Vitamin D and juvenile systemic lupus erythematosus: Lights,shadows and still unresolved issues

Systemic lupus erythematosus (SLE) and juvenile SLE (jSLE) are autoimmune disorders naturally associated with several genetic, environmental, hormonal, and immunological contributing factors. It has been assumed that vitamin D deficiency may have a role in the immune activation of patients with SLE and play an active part in many comorbidities and even complications. A host of clinical studies suggested that vitamin D exerts inhibitory effects on many immunological abnormalities associated with SLE, also in children and adolescents, while different reports have hypothesized that vitamin D may be associated with accelerated cardiovascular disease in SLE. This review updates and summarizes the information related to the immunoregulatory effects of vitamin D and its importance in jSLE, discusses the innumerable correlations between vitamin D and disease activity, including clinical expression and gene polymorphisms of vitamin D receptor as well as the recommendations for vitamin D supplementation in these patients. Despite the excitement raised by many data obtained about vitamin D and its influence on several aspects of the disease, further well-designed perspective trials are required to define the exact role that vitamin D may have in the management of both SLE and jSLE.     

Bone mineral density and vitamin D status in systemic lupus erythematosus (SLE): A systematic review

Despite the improvement in the quality of life of patients with SLE due to scientific and technological advances, SLE remains a disease that over the years may produce irreversible damage to patients. Osteoporosis and secondary bone fractures are two of the major causes of irreparable injury in patients with SLE. Vitamin D insufficiency may play a vital role both in reduced bone mineral density (BMD) and in the appearance of fractures, although its mechanisms of action are still unclear. We performed a systematic review of the literature in order to determine the prevalence and predictors of reduced vitamin D plasma levels, bone loss and the presence of fractures in SLE patients. Our review encompassed all English-language publications using Medline and EMBase electronic databases from their inception (1966 and 1980, respectively) to December 2016. We included all intervention studies and observational studies in which vitamin D plasma levels, BMD and bone loss were measured and applied to patients with SLE. Previous studies suggested an increase in bone loss and fracture in patients with SLE compared with general population and although there is a high prevalence of vitamin D insufficiency in the general population, previous studies had demonstrated lower vitamin D levels in patients with SLE compared to age-matched controls. The etiology of reduced bone mass and reduced vitamin D plasma levels in SLE is multifactorial and includes a variety of intrinsic factors related to the disease itself and treatment side effects. SLE patients are at risk for developing these two comorbidities (reduced vitamin D plasma levels and low BMD) and it is therefore essential to study, monitor, prevent and treat bone metabolism disorders in SLE patients.     

Vitamin D(3) and its synthetic analogs inhibit the spontaneous in vitro immunoglobulin production by SLE-derived PBMC

The production of high-affinity pathogenic autoantibodies in systemic lupus erythematosus (SLE) may result from aberrant immune regulation. Since 1,25 dihydroxy vitamin D(3) (1,25 D(3)) has immunoregulatory activity, we examined effects of 1,25 D(3) and its analogs HM, V, MC1288, and KH1060 on autoantibody production and proliferation of SLE PBMC. We found, in SLE, a higher percentage of T, B, and NK expressing vitamin D(3) receptors (VDRs) (P = 0.034, 0.006, 0.012, respectively). Incubating SLE PBMC with 1,25 D(3) compounds significantly reduced proliferation, polyclonal and anti-dsDNA IgG production, and the percentages of CD3(+)/DR(+) T and B (CD19(+)) cells, while elevating NK (CD16(+)) cells (P < 0.001). 1,25 D(3) analogs were more potent than the natural compound: KH1060 up-regulated CD14 expression by SLE monocytes (P < 0.001), inhibited polyclonal and anti-dsDNA IgG production by SLE-derived B lymphoblasts, and induced apoptosis of activated B lymphoblasts. These data suggest that 1,25 D(3) compounds can offer novel approaches to the clinical management of SLE.     

