International Journal of Rheumatic Diseases 2014

REVIEW ARTICLE

Vitamin D and systemic lupus erythematosus: continued evolution Kristy S. YAP1,2 and Eric F. MORAND1,2 1 Rheumatology, Monash Health, Monash University, , and 2Centre for Inflammatory Diseases, Monash University, Melbourne, Victoria, Australia

Abstract Vitamin D is a steroid hormone that has well-established roles in calcium and bone metabolism. Vitamin D has more recently become recognized for its role in the immune response and its potential immunomodulatory effects in autoimmune diseases, including systemic lupus erythematosus (SLE). This review provides a summary of the recent literature regarding vitamin D and SLE, as well as current recommendations for vitamin D supplementation in patients with SLE. Key words: clinical aspects, systemic lupus erythematosus.

INTRODUCTION Vitamin D is a steroid hormone that plays an important role in calcium metabolism and bone homeostasis, by binding to the intracellular vitamin D receptor (VDR) in target tissues such as the gastrointestinal tract, kidneys, bones, parathyroid glands and skin. It exists in two physiological forms, vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). The primary source (80%) of vitamin D is the synthesis of vitamin D3 in the skin upon exposure to UVB radiation. Vitamin D3 is then metabolized in the liver to 25-hydroxyvitamin D (25(OH)D), which is the intermediate usually measured to determine a patient’s vitamin D status. 25 (OH)D is further metabolized in the kidneys to the active form, 1,25-dihydroxyvitamin D. Vitamin D has recently gained attention beyond its traditionally understood role in bone health and calcium homeostasis. The discovery of vitamin D receptors in immune cells, including antigen-presenting cells, natural killer cells, and B and T lymphocytes suggests that vitamin D may play an important role in the regu-

Correspondence: Dr Kristy Yap, Toronto Western Hospital, Room 1-412A East Wing, 399 Bathurst St., Toronto, ON, Canada, M5T 2S8. Email: [email protected]

lation of the immune response.1 Numerous autoimmune diseases have been associated with hypovitamosis D, including type 1 diabetes mellitus,2 multiple sclerosis,3 rheumatoid arthritis4 and systemic lupus erythematosus (SLE).3,5–8 In this review, the recent literature regarding the potential relationship between vitamin D status and SLE will be examined. While the precise role of vitamin D in SLE, and hence the role of vitamin D testing and replacement therapy, remains unresolved, the emerging evidence makes it clear that further investigation is justified.

VITAMIN D AND IMMUNE FUNCTION Systemic lupus erythematosus is a chronic multisystem inflammatory autoimmune disease that is characterized by a number of immunological abnormalities.9 Current theories regarding the pathogenesis of SLE center around aberrant apoptosis and/or netosis, resulting in availability of nuclear antigens to the immune system, and the uptake of nucleic acid-containing immune complexes by plasmacytoid dendritic cells resulting in the activation of type I interferon (IFN) overexpression. The resulting inflammatory milieu drives the development of T cells into the proinflammatory pathways, defective function of regulatory T cells (Tregs) leading to hyperactivity of

© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd

K. S. Yap and E. F. Morand

Th cells, and survival and activation of autoreactive B cells that produce autoantibodies.10 A number of lines of evidence suggest that vitamin D has inhibitory impacts on many of the immunological abnormalities associated with SLE (Fig. 1). These include observations that vitamin D can be associated with downregulation of the Th1 immune response and the proliferation of activated B cells,11 while upregulating Tregs.12 More recently, there have been studies looking directly at the immunological effects of vitamin D deficiency in SLE patients. 1,25-dihydrovitamin D3 has been shown to inhibit dendritic cell maturation and expression of IFN-a induced genes in patients with SLE.13 A recent prospective study in which 20 SLE patients with vitamin D deficiency were supplemented with vitamin D showed that vitamin D repletion induced a preferential increase in na€ıve CD4+ T cells, an increase of regulatory T cells and a decrease of effector Th1 and Th17 cells. Vitamin D repletion also induced a decrease of memory B cells and anti-DNA antibodies.14 Ritterhouse et al. found that vitamin D deficiency (25 (OH)D < 20 ng/mL) was associated with higher serum IFN-a and higher B-cell activation in SLE patients. This could contribute to increased production of autoantibodies directed against nucleic acids.15

