Does adding single nucleotide polymorphisms to risk algorithms improve cardiovascular disease risk prediction in rheumatoid arthritis? An internal and external validation of a clinical risk score.

OBJECTIVES: Current risk algorithms do not accurately predict cardiovascular disease(CVD) risk in rheumatoid arthritis(RA). An area of interest is that of single nucleotide polymorphisms(SNPs), of which several have been associated with CVD in the general population. We investigated whether these SNPs are associated with CVD in RA and whether SNPs could improve CVD risk prediction in RA. METHODS: 60 SNPs were genotyped in 353 RA patients. Logistic and Cox regression analyses were performed to identify SNPs that were associated with CVD(n=99). A prediction model with clinical variables was made. SNPs were added to investigate the additional predictive value. Both models were internally validated. External validation was done in a separate cohort(n=297). RESULTS: rs3184504, rs4773144, rs12190287, and rs445925 were significantly associated with new CVD. The clinical prediction model consisted of age, sex, body mass index(BMI), systolic blood pressure(SBP), high-density lipoprotein cholesterol(HDLc) and creatinine with an area under the curve(AUC) 0.74, p=0.03. Internal validation resulted in AUC 0.76 (p<0.01). A new model was made including SNPs and resulted in a model with rs17011666 and rs801426, age, total cholesterol(TC) and HDLc, which performed slightly better with AUC 0.77,p<0.01. External validation resulted in a good fit for the clinical model, but a poor fit for the SNP model. CONCLUSIONS: Several SNPs were associated with CVD in RA. Risk prediction slightly improved after adding SNPs to the models, but the clinical relevance is debatable. However, larger studies are needed to determine more accurately the additional value of these SNPs to CVD risk prediction algorithms.

Effect of anti-inflammatory therapy on vascular biomarkers for subclinical cardiovascular disease in rheumatoid arthritis patients.

OBJECTIVE: To assess the effect of 4 years of anti-inflammatory therapy on markers of subclinical vascular disease in rheumatoid arthritis patients. METHODS: Carotid intima media thickness (IMT), augmentation index (AIx@75) and pulse wave velocity (PWV) measurements were performed repeatedly in 61 RA patients (30 early RA starting with csDMARDs and 31 established RA starting with adalimumab) for 4 years. These markers were also measured in 29 controls with osteoarthritis at baseline (BL). RESULTS: IMT and AIx@75 at BL were higher in RA compared to OA, while PWV was higher in OA. In RA patients, AIx@75 and PWV decreased in the first 6 months after starting anti-inflammatory therapy. At 48 M, the level of AIx@75 remained lower than before therapy, while PWV at 48 M was comparable to BL (AIx@75: BL 28% (95% confidence interval 25-30%), 6 M 23% (20-26%), 48 M 25% (22-28%); PWV: BL 8.5 (7.8-9.2), 6 M 8.0 (7.1-8.9), 48 M 8.6 (7.6-9.6) m/s). IMT remained stable. There was an effect of disease activity (longitudinally, adjusted for changes over time) on IMT, AIx@75 and PWV. CONCLUSION: This study suggests modest beneficial changes in some surrogate markers of subclinical vascular disease after anti-inflammatory therapy. These changes were associated with improvement in disease activity markers. Whether or not these beneficial changes ultimately predict a reduction in clinicalcardiovascular endpoints remains to be established in prospective studies.

Interferon regulatory factor 5 gene variants rs2004640 and rs4728142 are associated with carotid intima media thickness but not with cardiovascular events in rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) is associated with cardiovascular (CV) morbidity and mortality. Interferon regulatory factor 5 (IRF5) gene polymorphisms rs2004640 and rs4728142 have been associated with autoimmune diseases, but also with atherosclerosis. Differences in IRF5 gene expression can lead to the production of different interferons and might play a role in the atherogenic process in RA. METHODS: We investigated the effects of IRF5 gene variants rs2004640 and rs4728142 on clinical parameters related to atherosclerosis, such as cIMT (in subgroup n=101), and new CV events (in whole cohort n=353). RESULTS: For rs2004640, cIMT values at baseline were highest within the group of patients carrying the GG-genotype, followed by GT- and TT- genotypes, which was statistically significant. Over time patients with the TT-genotype had the highest increase in cIMT. For rs4728142 cIMT values were also the highest for patients with the GG-genotype at baseline, but the difference between the groups was not statistically significant. Over time the highest increase in cIMT was in the patients with the AA-genotype. Both rs2004640 and rs4728142 were not associated with new CV events during follow-up. CONCLUSIONS: IRF5 alleles are associated with changes in cIMT, but not with new CV events in RA. Although these findings implicate a role of the IRF5 transcription pathway in atherosclerosis, IRF5 single nucleotide polymorphisms do not appear to increase the risk of future CV events.

