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We evaluated the epidemiologic evidence that vitamin D may be related to human autoimmune disease risk.
PubMed limited to English from inception through April 2010 was searched using keywords: “vitamin D”, “autoimmune” and autoimmune disease names. We summarized in vitro, animal, and genetic association studies of vitamin D in autoimmune disease pathogenesis. We sorted studies by design and disease and performed a systematic review of: a) cross-sectional data concerning vitamin D level and autoimmune disease; b) interventional data on vitamin D supplementation in autoimmune diseases and c) prospective data linking vitamin D level or intake to autoimmune disease risk.
Vitamin D has effects on innate and acquired immune systems and vitamin D receptor polymorphisms have been associated with various autoimmune diseases. In experimental animal models, vitamin D supplementation can prevent or forestall autoimmune disease. We identified 76 studies in which vitamin D levels were studied in autoimmune disease patients, particularly with active disease, and compared to controls. Nineteen observational or interventional studies assessed the effect of vitamin D supplementation as therapy for various autoimmune diseases (excluding psoriasis and vitiligo) with a range of study approaches and results. The few prospective human studies performed conflict as to whether vitamin D level or intake is associated with autoimmune disease risk. No interventional trials have investigated whether vitamin D affects human autoimmune disease risk.
Cross-sectional data point to a potential role of vitamin D in autoimmune disease prevention, but prospective interventional evidence in humans is still lacking.
The cause of the breakdown in immune tolerance that allows for the development of immunity to self-targets in autoimmune diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and multiple sclerosis (MS) is unknown. It is hypothesized that environmental exposures, including factors that stimulate endogenous inflammation, trigger the development of autoimmunity in genetically susceptible individuals(1). Autoimmune diseases cluster within families and within individuals, with many individuals developing more than one autoimmune disease(2-4). Polymorphisms in several genes have been associated with increased susceptibility to multiple autoimmune diseases(2, 5-8). Autoimmune diseases also share epidemiologic risk factors such as cigarette smoking and crystalline silica exposure(9, 10). Many autoimmune diseases are characterized by activation of the adaptive immune system with associated innate immune cell activation leading to inappropriately elevated levels of widespread systemic inflammation, in particular tumor necrosis factor-α (TNFα) and interleukins-1 and -6 (IL-1 and IL-6), potent cytokines produced by macrophages and monocytes among other cell types.
The Autoimmune Diseases Coordinating Committee of the National Institutes of Health estimated that 23.5 million Americans were affected by one or more autoimmune diseases in 2005(11). This number appears to be growing and is almost certainly an underestimate(12). For unknown reasons, most autoimmune diseases are more common among women than men, although this is less true after menopause(13). Together, autoimmune diseases are the third leading cause of morbidity in the industrialized world and are a leading cause of mortality among women(14, 15). With the exceptions of celiac sprue and pernicious anemia, there are no current means for the prevention or cure of most autoimmune diseases. Treatment of autoimmunity often consists of corticosteroids, immunosuppressant agents and biologic agents that target anti-tumor necrosis factor and other inflammatory cytokines. The 2005 NIH report estimated that the annual direct and indirect costs of autoimmune diseases in the U.S. far exceed $100 billion annually.
Vitamin D, obtained from diet, supplements, or conversion of 7-dehydrocholesterol in the skin by ultraviolet-B radiation, is hydroxylated in the liver to 25-hydroxyvitamin D [25(OH)D], the major circulating vitamin D metabolite(16, 17), which is further synthesized by 1α-hydroxylase to the active form, 1,25-dihydroxyvitamin D [1,25(OH)2D]. Current dietary recommendations are geared only to prevent quite low vitamin D levels. Circulating 1,25(OH)2D has a very short half life and is tightly regulated by parathyroid hormone (PTH). Fibroblast growth factor 23 (FGF23), which is produced in osteoblasts, is also important in regulating 1,25 (OH)2 production in the kidney(18). “Normal” levels for 25(OH) D at most laboratories are >20ng/ml. However, at 25(OH)D levels below 30ng/ml, PTH secretion is increased, suggesting that the current “normal” levels for vitamin D are inadequate.(19-21) Vitamin D deficiency using the current standard for serum25(OH)D level is relatively common. In one study, over 50% of inpatients at Massachusetts General Hospital had low 25(OH)D levels(22).
