|Year : 2017 | Volume
| Issue : 4 | Page : 219-222
Vitamin D and autoimmune diseases
Shir Azrielant1, Yehuda Shoenfeld2
1 Sheba Medical Center, The Zabludowicz Center for Autoimmune Diseases, Tel-Hashomer, Ramat-Gan; Sackler Faculty of Medicine, Tel-Aviv University, Israel
2 Sheba Medical Center, The Zabludowicz Center for Autoimmune Diseases, Tel-Hashomer, Ramat-Gan; Sackler Faculty of Medicine, Tel-Aviv University; Tel-Aviv University, Incumbent of the Laura Schwarz-Kip Chair for Research of Autoimmune Diseases, Ramat-Aviv, Tel-Aviv, Israel
|Date of Web Publication||16-Nov-2017|
Sheba Medical Center, Zabludowicz Center for Autoimmune Diseases, Tel-Hashomer 5265601
Source of Support: None, Conflict of Interest: None
Vitamin D and its deficiency are becoming a subject of great interest in recent years. In addition to the well-known role of vitamin D in maintaining bone health, evidence from recent years are accumulating in favor of its importance in the functioning of the immune system. The association between vitamin D deficiency and autoimmune diseases has been supported by epidemiological studies, demonstrating higher prevalence of vitamin D deficiency among autoimmune patients, in comparison to the general population. Vitamin D was also associated to various autoimmune diseases in both molecular and interventional studies; among the associated diseases are: systemic lupus erythematosus, type 1 diabetes mellitus, multiple sclerosis and others. In this review, relevant literature on the association between autoimmunity and vitamin D deficiency will be reviewed and discussed, as well as a summary of important recommendations for vitamin D supplementations in autoimmune patients.
Keywords: Autoimmunity, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes mellitus, Vitamin D
|How to cite this article:|
Azrielant S, Shoenfeld Y. Vitamin D and autoimmune diseases. Indian J Rheumatol 2017;12:219-22
| Introduction|| |
Genetic, immunological, hormonal, and environmental factors are assumed to contribute to the development of autoimmune diseases. One of the environmental factors studied has been Vitamin D., Vitamin D has a significant role in various processes of the immune system,, and its receptors (Vitamin D receptor) were found in immune cells, including macrophages, dendritic cells, B-cells, and T-cells.,,,In vitro studies showed an attenuating effect of Vitamin D on various immune cells of the immune system: neutrophils, dendritic cells, and T regulatory cells (Treg).,, In terms of its activity on immune cells, Vitamin D was shown to have an inhibitory effect on Th1 cells, leading to a decrease in Th1 cytokine production,,, and possibly by increasing Th2 cytokines, and leading to an immunologic shift toward Th2., There is some evidence that Vitamin D modulates the activity of Th17 cells, which are known for their role in autoimmunity, and increases the population of Treg cells, thereby promoting tolerance.,, In an in vitro study, Vitamin D was shown to inhibit autoantibody production and secretion.
Vitamin D deficiency is becoming more common. Epidemiological studies suggest Vitamin D deficiency is prevalent in the general population even in sunny countries like Israel, but even more so among autoimmune patients.,,,, Vitamin D deficiency's definition is still under controversy; one accepted definition is a serum level of 25-hydroxy-vitamin D (25[OH]D) under 30–40 ng/ml, which is the necessary level for maintaining bone health. Within the normal range of serum Vitamin D concentration, an optimal level for the functioning of the immune system is yet to be determined.
| Systemic Lupus Erythematosus|| |
Much of the evidence for the association between Vitamin D and autoimmunity comes from research of systemic lupus erythematosus (SLE). Vitamin D deficiency is more common in SLE patients than in healthy controls,, as in many other autoimmune diseases; however, SLE patients are even more prone to develop Vitamin D deficiency, as they are advised to avoid sun exposure, due to photosensitivity.
Low levels of Vitamin D were associated with higher SLE activity.,,, Vitamin D levels were also associated with other manifestations of the disease and its comorbidities, such as cognitive impairment, insulin resistance, and sleep disturbances.
Analysis of the intervening variables for the association between Vitamin D levels and SLE found that the most significant were medications (hydroxychloroquine, steroids, and Vitamin D supplements), body mass index, renal function, and proteinuria.
