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Another Bite at the APPLE

New studies suggest link between vitamin D deficiency and atherosclerosis in pediatric lupus patients

Innovations in Pediatric - Winter 2016 - View Full PDF


Program Director, Pediatric Rheumatology, UH Rainbow Babies & Children’s Hospital Assistant Professor of Pediatrics, Case Western Reserve University School of Medicine

When it launched in 2003, the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial aimed to determine whether atorvastatin could slow the progression of atherosclerosis in children, teens and young adults with systemic lupus erythematosus (SLE).

“Kids with lupus grow up to be adults who have early heart attacks, especially women, who are the majority of lupus patients,” says Angela Byun Robinson, MD, a pediatric rheumatologist at University Hospitals Rainbow Babies & Children’s Hospital. “For a woman with lupus, her risk of having a heart attack is 50 times that of a healthy woman. We don’t know when that starts. The APPLE trial was designed to see whether atorvastatin could help decrease that risk.” 

The APPLE trial showed no significant difference in carotid intima medial thickness (CIMT) between SLE patients taking the statin and those taking a placebo. But the wealth of data gathered in the trial got Dr. Robinson and her colleagues thinking – especially about the role of vitamin D.

“We were interested in looking at vitamin D and how it correlates to disease activity and atherosclerosis in these patients,” Dr. Robinson says. “Since lupus patients tend to have low vitamin D and tend to have atherosclerosis, wouldn’t it be interesting if there were a link between the two?” The project was funded through a pilot grant from the UH Rainbow Babies & Children’s Hospital Department of Pediatrics and a grant from the National Institutes of Health (NIH) to Case Western Reserve University School of Medicine. 

In re-analyzing the APPLE trial data, Dr. Robinson and her colleagues have confirmed that vitamin D deficiency and insufficiency are indeed common in pediatric SLE patients, despite many of these patients taking daily vitamin D supplements. Plus, they’ve shown that patients’ vitamin D status is correlated with the inflammatory marker high-sensitivity C-reactive protein (hsCRP) – the first time this has been shown in pediatric lupus patients. These results were published in the journal Lupus Science and Medicine. 

“The association between vitamin D deficiency and hsCRP is novel in pediatric lupus and suggests that vitamin D deficiency may contribute to heightened inflammation and cardiovascular risk in this high-risk population,” Dr. Robinson says.

In another subgroup analysis, also published in Lupus Science and Medicine, Dr. Robinson and colleagues have shown that pediatric lupus patients with higher vitamin D levels are more likely to benefit from atorvastatin therapy. 

“For the first time in SLE, we find that vitamin D status may affect response to atorvastatin in cardiovascular disease risk and CIMT progression over time,” Dr. Robinson says. “These findings suggest that underlying vitamin D deficiency may negatively impact the efficacy of atorvastatin in atherosclerosis prevention.”

For Dr. Robinson, these findings point to the need for increased monitoring of vitamin D levels in pediatric lupus patients. 

“We should be checking,” she says. “There is some suggestion that if you get their vitamin D levels more toward normal, it could be beneficial to them. It’s not necessarily part of the standard of care, but more and more of us are checking it frequently. We don’t have a great idea of what the optimal vitamin D level should be for these kids, but we do know now that if you are severely deficient, it’s not good for your bones, not good for your cardiovascular health and not good in terms of inflammation.” 

Contact Dr. Robinson at