Open access peer-reviewed chapter

Vitamin D in Rheumatic Diseases: Interpretation and Significance

Written By

Binit Vaidya and Shweta Nakarmi

Submitted: 13 June 2018 Reviewed: 18 July 2019 Published: 08 August 2019

DOI: 10.5772/intechopen.88677

From the Edited Volume

Fads and Facts about Vitamin D

Edited by Edward T. Zawada Jr.

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Abstract

The pleiotropic effects of vitamin D on the various metabolic, anticancer, and immunomodulatory functions of the body based on the presence of vitamin D receptors (VDR) on various cell types has been recognized worldwide now. Of few understood mechanisms of immunomodulatory actions of vitamin D are the suppressive action on the maturation of antigen-presenting cells and decrease in the levels of pro-inflammatory cytokines. Vitamin D deficiency has been implicated in the immune diseases like rheumatic diseases, asthma, psoriasis, and multiple sclerosis. Vitamin D deficiency has been associated with increased frequency and severity of disease flares in rheumatic diseases like lupus and rheumatoid arthritis. Other studies have shown higher prevalence of persistence and evolution in to more definite rheumatic disorder in undifferentiated arthritis and undifferentiated connective tissue disorder patients with vitamin D deficiency. Multiple factors like avoidance of sunlight, the use of corticosteroids and hydroxychloroquine, skin pigmentation, etc. should be considered when evaluating vitamin D levels in these patients, needless to say the consideration of higher-dose supplement for these patients. It is thus prudent that all patients with established or undifferentiated rheumatic diseases are evaluated for vitamin D status and an adequate supplementation is recommended to prevent the associated consequences.

Keywords

  • vitamin D
  • vitamin D deficiency
  • immunomodulation
  • rheumatic diseases
  • inflammation

1. Introduction

Vitamin D has two bioequivalent forms, D2 (ergocalciferol) and D3 (cholecalciferol). It is synthesized mainly from 7-dehydrocholesterol in keratinocytes of the skin stimulated by UVB of sunlight and metabolized in the liver to 25(OH)D and subsequently converted to its active form 1,25(OH)2D in the kidney [1, 2]. It maintains calcium and phosphorus homeostasis, optimizes bone health and muscle function and immunomodulation, has antiproliferative effect on keratinocytes, and suppresses cytokine production [3, 4]. Serum 25(OH)D3 level of at least 50 nmol/l is considered to be optimal for bone health and extra skeletal effects [5]. The term hypovitaminosis D includes vitamin D insufficiency and deficiency. Vitamin D insufficiency is defined as a serum 25(OH)D concentration of 21–29 ng/ml (50–75 nmol/L), whereas deficiency means serum 25(OH)D level of <20 ng/ml (<50 nmol/L) [6].

Vitamin D is also known as the sunshine vitamin. The importance of sunlight for human health came into light with the industrial revolution in Northern Europe [7]. Sniadecki first published an article in 1822 about high prevalence of rickets in children who lived in the inner city in comparison to those who lived in the rural areas [8]. Many observations regarding the sun exposure and rickets have been published in the course of time. Studies have also revealed the high prevalence of vitamin D deficiency in general population, mostly owing to lack of sun exposure.

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2. Vitamin D structure, synthesis, and metabolism

Vitamin D is a fat-soluble seco-steroid made from four cholesterol rings IOM (Institute of Medicine) [9]. It has two bioequivalent forms, D2 (ergocalciferol) and D3 (cholecalciferol). Vitamin D2 is derived from the plant sterol ergosterol [1, 9]. Vitamin D from the diet or dermal synthesis is biologically inactive [10]. Vitamin D3 is synthesized mainly from 7-dehydrocholesterol in keratinocytes of the skin stimulated by UVB of sunlight [3]. Under the influence of sunlight (ultraviolet radiation, action spectrum 280–320 nM, or UVB), 7-dehydrocholesterol in the epidermis is converted to vitamin D (Figure 1). Keratinocytes express the vitamin D receptor (VDR) due to which they are capable of responding to the 1,25(OH)2D produced [11]. Both UVB intensity and skin pigmentation level contribute to the rate of D3 formation [12]. D3 is converted to 25(OH)D (calcidiol) in the liver by a number of enzymes. 25-Hydroxyvitamins D2 and D3 produced by the liver enter the circulation and the kidney bound to vitamin D-binding protein. The kidney metabolizes 25(OH)D to the active metabolite 1,25(OH)2D3.