Vitamin D is an inexpensive and relatively safe nutritional supplement, widely held to have anti-inflammatory and immunomodulating effects. The purported health benefits of this inexpensive and available dietary supplement have received enormous attention in both the medical literature and the popular press(23-26). It has been widely hypothesized that vitamin D deficiency acts as an environmental trigger for the induction of autoimmunity, and that high-dose vitamin D supplementation could be preventive(27-34), yet the scientific evidence appears to conflict. The Agency for Healthcare Research and Quality recently performed a systematic review entitled, “Vitamin D and Calcium: A Systematic Review of Health Outcomes”, published in August 2009(35). The report investigated the published literature regarding serum 25 (OH) D or 1,25 (OH)2 D concentrations and multiple disease outcomes, including autoimmune diseases. The review did not include studies investigating sunlight exposure as a source of vitamin D intake, nor did it include studies in which dietary intake of vitamin D was assessed without measurement of serum levels, as nutrient composition tables for vitamin D were thought to be inadequate. The report also excluded cross-sectional and retrospective case-control studies where the measure of exposure occurred after or concurrent with the outcome. After these exclusions, no studies were identified that addressed the relationship between vitamin D and incident autoimmune disease. We sought to perform an extensive systematic review of the published literature to evaluate the strength of all types of evidence linking vitamin D intake to the risk of incident autoimmune diseases.
We searched the PubMed database from inception through April 2010 restricted to English language and human studies with the following search terms “vitamin D AND”: “autoimmune disease”; “autoimmunity”, “rheumatoid arthritis”; “spondylitis”: “spondyloarthropathy”; “psoriatic arthritis”; “systemic lupus erythematosis”; “scleroderma”; “systemic sclerosis”; “myositis”; “dermatomyositis”; “polymyositis”; “vasculitis”; “polymyalgia rheumatica”; “type 1 diabetes”; “multiple sclerosis; “autoimmune thyroiditis“; “Graves”; “Hashimoto's”; “inflammatory bowel disease”; “Crohn's disease”; “ulcerative colitis”; “vitiligo”; “autoimmune hepatitis”; “Behcet's”; “uveitis”; “Addison's”. We excluded review articles, case reports and studies primarily related to bone metabolism or osteoporosis (unless they included relevant data on vitamin D levels). Studies on the topical and parenteral treatment of psoriasis and vitiligo with vitamin D analogs were beyond the scope of this review and treatment with vitamin D-related compounds has been extensively reviewed in a systematic manner (e.g. (36). In addition, primary biliary cirrhosis and celiac disease were not included in the PubMed search since loss of fat-soluble vitamins is common in these diseases and vitamin D deficiency is highly prevalent in cirrhotics(37).We also conducted hand searches of reference lists to add to our list of manuscripts.
We aimed to address the following questions: 1) What are the cross-sectional data linking vitamin D to autoimmune disease?; 2) What are the prospective data linking vitamin D to the risk of future autoimmune disease? 3) What are the interventional data concerning dietary and/or supplemental vitamin D and risk of autoimmune disease? We carefully reviewed the abstracts of the studies identified and selected those relevant to our questions to perform a systematic review of the strengths and weaknesses of this literature. We included and qualitatively summarized background basic science studies, both in vitro and in animal models, genetic studies, studies of vitamin D's effects upon biomarkers of systemic inflammation, as well as ecologic/geographic epidemiologic studies of the incidence or prevalence of autoimmune diseases according to latitude (potentially related to vitamin D from UV light).
