Elsevier

Autoimmunity Reviews

Volume 17, Issue 3, March 2018, Pages 290-300
Autoimmunity Reviews

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

https://doi.org/10.1016/j.autrev.2018.01.004Get rights and content

Abstract

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.

Introduction

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disorder characterized by heterogeneous clinical manifestations of variable severity with involvement of skin, joints, blood cells, brain, kidney, though every organ of the human body might be involved [[1], [2], [3]]. In 15–20% of patients the disease starts in childhood or adolescence, being named juvenile-onset systemic lupus erythematosus (jSLE): this peculiar form of the disease requires long-term and often aggressive treatments, because clinical presentation is frequently more severe than in adults with SLE or often characterized by life-threatening involvement of kidney and central nervous system [4]. The autoimmune mechanisms responsible for SLE and jSLE and numerous agents contributing to their onset and progression are not completely clarified, but both genetic background and environmental factors have a clear position in the pathogenesis [5]. Tipically, SLE and jSLE patients develop T and B cell-mediated autoimmune responses against a host of self-antigens, mostly intracellular [6]. This is the precondition causing the development of immune complexes, whose deposition in many tissues provokes local inflammation and tissue damage with progressive multiple clinical phenomena [3,7].

In the last decade, vitamin D has attracted the attention of many clinicians beyond its conventional role related to bone and calcium homeostasis: vitamin D receptors have been discovered in immune cells, including antigen-presenting cells, natural killer cells, and B and T lymphocytes [6,8], leading to hypothesize a potential role of vitamin D in the regulation of immune responses in different autoimmune disorders [8]. Vitamin D deficiency has also been associated with the pathogenesis of SLE [9,10], and its supplementation seemed to improve disease outcome in an animal model of SLE [11]. Indeed, vitamin D deficiency may be correlated with impaired bone mass achievement and development of osteoporosis as well as with bone fractures in both SLE [12] and jSLE [13,14].

Aim of this review is to focus on the most recent data from the medical literature regarding the relationship between vitamin D, SLE and mostly jSLE. Studies have been searched from the electronic databases of PubMed and Cochrane Library until September 2017. The retrieving words have been “vitamin D”, “vitamin D receptor (VDR)” and “systemic lupus erythematosus” (both SLE and jSLE) to enter the databases; additional reports were identified and analyzed through the specific references cited in the retrieved articles.

Section snippets

The basic principles of vitamin D metabolism in the body and in the immune system

Vitamin D is a steroid hormone with a well-known master role in calcium metabolism and bone homeostasis [15], existing in two fat-soluble physiological forms: one of vegetable origin (vitamin D2 or ergocalciferol) and one of animal origin (vitamin D3 or cholecalciferol) [[15], [16], [17]]. The primary source (80%) is synthesis of vitamin D3 in the skin after exposure to ultraviolet B light (∼280-to-315 nm), while approximately 20% of vitamin D is exogenously acquired from foods, in particular

Vitamin D deficiency in patients with systemic lupus erythematosus

In 1979 low levels of vitamin D were reported in patients with SLE [39] and, afterwards, the disease has been potentially linked to vitamin D deficiency [13,37,[40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51]]. Prevalence of vitamin D insufficiency has been estimated between 38 and 96% in SLE [37,47,[52], [53], [54], [55], [56], [57]], while in the general population it ranges from 8 to >30% [37,47,[54], [55], [56], [57], [58], [59], [60]]. These results are quite similar

The role of genetics in vitamin D balance and systemic lupus erythematosus

Another factor contributing to low vitamin D levels in SLE might be the genetic influence. For example, Wang et al. [82] evaluated 33.996 non-SLE individuals of European descent, finding that a genetic variation might contribute to vitamin D insufficiency. In addition, whereas the polymorphism of the VDR gene was found to be associated with many diseases, including osteoporosis, autoimmune diseases, and many types of cancer [83], further data have suggested that VDR polymorphisms may also

Vitamin D deficiency and comorbidities of systemic lupus erythematosus, with emphasis to bone health

Many observational studies suggest that vitamin D insufficiency or deficiency may contribute to multiple comorbid conditions and potential complications of SLE [[102], [103], [104], [105]]. It is notable that the same ethnic disparities seen in the prevalence of vitamin D deficiency are observed in the prevalence of SLE, with African Americans and Hispanics having a disproportionately higher risk of developing SLE and its most severe sequels [102]. However, this may be also related to

Vitamin D, immune system and infectious diseases in systemic lupus erythematosus

Patients with SLE and jSLE have defective mechanisms in the innate immune response, such as inappropriate activation of Toll-like receptors for self-antigens, decreased clearance of apoptotic cells, deficiency of mannose-binding lectin, and complement deficiency. Furthermore, both SLE or jSLE patients have many abnormalities in their adaptive immune responses, with loss of self-tolerance for T and B lymphocytes and production of various antibodies against self-antigens as well as decrease in

Vitamin D and cardiovascular disease in systemic lupus erythematosus

Vitamin D deficiency may determine endothelial dysfunction, resulting in decreased vasodilation, proinflammatory and/or prothrombotic changes, and increased arterial stiffness in the cardiovascular system [144]. In fact, 1,25(OH)2D3 interacts and activates immune cells to release cytokines and transfers specific signals as immune modulators [59]. SLE causes an increased risk of cardiovascular disease (CVD) at an earlier age than in the general population [145], and younger female patients with

Systemic lupus erythematosus and fatigue: a role for vitamin D?

Patients with SLE often experience severe fatigue [160], and >50% report it as their most disabling symptom [161]. In SLE the etiology of fatigue is multifactorial and appears to be associated with poor physical activity, presence of obesity, impaired sleep quality, mood disorders such as depression, anxiety or cognitive dysfunction, vitamin D deficiency/insufficiency, and comorbidities such as fibromyalgia [160,161]. Some data suggest that vitamin D deficiency may be related to fatigue in

Vitamin D supplementation in systemic lupus erythematosus

Despite the high prevalence of vitamin D deficiency in SLE, to date there are no published guidelines for the specific dosage of vitamin D supplementation in these patients. For example, the American College of Rheumatology recommends a daily intake of 800–1000 IU per day of vitamin D at the introduction of corticosteroids [163]. A recent review suggested to take near 1000–3000 IU/day in children and adolescents with rheumatologic disorders [164]. Vitamin D supplementation in patients with SLE

Conclusive remarks

Vitamin D deficiency is commonly observed in patients with SLE and also in the youngest patients with jSLE, being related to ethnicity, season of evaluation, geographic position, sun avoidance, and medications administered. The use of vitamin D supplementation in the context of corticosteroid therapy is well-established, though the potential contribution of vitamin D deficiency to SLE, and hence of vitamin D replacement to the management of SLE is a concept that has emerged only recently. The

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in any public, commercial or not-for-profit sector.

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