K. M. J. Douglas

Statin use in rheumatoid arthritis in relation to actual cardiovascular risk: evidence for substantial undertreatment of lipid-associated cardiovascular risk?

Background Cardiovascular disease (CVD) is partially attributed to traditional cardiovascular risk factors, which can be identified and managed based on risk stratification algorithms (Framingham Risk Score, National Cholesterol Education Program, Systematic Cardiovascular Risk Evaluation and Reynolds Risk Score). We aimed to (a) identify the proportion of at risk patients with rheumatoid arthritis (RA) requiring statin therapy identified by conventional risk calculators, and (b) assess whether patients at risk were receiving statins. Methods Patients at high CVD risk (excluding patients with established CVD or diabetes) were identified from a cohort of 400 well characterised patients with RA, by applying risk calculators with or without a ×1.5 multiplier in specific patient subgroups. Actual statin use versus numbers eligible for statins was also calculated. Results The percentage of patients identified as being at risk ranged significantly depending on the method, from 1.6% (for 20% threshold global CVD risk) to 15.5% (for CVD and cerebrovascular morbidity and mortality) to 21.8% (for 10% global CVD risk) and 25.9% (for 5% CVD mortality), with the majority of them (58.1% to 94.8%) not receiving statins. The application of a 1.5 multiplier identified 17% to 78% more at risk patients. Conclusions Depending on the risk stratification method, 2% to 26% of patients with RA without CVD have sufficiently high risk to require statin therapy, yet most of them remain untreated. To address this issue, we would recommend annual systematic screening using the nationally applicable risk calculator, combined with regular audit of whether treatment targets have been achieved.

Platelet function in rheumatoid arthritis: arthritic and cardiovascular implications

Patients with rheumatoid arthritis (RA) are at high risk of cardiovascular events. Platelet biomarkers are involved in inflammation, atherosclerosis and thrombosis. Cardiovascular and RA-associated factors can alter the structure and function of platelets, starting from megakaryocytopoiesis. Reactive megakaryocytopoiesis increases circulating platelets count and triggers hyperactivity. Hyperactive platelets target synovial membranes with subsequent local rheumatoid inflammation. Hyperactive platelets interact with other cells, and target the vascular wall. Accumulating evidence suggests that disease modifying anti-rheumatic drugs (DMARD) decrease platelet activity.

Methotrexate therapy associates with reduced prevalence of the metabolic syndrome in rheumatoid arthritis patients over the age of 60- more than just an anti-inflammatory effect? A cross sectional study

IntroductionThe metabolic syndrome (MetS) may contribute to the excess cardiovascular burden observed in rheumatoid arthritis (RA). The prevalence and associations of the MetS in RA remain uncertain: systemic inflammation and anti-rheumatic therapy may contribute. Methotrexate (MTX) use has recently been linked to a reduced presence of MetS, via an assumed generic anti-inflammatory mechanism. We aimed to: assess the prevalence of the MetS in RA; identify factors that associate with its presence; and assess their interaction with the potential influence of MTX.MethodsMetS prevalence was assessed cross-sectionally in 400 RA patients, using five MetS definitions (National Cholesterol Education Programme 2004 and 2001, International Diabetes Federation, World Health Organisation and European Group for Study of Insulin Resistance). Logistic regression was used to identify independent predictors of the MetS. Further analysis established the nature of the association between MTX and the MetS.ResultsMetS prevalence rates varied from 12.1% to 45.3% in RA according to the definition used. Older age and higher HAQ scores associated with the presence of the MetS. MTX use, but not other disease modifying anti-rheumatic drugs (DMARDs) or glucocorticoids, associated with significantly reduced chance of having the MetS in RA (OR = 0.517, CI 0.33–0.81, P = 0.004).ConclusionsThe prevalence of the MetS in RA varies according to the definition used. MTX therapy, unlike other DMARDs or glucocorticoids, independently associates with a reduced propensity to MetS, suggesting a drug-specific mechanism, and makes MTX a good first-line DMARD in RA patients at high risk of developing the MetS, particularly those aged over 60 years.

