Trends in all-cause and cardiovascular mortality in patients with incident rheumatoid arthritis: a 20-year follow-up matched case-cohort study.

OBJECTIVES: To examine all-cause and cardiovascular disease (CVD) mortality in consecutive cohorts of patients with incident RA, compared with population comparators. METHODS: The Oslo RA register inclusion criteria were diagnosis of RA (1987 ACR criteria) and residency in Oslo. Patients with disease onset 1994-2008 and 10 matched comparators for each case were linked to the Norwegian Cause of Death Registry. Hazard ratios for all-cause and CVD mortality were calculated for 5, 10, 15 and 20 years of observation using stratified cox-regression models. Mortality trends were estimated by multivariate cox-regression. RESULTS: 443, 479 and 469 cases with disease incidence in the periods 94-98, 99-03 and 04-08 were matched to 4430, 4790 and 4690 comparators, respectively. For cases diagnosed between 1994 and 2003, the all-cause mortality of cases diverged significantly from comparators after 10 years of disease duration [hazard ratio (95% CI) 94-98 cohort 1.42 (1.15-1.75): 99-03 cohort 1.37 (1.08-1.73)]. CVD related mortality was significantly increased after 5 years for the 94-98 cohort [hazard ratio (95% CI) 1.86 (1.16-2.98) and after 10 years for the 99-03 cohort 1.80 (1.20-2.70)]. Increased mortality was not observed in the 04-08 cohort where cases had significantly lower 10-year all-cause and CVD mortality compared with earlier cohorts. CONCLUSION: All-cause and CVD mortality were significantly increased in RA patients diagnosed from 1994 to 2003, compared with matched comparators, but not in patients diagnosed after 2004. This may indicate that modern treatment strategies have a positive impact on mortality in patients with RA.

Large molecular size EDTA-resistant complexes containing S100A12, ERAC, in serum during inflammatory conditions.

The pro-inflammatory, leukocyte-derived S100A12 protein occurs as calcium-dependent oligomers in serum, while EDTA plasma from the majority of healthy individuals contains only monomers. Addition of 5 mM EDTA to serum leads to a rapid dissociation of the oligomers in most samples. However, using gel permeation chromatography, we have found that sera from some patients and seemingly healthy individuals contain molecular complexes in the 400-1000 kDa range reacting with anti-S100A12 even in the presence of EDTA; for these we introduce the name ERAC (EDTA Resistant S100A12 Complexes). Based upon monoclonal antibodies and the lateral flow principle, we have developed a quantitative rapid ERAC test giving results within 10 minutes. The highest prevalence of ERAC positivity was found in sera from patients with concomitant rheumatoid arthritis and coronary heart disease. The structure of ERAC is not yet known. Further studies are needed to analyse the mechanism behind the appearance of ERAC and the possible association with inflammatory-related diseases.

Remission is the goal for cardiovascular risk management in patients with rheumatoid arthritis: a cross-sectional comparative study.

OBJECTIVES: To compare markers of cardiovascular disease (CVD) risk between patients with rheumatoid arthritis (RA) in an active disease state and those with RA in remission, and to compare both groups with community controls. METHODS: 113 patients with RA and 86 community controls were assessed across a panel of biomarkers for CVD. RA in remission was defined as Clinical Disease Activity Index ≤2.8. Community controls were selected at random by Statistics Norway, and controls were matched with patients in the cohorts in strata using details of age, sex and residential area. A panel of biomarkers (N-terminal pro-brain natriuretic peptide (NT-proBNP), total cholesterol, reactive hyperaemia index (RHI), pressure measurements, measures of arterial stiffness and intima-media thickness) were compared between patients with active RA and those with RA in remission. Both groups were compared with controls. In addition, biomarker levels were compared across subgroups based on anticyclic citrullinated peptide status, level of joint destruction and presence of extra-articular manifestations. RESULTS: Patients with active RA had significantly higher levels of NT-proBNP, brachial systolic pressure, augmentation index and central systolic pressure but lower cholesterol than patients in remission and controls. In addition, patients with active RA had significantly higher levels of pulse wave velocity and worse RHI than patients in remission. Comparison across other subgroups gave less consistent differentiations in levels of CVD risk markers. CONCLUSION: Patients with active RA, but not those in remission, had significantly increased levels of CVD risk markers. These results link inflammatory activity to markers of CVD risk in patients with RA and may indirectly support the notion that remission in RA confers diminished cardiovascular morbidity.