To explore the potential for publication bias among studies of vitamin D intake and risk of developing autoimmune disease, a funnel plot was created for these studies by plotting the risk estimates (odds ratios or relative risks) of developing an autoimmune disease in each study (x axis) against the number of autoimmune cases in each study (y axis). (A pattern resembling a symmetrical inverted funnel is generally interpreted as showing no significant publication bias, whereas the absence of studies in the lower sections of an inverted funnel, where small studies would lie, implies the presence of publication bias.)(38)
We identified 1446 potentially relevant studies through our literature search and sorted and reviewed them as in Figure 1. Two hundred and forty-two were immediately excluded as irrelevant to this review, leaving 1204 that were reviewed in further detail. Basic science and in vitro studies, genetic studies, ecological studies, and studies of biomarkers of inflammation, were reviewed and summarized in the text. The human epidemiologic studies were sorted into epidemiologic studies of vitamin D levels in existing autoimmune disease (Table 1), studies and trials of vitamin D supplementation in existing autoimmune disease (Table 2), epidemiologic studies of vitamin D level and risk of autoimmune disease (Table 3) and epidemiologic studies of vitamin D intake and risk of autoimmune disease (Table 4). We reviewed the evidence in each of the studies these tables in detail and summarized it in the text.
Through binding to the vitamin D receptor (VDR), the lipid-soluble active 1,25(OH)2D regulates an array of genes, many involved in inflammation and acquired and innate immune responses(27, 39-42). VDRs are found at high levels on dendritic cells, T and B lymphocytes and macrophages. The function of these cells is profoundly affected by binding of activated 1,25 (OH)2D(43-47). The 1α-hydroxylase that converts 25(OH)D to its active form is expressed in the kidney, in activated macrophages, dendritic cells and other tissues(29, 48, 49). This form of the enzyme, unlike that in the kidney, is not regulated by parathyroid hormone, but rather inducible by factors including interferon gamma and is downregulated with dendritic cell maturation(50). The expression of VDRs on resting CD4+ T cells increases 5 fold with T cell activation(51). 1,25(OH)2D inhibits the expression of interleukin(IL)-2, an important growth factor for T lymphocytes, and suppresses the secretion of Th1 cytokines IL-12, interferon gamma, and tumor necrosis factor, while increasing IL-4, IL-5 and IL-10, leading to the development of a Th2-skewed T cell population.(52-58) The addition of 1,25(OH)2D to CD4+ T cells also inhibits the expression of IL-6, a co-factor stimulating Th17 cells, important in the development of autoimmunity(59, 60). When added to SLE-patient derived B cells in vitro, 1,25(OH)2D inihibits autoantibody production(61).
In vitro, 1,25(OH)2D inhibits the differentiation of monocytes into dendritic cells and blocks the stimulatory effects that T cells have on them(58, 62, 63). Instead, 1,25(OH)2D promotes monocyte differentiation into macrophages, prevents them from releasing inflammatory cytokines and chemokines(64), and reduces their capacity to present antigens to lymphocytes by decreasing MHC-II molecule cell surface expression(39, 65). 1,25(OH)2D-VDR transcriptional signaling also exerts anti-inflammatory effects through the down-regulation of the prostaglandin (PG) pathway and cyclooxygenase-2 (COX-2)(66) and tolerizing effects through capacity to convert CD4 T cells into IL-10-secreting T regulatory cells, suppressing the proliferation of responder T cells.(67). 1,25(OH)2D interacts with VDRs on osteoblasts, stimulating expression of the receptor activator of nuclear factor kB (NFkB) ligand (RANKL)(27). Immature dendritic cells that have differentiated from monocytes in the presence of 1,25(OH)2D respond poorly to inflammatory chemokines that regulate dendritic cell maturation and migration to lymph nodes(45). Experimental data show that 25(OH)D can inhibit pro-inflammatory cytokines such as IL-6 and TNF-α, decrease serum levels of C- reactive peptide (CRP), and upregulate production of the anti-inflammatory cytokine interleukin-10 (IL-10)(44). 1,25(OH)2D downregulates dendritic cell production of IL-12 and augments IL-10, important in the development of T regulatory (Treg) cells(27, 58). As dendritic cells are central to the maintenance of both protective immunity and self-tolerance(68, 69), vitamin D's influence on their maturation and function could have consequences on autoimmune disease risk and/or progression. However, as the pathogenesis of autoimmune disease itself is still unclear, many of pathways implicated suggest a potential role of vitamin D insufficiency in disease progression, but it is not clear to what role in the triggering of autoimmune disease vitamin D intake or deficiency play.
