Karen M. J. Douglas

Excess recurrent cardiac events in rheumatoid arthritis patients with acute coronary syndrome

Background: Cardiovascular mortality is increased in rheumatoid arthritis. Possible reasons include an increased incidence of ischaemic heart disease or worse outcome after acute coronary syndrome (ACS). Objectives: To assess the outcome of ACS in rheumatoid arthritis compared with case matched controls in the context of underlying cardiac risk factors, clinical presentation, and subsequent management. Methods: 40 patients with rheumatoid arthritis and ACS identified from coronary care admission registers between 1990 and 2000 were case matched as closely as possible for age, sex, classical cardiovascular risk factors, type and severity of ACS, and admission date (±3 months) with 40 controls. A standardised proforma was used for detailed case note review. Results: Age, sex, other cardiovascular risk factors, and type and severity of presenting ACS were not significantly different between cases and controls. Recurrent cardiac events were commoner in rheumatoid arthritis (23/40, 57.5%) than controls (12/40, 30%) (p = 0.013); there were 16/40 deaths in rheumatoid arthritis (40%) v 6/40 (15%) in controls (p = 0.012). Recurrent events occurred earlier in rheumatoid arthritis (log rank survival, p = 0.05). Presentation with chest pain occurred in all controls compared with 33/40 rheumatoid patients (82%) (p = 0.006); collapse occurred in one control (2.5%) v 7/40 rheumatoid patients (17.5%) (p = 0.025). Treatment during the ACS was not significantly different in the two groups. Conclusions: Recurrent ischaemic events and death occur more often after ACS in rheumatoid arthritis. Atypical presentation is commoner in rheumatoid arthritis. There is an urgent need to develop identification and intervention strategies for ACS specific to this high risk group.

Inflammation and atherosclerosis in rheumatoid arthritis.

Rheumatoid arthritis (RA) associates with increased cardiovascular mortality. This appears to be predominantly due to ischaemic causes, such as myocardial infarction and congestive heart failure. The higher prevalence of cardiac ischaemia in RA is thought to be due to the accelerated development of atherosclerosis. There are two main reasons for this, which might be inter-related: the systemic inflammatory load, characteristic of RA; and the accumulation in RA of classical risk factors for coronary heart disease, which is reminiscent of the metabolic syndrome. We describe and discuss in the context of RA the involvement of local and systemic inflammatory processes in the development and rupture of atherosclerotic plaques, as well as the role of individual risk factors for coronary heart disease. We also present the challenges facing the clinical and scientific communities addressing this problem, which is receiving increasing attention.

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 ⩾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 (F1–354 = 8.663, p = 0.000), and this was followed by lipid-lowering treatment (F1–354 = 7.651, p = 0.000), age (F1–354 = 7.541, p = 0.000), antihypertensive treatment (F1–354 = 4.997, p = 0.000) and gender (F1–354 = 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.

Association of mean platelet volume with hypertension in rheumatoid arthritis.

Rheumatoid arthritis (RA) is one of the most common chronic inflammatory disorders associated with enhanced cardiovascular morbidity and mortality. Established high prevalence of classical cardiovascular risk factors may only partly explain cardiovascular phenomenon in this disease. Emerging risk factors, markers of inflammation and prothrombotic state such as platelet size are believed to reflect activity of RA. We aimed to study mean platelet volume (MPV) in a cohort of patients with RA and to clarify possible effects of classical cardiovascular and RA-associated risk factors on MPV. Demographic, clinical and a wide range of laboratory parameters, including MPV and platelet count, were obtained for 400 RA patients. Platelet size and count were also assessed in 360 non-RA controls from the local population. We found significantly increased MPV in RA patients compared with controls (P=0.001). The difference retained significant after adjustment for age and sex. High values of MPV (>or=10.7 femtoliter [fL]) were more frequent in RA patients than in controls (21% vs. 9.2%; P<0.0001). In RA patients, blood pressure greater than 140/90 mmHg was associated with high levels of MPV (Odds Ratio [OR] 2.2, 95% Confidence Interval [CI] 1.3-3.7; P=0.003). It is possible that MPV as a surrogate marker of platelet function reflects enhanced vascular risk. To further explore the role of MPV as a marker for cardiovascular risk in RA, prospective studies are warranted.

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.

