Dialogue: Vitamin D, statins and atherosclerotic progression in paediatric lupus

Correspondence to Gary S Gilkeson; [email protected] In the last six months, Lupus Science and Medicine has published two papers by Robinson et al 2 that were secondary analyses and substudies of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) study. The major emphasis of the two papers was (1) the association of vitamin D levels at baseline with inflammatory markers, ethnicity, season, lipid status and disease damage in the first paper, (2) and with progression of carotid intimal thickening in patients treated with atorvastatin in the second paper. The original APPLE study was designed to evaluate whether statin therapy (atorvastatin) could affect atherosclerosis progression over a 3-year period in paediatric patients without hypercholesterolaemia. The significance of this study is obvious, given the accelerated atherosclerosis reported in patients with lupus. There was no statistically significant effect of atorvastatin on carotid intimal thickening progression. Studying underlying mechanisms of this proatherosclerotic effect of lupus in paediatric patients devoid of many of the confounding risk factors present in adults with lupus provides an opportunity to assign causation and response to treatment. The Lupus Atherosclerosis Prevention Study assessed the effect of statins on atherosclerotic disease progression in 200 adults with no clinical evidence of vascular disease and without elevated cholesterol levels. Like the APPLE study, statin therapy had no significant impact on atherosclerotic progression in adults with lupus. The studies published in Lupus Science and Medicine addressed whether vitamin D status at baseline affected progression of carotid atherosclerosis. Vitamin D is reported to have myriad physiological effects. A number of published reports, primarily retrospective analyses, suggest a role for vitamin D in bone health, atherosclerosis, efficacy of statin therapy, cancer and autoimmune diseases. Investigators have reported lower vitamin D in patients with lupus versus non-lupus controls. In addition, low vitamin D levels have been associated with more lupus disease flares and end organ damage. These combined observations provided the biological rationale for examining whether vitamin D levels affected the results of the APPLE trial. In the first paper, the authors determined the variables associated with vitamin D status at baseline. Perhaps not surprisingly, over 90% of participants in the trial had vitamin D insufficiency (25(OH)D <30 ng/mL), whereas 30% were vitamin D deficient (<20 ng/mL) and 10% were severely deficient (<10 ng/mL). The participants were divided into two groups: <20 and >20 ng/mL of 25(OH)D for comparison (n=61 vs n=140, respectively). As expected, there was a correlation between the serum vitamin D levels and the season in which the blood was drawn. There was also a significant correlation with ethnicity, with African– Americans having the highest percentage of vitamin D deficiency. Other ‘lupus’ factors that correlated with vitamin D deficiency at baseline were longer disease duration and more organ damage as measured by the Systemic Lupus International Cooperating Clinics (SLICC) damage index. The primary finding of the paper was that low vitamin D levels at baseline were associated with a high sensitivity C reactive protein (hsCRP) (2.2 in the vitamin D-insufficient group vs 4.6 in the vitamin D-deficient group). Higher low-density lipoprotein cholesterol levels were also associated with vitamin D insufficiency. In a multivariate analysis controlling for other variables, hsCRP remained significantly associated with vitamin D status. The primary limitation of this study was that the associations between vitamin D status and baseline variables did not include baseline carotid intima-media thickness (CIMT), a measure of atherosclerosis. Thus, the second paper by the same authors was of greater interest since this study examined the interaction between vitamin D deficiency (serum 25(OH) ▸ http://dx.doi.org/10.1136/ lupus-2014-000037