Vitamin D in rheumatoid arthritis—towards clinical application

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Abstract

In addition to its well-documented involvement in mineral homeostasis, vitamin D seems to have broad effects on human health that go beyond the skeletal system. Prominent among these so-called nonclassical effects of vitamin D are its immunomodulatory properties. In vitro studies have shown anti-inflammatory effects of 1,25-dihydroxyvitamin D (1,25(OH)2D), the active form of vitamin D. In addition, epidemiological analysis of patients with established inflammatory disease identified associations between vitamin D deficiency (low serum concentrations of inactive 25-hydroxyvitamin D, abbreviated to 25(OH)D) and inflammatory conditions, including rheumatoid arthritis (RA). The association of vitamin D deficiency with RA severity supports the hypothesis of a role for vitamin D in the initiation or progression of the disease, or possibly both. However, whether 25(OH)D status is a cause or consequence of RA is still incompletely understood and requires further analysis in prospective vitamin D supplementation trials. The characterization of factors that promote the transition from preclinical to clinical phases of RA has become a major focus of research, with the aim to facilitate earlier diagnosis and treatment, and improve therapeutic outcomes. In this Review, we aim to describe the current knowledge of vitamin D and the immune system specifically in RA, and discuss the potential benefits that vitamin D might have on slowing RA progression.

Key Points

  • Nonclassical effects of vitamin D have been recognized for many years, but were only accepted as an important component of vitamin D physiology in the past decade

  • Prominent among the nonclassical effects of vitamin D are its anti-inflammatory properties

  • Vitamin D deficiency is prevalent worldwide and has been linked to several chronic inflammatory diseases, including rheumatoid arthritis (RA)

  • Randomized controlled trials of vitamin D supplementation in prospective at-risk cohorts and in patients with active RA are needed to assess the effect of vitamin D on disease initiation and progression

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Figure 1: Renal and extra-renal vitamin D metabolism in RA progression.
Figure 2: Vitamin D status and synovial immune cell function.

References

  1. 1

    Yarwood, A., Huizinga, T. W. & Worthington, J. The genetics of rheumatoid arthritis: risk and protection in different stages of the evolution of RA. Rheumatology (Oxford) http://dx.doi.org/10.1093/rheumatology/keu323.

  2. 2

    Lu, B., Solomon, D. H., Costenbader, K. H. & Karlson, E. W. Alcohol consumption and risk of incident rheumatoid arthritis in women: a prospective study. Arthritis Rheumatol. 66, 1998–2005 (2014).

  3. 3

    Kallberg, H. et al. Alcohol consumption is associated with decreased risk of rheumatoid arthritis: results from two Scandinavian case–control studies. Ann. Rheum. Dis. 68, 222–227 (2009).

  4. 4

    Pattison, D. J. et al. Vitamin C and the risk of developing inflammatory polyarthritis: prospective nested case–control study. Ann. Rheum. Dis. 63, 843–847 (2004).

  5. 5

    Pattison, D. J. et al. Dietary risk factors for the development of inflammatory polyarthritis: evidence for a role of high level of red meat consumption. Arthritis Rheum. 50, 3804–3812 (2004).

  6. 6

    Rosell, M. et al. Dietary fish and fish oil and the risk of rheumatoid arthritis. Epidemiology 20, 896–901 (2009).

  7. 7

    Klareskog, L. et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 54, 38–46 (2006).

  8. 8

    Holick, M. F. Vitamin D deficiency. N. Engl. J. Med. 357, 266–281 (2007).

  9. 9

    Haussler, M. R. et al. The nuclear vitamin D receptor controls the expression of genes encoding factors which feed the “Fountain of Youth” to mediate healthful aging. J. Steroid Biochem. Mol. Biol. 121, 88–97 (2010).

  10. 10

    Hewison, M. Vitamin D and the intracrinology of innate immunity. Mol. Cell. Endocrinol. 321, 103–111 (2010).

  11. 11

    Hewison, M. Antibacterial effects of vitamin D. Nat. Rev. Endocrinol. 7, 337–345 (2011).

  12. 12

    Adams, J. S. & Hewison, M. Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nat. Clin. Pract. Endocrinol. Metab. 4, 80–90 (2008).

  13. 13

    Adams, J. S. & Hewison, M. Update in vitamin D. J. Clin. Endocrinol. Metab. 95, 471–478 (2010).

