Vitamin D—update for the pediatric rheumatologists
© Vojinovic and Rolando; licensee BioMed Central. 2015
Received: 22 December 2014
Accepted: 22 May 2015
Published: 29 May 2015
Vitamin D, upon its discovery one century ago, was classified as a vitamin. This classification still greatly affects our perception about its biological role. 1,25(OH)2D (now known as the D hormone) is a pleiotropic steroid hormone that has multiple biologic effects. It is integral to the regulation of calcium homeostasis and bone turnover as well as having anti-proliferative, pro-differentiation, anti-bacterial, immunomodulatory and anti-inflammatory properties within the body in various cells and tissues. Vitamin D (cholecalciferol) should be considered a nutritional substrate that must be ingested or synthesized in sufficient amounts for the further synthesis of the very important regulatory steroid hormone (D hormone), especially in patients with pediatric rheumatic diseases (PRD).
Vitamin D insufficiency or deficiency was shown to be pandemic and associated with numerous chronic inflammatory and malignant diseases and even with increased risk of mortality. Several studies have demonstrated that a high percentage of children with pediatric rheumatic diseases (PRD-e.g., JIA, jSLE) have a vitamin D deficiency or insufficiency which might correlate with disease outcome and flares. Glucocorticoids used to treat disease may have a regulatory effect on vitamin D metabolism which can additionally aggravate bone turnover in PRD. An effort to define the optimal serum 25(OH)D concentrations for healthy children and adults was launched in 2010 but as of now there are no guidelines about supplementation in PRD.
In this review we have tried to summarize the strong evidence now suggesting that as the knowledge of the optimal approach to diagnosis and treatment PRD has evolved, there is also an emerging need for vitamin D supplementation as an adjunct to regular disease treatment. So in accordance with new vitamin D recommendations, we recommend that a child with rheumatic disease, especially if treated with steroids, needs at least 2-3 time higher doses of vitamin D than the dose recommended for age (approximately 2000 UI/day). Vitamin D supplementation has become an appealing and important adjunct treatment option in PRD.
KeywordsVitamin D recommendations Juvenile idiopathic arthritis Juvenile systemic lupus erythematosus D hormone Pediatric rheumatic diseases
One century after its discovery and three Nobel prizes awarded for discoveries in this topic , we have clear evidences that the so-called vitamin D is in fact a pleiotropic steroid hormone similar to other steroid hormones. Unfortunately, its primary classification into the vitamins still deeply influences our professional perception about 1,25(OH)2D biological function and impact on the occurrence and outcome of the some rheumatic diseases . It is necessary to distinguish cholecaliferol (commonly called vitamin D), a nutritional precursor compound, from the 1,25(OH)2D-vitamin D hormonal form. This hormonal form is synthetized after a complex, endocrine-regulated biochemical process. This 1,25(OH)2D D hormone has its own endocrine, paracrine and autocrine control . As hormone is defined as a chemical substance produced in one part of the body that stimulates functional activity in another part , it is clear that what we call vitamin D does not fulfill the vitamin definition criteria but rather those for a hormone. We will discuss the biologic roles of vitamin D in this review as that of the D hormone.
When prescribing medication for the treatment of rheumatic diseases, most of pediatric rheumatologists do not recommend vitamins as mandatory, including vitamin D. Yet newer scientific studies may soon change that approach. Beside regulation of calcium homeostasis and bone turnover, the D hormone has proven antiproliferative, pro-differentiation, anti-bacterial, immunomodulatory and anti-inflammatory properties within the body in various cells and tissues [2, 3]. This effects can be achieved only if the D hormone (1,25(OH)2D) itself, or its agonist, is bound to vitamin D receptor (VDR). The discovery that vitamin D receptor agonists possess immunomodulatory and anti-tumor properties prompted research to investigate the possibility that these agonists might be used as a therapeutic agent for different autoimmune and malignant diseases [7,8].