VITAMIN D DEFICIENCY IN SLE Vitamin D deficiency is a state which has been detected in all ages and ethnicities, but is particularly evident among populations with darker skin pigmentation living farther from the equator. A recent study that consisted mostly of African American and Hispanic patients with SLE found that 29% of African American

patients had serum vitamin D levels < 10 ng/mL.13 A possible mechanism is thought to be that melanin protects against the harmful effects of UV radiation at the expense of reduced vitamin D production.16 In SLE patients, a number of recent studies have reported the prevalence of vitamin D insufficiency to be between 38–96%,6,17–21 and the prevalence of vitamin D deficiency to be between 8–30%.6,19–22 The wide variation in the rates of vitamin D deficiency reported relates to many factors, such as the age of the patients recruited, disease duration, geographic location, season at the time of the study, ethnicity, medications used and the accuracy of the vitamin D assay method used. Most studies use a cutoff of 30 ng/mL to define vitamin D insufficiency and 10–20 ng/mL to define vitamin D deficiency. Vitamin D deficiency has also been studied as a potential environmental trigger for SLE. A populationbased inception cohort study of 123 newly diagnosed SLE patients in South Carolina (USA) found that lower 25(OH)D levels were found in these patients compared to 240 population controls. This was statistically significant in Caucasians after controlling for age, sex, season and smoking.5 Ritterhouse et al.15 found that serum 25(OH)D levels were significantly lower in 32 female European American patients with SLE compared to an equal number of matched controls. Of note, vitamin D deficiency was also more frequent among otherwise healthy control subjects with antinuclear antibodies compared with those without, suggesting that vitamin D deficiency may play a role in triggering autoimmunity per se. In contrast, the Nurses Health Study and Nurses Health Study II prospective analyses of over 180 000

Via TLRs

+

IFN-α15

Plasmacytoid dendritic cell

+

VDR CD4+T cell

Myeloid dendritic cell

Th114 Treg14

IFN signature13

VDR

Th17

Macrophage

VDR B cell

Antibodies against self nucleic acids B-cell activation15

2

Proinflammatory cytokines (IL-1, IL-6, IL-18, TNF-α)51

Figure 1 How vitamin D deficiency may aggravate the immunological abnormalities in SLE. Vitamin D deficiency is associated with increased B cell activation and increased IFNa activity. B cell hyperactivity contributes to an increased production of autoantibodies. This in turn leads to increased IFNa production from plasmacytoid dendritic cells via TLR signalling mediated by immune complexes. TLR, Toll-like receptors; Treg, regulatory T cells; IFN-a, interferon alpha.

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Vitamin D and SLE

women followed up for 22 years found no significant evidence for the association between dietary vitamin D intake and subsequent development of SLE.23 A further study in these subjects also did not identify any significant relationship between dietary vitamin intake during adolescent years and the subsequent development of SLE in adult years.24 However, there were some imitations to these studies. Data on dietary vitamin D intake was obtained from self-reported questionnaires, and dietary intake accounts for < 20% of stored vitamin D; moreover, serum 25(OH)D levels were not reported. Finally, these results may be applicable only to a Caucasian female population. As well as associations with low vitamin D levels, vitamin D receptor (VDR) gene polymorphisms may play a role in the risk of SLE. A recent meta-analysis supported earlier conclusions that the BsmII B VDR allele may be a risk factor for SLE onset among overall populations and Asians, while the FokI FF VDR genotype is a risk factor for SLE susceptibility in Asians.25

RISK FACTORS FOR VITAMIN D DEFICIENCY IN SLE Patients with SLE are unusually prone to vitamin D deficiency. SLE patients are often photosensitive, whereby exposure to UVB may trigger dermatological and even systemic flares of SLE. As a result, patients with SLE are advised to avoid unnecessary exposure to sunlight and apply sunscreen when outdoors. This potentially contributes to lower levels of vitamin D since the primary source of vitamin D is from photoconversion of D3 in the skin upon exposure to UVB radiation. The avoidance of sun and the use of sunscreen has been implicated as a risk factor for vitamin D deficiency in SLE patients.26,27 Second, SLE patients frequently have renal involvement, and the 1-hydroxylation of vitamin D into its active form may be disrupted in significant renal disease. A recent study from Thailand looked at the relationship between serum vitamin D in SLE patients with lupus nephritis (LN): 108 patients were divided into three groups consisting of inactive SLE, active SLE without LN and active SLE with LN. The authors found that active SLE patients with LN had significantly lower vitamin D levels than the other groups, suggesting that nephritis is a significant predictor of vitamin D deficiency in SLE.19 However, a contributing factor for this result could be the higher doses of corticosteroid used in SLE patients with LN.