Figure 1.

Overview of vitamin D, UpToDate 2019.

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3. Sources of vitamin D

More than 90% of vitamin D requirement comes from sunlight. According to Holick, exposure of ≥20% of the body’s surface to either direct sunlight or tanning bed radiation is effective in increasing blood concentrations of vitamin D3 and 25-hydroxyvitamin D3 [25(OH)D3]. One minimal erythemal dose (MED) is equivalent to 10–50 times the recommended intakes [3]. Oily fishlike salmon, mackerel, sardines, and cod liver oil are also considered good sources of vitamin D [13].

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4. Causes of vitamin D deficiency

There are numerous causes of vitamin D deficiency. Decreased synthesis from the skin is one of the main causes. Less exposure to sunlight, lifestyle, skin pigmentation, abundant use of sunscreen lotion, and geographical variation owe to less dermal synthesis. Decreased bioavailability due to malabsorption, decreased synthesis of active form of vitamin D due to liver or renal failure, or increased catabolism with the use of various medications like glucocorticoids and anticonvulsants also cause deficiency. VDD is also seen in diseases like rickets, osteomalacia, hyperparathyroidism, and granulomatous disorders [14].

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5. Daily recommended dose of vitamin D

The daily recommended allowance of vitamin D is 400–600 IU in children and adults and 800 IU in adults >70 years [9].

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6. Clinical applications

  1. Bone and vitamin D: Vitamin D maintains calcium and phosphorus homeostasis and optimizes bone health and muscle function [4]. Adequate vitamin D is necessary to prevent rickets and osteomalacia [3]. Though still controversial, it is reported that calcium and vitamin D supplementation prevents fall risk and also decreases the osteoporotic fracture in older adults [15]. Vitamin D supplementation of 700–800 IU per day reduces falls and fractures in older adults [16].

  2. PTH and vitamin D: There is an inverse relationship between circulating 25(OH)D levels and parathyroid hormone (PTH) [1].

  3. Muscle function and vitamin D: There are several studies that suggest a relationship between vitamin D and muscle function. Though improvement of muscle strength with supplementation of vitamin D has been observed in few trials [17, 18], the causal relation has not been established yet.

  4. Skin and vitamin D: 1,25(OH)2D analogs calcipotriol and maxacalcitol can be used for the treatment of the hyperproliferative skin diseases like psoriasis [3, 19] and non-melanoma skin cancer [20].

  5. Cancer and vitamin D: Vitamin D deficiency has been associated with cancers, especially colorectal [21, 22]. Calcium and 1,25(OH)2D3 participate in the regulation of keratinocyte proliferation and differentiation and may prevent the development of skin cancer [20]. Observational studies have shown the relationship between vitamin D deficiency and carcinoma of the breast, colon, and thyroid [3], but the results are not consistent.

  6. Immune system and vitamin D: Vitamin D is a potent immunomodulator. 1,25(OH)2D decreases the maturation of dendritic cells (DCs) decreasing their ability to present antigen and to activate T cells [23]. Furthermore, it suppresses production of IL-12 (important for Th1 development), IL-23, and IL-6 (important for Th17 development) [24]. But, there is no any approved vitamin D drug for immune modulation [1]. Studies have suggested an association of vitamin D with autoimmune diseases like multiple sclerosis [25] and asthma [26].

  7. Cardiovascular disease and vitamin D: There is an inverse relationship between vitamin D deficiency and risk of heart disease, myocardial infarction, and early death. Low vitamin D causes increased parathyroid hormone release, inflammation, proliferation of vascular smooth muscle cells, insulin resistance, thrombogenicity, dyslipidemia, and progressive extracellular matrix remodeling. All of these are associated with increased risk of ischemic heart disease, myocardial infarction, and early death [27, 28].