Randomized controlled trials providing recommendations for vitamin D supplementation in pediatric patients with PRD are lacking. Yet several recent studies have supported the importance of and necessity for vitamin D supplementation within standard treatment protocols and guidelines of rheumatic diseases in childhood. A study of Arkema et al.  investigated the association between UV-B light exposure and the risk of developing rheumatoid arthritis (RA) among women enrolled in two large prospective cohort studies [the Nurses’ Health Study (NHS) and the NHSII]. These studies confirmed a significantly decreased risk of RA with higher UV-B exposure especially between birth and age 15 years. Nisar et al.  published a systemic literature review and meta-analysis of current evidence on vitamin D in JIA, summarizing data from 19 papers that were largely supporting positive benefits. Robinson et al.  presented data from Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial and found vitamin D deficiency to be common in pediatric lupus and independently associated with elevated hsCRP and an increased cardiovascular disease risk. Finally, Holick reviewed recent recommendations and clinical guidelines  and suggested that vitamin D supplementation of up to 2000 IU/d appears to be safe and well tolerated in children with chronic diseases.
Cholecalciferol is pre-hormonal form of D hormone that must be ingested or generated in the skin where one of the rings of the precursor molecule (7-dehydrocholesterol) is broken down by ultraviolet B-light (UV-B, sun light). In part this explains why, when discovered a century ago, it was classified as vitamin. Actually, as previously noted, this substance is a member of a group of steroid molecules (secosteroids) with a common A, B, C and D ring structure derived from the cyclo-pentano-perhydrophenanthrene ring structure, very similar to cholesterol .
After the UV-B activity, this compound undergoes a very complex metabolic process that is controlled by classic endocrine feed-back mechanisms and becomes a biologically active hormone. It must be first hydroxylated in the liver, at the carbon 25-position by 25-hydroxylase, to form 25(OH)D, known as a calcidiol or calcifediol. Several cytochrome P450 (CYP) isoforms (including the mitochondrial CYP27A1 and the microsomal CYP2R1, CYP3A4 and CYP2J3) accomplish this hydroxylation step. CYP2R1 is thought to be the high-affinity 25-hydroxylase . The 25(OH)D form is the most plentiful and stable pre-hormonal metabolite of vitamin D in human serum with a high affinity to bind serum vitamin D binding protein (VDBP) and other albumin superfamily proteins in the blood. As such, the 25(OH)D level in the serum is the best indicator of vitamin D entering the host, either by cutaneous synthesis or by ingestion in the diet. Nevertheless, this 25(OH)D form is still not a hormone, rather a pre-hormonal form of the natural hormone, and does not exert any biological activity in the body .
Calcidiol (25(OH)D) is then transported through the bloodstream, bound to vitamin D binding protein (VDBP), to the proximal tubule of the kidney, where it is hydroxylated at the 1α-position to form the final biologically active form of D hormone named calcitriol (1α,25(OH)2D), by the enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) . Activity of this enzyme is increased by parathyroid hormone (PTH) secreted by the parathyroid gland, which is the pivotal activator of CYP27B1 in proximal tubule cells and decreases with aging . Thereafter, the synthesized calcitriol becomes the real D hormone with full biological activity similar to other steroid hormones. The D hormone increases intestinal calcium absorption and mobilizes calcium from the skeleton while calcium level in blood regulates PTH secretion and CYP27B1 activity. These activities are clear examples of endocrine regulation due to D hormone production.
D hormone biological activity
For many years it was believed that regulation of calcium homeostasis within the body with a positive influence on bone turnover were the only crucial roles of this hormone. These roles were why it was considered to be a vitamin critical for bone health. This tenet remains correct, but it is now understood that all monocyte-macrophage derived cells, including those present in many tissues and various epithelia, are able to express 1α-hydroxylase and to synthesize calcitriol locally, if there is a availability of the 25(OH)D substrate . Synthetized D hormone can act on cells and in the tissues in an autocrine or paracrine manner, and the synthesized D-hormone (calcitriol) serves as connection between extracellular stimuli and genomic response of the cells .
