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  • Covid 19
    • Vitamin D could be a piece of COVID-19's 'complex puzzle,' Israeli scientists say, after a new study finds a link between deficiency and severe illness
    • Vitamin D deficiency tied to increased COVID-19 risk, unique UF data study finds
    • Dr. Zorba Paster: Vitamin D deficiency connected to COVID-19 cases
    • Study suggests high vitamin D levels may protect against COVID-19, especially for Black people
    • 1 in 4 COVID patients hospitalized while vitamin D deficient die – Israeli study
    • Vitamin D and COVID-19 Research
    • Minister urged to recommend vitamin D supplements in Covid-19 strategy
    • Other countries are treating COVID patients with probiotics and vitamin D — why aren’t we?
    • MP David Davis calls for Vitamin D therapy to be rolled out 'immediately' after study finds it can 'reduce Covid deaths by up to 60%'
    • Patients Hospitalized With COVID-19 Have Low Levels of 25-Hydroxyvitamin D
    • Vitamin D, other everyday vitamins could counter coronavirus effects:.
    • Experts send Vitamin D and Covid-19 open letter to world's governments
    • A Functional Medicine Approach To Protect Against the Flu
    • Over 80% of Hospitalized COVID-19 Patients Have Vitamin D Deficiency, Study Finds
    • Vitamin D helps the body fight coronavirus, major Israeli study claims
    • Vitamin D deficiency increased risk of COVID in healthcare workers, new study shows
    • People With Low Vitamin D More Likely to Have COVID, Study Finds
    • Vitamin D for COVID-19: a case to answer?
    • Vitamin D helps the body fight coronavirus, major Israeli study claims
    • Researchers investigating possible link between vitamin D deficiency and COVID-19
    • UK public health bodies reviewing vitamin D's effects on coronavirus
    • Parents can help children deal with coronavirus-related anxiety
    • Does Vitamin D Protect Against More Severe Complications of Coronavirus?
    • Should people take vitamin D to ward off the new coronavirus?
    • Can taking Vitamin D save your life?
    • People with low vitamin D levels more likely to die from coronavirus, study finds
    • COVID-19: Vitamin D Linked to COVID-19 Deaths
    • Vitamin D Defense – Protection against COVID-19
    • GET YOUR VITAMINS Scientists investigate link between coronavirus survival rates and Vitamin D
    • FOODVitamin D and Coronavirus
    • Low Vitamin D Levels Linked To Acute Respiratory Distress Syndrome
    • 'Take Vitamin-D' says government as evidence emerges it could help fight coronavirus symptoms
    • Low Vitamin D linked to poor lung function
    • Study finds Vitamin D can build coronavirus resistance
    • Vitamin D may help reduce the risk of the coronavirus, study says
    • Can Vitamin D Lower Your Risk of COVID-19?
    • A lesson from the 1918 influenza pandemic!
    • Vitamin D: Deficiency May Increase Coronavirus Infection Risk
    • Research finds vitamin D is important for respiratory health
  • Breast Cancer
    • Breast cancer: Vitamin D could lower risk by 21% in Black and Hispanic women
    • Vitamin D and Breast Cancer Survival: What You Should Know
    • High intake of vitamin D, calcium and phosphorus may reduce breast cancer risk
    • Obesity and Vitamin D Deficiency May Indicate Greater Risk for Breast Cancer
    • Women with high levels of vitamin D ‘are almost a third more likely to survive breast cancer’
    • Fact Check: Breast Cancer and Nutritional Supplements
    • Vitamin D Deficiency May Promote Spread of Some Breast Cancers
    • Vitamin D may double chances of surviving breast cancer
    • OMEGA-3s Inhibit Breast Cancer Tumour Growth, U of G Study Finds
    • Probiotics and Cancer
  • News & Information
    • Headline news, the latest stories >
      • 9 things that could happen if you're not getting enough vitamin D
      • Vitamin D: Recent research uncovers new benefits
      • Start the Week Off Right: Get more Vitamin D in your diet
      • Vitamin D deficiency – who is at risk?
      • Men who have good levels of vitamin D in their bachelor years will have healthy and strong kids, study finds