NT-proBNP predicts mortality in patients with rheumatoid arthritis: results from 10-year follow-up of the EURIDISS study.

OBJECTIVES: Patients with rheumatoid arthritis (RA) have a higher mortality than the general population, and this increased mortality is related to demographic and disease variables. N-terminal pro-brain natriuretic peptide (NT-proBNP) is a predictor of mortality both in general and patient populations, but has not been shown to predict mortality in patients with RA. This study examines whether NT-proBNP can further improve the prediction of mortality in RA. METHODS: 182 patients with RA of 5-9 years disease duration were comprehensively examined in 1997. Serum samples were frozen and later batch analysed for NT-proBNP levels and other biomarkers. Adjusted univariate and logistic regression analyses were performed with death within the 10-year follow-up period as the dependent variable. Significant predictors were also examined as dichotomised variables. RESULTS: Mortality was predicted in univariate analyses by the following variables: age, sex, homozygosity for HLA-DRB1 shared epitope alleles, Health Assessment Questionnaire, 28-joint Disease Activity Score (DAS28) and NT-proBNP. A multivariate model with age, sex, DAS28 and NT-proBNP as independent variables showed the greatest discrimination. CONCLUSION: NT-proBNP provided incremental information in the prediction of mortality in this cohort of patients with RA.

Functional and structural vascular biomarkers in women 1 year after a hypertensive disorder of pregnancy.

OBJECTIVES: Women with a previous hypertensive disorder of pregnancy (HDP: gestational hypertension and preeclampsia) have increased long-term cardiovascular disease risk. Recent meta-analyses show adverse levels of non-invasive functional and structural cardiovascular risk markers such as pulse wave velocity (PWV), heart-rate adjusted augmentation index (AIx75), carotid intima-media thickness (CIMT), and reactive hyperemia index (RHI) after HDPs, and suggest using these for cardiovascular risk stratification. However, it is not known if a previous HDP predict levels of these markers beyond classical cardiovascular risk factors. Study design and main outcome measures. We assessed PWV, AIx75, CIMT, RHI, classical cardiovascular risk factors, and pregnancy characteristics in 221 women 1 year postpartum (controls: 95, previous HDP: 126). Uni- and multi- variate regression analysis were conducted to assess associations between previous HDP and PWV, AIx75, CIMT or RHI. We adjusted for classical cardiovascular risk factors and pregnancy characteristics. A p-level < 0.05 was considered statistically significant. RESULTS: PWV was associated with previous HDP on univariate analysis. This effect was confounded by blood pressure and not significant after adjustment. We found no significant associations between AIx75, RHI, CIMT, and a previous HDP, neither before nor after adjustments. CONCLUSIONS: Associations between a previous HDP and PWV, AIx75, CIMT, or RHI 1 year postpartum can largely be explained by adverse levels of classical cardiovascular risk markers in women with a previous HDP. Women with previous HDP should receive primary prevention of cardiovascular disease, but PWV, AIx75, CIMT or RHI are unlikely to aid in cardiovascular risk stratification 1 year postpartum.

Effects of Vitamin D Supplementation on Insulin Sensitivity and Insulin Secretion in Subjects With Type 2 Diabetes and Vitamin D Deficiency: A Randomized Controlled Trial.