International Journal of Rheumatic Diseases 2014

Third, certain medications used for the treatment of SLE may aggravate vitamin D deficiency. Chronic corticosteroid use reduces intestinal absorption and accelerates the catabolism of 25(OH)D and 1,25(OH)2D through an increase in 24a-hydroxylase activity.28,29 Patients taking corticosteroids may therefore require higher daily doses of vitamin D to maintain adequate levels. In addition, patients with SLE often take hydroxychloroquine, which is also suspected to lower the conversion of vitamin D2 to the active vitamin D3.30 One study found that hydroxychloroquine use was associated with higher vitamin D levels,26 although another study did not find any association.6 Finally, another contributing factor to low vitamin D levels observed in SLE patients could be genetic variation. Wang et al.31 looked at 33 996 non-SLE individuals of European descent and found that genetic variation contributed to vitamin D insufficiency.

CONSEQUENCES OF VITAMIN D INSUFFICIENCY/DEFICIENCY IN SLE Vitamin D deficiency and disease activity in SLE There have been a number of cross-sectional studies examining associations of vitamin D deficiency and SLE disease activity in recent years. Most, but not all, studies have shown an association of 25(OH)D deficiency with increased SLE disease activity.20,32–34 However, it has not yet been possible to determine whether low vitamin D is a cause of disease exacerbation in SLE, or vice versa. Table 1 summarizes the recent clinical studies examining the relationship between hypovitaminosis D and SLE activity. Most studies were cross-sectional. A recent cross-sectional study looking at 290 Chinese patients with SLE found that vitamin D deficiency (< 15 ng/mL) was found in 27% of patients. Moreover, vitamin D was significantly inversely correlated with disease activity measured by total SLE Disease Activity Index (SLEDAI) scores and physician global assessment (PGA), mainly contributed to by renal, musculoskeletal and hematological activity. In addition, 25(OH)D3 levels were significantly lower in patients who had disease flares than those without.20 Another study from the same cohort found that vitamin D levels were inversely associated with titers of anti-C1q and anti-doublestranded DNA (anti-dsDNA).35 Other studies have shown that lower levels of 25 (OH)D3 were associated with renal disease and the degree of proteinuria. SLE patients with lupus nephritis were found to have significantly lower vitamin D levels

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K. S. Yap and E. F. Morand

Table 1 Recent clinical studies of disease activity and hypovitaminosis D in SLE Study (year)

Ethnicity or location

tudy design

Patients (n)

Disease activity measure

Findings

References

Lertratanakul et al. (2014)

54% Caucasian 17% Black 23% Asian Indian

International Inception Cohort Cross-sectional

875

SLEDAI-2K

Lower baseline 25(OH)D levels were associated more active SLE at baseline

39

Cross-sectional

129 SLE 100 Controls

SLEDAI

8

Petri et al. (2013)

54% Caucasian 37% Black

Prospective cohort Longitudinal (128 weeks)

1006

SELENASLEDAI

Abou-Raya et al. (2013)

Egypt

Randomized placebo-controlled trial (2 : 1)

267

SLEDAI

Sumethkul et al. (2012)

Thailand

Cross-sectional

108

SLEDAI

Mok et al. (2012)

Chinese

Cross sectional

290

SLEDAI SDI

Mok et al. (2012)

Chinese

Cross sectional

290

SLEDAI SDI

Yeap et al. (2012)

Malaysian

Prospective cohort

38

SLEDAI

Reynolds et al. (2012)

United Kingdom 92% Caucasian Australia 79% Caucasian Egyptian

Cross sectional cohort

75

SLEDAI-2K

Cross sectional Cohort study

SLEDAI-2K SDI

Cross-sectional

73 24 SLE 21 control 60

Serum 25(OH)D3 correlated inversely with SLEDAI scores, anti-dsDNA, plasma IFN-a, and levels of IFN-ainduced gene expression A 20 ng/mL increase in 25 (OH)D3 level was associated with a significant decrease in the odds of having a high disease activity score clinically important proteinuria Supplementation with oral cholecalciferol (200 IU)/ day resulted in significant improvement in proinflammatory cytokines and disease activity scores 25(OH)D3 levels correlated significantly with serum albumin, but inversely with SLEDAI and proteinuria 25(OH)D3 levels correlated inversely with PGA, total SLEDAI 25(OH)D3 levels correlated inversely with SLE activity, anti-C1q, anti-dsDNA titers Significant negative correlation between SLEDAI scores and 25(OH)D3 25(OH)D3 deficiency was associated with higher BMI, insulin resistance, aortic stiffness and SLEDAI No relation between 25(OH) D3 status and fatigue