      • Father's pre-conception vitamin D intake linked to child height and weight at 5 years old
      • Nearly 1 billion people lacking vitamin D
      • Vitamin D supplements could improve fertility
      • Vitamin D and probiotics, perfect friends
      • Inflammatory bowel disease: Vitamin D could ease symptoms of Crohn’s, colitis and IBS
      • All Scots advised to take vitamin D says new health guidance
      • Probiotic may boost vitamin D levels
      • Vitamin D can help you be strong and healthy
    • Cancer >
      • Study finds association between vitamin D, BMI and advanced cancer
      • Study Finds Vitamin D Supplements Reduce Risk of Developing Advanced Cancer
      • Effect of serum 25-hydroxyvitamin D level on lung, breast, colorectal and prostate cancers: a nested case-control study
      • Vitamin D cuts colitis risk in cancer patients on immunotherapy by 65%
      • High Dose Vitamin D Beneficial For Colon Cancer
      • Prompting leukemia cells to die
      • Everything You Need to Know About Vitamin D and Cancer Prevention
      • Obesity and Vitamin D Deficiency May Indicate Greater Risk for Breast Cancer
      • Higher Vitamin D Levels Associated With Lower Risks Of Liver Cancer And Death From Chronic Liver Disease
      • More the Vitamin D, lesser the breast cancer risk
      • Scientists detect new ovarian cancer target
      • Higher vitamin D levels cut colorectal cancer risk
      • Vitamin D linked to lower risk of cancer- study
      • More vitamin D may be associated with lower cancer risk
      • New study suggests link between low vitamin D status and increased risk of ovarian cancer
      • Vitamin D relieves joint, muscle pain for breast cancer patients
      • Low Vitamin D Linked to Bladder Cancer
      • Low vitamin D levels increase risk for bladder cancer
      • Can Vitamin D prevent colon cancer?
      • Vitamin D fights pancreatic cancer
      • Vitamin D levels can affect aggressiveness of melanomas
      • Pancreatic Cancer Survical
      • TNBC
      • Vitamin D Melanoma
    • Childrens Health >
      • High-Dose Vitamin D Well Tolerated in Pediatric Patients
      • Why it’s so hard to identify seasonal depression in kids, and how to help
      • Vitamin D During Pregnancy May Benefit Children’s Bones
      • Vitamin D Deficiency linked to Anxiety and depression in Teens
      • Vitamin D During Pregnancy May Improve Dental Health of Babies
      • Newborns with Vitamin D Deficiency Have Higher Risk of Later Schizophrenia
      • Vitamin D-rich Diet May Decrease Cholesterol in Kids
      • Vitamin D Supplements To Curb Rise In Rickets
      • High vitamin D levels linked to lower cholesterol in children
      • Study Links Low Vitamin D Levels with Fracture Susceptibility and Severity
      • Vitamin D deficiency associated with pediatric obesity
      • Can Vitamin D Deficiency in Children Affect the Severity of Illnesses?
      • Can Vitamin D Reduce Risk of Pre-eclampsia in Pregnancy?
      • Warning to pregnant women on vitamin D: Shortages leads to children with poor motor skills
      • Development fears for children of expectant mothers with low vitamin D levels
      • Vitamin D deficiency during pregnancy tied to autism risk
      • Another reason for obese children to go outside: Overweight youngsters with a vitamin D deficiency at risk of heart disease as they grow older
      • Taking Vitamin D During Pregnancy Shows Promise in Preventing Autism
      • Vitamin D deficiency found in children with digestive disorder, UMass study finds
      • Vitamin D deficiency in children exponentially increased in recent years, study finds
      • Maternal Preferences for Vitamin D Supplementation in Breastfed Infants
      • Prenatal Vitamin D Could Lower Baby's ADHD Risk, While Some Diabetes Drugs May do the Opposite
      • Neonatal Vitamin D Levels Appear to Affect MS Risk Later in Life
      • Vitamin D May Improve Symptoms in Children with Autism
      • October is Children’s Health Month
      • Vitamin D Intake During Pregnancy May Protect Against ADHD in Children
      • Regular vitamins likely unnecessary for children with healthy diets, doctor says
      • VITAMIN D DEFICIENCY LEADS TO STRESS FRACTURES IN 15-YEAR-OLD
