Abstract: Vitamin D deficiency is highly prevalent in the general population including individuals with rheumatoid arthritis (RA). Autocrine regulation of vitamin D modulates important biologic processes including immune responses. Vitamin D deficiency has been implicated in the pathogenesis of several autoimmune diseases including RA. Vitamin D regulates both the innate and adaptive immune responses. Recent evidence indicates that vitamin D's effects on the innate immune system are predominantly through the toll-like receptors (TLR) and on the adaptive immune system through T cell differentiation, particularly the Th17 response. As Th17 cells are critical in the pathogenesis of RA, this has led to an interest in the effects of vitamin D deficiency in RA. Several studies have looked at the association of vitamin D deficiency with markers of disease activity in RA with somewhat mixed results. Based on these results, although the role of vitamin D in mediating various biological processes is well defined, this has not translated into meaningful clinical associations in RA. Herein, we review the immune-modulatory role of vitamin D and its effects on pathogenesis, disease activity, and cardiovascular risk in RA.
Over the past decade significant insights have been gained into the role of vitamin D in health and disease. We now understand that vitamin D is a steroid hormone with pleiotropic effects. Other than the “classical” effects related to bone metabolism, vitamin D has several “non-classical” effects including possible roles in cancer, metabolic syndrome, immune disorders, and dementia among others (Bikle, 2009).
In addition to earlier understanding that vitamin D undergoes hydroxylation to 25 hydroxy vitamin D (25(OH)D) in the liver, and further activation to 1,25 dihydroxy vitamin D 1,25(OH)2D in the kidney, we now know that there is an autocrine component to vitamin D metabolism. CYP27B is the α hydroxylase enzyme that adds the hydroxyl group to 25(OH)D to create the active form 1,25(OH)2D. 1,25(OH)2D binds to the nuclear vitamin D receptor (VDR) and regulates the transcription of more than 200 genes. CYP27B is found in multiple cell types including epithelial cells in the skin, lung, and colon, immune cells, and osteocytes, enabling these cells to locally generate active vitamin D and control its metabolism. VDR is also present in these cells indicating that these cells are responsive to vitamin D (Haussler et al., 2011). These autocrine mechanisms are important for the “non-classical” effects of vitamin D (Holick et al., 2007).
Vitamin D deficiency is very prevalent in the general population (van Schoor and Lips, 2011). During winter months in the northern hemisphere vitamin D deficiency can affect up to 50% of the population. The incidence of vitamin D deficiency may also be increasing (Looker et al., 2008). Normal vitamin D levels are hard to define as there is significant inter-individual variation. Vitamin D deficiency is defined as serum 25(OH)D levels less than 20 ng/ml and insufficiency as serum 25(OH)D less than 30 ng/ml. These cut-offs are determined by the effect of 25(OH)D on parathyroid hormone (PTH) levels. 25(OH)D provides the substrate for tissues that autoregulate local 1,25(OH)2D levels. It is unclear how serum levels of 25(OH)D affect this autocrine regulation and the associated non-classical effects.
Over the past decade the immunomodulatory role of vitamin D has become more defined. Vitamin D deficiency has been linked to several autoimmune diseases including type 1 diabetes, multiple sclerosis, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). In this review we will describe studies examining vitamin D deficiency in RA, including the role of vitamin D deficiency in disease activity and cardiovascular morbidity in RA.