Association of interleukin-6 (IL-6)-174G/C gene polymorphism with cardiovascular disease in patients with rheumatoid arthritis: The role of obesity and smoking

BACKGROUNDnCardiovascular morbidity and mortality are increased in rheumatoid arthritis (RA). Interleukin-6 (IL-6) is high in RA and, together with smoking and obesity, an important contributor to the development of cardiovascular disease (CVD). The present study examined the potential association of IL-6-174 G/C polymorphism, together with obesity and smoking, with the presence of CVD in RA patients.nnnMETHODS AND RESULTSnDNA samples were collected from 383 RA patients (who also had extensive clinical and laboratory evaluations). IL-6-174 G/C was identified using real time PCR and melting curve analysis. Serum IL-6 levels were measured in a subgroup of 135 RA patients to examine the functionality of the polymorphism. Carriers of the IL6-174C-allele demonstrated increased prevalence of CVD (26.2% vs. 17.0%, p=0.041). There was a significant association with CVD, even after adjustment for traditional CVD risk factors (OR=1.92, 95%CI: 1.03 to 3.58, p=0.041). IL-6 levels were significantly increased in C-allele carriers [14.02 (3.21-38.81) vs. 4.48 (2.25-16.5), p=0.028]. No significant interactions were observed between adiposity and IL6-174G/C genotypes. There was only a trend for an interaction between ever smoking and IL6 C-allele carriers on CVD.nnnCONCLUSIONnThe IL-6-174C-allele may associate with CVD in RA patients and possibly exerts its effect via increased inflammation. This finding, if confirmed in future studies, may be used as a part of a genetic screening tool for RA patients at high CVD risk.

Lack of association between glucocorticoid use and presence of the metabolic syndrome in patients with rheumatoid arthritis: a cross-sectional study

IntroductionRheumatoid arthritis (RA) associates with excessive cardiovascular morbidity and mortality, attributed to both traditional and novel cardiovascular risk factors. The metabolic syndrome, a cluster of classical cardiovascular risk factors, including hypertension, obesity, glucose intolerance, and dyslipidaemia, is highly prevalent in RA. Reports suggest that long-term glucocorticoid (GC) use may exacerbate individual cardiovascular risk factors, but there have been no studies in RA to assess whether it associates with the metabolic syndrome. We examined whether GC exposure associates with the presence of metabolic syndrome in patients with RA.MethodsRA patients (n = 398) with detailed clinical and laboratory assessments were categorised into three groups according to GC exposure: no/limited (<3 months) exposure (NE), low-dose (<7.5 mg/day) long-term exposure (LE), and medium-dose (greater than or equal to 7.5 mg to 30 mg/day) long-term exposure (ME). The metabolic syndrome was defined using the National Cholesterol Education Programme III guidelines. The association of GC exposure with the metabolic syndrome was evaluated using binary logistic regression.ResultsThe metabolic syndrome was present in 40.1% of this population and its prevalence did not differ significantly between the GC exposure groups (NE 37.9% versus LE 40.7% versus ME 50%, P = 0.241). Binary logistic regression did not demonstrate any increased odds for the metabolic syndrome when comparing ME with LE (odds ratio = 1.64, 95% confidence interval 0.92 to 2.92, P = 0.094) and remained non significant after adjusting for multiple potential confounders.ConclusionsLong-term GC exposure does not appear to associate with a higher prevalence of the metabolic syndrome in patients with RA. The components of the metabolic syndrome may already be extensively modified by other processes in RA (including chronic inflammation and treatments other than GCs), leaving little scope for additive effects of GCs.