Vitamin D deficiency in systemic lupus erythematosus

Evidence from animal models and prospective studies of RA, multiple sclerosis, and type-1 diabetes suggest an important role for vitamin D as a modifiable environmental factor in autoimmune disease. This role has not been well studied in human SLE. We compared serum 25-hydroxyvitamin D (25(OH)D) levels between recently diagnosed SLE cases and matched controls, and examined disease characteristics in relationship to 25(OH)D among cases. Data from a population-based cohort of 123 recently diagnosed SLE patients and 240 controls were used. We found a trend toward lower 25(OH)D levels in cases compared to controls, which was statistically significant in Caucasians (p=0.04), controlling for age, sex, season, and smoking. Overall, 67% of the subjects were vitamin D deficient, with mean levels significantly lower among African Americans (15.9 ng/ml) compared to Caucasians (31.3 ng/ml). Critically low vitamin D levels (<10 ng/ml) were found in 22 of the SLE cases, with presence of renal disease being the strongest predictor (OR 13.3, p<0.01) followed by photosensitivity (OR 12.9, p<0.01). These results suggest vitamin D deficiency as a possible risk factor for SLE and provide guidance for future studies looking at a potential role of vitamin D in the prevention and/or treatment of SLE.     

Dietary factors regulate cytokines in murine models of systemic lupus erythematosus

Cytokines play the active roles in the pathogenesis of systemic lupus erythematosus (SLE) and contribute significantly to the immune imbalance in this disease. Conservative therapeutic approaches, such as dietary modifications have been shown to have some beneficial impact on the disease activity of the SLE. Over the past years, accumulating evidences have supported a major role for specific dietary factors, including calorie restriction, n−3/n−6 fatty acids, vitamin A, vitamin D, vitamin E, phytoestrogens or herbal medicine in the regulation of cytokines involved in SLE development. Although there are many reviews that discuss the issue of nutrition and immunity, there are relatively few articles that focus on the regulation of cytokines by dietary factors. This concise review will summarize those animal studies that investigated not only the outcome of autoantibody production and proteinuria, but also cytokines production. However, the field of dietary factors in the immunomodulation of SLE is still in its infancy. More clinical studies are needed to confirm the preliminary results and advance the knowledge in this field. Lifestyle modification and adjustments in diet are important and encouraged to be suggested as an adjuvant therapy for SLE.     

Vitamin D supplementation ameliorates arthritis but does not alleviates renal injury in pristane-induced lupus model

Systemic lupus erythematosus (SLE) is a multifactorial and autoimmune inflammatory disease with pleomorphic clinical manifestations involving different organs and tissues. The study of different murine models has provided a better understanding of these autoimmune phenomena. Pristane-induced lupus represents a suitable model to study factors that could influence the induction and/or progression of SLE, including genetic factors. The objective of the present study was to evaluate the development and evolution of SLE after vitamin D supplementation in PIL model. Here, we evaluated the effects of vitamin D supplementation in model of pristane-induced SLE in female BALB/c mice. The animals were randomly divided into three groups: control group (CO), pristane-induced lupus group (PIL) and pristane-induced lupus group plus vitamin D (VD). Lupus was induced in PIL and VD groups using pristane. PIL group showed arthritis and kidney injury, characterized by increased proteinuria, glomerular mesangial expansion and inflammation. Moreover, PIL model showed increased levels of IL-6, TNF-α and IFN-γ in serum. We observed that treatment with vitamin D improved arthritis through reduced of incidence and arthritis clinical score and edema, but does not influenced renal injury. Treatment with vitamin D was not able to reduce proteinuria levels, decrease mesangial hypercellularity or IgG and IgM deposition in the kidney. Vitamin D supplementation did not alter IL-6, TNF-α, IL-2 and IL-4, but reduce IFN-γ. These results support that the role of vitamin D may be different depending on acting site, what could explain different responses according clinical phenotype. Therefore, further investigations of vitamin D are needed to explore the supplement dosage, timing, and the molecular basis in SLE.     

Vitamin D and systemic lupus erythematosus - The hype and the hope

Over the past 20 years, much has been written about the potential role of vitamin D in on adverse health outcomes. In recent years, evidence has accumulated regarding the effect of vitamin D on the immune system, and its different cells. Some studies have noted lower vitamin D concentrations in patients with SLE. These epidemiological data still not answer the question: is vitamin D deficiency the cause or the effect? To answer this, we will discuss the association between vitamin D deficiency and SLE and review the evidence from interventional studies.     

Correlation between disease activity of pediatric-onset systemic lupus erythematosus and level of vitamin D in Taiwan: A case–cohort study

Background

Vitamin D deficiency has been associated with systemic lupus erythematosus (SLE), but there is no consensus on the role of serum vitamin D in evaluating or predicting disease activity. This study aimed to demonstrate the direct correlation between vitamin D level and pediatric-onset SLE disease activity by a retrospective cohort study design.

