Vitamin D, omega-3 supplements reduced risk for incident autoimmune disease
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The use of vitamin D3 or omega-3 fatty acid supplements over a 5-year period may reduce the incidence of autoimmune disease in older adults by 25% to 30%, according to data presented at ACR Convergence 2021.
“In past ecologic observations, inflammatory bowel disease, multiple sclerosis and type 2 diabetes have been shown to be more prevalent at northern latitudes, where circulating vitamin D levels are lower,” Karen Costenbader, MD, MPH, director of the Lupus Program at Brigham and Women's Hospital, told attendees at the virtual meeting. “Both high plasma 25-OH vitamin D and high residential UV exposure were associated with a decreased risk for rheumatoid arthritis among women in the Nurses’ Health Study in our past work.”
“In past observational studies, lower RA risk has been observed in those with increased fatty fish intake,” she added. “In another study, higher [omega-3 (n-3)] fatty acid-to-total lipid proportion in [red blood cell] membranes was associated with a lower prevalence anti-CCP and rheumatoid factor antibodies, and lower progression to inflammatory arthritis among healthy volunteers.”
However, to date, no prospective randomized trials have tested the effects of vitamin D or omega-3 fatty acid supplementation on the incidence of autoimmune diseases over time, Costenbader noted. To examine both for the prevention of autoimmune disease, she and colleagues conducted VITAL, a large, nationwide, randomized, double-blind, placebo-controlled trial. The researchers enrolled a total of 25,871 adults aged 50 years or older, for men, and 55 years or older, for women.
These participants were first randomized 1:1 to receive either 2,000 UI per day of vitamin D3 or placebo, and then, in a two-by-two factorial design, again randomized 1:1 to either 1 mg per day of n-3 fatty acids or placebo. Randomization occurred from November 2011 to March 2014, with treatment continuing through December 2017. Physician-diagnosed autoimmune diseases were reported by participants each year and confirmed via medical records.
The primary endpoint was total incident autoimmune disease, including RA, polymyalgia rheumatica, autoimmune thyroid disease, psoriasis and others. Secondary endpoints included individual most common autoimmune diseases and probable autoimmune disease, defined as evidence of autoimmune disease that nonetheless lacks sufficient medical record data to confirm. The researchers used Cox regression models to calculate hazard ratios of incident autoimmune diseases.
According to the researchers, during a median follow-up of 5.3 years, 117 participants from the vitamin D group were confirmed to have developed an autoimmune disease, compared with 150 in the placebo group (HR = 0.78; 95% CI, 0.61-1). Excluding the first 2 years in pre-specified analyses of the primary endpoint, the hazard ratio for vitamin D3 was 0.61 (95% CI, 0.43-0.86).
Meanwhile, 123 participants in the omega-3 fatty acids group had confirmed autoimmune disease, compared with 144 in the placebo group (HR = 0.85; 95% CI, 0.67-1.09). Excluding the first 2 years, the hazard ratio for the primary endpoint was 0.9 (95% CI, 0.64-1.26).
When analyzed based on factorial design subgroups, hazard ratios for all three active arms compared with placebo/placebo were reduced by 25% to 30%, according to the researchers. In addition, number needed to treat with both supplements for 5 years to prevent one autoimmune disease was 167 (95% CI, 94-769).
“The reduced incidence of RA and polymyalgia rheumatica are very important for rheumatology,” Costenbader said. “The more pronounced effect after 2 to 3 years of use with vitamin D makes sense biologically and supports long-term use. There is an ongoing extension study confirming incident cases in further follow-up. The clinical importance of these results is very high given that these are well-tolerated, non-toxic supplements, that there are no other known effective therapies to reduce incidence for autoimmune diseases.”
Perspective
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David A. McLain, MD, MACR, FACP, FRCP
In the 1970s, Danish professor Jørn Dyerberg, MD, was studying Inuits and found that, despite a high fat diet, they had very low rates of heart disease. From this observation, he discovered the protective effects of omega-3 fatty acids (EPA and DHA) from marine sources on cardiovascular health.
Since 1970, there have been 25,000 studies exploring the benefits of n-3 fatty acid supplementation. Besides cardiovascular health, researchers have studied the effect of n-3 fatty acids on brain and eye health and inflammatory disorders. Vitamin D, historically, has been associated with bone metabolism regulation. The discovery of vitamin D receptors in immune cells, such as dendritic cells, monocytes and activated T cells explains modulation of immunological functions and the potential role vitamin D in the prevention of autoimmune disease.
The present study is very impressive; it is double blind, placebo controlled and had over 25,000 participants. The study had 51% women, which is very close to the U.S. Census figure of 50.8%. However, the number of non-Hispanic whites was 70.6%, which is higher that the census figure of 60.1%. African American participation was 20% in the study and above the census figure of 13.4%. It appears that the other racial/ethnic groups – at 9% –were underrepresented Hispanic and Asian Americans.
A study of this kind is very difficult to conduct as the diseased patients made up a small proportion of the population studied. Furthermore, it is difficult to control unauthorized consumption of OTC supplements in the placebo group and difficult to fund research on supplements that are easily available from multiple sources. This is important research, and we hope to see more of it.
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Costenbader K. Abstract 0957. Presented at: ACR Convergence 2021; November 5-9, 2021 (virtual meeting).
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