  8. Diabetes mellitus and vitamin D: Vitamin D deficiency is associated with insulin resistance. 1,25(OH)2D promotes increased lipogenesis and decreased lipolysis. The pancreatic B cell expresses the VDR, and 1,25(OH)2D promotes insulin secretion [29].

  9. Neurological disorder and vitamin D: Vitamin D plays an important role in brain development as it has effects on neuronal proliferation, differentiation, migration, and apoptosis [30].

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7. Vitamin D and immunomodulation

Vitamin D is involved in modulation of immune responses and has an important role in some autoimmune diseases like multiple sclerosis, diabetes mellitus, psoriasis, systemic lupus erythematosus (SLE), RA, etc. [31]. The biological effects or immunomodulation is mediated by the vitamin D receptor (VDR) which belongs to the nuclear hormone receptor family and is expressed in most cell types including macrophages, dendritic cells, B and T lymphocytes, and neutrophils [31, 32].

Along with the modulatory effects on T and B cell functions, VDR agonists inhibit the differentiation and maturation of DCs, thus influencing the function of DCs and promoting tolerogenic properties that favor the induction of regulatory T cells. VDR also downregulate expression of the costimulatory molecules CD40, CD80, and CD86, decrease production of IL-12, and increase production of IL-10. The inhibition of DC differentiation and maturation and production of pro-inflammatory mediators play an important role in the immunoregulatory activity of 1,25(OH)2D3 [33, 34].

1,25(OH)2D3 also plays an important role in the maintenance of B cell homeostasis. It has potent effects on functions of B cell, including induction of apoptosis and inhibition of proliferation, generation of memory B cells, plasma cell differentiation, and immunoglobulin production [35].

According to Grant, there is evidence in support of vitamin D reducing the risk of many autoimmune diseases including such as multiple sclerosis and type 1 diabetes mellitus. However, evidence for rheumatoid arthritis, osteoarthritis, type 2 diabetes mellitus, hypertension, and stroke is weak [36].

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8. SLE

Vitamin D deficiency is quite prevalent in SLE patients which may be attributable to various reasons. Avoidance of sunshine, photoprotection, renal insufficiency, and the use of medications which alter the metabolism of vitamin D or downregulate the functions of the vitamin D receptor like glucocorticoids, anticonvulsants, antimalarials, and the calcineurin inhibitors are some of the causes of VDD as shown in Figure 2 [37]. In a study by Toloza, vitamin D insufficiency was found in 66.7% and deficiency in 17.9% of SLE patients [38]. The frequency varied in different studies: Saudi Arabia (89.7%) [39], Norway (82%) [40], Poland (71%) [41], Hong Kong (27%) [42], and the United States (20%) [43]. Low serum vitamin D levels were related to cumulative glucocorticoid dose [38]. Corticosteroids accelerate the catabolism of 25(OH)D and 1,25(OH)2D and have a significant role in secondary osteoporosis [44]. Patients taking corticosteroids often require higher daily doses of vitamin D to maintain adequate levels [45]. Similarly, a commonly used antimalarial, hydroxychloroquine (HCQ), inhibits conversion of 25(OH)D to 1,25(OH)2D leading to low levels of vitamin D [46].

Figure 2.

The two-sided relation between vitamin D and SLE showing that low levels of vitamin D resulted from SLE and SLE complications that come from vitamin D deficiency [37].

A review by Sakthiswary demonstrated a substantial evidence in support of the association between vitamin D levels and SLE disease activity. However, vitamin D level is not associated with organ damage [47]. A study by Suzan showed a significant negative correlation that existed between 25(OH)D and anti-dsDNA and a positive correlation between 25(OH)D levels and C4 [48]. Another similar study showed a significant negative correlation between the serum concentration of vitamin D and the standardized values of disease activity scores as measured by the SLEDAI-2K and ECLAM scales [49]. An Australian study showed that low vitamin D was associated with a higher disease activity and an increase in serum vitamin D was associated with reduced disease activity over time [50]. Improving vitamin D status may improve other common manifestations as well, such as fatigue [51] and cognitive dysfunction [52].