  14. 14

    Hong, Q. et al. Associations between serum 25-hydroxyvitamin D and disease activity, inflammatory cytokines and bone loss in patients with rheumatoid arthritis. Rheumatology (Oxford) 53, 1994–2001 (2014).

  15. 15

    Aho, K. et al. When does rheumatoid disease start? Arthritis Rheum. 28, 485–489 (1985).

  16. 16

    Kurki, P., Aho, K., Palosuo, T. & Heliovaara, M. Immunopathology of rheumatoid arthritis. Antikeratin antibodies precede the clinical disease. Arthritis Rheum. 35, 914–917 (1992).

  17. 17

    Aho, K., von Essen, R., Kurki, P., Palosuo, T. & Heliovaara, M. Antikeratin antibody and antiperinuclear factor as markers for subclinical rheumatoid disease process. J. Rheumatol. 20, 1278–1281 (1993).

  18. 18

    van Steenbergen, H. W., Huizinga, T. W. & van der Helm-van Mil, A. H. The preclinical phase of rheumatoid arthritis: what is acknowledged and what needs to be assessed? Arthritis Rheum. 65, 2219–2232 (2013).

  19. 19

    Gerlag, D. M. et al. EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis. Ann. Rheum. Dis. 71, 638–641 (2012).

  20. 20

    Haussler, M. R. et al. The role of vitamin D in the FGF23, klotho, and phosphate bone-kidney endocrine axis. Rev. Endocr. Metab. Disord. 13, 57–69 (2012).

  21. 21

    Adams, J. S. et al. Vitamin D-directed rheostatic regulation of monocyte antibacterial responses. J. Immunol. 182, 4289–4295 (2009).

  22. 22

    Liu, P. T. et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311, 1770–1773 (2006).

  23. 23

    Bell, N. H., Stern, P. H., Pantzer, E., Sinha, T. K. & DeLuca, H. F. Evidence that increased circulating 1α, 25-dihydroxyvitamin D is the probable cause for abnormal calcium metabolism in sarcoidosis. J. Clin. Invest. 64, 218–225 (1979).

  24. 24

    Adams, J. S. & Gacad, M. A. Characterization of 1α-hydroxylation of vitamin D3 sterols by cultured alveolar macrophages from patients with sarcoidosis. J. Exp. Med. 161, 755–765 (1985).

  25. 25

    Hayes, M. E., Denton, J., Freemont, A. J. & Mawer, E. B. Synthesis of the active metabolite of vitamin D, 1,25(OH)2D3, by synovial fluid macrophages in arthritic diseases. Ann. Rheum. Dis. 48, 723–729 (1989).

  26. 26

    Mawer, E. B. et al. Evidence for nonrenal synthesis of 1,25-dihydroxyvitamin D in patients with inflammatory arthritis. J. Bone Miner. Res. 6, 733–739 (1991).

  27. 27

    Gates, S., Shary, J., Turner, R. T., Wallach, S. & Bell, N. H. Abnormal calcium metabolism caused by increased circulating 1,25-dihydroxyvitamin D in a patient with rheumatoid arthritis. J. Bone Miner. Res. 1, 221–226 (1986).

  28. 28

    Oelzner, P. et al. Relationship between disease activity and serum levels of vitamin D metabolites and PTH in rheumatoid arthritis. Calcif. Tissue Int. 62, 193–198 (1998).

  29. 29

    Kroger, H., Penttila, I. M. & Alhava, E. M. Low serum vitamin D metabolites in women with rheumatoid arthritis. Scand. J. Rheumatol. 22, 172–177 (1993).

  30. 30

    Patel, S. et al. Association between serum vitamin D metabolite levels and disease activity in patients with early inflammatory polyarthritis. Arthritis Rheum. 56, 2143–2149 (2007).

  31. 31

    Adami, S. et al. Extrarenal synthesis of 1,25-dihydroxyvitamin D: sensitivity to glucocorticoid treatment. Clin. Sci. (Lond.) 72, 329–334 (1987).

  32. 32

    Gyetko, M. R., Hsu, C. H., Wilkinson, C. C., Patel, S. & Young, E. Monocyte 1α-hydroxylase regulation: induction by inflammatory cytokines and suppression by dexamethasone and uremia toxin. J. Leukoc. Biol. 54, 17–22 (1993).