      • Breastfeeding Moms Aren't Getting Enough of This Essential Vitamin
      • Why children’s allergies are on the rise and how dirt may hold key to reducing cases
      • Babies born to mothers with lack of Vitamin D 'more likely to have learning difficulties'
      • Vitamin D reduces Wheezing
      • Vitamin deficiencies may be linked to migraines in children
      • Vitamin D and MS
      • Less body fat for toddlers taking vitamin D
    • Sports & Endurance >
      • How Optimizing Your Vitamin D Status Promotes Muscle Health & Function
      • Reevaluating Vitamin D as a Sports Supplement
      • The Risks of Being Vitamin D Deficient as an Athlete
      • Vitamin D levels in blood tied to cardiorespiratory fitness
      • What We Know About Vitamin D and Performance
      • Girls with high level of vitamin D have stronger muscles
      • Increased vitamin D intake improves muscle strength and athletic performance
      • Low vitamin D levels associated with higher risk of muscle strain among elite-level football players
      • Are athletes realizing the importance of vitamin D before the general public?
      • Why Vitamin D Is Extra Important for Athletes
      • Optimizing athletic performance through research
      • Nearly 60% Of College Football Athletes Don’t Get Enough D
      • A spotlight on vitamin D
      • High levels of vitamin D may improve muscle strength
      • Low levels of vitamin D may increase risk of fractures in active people
      • Why Vitamin D Is Extra Important for Athletes
      • Low Vitamin D weaker athlete
      • Vitamin D profile in National Football League players.
      • Endurance and D
      • Peak Athletic Performance and Vitamin D
    • General Health >
      • Vitamin D Supplements Linked to Slower Epigenetic Aging
      • Many of us have a vitamin D deficiency and don't know it
      • Vitamin D Helps Modulate Blood Sugar & Promotes Metabolic Health
      • Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial
      • HEALTH AND WELLNESS The 4 vitamins and supplements this immunologist takes every day to strengthen her immune system: ‘Your body will thank you’
      • If You've Hit A Wall Combating Dry Skin, You May Be Lacking This Vitamin
      • Vitamin D supplements lower risk of autoimmune disease, researchers say
      • Vitamin D3, but not D2, linked to improved immunity
      • Vitamin D and fish oil supplements reduce risk of autoimmune conditions
      • Vitamin D deficiency visible for the first time in teeth after cremation
      • Body pain and tiredness? Could be lack of vitamin D
      • This Little-Known Factor Doubles (Or More) Your Vitamin D Needs
      • 5 Vitamin D Benefits You Should Know About
      • Vitamin D Benefits
      • 7 Reasons to make sure you get enough Vitamin D Accoring to the Doctors
      • Very high dosages of vitamin D may delay frailty in old age
      • Vitamin D deficiency: Could a lack of the sunshine vitamin be causing your cold?
      • Hidden hunger: the crucial health role of Omega 3 and Vitamin D
      • Vitamin D: the superstar of prevention
      • Is Dry Skin A Sign Of Vitamin D Deficiency? Know How It Can Affect Your Skin
      • Coping with seasonal affective disorder
      • Skin Warning Signs That May Indicate You Have Vitamin D Deficiency
      • Vitamin D increases protection against infection, new model suggests
      • Vitamin D deficiency linked with increased risk of death, particularly from diabetes: study
      • People with diabetes, hypertension are Vitamin D deficit: Study
      • Intake of vitamin D supplementation may slow diabetes progression
      • New study sheds light on the role of vitamin D in muscle cells
      • Why you can't absorb vitamin D through a sunny window
      • Vitamin D Benefits That’ll Make You Take the Nutrient More Seriously
      • 5 tips to improve your cognitive functions
      • 5 Ways Women Can Keep Their Bones Healthy
      • Flu Prevention Tips
      • Vitamin D Deficiency Linked to Disease Severity, Mortality Risk in IPF Patients
      • 6 Health Problems That Are Caused Due To Vitamin D Deficiency