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9. RA

The role of hypovitaminosis D in the pathogenesis of rheumatoid arthritis has been the topic of interest in the recent past. Lower vitamin D levels possess increased risk for RA [53]. 1,25(OH)2D3 contributes to the regulation of matrix metalloproteinase and prostaglandin E2 production by synovial fibroblasts and articular chondrocytes in RA [54].

High rates of vitamin D deficiency have been observed in patients with rheumatic diseases. A study demonstrated that in patients with RA, VDD was seen in 64% and insufficiency in 28%. Similarly, in spondyloarthritis (SpA) patients 48% had VDD and 35% had insufficiency [55]. The prevalence of VDD is quite in RA patients. The COMEDRA study showed that 55.8% of RA patients had vitamin D insufficiency and 3.6% had deficiency [56]. Eighty-four percent of RA patients were VDD in a recently published study by Meena. It also showed a significant inverse correlation between serum vitamin D levels and RA disease activity [57]. A meta-analysis by Lee and Bae supported this result suggesting that the vitamin D level is associated with susceptibility to RA and RA activity [58]. Similarly, a negative association between serum vitamin D and RA disease activity was demonstrated in few studies [59, 60, 61, 62]. Levels of 25(OH)D3 were also found to be negatively correlated to CRP and ESR [62]. However, relationship between 25(OH)D and levels of rheumatoid factor or anti-cyclic citrullinated peptide antibodies has not been established yet [63].

The COMORA study showed that vitamin D was insufficient in 54.6% and deficient in 8.5% of the RA patients. Low levels of vitamin D were associated with disease activity of RA and corticosteroid dosage and comorbidities like lung disease and osteoporosis therapy [64].

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10. CTD

In comparison to healthy adults, VDD is more prevalent in people with autoimmune diseases including connective tissue diseases (CTDs) [65]. It may also have a pivotal role in progression of undifferentiated CTDs to well-defined and more severe disease [65]. There are few evidences which showed the antifibrotic property of vitamin D [66]. Low vitamin D levels are also associated with more severe disease, low diffusing capacity for carbon monoxide (DLCO), and advanced-stage nailfold capillaroscopy changes in patients with scleroderma [67, 68]. However, a recent meta-analysis revealed that though VDD is quite common in scleroderma patients, it does not correlate to the disease activity [69].

Over the years, it has been proven that vitamin D is necessary for optimum muscle and bone health. In CTDs, vitamin D levels correlate with intensity of muscle weakness [68, 70]. It may also be considered as one of the risk factors in developing myositis [71]. However, the role of vitamin D in myositis or other CTDs has not been established yet. Studies have shown that in fibromyalgia, VDD is correlated with pain and disease activity [72] and correction of deficiency improves the symptoms [73].

11. Undifferentiated arthritis

Significant association has been reported between vitamin D deficiency and nonspecific musculoskeletal pain, arthralgias, or undifferentiated arthritis [74, 75]. A positive correlation of VDD with undifferentiated arthritis [76] and early inflammatory arthritis [77] has been observed. It has also shown VDD as one of the risk factors of disease progression to RA [76, 78].