Vitamin D and the Immune System
Vitamin D modulates the innate immune system through its effects on monocytes, macrophages, and dendritic cells. Vitamin D may be involved in anti-microbial host defense, and also affect wound healing through its immune effects. Pathogen recognition by toll-like receptors (TLR) leads to altered vitamin D metabolism in the TLR expressing cell. For example human macrophages treated with mycobacterial lipoprotein have TLR2 mediated expression of VDR as well as induction of CYP27B (Liu et al., 2007). Similarly lipopolysaccharide signaling through TLR4 receptors leads to enhanced CYP27B expression in monocytes (Stoffels et al., 2006). This autocrine regulation causes increased generation of 1,25(OH)2D locally. 1,25(OH)2D enhances the expression of the microbicidal molecule cathelicidin in monocytes that are exposed to pathogenic stimuli (White et al., 2010). Wound healing also involves the innate immune system. Transforming growth factor beta 1 (TGFβ1), a key cytokine in wound healing, increases expression of CYP27B and subsequently 1,25(OH)2D in keratinocytes (Schauber et al., 2007; Werner et al., 2007). Vitamin D may also regulate the innate immune system by reducing the expression of TLR2 and TLR4 on monocytes which may be one of the mechanisms by which it limits autoimmunity (Sadeghi et al., 2006).
In adaptive immunity 1,25(OH)2D may alter the tolerogenicity and cytokine profiles of antigen presenting cells (APC) which may in turn modulate APC mediated T cell activation. Monocytes cultured with 1,25,(OH)2D show reduced expression of MHC class II and co-stimulatory molecules thereby reducing T cell stimulating capacity (Rigby et al., 1990; Almerighi et al., 2009). 1,25(OH)2D modulation of dendritic cells also alters their capacity to trigger T cell production and differentiation. 1,25(OH)2D causes a shift in cytokine production by dendritic cells by inhibition of interleukin-12 (IL-12) and IL-23 with an increase in IL-10 production, resulting in change of T cell polarization from a T helper 1 (Th1) and Th17 response to a Th2 and regulatory T cell (Treg) predominant response (Penna and Adorini, 2000; van Halteren et al., 2002; Unger et al., 2009). Lack of suppression of the Th17 response in vitamin D deficiency likely contributes to the augmented immune response in vitamin D deficiency.
APC independent effects of vitamin D are also seen in T and B lymphocytes, with expression of VDR in activated T and B cells but not resting cells (Provvedini and Manolagas, 1983; Bhalla et al., 1983). In humans, vitamin D suppresses IL-17 and interferon (IFN) while increasing IL-10 and IL-4 thus affecting T cell polarization, with a reduction in the Th17 response (Joshi et al., 2011). Chang et al. (2010) reported that treatment of CD4+ T cells with 1,25(OH)2D inhibited cytokine production by Th17 cells that expressed VDR but not VDR deficient cells. Unpublished data from our study shows that serum levels of 25(OH)D were inversely associated with serum IL-17 levels in 87 RA patients, supporting a putative effect of vitamin D on Th17 polarization (Ranganathan et al., submitted). B lymphocytes express both VDR and CYP27B and therefore have the ability to locally produce 1,25(OH)2D (Heine et al., 2008). In B lymphocytes, VDR mediated effects include suppression of B lymphocyte proliferation, and differentiation to plasma cells and memory B cells (Chen et al., 2007).
Vitamin D and RA
i) Vitamin D in the pathogenesis of RA
In murine models of collagen-induced arthritis, 1,25(OH)2D prevents both the onset and progression of arthritis (Cantorna et al., 1998). When tumor necrosis factor (TNF) transgenic mice (which spontaneously develop arthritis) are interbred with VDR (VDR-/-) deficient mice, the VDR deficient TNF transgenic mice have earlier onset of a more aggressive chronic arthritis, suggesting that signaling via VDR is implicated in the pathogenesis of arthritis (Zwerina et al., 2011). VDR is expressed on the synoviocytes and chondrocytes of inflamed joints in RA patients (Tetlow et al., 1999). More recently the association of VDR gene polymorphisms with susceptibility to RA has been examined. A recent meta-analysis showed a significant association of the FokI polymorphism in the VDR gene with susceptibility to RA in Europeans. Another study demonstrated an association of this polymorphism with susceptibility to RA in Native Americans (Lee et al., 2011; Hitchon et al., 2012). Several studies have also shown VDR polymorphisms to influence systemic bone loss in RA (Ranganathan, 2009).
ii) Vitamin D deficiency in RA
Although there is an overall high prevalence of vitamin D deficiency in RA, some studies have found similar serum levels of 25(OH)D in RA and control populations (Turhanoglu et al., 2011; Bird et al., 1982; Cutolo et al., 2006). Feser et al. (2009) measured serum vitamin D levels in 76 subjects who were either cyclic citrullinated protein (CCP) or rheumatoid factor (RF) positive but without clinical evidence of RA. They found that 25(OH)D levels in these subjects who were at high risk of developing RA did not differ from 154 antibody negative controls.
