Cartilage turnover and intra-articular corticosteroid injections in knee osteoarthritis.

Intra-articular corticosteroid injections (IACI) are commonly used interventions for pain relief in patients with knee osteoarthritis (OA). Biomarkers may be helpful in further elucidating how IACI exert their effect. The aim of this study is to look at the response of biomarkers of cartilage and bone metabolism after IACI in knee OA. Eighty subjects with symptomatic knee OA [45% male, mean age (SD) 64 (11) years] underwent routine knee joint injection with 40 mg triamcinolone acetonide and 4 ml 1% lignocaine. Knee pain (as pain subscale of WOMAC VAS) and biomarkers [C-telopeptides of type-II collagen (uCTX-II), and N-telopeptides of type-I collagen in urine; cartilage oligomeric matrix protein (COMP), hyaluronic acid, N-terminal propeptide of type-IIA collagen, and human cartilage glycoprotein-39 (YKL-40) in serum] were measured at baseline and 3 weeks after IACI. Radiographic severity of disease was evaluated using knee radiographs. Median uCTX-II, a cartilage degradation marker, was lower at 3 weeks post IACI compared with baseline: 306.3 and 349.9 ng/mmol, respectively (p < 0.01), which remained significant after Bonferroni correction. Apart from a weak trend of lower sCOMP post IACI (p = 0.089), other biomarkers showed no change after IACI. Both baseline uCTX-II values and the change in uCTX-II from baseline to 3 weeks post injection correlated with radiographic severity of joint space narrowing, but not osteophyte grade. No association between uCTX-II and pain was observed. This observational study suggests that IACI in knee OA may reduce cartilage degradation in the short term.

In vivo microvascular and macrovascular endothelial function is not associated with circulating dimethylarginines in patients with rheumatoid arthritis: a prospective analysis of the DRACCO cohort.

OBJECTIVES: To examine associations between asymmetric (ADMA), symmetric dimethylarginine (SDMA) and ADMA:SDMA ratio with assessments of endothelial function and coronary artery perfusion in RA patients. METHODS: ADMA and SDMA levels were measured in 197 RA individuals [144 (77.4%) females, median age: 66 years (quartiles: 59-73)]. Patients underwent assessments of microvascular endothelium-dependent and endothelium-independent function, macrovascular endothelium-dependent and endothelium-independent function and vascular morphology (pulse wave analysis, carotid intima-media thickness (cIMT), and carotid plaque). Coronary perfusion was assessed by subendocardial viability ratio (SEVR). RESULTS: SEVR correlated with SDMA (r = 0.172, p = 0.026) and ADMA:SDMA (r = -0.160, p = 0.041) in univariable analysis, but not in multivariable analysis accounting for confounding factors. Neither ADMA:SDMA ratio nor SDMA were significantly correlated with microvascular or macrovascular endothelial function, or with arterial stiffness and cIMT. Within subgroup of patients (n = 26) with high inflammatory markers, a post-hoc analysis showed that SDMA and the ADMA:SDMA ratio were significantly associated with endothelium-dependent microvascular function in univariable analysis, with Pearson's r correlation coefficients of -0.440 (p = 0.031) and 0.511 (p = 0.011), respectively. Similar finding were established between ADMA:SDMA ratio and arterial stiffness in univariable analysis, with Pearson's r of 0.493, (p = 0.024). CONCLUSION: Dimethylarginines were not found to be significantly associated with several assessments of vascular function and morphology in patients with RA, however, post-hoc analysis indicates that there may be associations in patients with raised inflammatory markers. Our results suggest that dysregulated NO metabolism may not be the sole mechanism for the development of preclinical atherosclerosis in RA.

Symmetric Dimethylarginine Is Not Associated with Cumulative Inflammatory Load or Classical Cardiovascular Risk Factors in Rheumatoid Arthritis: A 6-Year Follow-Up Study.