References

  1. 1. Bikle DD. Vitamin D metabolism, mechanism of action, and Clinical Applications. Chemistry and Biology. 2014;21(3):319-329
  2. 2. Kennel KA, Drake MT, Hurley DL. Vitamin D deficiency in adults: When to test and how to treat. Mayo Clinic Proceedings. 2010;85(8):752-758
  3. 3. Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. The American Journal of Clinical Nutrition. 2004;80(6 Suppl):1678S-1688S
  4. 4. Nussey S, Whitehead S. The parathyroid glands and vitamin D. In: Endocrinology: An Integrated Approach. England, Oxford: BIOS Scientific Publishers; 2001
  5. 5. Ebeling PR. Vitamin D and bone health: Epidemiologic studies. BoneKEy Reports. 2014;3:511. DOI: 10.1038/bonekey.2014.6 Published: 5 March 2014
  6. 6. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of Vitamin D deficiency: An Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology and Metabolism. 2011;96(7):1911-1930
  7. 7. Holick MF. Vitamin D: A millenium perspective. Journal of Cellular Biochemistry. 2003;88(2):296-307
  8. 8. Mozolowski W. Jędrzej Sniadecki (1768-1838) on the cure of rickets. Nature. 1939;143(3612):121-124
  9. 9. IOM (Institute of Medicine). Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press; 2011
  10. 10. Christakos S, Ajibade DV, Dhawan P, et al. Vitamin D: Metabolism. Endocrinology and Metabolism Clinics of North America. 2010;39(2):243-253
  11. 11. Bikle DD. Vitamin D and the skin: Physiology and pathophysiology. Reviews in Endocrine & Metabolic Disorders. 2012;13(1):3-19
  12. 12. Holick MF, MacLaughlin JA, Clark MB, et al. Photosynthesis of previtamin D3 in human skin and the physiologic consequences. Science. 1980;210(4466):203-205
  13. 13. The British Dietetic Association. The Food Factsheet-Vitamin D. 2016. Available from: https://www.bda.uk.com/foodfacts/VitaminD.pdf
  14. 14. Holick MF. Vitamin D deficiency. The New England Journal of Medicine. 2007;357:266-281
  15. 15. Ringe JD. The effect of Vitamin D on falls and fractures. Scandinavian Journal of Clinical and Laboratory Investigation. 2012;72(Suppl. 243):73-78
  16. 16. Bordelon P, Ghetu MV, Langan R. Recognition and management of Vitamin D deficiency. 2009;80(8):841-846. Available from: www.aafp.org/afp
  17. 17. Glerup H, Mikkelsen K, Poulsen L, et al. Hypovitaminosis D myopathy without biochemical signs of osteomalacic bone involvement. Calcified Tissue International. 2000;66(6):419-424
  18. 18. Plotnikoff GA, Quingley JM. Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain. Mayo Clinic Proceedings. 2003;78(12):1463-1470
  19. 19. Noborio R, Kobayashi K, Shintani Y, et al. Comparison of the efficacy of calcipotriol and maxacalcitol in combination with narrow-band ultraviolet B therapy for the treatment of psoriasis vulgaris. Photodermatology, Photoimmunology & Photomedicine. 2006;22(5):262-264
  20. 20. Bikle DD. Vitamin D and skin cancer. The Journal of Nutrition. 2004;134(12 Suppl):3472S-3478S
  21. 21. Otani T, Iwasaki M, Sasazuki S, et al. Plasma vitamin D and risk of colorectal cancer: The Japan Public Health Center-based prospective study. British Journal of Cancer. 2007;97(3):446-451
  22. 22. Jenab M, Bueno-de-Mesquita H, Ferrari P, et al. Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations: A nested case-control study. BMJ. 2010:340, b5500
  23. 23. Van Etten E, Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin D3: Basic concepts. The Journal of Steroid Biochemistry and Molecular Biology. 2005;97(1–2):93-101
  24. 24. Daniel C, Sartory NA, Zahn N, et al. Immune modulatory treatment of trinitrobenzene sulfonic acid colitis with calcitriol is associated with a change of a T helper (Th) 1/Th17 to a Th2 and regulatory T cell profile. The Journal of Pharmacology and Experimental Therapeutics. 2008;324(1):23-33
