Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial
Jill Hahn, Nancy R Cook, Erik K Alexander, Sonia Friedman, Joseph Walter, Vadim Bubes, Gregory Kotler, I-Min Lee, JoAnn E Manson, Karen H Costenbader, Jill Hahn, Nancy R Cook, Erik K Alexander, Sonia Friedman, Joseph Walter, Vadim Bubes, Gregory Kotler, I-Min Lee, JoAnn E Manson, Karen H Costenbader
Abstract
Objective: To investigate whether vitamin D and marine derived long chain omega 3 fatty acids reduce autoimmune disease risk.
Design: Vitamin D and omega 3 trial (VITAL), a nationwide, randomized, double blind, placebo controlled trial with a two-by-two factorial design.
Setting: Nationwide in the United States.
Participants: 25 871 participants, consisting of 12 786 men ≥50 years and 13 085 women ≥55 years at enrollment.
Interventions: Vitamin D (2000 IU/day) or matched placebo, and omega 3 fatty acids (1000 mg/day) or matched placebo. Participants self-reported all incident autoimmune diseases from baseline to a median of 5.3 years of follow-up; these diseases were confirmed by extensive medical record review. Cox proportional hazard models were used to test the effects of vitamin D and omega 3 fatty acids on autoimmune disease incidence.
Main outcome measures: The primary endpoint was all incident autoimmune diseases confirmed by medical record review: rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, psoriasis, and all others.
Results: 25 871 participants were enrolled and followed for a median of 5.3 years. 18 046 self-identified as non-Hispanic white, 5106 as black, and 2152 as other racial and ethnic groups. The mean age was 67.1 years. For the vitamin D arm, 123 participants in the treatment group and 155 in the placebo group had a confirmed autoimmune disease (hazard ratio 0.78, 95% confidence interval 0.61 to 0.99, P=0.05). In the omega 3 fatty acids arm, 130 participants in the treatment group and 148 in the placebo group had a confirmed autoimmune disease (0.85, 0.67 to 1.08, P=0.19). Compared with the reference arm (vitamin D placebo and omega 3 fatty acid placebo; 88 with confirmed autoimmune disease), 63 participants who received vitamin D and omega 3 fatty acids (0.69, 0.49 to 0.96), 60 who received only vitamin D (0.68, 0.48 to 0.94), and 67 who received only omega 3 fatty acids (0.74, 0.54 to 1.03) had confirmed autoimmune disease.
Conclusions: Vitamin D supplementation for five years, with or without omega 3 fatty acids, reduced autoimmune disease by 22%, while omega 3 fatty acid supplementation with or without vitamin D reduced the autoimmune disease rate by 15% (not statistically significant). Both treatment arms showed larger effects than the reference arm (vitamin D placebo and omega 3 fatty acid placebo).
Study registration: ClinicalTrials.gov NCT01351805 and NCT01169259.
Conflict of interest statement
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the National Institutes of Health for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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References
- Cooper GS, Stroehla BC. The epidemiology of autoimmune diseases. Autoimmun Rev 2003;2:119-25. 10.1016/S1568-9972(03)00006-5
- Hayter SM, Cook MC. Updated assessment of the prevalence, spectrum and case definition of autoimmune disease. Autoimmun Rev 2012;11:754-65. 10.1016/j.autrev.2012.02.001
- Roberts MH, Erdei E. Comparative United States autoimmune disease rates for 2010-2016 by sex, geographic region, and race. Autoimmun Rev 2020;19:102423. 10.1016/j.autrev.2019.102423
- Rose NR. Prediction and prevention of autoimmune disease in the 21st century: a review and preview. Am J Epidemiol 2016;183:403-6. 10.1093/aje/kwv292
- Kriegel MA, Manson JE, Costenbader KH, eds. Does vitamin D affect risk of developing autoimmune disease? A systematic review. Seminars in arthritis and rheumatism. Elsevier, 2011.
