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
). Polymorphisms in several genes have been associated with increased susceptibility to multiple autoimmune diseases(2
). Autoimmune diseases also share epidemiologic risk factors such as cigarette smoking and crystalline silica exposure(9
). 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
). 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
), which is further synthesized by 1α-hydroxylase to the active form, 1,25-dihydroxyvitamin D [1,25(OH)2
D]. Current dietary recommendations are geared only to prevent quite low vitamin D levels. Circulating 1,25(OH)2
D 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
) 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
). 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
), 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.