  25. 25. Munger KL, Levin LI, Hollis BW, et al. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296(23):2832-2838
  26. 26. Arshi S, Fallahpour M, Nabavi M, et al. The effects of Vitamin D supplementation on airway functions in mild to moderate persistent asthma. Annals of Allergy, Asthma & Immunology. 2014;113(4):404-409
  27. 27. Brøndum-Jacobsen P, Benn M, Jensen GB, et al. 25-Hydroxyvitamin D levels and risk of ischemic heart disease, myocardial infarction, and early death-population-based study and meta-analyses of 18 and 17 studies. Arteriosclerosis, Thrombosis, and Vascular Biology. 2012;32(11):2794-2802
  28. 28. McGreevy C, Williams D. New insights about vitamin D and cardiovascular disease. Annals of Internal Medicine. 2011;155:820-826
  29. 29. Mitri J, Dawson-Hughes B, Hu FB, Pittas AG. Effects of vitamin D and calcium supplementation on pancreatic b cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: The calcium and vitamin D for diabetes mellitus (CaDDM) randomized controlled trial. The American Journal of Clinical Nutrition. 2011;94(2):486-494
  30. 30. Eyles DW, Feron F, Cui X, et al. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009;34(Suppl. 1):S247-S257
  31. 31. Adorini L, Penna G. Control of autoimmune diseases by the vitamin D endocrine system. Nature Clinical Practice Rheumatology. 2008;4:404-412
  32. 32. Gatenby P, Lucas R, Swaminathan A. Vitamin D deficiency and risk for rheumatic diseases: an update. Current Opinion in Rheumatology. 2013, 2013;25:184-191. DOI: 10.1097/BOR.0b013e32835cfc16
  33. 33. Adorini L, Giarratana N, Penna G. Pharmacological induction of tolerogenic dendritic cells and regulatory T cells. Seminars in Immunology. 2004;16(2):127-134
  34. 34. Etten EV, Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin D3: Basic concepts. Journal of Steroid Biochemistry and Molecular Biology. 2005;97:93-101
  35. 35. Chen S et al. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. Journal of Immunology. 2007;179:1634-1647
  36. 36. Grant WB. Epidemiology of disease risks in relation to vitamin D insufficiency. Progress in Biophysics and Molecular Biology. 2006;92:65-79
  37. 37. Hassanalilou T, Khalili L, Ghavamzadeh S, et al. Role of vitamin D deficiency in systemic lupus erythematosus incidence and aggravation. Autoimmunity Highlights. 2018;9(1). DOI: 10.1007/s13317-017-0101-x
  38. 38. Toloza SM, Cole DE, Gladman DD, et al. Vitamin D insufficiency in a large female SLE cohort. Lupus. 2010;19(1):13-19. DOI: 10.1177/0961203309345775. Epub: 6 November 2009
  39. 39. Damanhouri LH. Vitamin D deficiency in Saudi patients with systemic lupus erythematosus. Saudi Medical Journal. 2009;30(10):1291-1295
  40. 40. Szodoray P, Tarr T, Bazso A, et al. The immunopathological role of vitamin D in patients with SLE: Data from a single centre registry in Hungary. Scandinavian Journal of Rheumatology. 2011;40(2):122-126
  41. 41. Bogaczewicz J, Sysa-Jedrzejowska A, Arkuszewska C, et al. Prevalence of autoantibodies directed against 1,25(OH)2D3 inpatients with systemic lupus Erythematosus. Pol MerkurLekarski. 2010;28(164):103-107
  42. 42. Mok CC, Birmingham DJ, Ho LY, et al. Vitamin D deficiency as marker for disease activity and damage in systemic lupus erythematosus: A comparison with anti-dsDNA and anti-C1q. Lupus. 2012;21(1):36-42
  43. 43. Thudi A, Yin S, Wandstrat AE, et al. Vitamin D levels and disease status in Texas patients with systemic lupus erythematosus. The American Journal of the Medical Sciences. 2008;335(2):99-104