Vitamin D status in patients with systemic lupus erythematosus (SLE): A systematic review and meta-analysis

BackgroundSystemic lupus erythematosus (SLE) is a systemic autoimmune disease where chronic inflammation and tissue or organ damage is observed. Due to various suspected causes, inadequate levels of vitamin D (a steroid hormone with immunomodulatory effects) has been reported in patients with SLE, however, contradictory.AimsThe aim of this systematic review and meta-analysis was to evaluate the serum levels of vitamin D in patients with SLE in compared to healthy controls.MethodsPubMed, SCOPUS, ScienceDirect and Google Scholar electronic databases were searched systematically without restricting the languages and year (up to March 2, 2019) and studies were selected based on the inclusion criteria. Mean difference (MD) along with 95% confidence intervals (CI) were used and the analyses were carried out by using a random-effects model. Different subgroup and sensitivity analyses were conducted. Study quality was assessed by the modified Newcastle-Ottawa Scale (NOS) and publication bias was evaluated by a contour-enhanced funnel plot, Begg's and Egger's tests.ResultsWe included 34 case-control studies (2265 SLE patients and 1846 healthy controls) based on the inclusion criteria. Serum levels of vitamin D was detected significantly lower in the SLE patients than that in the healthy controls (MD: −10.44, 95% CI: −13.85 to −7.03; p < .00001). SLE patients from Asia (MD: −13.75, 95% CI: −21.45 to −6.05; p = .0005), South America (MD: -3.16, 95% CI: −4.62 to −1.70; p < .0001) and Africa (MD: −16.15, 95% CI: −23.73 to −8.56; p < .0001); patients residing below 37° latitude (MD: −11.75, 95% CI: −15.79 to −7.70; p < .00001); serum vitamin D during summer season (MD: -7.89, 95% CI: −11.70 to −4.09; p < .0001), patients without vitamin D supplementation (MD: -15.57, 95% CI: −19.99 to −11.14; p < .00001) or on medications like hydroxychloroquine, corticosteroids or immunosuppressants without vitamin D supplementation (MD: -16.46, 95% CI: −23.86 to −9.05; p < .0001) are in higher risk in presenting inadequate serum levels of vitamin D. The results remained statistically significant from different sensitivity analyses which represented the robustness of this meta-analysis. According to the NOS, 91.2% of the studies were considered as of high methodological quality (low risk of bias). No significant publication bias was detected from contour-enhanced and trim and fill funnel plots or Begg's test.ConclusionInadequate levels of serum vitamin D is significantly high in patients with SLE compared to healthy subjects, therefore, vitamin D supplementation with regular monitoring should be considered as part of their health management plans.     

Immunomodulators in SLE: Clinical evidence and immunologic actions

Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease. Current treatment strategies rely heavily on corticosteroids, which are in turn responsible for a significant burden of morbidity, and immunosuppressives which are limited by suboptimal efficacy, increased infections and malignancies. There are significant deficiencies in our immunosuppressive armamentarium, making immunomodulatory therapies crucial, offering the opportunity to prevent disease flare and the subsequent accrual of damage. Currently available immunomodulators include prasterone (synthetic dehydroeipandrosterone), vitamin D, hydroxychloroquine and belimumab. These therapies, acting via numerous cellular and cytokine pathways, have been shown to modify the aberrant immune responses associated with SLE without overt immunosuppression.Vitamin D is important in SLE and supplementation appears to have a positive impact on disease activity particularly proteinuria. Belimumab has specific immunomodulatory properties and is an effective therapy in those with specific serological and clinical characteristics predictive of response. Hydroxychloroquine is a crucial background medication in SLE with actions in many molecular pathways. It has disease specific effects in reducing flare, treating cutaneous disease and inflammatory arthralgias in addition to other effects such as reduced thrombosis, increased longevity, improved lipids, better glycemic control and blood pressure. Dehydroeipandrosterone is also an immunomodulator in SLE which can have positive effects on disease activity and has bone protective properties.This review outlines the immunologic actions of these drugs and the clinical evidence supporting their use.     