Two longitudinal cohort studies prospectively examined the incidence of RA in relation to vitamin D intake. In the Iowa women’s health study, 158 cases of RA were reported in 29,386 women who were followed prospectively for 11 years. High intake of vitamin D both dietary as well as in the form of supplements was associated with a lower incidence of RA. This study estimated dietary intake based on a self reported questionnaire and did not take into account sunlight exposure (Merlino et al., 2004). In contrast, in a larger cohort of 186,389 women followed in the Nurses Health Study and Nurses Health Study II, there was no correlation between vitamin D intake and the incidence of RA (Costenbader et al., 2008).
Another study looked at the incidence of RA in blood donors. Serum vitamin D levels were determined in 79 RA patients who had donated blood multiple times before the onset of RA. Serum levels of 25(OH)D were determined in samples donated one, two, and five years before the onset of symptoms of RA and compared to samples from age and sex matched controls. There was no correlation between serum levels of vitamin D and later development of RA (Nielen et al., 2006).
iii) Vitamin D deficiency and disease activity in RA
Several studies have evaluated the relationship between serum vitamin D levels and disease activity in RA (Table 1). Kroger et al. (1993) were among the first to report that serum levels of 1,25(OH)2D, the active hormonal form, were significantly lower in women with RA who had an erythrocyte sedimentation rate (ESR) >30 mm/hour, implying that lower levels of vitamin D may be associated with active RA. There was no correlation between serum 25(OH)D levels and ESR in this study. Similar results were reported by Oelzner et al. (1998); in their study higher C reactive protein (CRP) levels correlated with lower 1,25(OH)2D but not 25(OH)D levels in RA. Cutolo et al. (2006) compared the prevalence of vitamin D deficiency between patients with RA and controls in northern (Estonia) and southern (Italy) Europe, both during winter and summer months. Patients from northern Europe had lower vitamin D levels in winter as well as summer when compared to patients from southern Europe; this was also true for the control populations. There was an inverse correlation between serum vitamin D levels and Disease Activity Score 28 (DAS28), a standardized measure of RA disease activity, during the summer months in northern Europe and winter months in southern Europe in these patients.
Craig et al. (2010) evaluated 266 African American women with RA, and found a 50% prevalence of vitamin D insufficiency in this population defined as serum 25(OH)D levels <37.5 nmol/l in this study. In an unadjusted analysis 25(OH)D levels were inversely related to pain (p=0.04), swollen joint counts (p=0.04), and DAS28 (p=0.05). However, this significance was lost after multivariate adjustment. Welsh et al. (2011) found that among 170 consecutive patients with RA, 25(OH)D levels correlated with ESR but not CRP or DAS 28; improvement in ESR, CRP, and DAS28 after adalimumab therapy was not associated with a corresponding increase in vitamin D levels. Kerr et al. (2011) found in 850 patients from the Veterans Administration (VA) databases, that serum 25(OH)D levels correlated with CRP and tender joint counts only in patients who were 25(OH)D deficient (<20 ng/ml,) but not in patients who were 25(OH)D insufficient (<30 ng/ml).