In vivo, supplementation with 1,25(OH)2D forestalls the development of inflammatory arthritis, autoimmune encephalomyelitis (a model for MS), type I diabetes and autoimmune thyroiditis in experimental animal models(70-74). Treatment with a low calcemic vitamin D analog had a prophylactic as well as therapeutic effect on a murine model of Th1-like colitis(75). Administration of 1,25(OH)2D or its analogs to non-obese diabetic mice modulates the expression of chemokines and cytokines and prevents diabetes(76). Vitamin D receptor knock-out mice develop severe diarrhea, rectal bleeding, and marked body weight loss, leading to death in 2 weeks. Thus, vitamin D deficiency, it is thought to compromise the mucosal barrier and increase susceptibility to mucosal damage and potentially the risk of inflammatory bowel disease(77).
Cross-sectional studies in healthy and ill populations suggest potential favorable effects of vitamin D—as measured by circulating 25(OH)D, sun exposure, or dietary or supplement intake—on inflammatory biomarkers(78-80). Inverse associations between serum vitamin D levels and serum CRP concentrations have been found in patients with diabetes mellitus, atherosclerotic vascular disease, inflammatory polyarthritis,and prolonged chronic illness(35, 81, 82). Increased TGF-β serum levels were observed when vitamin D was given for a 6 month period to 16 subjects with MS(83). TNF-α, IFN-γ, and IL-13 levels, however, did not change after supplementation. In a trial involving 200 overweight subjects enrolled in a weight loss program, participants were randomized to vitamin D (83 ug/d) or placebo in a double-blind manner for 12 months and serum TNF- α levels did decrease more in the vitamin D group than in the placebo group marker (10.2% compared with 3.2% decrease; p 0.049)(84). In a recent interventional study, 324 adults were assigned to 20,000 IU of vitamin D per week, 40,000 IU vitamin D per week or placebo. Multiple cytokines, including interleukin (IL)-2, -4, -5, -10, -12, -13, -17, intercellular adhesion molecule-1, interferon-gamma, monocyte chemotactic protein-1, and high CRP, were measured at the start and end of one year. No significance differences in changes levels of any of these cytokines was detected, nor was there any indication of a polarization of the T cells towards a Th2 dominant type(85).
Evidence comes from ecologic observations that several autoimmune diseases, including inflammatory bowel disease, MS, and type I diabetes and RA are more prevalent at Northern latitudes where sun exposure is reduced(86-92). The strongest ecologic evidence linking vitamin D with autoimmune disease risk is for MS (93). An increased prevalence of MS at Northern, compared to Southern, latitudes has long been observed and a strong inverse correlation of MS incidence with UV light exposure is also seen(91, 94). MS has also been associated with birth during the winter compared to other seasons of the year and it is hypothesized that this could reflect low maternal vitamin D during pregnancy(95). Lastly, seasonal variation in MS relapses detected by MRI has been observed, with increased flares occurring during the winter compared to summer months(96).
Polymorphisms in the VDR gene have been associated with increased risk of multiple autoimmune diseases, including Hashimoto's thyroiditis, IBD, Graves’ disease, RA, SLE, primary biliary cirrhosis, autoimmune hepatitis, Addison's disease, vitiligo, celiac disease and type I diabetes, as well as MS in humans(97-112). A vitamin D response element (VDRE) is found in the promoter region of the HLA DRB1*1501 allele, an allele strongly associated with MS susceptibility pathogenesis in Caucasians(112). However, not all of the polymorphisms associated with autoimmune diseases in past studies have known functional consequences and the strengths of the associations vary. Moreover, not all of these associations have been replicated.
Circulating 25(OH)D, reflecting all sources of vitamin D exposure with a half-life of 2-3 weeks, has been used in epidemiologic studies as a comprehensive and stable indicator of vitamin D status(17, 113). Some studies have assessed 1,25(OH)2D levels, but as the half-life of 1,25(OH)D is only 4 hours and this metabolite dependent on fluctuating calcium need, these results are harder to interpret (113). Studies of vitamin D levels comparing populations with and without existent autoimmune diseases have been conducted around the world and with somewhat conflicting results. In RA, for example, two past studies revealed lower levels of 25(OH)D in RA patients than in healthy matched controls(114, 115), but five studies did not find such a difference (116-119, 120 ). Patel and colleagues found a strong inverse association between baseline levels of serum 25(OH)D in patients with newly diagnosed early inflammatory polyarthritis (45%of whom were classified as having RA at 1 year) and baseline disease activity, as assessed by tender joint counts, RA disease activity scores (DAS28) and health assessment questionnaires (HAQ) scores(121). For each 10-ng/ml increase in 25(OH)D, they found a decrease in the DAS28 of 0.3 and in the C-reactive peptide level of approximately 25%. At 1 year, only significant inverse association between higher baseline vitamin D levels lower HAQ scores. In a large group of individuals at increased risk for RA, however, plasma 25(OH) D concentrations were not associated with the presence of RA-related autoantibodies(122).