Arterial wall inflammation in rheumatoid arthritis is reduced by anti-inflammatory treatment.

BACKGROUND: Rheumatoid arthritis (RA) patients have an increased risk of cardiovascular disease (CVD), partly due to an increased prevalence of cardiovascular risk factors, but also due to chronic systemic inflammation inducing atherosclerotic changes of the arterial wall. The aim of this study was to determine whether anti-inflammatory therapy for the treatment of RA has favorable effects on arterial wall inflammation in RA patients. METHODS: Arterial wall inflammation before and after 6 months of anti-inflammatory treatment was assessed in 49 early and established RA patients using 18F-fluorodeoxyglucose-positron emission tomography with computed tomography (18F-FDG-PET/CT). Arterial 18F-FDG uptake was quantified as maximum standardized uptake value (SUVmax) in the thoracic aorta, abdominal aorta, carotid, iliac and femoral arteries. Early RA patients (n = 26) were treated with conventional synthetic disease modifying anti-rheumatic drugs with or without corticosteroids, whereas established RA patients (n = 23) were treated with adalimumab. RESULTS: In RA patients, overall SUVmax was over time reduced by 4% (difference -0.06, 95%CI -0.12 to -0.01, p = 0.02), with largest reductions in carotid (-8%, p = 0.001) and femoral arteries (-7%, p = 0.005). There was no difference in arterial wall inflammation change between early and established RA patients (SUVmax difference 0.003, 95%CI -0.11 to 0.12, p = 0.95). Change in arterial wall inflammation significantly correlated with change in serological inflammatory markers (erythrocyte sedimentation rate and C-reactive protein). CONCLUSION: Arterial wall inflammation in RA patients is reduced by anti-inflammatory treatment and this reduction correlates with reductions of serological inflammatory markers. These results suggest that anti-inflammatory treatment of RA has favorable effects on the risk of cardiovascular events in RA patients.

Arterial wall inflammation is increased in rheumatoid arthritis compared with osteoarthritis, as a marker of early atherosclerosis.

OBJECTIVE: RA is associated with higher risk of cardiovascular (CV) disease. Ongoing systemic inflammation is presumed to accelerate atherosclerosis by increasing inflammation in the arterial wall. However, evidence supporting this hypothesis is limited. We aimed to investigate arterial wall inflammation in RA vs OA, and its association with markers of inflammation and CV risk factors. METHODS: 18-fluorodeoxyglucose PET combined with CT (18F-FDG-PET/CT) was performed in RA (n = 61) and OA (n = 28) to investigate inflammatory activity in the wall of large arteries. Secondary analyses were performed in patients with early untreated RA (n = 30), and established RA, active under DMARD treatment (n = 31) vs OA. RESULTS: Patients with RA had significantly higher 18F-FDG uptake in the wall of the carotid arteries (beta 0.27, 95%CI 0.11-0.44, P <0.01) and the aorta (beta 0.47, 95%CI 0.17-0.76, P <0.01) when compared with OA, which persisted after adjustment for traditional CV risk factors. Patients with early RA had the highest 18F-FDG uptake, followed by patients with established RA and OA respectively. Higher ESR and DAS of 28 joints values were associated with higher 18F-FDG uptake in all arterial segments. CONCLUSION: Patients with RA have increased 18F-FDG uptake in the arterial wall compared with patients with OA, as a possible marker of early atherosclerosis. Furthermore, a higher level of clinical disease activity and circulating inflammatory markers was associated with higher arterial 18F-FDG uptake, which may support a role of arterial wall inflammation in the pathogenesis of vascular complications in patients with RA.

The Effect of Anti-TNF Therapy on Cardiac Function in Rheumatoid Arthritis: An Observational Study.

