Role of Vitamin D in Rheumatoid Arthritis Pathogenesis
Vitamin D Overview
Vitamin D is a fat-soluble vitamin that is found in two main forms: vitamin D<sub>2</sub> (ergocalciferol) and vitamin D<sub>3</sub> (cholecalciferol). Both are first metabolized by the liver, where they are converted to 25(OH)D (calcifediol). Thereafter, they are converted by the kidneys to 1,25(OH)<sub>2</sub>D<sub>3</sub> (calcitriol), a biologically active hormone. Vitamin D<sub>2</sub> is largely manufactured from plant-based sources and then added to foods to fortify them, whereas vitamin D<sub>3</sub> is predominantly made in the skin when 7-dehydrocholesterol is converted to the vitamin upon exposure to sunlight, but it can also be obtained from some animal-based sources, such as salmon and other fatty fish. Vitamin D produced in the skin can last up to twice as long in the blood compared with ingested vitamin D. Most laboratories consider a vitamin D level of 20 to 50 ng/mL to be adequate for healthy persons and a level <12 ng/mL to indicate deficiency. Treatment of deficiency may include supplementation and increased sun exposure.
Vitamin D Levels and RA Development
Vitamin D is known to play a key role in the regulation of immune function, and many inflammatory autoimmune diseases, including RA, have been associated with vitamin D deficiency.<sup>1,2</sup> A 2012 meta-analysis that assessed the link between vitamin D intake and the development of RA included 3 cohort studies involving 215,757 participants and 874 incident cases of RA.<sup>3</sup> The study found an association between total vitamin D intake and RA incidence (relative risk [RR] of the highest vs the lowest group, 0.758; 95% confidence interval [CI] 0.577-0.937; <i>P</i> =.047), without between-study heterogeneity (P =.595). Individuals in the highest intake group had a 24.2% lower risk of developing RA than those in the lowest intake group. There was also a significant association between vitamin D supplement intake and RA incidence (RR, 0.764; 95% CI, 0.628-0.930; <i>P</i> =.007), without between-study heterogeneity, indicating increased RA risk with low vitamin D intake. <i>Photo Credit: Zephyr / Science Source</i>
CARMA Study: Mounting Evidence of Risk
In 2015, a cross-sectional analysis of the cardiovascular in rheumatology (CARMA) study found that patients with RA were at increased risk for 25(OH)D (calcifediol) deficiency compared with patients without chronic inflammatory rheumatic diseases (CIRD).<sup>1</sup> The study defined calcifediol deficiency as a 25(OH)D level <20 ng/mL. In the study, median serum calcifediol levels were 20.4 ng/mL (range, 14.4-29.2 ng/mL) for patients with RA and 24.8 ng/mL (range, 18.4-32.6 ng/mL) for non-CIRD patients. Calcifediol deficiency was detected in 40.5% of RA patients and 26.7% of non-CIRD patients. The positive association between RA and calcifediol deficiency reached statistical significance (<i>P</i> =.012).<sup>1</sup> <i>Photo Credit: Moredun Animal Health Ltd / Science Source</i>
Immunomodulatory and Immunosuppressive Roles of Vitamin D
Vitamin D is known to be involved in the regulation and proliferation of Th1 and Th17 lymphocytes and in ameliorating inflammatory disorders arising from autoimmune diseases, but the mechanism by which this is achieved remains unclear.<sup>4</sup> An extensive literature review by Iranian researchers suggests that 1,25(OH)<sub>2</sub>D<sub>3</sub> (calcitriol), the most biologically active form of vitamin D, achieves its immunosuppressive and immunomodulatory action by acting on antigen-presenting cells and activated T and B cells with the help of the vitamin D receptors (VDRs) present on each of these cells.<sup>4</sup> Following vitamin D supplementation, qualitative and quantitative changes in the immune system have been observed, including downregulation of Th1 and upregulation of Th2 cells, which have been associated with a lower risk of subsequent autoimmune response; however, this finding has largely come from experimental animal models, indicating a need for further assessment in humans.<sup>4</sup>
Role of Vitamin D and VDR in Human RA Pathogenesis