In SLE, at least six case-control studies have now demonstrated a lower level of 25(OH) D in SLE cases than in matched controls(118, 123-127). Several studies have found that lower levels of vitamin D correlate with more active SLE (125, 126, 128-131), but several others have not confirmed this(118, 123, 132-134). One study showed that 25(OH)D level was lower in hydroxychloroquine users than non-users and hydroxychloroquine is known to inhibit the synthesis of vitamin D(135). A case-control study from Hungary reported lower 25(OH)D levels in individuals with undifferentiated connective tissue disease (before starting medications) than controls in summer and winter seasons, and demonstrated that levels were lower in those with more active manifestations and among the 35 who developed into a diagnosed connective tissue disease within 2.3 years of follow-up(136). A study involving 113 children with SLE, juvenile RA or juvenile dermatomyositis did not find an abnormal prevalence of 25(OH)D or 1,25(OH)D deficiency, although the study's primary goal was to assess osteocalcin levels(134).
There have been four case-control studies comparing 25(OH) D and 1,25 (OH) D levels in patients with ankylosing spondylitis to healthy controls. A study of 100 AS patients and 58 controls in Turkey found that 25(OH) D levels were lower in patients than controls(137), but an earlier study of 38 AS patients and 52 controls in Germany had not detected a significant difference(138). Two studies by Lange have found that 1,25(OH)D levels are lower in ankylosing spondylitis patients and negatively correlated with disease activity, thought possibly related to the high prevalence of osteoporosis seen in this disease(139, 140). Seventy-six ankylosing spondylitis patients had significantly lower 25(OH) levels than did 120 psoriatic arthritis patients, and a significant negative correlation between C-reactive peptide levels and 25(OH) D levels was reported in the combined cohort of these patients in a study by Teichmann(141).
We found eight past studies addressing vitamin D levels in patients with scleroderma. Of the five case-control studies, two demonstrated lower 25(OH) D levels in patients with scleroderma than controls(142, 143), and three did not(144-146). In two case-only analyses, it was found that 25(OH)D levels were, not surprisingly, lower in those with more severe underlying scleroderma, more longstanding disease, more disease activity, more pulmonary hypertension and lower diffusing lung capacity(147, 148).
In type I DM, there have been at least nine studies documenting lower 25(OH) D levels in established or new onset type I diabetes patients, compared to matched controls(149-157), and only one published study that did not confirm this(158). It has also been shown that 25(OH)D levels are lower in individuals with poorly controlled type I diabetes(159), ketoacidosis(160, 161), incipient nephropathy or tubulointerstitial damage(150, 157).
In MS as well, there have now been several studies reporting that 25(OH) D levels are lower in cases with MS than in healthy controls (162-168), and two that have not(169, 170). Lower vitamin D levels have been found in MS patients especially during the summer, compared to winter months(171), in those with progressive as opposed to relapsing-remitting forms of the disease(172), and associated with increased disability in MS(163, 166), and clinical activity and risk of relapse(162, 167, 168, 172).
Two case-control studies have reported lower 25(OH)D levels in patients with Crohn's disease compared to controls(173 , 174), and a three of four studies have found that levels are lower in those with active inflammatory bowel disease(173-176). The only study of the association between vitamin D level and thyroid autoimmunity was conducted in India where a large group of over 600 healthy individuals were screened for anti-thyroid antibodies. A weak but significant inverse correlation was found between vitamin D level and titer of anti-thyroid peroxidase autoantibodies(177). One cross-sectional case-only study of 25(OH) D levels in patients with vitiligo reported apparently low levels, without controlling for season(178). We found no epidemiologic studies of vitamin D levels in existing pernicious anemia, vasculitis, adult inflammatory myositis, polymylagia rheumatica, Addison's disease, uveitis, or Behcet's disease.
