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

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.

[1]  R. Snyderman.  Duke Clinical Research Institute , 2016 .

[2]  E. Yow,et al.  Vitamin D deficiency is common and associated with increased C-reactive protein in children and young adults with lupus: an Atherosclerosis Prevention in Pediatric Lupus Erythematosus substudy , 2014, Lupus Science & Medicine.

[3]  P. Norman,et al.  Vitamin D and cardiovascular disease. , 2014, Circulation research.

[4]  L. Magder,et al.  Vitamin D deficiency does not predict progression of coronary artery calcium, carotid intima-media thickness or high-sensitivity C-reactive protein in systemic lupus erythematosus. , 2013, Rheumatology.

[5]  E. Yow,et al.  Secondary analysis of APPLE study suggests atorvastatin may reduce atherosclerosis progression in pubertal lupus patients with higher C reactive protein , 2013, Annals of the rheumatic diseases.

[6]  G. Nunnari,et al.  Immuno-modulatory effects of vitamin D3 in human monocyte and macrophages. , 2012, Cellular immunology.

[7]  S. Humphries,et al.  Measurements of carotid intima-media thickness and of interadventitia common carotid diameter improve prediction of cardiovascular events: results of the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study. , 2012, Journal of the American College of Cardiology.

[8]  C. Rabinovich,et al.  Disease activity, proteinuria, and vitamin D status in children with systemic lupus erythematosus and juvenile dermatomyositis. , 2012, The Journal of pediatrics.

[9]  F. Gottrand,et al.  Increased intima-media thickness of the carotid artery in childhood: a systematic review of observational studies , 2011, European Journal of Pediatrics.

[10]  M. Kumari,et al.  Vitamin D is Linked to Carotid Intima-Media Thickness and Immune Reconstitution in HIV-Positive Individuals , 2011, Antiviral therapy.

[11]  L. Magder,et al.  Lupus Atherosclerosis Prevention Study (LAPS) , 2010, Annals of the rheumatic diseases.

[12]  T. Pieber,et al.  Vitamin D and Cardiovascular Disease , 2010, Nutrients.

[13]  Paul M Ridker,et al.  Inflammation in atherosclerosis: from pathophysiology to practice. , 2009, Journal of the American College of Cardiology.

[14]  S. Hailpern,et al.  Prevalence and Associations of 25-Hydroxyvitamin D Deficiency in US Children: NHANES 2001–2004 , 2009, Pediatrics.

[15]  K. Schechtman,et al.  1,25(OH)2 Vitamin D Inhibits Foam Cell Formation and Suppresses Macrophage Cholesterol Uptake in Patients With Type 2 Diabetes Mellitus , 2009, Circulation.

[16]  D. D. de Luis,et al.  Vitamin D Levels and Lipid Response to Atorvastatin , 2009, International journal of endocrinology.

[17]  J. Burnham,et al.  Hypovitaminosis D is associated with greater body mass index and disease activity in pediatric systemic lupus erythematosus. , 2009, The Journal of pediatrics.

[18]  J. Vieira,et al.  Vitamin D deficiency in patients with active systemic lupus erythematosus , 2009, Osteoporosis International.

[19]  J. Schwartz,et al.  Effects of Vitamin D Supplementation in Atorvastatin‐Treated Patients: A New Drug Interaction With an Unexpected Consequence , 2009, Clinical pharmacology and therapeutics.

[20]  B. Boehm,et al.  Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. , 2008, Archives of internal medicine.

[21]  G. Ruiz-Irastorza,et al.  Vitamin D deficiency in systemic lupus erythematosus: prevalence, predictors and clinical consequences. , 2008, Rheumatology.

[22]  V. Pascual,et al.  The innate immune system in SLE: type I interferons and dendritic cells , 2008, Lupus.

[23]  J. Adams,et al.  Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity , 2008, Nature Clinical Practice Endocrinology &Metabolism.

[24]  L. Magder,et al.  Predictors of high sensitivity C-reactive protein levels in patients with systemic lupus erythematosus , 2008, Lupus.

