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The use of vitamin D and omega-3 fatty acid supplementation was associated with a decreased likelihood of autoimmune disease in an ancillary analysis of a large randomized trial.

During 5 years of follow-up in a cohort of almost 17,000 adults, there were 123 incident cases of autoimmune disease among those who were taking vitamin D supplements daily, while there were 155 among those on placebo, for a hazard ratio of 0.78 (95% CI 0.61-1.00, P=0.045), reported Karen Costenbader, MD, of Brigham and Women's Hospital in Boston.

"I don't have to convince this audience of the burden of autoimmune diseases. These diseases affect 5% to 8% of the population, or 15 to 20 million Americans. They are among the top 10 causes of death among women under 65 in the U.S. and the second most common cause of chronic illness," she said in a plenary session at the 2021 virtual annual meeting of the American College of Rheumatology.

There currently is no means of preventing autoimmune diseases, which include conditions such as rheumatoid arthritis, polymyalgia rheumatica, and psoriasis.

Vitamin D is a pleiotropic hormone with wide regulatory actions. It binds to the nuclear vitamin D receptor and regulates an array of genes involved in innate and adaptive immune responses, she explained.

Ecological observations have demonstrated that autoimmune diseases such as inflammatory bowel disease, multiple sclerosis, and type 1 diabetes are more prevalent at northern latitudes where vitamin D levels typically are lower. In previous observational studies, high residential ultraviolet exposures have been associated with lower risks of Crohn's disease, and also with decreased rates of rheumatoid arthritis. However, no prospective trial has tested the effects of supplementation with vitamin D and the incidence of autoimmune disease over time.

Omega 3 fatty acids are abundant in fish. These compounds suppress the biosynthesis of inflammatory arachidonic acid-derived eicosanoids and regulate the inflammatory transcription factors nuclear factor kappa B and peroxisome proliferator activated receptor. Previous studies have found that higher intake of omega-3 fatty acids was associated with a lower incidence of rheumatoid arthritis and a decreased prevalence of seropositivity. To date, no prospective study has evaluated the effects of daily use of omega 3 fatty acids on the incidence of autoimmune disease.

To address these knowledge gaps, Costenbader's group analyzed data from the vitamin D and omega 3 (VITAL) trial, which included almost 26,000 men ages 50 and older and women 55 and older.

The primary analysis of VITAL was for the incidence of cancer and cardiovascular disease; no decrease in risk was observed for those conditions.

In this ancillary study, the outcome of interest was the incidence of all autoimmune diseases among the 16,956 participants who had undergone assays for 25 (OH) vitamin D and had plasma omega-3 index measurements.

First, participants were randomized to vitamin D, 2,000 IU/day (n=12,937) or placebo (n=12,937), and then in a 2 × 2 factorial design they were again randomized to omega 3 fatty acids, 1 g/day (n=6,468) or placebo (n=6,469) in the active vitamin D arm and to omega 3 fatty acids, 1 g/day (n=6,468) or placebo (n=6,469) in the placebo group of the vitamin D randomization arm.

Median follow-up was 5.3 years.

Participants' mean age was 67, and the groups were well matched on factors such as demographics, vitamin D levels and intake, and family history.

The cumulative incidence curves for vitamin D supplementation versus placebo begin to diverge after 2 to 3 years of follow-up, "which makes sense biologically and supports long-term use," she said.

For omega-3 supplementation, there were 130 confirmed cases of autoimmune disease in the active treatment group and 148 cases in the placebo group (HR 0.85, 95% CI 0.67-1.09, P=0.20). In an additional analysis comparing patients who had initially been randomized to the vitamin D placebo arm, there were 67 confirmed cases in the re-randomized omega-3 supplementation group and 88 in the placebo group (HR 0.74, 95% CI 0.54-1.03, P=0.07). In that analysis, there were 63 cases in the vitamin D plus omega-3 group and 88 cases in the placebo/placebo arm, for a hazard ratio of 0.69 (95% CI 0.49-0.96, P=0.03).

There were no significant differences in adverse events between the active and placebo groups.

"Supplementation for 5 years with vitamin D3 and/or omega-3 fatty acids reduced incident autoimmune disease by 25% to 30% in older adults versus those who received neither supplement," she concluded.

"The clinical importance of these findings is high, given that these are well tolerated, nontoxic supplements and that there are no other effective therapies to reduce the incidence of autoimmune diseases," she commented.

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