To further investigate this association, interventional studies were done, using Vitamin D supplementation. The conventional doses described in the literature are 800, 2000, and 4000 IU/day., In a large-scale cohort study, Vitamin D supplementation was given to lupus patients who had Vitamin D levels lower than 40 ng/ml. Improvement in proteinuria was shown in patients with higher 25(OH)D levels; also, a correlation was observed between disease activity and the change in 25(OH)D values, but only in patients who were Vitamin D-deficient at the beginning of the study. No effect on disease activity was found after increasing Vitamin D levels above 40 ng/mL.
| Multiple Sclerosis|| |
Proof for the association between Vitamin D and multiple sclerosis (MS) arose from epidemiological studies. A review from 2008 suggests that distance from the equator is the strongest risk factor for MS, seemingly due to ultraviolet (UV) radiation exposure, and that emigration from cold countries to sunny ones decreased the risk for the disease.
Analysis of dietary and supplementary Vitamin D intake in two large cohorts of nurses, with over 90,000 participants each, demonstrated lower risk for MS in women with high Vitamin D intake, compared to women with low intake, and Vitamin D supplementation was inversely associated with MS risk. Notably, high dietary intake of Vitamin D alone did not generate similar association.
Vitamin D was reported to be an early predictor of MS activity and progression, with slower progression and low disease activity in patients with high serum Vitamin D levels at the time of MS diagnosis., A seasonal pattern was described for manifestations MS, a pattern that could be attributed to changing levels of Vitamin D in different seasons.
| Type 1 Diabetes Mellitus|| |
The prevalence of diabetes mellitus type 1 (DM1) is highly dependent on geographic location. In a research on this matter, researchers demonstrated a correlation between the disease's rates and distance from the equator and assumed this correlation to be, at least in part, explained by distribution of UV-B irradiance, the main source of Vitamin D in humans. Supplementation studies also support this conclusion. Studies have shown that Vitamin D supplementation in early life reduced the risk for developing DM1 later on, improved glycemic control in pediatric patients who suffered from Vitamin D deficiency, and correlated with lower prevalence of diabetic nephropathy.
| Miscellaneous|| |
Vitamin D deficiency was found to be more common among patients with inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and psoriasis  compared to controls; low levels of Vitamin D were associated with higher disease activity in IBD and RA.,
| Conclusion|| |
Vitamin D has a crucial role in the functioning of the immune system. Vitamin D was shown to be an immunomodulator in various molecular studies. Therefore, maintaining normal levels of Vitamin D is important.
Vitamin D deficiency is common in patients with autoimmune diseases, as was seen in patients with MS, type 1 diabetes, IBD, and RA, and seems to affect the activity and outcomes of these autoimmune diseases.
Vitamin D is very safe to use, and adverse effects and toxicity are rarely reached, even at doses as high as 10,000 IU; therefore, although further studies are needed to determine the exact mechanism of the effect of Vitamin D in autoimmune diseases, we recommend considering Vitamin D supplementation in all autoimmune patients based on existing evidence. Currently, there is no across-the-board recommendation for vitamin D supplementation dosage in autoimmune patients. However, based on previous interventional studies, supplementation dosage of 800–1000 units per day seems to be appropriate.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Arnson Y, Amital H, Shoenfeld Y. Vitamin D and autoimmunity: New aetiological and therapeutic considerations. Ann Rheum Dis 2007;66:1137-42.
Cutolo M, Otsa K, Uprus M, Paolino S, Seriolo B. Vitamin D in rheumatoid arthritis. Autoimmun Rev 2007;7:59-64.
Holick MF. Sunlight and Vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 2004;80:1678S-88S.
Mok CC. Vitamin D and systemic lupus erythematosus: An update. Expert Rev Clin Immunol 2013;9:453-63.
Bhalla AK, Amento EP, Clemens TL, Holick MF, Krane SM. Specific high-affinity receptors for 1,25-dihydroxyvitamin D3 in human peripheral blood mononuclear cells: Presence in monocytes and induction in T lymphocytes following activation. J Clin Endocrinol Metab 1983;57:1308-10.
Peelen E, Knippenberg S, Muris AH, Thewissen M, Smolders J, Tervaert JW, et al.
Effects of Vitamin D on the peripheral adaptive immune system: A review. Autoimmun Rev 2011;10:733-43.
Handono K, Sidarta YO, Pradana BA, Nugroho RA, Hartono IA, Kalim H, et al.
Vitamin D prevents endothelial damage induced by increased neutrophil extracellular traps formation in patients with systemic lupus erythematosus. Acta Med Indones 2014;46:189-98.
Wahono CS, Rusmini H, Soelistyoningsih D, Hakim R, Handono K, Endharti AT, et al.