Symmetric dimethylarginine (SDMA) indirectly inhibits nitric oxide (NO) synthesis and predicts cardiovascular and all-cause mortality in high-risk patients. The aim of our study was to investigate the associations of cumulative inflammatory burden (assessed by serial measurements of inflammatory markers) and classical cardiovascular (CV) disease risk factors with SDMA in RA patients. 201 RA patients (155 females, median age 67 (59-73)) were assessed at baseline (2006). Classical CV disease risk factors were recorded and systemic inflammation was determined by the measurement of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). At follow-up (2012) SDMA levels were measured by enzyme-linked immunosorbent assay. Mean SDMA levels in RA population were 0.40 (0.40-0.53) µmol/L. No significant association between SDMA and cumulative inflammatory load was established in the analysis. SDMA levels were not found to be significantly related to CV disease risk factors. We explored the potential relationship between SDMA and cumulative inflammatory burden in patients with RA and obtained negative results. SDMA did not relate to CV disease risk factors in our population and its clinical significance as a surrogate marker of endothelial dysfunction in patients with RA remains to be determined.

Association between corrected QT interval and inflammatory cytokines in rheumatoid arthritis.

OBJECTIVE: Corrected QT (QTc) interval predicts all-cause and cardiovascular mortality and may contribute to the increased mortality risk in rheumatoid arthritis (RA). Animal experiments have shown that proinflammatory cytokines [tumor necrosis factor (TNF)-α and interleukin 1 (IL-1)] can prolong cardiomyocyte action potential. We sought to determine whether elevations in circulating inflammatory cytokines were independently associated with QTc prolongation in patients with RA. METHODS: One hundred twelve patients [median age 62 (interquartile range 17) yrs; 80 women (71%)] from a well-characterized RA cohort underwent baseline 12-lead electrocardiograms for QT interval measurement and contemporary blood sampling to assess concentrations of inflammatory markers including C-reactive protein (CRP), TNF-α, and interleukins (IL-1α, IL-1ß, IL-6, IL-10). QTc was calculated using the Bazett (QTBAZ = QT ÷ √RR) and Framingham Heart Study (QTFHS = QT + 0.154 × [1 - RR]) heart rate correction formulas. RESULTS: Inflammatory cytokines (TNF-α, IL-1ß, IL-6, IL-10) were positively correlated with QTBAZ (Spearman rank correlation coefficient rho = 0.199, 0.210, 0.222, 0.333; all p < 0.05). In multivariable regression analysis, these associations were all confounded by age except IL-10, where higher tertile groups were independently and positively associated with QTBAZ (ß = 0.202, p = 0.023) and QTFHS (ß = 0.223, p = 0.009) when compared to the lower tertile. CRP (per unit increase) was independently associated with QTBAZ (ß = 0.278, p = 0.001), but not QTFHS. CONCLUSION: To our knowledge, ours is the first study demonstrating a contemporary link between inflammatory cytokines and QT interval in humans. Our results suggest that a lower inflammatory burden may protect against QTc prolongation in patients with RA. However, further studies are required to confirm the effects of pro- and antiinflammatory cytokines on QTc interval.

Cumulative inflammation associates with asymmetric dimethylarginine in rheumatoid arthritis: a 6 year follow-up study.

OBJECTIVE: The aim of the present study was to investigate the associations of cumulative inflammatory burden (assessed by serial measurements of inflammatory markers) and classical cardiovascular disease (CVD) risk factors with asymmetric dimethylarginine (ADMA) in a large prospective cohort of patients with established RA. METHODS: Two hundred and one RA patients [155 females, median age 67 years (range 59-73)] were assessed at baseline (2006) for the presence of classical CVD risk factors and determination of systemic inflammation by CRP and ESR. Global CVD risk was identified by the Framingham Risk Score and the Reynolds Risk Score. At follow-up (2012), ADMA levels were measured by ELISA. A quarterly measurement of CRP and ESR for each year the patient was in the study was used to produce an average area under the curve (AAUC) for ESR and CRP. RESULTS: Regression analysis revealed that baseline ESR in 2006 and the AAUC of ESR and CRP all had significant positive relationships with current ADMA (P = 0.004, P < 0.001 and P = 0.002, respectively). Baseline CRP in 2006 was not a significant predictor of ADMA (P = 0.093), although this relationship was in the same direction as the other factors. These results remained consistent after adjustment for classical CVD risk factors. CONCLUSION: Cumulative inflammatory burden is positively associated with ADMA levels, suggesting a potential pathogenic mechanism through which chronic systemic inflammation exerts deleterious effects on nitric oxide metabolism and endothelial homeostasis. This association is independent of classical CVD risk factors.