  44. 44. Patschan D, Loddenkemper K, Buttgereit F. Molecular mechanisms of glucocorticoid-induced osteoporosis. Bone. 2001;29:498-505
  45. 45. Kamen DL. Vitamin D in lupus: New kid on the block? Bulletin of the NYU Hospital for Joint Diseases. 2010;68(3):218-222
  46. 46. Barré PE, Gascon-Barré M, Meakins JL, Goltzman D. Hydroxychloroquine treatment of hypercalcemia in a patient with sarcoidosis undergoing hemodialysis. The American Journal of Medicine. 1987;82:1259-1262
  47. 47. Sakthiswary R, Raymond AA. The clinical significance of Vitamin D in systemic lupus erythematosus: A systematic review. PLoS One. 2013;8(1):e55275. DOI: 10.1371/journal.pone.0055275
  48. 48. Suzan M A, Aisha M S. Vitamin D deficiency in patients with systemic lupus erythematosus. Oman Medical Journal. 2013;28(1):42-47. DOI: 10. 5001/omj.2013.10
  49. 49. Amital H, Szekanecz Z, Szucs G, et al. Serum concentrations of 25-OH vitamin D in patients with systemic lupus erythematosus (SLE) are inversely related to disease activity: Is it time to routinely supplement patients with SLE with vitamin D? Annals of the Rheumatic Diseases. 2010;69(6):1155-1157
  50. 50. Yap KS, Northcott M, AB-Y H, et al. Association of low vitamin D with high disease activity in an Australian systemic lupus erythematosus cohort. Lupus Science and Medicine. 2015;2:e000064. DOI: 10.1136/lupus2014-000064
  51. 51. Ruiz-Irastorza G, Gordo S, Olivares N, et al. Changes in vitamin D levels in patients with systemic lupus erythematosus: Effects on fatigue, disease activity, and damage. Arthritis Care & Research (Hoboken). 2010;62(8):1160-1165
  52. 52. Przybelski RJ, Binkley NC. Is vitamin D important for preserving cognition? A positive correlation of serum 25-hydroxyvitamin D concentration with cognitive function. Archives of Biochemistry and Biophysics. 2007;460(2):202-205
  53. 53. Deane K, Demoruelle MK, Kelmenson LB, et al. Genetic and environmental risk factors for rheumatoid arthritis. Best Practice & Research. Clinical Rheumatology. 2017;31(2017):3-18
  54. 54. Tetlow LC, Woolley DE. 1999 The effects of 1α,25-dihydroxyvitamin D3 on matrix metalloproteinase and prostaglandin E2 production by cells of the rheumatoid lesion [peer-reviewed primary research]. Available from: http://arthritisresearch.com/14oct99/ar0101p01
  55. 55. Tsirogianni A, Hadjicostas P. AB0821 high prevalence of vitamin d3 deficiency in patients with rheumatic diseases and musculoskeletal disorders in cyprus. Annals of the Rheumatic Diseases. 2017;76:1345
  56. 56. Cecchetti S, Tatar Z, Galan P, et al. Prevalence of vitamin D deficiency in rheumatoid arthritis and association with disease activity and cardiovascular risk factors: data from the COMEDRA study. Clinical and Experimental Rheumatology. 2016;34(6):984-990. Epub: 30 September 2016
  57. 57. Meena N, Chawla SPS, Garg R, et al. Assessment of vitamin D in rheumatoid arthritis and its correlation with disease activity. Journal of Natural Science, Biology and Medicine. 2018, 2018;9(1):54-58. DOI: 10.4103/jnsbm.JNSBM_128_17
  58. 58. Lee YH, Bae SC. Vitamin D level in rheumatoid arthritis and its correlation with the disease activity: A meta-analysis. Clinical and Experimental Rheumatology. 2016;34:827-833
  59. 59. 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
  60. 60. Welsh P, Peters MJ, McInnes IB, et al. Vitamin D deficiency is common in patients with RA and linked to disease activity, but circulating levels are unaffected by TNFα blockade: Results from a prospective cohort study. Annals of the Rheumatic Diseases. 2011;70(6):1165-1167. DOI: 10.1136/ard.2010.137265. Epub: 3 November 2010
