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      Vitamin D status is a determinant of atorvastatin effect on carotid intima medial thickening progression rate in children with lupus: an Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) substudy

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      1 , 2 , 3 , 1 , 4 , 5
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      Lupus Science & Medicine
      BMJ Publishing Group
      Systemic Lupus Erythematosus, Childhood/paediatric lupus, Inflammation, Cardiovascular Disease

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          Abstract

          Objective

          Epidemiological associations suggest that vitamin D status may play a role in inflammation and progression of atherosclerosis. Using frozen serum, carotid intima medial thickness (CIMT) measurements and other existing data from the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial, we assessed interactions between serum 25-hydroxyvitamin D (25(OH)D), atorvastatin randomisation and CIMT progression rate.

          Methods

          Participants in the 3-year APPLE trial were randomised to placebo or atorvastatin and CIMT progression rate was measured. Baseline frozen serum was used to measure 25(OH)D concentrations. Mixed effect longitudinal models for CIMT progression at 3 years were used to evaluate interaction between vitamin D deficiency (serum 25(OH)D <20 ng/mL) at baseline and atorvastatin or placebo treatment, adjusting for key systemic lupus erythematosus disease variables and cardiovascular risk factors.

          Results

          201/221 APPLE participants had available samples and were included in this analysis; 61/201 (30%) had vitamin D deficiency at baseline. In adjusted longitudinal modelling, there was significant interaction between baseline vitamin D deficiency and atorvastatin randomisation in 3-year progression of mean-max CIMT. In four out of six carotid segments, there was a greater decrease in mean-max CIMT progression rate in subjects who were treated with atorvastatin compared with placebo if they had baseline serum 25(OH)D levels ≥20 ng/mL.

          Conclusions

          Subjects with serum 25(OH)D ≥20 ng/mL had less mean-max CIMT progression following 3 years of atorvastatin treatment. Results from secondary analyses must be interpreted cautiously, but findings suggest that underlying vitamin D deficiency may be involved in response to atorvastatin in atherosclerosis prevention.

          Trial registration number

          NCT00065806.

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          Most cited references35

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          Inflammation in atherosclerosis: from pathophysiology to practice.

          Until recently, most envisaged atherosclerosis as a bland arterial collection of cholesterol, complicated by smooth muscle cell accumulation. According to that concept, endothelial denuding injury led to platelet aggregation and release of platelet factors which would trigger the proliferation of smooth muscle cells in the arterial intima. These cells would then elaborate an extracellular matrix that would entrap lipoproteins, forming the nidus of the atherosclerotic plaque. Beyond the vascular smooth muscle cells long recognized in atherosclerotic lesions, subsequent investigations identified immune cells and mediators at work in atheromata, implicating inflammation in this disease. Multiple independent pathways of evidence now pinpoint inflammation as a key regulatory process that links multiple risk factors for atherosclerosis and its complications with altered arterial biology. Knowledge has burgeoned regarding the operation of both innate and adaptive arms of immunity in atherogenesis, their interplay, and the balance of stimulatory and inhibitory pathways that regulate their participation in atheroma formation and complication. This revolution in our thinking about the pathophysiology of atherosclerosis has now begun to provide clinical insight and practical tools that may aid patient management. This review provides an update of the role of inflammation in atherogenesis and highlights how translation of these advances in basic science promises to change clinical practice.
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            Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study.