The autoimmune-associated genetic variant PTPN22 R620W enhances neutrophil activation and function in patients with rheumatoid arthritis and healthy individuals.

OBJECTIVES: A genetic variant of the leukocyte phosphatase PTPN22 (R620W) is strongly associated with autoimmune diseases including rheumatoid arthritis (RA). Functional studies on the variant have focussed on lymphocytes, but it is most highly expressed in neutrophils. We have investigated the effects of the variant on neutrophil function in health and in patients with RA. METHODS: Healthy individuals and patients with RA were genotyped for PTPN22 (R620W) and neutrophils isolated from peripheral blood. Neutrophil adhesion and migration across inflamed endothelium were measured. Calcium (Ca(2+)) release and reactive oxygen species (ROS) production in response to fMLP stimulation were also assessed. RESULTS: Expression of R620W enhanced neutrophil migration through cytokine activated endothelium (non-R620W=24%, R620W=45% migrating cells, p<0.001). Following fMLP stimulation, neutrophils that were heterozygous and homozygous for R620W released significantly more Ca(2+) when compared to non-R620W neutrophils, in healthy individuals and patients with RA. fMLP stimulation, after TNF-α priming, provoked more ROS from neutrophils heterozygous for R620W in patients with RA (non-R620W vs R620W=∼1.75-fold increase) and healthy individuals (non-R620W vs R620W=fourfold increase) and this increase was statistically significant in healthy individuals (p<0.001) but not in patients with RA (p<0.25). CONCLUSIONS: Expression of PTPN22 (R620W) enhanced neutrophil effector functions in health and RA, with migration, Ca(2+) release and production of ROS increased. Neutrophils are found in large numbers in the RA joint, and this hyperactivity of R620W cells may directly contribute to the joint damage, as well as to the initiation and perpetuation of the chronic immune-mediated inflammatory processes driving the disease.

Serum samples that have been stored long-term (>10 years) can be used as a suitable data source for developing cardiovascular risk prediction models in large observational rheumatoid arthritis cohorts.

OBJECTIVE: There is an unmet need for a specific cardiovascular risk (CV) algorithm for rheumatoid arthritis (RA) patients. Lipoprotein data are often not available in RA cohorts but could be obtained from frozen blood samples. The objective of this study was to estimate the storage effect on lipoproteins in long-term (>10 years) frozen serum samples. METHODS: Data were used from an inception RA cohort. Multiple serum samples from 152 patients were analyzed for lipoproteins, being frozen for 1-26 years at -20°C. Storage effect on lipoproteins was estimated using longitudinal regression analyses and a lipid decay correction factor was developed. Clinical impact of the storage effect on lipoproteins was assessed by calculating the number of patients reclassified to another CV risk group according to the SCORE risk calculator after applying the decay correction factor. RESULTS: There was a significant effect of storage time on total cholesterol (TC) (P<0.001) and high density lipoprotein cholesterol (HDL-c) levels (P<0.001), not LDL-c (P=0.83). The lipid decay correction factor was 0.03 mmol/L and 0.024 mmol/L per additional year of storage for TC and HDL-c, respectively. The TC:HDL ratio decreased after correction for storage effect. After correction, only 5% of patients were reclassified to another CV risk group. CONCLUSION: A modest storage decay effect on lipoproteins was found that is unlikely to significantly affect CV risk stratification. Serum samples that have been stored long-term (>10 years) can be used to obtain valid lipid levels for developing CV risk prediction models in RA cohorts, even without applying a decay correction factor.