Cross-sectional

159

SLEDAI

Mandal et al. (2014)

Stockton et al. (2012) Hamza et al. (2011) Souto et al. (2011)

4

Brazil 68% Caucasian

SLEDAI

Lower 25(OH)D3 levels associated with more active SLE 25(OH)D3 levels did not correlate with SLEDAI score

17

50

19

20

35

7

34

46

22

21

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Vitamin D and SLE

Table 1 (continued) Study (year)

Ethnicity or location

tudy design

Patients (n)

Disease activity measure

Findings

References

Ben-Zvi et al. (2012)

71% Black 22% Hispanic 5% Caucasian European Isreali

Cross-sectional

198

SLEDAI

25(OH)D3 levels inversely correlated with SLEDAI

13

Cross-sectional

378

SLEDAI-2K ECLAM

33

Ruiz-Irastorza et al. (2010)

Spain 98% Caucasian

60

SLEDAI SDI

Toloza et al. (2010)

Canada 65% Caucasian 15% Black

Observational Longitudinal study Prospective cohort Prospective Cohort

124

SLEDAI-2K SLICC/SDI

25(OH)D3 levels inversely correlated with disease activity Change in 25(OH)D3 associated inversely with selfreported fatigue but not with disease activity No association between 25 (OH)D3 levels and SLEDAI2K, SLICC/SDI.

Amital et al. (2010)

45

6

BMI, body mass index; ECLAM, European Consensus Lupus Activity Measurement; IFN, interferon; PGA, Physician Global Assessment; SLEDAI-2K, SLE Disease Activity Index 2000; SLICC/SDI, Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index.

than those with inactive SLE and SLE without LN. As well, SLE patients with LN had almost six times the risk of vitamin D deficiency compared to those without lupus nephritis.19

Vitamin D and cardiovascular risk factors Cardiovascular disease (CVD) is a major cause of morbidity and mortality in SLE, and patients with SLE are at increased risk of CVD at an earlier age than the general population.36 The mechanisms for accelerated atherosclerosis in SLE are not completely understood, but disease duration and higher homocysteine levels have been associated with carotid plaque progression.37 Other contributing factors include traditional risk factors such as higher low-density lipoprotein (LDL) levels and smoking, as well as disease-specific risk factors such as higher serum C3 levels and the presence of various proinflammatory cytokines.16,38 Vitamin D may play a role in the acceleration of CVD observed in SLE. For example, vitamin D deficiency has been associated with certain atherosclerotic risk factors. Mok et al.20 found that vitamin D deficiency was associated with dyslipidemia in SLE patients with vascular risk factors. Wu et al.32 studied 181 patients with SLE and demonstrated that low serum vitamin D was associated with diastolic blood pressure, LDL cholesterol, lipoprotein (a) and body mass index (BMI). Another study showed an association between vitamin D defi-

International Journal of Rheumatic Diseases 2014

ciency and increased aortic stiffness in SLE patients.34 This was demonstrated by an increase in arterial pulse wave velocity that persisted even after adjusting for SLEDAI-2K score. More recently, a study in an international inception cohort found an association between higher baseline 25(OH)D levels and lower risk for future CVD in SLE patients.39 In contrast, Kiani et al.40 studied 200 patients enrolled in the Lupus Atherosclerosis Prevention Study over 2 years and found that 25(OH)D levels were not associated with any subclinical measure of atherosclerosis. Vitamin D deficiency was associated with higher high sensitivity C-reactive protein (hsCRP) at baseline, but it did not predict a change in the hsCRP after 2 years.