Both 1,25(OH)<sub>2</sub>D<sub>3</sub> (calcitriol) and the VDR have been implicated in the pathogenesis of RA and other autoimmune diseases. A study by Chinese investigators suggests that calcitriol and VDR inhibit the activation of CD4+T cells and suppress the immune response of RA by inhibiting the protein kinase C δ (PKCδ)/extracellular signal-regulated kinase (ERK) pathway and promoting DNA methylation of CD11a, CD70, and CD40L.<sup>5</sup> The study evaluated blood samples of 137 patients with RA, 130 patients with systemic lupus erythematosus (SLE), and 130 healthy controls. Compared with healthy controls, RA and SLE patients had lower serum calcitriol levels and less VDR mRNA expression. Following treatment with increased concentrations of calcitriol, VDR mRNA expression and DNA methylation levels of CD11a, CD70, and CD40L declined, while expressions of PKCδ, ERK1/2, CD11a, CD70, and CD40L in CD4+T cells increased across patient groups.<sup>5</sup>
Vitamin D and Correlation With Disease Activity
An inverse association between RA disease activity and vitamin D levels has been observed, with higher 25(OH)D levels associated with reduced RA symptoms. In a 2012 meta-analysis of 8 studies involving 2885 RA patients and 1084 controls, only 1 study found no correlation between vitamin D levels and disease activity among 85 RA patients, but these patients had a high incidence of vitamin D deficiency, potentially affecting outcomes.<sup>3</sup> Two recent meta-analyses support an inverse association between RA and vitamin D levels.<sup>6,7</sup> In the first, which included 13 studies involving 924 RA patients, a significant inverse correlation was found between vitamin D level and disease activity score 28 (DAS28; correlation coefficient [r], −0.278; 95% CI, −0.393 to −0.153; <i>P</i> =1.8 x 10−5). In the second meta-analysis, which included 24 reports involving 3489 patients, RA levels and DAS28 scores were also significantly inversely associated (r, −0.13; 95% CI, −0.16 to −0.09; <i>P</i> =.02). <i>Credit: Dr Ray Clark FRPS & Mervyn de Calcina-Goff FRPS / Science Source</i>
Vitamin D and RA Recurrence
In addition to being associated with increased RA disease activity, low vitamin D levels have been reported to be a risk factor for RA recurrence.<sup>8</sup> In a Chinese study that included 377 patients with RA remission who were divided into a normal vitamin D group and a deficient group that was randomly allocated to receive treatment with or without vitamin D, the RA recurrence rate at 24 months was 16.7%, 19.0%, and 29.5% for the normal vitamin D group (n=168), vitamin D treatment subgroup (n=84), and non-vitamin D treatment subgroup (n=88), respectively.<sup>8</sup> The difference in recurrence rates between the normal vitamin D group vs the non-vitamin D treatment subgroup reached statistical significance, whereas the difference in recurrence rates between the vitamin D treated and untreated subgroups did not.<sup>8</sup> <i>Credit: Biophoto / Science Source</i>
Vitamin D and Cardiovascular Risk
Patients with RA are at increased risk of developing many comorbidities, including cardiovascular diseases, increasing their risk for morbidity and mortality. Cardiovascular disease accounts for almost 40% of deaths in RA patients, making it a leading cause of death in these patients.<sup>9</sup> Suboptimal vitamin D levels, which have also been associated with an increased risk of cardiovascular diseases and all-cause mortality, are common in patients with RA, with epidemiological data indicating suboptimal levels in up to 60% of RA patients.<sup>4</sup> Subsequently, there has been considerable interest in exploring the association between vitamin D and cardiovascular disease in RA patients, including how vitamin D might mediate the RA-associated inflammation that can lead to arterial stiffness and other cardiovascular abnormalities.
Vitamin D and Cardiovascular Homeostasis
RA-related inflammation can cause blood vessels to narrow and cardiovascular tissue to swell, leading to atherosclerosis, heart failure, and other cardiovascular diseases. RA patients have been found to have impairment in the number and activity of circulating proangiogenic hematopoietic cells, including CD34+, which can impair endothelial function and affect cardiovascular homeostasis. A small study has suggested vitamin D plays a role in endothelial homeostasis in RA patients.<sup>10</sup> In the study, which included 27 RA patients and 41 healthy controls, CD34+ count and vitamin D levels were lower and fibrinogen, C-reactive protein, pulse wave velocity (PWV), and carotid intima-media thickness (cIMT) were higher in RA patients vs controls.<sup>10</sup> CD34+ cell number appeared to be associated with vitamin D levels and were negatively correlated to fibrinogen and early atherosclerosis markers (PWV and cIMT). Additionally, vitamin D levels appeared inversely associated with fibrinogen.