The relationship between cardiovascular disease risk prediction scores and vascular function and morphology in rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) are at an increased risk for cardiovascular disease (CVD) resulting from impairments in vascular function and morphology. CVD risk prediction scores can identify patients at high risk of CVD, but little is known about whether they relate with assessments of vascular function and morphology which provide early indication of subclinical atherosclerosis. The objective of the present study was to examine the relationship of several CVD risk prediction scores with assessments of vascular function and morphology in patients with RA. METHODS: Framingham risk score, Systematic Coronary Risk Evaluation for total cholesterol and ratio of total cholesterol to high-density lipoprotein, as well as Reynolds Risk Score, and QRISK2 were calculated in 201 RA patients (155 females, median (25th to 75th percentile) age: 61 (53-67)) who were examined at baseline (2006). The European League Against Rheumatism (EULAR) multiplication factor was also applied to the algorithms. At a 6-year follow-up (2012) visit the patients underwent assessments of microvascular and macrovascular endothelium-dependent and endothelium-independent function, along with assessment of carotid atherosclerosis. RESULTS: All five CVD risk prediction scores measured at baseline were significantly correlated with vascular function and morphology at follow-up. Application of the EULAR multiplication factor did not change any of the associations. CONCLUSIONS: Five commonly used CVD risk prediction scores associate with assessments of vascular function and morphology over a 6-year follow-up period suggesting that these CVD risk prediction scores may also reflect subclinical atherosclerotic changes.

Three months of moderate-intensity exercise reduced plasma 3-nitrotyrosine in rheumatoid arthritis patients.

PURPOSE: Rheumatoid arthritis (RA) patients display high levels of oxidative stress. Transient exercise-induced increases in oxidative stress are thought to be adaptive in healthy populations. This study investigated the effect of exercise on markers of oxidative stress in RA, following acute exercise and a period of exercise training. METHODS: Acute exercise study: RA patients (N = 12, age: 56 ± 11) undertook a bout of exercise (30-40 min, 70 % VO2MAX), and blood samples were taken before and after exercise to assess markers of oxidative stress. Training study: RA patients (N = 19, age: 56 ± 10) were randomised into either a control or exercise group, who undertook 3 exercise sessions per week (30-40 min @70 % VO2MAX) for 3 months. Plasma markers of oxidative stress (protein carbonyls (PC), lipid hydroperoxides (LOOH), 3-nitrotyrosine (3-NT), total antioxidant capacity (TAC) and catalase (CAT) activity), inflammation (interleukin-8 (IL-8) and C-reactive protein (CRP)) and nitric oxide metabolites (NOx) were assessed before and after training. RESULTS: Acute exercise study: Protein carbonyls (PC) (+18 %) and NOx (+27 %) were significantly increased following exercise. Training study: 3-nitrotyrosine (3-NT) decreased (2.18 ± 1.78 to 1.10 ± 0.93 µM) in the exercise group only, alongside increases in aerobic fitness (24.45 ± 4.98 to 27.10 ± 4.51 ml/kg/min(-1)) and reductions in disease activity score (DAS: 3.47 ± 1.17 to 2.88 ± 0.76). PC, LOOH, TAC, IL-8, CRP and NOx concentrations, and CAT activity were unchanged in both groups. CONCLUSIONS: Aerobic exercise training did not increase markers of oxidative stress in RA patients. 3-Nitrotyrosine and disease activity were decreased following exercise training.

Classical cardiovascular disease risk factors associate with vascular function and morphology in rheumatoid arthritis: a six-year prospective study.

INTRODUCTION: Patients with rheumatoid arthritis (RA) are at an increased risk for cardiovascular disease (CVD). An early manifestation of CVD is endothelial dysfunction which can lead to functional and morphological vascular abnormalities. Classical CVD risk factors and inflammation are both implicated in causing endothelial dysfunction in RA. The objective of the present study was to examine the effect of baseline inflammation, cumulative inflammation, and classical CVD risk factors on the vasculature following a six-year follow-up period. METHODS: A total of 201 RA patients (155 females, median age (25th to 75th percentile): 61 years (53 to 67)) were examined at baseline (2006) for presence of classical CVD risk factors and determination of inflammation using C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). At follow-up (2012) patients underwent assessments of microvascular and macrovascular endothelium-dependent and endothelium-independent function, along with assessment of carotid atherosclerosis. The CRP and ESR were recorded from the baseline study visit to the follow-up visit for each patient to calculate cumulative inflammatory burden. RESULTS: Classical CVD risk factors, but not RA disease-related inflammation, predicted microvascular endothelium-dependent and endothelium-independent function, macrovascular endothelium-independent function and carotid atherosclerosis. These findings were similar in a sub-group of patients free from CVD, and not receiving non-steroidal anti-inflammatory drugs, cyclooxygenase 2 inhibitors or biologics. Cumulative inflammation was not associated with microvascular and macrovascular endothelial function, but a weak association was apparent between area under the curve for CRP and carotid atherosclerosis. CONCLUSIONS: Classical CVD risk factors may be better long-term predictors of vascular function and morphology than systemic disease-related inflammation in patients with RA. Further studies are needed to confirm if assessments of vascular function and morphology are predictive of long-term CV outcomes in RA.