It is recognized that 1α,25(OH)2D has high affinity to bind vitamin D receptor (VDR) due to the presence of an OH group at the 1α position. The VDR gene shows its highest expression in tissues with high metabolic activity, such as kidneys, bone and gut, but has low to moderate expression in nearly all other human tissues. VDR, when bound to hormone, heterodimerizes with the retinoic acid-X-receptor (RXR) and this complex binds to the vitamin D responsive element (VDRE) acting as a transcriptional factor to enhance or repress gene transcription .
It has been estimated that at least 200 tissues and as many as 2000 genes are directly or indirectly controlled by this transcriptional complex . Only high doses of D hormone can induce genetic effects including immunomodulatory actions  while physiological actions have to be mediated via the genetic and epigenetic regulatory actions of the VDR transcriptional complex . VDR protein has been detected both in the cytosol (associated with sarcoplasmic reticulum Ca2 + −ATPase) and in plasma membranes. This ubiquitous presence of the VDR protein may explain some of the rapid non-genomic actions of 1α,25(OH)2D such as calcium up-take that are related to calcium homeostasis and bone mineralization .
The signaling pathways of all steroid hormones (glucocorticoid, sex hormones) occur through cellular and nuclear hormone receptors . All of these hormones influence bone formation and immune regulation. Steroid nuclear receptors, when bound to their agonist hormone, under control of co-regulators, catalyze or mediate chromatin remodeling, epigenetic modification, receptor recycling, and ultimately gene expression . Gene regulation appears to be modulated by dual modifications of histone acetylation and DNA methylation. The 1α,25(OH)2D hormone has been shown to be a potent genetic and epigenetic regulator. This could be explanation for the possible pathogenetic role of low vitamin D status in immune-mediated diseases [24, 25].
Using the same signaling pattern, 1,25(OH)2D, locally produced in the tissues, exerts its effects on several immune cells, including macrophages, dendritic cells (DCs), T and B cells.
Macrophages and DCs constitutively express vitamin D receptor (VDR), whereas VDR expression in T cells is up-regulated after activation . In macrophages and monocytes, 1,25(OH)2D positively influences its own effects by increasing the expression of VDR and the cytochrome P450 protein CYP27B1 (autocrine regulation). Toll-like-receptor (TLR)-mediated signals can also increase the expression of VDR.
The 1,25(OH)2D hormone also induces monocyte proliferation and production of interleukin-1 (IL-1) and cathelicidin (an antimicrobial peptide) by macrophages, thereby contributing to innate immune response [28, 29]. The 1,25(OH)2D hormone decreases DC maturation, inhibiting up- regulation of the expression of MHC class II, CD40, CD80 and CD86. In addition, it decreases IL-12 production of DCs and induce production of IL-10.
In T cells, 1,25(OH)2D decreases the production of IL-2, IL-17 and interferon-γ(IFNγ) and attenuates the cytotoxic activity and proliferation of CD4+ and CD8+ T cells . The 1,25(OH)2D hormone might also promote the development of forkhead box protein 3 (FOXP3) + regulatory T (TReg) cells and IL-10-producing T regulatory type 1 (TR1) cells [31,32]. Finally, 1,25(OH)2D blocks B cell proliferation, plasma-cell differentiation and immunoglobulin production .
It is clear that the D hormone exerts its effects on many crucially important immunoregulatory proteins and cells . Some of them are recognized as possible causative immune factors for the development of PRDs. Due to the D hormone’s proven capability to induce tolerogenic immune response, improve impaired T and B cell function, and enhance innate immunity response, a deficiency or insufficiency of D hormone may well have causative or risk factor effects  in pediatric rheumatic diseases.