In sum, many, but not all case-control studies, circulating levels of 25(OH)D and occasionally 1,25 (OH)2D have been found to be lower in subjects with various autoimmune diseases than in matched healthy controls. The evidence pointing to lower vitamin D levels in existing disease is not equally strong for all autoimmune diseases and some diseases have yet to be studied. The differences between the many similar studies of a specific disease may relate to their different sizes and the heterogeneity in their statistical power, as well as to adjustment for confounding factors. Taken together, it is also apparent from these studies that ethnic origin (179), season of the year (180), and disability (163, 166), have strong effects on circulating vitamin D levels and it is not clear that all of these cross-sectional studies controlled for these important confounders. Additionally, disease activity and disability, glucocorticoid use(132), serum creatinine(132), microalbuminuria(157), ketoacidosis(160, 161), and use of hydroxychloroquine(135) influence circulating vitamin D levels. Hydroxychloroquine prescribed in several autoimmune diseases may inhibit the conversion of 25(OH) D to 1,25(OH)2D(135). Thus, while interesting, the major limitation of these cross-sectional studies is that reverse causation is very likely. Low vitamin D level may be the consequence, not the cause, of active autoimmune disease.
Several small open-label studies and interventional trials have tested the effects of supplementation with vitamin D, or its analogs, on the activity of established autoimmune diseases. In a double-blind trial conducted in 1973, oral calciferol (100,000 IU/d) for one year was administered to 25 subjects who were compared to 24 subjects who received a placebo. The intervention group had improved hand strength, decreased morning stiffness and need for analgesics/anti-inflammatory medications and decreased erythrocyte sedimentation rate (ESR). (181) In a more recent study, high dose 1-alpha (OH) D3 (alphacalcidiol) reduced pain and CRP levels in 19 RA subjects in a 3 month open-label trial(182).
Two small open-label studies of 6 months each have shown some promise for oral alphacalcidol (0.25 ug twice/d and 1,25(OH)D in reducing disease activity and tender joint counts in psoriatic arthritis(183 , 184). In an open-label observational study of 60 SLE patients in Spain who took vitamin D3 supplementation for two years, significant improvement was seen in subject fatigue, as measure by a visual analog scale, but not SLE disease activity measures(185). Ongoing NIH-sponsored trial is investigating vitamin D supplementation on disease activity and interferon-related cytokine activation (“the interferon signature”) in SLE.
Five small trials have now studied the effects of oral calcidiol supplementation on scleroderma, morphea or linear scleroderma(186-190). While earlier open-label studies had shown some benefit, in particular for morphea, the most recent randomized trial found that calcitriol was not more effective than placebo in patients with morphea, and the scleroderma group in that trial (n=7) was too small to any draw conclusions(190). On the other hand, randomized trials in Italy and China have now shown that vitamin D supplementation in individuals with latent autoimmune diabetes (autoantibodies highly associated with the development of type 1 diabetes) can forestall the development of type 1 diabetes, although it only temporarily reduces the amount of insulin required(191, 192).
We found five small studies or trials of vitamin D supplementation for MS. Fewer exacerbations of disease were seen among 16 MS patients given daily cod liver oil vitamin D for a year in an open-label study in 1986(193). In another open-label study of calcium and escalating doses of vitamin D supplementation in 12 MS patients, there did not appear to be an effect on disease progression or activity but the number of gadolinium-enhancing lesions per patient appeared decreased after just 12 weeks(194). In the largest randomized controlled trial yet, 25 MS subjects were randomized to doses of up to 40,000 IU/day over 28 weeks, followed by 10,000 IU/day for 12 weeks over 52 weeks and 24 MS subjects were randomized to placebo. While the treatment group appeared to have fewer relapse events, the difference was not statistically significant (p=0.09) possibly due to insufficient statistical power(195). Thus far, the studies have been small and inconclusive and larger scale trials are called for.
Lastly, one open-label trial in Eastern Europe has compared the effects of supplementation with 25(OH)D to those of 1,25(OH)D for Crohn's disease and found that 1,25 D supplementation was associated with a significantly greater decrease in disease activity (assessed by Crohn's Disease Activity Index) (196).