- Ding Y, Liao W, He XJ, Xiang W. Effects of 1,25(OH)2 D3 and vitamin D receptor on peripheral CD4+ /CD8+ double-positive T lymphocytes in a mouse model of systemic lupus erythematosus. J Cell Mol Med 2017;21:975-85. 10.1111/jcmm.13037
- Gallo D, Mortara L, Gariboldi MB, et al. . Immunomodulatory effect of vitamin D and its potential role in the prevention and treatment of thyroid autoimmunity: a narrative review. J Endocrinol Invest 2020;43:413-29. 10.1007/s40618-019-01123-5
- Yamamoto E, Jørgensen TN. Immunological effects of vitamin D and their relations to autoimmunity. J Autoimmun 2019;100:7-16. 10.1016/j.jaut.2019.03.002
- Altieri B, Muscogiuri G, Barrea L, et al. . Does vitamin D play a role in autoimmune endocrine disorders? A proof of concept. Rev Endocr Metab Disord 2017;18:335-46. 10.1007/s11154-016-9405-9
- Costenbader KH, Chang SC, Laden F, Puett R, Karlson EW. Geographic variation in rheumatoid arthritis incidence among women in the United States. Arch Intern Med 2008;168:1664-70. 10.1001/archinte.168.15.1664
- Murdaca G, Tonacci A, Negrini S, et al. . Emerging role of vitamin D in autoimmune diseases: An update on evidence and therapeutic implications. Autoimmun Rev 2019;18:102350. 10.1016/j.autrev.2019.102350
- Skaaby T, Husemoen LLN, Thuesen BH, Linneberg A. Prospective population-based study of the association between vitamin D status and incidence of autoimmune disease. Endocrine 2015;50:231-8. 10.1007/s12020-015-0547-4
- Giustina A, Adler R, Binkley N, et al. Consensus statement from 2nd International Conference on Controversies in Vitamin D. Reviews in Endocrine and Metabolic Disorders. 2020:1-28.
- Scragg R. Limitations of vitamin D supplementation trials: why observational studies will continue to help determine the role of vitamin D in health. J Steroid Biochem Mol Biol 2018;177:6-9. 10.1016/j.jsbmb.2017.06.006
- Akbar U, Yang M, Kurian D, Mohan C. Omega-3 fatty acids in rheumatic diseases: a critical review. J Clin Rheumatol 2017;23:330-9. 10.1097/RHU.0000000000000563
- Clark CCT, Taghizadeh M, Nahavandi M, Jafarnejad S. Efficacy of ω-3 supplementation in patients with psoriasis: a meta-analysis of randomized controlled trials. Clin Rheumatol 2019;38:977-88. 10.1007/s10067-019-04456-x
- Pedersen M, Stripp C, Klarlund M, Olsen SF, Tjønneland AM, Frisch M. Diet and risk of rheumatoid arthritis in a prospective cohort. J Rheumatol 2005;32:1249-52.
- Bassuk SS, Manson JE, Lee I-M, et al. . Baseline characteristics of participants in the VITamin D and OmegA-3 TriaL (VITAL). Contemp Clin Trials 2016;47:235-43. 10.1016/j.cct.2015.12.022
- Manson JE, Cook NR, Lee I-M, et al. VITAL Research Group . Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med 2019;380:33-44. 10.1056/NEJMoa1809944
- Manson JE, Cook NR, Lee I-M, et al. VITAL Research Group . Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med 2019;380:23-32. 10.1056/NEJMoa1811403
- Althouse AD, Below JE, Claggett BL, Cox NJ, de Lemos JA, Deo RC, et al. Recommendations for Statistical Reporting in Cardiovascular Medicine: A Special Report From the American Heart Association. Circulation. 2021.