Role of Vitamin D Supplementation
While studies have not shown vitamin D to be a magic bullet in treating or preventing RA, they have reported an improvement in symptoms and quality of life in RA patients who have or achieve normal serum vitamin D levels.<sup>3,6,7,11</sup> In one such study, patients receiving disease-modifying antirheumatic drugs who were identified to be vitamin D deficient (<20 ng/mL) and treated with high-dose vitamin D supplementation were found to have significant improvements in their DAS28 scores.<sup>11</sup> Patients received 60,0000 IU weekly for 6 weeks followed by 60,000 IU monthly for 3 months. Vitamin D supplementation guidelines for RA patients have yet to be developed, but administration of high-dose vitamin D as an oral weekly bolus has been found to safely and rapidly correct vitamin D deficiency in these patients.<sup>12</sup> Once normal levels are achieved, regular lower doses should be used to maintain adequate levels.<sup>12</sup>
Vitamin D has long been known to be crucial to bone health by regulating bone metabolism but has also been shown to play other crucial physiologic roles, including regulating the immune system.1,2 Subsequently, it can play an important role in the development of autoimmune diseases like rheumatoid arthritis (RA).
Increasing evidence indicates serum vitamin D levels and polymorphisms in enzymes involved in vitamin D metabolism can affect the risk of RA, influence disease activity and recurrence, and increase the risk of comorbidities, such as cardiovascular diseases. Therefore, vitamin D levels are an important consideration when treating patients with or at risk for RA.
- Urruticoechea-Arana A, Martín-Martínez MA, Castañeda S, et al. Vitamin D deficiency in chronic inflammatory rheumatic diseases: results of the cardiovascular in rheumatology [CARMA] study. Arthritis Res Ther. 2015;17:211.
- Wöbke TK, Sorg BL, Steinhilber D. Vitamin D in inflammatory diseases. Front Physiol. 2014;5:244.
- Song GG, Bae SC, Lee YH. Association between vitamin D intake and the risk of rheumatoid arthritis: a meta-analysis. Clin Rheumatol. 2012;31(12):1733-1739.
- Alhassan Mohammed H, Saboor-Yaraghi AA, Mirshafiey A, Vahedi H, Shiri-Shahsavar MR, Mousavi Nasl Khameneh A. Immunomodulatory and immunosuppressive roles of 1a,25(OH)2D3 in autoimmune diseases [published online November 29, 2016]. Scand J Immunol. . doi: 10.1111/sji.12512
- He XJ, Ding Y, Xiang W, Dang XQ. Roles of 1,25(OH)2D3 and vitamin D receptor in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus by regulating the activation of CD4+ T cells and the PKCδ/ERK signaling pathway. Cell Physiol Biochem. 2016;40:743-756.
- Lee YH, Bae SC. Vitamin D level in rheumatoid arthritis and its correlation with the disease activity: a meta-analysis. Clin Exp Rheumatol. 2016;34:827-833.
- Lin J, Liu J, Davies ML, Chen W. Serum vitamin D Level and rheumatoid arthritis disease activity: review and meta-analysis. PLoS ONE. 2016;11(1):e0146351. doi:10.1371/journal.pone.0146351
- Yang J, Liu L, Zhang Q2, Li M, Wang J. Effect of vitamin D on the recurrence rate of rheumatoid arthritis. Exp Ther Med. 2015;10:1812-1816.
- Dhawan SS, Quyyumi AA. Rheumatoid arthritis and cardiovascular disease. Curr Atheroscler Rep. 2008;10(2):128-133.
- Lo Gullo A, Mandraffino G, Bagnato G, et al. Vitamin D status in rheumatoid arthritis: inflammation, arterial stiffness and circulating progenitor cell number. PLoS One. 2015;10:e0134602.
- Chandrashekara S, Patted A. Role of vitamin D supplementation in improving disease activity in rheumatoid arthritis: an exploratory study [published online October 20, 2015]. Int J Rheum Dis. doi: 10.1111/1756-185X.12770
- Leventis P, Patel S. Clinical aspects of vitamin D in the management of rheumatoid arthritis. Rheumatology (Oxford). 2008;47(11):1617-1621. doi: 10.1093/rheumatology/ken296.
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