Cigarette smoking significantly increases basal metabolic rate in patients with rheumatoid arthritis

Objective: Basal metabolic rate (BMR) is the most important indicator of human metabolism and its abnormalities have been linked to undesirable health outcomes. Cigarette smoking associates with increased BMR in healthy individuals; it is also related with worse disease outcomes in patients with rheumatoid arthritis (RA), in whom BMR is high due to hypercatabolism caused by systemic inflammation. We aimed to investigate whether smokers with RA demonstrated higher BMR levels than their non-smoking counterparts. Methods: A total of 53 patients with RA (36 female, 17 male, 20 current smokers) were assessed for: BMR (indirect calorimetry), anthropometrical data, fat-free mass (bioelectrical impedance), physical function (health assessment questionnaire; HAQ) and disease activity (disease activity score DAS28 and C reactive protein). Results: RA smokers and non-smokers were not significantly different for age, height, weight, body mass index and fat-free mass. Compared to non-smokers, smokers with RA demonstrated significantly higher BMR (mean (SD) 1513.9 (263.3) vs 1718.1 (209.2) kcal/day; p<0.001) and worse HAQ (1.0 (0.8) vs 1.7 (0.8); p = 0.01). The BMR difference was significantly predicted by the interaction smoking/gender (p = 0.04). BMR was incrementally higher in light, moderate and heavy smokers (p = 0.018), and correlated with the daily number of cigarettes smoked (r = 0.68, p = 0.04). Conclusion: Current cigarette smoking further increases BMR in patients with RA and has a negative impact on patients’ self-reported functional status. Education regarding smoking cessation is needed for the RA 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 μmol l−1) vs 4.56±1.1 mg dl−1 (271.23±65.43 μmol 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 μmol 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.

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.

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 m2 and 12.75% had a GFR of less than 60 ml/minute per 1.73 m2. Multivariable analysis revealed significant associations between GFR and age (β = −0.370, p<0.001), female sex (β = −0.181, p=0.002), total cholesterol (β = −0.112, p=0.022), serum uric acid (SUA) (β = −0.425, p<0.001) and the presence of extra-articular disease, apart from sicca and/or nodules (β = −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.

Cigarette smoking associates with body weight and muscle mass of patients with rheumatoid arthritis: a cross-sectional, observational study

IntroductionRheumatoid arthritis (RA) is associated with altered metabolism leading to muscle wasting. In the general population, cigarette smoking is known to affect body composition by reducing fat and inhibiting muscle synthesis. Even though smoking has been implicated in the pathophysiology and progression of RA, its possible effects on body composition of such patients have not been studied. This cross-sectional study aimed to identify potential associations of smoking with body weight and composition of RA patients.MethodsA total of 392 patients (290 females) with RA were assessed for body mass index (BMI), body fat (BF), fat-free mass (FFM), and waist circumference. Erythrocyte sedimentation rate, C-reactive protein, Disease Activity Score-28, and Health Assessment Questionnaire score were used to assess disease activity and severity. Smoking habit (current smoker, ex-smoker, or never-smoker) and intensity (pack-years) were also noted.ResultsCurrent smokers had a significantly lower BMI compared with ex-smokers (mean difference: male -2.6, 95% confidence interval [CI]: -3.5 to -1.7; female: -2.6, 95% CI: -4.8 to -0.5) and never-smokers (mean difference: male -1.8, 95% CI: -3 to -0.6; female: -1.4, 95% CI: -2.4 to -0.4). Similarly, the BF of current smokers was lower compared with that of ex-smokers (mean difference: male: -4.3, 95% CI: -7.5 to -1.2; female: -3.4, 95% CI: -6.4 to -0.4) and never-smokers (mean difference: male: -3.3, 95% CI: -6.3 to -0.4; female: -2.1, 95% CI: -4 to -0.2). FFM did not differ between groups. Finally, current smokers had a significantly smaller waist circumference compared with ex-smokers only (mean difference: male: -6.2, 95% CI: -10.4 to -1.9; female: -7.8, 95% CI: -13.5 to -2.1). Following adjustments for age, disease duration, and HAQ score, smoking remained a significant predictor for BMI (P < 0.001), BF (P < 0.05), and waist circumference (P < 0.05). Pack-years were inversely correlated with BF (r = -0.46; P < 0.001), and heavy smokers exhibited a significantly lower FFM (P < 0.05) compared with all other participants.ConclusionWithin the limitations of a cross-sectional study, it appears that cigarette smoking associates with reduced BMI and BF in patients with RA and heavy smoking associates with lower muscle mass. Smoking cessation appears to associate with increased BMI, BF, and waist circumference in these patients. These results should be confirmed in prospective studies. Given the numerous adverse effects of smoking on general health and RA, patients should be actively advised against it. However, smoking cessation regimes in RA may need to include more general lifestyle counselling, particularly about weight control.