  33. 33

    Jeffery, L. E. et al. Availability of 25-hydroxyvitamin D3 to APCs controls the balance between regulatory and inflammatory T cell responses. J. Immunol. 189, 5155–5164 (2012).

  34. 34

    Zehnder, D. et al. Synthesis of 1,25-dihydroxyvitamin D3 by human endothelial cells is regulated by inflammatory cytokines: a novel autocrine determinant of vascular cell adhesion. J. Am. Soc. Nephrol. 13, 621–629 (2002).

  35. 35

    Ebert, R. et al. Down-regulation by nuclear factor κB of human 25-hydroxyvitamin D3 1α-hydroxylase promoter. Mol. Endocrinol. 18, 2440–2450 (2004).

  36. 36

    Manolagas, S. C., Werntz, D. A., Tsoukas, C. D., Provvedini, D. M. & Vaughan, J. H. 1,25-Dihydroxyvitamin D3 receptors in lymphocytes from patients with rheumatoid arthritis. J. Lab. Clin. Med. 108, 596–600 (1986).

  37. 37

    Wang, Y., Zhu, J. & DeLuca, H. F. Where is the vitamin D receptor? Arch. Biochem. Biophys. 523, 123–133 (2012).

  38. 38

    Tran, C. N., Lundy, S. K. & Fox, D. A. Synovial biology and T cells in rheumatoid arthritis. Pathophysiology 12, 183–189 (2005).

  39. 39

    Bugatti, S., Vitolo, B., Caporali, R., Montecucco, C. & Manzo, A. B cells in rheumatoid arthritis: from pathogenic players to disease biomarkers. Biomed. Res. Int. 2014, 681678 (2014).

  40. 40

    Li, H. et al. Cross talk between the bone and immune systems: osteoclasts function as antigen-presenting cells and activate CD4+ and CD8+ T cells. Blood 116, 210–217 (2010).

  41. 41

    van Hamburg, J. P. et al. TH17 cells, but not TH1 cells, from patients with early rheumatoid arthritis are potent inducers of matrix metalloproteinases and proinflammatory cytokines upon synovial fibroblast interaction, including autocrine interleukin-17A production. Arthritis Rheum. 63, 73–83 (2011).

  42. 42

    Sato, K. et al. TH17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J. Exp. Med. 203, 2673–2682 (2006).

  43. 43

    de Paz, B. et al. Cytokines and regulatory T cells in rheumatoid arthritis and their relationship with response to corticosteroids. J. Rheumatol. 37, 2502–2510 (2010).

  44. 44

    Nakano, S. et al. Immunoregulatory role of IL-35 in T cells of patients with rheumatoid arthritis. Rheumatology (Oxford) 54, 1498–1506 (2015).

  45. 45

    Thiolat, A. et al. Interleukin-35 gene therapy exacerbates experimental rheumatoid arthritis in mice. Cytokine 69, 87–93 (2014).

  46. 46

    Cooles, F. A., Isaacs, J. D. & Anderson, A. E. Treg cells in rheumatoid arthritis: an update. Curr. Rheumatol. Rep. 15, 352 (2013).

  47. 47

    Moradi, B. et al. CD4+CD25+/highCD127low/− regulatory T cells are enriched in rheumatoid arthritis and osteoarthritis joints—analysis of frequency and phenotype in synovial membrane, synovial fluid and peripheral blood. Arthritis Res. Ther. 16, R97 (2014).

  48. 48

    Dong, L. et al. Decreased expression of microRNA-21 correlates with the imbalance of TH17 and TREG cells in patients with rheumatoid arthritis. J. Cell. Mol. Med. 18, 2213–2224 (2014).

  49. 49

    Penna, G. & Adorini, L. 1α,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J. Immunol. 164, 2405–2411 (2000).

  50. 50

    Berer, A. et al. 1,25-Dihydroxyvitamin D3 inhibits dendritic cell differentiation and maturation in vitro. Exp. Hematol. 28, 575–583 (2000).

  51. 51

    Penna, G. et al. 1,25-dihydroxyvitamin D3 selectively modulates tolerogenic properties in myeloid but not plasmacytoid dendritic cells. J. Immunol. 178, 145–153 (2007).