Risk assessment for coronary heart disease in rheumatoid arthritis and osteoarthritis

Background: The risk of coronary heart disease (CHD) is increased in rheumatoid arthritis (RA). The reasons for this remain unknown, but traditional risk factors for CHD identified in the general population may be important contributors. Objective: To assess comparatively the prevalence of traditional CHD risk factors and the absolute 10‐year CHD risk in patients with RA or osteoarthritis (OA) without known cardiovascular co‐morbidity. Methods: Consecutive Caucasian hospital outpatients with RA (n=150) or OA (n=100) aged 40–75 years were assessed for known cardiovascular co‐morbidity, age, sex, smoking status, presence of diabetes mellitus (DM), height, weight, systolic blood pressure (BP), total cholesterol (TC) and HDL cholesterol. Absolute 10‐year CHD risk for each individual was calculated using the Joint British Societies CHD risk calculator. Results: Prevalence and distribution of known cardiovascular co‐morbid conditions were similar in RA (56/150, 37%) and OA (34/100, 34%). The resulting subgroups of patients without known co‐morbidity (RA: n=94; OA: n=66) were not significantly different for age, sex, DM, smoking, systolic BP or TC: HDL cholesterol ratio. There was no significant difference in the absolute 10‐year CHD risk between RA and OA (15.6±11.0 versus 14.8±9.3, p=0.63). However, a significant proportion of patients without known cardiovascular disease in both the RA and OA subgroups had a 10‐year CHD risk above the 15% or 30% risk levels, indicating the need for possible or definite intervention respectively. Over 80% of RA patients had at least 1 CHD risk factor that could be modified. Conclusion: Absolute 10‐year CHD risk was not different between RA and OA patients in this study. Substantial numbers of RA and OA patients have potentially modifiable CHD risk factors present. We suggest that CHD risk should be assessed and modifiable risk factors addressed in the routine rheumatology clinic setting.

Rheumatoid arthritis susceptibility genes associate with lipid levels in patients with rheumatoid arthritis

Introduction Rheumatoid arthritis (RA), a systemic inflammatory disease with complex genetic aetiology, associates with excess cardiovascular morbidity and mortality. Dyslipidaemia, a major cardiovascular risk factor has been reported to predate the onset of RA, thus suggesting a potential genetic link between the two conditions. The authors assessed whether RA susceptibility genes associate with the presence of dyslipidaemia in RA patients. Methods 400 well-characterised RA patients were included in this cross-sectional study. Fasting lipid profile (total cholesterol, high-density lipoproteins (HDL), low-density lipoproteins (LDL), triglycerides, apolipoproteins (ApoA and ApoB) and lipoprotein (a)) and four RA susceptibility genes (PTPN22, TRAF1/C5, STAT4 and human leucocyte antigen shared epitope (HLA-SE)) were assessed and associations were sought in both univariate and multivariate analyses. Results Following adjustment for age, sex and erythrocyte sedimentation rate, the G allele of TRAF1/C5 associated with lower total cholesterol (p=0.010), LDL (p=0.022) and ApoB (p=0.014); one or more copies of the shared epitope associated with lower ApoA (p=0.035) and higher ApoB:ApoA ratio (p=0.047); while STAT4 TT homozygotes had higher lipoprotein (a) (p=0.004). Conclusions RA susceptibility genes (TRAF1/C5, STAT4 and HLA-DRB1-SE) may be involved in the regulation of lipid metabolism in RA patients, thus contributing to cardiovascular disease (CVD) risk and adverse outcome. If these findings are replicated, such genotyping could be used to identify and target for prevention those RA patients most at risk of CVD. It will also be interesting to study the association of these genes with lipid levels in the general population and identify mechanisms to explain the link.