Congestive heart failure (CHF) is the second most prevalent cause of death in rheumatoid arthritis (RA). The systemic inflammatory state in RA patients is deemed responsible for this finding. Anti-inflammatory treatment with anti-tumor necrosis factor (anti-TNF) therapy decreases CV risk and subsequently might improve the cardiac function by lowering the overall inflammatory state. This study investigated the effect of anti-TNF on the cardiac function in RA patients. Fifty one RA patients were included, of which thirty three completed follow-up. Included patients were >18 years, had moderate-high disease activity and no history of cardiac disease. Patients were assessed at baseline and after six months of anti-TNF treatment. Patients underwent conventional Speckle tracking and tissue Doppler echocardiography in combination with clinical and laboratory assessments at baseline and follow-up. The left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) showed no changes during follow-up, LVEF 63% (±9) to 62% (±8) p = 0.097 and GLS -20 (±4) to -20 (±3) p = 0.79, respectively. Furthermore, E/e' nor E/A changed significantly between baseline and follow-up, respectively 8 (7-9) and 8 (7-9) p = 0.17 and 1.1 (±0.4) and 1.1 (±0.4) p = 0.94. Follow-up NT-proBNP decreased with 23%, from 89 ng/L (47-142) to 69 ng/L (42-155), p = 0.10. Regression analysis revealed no association between change in inflammatory variables and cardiac function. Echocardiography showed no effect of anti-TNF treatment on the cardiac function in RA patients with low prevalence of cardiac dysfunction. Moreover, NT-proBNP decreased, possibly indicating (subtle) improvement of the cardiac function.

Cardiovascular Event Risk in Rheumatoid Arthritis Compared with Type 2 Diabetes: A 15-year Longitudinal Study.

OBJECTIVE: Cardiovascular (CV) disease (CVD) risk is increased in rheumatoid arthritis (RA). However, longterm followup studies investigating this risk are scarce. METHODS: The CARRÉ (CARdiovascular research and RhEumatoid arthritis) study is a prospective cohort study investigating CVD and its risk factors in 353 patients with longstanding RA. CV endpoints were assessed at baseline and 3, 10, and 15 years after the start of the study and are compared to a reference cohort (n = 2540), including a large number of patients with type 2 diabetes (DM). RESULTS: Ninety-five patients with RA developed a CV event over 2973 person-years, resulting in an incidence rate of 3.20 per 100 person-years. Two hundred fifty-seven CV events were reported in the reference cohort during 18,874 person-years, resulting in an incidence rate of 1.36 per 100 person-years. Age- and sex-adjusted HR for CV events were increased for RA (HR 2.07, 95% CI 1.57-2.72, p < 0.01) and DM (HR 1.51, 95% CI 1.02-2.22, p = 0.04) compared to the nondiabetic participants. HR was still increased in RA (HR 1.82, 95% CI 1.32-2.50, p < 0.01) after additional adjustment for CV risk factors. Patients with both RA and DM or insulin resistance had the highest HR for developing CVD (2.21, 95% CI 1.01-4.80, p = 0.046 and 2.67, 95% CI 1.30-5.46, p < 0.01, respectively). CONCLUSION: The incidence rate of CV events in established RA was more than double that of the general population. Patients with RA have an even higher risk of CVD than patients with DM. This risk remained after adjustment for traditional CV risk factors, suggesting that systemic inflammation is an independent contributor to CV risk.

Noncanonical NF-κB signaling in microvessels of atherosclerotic lesions is associated with inflammation, atheromatous plaque morphology and myocardial infarction.

BACKGROUND AND AIMS: Neovascularization is associated with atherosclerotic plaque instability and increased chance of myocardial infarction (MI). Patients with chronic inflammatory diseases (CID) have increased risk of atherosclerosis, and evidence demonstrates that NF-κB inducing kinase (NIK)-mediated noncanonical NF-κB signaling in endothelial cells (EC) is linked to inflammation and angiogenesis. Here, we hypothesized NIK may also be activated in EC of atherosclerotic lesion microvessels. METHODS: Using cohorts of atherosclerotic lesions from coronary and carotid arteries, we quantified NIK expression in plaque microvessels and compared it to pathological markers, including inflammatory cell content, plaque characteristics and MI. Differences in gene transcripts were evaluated between stable and ruptured lesions. RESULTS: NIK+EC were present in both coronary and carotid lesions. In CID patients, plaques with stenosis >40% had an increased number of NIK+EC and higher content of immune cells (p < .05) as compared to controls. Immune cells per NIK+EC were also greater in CID patients (p < .05), with pronounced differences as stenosis increased. In unstable lesions, NIK+EC were elevated as were EC expressing CXCL12 (p < .05). NIK+EC were increased in lesions with lipid content >40% (p < .05) and more abundant in coronary artery lesions implicated in MI (p < .05). These vessels also associated with atheromatous rather than fibrous plaque morphology (p < .05). Transcriptomic profiling demonstrated components of noncanonical NF-κB pathway were also upregulated in ruptured plaques (p < .05). CONCLUSIONS: NIK+EC associate with chronic inflammation in advanced lesions and are linked to markers of local inflammation, lipid content, unstable plaque phenotype and development of MI. Therefore, targeting noncanonical NF-κB signaling may hold therapeutic potential for patients with atherosclerosis and cardiovascular disease.

