vitamin d and omega-3 dec autoimmune dz/correction of prior blog

 while I am on the subject of vitamin D, there was another article suggesting that vitamin D supplementation reduced autoimmune disease, again reinforcing its role in immune regulation (see vit d dec autoimmune dz vit d dec autoimmune dz VITAL bmj2022 in dropbox, or https://www.bmj.com/content/376/bmj-2021-066452, or doi.org/10.1136/bmj-2021-066452). thanks to rebecca skoler for bringing this to my attention

 

Details:

-- 25,871 participants enrolled in the VITAL randomized controlled trial in the US, comparing the effects of vitamin D 2000 IU (50mcg) per day or matched placebo and omega-3 fatty acids (1000 mg per day) or matched placebo, in a 2 x 2 factorial design [the fish oil capsules contained 460 mg of eicosapentaenoic acid and 380 mg docosahexaenoic acid]

    -- 12,786 men at least 50 years old and 13,085 women at least 55 years old at enrollment, all were required to limit vitamin D use from outside sources to no more than 800 IU per day and to avoid the use of fish oil supplements

    -- exclusion criteria included renal failure, cirrhosis, hypercalcemia, cancer, cardiovascular disease, or other serious illnesses

--all had a three-month placebo run-in period, then were randomized to treatment

-- mean age 67, non-Hispanic white 71%/Black 20%, geographical region Northeast 28%/Midwest 21%/West 23%/Southeast 28%, self-reported income <$50,000 in 37%, current supplemental vitamin D use up to 800 IU per day 43%, mean serum 25(OH)D 30.7 ng/mL with 13% <20 ng/mL; Omega index (serum eicosapentaenoic acid plus docosahexaenoic acid/total lipids) 2.6, BMI 28, physical activity 15 MET-hrs per week [equivalent to about 300 min/week of moderate-intensity exercise], current smoker 7%, family history of autoimmune disease 34%

-- there was a baseline questionnaire on clinical and lifestyle factors as well as vitamin D supplement use, and fish and dairy intake. Blood samples were obtained at baseline for 25(OH)D levels and the plasma omega-3 index of the fatty acid components (see above). Questionnaires were completed at 6 months and 1 year after randomization and then annually (questionnaire response rate was 93% and 81% took at least two thirds of the trial capsules

--Main outcomes:

    -- self-reported all incident autoimmune diseases (specifically rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, psoriasis, and “all others”) from baseline to a median of 5.3 years of follow-up

        -- autoimmune diseases were confirmed by extensive medical record review

    -- the roles of vitamin D and/or omega-3 fatty acids was assessed

 

Results:

-- Blood changes from supplementation:

    -- 25(OH)D levels increased 40%, from 29.8 ng/mL at baseline to 41.8 ng/mL at year one and changed minimally in the placebo group

    -- mean omega-3 index increased 54.7% to 4.1% at year one and changed < 2% in the placebo group

 

-- vitamin D arm: 123 participants in treatment versus 155 in placebo had confirmed autoimmune disease, 22% reduction, HR 0.78 (0.61-0.99), p=0.05

   -- secondary endpoint: confirmed plus probable autoimmune disease found in 210 versus 247 participants, 15% reduction with HR 0.85 (0.70-1.02), p=0.09

-- excluding the first two years of follow-up (to eliminate incipient cases):

    -- confirmed autoimmune diseases 54 versus 87, 39% decrease with HR 0.61 (0.43-0.86), p=0.005

    -- confirmed plus probable autoimmune diseases 94 versus 133, 31% decrease with HR 0.69 (0.53-0.90), p=0.007

-- Subgroup analysis, for vitamin D supplementation versus placebo:

    -- confirmed rheumatoid arthritis: 15 versus 24 people, HR 0.58 (0.30-1.13), p=0.11

    -- confirmed polymyalgia rheumatica: 32 versus 43 people, HR 0.70 (0.44-1.12), p=0.14

    -- confirmed other autoimmune disease 40 versus 56 people, HR 0.74 (0.49-1.11), p=0.15

        -- these were all with a strong trend to being significant, the rest of the subgroups were not so close

-- those with lower body mass index benefited more from vitamin D treatment for confirmed immune disease:

    -- BMI 18: 53% decreased risk, HR 0.47 (0.29-0.77)

    -- BMI 25: 31% decreased risk, HR 0.69 (0.52-0.90)

    -- BMI 30: nonsignificant 10% decreased risk, HR (0.69-1.19)

-- another subgroup analysis did not find any difference in those with baseline 25(OH)D levels <20, but there were only 12 people on vitamin D and 12 on placebo were in this group), or if >20 ng/mL (though near significant benefit with HR 0.77 (0.57-1.03))

 

the x-axis is followup years (ie, no difference until year 3)

 

-- for omega-3 fatty acids:

    -- primary endpoint of confirmed autoimmune disease: 130 versus 148 people, HR 0.85 (0.67-1.08), p=0.19

    -- secondary endpoint of confirmed plus probable autoimmune disease: 208 versus 249 people, 18% reduction with HR 0.82 (0.68-0.99), p=0.04 and statistically significant

    -- excluding the first two years of follow-up: neither confirmed nor confirmed plus probable autoimmune disease were even close to being significantly different from placebo

 

-- overall results, with reference arm being vitamin D placebo and omega-3 fatty acid placebo, with 88 participants having confirmed autoimmune disease:

    -- combination of vitamin D and omega-3 fatty acid (63 participants): 31% reduction, HR 0.69 (0.49-0.96)

    -- only vitamin D (60 participants): 32% reduction, HR 0.68 (0.48-0.94)