Studies to date have mainly been small and most open-label, and have include a range of vitamin D preparations, doses and durations. However, it appears that vitamin D may have an adjunctive role in amelioration of RA, MS, type I diabetes, and perhaps SLE and Crohn's disease. This evidence addresses the question of whether vitamin D has an effect upon established disease, but not upon the risk of developing an autoimmune disease de novo.
In the hierarchy of epidemiologic studies, stronger data for association with susceptibility is afforded by prospective studies. Additionally, prospective studies are able to address the potential role of vitamin D in the pathogenesis of autoimmune disease. The relation between vitamin D serum or plasma level—measured by circulating 25(OH)D——and the incidence of autoimmune diseases has been examined in only two prospective observational epidemiologic studies of RA and MS, but not in other autoimmune diseases. Serum 25(OH)D level was not related to future RA risk in a Dutch case-control study examining blood bank samples from 79 individuals who developed RA compared to 79 healthy controls, matched on age, sex, and time of blood donation(197). To address the question in MS, Munger and colleagues used banked blood samples from Department of Defense military recruits, 257 of whom had later developed MS. Higher serum levels of 25(OH)D were associated with significantly lower risk of incident MS, but only among whites, not Blacks nor Hispanics, and the effect was most pronounced for individuals under age 20(198).
Prospective epidemiologic data on vitamin D intake and the risk of developing autoimmune diseases have been systematically reviewed and summarized in Table 4. The diseases that have been studied include RA, SLE, type 1 DM and MS. For RA risk, the data have been somewhat conflicting. In the Iowa Women's Health Study, higher baseline vitamin D intake was associated with decreased risk of subsequent RA(199). In the Nurses’ Health Study, a prospective cohort study involving over 180,000 women with multiple dietary assessments over 20 years, intake of vitamin D was not related to risk of developing either SLE or RA(200). However, in the same cohort, an inverse relationship was discovered between higher intake of vitamin D from supplements, but not overall dietary intake and lower risk of incident MS up to 20 years later(201).
Several observational studies have addressed the association between maternal vitamin D intake in pregnancy, lactation, or intake in infancy and early childhood and the risk of developing type 1 diabetes. A meta-analysis of four case-control (202-204) was performed in 2008(205)omitted from table 4 due to redundancy). Pooled data from the case-control studies showed that the risk of type 1 diabetes was significantly reduced in infants who were supplemented with vitamin D compared to those who were not supplemented (pooled odds ratio 0.71, 95% CI 0.60 to 0.84). One large birth cohort study prospectively assessed vitamin D supplementation during the first year of life (as part of a ricket's prevention study), and confirmed cases of type 1 diabetes in the children up to 31 years later. They found a strongly protective effect of regular vitamin D supplementation in the first year of life: RR 0.12 (95% CI 0.03-0.510 (206).
Surrogate markers for the development of type 1 diabetes, glutamic acid decarboxylase or islet antigen-2 autoantibodies, which are highly associated with type 1 diabetes risk, have been used in a few prospective studies. Two birth cohorts of infants at high genetic risk of type 1 diabetes have investigated relationships between maternal intake of vitamin D during pregnancy and the development of this islet cell autoimmunity. A high maternal dietary intake of vitamin D in foods, but not supplements, assessed after pregnancy by questionnaire, was with associated with increased risk of islet cell autoantibodies among the children followed for an average of four years in an American birth cohort(207). A larger prospective birth cohort in Finland has reported no association between maternal vitamin D intake (also assessed post-partum by questionnaire) and risk of type 1 diabetes or islet cell autoantibodies in their high genetic risk offspring, followed up to 4.3 years, however(208).
Our funnel plot for the studies examining the relationship of vitamin D dietary intake and the risk of the four autoimmune diseases that have been studied, is shown in Figure 2. Given the dearth of studies, we have included studies of all four autoimmune diseases with substantial heterogeneity in design, exposure assessment and timing in relation to onset of disease/autoantibodies and outcomes. The plot appears slightly asymmetric, displaying potential publication bias with few small non-protective studies. However, given the small number of studies, no conclusions can be drawn.