  52. 52

    Sochorova, K. et al. Paricalcitol (19-nor-1,25-dihydroxyvitamin D2) and calcitriol (1,25-dihydroxyvitamin D3) exert potent immunomodulatory effects on dendritic cells and inhibit induction of antigen-specific T cells. Clin. Immunol. 133, 69–77 (2009).

  53. 53

    Wu, H. J. et al. Alternatively activated dendritic cells derived from systemic lupus erythematosus patients have tolerogenic phenotype and function. Clin. Immunol. 156, 43–57 (2015).

  54. 54

    Bartosik-Psujek, H., Tabarkiewicz, J., Pocinska, K., Stelmasiak, Z. & Rolinski, J. Immunomodulatory effects of vitamin D on monocyte-derived dendritic cells in multiple sclerosis. Mult. Scler. 16, 1513–1516 (2010).

  55. 55

    Pedersen, A. W. et al. Phenotypic and functional markers for 1α,25-dihydroxyvitamin D3-modified regulatory dendritic cells. Clin. Exp. Immunol. 157, 48–59 (2009).

  56. 56

    Penna, G. & Adorini, L. 1α,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J. Immunol. 164, 2405–2411 (2000).

  57. 57

    Colin, E. M. et al. 1,25-dihydroxyvitamin D3 modulates TH17 polarization and interleukin-22 expression by memory T cells from patients with early rheumatoid arthritis. Arthritis Rheum. 62, 132–142 (2010).

  58. 58

    Luo, J. et al. 1,25-dihydroxyvitamin D3 inhibits the RANKL pathway and impacts on the production of pathway-associated cytokines in early rheumatoid arthritis. Biomed. Res. Int. 2013, 101805 (2013).

  59. 59

    Neve, A., Corrado, A. & Cantatore, F. P. Immunomodulatory effects of vitamin D in peripheral blood monocyte-derived macrophages from patients with rheumatoid arthritis. Clin. Exp. Med. 14, 275–283 (2014).

  60. 60

    von Essen, M. R. et al. Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nat. Immunol. 11, 344–349 (2010).

  61. 61

    Jeffery, L. E. et al. 1,25-dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J. Immunol. 183, 5458–5467 (2009).

  62. 62

    Palmer, M. T. et al. Lineage-specific effects of 1,25-dihydroxyvitamin D3 on the development of effector CD4 T cells. J. Biol. Chem. 286, 997–1004 (2011).

  63. 63

    Ikeda, U. et al. 1α,25-dihydroxyvitamin D3 and all-trans retinoic acid synergistically inhibit the differentiation and expansion of TH17 cells. Immunol. Lett. 134, 7–16 (2010).

  64. 64

    Urry, Z. et al. The role of 1α,25-dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+ and IL-10+ CD4+ T cells. Eur. J. Immunol. 42, 2697–2708 (2012).

  65. 65

    Urry, Z. et al. Ligation of TLR9 induced on human IL-10-secreting TREGS by 1α,25-dihydroxyvitamin D3 abrogates regulatory function. J. Clin. Invest. 119, 387–398 (2009).

  66. 66

    Ranganathan, P. et al. Vitamin D deficiency, interleukin 17, and vascular function in rheumatoid arthritis. J. Rheumatol. 40, 1529–1534 (2013).

  67. 67

    Drozdenko, G., Heine, G. & Worm, M. Oral vitamin D increases the frequencies of CD38+ human B cells and ameliorates IL-17-producing T cells. Exp. Dermatol. 23, 107–112 (2014).

  68. 68

    Prietl, B. et al. Vitamin D supplementation and regulatory T cells in apparently healthy subjects: vitamin D treatment for autoimmune diseases? Isr. Med. Assoc. J. 12, 136–139 (2010).

  69. 69

    Prietl, B. et al. High-dose cholecalciferol supplementation significantly increases peripheral CD4+ TREGS in healthy adults without negatively affecting the frequency of other immune cells. Eur. J. Nutr. 53, 751–759 (2014).

  70. 70

    Ardalan, M. R. et al. Calcitriol started in the donor, expands the population of CD4+CD25+ T cells in renal transplant recipients. Transplant. Proc. 39, 951–953 (2007).

  71. 71

    Weyand, C. M., Fujii, H., Shao, L. & Goronzy, J. J. Rejuvenating the immune system in rheumatoid arthritis. Nat. Rev. Rheumatol. 5, 583–588 (2009).

  72. 72

    Richards, J. B. et al. Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women. Am. J. Clin. Nutr. 86, 1420–1425 (2007).

