Two years after the conclusion of a randomized study that demonstrated the benefits of daily Vitamin D and Omega-3 fatty acid (n-3-FA) supplementation in reducing the risk of autoimmune diseases, the beneficial effects of daily Vitamin D supplementation appear to have waned after the supplement was discontinued, while the protection provided by n-3 continued for at least two more years.
The VITAL randomized study, primarily aimed at investigating the effects of Vitamin D and n-3 supplementation on the occurrence of cancer and cardiovascular diseases, also showed that a 5-year Vitamin D supplementation was associated with a 22% reduction in confirmed autoimmune diseases, and a 5-year n-3-FA supplementation was linked to an 18% reduction in confirmed and probable autoimmune diseases.
Now, researchers including Karen H. Costenbader, MD, MPH, from Brigham & Women’s Hospital in Boston, Massachusetts, reported that in 21,592 VITAL participants who agreed to further observation for an additional 2 years after discontinuation, the protection against autoimmune diseases decreased. Daily Vitamin D (Cholecalciferol; 2000 IU/day) was no longer statistically significant, but the benefits of daily marine n-3 FAs (1g/day as fish oil capsule with 460 mg Eicosapentaenoic acid and 380 mg Docosahexaenoic acid) remained significant.
„The results of the VITAL observational extension suggest that Vitamin D supplementation should be administered on a continuous basis for long-term prevention [of autoimmune diseases]. However, the beneficial effect of n-3 fatty acids may persist for at least two years after discontinuation,“ they wrote in an article published in Arthritis and Rheumatology on January 25.
Costenbader told Medscape Medical News that the results of the observational extension study suggest that the benefits of Vitamin D „diminish more rapidly and should be continued over a longer period or indefinitely and not just for 5 years.“
In addition to the inequality in the duration of protective effects, the researchers also noted differences in the impact on different autoimmune diseases.
„The protective effect of Vitamin D appeared to be strongest in psoriasis, while with Omega-3 fatty acids, the protective effect was strongest in rheumatoid arthritis and inflammatory bowel diseases,“ she said.
In an interview with Medscape Medical News, Janet Funk, MD, MS, Deputy Research Director in the Department of Medicine and Professor at the School of Nutritional Science and Wellness at the University of Arizona, Tucson, who was not involved in the study, said that the results suggest that while each supplement may offer protection against autoimmune diseases, the effects are variable and may not apply to all patients.
„I think the results of the VITAL extension suggest that each supplement (or both together) may have benefits in reducing the risk of autoimmune diseases, including potential persistent effects after treatment, but these effects are nuanced (i.e. only in normal weight after treatment with Vitamin D) and possibly not uniform across all autoimmune diseases (including potential adverse effects for some—e.g., inverse association of earlier Omega-3 with psoriasis and tendency towards increased thyroid autoimmune disease with Vitamin D) though the study was not powered to make disease-specific conclusions,“ she said.
In an editorial to the study, rheumatologist Joel M. Kremer, MD, from Albany Medical College and the Corrona Research Foundation in Delray Beach, Florida, wrote, „[T]he study by Costenbader et al. has shed new light on the possibility that n-3 FA supplementation may prevent the onset of autoimmune disease. The sustained benefits they describe up to two years after stopping the supplements are consistent with the chronicity of FA species in cellular plasma membranes, where they serve as substrates for a variety of important metabolic and inflammatory pathways.“
To test whether supplementation with Vitamin D or marine-derived long-chain n-3 fatty acids over time can protect against autoimmune diseases, Costenbader and colleagues conducted a VITAL ancillary study, with its primary endpoints being the occurrence of cancer and cardiovascular diseases.
In total, 25,871 participants were enrolled, including 12,786 men aged 50 and above and 13,085 women aged 55 and above. The study utilized a 2×2 factorial design, where patients were randomly assigned to either 2000 IU Vitamin D per day or placebo, and then further randomized to either 1g/day n-3 FAs or placebo in both the primary Vitamin D and placebo randomization arms.
In a multivariate analysis adjusted for age, gender, race, and other supplements, Vitamin D alone was associated with a Hazard Ratio (HR) of 0.68 (P = .02) for autoimmune disease, n-3 alone was associated with a non-significant HR of 0.74, and the combination was associated with a HR of 0.69 (P = .03). However, when probable cases of autoimmune diseases were included, the effect of n-3 was significant with a HR of 0.82.
In the current analysis, Costenbader and colleagues reported observational data from 21,592 VITAL participants, representing 83.5% of the originally randomized individuals and 87.9% of individuals who were still alive and could be contacted at the end of the study.
As in the initial study, researchers used annual questionnaires to assess the occurrence of autoimmune diseases during the randomized follow-up. Participants were surveyed for newly diagnosed, physician-diagnosed rheumatoid arthritis, polymyalgia rheumatica, psoriasis, thyroid autoimmune diseases, and inflammatory bowel diseases. Participants were also able to report any other new autoimmune disease diagnoses.
There were 236 new cases of confirmed autoimmune diseases identified since the initial study results were published, as well as 65 probable cases identified during the mean 5.3 years of the randomized portion, and 42 probable cases diagnosed during the two-year observation phase.
The researchers found that after the two-year observation period, 255 participants who were originally randomized to receive Vitamin D developed a newly confirmed autoimmune disease compared to 259 of the originally randomized participants who received a Vitamin D placebo. This resulted in a non-significant HR of 0.98.
Adding probable autoimmune cases to confirmed cases made little difference, resulting in a non-significant adjusted HR of 0.95.
In contrast, there were 234 confirmed cases of autoimmune diseases in patients originally assigned to the n-3 group, compared to 280 in patients randomized to the n-3 placebo group, which corresponded to a statistically significant HR of 0.83 for newly occurring autoimmune diseases with n-3.
Costenbader and colleagues acknowledged that the study was limited by the use of doses for cancer or cardiovascular disease prevention and that higher doses meant for high-risk populations or nutrient-deficient groups might show greater effects of supplementation. Additionally, they pointed out that determining the timing and onset of a disease is difficult, and the low number of cases occurring during the two-year observation period precluded a detailed analysis of individual autoimmune diseases.
The study was funded by grants from the National Institutes of Health. Costenbader, Funk, and Kremer reported no relevant financial relationships.