‘Concealing the Evidence’: The Importance of Appearance Concerns for Patients with Systemic Lupus Erythematosus

Outwardly visible signs associated with systemic lupus erythematosus (SLE) can include facial rashes, alopecia and weight gain. We sought to understand the concerns of SLE patients about their appearance and the recognition of this by healthcare professionals. Semi-structured interviews were carried out with 10 women aged 26-68 years diagnosed with SLE for one to 12 years. Data were analysed with Interpretative Phenomenological Analysis (IPA); this seeks to describe and provide understanding of people’s experience of a phenomenon by studying in-depth a small number from a relatively homogeneous group (women with SLE in the present study). Analysis revealed three themes concerning appearance issues. Participants described public self-consciousness after the onset of SLE. Cosmetics and clothing were used skilfully to appear ‘normal’, hide the ‘self’ and assert control but could increase feelings of difference and isolation. Self-imposed isolation was also described and may relate to depression. The understanding of family, friends, colleagues and healthcare providers was also important. Awareness of the psychosocial concerns of SLE patients with life-changing skin disease may enable multidisciplinary healthcare teams to offer a more sensitive, practical service. The physical and emotional needs of SLE patients need to be ascertained and appropriate educational and psychological services are required.

Prolonged QTc interval predicts all-cause mortality in patients with rheumatoid arthritis: an association driven by high inflammatory burden

OBJECTIVEnRA associates with an increased rate of sudden cardiac death (SCD). A prolonged QTc interval has been associated with arrhythmogenic and SCD in patients with long QT syndrome. Despite the previously reported contemporary association of CRP with SCD, thus far no studies have examined the association of QTc with mortality in RA, a condition characterized by high inflammatory burden. The aim of this study was to examine the role of electrocardiography (QT corrected interval) in predicting all-cause mortality in patients with RA who have an increased rate of SCD and a high inflammatory burden.nnnMETHODSnThree hundred and fifty-seven RA patients with detailed baseline clinical characterization and 12-lead ECGs were followed up for a mean of 73.0 (S.D. 18.3) months. Linear and Cox regression analyses were used to identify variables that associate with QTc and examine its association with all-cause mortality.nnnRESULTSnThe patients mean age was 60.6 (S.D. 12.0) years, 267 (74.8%) were females and 54 (15.1%) died during the follow-up period. Age (β = 0.231, P < 0.001), gender (β = 0.137, P = 0.008) and CRP (β = 0.144, P = 0.006) associated independently with QTc in RA patients. The crude hazard ratio (HR) for total mortality per 50-ms increase in QTc was 2.17 (95% CI 1.21, 3.90). This association remained significant [HR = 2.18 (95% CI 1.09, 4.35)] after adjustment for identified confounders (cardiovascular and RA specific), but was lost [HR = 1.73 (95% CI 0.83, 3.62)] when CRP was included in the model.nnnCONCLUSIONnA 50-ms increase in QTc interval associates with a doubling of the hazard for all-cause mortality in patients with RA. The observed contemporary association of QTc with CRP levels indicates a potentially hazardous interplay between inflammation and arrhythmogenesis. Future studies are needed to confirm the above findings and explore underlying mechanisms.

Are Lipid Ratios Less Susceptible to Change With Systemic Inflammation Than Individual Lipid Components in Patients With Rheumatoid Arthritis

Rheumatoid arthritis (RA) associates with excess cardiovascular risk and there is a need to assess that risk. However, individual lipid levels may be influenced by disease activity and drug use, whereas lipid ratios may be more robust. A cross-sectional cohort of 400 consecutive patients was used to establish factors that influenced individual lipid levels and lipid ratios in RA, using multiple regression models. A further longitudinal cohort of 550 patients with RA was used to confirm these findings, using generalized estimating equations. Cross-sectionally, higher C-reactive protein (CRP) levels correlated with lower levels of total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), and high-density lipoprotein-cholesterol ([HDL-C] P ≤ .015), whereas lipid ratios did not correlate with CRP. The findings were broadly replicated in the longitudinal data. In summary, the effects of inflammation on individual lipid levels may underestimate lipid-associated cardiovascular disease (CVD) risk in RA, thus lipid ratios may be more appropriate for CVD risk stratification in RA.