D hormone and pediatric rheumatic diseases
Bone health in children
Children and adolescents need to achieve peak bone mass by age 18 years or enter adulthood with suboptimal bone mass and risk of osteoporosis as adults . The inflammatory nature of PRDs may reduce the ability to achieve peak bone mass  due to the inflammation, pain, decreased activity, and other factors. The necessity to use glucocorticoids for the treatment of pediatric rheumatic diseases is an additional risk factor for bone mass loss during childhood and adolescence . It has been shown that patients with JIA and jSLE and other chronic inflammatory diseases have an increased fracture risk . Glucocorticoids may have a regulatory effect on vitamin D metabolism which, in the presence of low vitamin D levels, may additionally negatively affect bone turnover .
The US Centers for Disease Control and Prevention (CDC) reported in 2006 that healthy children in the US are vitamin D deficient in approximately 9–11 % at age 1–8 years, 19–22 % at age 9–13 years and 22 % at age 14–18 years . The possible significance of vitamin D deficiency in JIA was noted more than 20 years ago [48, 49]. Recently Pelajo et al.  reported that 20 % of all children attending clinic were vitamin D deficient while children with autoimmune disorders had a 2–3 fold greater probability of being vitamin D deficient compared to children with non-autoimmune conditions. Soybilgic et al.  assessed practices of North American pediatric rheumatologists regarding monitoring, prevention, and treatment of low bone mineral density (BMD) in children on long-term glucocorticoid treatment and found that 79 % "rarely" or "never" obtained a baseline BMD measurement prior to initiation of glucocorticoid therapy. Yet despite the lack of BMD assessment, 93 % "frequently" or "always" prescribed calcium for patients on long-term corticosteroid therapy, 81 % "frequently" or "always" prescribed vitamin D, and 40 % of the survey responders prescribed combined calcium/vitamin tablets.
Juvenile Idiopathic Arthritis (JIA)
Juvenile Systemic Lupus Erythematosus (jSLE) and Dermatomyositis (JDM)
Furthermore, vitamin D deficiency strongly correlated with SLEDAI, C4 level and BMD (low spine and whole body) . Stagi et al.  has shown that jSLE patients exhibit lower 25(OH)D levels than controls with the lower values observed in patients with active vs. inactive disease.
Urinary losses of 25(OH)D and vitamin D binding protein (DBP) could be a reason for the low vitamin D status in pediatric lupus patients . Robinson et al. reported vitamin D deficiency in jSLE patients, an inverse relationship between 25(OH)D levels and proteinuria, and an association with proliferative glomerulonephritis in patients with jSLE . The same group published very interesting data as results of the APPLE study (Atherosclerosis Prevention in Pediatric Lupus Erythematosus) . Briefly, the study confirmed that vitamin D deficiency is common in jSLE and independently associated with elevated hsCRP .
Additionally, jSLE patients with serum 25(OH)D ≥ 20 ng/mL had less mean-max CIMT (carotid intima medial thickness) progression following 3 years of atorvastatin treatment that could suggest that vitamin D deficiency may contribute to heightened inflammation and cardiovascular risk .
Data about vitamin D levels in JDM is very limited. Two studies, both including a small number of patients, observed that 25(OH)D level to be lower among children with high disease activity compared to low disease activity JDM patients [48, 63]. One recent study confirmed a significant association of low 25(OH)D serum levels with idiopathic inflammatory myopathies, including JDM .
It is very interesting to point out that association of vitamin D deficiency with pediatric rheumatic diseases may not be the only biologically important D hormone pathway. Polymorphism of genes regulating D hormone synthesis may be connected with the presence or severity of many rheumatic diseases . Polymorphisms in vitamin D pathway related genes has been found to be associated with increased likelihood of being vitamin D deficient . Ellis et al.  recently published data about impressive evidence of gene epistasis among all genes (GC, VDR, CYP24A1, CYP2R1, and DHCR7) regulating D hormone synthesis as well as the PTPN2 gene which is a vitamin D responsive gene determining susceptibility to JIA and type 1 diabetes. Several studies indicated a possible association of VDR receptor gene polymorphism with RA and JIA [70, 71]. In our study, we have found that presence of f variant of FokI VDR polymorphism was associated with a worse outcome and a longer need for biologic treatment in JIA patients .