      • Vitamin D deficiency - does your hair look like this? Warning signs of deficiency revealed
      • Winter Increases Risk Of High Blood Pressure
      • 4 smart tricks to overcome chronic fatigue syndrome without popping pills
      • What can a psychiatrist tell us about vitamin D?
      • Vitamin D for Asthma
      • Researchers discover a new gear in life's clock: Vitamin D
      • Can vitamin D prevent the flu?
      • Vitamin D: It’s that time of the year
      • What's the link between cold weather and the common cold?
      • 11 Sneaky Causes of Vitamin D Deficiency
      • Are you smarter in summer? Brain health changes with the seasons
      • What's the link between vitamin D, gum health, and diabetes?
      • Infection Risk Lower in Dialysis Patients with High, Normal Vitamin D
      • Researchers Find Link Between Vitamin D and Asbestosis
      • We Can Thank Poor Evolutionary Design for Vitamin D Deficiencies
      • Vitamin D deficiency ups diabetes risk in women: Study
      • REASONS WHY YOU SHOULD BE TAKING VITAMIN D SERIOUSLY
      • Is vitamin D deficiency to blame for lung disease?
      • Many people lack Vitamin D — even in the Sunshine State
      • Vitamin D deficiency may up diabetes risk
      • Low Vitamin D Linked to Metabolic Syndrome in Postmenopausal Women
      • Vitamin D deficiency: How to reverse a shortfall and stop painful symptoms
      • Vitamin D could provide psoriasis relief
      • Is vitamin D really a cure-all – and how should we get our fix?
      • Study confirms vitamin D protects against colds and flu
      • The Benefits of Vitamin D – Why It’s the Sexiest Vitamin Around
      • Research finds vitamin D is important for respiratory health
      • Is Vitamin D Really Effective For Cold and Flu
      • Vitamin D deficiency: 6 symptoms
      • Vitamin D could help millions of people with irritable bowel syndrome
      • Frailty not ‘inevitable result of ageing’, can be reversed
      • Should ALL pregnant women take vitamin D?
      • Vitamin D supplementation may be more effective than sun exposure at raising vitamin D levels
      • Study confirms vitamin D protects against colds and flu
      • 7 Benefits of Vitamin D You Might Want to Know About
      • Could Fish Oil, Vitamin D Help Ease Lupus?
      • Study confirms vitamin D protects against colds and flu
      • Are YOU vitamin D deficient? 6 signs even your doctor might miss
      • Top Myths of Vitamin D
      • Vitamin D May Lower Asthma Attack Risks
      • Vitamin D supplements may reduce asthma severity
      • The Shocking Truth About Vitamin D Deficiency And Its Repercussions
      • Vitamin D Might Be The Key Ingredient In Vitiligo Treatment
      • Vitamin D insufficiency linked to lower virologic response in HBV
      • BACK TO SCHOOL COLD PREVENTION
      • Too little vitamin D may hinder recovery of injured corneas
      • Gut reaction to a healthy life
      • Low Vitamin D Levels Increases the Risk for Chronic Headaches
      • Vitamin D Levels Predict Multiple Sclerosis Progression
      • Study Links Certain Jobs to Vitamin D Deficiency
      • Can Vitamin D Improve Sunburn?
      • Vitamin D guidelines need to be updated – here’s why
      • Daily fruit smoothie helps couples trying to start a family
      • Vitamin D deficiency could cause deadly diseases, warn UAE doctors
      • Vitamin D Deficiency May Cause Early Menopause
      • Lactose intolerance linked to lower vitamin D levels
      • Vitamin D Helps Friendly Bacteria Repopulate The Gut, Making It The Perfect Campanion To Probiotic Supplements
      • Sunscreen ‘is making us vitamin D deficient’, controversial study claims
      • Widespread Vitamin D Deficiency Likely Due to Sunscreen Use, Increase of Chronic Diseases
      • Doctor’s Tip: The low-down on vitamin D
      • Pet vet: Understanding the importance of vitamin D for pets
      • Vitamin D could provide psoriasis relief
      • Can A Vitamin Deficiency Cause Depression?
      • Increased Fracture Risk: Seniors Not Taking Vitamin D Supplements
      • 11 surprising things you might not know about vitamin D
      • What is rickets, what causes the condition, is there a cure and how can I prevent Vitamin D deficiency?