    -- only omega-3 fatty acids (67 participants): nonsignificant 26% reduction, HR 0.74 (0.54-1.03)

 

-- further subgroup analysis found that those on both vitamin D and omega-3 had decrease in definite rheumatoid arthritis, HR 0.23 (0.07-0.81), p=0.02

-- for those with a family history of autoimmune disease, omega-3 did have a significant 34% decreased risk, HR 0.66 (0.43-0.99)

 

Commentary:

-- autoimmune disease is quite common: third leading cause of morbidity in the industrialized world and a leading cause of mortality among women

-- without effective treatments, morbidity can be significantly functionally impairing in people with these chronic conditions, with major personal, family, community, and societal effects, as well as economic burdens

-- vitamin D has multiple effects on the immune system, as enumerated in prior blogs (see http://gmodestmedblogs.blogspot.com/2020/05/covid-vitamin-d-deficiency-may-lead-to.html and http://gmodestmedblogs.blogspot.com/2022/02/covid-high-vit-d-prior-to-covid.html ), including the inhibition of inflammatory cytokines and autoantibody production

-- animal models do suggest that vitamin D inhibits the development or progression of autoimmune disease, though human observational studies have had conflicting results

-- randomized controlled trials of people with rheumatoid arthritis, lupus, and psoriasis have found some improvement by omega-3 fatty acids (for example a Danish study found that each increase in intake of 30 g/d of fat fish was associated with an almost significant 49% reduction in the risk of rheumatoid arthritis, p=0.06, though there was no effect from dietary intake of vitamin D (see https://pubmed.ncbi.nlm.nih.gov/15996059/ ). Animal studies have found that omega-3 fatty acids also inhibit the production of inflammatory cytokines

-- the VITAL study was designed to assess the benefits of vitamin D and omega-3 fatty acids in the prevention of cancer and cardiovascular disease, though aggregate incident autoimmune disease was a prespecified endpoint

    --​ the overall VITAL study did not find benefit for reducing invasive cancer, though was very close to significant for total cancer mortality with HR 0.83 (0.67-1.02), reaching significance after excluding the first 2 years with HR 0.75 (0.59-0.96), and more so in those with BMI <25. No benefit for cardiovascular endpoints or cancer incidence (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089819/pdf/nihms-1546285.pdf )

 

-- The VITAL autoimmune study found a pretty clear benefit of vitamin D supplementation for the aggregate endpoint of autoimmune diseases, with the curves splaying after about three years of vitamin D supplementation. This was not true for the omega-3 fatty acids. There were too few cases of autoimmune diseases to have reliable assessments of most of the individual autoimmune diseases, though the combination of vitamin D and omega-3 fatty acids did seem to decrease both definite and probable rheumatoid arthritis incident cases

    --but, overall, there was not so clear benefit for omega-3 fatty acids alone or in combination with vitamin D above those for just the vitamin D

-- this trial did not gear vitamin D therapy to baseline 25(OH)D levels, and on average those levels were really quite good (30 ng/mL). There were only 24 people, however, in the 25(OH)D <20ng/mL group (12 on vitamin D and 12 on placebo), so too few to have meaningful analysis. 

    -- But, that being said, and given that vitamin D is cheap and has minimal adverse effects, the positive findings in this study would support simply giving 2000IU vitamin D supplements to all women >55yo and men >50yo

 

Limitations:

-- the three months run-in period on placebo does preselect for people who are more adherence to the intervention (and they were), which may undercut the generalizability to the population as a whole

-- though, as per last blog on vitamin D and covid outcomes, we do not really know what the sufficient 25(OH)D is for appropriate immunologic function. this group at baseline in VITAL had an impressive 25(OH)D level, at 29.8 ng/mL, and the geographical distribution of these study participants included a reasonably large sample from the middle to northern United States. This 25(OH)D level is much higher than I would have expected (at least what i have found in my experience), which makes me wonder about potential biases in the population involved in the study. There certainly could be a bias in the healthful behaviors in those who decided to participate in a long-term study such as this one (and on average this group did lots of exercise), which would limit generalizability of the results. That being said, it was impressive that vitamin D supplementation beyond that baseline did seem to do decrease incident confirmed autoimmune diseases, especially two years or so after enrollment, suggesting that the increase of the average vitamin D level to 41.8 ng/mL did seem to confer benefit

-- it would have been useful to have a wider array of baseline 25(OH)D levels in this large study, since it might well turn out that there is a threshold of 25(OH)D levels below which supplementation decreases autoimmune disease incidence most significantly.

-- this large study was still pretty short-term to provide more definitive evidence. there were relatively few people who developed autoimmune disease, limiting the full evaluation of these supplements. Hopefully follow up will continue...

 

so, an interesting study finding that even those with "sufficient" 25(OH)D levels on average (30ng/mL) did show significant benefit from vitamin D 2000IU supplement in decreasing incident autoimmune diseases. This would suggest that there may be some advantage to everyone just taking 2000 IU (50mcg) of vitamin D a day pretty much independent of their baseline 25(OH)D levels.

 

CORRECTION: thanks to Anna Wald for picking this up: i was misled by the article itself on vitamin D and decreased covid intensity (see http://gmodestmedblogs.blogspot.com/2022/02/covid-high-vit-d-prior-to-covid.html ): their suggestion of a 14-fold increase with low vitamin D levels is actually not accurate. they used Odds Ratios instead of Relative Risks, the latter being correlated with the actual increased risk. rough calculation is that it is about 5-fold risk. still really high. still highly statistically significant. but wanted to inform all....

geoff

 

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