OBJECTIVE: In observational studies, low vitamin D levels are associated with type 2 diabetes (T2D), impaired glucose metabolism, insulin sensitivity, and insulin secretion. We evaluated the efficacy of vitamin D supplementation on insulin sensitivity and insulin secretion in subjects with T2D and low vitamin D (25-hydroxyvitamin D [25(OH)D] <50 nmol/L). RESEARCH DESIGN AND METHODS: Sixty-two men and women with T2D and vitamin D deficiency participated in a 6-month randomized, double-blind, placebo-controlled trial. Participants received a single dose of 400,000 IU oral vitamin D3 or placebo, and the vitamin D group received an additional 200,000 IU D3 if serum 25(OH)D was <100 nmol/L after 4 weeks. Primary end points were total Rd by euglycemic clamp with assessment of endogenous glucose production and first-phase insulin secretion by intravenous glucose tolerance test. RESULTS: In the vitamin D group, the mean ± SD baseline serum 25(OH)D of 38.0 ± 12.6 nmol/L increased to 96.9 ± 18.3 nmol/L after 4 weeks, 73.2 ± 13.7 nmol/L after 3 months, and 53.7 ± 9.2 nmol/L after 6 months. The total exposure to 25(OH)D during 6 months (area under the curve) was 1,870 ± 192 and 1,090 ± 377 nmol/L per week in the vitamin D and placebo groups, respectively (P < 0.001). Insulin sensitivity, endogenous glucose production, and glycemic control did not differ between or within groups after treatment (P = 0.52). First-phase insulin secretion did not change significantly after treatment (P = 0.10). CONCLUSIONS: Replenishment with a large dose of vitamin D3 to patients with T2D and vitamin D deficiency did not change insulin sensitivity or insulin secretion. These findings do not support such use of therapeutic vitamin D3 supplementation to improve glucose homeostasis in patients with T2D.

Glucosepane and oxidative markers in skin collagen correlate with intima media thickness and arterial stiffness in long-term type 1 diabetes.

AIMS: To study intima media thickness (cIMT) and arterial stiffness in type 1 diabetes of long duration, and their associations with the collagen cross-linker glucosepane and inflammatory and oxidative markers. METHODS: Twenty-seven individuals with type 1 diabetes mellitus of 40 years duration from the Oslo Study cohort and 24 age-matched controls were included. cIMT measurements of the carotid artery were performed longitudinally. Pulse wave velocity (PWV), augmentation index (AIx) and augmentation pressure (AP) were assessed cross-sectionally. Glucosepane and the oxidative product methionine sulfoxide (MetSO) were determined in skin collagen by liquid chromatography-mass spectrometry. Circulating inflammatory markers were determined by ELISAs. RESULTS: The diabetes patients had significantly increased cIMT and arterial stiffness compared to controls. Significant correlations were noted for skin glucosepane with cIMT (r=0.41) and PWV (r=0.44). Skin MetSO and monocyte chemoattractant protein-1 (MCP-1) correlated significantly with AIx and AP. After correcting for age and mean arterial pressure in multiple linear regression analysis, MetSO and MCP-1 were both independently associated with AIx and AP. CONCLUSIONS: These results suggest more premature atherosclerosis and arterial pathology in individuals with diabetes compared to age-matched controls. They also suggest an association between the arterial pathology and markers of collagen crosslinking, oxidative damage and inflammation in type 1 diabetes patients of forty years disease duration.

The L-arginine/asymmetric dimethylarginine ratio is improved by anti-tumor necrosis factor-α therapy in inflammatory arthropathies. Associations with aortic stiffness.

BACKGROUND: Anti-Tumor Necrosis Factor (TNF)-α therapy improves vascular pathology in inflammatory arthropathies such as rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. The l-arginine/ADMA ratio is important for modulation of the nitric oxide synthase activity. We examined the effect of TNF-α antagonists on ADMA and l-arginine/ADMA, and associations between ADMA, L-arginine/ADMA, aortic stiffness and carotid intima media thickness (CIMT) in patients with inflammatory arthropathies. METHODS: Forty-eight patients who started with anti-TNF-α therapy were compared with a non-treated group of 32 patients. Plasma ADMA and L-arginine were assessed at baseline, 3 and 12 months. In a subgroup of 55 patients, aortic pulse wave velocity (aPWV) was measured at baseline, 3 and 12 moths, and CIMT was examined at baseline and 12 months. RESULTS: Anti-TNF-α therapy increased the L-arginine/ADMA ratio (mean [SD]) in the treatment group compared to the control group after 3 months (12 [29] vs. -13 [20], P < 0.001) and 12 months (7 [27] vs. -8 [19], P = 0.008), but did not affect ADMA (3 months: 0.00 [0.09] µmol/L vs. 0.02 [0.07] µmol/L, P = 0.42, 12 months: 0.01 [0.08] µmol/L vs. 0.01 [0.09] µmol/L, P = 0.88). Baseline aPWV was associated with ADMA (P = 0.02) and L-arginine/ADMA (P = 0.02) in multiple regression analyses, and the L-arginine/ADMA ratio was continuously associated with aPWV after initiation of anti-TNF-α therapy (P = 0.03). ADMA and L-arginine/ADMA were not correlated with CIMT. CONCLUSION: Anti-TNF-α therapy improved the L-arginine/ADMA ratio in patients with inflammatory arthropathies. ADMA and the L-arginine/ADMA ratio were associated with aPWV, and might have a mechanistic role in the aortic stiffening observed in these patients.

