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