A multi-parameter response prediction model for rituximab in rheumatoid arthritis.

OBJECTIVES: To validate the IFN response gene (IRG) set for the prediction of non-response to rituximab in rheumatoid arthritis (RA) and assess the predictive performance upon combination of this gene set with clinical parameters. METHODS: In two independent cohorts of 93 (cohort I) and 133 (cohort II) rituximab-starting RA patients, baseline peripheral blood expression of eight IRGs was determined, and averaged into an IFN score. Predictive performance of IFN score and clinical parameters was assessed by logistic regression. A multivariate prediction model was developed using a forward stepwise selection procedure. Patients with a decrease in disease activity score (ΔDAS28)≥1.8 after 6 months of therapy were considered responders. RESULTS: The mean IFN score was higher in non-responders compared to responders in both cohorts, but this difference was most pronounced in patients who did not use prednisone, as described before. Univariate analysis in cohort I showed that baseline DAS28, IFN score, DMARD use and negativity for IgM-RF and/or ACPA were associated with rituximab non-response. The multivariate model consisted of DAS28, IFN score and DMARD use, which showed an area under the curve (AUC) of 0.82. In cohort II, this model revealed a comparable AUC in PREDN-negative patients (0.78), but AUC in PREDN-positive patients was significantly lower (0.63), which seemed due to effect modification of the IFN score by prednisone. CONCLUSIONS: Combination of predictive parameters provided a promising model for the prediction of non-response to rituximab, with possibilities for optimization via definition of the exact interfering effect of prednisone on IFN score. TRIAL REGISTRATION (COHORT II, SMART TRIAL): NCT01126541, registered 18 May 2010.

The Effects of 5-year Etanercept Therapy on Cardiovascular Risk Factors in Patients with Psoriatic Arthritis.

OBJECTIVE: To investigate the effects of etanercept (ETN) on lipid metabolism and other known cardiovascular disease (CVD) risk factors in patients with psoriatic arthritis (PsA). METHODS: In an observational cohort of 118 consecutive patients with PsA, CVD risk factors were assessed over 5 years. Mixed-model analyses were performed to investigate the effects of ETN therapy on CVD risk factors over time. RESULTS: Disease Activity Score in 28 joints, C-reactive protein (CRP), and erythrocyte sedimentation rate decreased during therapy with ETN. There was an increase in total cholesterol (TC), high-density lipoprotein cholesterol (HDLc), and low-density lipoprotein cholesterol. The TC/HDLc ratio remained unaltered. The apolipoprotein B to apolipoprotein A-I (apoB/apoA-I) ratio decreased significantly. An increase in CRP was associated with an increase in the apoB/apoA-1 ratio. CONCLUSION: Serum lipid concentrations showed small changes over a 5-year period of ETN therapy and were inversely associated with inflammatory markers. Other CVD risk factors remained stable. The apoB/apoA-1 ratio decreased over time and an increase in disease activity was associated with an increase in this ratio. However, this modest lipid modulation cannot explain the observed beneficial CV effects of ETN, and ETN likely exerts those effects through inflammation-related mechanisms.

IL-32 promoter SNP rs4786370 predisposes to modified lipoprotein profiles in patients with rheumatoid arthritis.

Patients with rheumatoid arthritis (RA) are at higher risk of developing cardiovascular diseases (CVD). Interleukin (IL)-32 has previously been shown to be involved in the pathogenesis of RA and might be linked to the development of atherosclerosis. However, the exact mechanism linking IL-32 to CVD still needs to be elucidated. The influence of a functional genetic variant of IL-32 on lipid profiles and CVD risk was therefore studied in whole blood from individuals from the NBS cohort and RA patients from 2 independent cohorts. Lipid profiles were matched to the specific IL-32 genotypes. Allelic distribution was similar in all three groups. Interestingly, significantly higher levels of high density lipoprotein cholesterol (HDLc) were observed in individuals from the NBS cohort and RA patients from the Nijmegen cohort homozygous for the C allele (p = 0.0141 and p = 0.0314 respectively). In contrast, the CC-genotype was associated with elevated low density lipoprotein cholesterol (LDLc) and total cholesterol (TC) in individuals at higher risk for CVD (plaque positive) (p = 0.0396; p = 0.0363 respectively). Our study shows a functional effect of a promoter single-nucleotide polymorphism (SNP) in IL32 on lipid profiles in RA patients and individuals, suggesting a possible protective role of this SNP against CVD.