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      Restoration of regulatory and effector T cell balance and B cell homeostasis in systemic lupus erythematosus patients through vitamin D supplementation

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          Abstract

          Introduction

          Systemic lupus erythematosus (SLE) is a T and B cell-dependent autoimmune disease characterized by the appearance of autoantibodies, a global regulatory T cells (Tregs) depletion and an increase in Th17 cells. Recent studies have shown the multifaceted immunomodulatory effects of vitamin D, notably the expansion of Tregs and the decrease of Th1 and Th17 cells. A significant correlation between higher disease activity and lower serum 25-hydroxyvitamin D levels [25(OH)D] was also shown.

          Methods

          In this prospective study, we evaluated the safety and the immunological effects of vitamin D supplementation (100 000 IU of cholecalciferol per week for 4 weeks, followed by 100 000 IU of cholecalciferol per month for 6 months.) in 20 SLE patients with hypovitaminosis D.

          Results

          Serum 25(OH)D levels dramatically increased under vitamin D supplementation from 18.7±6.7 at day 0 to 51.4±14.1 (p<0.001) at 2 months and 41.5±10.1 ng/mL (p<0.001) at 6 months. Vitamin D was well tolerated and induced a preferential increase of naïve CD4 + T cells, an increase of regulatory T cells and a decrease of effector Th1 and Th17 cells. Vitamin D also induced a decrease of memory B cells and anti-DNA antibodies. No modification of the prednisone dosage or initiation of new immunosuppressant agents was needed in all patients. We did not observe SLE flare during the 6 months follow-up period.

          Conclusions

          This preliminary study suggests the beneficial role of vitamin D in SLE patients and needs to be confirmed in randomized controlled trials.

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          Most cited references23

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          Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus.

          M Hochberg (1997)
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            Combined oral contraceptives in women with systemic lupus erythematosus.

            Oral contraceptives are rarely prescribed for women with systemic lupus erythematosus, because of concern about potential negative side effects. In this double-blind, randomized, noninferiority trial, we prospectively evaluated the effect of oral contraceptives on lupus activity in premenopausal women with systemic lupus erythematosus. A total of 183 women with inactive (76 percent) or stable active (24 percent) systemic lupus erythematosus at 15 U.S. sites were randomly assigned to receive either oral contraceptives (triphasic ethinyl estradiol at a dose of 35 microg plus norethindrone at a dose of 0.5 to 1 mg for 12 cycles of 28 days each; 91 women) or placebo (92 women) and were evaluated at months 1, 2, 3, 6, 9, and 12. Subjects were excluded if they had moderate or high levels of anticardiolipin antibodies, lupus anticoagulant, or a history of thrombosis. The primary end point, a severe lupus flare, occurred in 7 of 91 subjects receiving oral contraceptives (7.7 percent) as compared with 7 of 92 subjects receiving placebo (7.6 percent). The 12-month rates of severe flare were similar: 0.084 for the group receiving oral contraceptives and 0.087 for the placebo group (P=0.95; upper limit of the one-sided 95 percent confidence interval for this difference, 0.069, which is within the prespecified 9 percent margin for noninferiority). Rates of mild or moderate flares were 1.40 flares per person-year for subjects receiving oral contraceptives and 1.44 flares per person-year for subjects receiving placebo (relative risk, 0.98; P=0.86). In the group that was randomized to receive oral contraceptives, there was one deep venous thrombosis and one clotted graft; in the placebo group, there was one deep venous thrombosis, one ocular thrombosis, one superficial thrombophlebitis, and one death (after cessation of the trial). Our study indicates that oral contraceptives do not increase the risk of flare among women with systemic lupus erythematosus whose disease is stable. Copyright 2005 Massachusetts Medical Society.
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              Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation.

              1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) can modulate immune responses, but whether it directly affects B cell function is unknown. Patients with systemic lupus erythematosus, especially those with antinuclear Abs and increased disease activity, had decreased 1,25(OH)(2)D(3) levels, suggesting that vitamin D might play a role in regulating autoantibody production. To address this, we examined the effects of 1,25(OH)(2)D(3) on B cell responses and found that it inhibited the ongoing proliferation of activated B cells and induced their apoptosis, whereas initial cell division was unimpeded. The generation of plasma cells and postswitch memory B cells was significantly inhibited by 1,25(OH)(2)D(3), although the up-regulation of genetic programs involved in B cell differentiation was only modestly affected. B cells expressed mRNAs for proteins involved in vitamin D activity, including 1 alpha-hydroxylase, 24-hydroxylase, and the vitamin D receptor, each of which was regulated by 1,25(OH)(2)D(3) and/or activation. Importantly, 1,25(OH)(2)D(3) up-regulated the expression of p27, but not of p18 and p21, which may be important in regulating the proliferation of activated B cells and their subsequent differentiation. These results indicate that 1,25(OH)(2)D(3) may play an important role in the maintenance of B cell homeostasis and that the correction of vitamin D deficiency may be useful in the treatment of B cell-mediated autoimmune disorders.
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                Author and article information

                Journal
                Arthritis Res Ther
                Arthritis Res. Ther
                Arthritis Research & Therapy
                BioMed Central
                1478-6354
                1478-6362
                2012
                17 October 2012
                : 14
                : 5
                : R221
                Affiliations
                [1 ]UPMC Université Paris 6, UMR 7211, F-75013 Paris, France
                [2 ]Centre National de la Recherche Scientifique (CNRS), UMR 7211, Paris, France
                [3 ]INSERM, UMRS959; Groupe Hospitalier Pitié-Salpétrière, 47 boulevard de l'Hôpital, 75013 Paris, France
                [4 ]Department of Internal Medicine, Hôpital Foch, 40 rue Worth, 92150 Suresnes, France
                [5 ]Department of Biotherapy, Groupe Hospitalier Pitié-Salpétrière, 47 boulevard de l'Hôpital, 75013 Paris, France
                [6 ]Department of Pharmacology, Groupe Hospitalier Pitié-Salpétrière, 47 boulevard de l'Hôpital, 75013 Paris, France
                [7 ]Department of Internal Medicine, Groupe Hospitalier Pitié-Salpétrière, 47 boulevard de l'Hôpital, 75013 Paris, France
                [8 ]P3S post-genomic platform, Groupe Hospitalier Pitié-Salpétrière, 47 boulevard de l'Hôpital, 75013 Paris, France
                [9 ]Department of Immunology, Groupe Hospitalier Pitié-Salpétrière, 47 boulevard de l'Hôpital, 75013 Paris, France
                Article
                ar4060
                10.1186/ar4060
                3580532
                23075451
                6bff9544-4d14-4a7a-b2a7-075ba41a259c
                Copyright ©2012 Terrier et al.; licensee BioMed Central Ltd.

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 10 March 2012
                : 10 July 2012
                : 5 September 2012
                Categories
                Research Article

                Orthopedics
                Orthopedics

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