A larger study looked at 1,191 RA patients and 1,019 controls at 22 Italian rheumatology centers. Lower serum 25(OH)D levels were associated with active disease manifested by a DAS28>3.1 (p<0.001), lack of remission (p=0.05), and poor response to therapy (p=0.02). This association persisted after adjusting for body mass index (BMI) and sunlight exposure. Daily sun exposure quantified in minutes also correlated with disease remission, treatment response, swollen joint counts, DAS 28 scores, and health assessment questionnaire (HAQ) scores (Rossini et al., 2010). Haque et al. (2010) reported that DAS28 scores, HAQ scores, and pain as assessed by a visual analog scale inversely correlated with serum 25(OH)D levels in RA patients. Similar results were reported by Patel et al. (2007) who reported that every 10 ng/ml increase in 25(OH)D levels was associated with a decrease in DAS28 scores by 0.3, and a reduction in CRP by 25%.
Although these studies point toward an association between vitamin D deficiency and disease activity in RA, the results are mixed and there are many confounding factors. It is possible that low vitamin D levels are not truly associated with disease activity in RA, but instead reflect a sedentary lifestyle leading to poor sun exposure or higher BMI in patients with severe RA. There is also some data to suggest that vitamin D levels may decrease in the face of an acute phase response thus explaining low levels in patients with more severe disease (Reid et al., 2011). Chronic musculoskeletal pain is also known to occur in vitamin D deficiency and may contribute to higher tender joint counts or higher scores on patient reported scales of pain and functionality in RA.
Unfortunately few studies have measured the effects of vitamin D supplementation on disease activity in RA in a prospective fashion. In one open label study, 19 patients with RA on methotrexate therapy were treated with 2 µg/day of alfacalcidiol 1(OH)D3 for a period of 3 months. Disease activity was monitored by ESR and the Ritchie articular index (RAI), a measure of RA disease activity. After 3 months of therapy, 89% of patients experienced an improvement in disease activity, with 45% (9/19) going into remission (Andjelkovic et al., 1999).
iv) Vitamin D deficiency and cardiovascular disease in RA
There is a significant burden of cardiovascular disease (CVD) in patients with RA. CVD accounts for 50% of all mortality in patients with RA and this is only partly explained by the increased prevalence of traditional cardiovascular risk factors in RA such as smoking and higher BMI (Solomon et al., 2003; Avina-Zubeta et al., 2008).
Inflammation in RA leads to atherosclerosis through several mechanisms such as functional and quantitative lipid abnormalities, inflammatory cytokine-mediated endothelial dysfunction, and increased expression of adhesion molecules (Cavagna et al., 2012). Data from observational cohorts suggest that vitamin D deficiency is associated with a higher incidence of CVD and cardiovascular risk factors such as type II diabetes, metabolic syndrome, and hypertension when compared to vitamin D sufficient populations. One possible mechanism may be increased renin angiotensin system (RAS) activation in vitamin D deficiency leading to hypertension as well as vascular endothelial and smooth muscle dysfunction (Annuzzi et al., 2012).
There is recent literature emerging on the impact of serum vitamin D levels on cardiovascular risk in RA patients (Table 2). Baker et al. (2012) looked at the association of serum 25(OH)D levels with dyslipidemia and metabolic syndrome in 499 RA patients. Serum low density lipoprotein (LDL) and triglyceride levels were inversely associated with 25(OH)D (p<0.01), but high density lipoprotein (HDL) levels were not. Low vitamin D levels were associated with an increased risk of metabolic syndrome in patients who were vitamin D deficient, that is with serum 25(OH)D level <20 ng/ml odds ratio (OR) 3.45, confidence interval (CI)1.75-6.80; p<0.001. In another study by Goshayeshi et al. (2012) in 120 RA patients serum vitamin D levels were associated with metabolic syndrome (p=0.04) but not with fasting blood sugars, lipid components, or blood pressure.
Among 186 participants from the Evaluation of Subclinical Cardiovascular Disease and Predictors of Events in Rheumatoid Arthritis (ESCAPE RA) study, vitamin D insufficient patients 25(OH)D<30 ng/ml when compared to vitamin D sufficient patients 25(OH)D>45 ng/ml were more likely to be of non-Caucasian race (p=0.01), have higher BMI (p=0.05), higher DAS28 scores (3.4 vs. 2.8, p=0.01), and have RF or CCP antibodies (83% vs. 64%, p=0.06). There was a significant positive correlation between serum 25(OH)D and HDL levels and a significant inverse correlation between serum 25(OH)D and intercellular adhesion molecule (ICAM-1) and E-selectin levels after adjusting for confounding variables (Haque et al., 2012).