Vitamin D and bone health SLE patients are at higher risk for osteoporosis and fragility fractures, compared to age-matched controls.41 Vitamin D deficiency is one of the many risk factors for osteoporosis among patients with SLE, in addition to persistent disease activity, chronic glucocorticoid use, renal insufficiency, premature menopause and physical inactivity as the result of pain and fatigue.42 Low levels of vitamin D results in depletion of bone calcium reserves in an attempt to correct for reduced calcium absorption from the gastrointestinal tract. A recent longitudinal study looked at 38 premenopausal Malaysian

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K. S. Yap and E. F. Morand

patients with SLE and found that those with vitamin D deficiency (< 20 ng/mL) had lower femoral neck bone mineral density as compared to those with vitamin D insufficiency (21–30 ng/mL). After 2 years of boneactive medication, there was a trend toward better bone density in those that were originally vitamin D insufficient as compared to those that were vitamin D deficient.7

Vitamin D and fatigue Patients with SLE often experience elevated levels of fatigue.43 In fact, more than 50% of SLE patients report it as their most disabling symptom.44 Vitamin D deficiency has been found to be related to fatigue in SLE. Ruiz-Irastorza et al.26 reported on a study of 98 patients with SLE which found an association between self-rated fatigue score as assessed by visual analog scale and low vitamin D levels. A longitudinal follow-up of these patients 2 years later showed that improvements in vitamin D level correlated with significant reductions in fatigue score.45 However, there have been other studies which have found no significant correlation between vitamin D and fatigue.46

VITAMIN D SUPPLEMENTATION IN SLE:A THERAPEUTIC EFFECT? Due to the high prevalence of vitamin D deficiency in the general population, it would be simple to recommend that patients with SLE be screened for vitamin D deficiency and routinely treated with supplementation. However, to date there are no published guidelines for the specific dosage of vitamin D supplementation in patients with SLE. The American College of Rheumatology recommends a daily intake of 800–1000 IU per day of vitamin D in patients on commencement of glucocorticoids.47 It is also noted that glucocorticoids can interfere with vitamin D absorption and higher doses of supplementation may be required to attain therapeutic serum levels.48 Other factors to take into consideration include dark skin pigmentation, BMI and sun exposure based on geographic location. An Australian position statement on vitamin D and adult bone health recommends treatment of vitamin D deficiency with 3000– 5000 IU per day for 6–12 weeks followed by a maintenance dose of 1000–2000 IU per day.49 Recent trials have provided some insight into the potential benefit of vitamin D supplementation in SLE patients. Abou-Raya et al.50 randomized 267 SLE patients in a 2 : 1 ratio to receive either oral cholecalciferol 2000 IU/day or placebo. After 12 months, there

6

was a significant improvement in the levels of proinflammatory cytokines (interleukin [IL]-1, IL-6, IL-18, tumor necrosis factor-a), anti-dsDNA, C4, hemostatic markers (fibrinogen, von Willebrand factor) and disease activity scores in the treatment group compared to the placebo group. Petri et al.17 investigated the effects of vitamin D in 1006 patients over 128 weeks. On a first visit, 25(OH)D levels < 40 ng/mL were found in 76% of patients of whom 85% were African American. These patients received supplementation with 50 000 units of vitamin D2 (ergocalciferol) weekly and a modest but significant reduction in the risk of high disease activity was observed in association with increases in 25(OH)D in the subset of patients with low levels of vitamin D at baseline. In neither of these studies were high levels of vitamin D attained and no robust conclusion regarding the efficacy of vitamin D supplementation, or correction of vitamin D deficiency on SLE disease activity can yet be drawn. It is important to note that vitamin D supplementation may not always be completely safe. Vitamin D toxicity is possible although rare, and is usually caused by excessive oral intake through supplementation. The main complications thereof are hypercalciuria and hypercalcemia, although hypercalcemia is generally not seen until serum vitamin D levels reach 220 nmol/L and is most frequent when over 500 nmol/L.51 Vitamin D intoxicated patients can present with symptoms of hypercalcemia (headache, nausea, vomiting, diarrhea) and renal stones. Ideally, a baseline vitamin D level should be measured to guide replacement. The Australian position statement on vitamin D in adults recommends that vitamin D levels are checked after 3 months given the individual variation of response to vitamin D supplementation.49

CONCLUSIONS Vitamin D deficiency is commonly observed in patients with SLE, and may be contributed to by ethnicity, geography, season, medication use and sun avoidance. The use of vitamin D supplementation in the context of glucocorticoid therapy is well established, but the potential contribution of vitamin D deficiency to SLE, and hence of vitamin D replacement to SLE therapy, is a concept that has only recently emerged. The reported effects of vitamin D on the immune system create a plausible explanation for exacerbation of SLE in the setting of vitamin D deficiency, and many but not all studies support the existence of such an association. Intervention studies to examine the potential benefits for vitamin D

International Journal of Rheumatic Diseases 2014

Vitamin D and SLE

therapy have so far focused on fixed doses of vitamin D, and it remains unknown whether correction of vitamin D deficiency offers benefit to SLE patients over and above those expected in regard to bone health. Future studies should include randomized trials which focus on the clinical effect in SLE of correcting vitamin D deficiency.