Topics on vitamin D in systemic lupus erythematosus: analysis of evidence and critical literature review

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multiorgan inflammation, linked to the loss of immune tolerance to self-antigens and the production of a diversity of autoantibodies. The phenotype and progression of SLE have been linked to a combination of environmental, genetic, and hormonal factors. One such environmental factor is vitamin D, a vital hormone with well-established effects on mineral metabolism, skeletal health, and effects on cardiovascular system. The purpose of this article is to make the analysis of evidence and literature review of the pleomorphic effects of Vitamin D in SLE. The article is structured in topics of interest based in the authors’ opinion and summarizes the evidence of studies and trials of vitamin D in SLE

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Immunomodulatory vitamin D effects on regulatory T-cells and cytokines in an in vitro study on patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting various organs. Decreased numbers of regulatory T-cells (Treg cells; CD4⁺CD25^highFoxp3⁺) are associated with the pathogenesis of SLE. A vitamin D deficiency was observed in many lupus patients. In the present study, peripheral blood mononuclear cells were isolated and cultured in the presence or absence of vitamin D, and total Tregs percentage was analyzed by flow cytometry. In addition, the level of expressions of Foxp3, TGFβ, and IL6 genes were analyzed by real-time-PCR. The results indicated that vitamin D treatment increased the percentage of Treg cells, and the expression of Foxp3 and TGFβ, and decreased the expression of IL6 in SLE patients.     

Serum Levels of IL-6, IL-10, IL-12, IL-17 and IFN-γ and Their Association with Markers of Bone Metabolism in Vitamin D-Deficient Female Students

Different studies have shown the regulatory effects of vitamin D₃ on the immune system and bone metabolism. Regarding the effects of vitamin D on immune cells and the importance of cytokines on bone metabolism, we assessed the association between serum levels of interleukin (IL)-6, IL-10, IL-12, IL-17 and IFN-γ cytokines and bone metabolism markers (Ca, P, PTH, ALP) in female students with vitamin D deficiency compared with control group. A total of 100 subjects with 25-hydroxy vitamin D₃ (25-(OH) D₃) deficiency were selected as case and 100 subjects with sufficient 25-hydroxy vitamin D₃ (25-(OH) D₃) were selected as the control group. The serum levels of IL-6, IL-10, IL-12, IL-17 and IFN-γ were measured by ELISA method. Ionized Ca, PTH, P, ALP levels were also determined in all participants. The results showed a statistically significant positive correlation between the levels of ALP with IFN-γ, PTH with IL-17 and a significant negative correlation between P with IL-10 in vitamin D deficient group. The results suggest that IL-17, IFN-γ and IL-10 are important mediators of bone metabolism and vitamin D affect bone metabolism, at least in part, through immune system. In addition, not only vitamin D affect bone metabolism but also modulates immune responses.     

Vitamin D metabolism and function during pregnancy and the neonatal period

Recent evidence suggests that vitamin D plays an important role in calcium homeostasis during pregnancy and early extrauterine life. Vitamin D is metabolized by successive hydroxylations to 25-hydroxyvitamin D and then to 1,25-dihydroxyvitamin D, the most potent known metabolite of the vitamin. During pregnancy, the concentrations of this metabolite in maternal serum increase in parallel with the increased need to absorb dietary calcium. 1,25-Dihydroxyvitamin D is produced in the fetoplacental unit as well as in the maternal kidneys. Receptors for 1,25-dihydroxyvitamin D appear to be present in the placenta suggesting that the placenta may be a target for vitamin D action. Developmental changes in vitamin D metabolism and action have been documented in the neonate as well as in the mother and fetus. Clinical studies indicate that adequate vitamin D intake is important during pregnancy. Administration of vitamin D or its metabolites appears to be useful in the treatment of neonatal disorders.     

Disturbances of vitamin D metabolism and action during clinical and experimental magnesium deficiency

It has been known since the 1920s that magnesium is influential in calcium homeostasis. In the 1970s it was documented that parathyroid secretion and activity may be impaired in magnesium deficiency. In the past two decades a variety of studies have indicated alterations in circulating vitamin D metabolites in humans, although these observations are not entirely consistent. Animal studies have not consistently demonstrated impaired vitamin D metabolism during relatively brief periods of magnesium deprivation, despite in vitro magnesium dependence of 1 alpha-hydroxylase activity. Studies of the administration of active vitamin D metabolites to humans and animals suggest that skeletal resistance to these compounds in magnesium deficiency may, in part, explain their reduced calcaemic effect during magnesium deficiency.     