Optimal D hormone levels
The best method to determine a person’s vitamin D status is to measure the circulating level of 25(OH)D. Serum levels of 1α,25(OH)2D are often normal or even elevated in both children and adults who are vitamin D deficient due to its very short half-life and tight physiological control by PTH which can increase renal production of calcitriol (by stimulating 1α-hydroxylase activity). The vitamin D hormonal form is synthetized and accumulated to a large degree in the tissues but there it cannot be measured .
Recommendations for patents at risk for D deficiency (JIA and other rheumatic inflammatory diseases)
IOM recommendations for healthy children
IOM recommendations for healthy children at risk of vitamin D deficiency
Proposed recommendation for children with rheumatic diseases
EAR IU (μg)/day
RDA IU (μg)/day
UL IU (μg)/day
Daily requirement IU/day
As discussed earlier, supplementation with vitamin D (cholecalciferol) is unfortunately not common in everyday pediatric rheumatology practice . Additionally there is huge variety of formulations (ergocalciferol or cholecalciferol, with or without calcium) used in multiple different dosing regimens. Cholecalciferol (D3) should be the preferred form for supplementation as it was shown that it can yield greater increases in 25(OH)D compared to an equivalent dose of ergocalferol (D2). Additionally, 25(OH)D is the required substrate for conversion to1,25(OH)2D at the cellular level and D2 (ergocalciferol) does not have the long-term potency as D3 . Supplementation with calcitriol (1,25(OH)2D – final hormonal form) or other vitamin D analogues is generally recommended only for children with chronic kidney disease, patients taking anticonvulsants or suffering from malabsorption syndromes. The patients are usually unable to metabolize cholecalciferol to the hormonal form .
Among pediatric rheumatologists, there may be fear that using higher vitamin D doses could carry a risk of hypercalcemia and toxicity. We doubt this concern is justified since infants who received the huge doses of 200,000–600,000 IU of vitamin D2 or vitamin D3 orally for vitamin D deficiency have had no reports of toxicity. Rather neonates treated with 2000 IU of vitamin D3 during the first year of life appeared to have a reduced risk of developing an autoimmune disease, ie type 1 diabetes, and did not experience toxicity . Also, the risk of hypercalcemia can be lowered if additional calcium intake is avoided since it has been shown that calcium has limited potential to effect bone acquisition .
D hormone as a natural compound is necessary to be present in high concentrations in cells and tissues to achieve genetic and epigenetic effects. This is why pharmaceutical companies focused on the development of more than 3000 D hormone analogs (agonists) . There is some evidence that vitamin D analogs can even overcome steroid resistance  and improve disease outcome  but randomized controlled trials and other studies are needed.
Vitamin D deficiency has clearly been recognized as pandemic and connected with numerous non-infectious diseases with increased incidence in the modern age (cardiovascular, malignant, autoimmune, cognitive etc.) and even increased risk of mortality [74, 79–81]. From epidemiological studies it is clear that vitamin D deficiency is associated with numerous diseases but it is not totally clear if it is a cause or a effect. Due to disease and medication effects, children with rheumatic diseases have additional needs for vitamin D supplementation. It is reasonable to assume that a child with a rheumatic disease, especially if treated with steroids, needs at least double the daily recommended dose of vitamin D for age (approximately 2000 UI/day) . This high dose is needed as immunomodulatory and epigenetic benefits from 1,25(OH)D (hormonal form of vitamin D) can be achieved only when high levels are present in the tissues . Vitamin D supplementation is an appealing adjunct treatment option in JIA and other inflammatory rheumatic diseases due to its pleiotropic effects, which may both minimize bone fragility and attenuate the immune hyperactivation. It is clear that it is now of great importance that pediatric rheumatologists use vitamin D supplementation for children with rheumatic diseases as well as systematically collect data about vitamin D and disease severity and outcome that will inform Vitamin D guidelines in the future.
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