The association between functional and morphological assessments of endothelial function in patients with rheumatoid arthritis: a cross-sectional study.

INTRODUCTION: Patients with rheumatoid arthritis (RA) are at an increased risk for cardiovascular disease (CVD). One of the earliest manifestations of CVD is endothelial dysfunction (ED), which can lead to functional and morphological vascular abnormalities. Several non-invasive assessments of vascular function and morphology can be utilised to assess vascular health, but little is known about the association between each of these assessments in patients with RA, and they tend to be used interchangeably in the literature. The objective of the present study was to examine associations between measures of vascular function and morphology in patients with RA. METHODS: A total of 201 RA patients (155 females, median (25th to 75th percentile) age: 67 (59 to 73)) underwent assessments of microvascular endothelium-dependent and endothelium-independent function (laser Doppler imaging with iontophoresis of acetylcholine and sodium-nitroprusside respectively), macrovascular endothelium-dependent and endothelium-independent function (flow-mediated dilatation and glyceryl-trinitrate-mediated dilation respectively), and vascular morphology (pulse wave analysis, carotid intima-media thickness (cIMT), and carotid plaque). RESULTS: Spearman's correlations revealed that from the functional parameters, only macrovascular endothelium-independent function was inversely associated with cIMT (-0.294 (P < 0.001)) after applying the Bonferroni correction for multiple comparisons. For carotid plaque, t tests showed that macrovascular endothelium-independent function was lower in patients with plaque than without (15.5 ± 8.3 vs. 23.1 ± 9.1%, P = 0.002, respectively). CONCLUSIONS: With the exception of macrovascular endothelium-independent function, all other measures of vascular function were not associated with vascular morphology. This suggests that different assessments of vascular function and morphology in patients with RA reflect quite distinct mechanisms and phases of the atherosclerotic process and should not be used interchangeably.

Derangement of hemostasis in rheumatoid arthritis: association with demographic, inflammatory and metabolic factors.

Disturbance of fibrinolysis is common in rheumatoid arthritis (RA), and it may be associated with the increased cardiovascular risk observed in this population. We aimed to assess coagulation derangement and investigate whether abnormalities are influenced by demographic, inflammatory or metabolic factors in patients with RA. Levels of tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI-1), fibrinogen, prothrombin fragment 1 + 2 (PF1 + 2), thrombomodulin (TM), protein C and Von Willebrand factor (vWF) were compared between 141 RA patients and 50 healthy hospital controls. Within RA, coagulation factors were assessed alongside several demographic, inflammation and metabolic indicators. RA patients had higher levels of coagulation factors than controls. After correction for age and sex, having RA predicted increased tPA (B = 0.15, P < 0.001), PAI-1 (B = 0.21, P < 0.001), fibrinogen (B = 0.86, P < 0.001), PF1 + 2 (B = 0.20, P < 0.001), and TM (B = 0.01, P = 0.03) levels. CRP correlated positively with tPA (P < 0.05), fibrinogen (P < 0.001), TM (P < 0.05), PF1 + 2 (P < 0.001) and vWF (P < 0.001). Metabolic factors linked with coagulation factors were hypertriglyceridaemia (tPA, P < 0.05; PAI-1, P < 0.05; protein C, P < 0.05) and insulin resistance (tPA, P < 0.01; PAI-1, P < 0.01; vWF, P < 0.05). Imbalance of coagulation and fibrinolytic mechanisms is common in RA and associates with age, inflammation, and metabolic factors. Further studies may determine whether these abnormalities are the consequence of acute inflammation or markers of vascular dysfunction.

The role of inflammation, the autonomic nervous system and classical cardiovascular disease risk factors on subendocardial viability ratio in patients with RA: a cross-sectional and longitudinal study.