  73. 73

    Zhu, H. et al. Increased telomerase activity and vitamin D supplementation in overweight African Americans. Int. J. Obes. (Lond.) 36, 805–809 (2012).

  74. 74

    Liaskou, E. et al. Loss of CD28 expression by liver-infiltrating T cells contributes to pathogenesis of primary sclerosing cholangitis. Gastroenterology 147, 221–232 (2014).

  75. 75

    Fujii, H., Shao, L., Colmegna, I., Goronzy, J. J. & Weyand, C. M. Telomerase insufficiency in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 106, 4360–4365 (2009).

  76. 76

    Moura, R. A., Graca, L. & Fonseca, J. E. To B or not to B the conductor of rheumatoid arthritis orchestra. Clin. Rev. Allergy Immunol. 43, 281–291 (2012).

  77. 77

    Panayi, G. S. B cells: a fundamental role in the pathogenesis of rheumatoid arthritis? Rheumatology (Oxford) 44 (Suppl. 2), ii3–ii7 (2005).

  78. 78

    Schlegel, P. M., Steiert, I., Kotter, I. & Muller, C. A. B cells contribute to heterogeneity of IL-17 producing cells in rheumatoid arthritis and healthy controls. PLoS ONE 8, e82580 (2013).

  79. 79

    Olalekan, S. A., Cao, Y., Hamel, K. M. & Finnegan, A. B cells expressing IFN-γ suppress TREG-cell differentiation and promote autoimmune experimental arthritis. Eur. J. Immunol. 45, 988–998 (2015).

  80. 80

    Yeo, L. et al. Cytokine mRNA profiling identifies B cells as a major source of RANKL in rheumatoid arthritis. Ann. Rheum. Dis. 70, 2022–2028 (2011).

  81. 81

    Yeo, L. et al. Expression of FcRL4 defines a pro-inflammatory, RANKL-producing B cell subset in rheumatoid arthritis. Ann. Rheum. Dis. 74, 928–935 (2014).

  82. 82

    Daien, C. I. et al. Regulatory B10 cells are decreased in patients with rheumatoid arthritis and are inversely correlated with disease activity. Arthritis Rheumatol. 66, 2037–2046 (2014).

  83. 83

    Chen, S. et al. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J. Immunol. 179, 1634–1647 (2007).

  84. 84

    Heine, G. et al. 1,25-dihydroxyvitamin D3 promotes IL-10 production in human B cells. Eur. J. Immunol. 38, 2210–2218 (2008).

  85. 85

    Barone, F., Nayar, S. & Buckley, C. D. The role of non-hematopoietic stromal cells in the persistence of inflammation. Front. Immunol. 3, 416 (2012).

  86. 86

    Filer, A. The fibroblast as a therapeutic target in rheumatoid arthritis. Curr. Opin. Pharmacol. 13, 413–419 (2013).

  87. 87

    Laragione, T., Shah, A. & Gulko, P. S. The vitamin D receptor regulates rheumatoid arthritis synovial fibroblast invasion and morphology. Mol. Med. 18, 194–200 (2012).

  88. 88

    Feng, X. et al. Modulatory effect of 1,25-dihydroxyvitamin D3 on IL1β-induced RANKL, OPG, TNFα, and IL-6 expression in human rheumatoid synoviocyte MH7A. Clin. Dev. Immunol. 2013, 160123 (2013).

  89. 89

    Zwerina, K. et al. Vitamin D receptor regulates TNF-mediated arthritis. Ann. Rheum. Dis. 70, 1122–1129 (2011).

  90. 90

    Reid, D. et al. The relation between acute changes in the systemic inflammatory response and plasma 25-hydroxyvitamin D concentrations after elective knee arthroplasty. Am. J. Clin. Nutr. 93, 1006–1011 (2011).

  91. 91

    Broder, A. R., Tobin, J. N. & Putterman, C. Disease-specific definitions of vitamin D deficiency need to be established in autoimmune and non-autoimmune chronic diseases: a retrospective comparison of three chronic diseases. Arthritis Res. Ther. 12, R191 (2010).

  92. 92

    Costenbader, K. H., Feskanich, D., Holmes, M., Karlson, E. W. & Benito-Garcia, E. Vitamin D intake and risks of systemic lupus erythematosus and rheumatoid arthritis in women. Ann. Rheum. Dis. 67, 530–535 (2008).