In our study of 87 patients with RA, we measured large artery compliance by pulse wave velocity (PWV) and microvascular endothelial function by reactive hyperemia index (RHI). We quantified cardiovascular risk factors, serum 25(OH)D, and IL-17 levels, and measured disease activity by DAS28. In the whole cohort and vitamin D insufficient group 25(OH)D<30 ng/ml, serum 25(OH)D was inversely associated with IL-17 after adjusting for confounders (p=0.02). In vitamin D deficient patients 25(OH)D<20 ng/ml serum 25(OH)D was positively associated with microvascular function after adjusting for confounders (p=0.04). Our findings suggest that vitamin D deficiency in RA may affect Th17 responses and microvascular endothelial function (Ranganathan et al., submitted).
The effects of vitamin D supplementation on cardiovascular markers have been examined in the general population but not in RA. A recent Cochrane meta-analysis of studies looking at vitamin D supplementation in 42,589 subjects for a median of 2 years did not find any effect on cardiovascular mortality (Bjelakovic et al., 2011). Similarly, another study looking at the effects of vitamin D supplementation on markers of endothelial dysfunction and cardiovascular risk factors did not yield significant results (Annuzzi et al., 2012).
Significant progress has been made in understanding the biology of vitamin D especially with regard to its autocrine control and non-classical effects. Parallel efforts attempting to understand the effects of vitamin D on disease processes have led to association of vitamin D deficiency with various chronic diseases. There is clear evidence supporting the immune modulatory effects of vitamin D particularly its effects on antigen presenting cells and T cell polarization which may translate to similar effects in RA.
There is a high prevalence of vitamin D deficiency in RA. Studies of the effects of vitamin D deficiency on disease activity in RA have yielded mixed results. Most studies have looked at the association between vitamin D deficiency and multiple markers of disease activity in RA. These studies often found significant associations with some but not all markers of disease activity. Also no single marker of disease activity has been consistently associated with vitamin D deficiency across studies. Some studies did not adjust for confounding factors while others reported loss of significant associations after adjusting for confounders such as BMI. Of note is the large multicenter study by Rossini et al. (2010) which showed a significant association of vitamin D deficiency with DAS28 scores and response to therapy after adjusting for confounding factors. Data are even scarcer on the effects of vitamin D supplementation on disease activity in RA, as well as on cardiovascular risk in both RA and the general population in a prospective fashion; most of these studies have been cross-sectional. Moreover vitamin D sufficiency may be a reflection of socio-demographic factors including diet, BMI, physical activity, and general health, all of which may be confounders influencing the association of vitamin D with chronic diseases, including RA (Figure 1). Vitamin D supplementation does not appear to alter cardiovascular risk in the general population, perhaps pointing to the fact that vitamin D deficiency may be an epiphenomenon and not truly associated with cardiovascular disease. So, at present although the role of vitamin D in mediating various biological processes is well defined, this has not translated into meaningful clinical associations with disease including RA.
Furthermore, it is unclear what serum levels of 25(OH)D are required to maintain optimal autocrine regulation. In conclusion, although vitamin D has myriad effects on the immune system, the exact mechanisms underlying such effects and the optimum supplementation doses needed for its adequate autocrine function especially in immune cells remain poorly defined. Further studies are needed to fully understand its mechanistic roles in RA, and evaluate the potential of vitamin D supplementation in the RA treatment paradigm for modulating disease activity and possibly cardiovascular risk in this disease.
The authors report no conflicts of interest.
Prabha Ranganathan, M.D., M.S., Division of Rheumatology, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8045, St. Louis, Missouri 63110, USA.
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