Study: Vitamin D can protect against autoimmune diseases

reference

Hahn J, Cook NR, Alexander EK, et al. Dietary supplementation with vitamin D and marine omega-3 fatty acids and emerging autoimmune diseases: Randomized controlled VITAL study.BMJ. 2022;376:e066452.

Objective

To examine the effect of vitamin D and fish oil supplementation alone and in combination on the 5-year incidence of new-onset autoimmune diseases in an older population

design

Randomized, double-blind, placebo-controlled trial with a 2 × 2 factorial design

Participant

This study included 25,871 participants, including 12,786 men aged ≥ 50 years (51%) and 13,085 women aged ≥ 55 years. The average age was 67.1 years. Individuals with a previous diagnosis of renal failure or dialysis, liver cirrhosis, hypercalcemia, cancer (other than non-melanoma skin cancer), cardiovascular disease, or other serious medical conditions were excluded. Of the 25,871 participants, 5,106 were Black and 2,152 were from other non-White racial and ethnic groups.

intervention

Participants were randomly assigned to one of four groups:

1. Omega-3-Fettsäure (1.000 mg/Tag; 460 mg Eicosapentaensäure und 380 mg Docosahexaensäure) und Vitamin-D-Supplementierung (2.000 IE/Tag)
2. Omega-3-Fettsäure (1.000 mg/Tag) und Placebo
3. Vitamin-D-Supplementierung (2.000 IE/Tag) und Placebo
4. Placebo

Participants self-reported many health outcomes each year for 5 years, and a comprehensive medical examination confirmed the reported illnesses.

Evaluated study parameters

Participants completed baseline questionnaires on lifestyle factors and were asked about vitamin D supplementation and consumption of fish and dairy products. Blood samples were collected from 16,956 participants and analyzed for 25-hydroxyvitamin D and plasma omega-3 index. Participants completed repeat questionnaires 6 months and 1 year after randomization, then annually for 5 years. Participants were asked specifically about new-onset, clinically diagnosed rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, psoriasis, and inflammatory bowel disease and were also given a blank space in which to enter any new autoimmune diagnosis.

Key findings

In older adults, taking vitamin D (2,000 IU) daily for 5 years reduced the incidence of autoimmune diseases by 22%. Omega-3 fatty acid supplementation alone reduced the incidence of autoimmune diseases by 15%, but was not statistically significant. The combination of vitamin D and omega-3 did not appear to have any significant additional benefit. Omega-3 supplementation alone appeared to be more beneficial in preventing the onset of autoimmune disease in individuals with a positive family history and also appeared to have a greater effect in the later years of the study.

transparency

The National Institutes of Health funded this study, and each author disclosed no affiliation with any entity that could potentially benefit financially from the study.

Effects on practice

The VITAL study was a large, randomized, controlled, double-blind study that ran from 2011 to 2017. The primary results of this major undertaking were:

1. Anzahl der Teilnehmer mit invasivem Krebs jeglicher Art und
2. Anzahl der Teilnehmer mit einem schwerwiegenden kardiovaskulären Ereignis (zusammengesetzter Endpunkt aus Myokardinfarkt, Schlaganfall und Tod aufgrund kardiovaskulärer Ursachen).

The results of this study have resulted in 25 publications to date, and researchers continue to mine the data for new information on topics such as urinary incontinence, metabolic health and bone density.¹The primary objectives of this study produced disappointing results, as cancer or cardiovascular risk was not changed by either vitamin D or omega-3 fatty acid supplementation.^2.3

Autoimmune diseases are widespread and appear to be becoming more common.⁴While the impact on quality of life, morbidity, mortality, and costs varies significantly depending on the specific diagnosis, overall, autoimmune diseases are a significant contributor to overall human suffering as well as healthcare costs. These costs are rising as new drugs such as biologics become the standard of care. For example, treating rheumatoid arthritis (RA) costs about $29,000 per year, which is typical for a serious autoimmune disease.⁵Additionally, experiencing an autoimmune disease can have a tremendous impact on an individual's quality of life and ability to engage in activities they enjoy. This study is very welcome as there have been few large-scale studies evaluating the prevention of autoimmune diseases.

It is possible that the omega-3 result was not statistically significant because the duration of the study was not long enough to fully show the benefit.

We have increasing evidence that low omega-3 index is a major risk factor for the development of autoimmune diseases such as rheumatoid arthritis.⁶There is also evidence that treating RA patients with new-onset rheumatoid arthritis with high doses (5.5 g) but not low doses (0.4 g) of omega-3 fatty acids may reduce disease activity levels and reduce medication escalation.⁷

One could argue that this study failed to demonstrate any benefit from omega-3 fatty acid supplementation due to insufficient dosage. This could be a possible bias on the part of the integrative community to expect positive results from a study like this. The authors did a good job of providing biological evidence that omega-3 was indeed adequately dosed. In fact, in the first year of the study, the omega-3 fatty acid index (Quest Diagnostics) increased by 54.7% to a mean of 4.1%, which is in the optimal range. It is possible that the omega-3 result was not statistically significant because the duration of the study was not long enough to fully show the benefit. Interestingly, the researchers found that the omega-3 effect was more pronounced toward the end of the study, reaching statistical significance with an 18% decrease in incidence when “probable autoimmune disease” was included.

Diploma

The VITAL study was a well-designed and comprehensive study involving a diverse population that aimed to evaluate the effects of vitamin D supplementation, with or without omega-3 supplementation, on the incidence of cancer and cardiovascular disease. Although there were disappointing results for these endpoints as well as several other secondary endpoints, it appears that vitamin D supplementation, with or without omega-3 supplementation, reduces the incidence of new-onset autoimmune diseases in people over 55 years of age. The study did an excellent job of ensuring adherence to treatment through the use of biomarkers.

There are 3 major challenges. First, many autoimmune diseases occur at younger ages than those recorded in this study. Second, many common autoimmune diseases such as Hashimoto's thyroiditis can persist for many years before major clinical symptoms appear, making it difficult to distinguish a new-onset disease. Third, despite the large size of the study with more than 25,000 participants, there were few new diagnoses of autoimmune disease. For example, only 123 participants in the vitamin D group had an autoimmune disease, compared to 155 in the placebo group. This illustrates that statements such as “Vitamin D supplementation reduces the incidence of autoimmune diseases by 22%” may have greater impact than they actually are.

This study did not include a cost analysis. That is, from a public health perspective, does preventing 32 emerging autoimmune diseases in a population of 25,000 save money through vitamin D supplementation? Such studies would be particularly helpful for nutritional supplements that are not typically covered by insurance. Despite these challenges, this study improves our understanding of the factors that increase the risk of autoimmune disease.