Effect of 1-year anti-TNF-α therapy on aortic stiffness, carotid atherosclerosis, and calprotectin in inflammatory arthropathies: a controlled study.

BACKGROUND: Premature arterial stiffening and atherosclerosis are increased in patients with inflammatory arthropathies such as rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). The proinflammatory protein calprotectin is associated with inflammatory arthropathies, vascular pathology, and acute coronary events. We examined the long-term effects of treatment with tumor necrosis factor (TNF)-α antagonists on aortic stiffness and carotid intima media thickness (CIMT) in patients with inflammatory arthropathies, and the relationships to the levels of calprotectin. METHODS: Fifty-five patients with RA, AS, or PsA and a clinical indication for anti-TNF-α therapy were included and followed with regular examinations for 1 year. Thirty-six patients starting with anti-TNF-α therapy were compared with a nontreatment group of 19 patients. Examinations included assessments of aortic stiffness (aortic pulse wave velocity, aPWV), CIMT, and plasma calprotectin. RESULTS: After 1 year, aPWV (mean (s.d.)) was improved in the treatment group, but not in the control group (-0.54 [0.79] m/s vs. 0.06 [0.61] m/s, respectively; P = 0.004), and CIMT progression (median (quartile cut-points, 25th and 75th percentiles)) was reduced in the treatment group compared to the control group (-0.002 [-0.038, 0.030] mm vs. 0.030 [0.011, 0.043] mm, respectively; P = 0.01). In multivariable analyses, anti-TNF-α therapy over time was associated with improved aPWV (P = 0.02) and reduced CIMT progression (P = 0.04), and calprotectin was longitudinally associated with aPWV (P = 0.02). CONCLUSIONS: Long-term anti-TNF-α therapy improved aortic stiffness and CIMT progression in patients with inflammatory arthropathies. Calprotectin may be a soluble biomarker reflecting aortic stiffening in these patients.

Early prediction of increased arterial stiffness in patients with chronic inflammation: a 15-year followup study of 108 patients with rheumatoid arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA), a chronic inflammatory disease, have increased cardiovascular morbidity and mortality. We investigated whether early markers of RA inflammatory disease activity could predict later increased levels of pulse-wave velocity (PWV) and augmentation index (AIx), 2 measures of arterial stiffness. METHODS: In total 238 patients with early RA were followed longitudinally and 108 were available for the 15-year followup examination. Comprehensive baseline clinical and radiographic data were collected in 1992. Arterial stiffness, measured as AIx and PWV (Sphygmocor apparatus), was recorded at the 15-year followup. Adjusted logistic univariate and multivariate analyses were performed with levels of AIx and PWV as the dependent variables, and variables reflecting baseline RA disease activity as possible predictors. The validity of the final models was examined in linear regression analyses. RESULTS: Baseline C-reactive protein (CRP) above the median predicted increased AIx (OR 3.52, 95% CI 1.04-11.90) and PWV (OR 4.84, 95% CI 1.39-16.83) at the 15-year assessment in multivariate models. Patients with elevated baseline CRP had significantly higher AIx (ß = 2.67, 95% CI 0.06-5.31, p = 0.045) and lnPWV (ß = 0.08, 95% CI 0.01-0.14, p = 0.02) after 15 years, after adjustments for age, sex, heart rate (AIx only) and mean arterial pressure. CONCLUSION: Inflammation early in the RA disease course was associated with increased AIx and PWV after 15 years. These findings support the importance of early control of the inflammatory process in patients with RA.

Changes in arterial stiffness during continued infliximab treatment in patients with inflammatory arthropathies.