INTRODUCTION: Evidence indicates that rheumatoid arthritis (RA) patients have increased susceptibility to myocardial ischaemia that contributes to myocardial infarction. The subendocardial viability ratio (SEVR) can be measured using pulse wave analysis and reflects myocardial oxygen supply and demand. The objective of the present study was to examine specific predictors of SEVR in RA patients, with a specific focus on inflammation and classical cardiovascular disease (CVD) risk factors. METHODS: Two patient cohorts were included in the study; a primary cohort consisting of 220 RA patients and a validation cohort of 127 RA patients. All patients underwent assessment of SEVR using pulse wave analysis. Thirty-one patients from the primary cohort who were about to start anti-inflammatory treatment were prospectively examined for SEVR at pretreatment baseline and 2 weeks, 3 months and 1 year following treatment. Systemic markers of disease activity and classical CVD risk factors were assessed in all patients. RESULTS: The SEVR (mean ± standard deviation) for RA in the primary cohort was 148 ± 27 and in the validation cohort was 142 ± 25. Regression analyses revealed that all parameters of RA disease activity were associated with SEVR, along with gender, blood pressure and heart rate. These findings were the same in the validation cohort. Analysis of longitudinal data showed that C-reactive protein (P < 0.001), erythrocyte sedimentation rate (P < 0.005), Disease Activity Score in 28 joints (P < 0.001), mean blood pressure (P < 0.005) and augmentation index (P < 0.001) were significantly reduced after commencing anti-TNFα treatment. Increasing C-reactive protein was found to be associated with a reduction in SEVR (P = 0.02) and an increase in augmentation index (P = 0.001). CONCLUSION: The present findings reveal that the SEVR is associated with markers of disease activity as well as highly prevalent classical CVD risk factors in RA, such as high blood pressure and diabetes. Further prospective studies are required to determine whether the SEVR predicts future cardiac events in RA.

Clinical remission following treatment with tumour necrosis factor-alpha antagonists is not accompanied by changes in asymmetric dimethylarginine in patients with rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) is characterised by impaired endothelial function which contributes to increased cardiovascular morbidity and mortality. Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase and contributes to endothelial dysfunction. The aim of the present longitudinal study was to investigate the effects of tumour necrosis factor alpha (TNFα) antagonists on serum concentrations of ADMA in RA patients. DESIGN AND METHODS: Thirty-five patients (age (mean ± SD) 55 ± 15 years, 21 women) who qualified for anti-TNFα therapy were included in the study. ADMA was measured by ELISA in all patients prior to starting anti-tumour necrosis factor alpha treatment, and 2 weeks and 3 months after initiation of treatment. Generalised estimating equations were used to analyse the change in a range of factors after the treatment commenced, and to test the relationship between ADMA and various inflammatory parameters. RESULTS: Anti-tumour necrosis factor alpha therapy significantly reduced ESR, CRP, fibrinogen and disease activity score 28 (all p<0.001). ADMA levels did not change significantly following 2 weeks or 3 months treatment using three different tumour necrosis factor alpha inhibitors, despite the fact that CRP (p=0.016), and DAS28 (p=0.025) were found to be significantly associated with ADMA levels after treatment with TNFα antagonists. CONCLUSION: ADMA levels do not change significantly during anti-TNF therapy, despite the fact that they associate with CRP and DAS28, which are significantly reduced during such treatment in patients with rheumatoid arthritis. Levels of inflammation after treatment with TNFα antagonists are significantly associated with ADMA levels in patients with rheumatoid arthritis.