- Sparks JA, Costenbader KH. Genetics, environment, and gene-environment interactions in the development of systemic rheumatic diseases. Rheum Dis Clin North Am 2014;40:637-57. 10.1016/j.rdc.2014.07.005
- Bouillon R, Marcocci C, Carmeliet G, et al. . Skeletal and extraskeletal actions of vitamin D: current evidence and outstanding questions. Endocr Rev 2019;40:1109-51. 10.1210/er.2018-00126
- Dankers W, Colin EM, van Hamburg JP, Lubberts E. Vitamin D in autoimmunity: molecular mechanisms and therapeutic potential. Front Immunol 2017;7:697. 10.3389/fimmu.2016.00697
- Stockinger B. Th17 cells: an orphan with influence. Immunol Cell Biol 2007;85:83-4. 10.1038/sj.icb.7100035
- 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. 10.1006/clim.2000.4998
- Korf H, Wenes M, Stijlemans B, et al. . 1,25-Dihydroxyvitamin D3 curtails the inflammatory and T cell stimulatory capacity of macrophages through an IL-10-dependent mechanism. Immunobiology 2012;217:1292-300. 10.1016/j.imbio.2012.07.018
- Fisher SA, Rahimzadeh M, Brierley C, et al. . The role of vitamin D in increasing circulating T regulatory cell numbers and modulating T regulatory cell phenotypes in patients with inflammatory disease or in healthy volunteers: a systematic review. PLoS One 2019;14:e0222313. 10.1371/journal.pone.0222313
- Li K, Huang T, Zheng J, Wu K, Li D. Effect of marine-derived n-3 polyunsaturated fatty acids on C-reactive protein, interleukin 6 and tumor necrosis factor α: a meta-analysis. PLoS One 2014;9:e88103. 10.1371/journal.pone.0088103
- Radzikowska U, Rinaldi AO, Çelebi Sözener Z, et al. . The influence of dietary fatty acids on immune responses. Nutrients 2019;11:2990. 10.3390/nu11122990
- Ramirez JL, Gasper WJ, Khetani SA, et al. . Fish oil increases specialized pro-resolving lipid mediators in PAD (the omega-pad II trial). J Surg Res 2019;238:164-74. 10.1016/j.jss.2019.01.038
- Serhan CN, Levy BD. Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. J Clin Invest 2018;128:2657-69. 10.1172/JCI97943
- Calder PC. Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance. Biochim Biophys Acta 2015;1851:469-84. 10.1016/j.bbalip.2014.08.010
- Costenbader KH, MacFarlane LA, Lee I-M, et al. . Effects of one year of vitamin D and marine omega-3 fatty acid supplementation on biomarkers of systemic inflammation in older US adults. Clin Chem 2019;65:1508-21. 10.1373/clinchem.2019.306902
- Gysemans CA, Cardozo AK, Callewaert H, et al. . 1,25-Dihydroxyvitamin D3 modulates expression of chemokines and cytokines in pancreatic islets: implications for prevention of diabetes in nonobese diabetic mice. Endocrinology 2005;146:1956-64. 10.1210/en.2004-1322
- Grenon SM, Owens CD, Nosova EV, et al. . Short-term, high-dose fish oil supplementation increases the production of omega-3 fatty acid-derived mediators in patients with peripheral artery disease (the OMEGA-PAD I Trial). J Am Heart Assoc 2015;4:e002034. 10.1161/JAHA.115.002034
- Zhang Y, Tan H, Tang J, et al. . Effects of vitamin D supplementation on prevention of type 2 diabetes in patients with prediabetes: a systematic review and meta-analysis. Diabetes Care 2020;43:1650-8. 10.2337/dc19-1708
- Pittas AG, Dawson-Hughes B, Sheehan P, et al. D2d Research Group . Vitamin D supplementation and prevention of type 2 diabetes. N Engl J Med 2019;381:520-30. 10.1056/NEJMoa1900906
- Dillon CF, Weisman MH, Miller FW. Population-based estimates of humoral autoimmunity from the U.S. National Health and Nutrition Examination Surveys, 1960-2014. PLoS One 2020;15:e0226516. 10.1371/journal.pone.0226516
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