Chronic inflammatory arthropathies such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) are associated with an increased risk of cardiovascular disease. TNF-α antagonists may improve vascular function in these patients and thus be beneficial with regard to cardiovascular disease. This study evaluated arterial stiffness and disease activity between two infusions with a TNF-α antagonist (infliximab) in patients with inflammatory arthropathies on long-term infliximab therapy. Augmentation index (AIx), aortic pulse wave velocity (aPWV), and disease activity were measured in 17 patients with RA, AS, or PsA who had been treated with infliximab for at least 12 months. The patients were examined immediately before their infliximab infusion and thereafter every 10th day until their next infusion scheduled at week 4-8. AIx and aPWV did not change during the period between two infliximab infusions. The patients had a temporary improvement in the general disease activity assessed on visual analogue scales by the patients (P = 0.04) and the investigator (P = 0.02) after the infusion. In the group of patients with RA, the Disease Activity Score (DAS28) changed significantly in a similar manner (P = 0.003). C-reactive protein and erythrocyte sedimentation rate remained unchanged. Infliximab infusions did not alter aortic pulse wave velocity or augmentation index in patients with inflammatory arthropathies who were on long-term infliximab therapy. Reductions in the general disease activity and DAS28 were not reflected in alterations of aortic stiffness or augmentation index.

Tumor necrosis factor-alpha antagonists improve aortic stiffness in patients with inflammatory arthropathies: a controlled study.

The chronic inflammatory state of rheumatoid arthritis and other inflammatory arthropathies, such as ankylosing spondylitis and psoriatic arthritis, contributes to the accelerated atherosclerosis associated with these conditions. This study evaluates the effect of treatment with tumor necrosis factor (TNF)-alpha antagonists on arterial stiffness in patients with inflammatory arthropathies. A total of 60 patients with rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis and clinical indication for anti-TNF-alpha therapy were included. Thirty-five patients started with anti-TNF-alpha therapy and were compared with a nontreatment group of 25 patients. Aortic stiffness (aortic pulse wave velocity), augmentation index, and disease activity were assessed at baseline and after 3 months. Aortic pulse wave velocity (mean+/-SD) was reduced in the treatment group but not in the control group (-0.50+/-0.78 m/s versus 0.05+/-0.54 m/s, respectively; P=0.002). Concomitantly, C-reactive protein and the disease activity score were reduced in the treatment group (-9.3+/-20.2 mg/L [P<0.001] and -0.74+/-0.91 [P=0.004]). Augmentation index remained unchanged in both groups (0.1+/-7.1% versus -1.0+/-5.8%, respectively; P=0.53). In a multivariate linear regression model, only treatment with TNF-alpha antagonist and change in mean arterial pressure predicted alterations in aortic pulse wave velocity. In summary, anti-TNF-alpha therapy improved aortic stiffness in patients with inflammatory arthropathies. These findings support the idea that anti-inflammatory treatment has a favorable effect on cardiovascular risk in patients with inflammatory arthropathies.

The association between disease activity and NT-proBNP in 238 patients with rheumatoid arthritis: a 10-year longitudinal study.

INTRODUCTION: Disease activity in patients with rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality, of which N-terminal pro-brain natriuretic peptide (NT-proBNP) is a predictor. Our objective was to examine the cross-sectional and longitudinal associations between markers of inflammation, measures of RA disease activity, medication used in the treatment of RA, and NT-proBNP levels (dependent variable). METHODS: Two hundred thirty-eight patients with RA of less than 4 years in duration were followed longitudinally with three comprehensive assessments of clinical and radiographic data over a 10-year period. Serum samples were frozen and later batch-analyzed for NT-proBNP levels and other biomarkers. Bivariate, multivariate, and repeated analyses were performed. RESULTS: C-reactive protein (CRP) levels at baseline were cross-sectionally associated with NT-proBNP levels after adjustment for age and gender (r2 adjusted = 0.23; P < 0.05). At the 10-year follow-up, risk factors for cardiovascular disease were recorded. Duration of RA and CRP levels were independently associated with NT-proBNP in the final model that was adjusted for gender, age, and creatinine levels (r2 adjusted = 0.38; P < 0.001). In the longitudinal analyses, which adjusted for age, gender, and time of follow-up, we found that repeated measures of CRP predicted NT-proBNP levels (P < 0.001). CONCLUSION: CRP levels are linearly associated with levels of NT-proBNP in cross-sectional and longitudinal analyses of patients with RA. The independent associations of NT-proBNP levels and markers of disease activity with clinical cardiovascular endpoints need to be further investigated.