Apolipoprotein E gene polymorphisms are strong predictors of inflammation and dyslipidemia in rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA), a condition with a strong genetic etiology, is associated with excess cardiovascular disease (CVD). Dyslipidemia in RA may be driven by inflammation and genetic factors. Apolipoprotein E (ApoE) is important for the regulation of lipid levels and CVD risk and immune function in the general population. We compared the frequency of 2 ApoE single-nucleotide polymorphisms (SNP) in patients with RA and controls, and studied the relationship of ApoE genotypes with lipids and inflammation in RA. METHODS: A total of 387 patients with well-characterized RA and 420 non-RA controls were studied. Two ApoE SNP, rs7412 (ApoE2) and rs429358 (ApoE4), were identified. RESULTS: Genotypic (p = 0.908) and allelic (p = 0.894) frequencies did not differ between RA and controls. Within RA, the E2 allele was associated with the lowest and E4 allele with the highest levels of total cholesterol (p = 0.007), low-density lipoproteins (p = 0.004), and apolipoprotein B (p = 0.009). The E4 allele was also associated with lower C-reactive protein (p = 0.007), erythrocyte sedimentation rate (p = 0.001), and Disease Activity Score (p = 0.015) compared to the E3 allele. E2 or E4 alleles were not associated with CVD in RA, although a trend was observed (p = 0.074). CONCLUSION: The frequency of ApoE polymorphisms did not differ between patients with RA and controls. ApoE genotypes are strongly linked to inflammation and lipid levels in RA, raising interest in the prognostic implications of ApoE genotypes.

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.

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.

Prevalence of risk factors for statin-induced myopathy in rheumatoid arthritis patients.

OBJECTIVES: Statins are widely prescribed in patients with rheumatoid arthritis (RA). Although statins offer overwhelming cardiovascular benefits, their use can be associated with the development of a statin-induced myopathy. Several factors increase the risk of developing statin-induced myopathy, including the single nucleotide polymorphism (SNP) rs4149056, located within the gene encoding solute carrier organic anion transporter (SLCO1B1). We aimed to identify the frequency of risk factors for statin-induced myopathy and establish whether the rs4149056 genotype is more prevalent in RA. METHODS: A total of 396 RA patients and 438 non-RA controls were studied. DNA samples were obtained from all patients. The SNP rs4149056 was identified using real-time polymerase chain reaction and melting curve analysis. Genotypic and allelic frequencies were calculated using the chi-squared test. RESULTS: Almost 80% of RA patients had one or more risk factor (range 1-5) for the development of statin-induced myopathy. Of the 74 RA patients treated with statins, 90% had one or more (range 1-4) risk factors. No differences in genotype or allelic frequencies were observed between RA patients and controls. CONCLUSIONS: RA patients harbour multiple risk factors for statin-induced myopathy. However, the frequency of the rs4149056 genotypes does not differ according to the presence of RA. Despite this, no cases of statin-induced myopathy were observed in this cohort over a period of four years of follow-up. Thus, we conclude that statin use among RA patients is probably safe, but large-scale prospective studies are needed to confirm this. In the meantime, it may be good practice systematically to consider and record myopathy risk factors in these patients.

Lack of an association of GNB3 C825T polymorphism and blood pressure in patients with rheumatoid arthritis.

G-protein beta 3 subunit (GNB3) C825T (rs5443) single nucleotide polymorphism (SNP) has been implicated as a risk factor for essential hypertension in the general population. The effects of this SNP may be more prominent in subjects with endothelial dysfunction (ED). Rheumatoid arthritis (RA) is associated with ED and has a high prevalence of hypertension. Thus far, this SNP has not been studied in RA patients. We genotyped 383 RA patients and 432 controls. GNB3 C825T was identified using real-time polymerase chain reaction (PCR) and melting curve analysis. There were no differences in the frequencies of the GNB3 C825T genotype and alleles between RA and controls. Within RA patients, prevalence of hypertension did not differ across genotypes. The TT versus CC+CT contrast yielded an adjusted odds ratio (OR) of 0.92 (95% CI: 0.49 to 1.76, p = 0.813), the contrast of TT+CT versus CC an adjusted OR of 2.17 (95% CI: 0.885 to 5.30, p = 0.091), whereas that of the T allele versus C allele an adjusted OR of 1.11 (95% CI: 0.76 to 1.61, p = 0.604). Systolic and diastolic blood pressure levels were not significantly different across the three genotypic groups. No significant interaction was observed between GNB3 825C/T polymorphism and serum endothelin levels. Data from the present study suggest that the T825 variant of the G protein beta 3 subunit gene is unlikely to constitute major susceptibility loci for essential hypertension in Caucasian RA patients. Further larger studies are required to confirm our findings and assess the interaction of rs5443 with environmental factors.