171 (21.8%) were optimally controlled. Multivariable logistic regression revealed age (OR = 1.054, CI: 1.02 to 1.07, P = 0.001), body mass index [BMI (OR = 1.06, CI: 1.003-1.121, P = 0.038)] and prednisolone use (OR = 2.39, CI: 1.02-5.6, P = 0.045) to be independently associated with the presence of HT. BMI (OR = 1.11, CI: 1.02-1.21, P = 0.002) and the presence of CVD (OR = 4.01, CI: 1.27-12.69, P = 0.018) associated with uncontrolled HT. CONCLUSIONS: HT is highly prevalent in RA, under-diagnosed particularly in the young, and under-treated particularly in old RA patients with CVD. RA patients receiving steroids should be specifically targeted for screening and treatment; those with any cardiovascular comorbidity may require particularly aggressive monitoring and treatment strategies.

Polypharmacy among people with rheumatoid arthritis: the role of age, disease duration and comorbidity.

BACKGROUND: People with rheumatoid arthritis (RA) often have comorbidities with associated disability and complex medication regimens. Little published evidence exists about why people with RA require so many medications, although it is logical to hypothesize that this may relate to older age, longer duration of RA, more active RA, worse functional disability and a greater number of comorbidities. OBJECTIVES: We set out to quantify polypharmacy in RA and identify its predictors in an observational cohort. METHODS: The case notes of 348 people receiving secondary care for RA were reviewed to record polypharmacy. The 28-joint Disease Activity Score (DAS28) was calculated and the Health Assessment Questionnaire (HAQ) and the Self-administered Comorbidity Questionnaire (SCQ) were completed. RESULTS: The mean total number of medications was 5.39, with a maximum of 16; of these, a mean of 2.41 medications were directly for RA. A mediational relationship was identified: older age and longer RA duration were significant predictors of a greater total number of medications, but these relationships were explained by the greater number of comorbidities in older participants and those with longer RA duration. Polypharmacy was not related to RA activity or functional disability. CONCLUSIONS: Polypharmacy is common among people with RA and associates with older age and longer RA duration through a greater number of comorbidities. Regular review of the full treatment plan of individuals with RA by pharmacists and other health professionals specializing in rheumatology, to weigh the benefits and risks of each medication and their interactions in light of RA activity and comorbidities, is advocated.

Association of serum uric acid with cardiovascular disease in rheumatoid arthritis.

OBJECTIVES: Elevated serum uric acid (SUA) levels have been associated with cardiovascular disease (CVD) in the general population. Rheumatoid arthritis (RA) is not thought to associate with high SUA but is characterized by increased CVD morbidity and mortality. We aimed to explore a potential association of SUA with CVD in RA patients and to evaluate whether such an association is present when the traditional CVD risk factors are taken into account. METHODS: . 400 consecutive RA patients were recruited in this cross-sectional study and had all traditional CVD risk factors and SUA assessed. The association of SUA levels with other variables was assessed using bivariate correlations. Subsequent binary logistic models with appropriate adjustments were used to test the independence of the association between SUA and CVD. RESULTS: SUA levels were significantly higher in RA patients with CVD (RA + CVD) compared with RA patients without CVD (RA - CVD) (5.68 +/- 1.81 mg dl(-1) vs 5.06 +/- 1.41 mg dl(-1), P = 0.001). After adjusting for CVD risk factors, physical function (health assessment questionnaire, HAQ) and use of diuretics and/or statins the association between SUA and CVD in RA patients remained significant [Odds ratio (OR) = 1.36, 95% confidence interval (CI) 1.04-1.79, P = 0.025]. Compared with subjects with SUA levels in the lowest quintile (<3.86 mg dl(-1)), those within the highest quintile (>/=6.38 mg dl(-1)) had a 6-fold increase in the odds of having CVD (adjusted OR 6.46, 95% CI 1.66-25.05, P = 0.007). CONCLUSIONS: This cross-sectional study suggests that SUA may be independently associated with CVD in RA patients. This needs to be confirmed in prospective studies.