Effects of 1,25(OH)2D3 in immune response regulation of systemic lupus erithematosus (SLE) patient with hypovitamin D. Int J Clin Exp Med 2014;7:22-31.
Toubi E, Shoenfeld Y. The role of Vitamin D in regulating immune responses. Isr Med Assoc J 2010;12:174-5.
Banica LM, Besliu AN, Pistol GC, Stavaru C, Vlad V, Predeteanu D, et al.
Dysregulation of anergy-related factors involved in regulatory T cells defects in systemic lupus erythematosus patients: Rapamycin and Vitamin D efficacy in restoring regulatory T cells. Int J Rheum Dis 2016;19:1294-303.
Handono K, Marisa D, Kalim H. Association between the low levels of Vitamin D and treg function in systemic lupus erythematosus patients. Acta Med Indones 2013;45:26-31.
Boonstra A, Barrat FJ, Crain C, Heath VL, Savelkoul HF, O'Garra A, et al.
1alpha, 25-dihydroxyvitamin D3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Immunol 2001;167:4974-80.
Cantorna MT. Vitamin D and autoimmunity: Is Vitamin D status an environmental factor affecting autoimmune disease prevalence? Proc Soc Exp Biol Med 2000;223:230-3.
Jeffery LE, Burke F, Mura M, Zheng Y, Qureshi OS, Hewison M, 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 2009;183:5458-67.
Cantorna MT, Woodward WD, Hayes CE, DeLuca HF. 1,25-dihydroxyvitamin D3 is a positive regulator for the two anti-encephalitogenic cytokines TGF-beta 1 and IL-4. J Immunol 1998;160:5314-9.
Joshi S, Pantalena LC, Liu XK, Gaffen SL, Liu H, Rohowsky-Kochan C, et al.
1,25-dihydroxyvitamin D (3) ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A. Mol Cell Biol 2011;31:3653-69.
Gregori S, Giarratana N, Smiroldo S, Uskokovic M, Adorini L. A 1alpha, 25-dihydroxyvitamin D (3) analog enhances regulatory T-cells and arrests autoimmune diabetes in NOD mice. Diabetes 2002;51:1367-74.
Prietl B, Pilz S, Wolf M, Tomaschitz A, Obermayer-Pietsch B, Graninger W, et al.
Vitamin D supplementation and regulatory T cells in apparently healthy subjects: Vitamin D treatment for autoimmune diseases? Isr Med Assoc J 2010;12:136-9.
Linker-Israeli M, Elstner E, Klinenberg JR, Wallace DJ, Koeffler HP. Vitamin D (3) and its synthetic analogs inhibit the spontaneous in vitro
immunoglobulin production by SLE-derived PBMC. Clin Immunol 2001;99:82-93.
Oren Y, Shapira Y, Agmon-Levin N, Kivity S, Zafrir Y, Altman A, et al.
Vitamin D insufficiency in a sunny environment: A demographic and seasonal analysis. Isr Med Assoc J 2010;12:751-6.
Orbach H, Zandman-Goddard G, Amital H, Barak V, Szekanecz Z, Szucs G, et al.
Novel biomarkers in autoimmune diseases: Prolactin, ferritin, Vitamin D, and TPA levels in autoimmune diseases. Ann N
Y Acad Sci 2007;1109:385-400.
Squance ML, Reeves GE, Tran HA. Vitamin D levels are associated with expression of SLE, but not flare frequency. Int J Rheumatol 2014;2014:362834.
Sabio JM, Vargas-Hitos JA, Martinez-Bordonado J, Navarrete-Navarrete N, Díaz-Chamorro A, Olvera-Porcel C, et al.
Association between low 25-hydroxyvitamin D, insulin resistance and arterial stiffness in nondiabetic women with systemic lupus erythematosus. Lupus 2015;24:155-63.
Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266-81.
Schneider L, Dos Santos AS, Santos M, da Silva Chakr RM, Monticielo OA. Vitamin D and systemic lupus erythematosus: State of the art. Clin Rheumatol 2014;33:1033-8.
Winkelmann RR, Kim GK, Del Rosso JQ. Treatment of cutaneous lupus erythematosus: Review and assessment of treatment benefits based on oxford centre for evidence-based medicine criteria. J Clin Aesthet Dermatol 2013;6:27-38.
Schoindre Y, Jallouli M, Tanguy ML, Ghillani P, Galicier L, Aumaître O, et al.
Lower Vitamin D levels are associated with higher systemic lupus erythematosus activity, but not predictive of disease flare-up. Lupus Sci Med 2014;1:e000027.