[25]  Michael J. Pencina,et al.  Vitamin D Deficiency and Risk of Cardiovascular Disease , 2008, Circulation.

[26]  P. Lipsky,et al.  Modulatory Effects of 1,25-Dihydroxyvitamin D3 on Human B Cell Differentiation , 2007, The Journal of Immunology.

[27]  M. Verhaar,et al.  Premature atherosclerotic cardiovascular disease in systemic lupus erythematosus. , 2007, Arthritis and rheumatism.

[28]  V. Nassonova,et al.  Current causes of death in systemic lupus erythematosus in Europe, 2000—2004: relation to disease activity and damage accrual , 2007, Lupus.

[29]  G. Targher,et al.  Serum 25‐hydroxyvitamin D3 concentrations and carotid artery intima‐media thickness among type 2 diabetic patients , 2006, Clinical endocrinology.

[30]  C. Treves,et al.  1,25‐Dihydroxyvitamin D3 inhibits tumor necrosis factor‐α‐induced adhesion molecule expression in endothelial cells , 2006 .

[31]  S. Shaftman,et al.  Vitamin D deficiency in systemic lupus erythematosus. , 2006, Autoimmunity reviews.

[32]  M. Abrahamowicz,et al.  Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus. , 2001, Arthritis and rheumatism.

[33]  L. Liou.  Serum and in vitro production of IL-1 receptor antagonist correlate with C-reactive protein levels in newly diagnosed, untreated lupus patients. , 2001, Clinical and experimental rheumatology.

[34]  P. Allavena,et al.  Vitamin D3 Affects Differentiation, Maturation, and Function of Human Monocyte-Derived Dendritic Cells1 , 2000, The Journal of Immunology.

[35]  P. Ridker,et al.  C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. , 2000, The New England journal of medicine.

[36]  T. Satoh,et al.  Clinical and laboratory features of lupus patients with complicating pulmonary disease. , 1999, Respiratory medicine.

[37]  K. Watson,et al.  Active serum vitamin D levels are inversely correlated with coronary calcification. , 1997, Circulation.

[38]  A. K. Jarvis,et al.  1,25-Dihydroxyvitamin D3 regulation of cardiac myocyte proliferation and hypertrophy. , 1997, The American journal of physiology.

[39]  R. D'Agostino,et al.  Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. , 1997, American journal of epidemiology.

[40]  L. Lind,et al.  Vitamin D is related to blood pressure and other cardiovascular risk factors in middle-aged men. , 1995, American journal of hypertension.

[41]  H. Spiegelberg,et al.  Immunosuppressive actions of 1,25-dihydroxyvitamin D3: preferential inhibition of Th1 functions. , 1995, The Journal of nutrition.

[42]  C. Kane,et al.  Isolation and characterization of renin-expressing cell lines from transgenic mice containing a renin-promoter viral oncogene fusion construct. , 1990, The Journal of biological chemistry.

[43]  R. Beaglehole,et al.  Myocardial infarction is inversely associated with plasma 25-hydroxyvitamin D3 levels: a community-based study. , 1990, International journal of epidemiology.

[44]  E. Yow,et al.  Use of atorvastatin in systemic lupus erythematosus in children and adolescents. , 2012, Arthritis and rheumatism.

[45]  S. Haque.  Ethics approval This study was conducted with the approval of the East London and City Health Authority Ethic Committee. Provenance and peer review Not commissioned; externally peer reviewed. , 2011 .

[46]  C. Treves,et al.  1,25-Dihydroxyvitamin D3 inhibits tumor necrosis factor-alpha-induced adhesion molecule expression in endothelial cells. , 2006, Cell biology international.

[47]  M. Cippitelli,et al.  Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene. , 1998, The Journal of clinical investigation.

[48]  H. Moutsopoulos,et al.  High C-reactive protein response in lupus polyarthritis. , 1983, Clinical and experimental rheumatology.

[49]  T. Takahashi.  [Erythematosus]. , 1971, Nihon rinsho. Japanese journal of clinical medicine.