  93. 93

    Manara, M. et al. Dietary intake of vitamin D during adolescence and risk of adult-onset systemic lupus erythematosus and rheumatoid arthritis. Clin. Exp. Rheumatol. 30, 714–719. (2012).

  94. 94

    Merlino, L. A. et al. Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women's Health Study. Arthritis Rheum. 50, 72–77 (2004).

  95. 95

    Hiraki, L. T. et al. Circulating 25-hydroxyvitamin D level and risk of developing rheumatoid arthritis. Rheumatology (Oxford) 53, 2243–2248 (2014).

  96. 96

    Nielen, M. M. et al. Vitamin D deficiency does not increase the risk of rheumatoid arthritis: comment on the article by Merlino et al. Arthritis Rheum. 54, 3719–3720 (2006).

  97. 97

    Feser, M. et al. Plasma 25,OH vitamin D concentrations are not associated with rheumatoid arthritis (RA)-related autoantibodies in individuals at elevated risk for RA. J. Rheumatol. 36, 943–946 (2009).

  98. 98

    Racovan, M. et al. Calcium and vitamin D supplementation and incident rheumatoid arthritis: the Women's Health Initiative Calcium plus Vitamin D trial. Rheumatol. Int. 32, 3823–3830 (2012).

  99. 99

    Park, Y. E. et al. Vitamin D status of patients with early inflammatory arthritis. Clin. Rheumatol. 34, 239–246 (2015).

  100. 100

    Song, G. G., Bae, S. C. & Lee, Y. H. Association between vitamin D intake and the risk of rheumatoid arthritis: a meta-analysis. Clin. Rheumatol. 31, 1733–1739 (2012).

  101. 101

    Di Franco, M. et al. Hypovitaminosis D in recent onset rheumatoid arthritis is predictive of reduced response to treatment and increased disease activity: a 12 month follow-up study. BMC Musculoskelet. Disord. 16, 53 (2015).

  102. 102

    Furuya, T. et al. Prevalence of and factors associated with vitamin D deficiency in 4,793 Japanese patients with rheumatoid arthritis. Clin. Rheumatol. 32, 1081–1087 (2013).

  103. 103

    Haga, H. J., Schmedes, A., Naderi, Y., Moreno, A. M. & Peen, E. Severe deficiency of 25-hydroxyvitamin D3 (25-OH-D3) is associated with high disease activity of rheumatoid arthritis. Clin. Rheumatol. 32, 629–633 (2013).

  104. 104

    Chen, J. et al. Vitamin D deficiency and low bone mineral density in native Chinese rheumatoid arthritis patients. Int. J. Rheum. Dis. 17, 66–70 (2014).

  105. 105

    Rossini, M. et al. Relationship of focal erosions, bone mineral density, and parathyroid hormone in rheumatoid arthritis. J. Rheumatol. 38, 997–1002 (2011).

  106. 106

    Rossini, M. et al. Vitamin D deficiency in rheumatoid arthritis: prevalence, determinants and associations with disease activity and disability. Arthritis Res. Ther. 12, R216 (2010).

  107. 107

    Nanes, M. S. Tumor necrosis factor-alpha: molecular and cellular mechanisms in skeletal pathology. Gene 321, 1–15 (2003).

  108. 108

    Scharla, S. H., Schacht, E. & Lempert, U. G. Alfacalcidol versus plain vitamin D in inflammation induced bone loss. J. Rheumatol. Suppl. 76, 26–32 (2005).

  109. 109

    Barrat, F. J. et al. In vitro generation of interleukin 10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (TH1)- and TH2-inducing cytokines. J. Exp. Med. 195, 603–616 (2002).

  110. 110

    Harry, R. A., Anderson, A. E., Isaacs, J. D. & Hilkens, C. M. Generation and characterisation of therapeutic tolerogenic dendritic cells for rheumatoid arthritis. Ann. Rheum. Dis. 69, 2042–2050 (2010).

  111. 111

    Volchenkov, R., Karlsen, M., Jonsson, R. & Appel, S. Type 1 regulatory T cells and regulatory B cells induced by tolerogenic dendritic cells. Scand. J. Immunol. 77, 246–254 (2013).