Yap KS, Morand EF. Vitamin D and systemic lupus erythematosus: Continued evolution. Int J Rheum Dis 2015;18:242-9.
Sakthiswary R, Raymond AA. The clinical significance of Vitamin D in systemic lupus erythematosus: A systematic review. PLoS One 2013;8:e55275.
Azrielant S, Shoenfeld Y. Eppur si muove: Vitamin D is essential in preventing and modulating SLE. Lupus 2016;25:563-72.
Tay SH, Ho CS, Ho RC, Mak A 25-hydroxyvitamin D3 deficiency independently predicts cognitive impairment in patients with systemic lupus erythematosus. PLoS One 2015;10:e0144149.
Gholamrezaei A, Bonakdar ZS, Mirbagher L, Hosseini N. Sleep disorders in systemic lupus erythematosus. Does Vitamin D play a role? Lupus 2014;23:1054-8.
Sahebari M, Nabavi N, Salehi M. Correlation between serum 25(OH) D values and lupus disease activity: An original article and a systematic review with meta-analysis focusing on serum VitD confounders. Lupus 2014;23:1164-77.
Petri M, Bello KJ, Fang H, Magder LS. Vitamin D in systemic lupus erythematosus: Modest association with disease activity and the urine protein-to-creatinine ratio. Arthritis Rheum 2013;65:1865-71.
Ebers GC. Environmental factors and multiple sclerosis. Lancet Neurol 2008;7:268-77.
Munger KL, Zhang SM, O'Reilly E, Hernán MA, Olek MJ, Willett WC, et al.
Vitamin D intake and incidence of multiple sclerosis. Neurology 2004;62:60-5.
Ascherio A, Munger KL, White R, Köchert K, Simon KC, Polman CH, et al.
Vitamin D as an early predictor of multiple sclerosis activity and progression. JAMA Neurol 2014;71:306-14.
Mowry EM, Waubant E, McCulloch CE, Okuda DT, Evangelista AA, Lincoln RR, et al.
Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol 2012;72:234-40.
Watad A, Azrielant S, Soriano A, Bracco D, Abu Much A, Amital H, et al.
Association between seasonal factors and multiple sclerosis. Eur J Epidemiol 2016;31:1081-9.
Mohr SB, Garland CF, Gorham ED, Garland FC. The association between ultraviolet B irradiance, Vitamin D status and incidence rates of type 1 diabetes in 51 regions worldwide. Diabetologia 2008;51:1391-8.
Hyppönen E, Läärä E, Reunanen A, Järvelin MR, Virtanen SM. Intake of Vitamin D and risk of type 1 diabetes: A birth-cohort study. Lancet 2001;358:1500-3.
Mohammadian S, Fatahi N, Zaeri H, Vakili MA. Effect of Vitamin D3 supplement in glycemic control of pediatrics with type 1 diabetes mellitus and Vitamin D deficiency. J Clin Diagn Res 2015;9:SC05-7.
Engelen L, Schalkwijk CG, Eussen SJ, Scheijen JL, Soedamah-Muthu SS, Chaturvedi N, et al.
Low 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 levels are independently associated with macroalbuminuria, but not with retinopathy and macrovascular disease in type 1 diabetes: The EURODIAB prospective complications study. Cardiovasc Diabetol 2015;14:67.
Ulitsky A, Ananthakrishnan AN, Naik A, Skaros S, Zadvornova Y, Binion DG, et al.
Vitamin D deficiency in patients with inflammatory bowel disease: Association with disease activity and quality of life. JPEN J Parenter Enteral Nutr 2011;35:308-16.
Kerr GS, Sabahi I, Richards JS, Caplan L, Cannon GW, Reimold A, et al.
Prevalence of Vitamin D insufficiency/deficiency in rheumatoid arthritis and associations with disease severity and activity. J Rheumatol 2011;38:53-9.
Orgaz-Molina J, Buendía-Eisman A, Arrabal-Polo MA, Ruiz JC, Arias-Santiago S. Deficiency of serum concentration of 25-hydroxyvitamin D in psoriatic patients: A case-control study. J Am Acad Dermatol 2012;67:931-8.
Cutolo M, Otsa K, Laas K, Yprus M, Lehtme R, Secchi ME, et al.
Circannual Vitamin D serum levels and disease activity in rheumatoid arthritis: Northern versus Southern Europe. Clin Exp Rheumatol 2006;24:702-4.
Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for Vitamin D. Am J Clin Nutr 2007;85:6-18.