While the development of an autoimmune response to self-antigens underlies all of these diseases, it is likely that vitamin D is not uniformly involved in the pathogenesis of each and every autoimmune disease and is more important in the etiology of some versus others among them. It is clear that not all autoimmune diseases have been equally studied and for most there is a dearth of evidence addressing the potential effects of vitamin D on autoimmune disease susceptibility. Past case-control studies may have been biased by subject recall, cohort studies may have been underpowered for small effects, and potential confounders such as socioeconomic status may not have been consistently well addressed. Prospective observational studies that rely on dietary intake are hampered by subjects’ ability to accurately recall food intake and by inadequate means of assessing vitamin D content of all foods. The inconsistency in epidemiologic data regarding vitamin D intake and risk of autoimmune disease has led to some debate and may result in part from the fact that oral vitamin D intakes in many of the studied populations were too low to produce significant effects, as well as limited within-population variability in intakes. The difference between high and low oral intakes in observational studies is generally only 300-400 IU/d. Given that a vitamin D3 intake of 1 μg [40 IU] increases circulating 25(OH)D by ~1 nmol/L,(209) such an increment would be expected to raise 25(OH)D by ≤10 nmol/L.
Misclassification of vitamin D status due to incomplete or single exposure assessments could also contribute to null or inconsistent findings. The critical window for vitamin D intake or level to affect risk of developing an autoimmune disease is not known and may vary according to disease: maternal intake during pregnancy, early life intake and intake during different phases of adulthood may not be equally relevant to different diseases. Possible health benefits of vitamin D may be offset by other components in dairy products, which are main dietary sources of vitamin D. Disentangling independent effects of vitamin D and calcium on risk of autoimmune disease in observational studies is difficult due to their high correlation in countries—including the U.S.—where milk is fortified with vitamin D. The use of vitamin D supplements in a trial setting would eliminate this problem.
Understanding of the pluripotent immunomodulating and anti-inflammatory effects of vitamin D is advancing. Despite the in vitro and animal evidence for vitamin D's potential to decrease systemic inflammation and prevent autoimmune disease in humans, there remains insufficient human data to firmly support the hypothesis that vitamin D intake is related to the risk of developing autoimmune disease. Data from laboratory studies and cross-sectional and observational epidemiologic investigations suggest a potential protective effect for vitamin D in autoimmune disease susceptibility.
The human epidemiologic and interventional evidence, however, is weak. Despite the multitude of cross-sectional and case-control studies that demonstrate lower levels of vitamin D among individuals with autoimmune diseases than healthy controls, these studies are not able to address causality. Reverse causality, that the disease process of an autoimmune disease, even in early disease, could lower circulating vitamin D concentration is a likely possibility in these studies. Prospective epidemiologic data on vitamin D status and whether intake level has any effect on the incidence of autoimmune diseases are limited or conflicting. There have been no large randomized trials of high-dose vitamin D supplements for the primary prevention of autoimmune diseases in a general population.
Confirming or refuting that elevated dietary vitamin D intake reduces systemic inflammation and/or the risk of incident autoimmune disease is critical, as no prophylactic therapy currently exists for these diseases. The growing enthusiasm for vitamin D supplementation, however, underscores the need for timely and rigorous testing of this hypothesis before use becomes so prevalent as to render it impossible. To understand the effects of moderate-to-high dose vitamin D supplementation, a high-quality, double-blind randomized controlled trial with a large sample size and long duration and designed specifically to include an assessment of these outcomes in a general population is necessary.
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Disclosure: The VITamin D and OmegA-3 TriaL (VITAL) is being conducted by our research group at Brigham and Women's Hospital, Harvard Medical School (PI: JoAnn E. Manson, MD, DrPH). VITAL is funded by the National Institutes of Health (National Cancer Institute, National Heart Lung and Blood Institute, and other institutes and agencies are co-sponsors). The VITAL ancillary study on autoimmune disease incidence is funded by the National Institute of Arthritis and Musculoskeletal Diseases and is being conducted by Karen H. Costenbader, MD, MPH (PI) and colleagues at Brigham and Women's Hospital, Harvard Medical School. Study vitamin D supplements are donated by Pharmavite LLC of Northridge, California.