      • Sunshine vitamin linked to fewer heart events: Meta­-analysis
      • Study finds link between vitamin D levels and severity of malabsorption issues
      • ‘Proof’ that Vitamin D can fight flu
      • Sunshine Is The Natural Treatment For Preventing Pre-diabetes, Type 2 Diabetes and More In Children and Adults
      • Vitamin D is not just beneficial, it’s a necessity
      • Vitamin D pills 'could stop colds or flu'
      • Vitamin D Supplementation: Protection from Respiratory Infections?
      • Relapse Risk Up With Low Vitamin D Levels in Ulcerative Colitis
      • Supplementation with vitamin D associated with improved testosterone, erectile function among middle-aged men
      • We all need the Vitamin D
      • 7 Signs and Symptoms of Vitamin D Deficiency People Often Ignore
      • 8 Surprising Things You Didn't Know Vitamin D Could Do For You
      • Low vitamin D level predicts CV morbidity, mortality in type 2 diabetes
      • 10 Things That Will Happen If You Lack Vitamin D
      • Vitamin D study outlines impact of supplements in seniors
      • Vitamin D deficiency and the risk of tuberculosis: a meta-analysis
      • Vitamin D improves gut flora and metabolic syndrome
      • Low Levels of Vitamin D May Be Tied to Balance Problems in Fibromyalgia Patients
      • High Levels of Vitamin D Supplements May Help Improve Lung Function in CF Patients, Study Shows
      • Vitamin D Modestly Tied to Sex Hormones in Older Population
      • Sun exposure as kids may prevent nearsightedness in later life
      • Vitamin D reduces respiratory infections, but there's a catch
      • Insufficient Sun Exposure Called Emerging Public Health Problem By World-renowned Researchers
      • Weight loss combined with vitamin D supplements can reduce inflammation linked to cancer and chronic diseases
      • Higher Doses of Vitamin D Can Lower Incidence of Respiratory Infection
      • Poor fertility linked to low vitamin D levels
      • Men and the Power of Vitamin D
      • Vitamin D and Immune Function
      • High quality evidence suggests vitamin D can reduce asthma attacks
      • The association between vitamin D and COPD risk, severity, and exacerbation: an updated systematic review and meta-analysis
      • How to boost your energy levels
      • Low Vitamin D Increases Mortality Risk
      • Air pollution and vitamin D deficiency linked to dementia.
      • The Vitamin D Deficiency Epidemic … 40% World’s Population Low on D
      • Low Vitamin D Linked with All-Cause Death
      • Your Family Doesn't Have To Get Sick This Fall
      • Vitamin D is essential for the elderly living without sunshine in their lives
      • Taking THIS vitamin could protect you against cancer, diabetes and Alzheimer’s
      • Vitamin D tablets may help reduce asthma attacks, review finds
      • Vitamin D Proven More Effective Than Both Anti-Viral Drugs and Vaccines at Preventing the Flu
      • Bring me sunshine: How I beat eczema
      • Insulin Resistance and Vitamin D
      • Diverticulitis risk lower with higher vitamin D
      • Vitamin D deficincy linked to problems in pregnancy.
      • High Doses of Vitamin D Unlikely to Help MS Patients, But Daily Low Dose Good for All,
      • Natural Vitamin D Supplement Effective for Nondialysis CKD-MBD
      • 8 Signs and Symptoms of Vitamin D Deficiency
      • Vitamin D deficiency could increase risk of diabetes related coronary heart disease
      • Low D may increase nonalcoholic fatty liver disease
      • Vitamin D for prostate health
      • Pregnant women with good intake of vitamin D lower risk
      • Fight infection like an Olympic athlete
      • Lack of vitamin D lowering fertility in Gulf, doctors say
      • Rayaldee Approved for Secondary Hyperparathyroidism Vitamin d Deficiency
      • Increase vitamin D levels to cut kidney problems
      • Sunbathers live longer
      • Crohn’s disease causes vitamin D deficiency
      • Taking vitamin D avoid new-onset diabetes risk
      • Vitamin D Deficiency Linked to Diabetic Retinopathy
      • UK sun not enough
      • morbidity and D
      • Macular and D
      • Are You Getting Enough Vitamin D
    • Heart Health >
