Feb 9, 2024
The beneficial effects of daily vitamin D appear to have diminished after the supplement was stopped, while the protection from n-3 FA persisted for at least two more years, two years after the conclusion of a randomized trial that demonstrated the benefit of n-3 FA and vitamin D supplementation for lowering risk for autoimmune diseases.
As previously reported, five years of vitamin D supplementation was linked to a 22% reduction in risk for confirmed autoimmune diseases, and five years of n-3 FA supplementation was linked to an 18% reduction in confirmed and probable incident autoimmune diseases. The randomized VITAL study was primarily intended to examine the effects of vitamin D and n-3 supplementation on incident cancer and cardiovascular disease.
The benefits of daily marine n-3 FAs (1 g/d as a fish-oil capsule containing 460 mg of eicosapentaenoic acid and 380 mg of docosahexaenoic acid) remained significant, according to investigators Karen H. Costenbader, MD, MPH, of Brigham & Women's Hospital in Boston, Massachusetts, and colleagues. Among 21,592 participants in VITAL who agreed to be followed for an additional 2 years after discontinuation, the protection against autoimmune diseases from daily vitamin D (cholecalciferol; 2000 IU/d) was no longer statistically significant.
The results of the VITAL observational extension indicate that continued vitamin D administration is recommended for the long-term protection of [autoimmune disorders]. However, the advantages of n-3 fatty acids can last for at least two years after stopping, according to an essay they wrote.
The findings of the observational extension study, according to Costenbader, indicate that the advantages of vitamin D "wear off more quickly, and it should be continued for a longer period of time or indefinitely, rather than only for 5 years." Costenbader made this statement to Medscape Medical News.
The researchers observed variations in the effects across various autoimmune disorders in addition to changes in the duration of the protective impact.
"The protective effect of vitamin D seemed strongest for psoriasis, while for omega-3 fatty acids, the protective effects were strongest for rheumatoid arthritis and inflammatory bowel disease," she stated.
The results suggest that while each supplement may offer protection against autoimmune diseases, the effects are inconsistent and may not apply to all patients, according to Janet Funk, MD, MS, vice chair of research in the Department of Medicine and professor in the School of Nutritional Science and Wellness at the University of Arizona, Tucson, Arizona, who was not involved in the study.
"I think the VITAL extension results suggest that either supplement (or both together) may have benefits in reducing risk of autoimmune diseases, including possible persistent effects posttreatment, but that these effects are nuanced (ie, only in normal weight post-vitamin D treatment) and possibly not uniform across all autoimmune diseases (including possible adverse effects for some — eg, inverse association between prior omega-3 and psoriasis and tendency for increased autoimmune thyroid disease for vitamin D), although the study was not powered sufficiently to draw disease-specific conclusions," she said.
In an editorial accompanying the study, rheumatologist Joel M. Kremer, MD, of Albany Medical College and the Corrona Research Foundation in Delray Beach, Florida, wrote that "[T]he studies by Costenbader, et al. have shed new light on the possibility that dietary supplements of n-3 FA [fatty acid] may prevent the onset of [autoimmune disease]. The sustained benefits they describe for as long as 2 years after the supplements are discontinued are consistent with the chronicity of FA species in cellular plasma membranes where they serve as substrates for a diverse array of salient metabolic and inflammatory pathways."
To test whether vitamin D or marine-derived long-chain n-3 FA supplementation could protect against autoimmune disease over time, Costenbader and colleagues piggybacked an ancillary study onto the VITAL trial, which had primary outcomes of cancer and cardiovascular disease incidence.
A total of 25,871 participants were enrolled, including 12,786 men aged 50 and older and 13,085 women aged 55 and older. The study had a 2 × 2 factorial design, with patients randomly assigned to vitamin D 2000 IU/d or placebo and then further randomized to either 1 g/d n-3 FAs or placebo in both the vitamin D and placebo primary randomization arms.
In multivariate analysis adjusted for age, sex, race, and other supplement arm, vitamin D alone was associated with a hazard ratio (HR) of 0.68 (P = .02) for incident autoimmune disease, n-3 alone was associated with a nonsignificant HR of 0.74, and the combination was associated with an HR of 0.69 (P = .03). However, when probable incident autoimmune disease cases were included, the effect of n-3 became significant, with an HR of 0.82.
Costenbader and colleagues presented observational data on 21,592 VITAL participants in the current research. This sample included 87.9% of those who were still alive and able to be contacted at the end of the study, as well as 83.5% of those who were initially randomized.
During the randomized follow-up, the researchers assessed incident autoimmune illnesses using annual questionnaires, just as they did in the original trial. Participants were questioned regarding psoriasis, autoimmune thyroid disease, polymyalgia rheumatica, inflammatory bowel disease, and rheumatoid arthritis with a recent onset and a doctor's diagnosis. Additionally, participants could list any additional diagnoses of autoimmune diseases.
There were 236 new cases of confirmed autoimmune disease that occurred since the initial publication of the trial results, as well as 65 probable cases identified during the median 5.3 years of the randomized portion, and 42 probable cases diagnosed during the 2-year observational phase.
The investigators found that after the 2-year observation period, 255 participants initially randomized to receive vitamin D had a newly developed confirmed autoimmune disease, compared with 259 of those initially randomized to a vitamin D placebo. This translated into a nonsignificant HR of 0.98
Adding probable autoimmune cases to the confirmed cases made little difference, resulting in a nonsignificant adjusted HR of 0.95.
In contrast, there were 234 confirmed autoimmune disease cases among patients initially assigned to n-3, compared with 280 among patients randomized to the n-3 placebo, translating into a statistically significant HR of 0.83 for new-onset autoimmune disease with n-3.
Costenbader and colleagues acknowledged that the study was limited by the use of doses intended to prevent cancer or cardiovascular disease and that higher doses intended for high-risk or nutritionally deficient populations might reveal larger effects of supplementation. In addition, they noted the difficulty of identifying the timing and onset of incident disease, and that the small number of cases that occurred during the 2-year observational period precluded detailed analyses 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.
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