  112. 112

    van Hamburg, J. P. et al. TNF blockade requires 1,25(OH)2D3 to control human TH17-mediated synovial inflammation. Ann. Rheum. Dis. 71, 606–612 (2012).

  113. 113

    Lee, Y. H., Bae, S. C., Choi, S. J., Ji, J. D. & Song, G. G. Associations between vitamin D receptor polymorphisms and susceptibility to rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis. Mol. Biol. Rep. 38, 3643–3651 (2011).

  114. 114

    Hitchon, C. A. et al. Vitamin D receptor polymorphism rs2228570 (Fok1) is associated with rheumatoid arthritis in North American natives. J. Rheumatol. 39, 1792–1797 (2012).

  115. 115

    Tizaoui, K. & Hamzaoui, K. Association between VDR polymorphisms and rheumatoid arthritis disease: Systematic review and updated meta-analysis of case-control studies. Immunobiology 220, 807–816 (2014).

  116. 116

    Yan, X. et al. Vitamin D-binding protein (group-specific component) has decreased expression in rheumatoid arthritis. Clin. Exp. Rheumatol. 30, 525–533 (2012).

  117. 117

    Wang, T. J. et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 376, 180–188 (2010).

  118. 118

    Jeffery, L. E. et al. Availability of 25-hydroxyvitamin D3 to APCs controls the balance between regulatory and inflammatory T cell responses. J. Immunol. 189, 5155–5164 (2012).

  119. 119

    Shahijanian, F. et al. The CYP27B1 variant associated with an increased risk of autoimmune disease is underexpressed in tolerizing dendritic cells. Hum. Mol. Genet. 23, 1425–1434 (2014).

  120. 120

    Papiha, S. S. & Pal, B. Gc (vitamin D binding protein) subtypes in rheumatoid arthritis. Hum. Genet. 70, 278–280 (1985).

  121. 121

    Chun, R. F. New perspectives on the vitamin D binding protein. Cell Biochem. Funct. 30, 445–456 (2012).

  122. 122

    Gomez-Vaquero, C. et al. Influence of the BsmI polymorphism of the vitamin D receptor gene on rheumatoid arthritis clinical activity. J. Rheumatol. 34, 1823–1826 (2007).

  123. 123

    Mosaad, Y. M. et al. Vitamin D receptor gene polymorphism as possible risk factor in rheumatoid arthritis and rheumatoid related osteoporosis. Hum. Immunol. 75, 452–461 (2014).

  124. 124

    Yarwood, A. et al. Enrichment of vitamin D response elements in RA-associated loci supports a role for vitamin D in the pathogenesis of RA. Genes Immun. 14, 325–329 (2013).

  125. 125

    Afzal, S., Brondum-Jacobsen, P., Bojesen, S. E. & Nordestgaard, B. G. Genetically low vitamin D concentrations and increased mortality: Mendelian randomisation analysis in three large cohorts. BMJ 349, g6330 (2014).

  126. 126

    Viatte, S. et al. The role of genetic polymorphisms regulating vitamin D levels in rheumatoid arthritis outcome: a Mendelian randomisation approach. Ann. Rheum. Dis. 73, 1430–1433 (2014).

  127. 127

    Yoshida, S. et al. A GC polymorphism associated with serum 25-hydroxyvitamin D level is a risk factor for hip fracture in Japanese patients with rheumatoid arthritis: 10-year follow-up of the Institute of Rheumatology, Rheumatoid Arthritis cohort study. Arthritis Res. Ther. 16, R75 (2014).

  128. 128

    Chun, R. F. et al. Vitamin D-binding protein directs monocyte responses to 25-hydroxy- and 1,25-dihydroxyvitamin D. J. Clin. Endocrinol. Metab. 95, 3368–3376 (2010).

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Acknowledgements

This work is supported by the following grants: Arthritis Research UK (Arthritis Research UK Rheumatoid Arthritis Pathogenies Centre of Excellence); EU FP7 HEALTH programme under the grant agreement FP7-HEALTH-F2-2012-305549.

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All authors contributed equally to all aspects of the manuscript (researching data for the article, discussions of its content, writing, review and editing of the manuscript before submission).

Correspondence to Martin Hewison.

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Jeffery, L., Raza, K. & Hewison, M. Vitamin D in rheumatoid arthritis—towards clinical application. Nat Rev Rheumatol 12, 201–210 (2016) doi:10.1038/nrrheum.2015.140

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