A subgroup of lupus patients with nephritis,innate T cell activation and low vitamin D is identified by the enhancement of circulating MHC class I-related chain A

The major histocompatibility complex (MHC) class I-related chain A (MICA) is induced upon stress, and labels malfunctioning cells for their recognition by cytotoxic lymphocytes. Alterations in this recognition and also abnormal natural killer (NK) functions have been found in systemic lupus erythematosus (SLE). MICA can be shed from cells, subsequently acting as a soluble decoy receptor (sMICA). Our purpose was to study circulating sMICA levels in relationship with the activation of innate pathways in PBMC in a cohort of lupus patients. NK cells were characterized by flow cytometry. Gene expression of Toll-like receptors (TLR), interferon (IFN)-I sensitive genes and MICA were separately analyzed in monocytes, T cells and B cells. Serum sMICA was measured with enzyme-linked immunosorbent assay (ELISA). In our cohort, NK cell counts dropped in relationship with disease activity. sMICA showed an inverse trend with NK cell counts, as well as a significant association with activity indices, but not with complement decrease. Levels of sMICA associated to proteinuria and active nephritis. A multivariate regression model revealed anti-nuclear antibody (ANA) titres, the up-regulation of TLR-4 in T cells and lower vitamin D as predictors of sMICA enhancement. Interestingly, vitamin D showed an inverse association with proteinuria and a strong correlation with T cell MICA mRNA levels. According to our data, circulating sMICA identifies a subgroup of lupus patients with low vitamin D, innate activation of T cells and nephritis. We propose that lymphocyte shedding could account for the enhancement of sMICA and reflect an immune evasion mechanism driving disease activation in lupus.     

Vitamin D3: a helpful immuno-modulator

The active metabolite of vitamin D, 1α, 25-dihydroxyvitamin D3 [1,25(OH)(2) D3], is involved in calcium and phosphate metabolism and exerts a large number of biological effects. Vitamin D3 inhibits parathyroid hormone secretion, adaptive immunity and cell proliferation, and at the same time promotes insulin secretion, innate immunity and stimulates cellular differentiation. The role of vitamin D3 in immunoregulation has led to the concept of a dual function as both as an important secosteroid hormone for the regulation of body calcium homeostasis and as an essential organic compound that has been shown to have a crucial effect on the immune responses. Altered levels of vitamin D3 have been associated, by recent observational studies, with a higher susceptibility of immune-mediated disorders and inflammatory diseases. This review reports the new developments with specific reference to the metabolic and signalling mechanisms associated with the complex immune-regulatory effects of vitamin D3 on immune cells.     

Effects of vitamin D on the peripheral adaptive immune system: a review

Epidemiological studies have shown that a poor vitamin D status is associated with an increased risk of several diseases, including autoimmune diseases. The immune regulatory function of vitamin D is thought to have an important role in these associations. Cells of the adaptive immune system have shown to be direct targets of the vitamin D metabolites. Besides being direct targets, cells of the adaptive immune system express the enzymes involved in the metabolism of vitamin D, enabling them to locally convert 25(OH)D into its active metabolite 1,25(OH)₂D. In this review, the effects of vitamin D on cells of the adaptive immune system are described. Experimental data in vitro show that vitamin D skews cells of the adaptive immune system toward a more tolerogenic status which might be exploited in the treatment of autoimmune diseases. However, it should be noticed that in vivo effects may differ from in vitro effects due to the cross-talk between different vitamin D sensitive cells, but data support the view that vitamin D is positively involved in maintaining or restoring immune homeostasis. Upcoming vitamin D supplementation trials will further elucidate the in vivo effects of vitamin D on the immune system and its potency to serve as an immune regulating agent in autoimmune diseases.     

Emerging role of vitamin D in autoimmune diseases: An update on evidence and therapeutic implications

Vitamin D plays a key role in in calcium homeostasis and, thus, provides an important support in bone growth by aiding in the mineralization of the collagen matrix. However, vitamin D performs various immunomodulatory, anti-inflammatory, antioxidant and anti-fibrotic actions. Autoimmune diseases result from an aberrant activation of the immune system, whereby the immune response is directed against harmless self-antigens. Does vitamin D play a role in the pathophysiology of autoimmune diseases? And, if so, what is its role? In the last decade, researchers’ interest in vitamin D and its correlations with autoimmune diseases has considerably increased. We conducted a literature review, covering the period January 1, 2009 through March 30, 2019, in PubMed. We analyzed more than 130 studies in order to find a correlation between vitamin D levels and its effect upon several autoimmune diseases. The analysis demonstrated an inverse association between vitamin D and the development of several autoimmune diseases, such as SLE, thyrotoxicosis, type 1 DM, MS, iridocyclitis, Crohn’s disease, ulcerative colitis, psoriasis vulgaris, seropositive RA, polymyalgia rheumatica. International multicenter study could allow us to confirm the data already present in the literature in the single clinical studies and to evaluate when to effectively supplement vitamin D in patients who do not take corticosteroids.