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13 Ben-Zvi I, Aranow C, Mackay M et al. (2010) The impact of vitamin D on dendritic cell function in patients with systemic lupus erythematosus. PLoS ONE 5, e9193. 14 Terrier B, Derian N, Schoindre Y et al. (2012) Restoration of regulatory and effector T cell balance and B cell homeostasis in systemic lupus erythematosus patients through vitamin D supplementation. Arthritis Res Ther 14, R221. 15 Ritterhouse LL, Crowe SR, Niewold TB et al. (2011) Vitamin D deficiency is associated with an increased autoimmune response in healthy individuals and in patients with systemic lupus erythematosus. Ann Rheum Dis 70, 1569– 74. 16 Shoenfeld N, Amital H, Shoenfeld Y (2009) The effect of melanism and vitamin D synthesis on the incidence of autoimmune disease. Nat Clin Pract Rheumatol 5, 99–105. 17 Petri M, Bello KJ, Fang H, Magder LS (2013) Vitamin D in systemic lupus erythematosus: modest association with disease activity and the urine protein-to-creatinine ratio. Arthritis Rheum 65, 1865–71. 18 Lertratanakul A, Wu P, Dyer AR et al. (2013) Risk factors in the progression of subclinical atherosclerosis in women with systemic lupus erythematosus. Arthritis Care Res 66, 1177–85. 19 Sumethkul K, Boonyaratavej S, Kitumnuaypong T et al. (2012) The predictive factors of low serum 25-hydroxyvitamin D and vitamin D deficiency in patients with systemic lupus erythematosus. Rheumatol Int 33, 1461–7. 20 Mok CC, Birmingham DJ, Leung HW, Hebert LA, Song H, Rovin BH (2012) Vitamin D levels in Chinese patients with systemic lupus erythematosus: relationship with disease activity, vascular risk factors and atherosclerosis. Rheumatology 51, 644–52. 21 Souto M, Coelho A, Guo C et al. (2011) Vitamin D insufficiency in Brazilian patients with SLE: prevalence, associated factors, and relationship with activity. Lupus 20, 1019–26. 22 Hamza RT, Awwad KS, Ali MK, Hamed AI (2011) Reduced serum concentrations of 25-hydroxy vitamin D in Egyptian patients with systemic lupus erythematosus: relation to disease activity. Med Sci Monit 17, CR711–8. 23 Costenbader KH, Feskanich D, Holmes M, Karlson EW, Benito-Garcia E (2007) Vitamin D intake and risks of systemic lupus erythematosus and rheumatoid arthritis in women. Ann Rheum Dis 67, 530–5. 24 Hiraki LT, Munger KL, Costenbader KH, Karlson EW (2012) Dietary intake of vitamin D during adolescence and risk of adult-onset systemic lupus erythematosus and rheumatoid arthritis. Arthritis Care Res 64, 1829–36. 25 Mao S, Huang S (2014) Association between vitamin D receptor gene BsmI, FokI, ApaI and TaqI polymorphisms and the risk of systemic lupus erythematosus: a metaanalysis. Rheumatol Int 34, 381–8. 26 Ruiz-Irastorza G, Egurbide MV, Olivares N, Martinez-Berriotxoa A, Aguirre C (2008) Vitamin D deficiency in sys-