            The authors ascertained cardiovascular events (myocardial infarction and angina pectoris) in 498 women with systemic lupus erythematosus seen at the University of Pittsburgh Medical Center from 1980 to 1993 (3,522 person-years). Subjects were stratified by age, and cardiovascular event incidence rates were determined. The authors compared these rates with cardiovascular event rates were determined. The authors compared these rates with cardiovascular event rates occurring over the same time period in 2,208 women of similar age participating in the Framingham Offspring Study (17,519 person-years). Age-specific rate ratios were computed to determine whether the cardiovascular events in the lupus cohort were greater than expected. The risk factors associated with cardiovascular events in women with lupus were determined. There were 33 first events (11 myocardial infarction, 10 angina pectoris, and 12 both angina pectoris and myocardial infarction) after the diagnosis of lupus: two thirds were under the age of 55 years at the time of event. Women with lupus in the 35- to 44-year age group were over 50 times more likely to have a myocardial infarction than were women of similar age in the Framingham Offspring Study (rate ratio = 52.43, 95% confidence interval 21.6-98.5). Older age at lupus diagnosis, longer lupus disease duration, longer duration of corticosteroid use, hypercholesterolemia, and postmenopausal status were more common in the women with lupus who had a cardiovascular event than in those who did not have an event. Premature cardiovascular disease is much more common in young premenopausal women with lupus than in a population sample. With the increased life expectancy of lupus patients due to improved therapy, cardiovascular disease has emerged as a significant threat to the health of these women. The impact of this problem has been underrecognized, with little focus placed on aggressive management of hypercholesterolemia and other possible risk factors.
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              Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus.

              The frequency of coronary heart disease (CHD) and stroke are increased in systemic lupus erythematosus (SLE), but the extent of the increase is uncertain. We sought to determine to what extent the increase could not be explained by common risk factors. The participants at two SLE registries were assessed retrospectively for the baseline level of the Framingham study risk factors and for the presence of vascular outcomes: nonfatal myocardial infarction (MI), death due to CHD, overall CHD (nonfatal MI, death due to CHD, angina pectoris, and congestive heart failure due to CHD), and stroke. For each patient, the probability of the given outcome was estimated based on the individual's risk profile and the Framingham multiple logistic regression model, corrected for observed followup. Ninety-five percent confidence intervals (95% CIs) were estimated by bootstrap techniques. Of 296 SLE patients, 33 with a vascular event prior to baseline were excluded. Of the 263 remaining patients, 34 had CHD events (17 nonfatal MIs, 12 CHD deaths) and 16 had strokes over a mean followup period of 8.6 years. After controlling for common risk factors at baseline, the increase in relative risk for these outcomes was 10.1 for nonfatal MI (95% CI 5.8-15.6), 17.0 for death due to CHD (95% CI 8.1-29.7), 7.5 for overall CHD (95% CI 5.1-10.4), and 7.9 for stroke (95% CI 4.0-13.6). There is a substantial and statistically significant increase in CHD and stroke in SLE that cannot be fully explained by traditional Framingham risk factors alone.
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                Author and article information

                Journal
                Lupus Sci Med
                Lupus Sci Med
                lupusscimed
                lupus
                Lupus Science & Medicine
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                2053-8790
                2014
                10 September 2014
                : 1
                : 1
                : e000037
                Affiliations
                [1 ]Department of Pediatrics, Rainbow Babies and Children's Hospital/Case Medical Center , Cleveland, Ohio, USA
                [2 ]Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine and Atlanta VA Medical Center, Atlanta, Georgia, USA
                [3 ]Duke Clinical Research Institute , Durham, North Carolina, USA
                [4 ]Department of Pediatrics, Duke University Medical Center , Durham, North Carolina, USA
                [5 ]Department of Medicine and Pediatrics, Case Medical Center , Cleveland, Ohio, USA
                Author notes
                [Correspondence to ] Dr Angela Byun Robinson; angela.robinson@ 123456uhhospitals.org
                Author information
                http://orcid.org/0000-0002-4021-5853
                Article
                lupus-2014-000037
                10.1136/lupus-2014-000037
                4225736
                25396067
                336697d3-438e-4875-9616-9c9b36d4c7c6
                Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

                History
                : 30 May 2014
                : 31 July 2014
                : 13 August 2014
                Categories
                Epidemiology and Outcomes
                1506
                2257

                systemic lupus erythematosus,childhood/paediatric lupus,inflammation,cardiovascular disease

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