  61. 61. Urruticoechea-Arana et al. Vitamin D deficiency in chronic inflammatory rheumatic diseases: Results of the cardiovascular in rheumatology [CARMA] study. Arthritis Research and Therapy. 2015;17:211. DOI: 10.1186/s13075-015-0704-4
  62. 62. Kostoglou-Athanassiou I, Athanassiou P, Lyraki A, et al. Vitamin D and rheumatoid arthritis. The rAdvEndocrinolMetab. 2012;3(6):181-187. DOI: 10.1177/2042018812471070
  63. 63. Feser M, Derber LA, Deane KD, et al. Plasma 25, OH vitamin D levels are not associated with rheumatoid arthritis-related autoantibodies in individuals at elevated risk for rheumatoid arthritis. The Journal of Rheumatology. 2009;36(5):943-946. DOI: 10.3899/jrheum.080764.
  64. 64. Hajjaj-Hassouni N, Mawani N, Allali F, et al. Evaluation of vitamin D status in rheumatoid arthritis and its association with disease activity across 15 countries: “The COMORA Study”. International Journal of Rheumatology. 2017;2017:8. DOI: 10.1155/2017/5491676. Article ID 5491676
  65. 65. Zold E, Szodoray P, Gaal J, et al. Vitamin D deficiency in undifferentiated connective tissue disease. Arthritis Research & Therapy. 2008;10:R123
  66. 66. Artaza JN, Norris KC. Vitamin D reduces the expression of collagen and key profibrotic factors by inducing an antifibrotic phenotype in mesenchymal multipotent cells. The Journal of Endocrinology. 2009;200:207-221
  67. 67. Zold E, Barta Z, Bodolay E. Vitamin D deficiency and connective tissue disease. Vitamins and Hormones. 2011:261-286. DOI: 10.1016/b978-0-12-386960-9.00011-3
  68. 68. Groseanu L, Bojinca V, Gudu T, et al. Low vitamin D status in systemic sclerosis and the impact on disease phenotype. European Journal of Rheumatology. 2016;3(2):50-55. DOI: 10.5152/eurjrheum.2015.0065
  69. 69. An L, Sun MH, Chen F, Li JR. Vitamin D levels in systemic sclerosis patients: A meta-analysis. Drug Design, Development and Therapy. 2017;11:3119-3125. DOI: 10.2147/DDDT.S144860. Published: 27 October 2017
  70. 70. Tanner SB, Harwell SA. More than healthy bones: A review of vitamin D in muscle health. Advances in Musculoskeletal Disease. 2015;7(4):152-159. DOI: 10.1177/1759720X15588521
  71. 71. Azali P, Barbasso Helmers S, Kockum I, et al. Low serum levels of vitamin D in idiopathic inflammatory myopathies. Annals of the Rheumatic Diseases. 2013;72(4):512-516. DOI: 10.1136/annrheumdis-2012-201849 Epub: 19 Septemper 2012
  72. 72. Makrani AH, Afshari M, Ghajar M, et al. Vitamin D and fibromyalgia: A meta-analysis. Korean Journal of Pain. 2017;30(4):250-257. DOI: 10.3344/kjp.2017.30.4.250
  73. 73. de Carvalho JF, da Rocha Araújo FAG, da Mota LMA, et al. Vitamin D supplementation seems to improve fibromyalgia symptoms: Preliminary results. The Israel Medical Association Journal. 2018;20(6):379-381
  74. 74. Heidari B, Heidari P, Tilaki KH. Relationship between unexplained arthralgia and vitamin D deficiency: A case control study. Acta Medica Iranica. 2014;52(5):400-405
  75. 75. Sheikh NI, Farooq R. Arthralgia an indicator of vitamin D3 deficiency and insufficiency. JIMDC. 2017;6(4)
  76. 76. Heidari B, Hajian-Tilaki K, Heidari P. The status of serum vitamin D in patients with rheumatoid arthritis and undifferentiated inflammatory arthritis compared with controls. Rheumatology International. 2012;32(4):991-995. DOI: 10.1007/s00296-010-1736-3. Epub: 19 January 2011
  77. 77. Park YE, Kim BH, Lee SG, et al. Vitamin D status of patients with early inflammatory arthritis. Clinical Rheumatology. 2015;34(2):239-246
  78. 78. Lee SG, Kim GT, Lee JW, et al. Vitamin D deficiency in patients with early inflammatory arthritis. In: 2013 ACR/ARHP Annual Meeting; Abstract number 394. 2013

Written By

Binit Vaidya and Shweta Nakarmi

Submitted: 13 June 2018 Reviewed: 18 July 2019 Published: 08 August 2019