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temic lupus erythematosus: prevalence, predictors and clinical consequences. Rheumatology 47, 920–3. Cusack C, Danby C, Fallon JC et al. (2008) Photoprotective behaviour and sunscreen use: impact on vitamin D levels in cutaneous lupus erythematosus. Photodermatol Photoimmunol Photomed 24, 260–7. Kamen DL (2009) Vitamin D in lupus – new kid on the block? Bull NYU Hosp Jt Dis 68, 218–22. Akeno N, Matsunuma A, Maeda T, Kawane T, Horiuchi N (2000) Regulation of vitamin D-1alpha-hydroxylase and -24-hydroxylase expression by dexamethasone in mouse kidney. J Endocrinol 164, 339–48. O’Leary TJ, Jones G, Yip A, Lohnes D, Cohanim M, Yendt ER (1986) The effects of chloroquine on serum 1, 25-dihydroxyvitamin D and calcium metabolism in sarcoidosis. N Engl J Med 315, 727–30. Wang TJ, Zhang F, Richards JB et al. (2010) Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 376, 180–8. Wu PW, Rhew EY, Dyer AR et al. (2009) 25-hydroxyvitamin D and cardiovascular risk factors in women with systemic lupus erythematosus. Arthritis Rheum 61, 1387–95. Amital H, Szekanecz Z, Szucs G et al. (2010) 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? Ann Rheum Dis 69, 1155–7. Reynolds JA, Haque S, Berry JL et al. (2012) 25-Hydroxyvitamin D deficiency is associated with increased aortic stiffness in patients with systemic lupus erythematosus. Rheumatology 51, 544–51. Mok C, Birmingham D, Ho L, Hebert L, Song H, Rovin B (2011) Vitamin D deficiency as marker for disease activity and damage in systemic lupus erythematosus: a comparison with anti-dsDNA and anti-C1q. Lupus 21, 36–42. Ward MM (1999) Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupus erythematosus. Arthritis Rheum 42, 338–46. Roman MJ, Crow MK, Lockshin MD et al. (2007) Rate and determinants of progression of atherosclerosis in systemic lupus erythematosus. Arthritis Rheum 56, 3412–9. Sarzi-Puttini P, Atzeni F, Doria A, Iaccarino L, Turiel M (2005) Tumor necrosis factor-a, biologic agents and cardiovascular risk. Lupus 14, 780–4. Lertratanakul A, Wu P, Dyer A et al. (2014) 25-Hydroxyvitamin D and cardiovascular disease in patients with systemic lupus erythematosus: data from a large international inception cohort. Arthritis Care Res 66, 1167–76.

40 Kiani AN, Fang H, Magder LS, Petri M (2013) Vitamin D deficiency does not predict progression of coronary artery calcium, carotid intima-media thickness or high-sensitivity C-reactive protein in systemic lupus erythematosus. Rheumatology 52, 2071–6. 41 Rhew EY, Lee C, Eksarko P et al. (2008) Homocysteine, bone mineral density, and fracture risk over 2 years of followup in women with and without systemic lupus erythematosus. J Rheumatol 35, 230–6. 42 Becker A, Fischer R, Scherbaum WA, Schneider M (2001) Osteoporosis screening in systemic lupus erythematosus: impact of disease duration and organ damage. Lupus 10, 809–14. 43 Zonana-Nacach A, Roseman JM, McGwin G et al. (1999) Systemic lupus erythematosus in three ethnic groups. VI: factors associated with fatigue within 5 years of criteria diagnosis. LUMINA Study Group. LUpus in MInority populations: NAture vs Nurture. Lupus 9, 101–9. 44 Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD (1989) The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 46, 1121–3. 45 Ruiz-Irastorza G, Gordo S, Olivares N, Egurbide M-V, Aguirre C (2010) Changes in vitamin D levels in patients with systemic lupus erythematosus: effects on fatigue, disease activity, and damage. Arthritis Care Res 62, 1160–5. 46 Stockton K, Kandiah D, Paratz J, Bennell K (2012) Fatigue, muscle strength and vitamin D status in women with systemic lupus erythematosus compared with healthy controls. Lupus 21, 271–8. 47 Grossman JM, Gordon R, Ranganath VK et al. (2010) American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoidinduced osteoporosis. Arthritis Care Res 62, 1515–26. 48 Zhou C (2006) Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia. J Clin Invest 116, 1703–12. 49 Nowson CA, McGrath JJ, Ebeling PR et al. (2012) Vitamin D and health in adults in Australia and New Zealand: a position statement. Med J Aust 196, 686–7. 50 Abou-Raya A, Abou-Raya S, Helmii M (2013) The effect of vitamin D supplementation on inflammatory and hemostatic markers and disease activity in patients with systemic lupus erythematosus: a randomized placebocontrolled trial. J Rheumatol 40, 265–72. 51 Vieth R (1999) Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 69, 842–56.

International Journal of Rheumatic Diseases 2014

Vitamin D and systemic lupus erythematosus: continued evolution.

Vitamin D is a steroid hormone that has well-established roles in calcium and bone metabolism. Vitamin D has more recently become recognized for its r...
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