      • STUDY NAILS DOWN A LINK BETWEEN VITAMIN D AND HEART HEALTH
      • Vitamin D-3 could 'reverse' ​damage to heart
      • Vitamin D and the Heart
      • Vitamin D Can Mend a Broken Heart
      • D deficiency linked to high blood pressure
      • Stress of open-heart surgery significantly reduces vitamin D levels, but supplementation helps
      • Vitamin D reduces early mortality: study
      • Vitamin D-3 could 'reverse' damage to heart
      • High Vitamin D Dose May Rapidly Cut Arterial Stiffness
      • Heart failure 12 times more likely in people with vitamin D deficiency
      • Exercise and vitamin D better together for heart health
      • Sunshine vitamin linked to fewer heart events: Meta­-analysis
      • Vitamin D levels could predict risk of poor cardiovascular health
    • Neurological health >
      • New Research Shows Vitamin D Deficiency Leads to Dementia
      • Vitamin D supplementation may reduce ADHD symptoms, finds study
      • low d linked to fall, sleep problems and depression
      • Potential link between vitamin d deficiency and loss of brain plasticity
      • SUNBATHE AND QUIT SMOKING TO REDUCE MS RISK IN SPAIN’S MALAGA SAY LEADING DOCTORS
      • At risk of getting, or have, multiple sclerosis? Load up on vitamin D: MS Society
      • 4 things you can do to prevent stroke
      • Vitamin D: The Only Dietary Supplement Showing Significant Benefit for MS
      • Vitamin D Supplementation May Help Ease Depression
      • Easing your winter blues this season
      • Reducing Vitamin D Levels in Women May Up the Risk of Multiple Sclerosis
      • UNBC study shows vitamin D boosts brain function
      • Vitamin D Eases Depression, Fatigue in Spinal Cord Patients
      • Sharon Ní Chonchúir on having a baby despite her MS
      • Dutch study confirms link between certain psychiatric disorders and vitamin D deficiency
      • Vitamin D Deficiency and Depression
      • Vitamin D During Pregnancy Reduces ADHD Risk
      • Low Levels of Vitamin D in Patients With Bipolar Disorder
      • Vitamin D Supplements Improve Cognition in Patients With MS
      • Can vitamin D prevent Alzheimers?
      • The signs you might have seasonal affective disorder
      • A deficiency of THIS essential vitamin could lead to MEMORY loss
      • Vitamin D levels predict risk of brain decline in Chinese elderly
      • Vitamin D and MS
      • Alzheimer's Q&A
    • Pain >
      • Vitamin D Reduces Need for Opioid Pain Relief in Cancer Patients
      • The association of calcium and vitamin D use with implant survival of total knee arthroplasty: A nationwide population-based cohort study
      • Vitamin D for Back Pain and Disc Degeneration in Postmenopausal Women
      • Vitamin D may expedite wound healing in burn patients
      • Vitamin deficiency can cause pain
      • What is the link between psoriatic arthritis and depression?
      • Neuropathic Pain in Rheumatoid Arthritis Linked to Vitamin D Deficiency
      • Vitamin D supplements could help pain management
      • Recent clinical trial discovers vitamin D supplementation reduces chronic low back pain
      • Chronic Headache Linked to Vitamin D Deficiency
      • With Vitamin D Deficiency More Prevalent Than Previously Thought, Pain & Stress Center Presents Solution
      • How vitamin D inhibits inflammation
      • Easy ways to relieve crippling knee pain
      • Vitamin D Supplementation and the Progression of Knee Osteoarthritis
      • Migraines Linked to Low Levels of Vitamin D
    • ​Weight Managment >
      • Research links lower vitamin D levels to excess body fat
      • Vitamin D is important for decreasing belly fat
      • Study finds association between vitamin D, BMI and advanced cancer
      • Weight loss combined with vitamin D supplements can reduce inflammation linked to cancer and chronic diseases
      • Vitamin D deficiency can cause weight gain
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  • Newborns with Vitamin D Deficiency Have Higher Risk of Later Schizophrenia
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  • Exercising and Taking Vitamin D and Omega-3 Supplements May Reduce Your Cancer Risk By 61%, Study Says

Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial

AbstractObjective To investigate whether vitamin D and marine derived long chain omega 3 fatty acids reduce autoimmune disease risk.

Design
 Vitamin D and omega 3 trial (VITAL), a nationwide, randomized, double blind, placebo controlled trial with a two-by-two factorial design.

Setting
 Nationwide in the United States.

Participants
 25 871 participants, consisting of 12 786 men ≥50 years and 13 085 women ≥55 years at enrollment.

Interventions
 Vitamin D (2000 IU/day) or matched placebo, and omega 3 fatty acids (1000 mg/day) or matched placebo. Participants self-reported all incident autoimmune diseases from baseline to a median of 5.3 years of follow-up; these diseases were confirmed by extensive medical record review. Cox proportional hazard models were used to test the effects of vitamin D and omega 3 fatty acids on autoimmune disease incidence.

Main outcome measures
 

The primary endpoint was all incident autoimmune diseases confirmed by medical record review: rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, psoriasis, and all others.

Results 

25 871 participants were enrolled and followed for a median of 5.3 years. 18 046 self-identified as non-Hispanic white, 5106 as black, and 2152 as other racial and ethnic groups. The mean age was 67.1 years. For the vitamin D arm, 123 participants in the treatment group and 155 in the placebo group had a confirmed autoimmune disease (hazard ratio 0.78, 95% confidence interval 0.61 to 0.99, P=0.05). In the omega 3 fatty acids arm, 130 participants in the treatment group and 148 in the placebo group had a confirmed autoimmune disease (0.85, 0.67 to 1.08, P=0.19). Compared with the reference arm (vitamin D placebo and omega 3 fatty acid placebo; 88 with confirmed autoimmune disease), 63 participants who received vitamin D and omega 3 fatty acids (0.69, 0.49 to 0.96), 60 who received only vitamin D (0.68, 0.48 to 0.94), and 67 who received only omega 3 fatty acids (0.74, 0.54 to 1.03) had confirmed autoimmune disease.

Conclusions
 

Vitamin D supplementation for five years, with or without omega 3 fatty acids, reduced autoimmune disease by 22%, while omega 3 fatty acid supplementation with or without vitamin D reduced the autoimmune disease rate by 15% (not statistically significant). Both treatment arms showed larger effects than the reference arm (vitamin D placebo and omega 3 fatty acid placebo).

Study registration 

ClinicalTrials.gov NCT01351805 and NCT01169259
IntroductionAutoimmune diseases, characterized by an inflammatory autoimmune response to self-tissues, are the third leading cause of morbidity in the industrialized world and a leading cause of mortality among women.12 Autoimmune diseases are chronic conditions with increasing prevalence with age and major societal and economic burdens due to a lack of effective treatments.34

Vitamin D and marine derived, long chain omega 3 fatty acids are two nutritional supplements investigated as potential autoimmune disease treatments. In vitro, the lipid soluble active form of vitamin D (1,25-hydroxyvitamin D) regulates genes involved in inflammation and acquired and innate immune responses.5 Animal models of autoimmune disease have reported vitamin D to be beneficial because it inhibits the development or progression of disease,5678 but observational studies have found conflicting results9101112; small trials of vitamin D supplementation in people with established autoimmune disease have mainly reported disappointing results.1314 Whether vitamin D supplementation can prevent autoimmune disease onset is still unknown and has not been tested in clinical trials. Randomized controlled trials of people with prevalent rheumatoid arthritis, systemic lupus erythematosus,15 and psoriasis16 have also shown improvements in outcomes with omega 3 fatty acids, but few studies have examined omega 3 fatty acids in autoimmune disease prevention. A Danish observational study found a 49% reduction in rheumatoid arthritis risk for each 30 g increase in daily fatty fish intake (≥8 g fat/100 g fish).17 However, randomized controlled trials examining omega 3 fatty acid intake and autoimmune disease risk are lacking.
We report the effects of vitamin D and omega 3 fatty acid supplementation on autoimmune disease incidence (including rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, and psoriasis) within the large scale vitamin D and omega 3 trial (VITAL) over approximately five years of randomized follow-up. We assessed whether the effects differed by age, sex, race, body mass index, and by baseline concentrations of vitamin D, or by eicosapentaenoic acid plus docosahexaenoic acid or dietary fish intake.

MethodsTrial design and oversightThis randomized, double blind, placebo controlled, two-by-two factorial design trial was conducted to examine the benefits and risks of vitamin D (cholecalciferol; 2000 IU/day) and marine omega 3 fatty acids (1 g/day as a fish oil capsule containing 460 mg of eicosapentaenoic acid and 380 mg of docosahexaenoic acid) in the prevention of cancer and cardiovascular disease among 25 871 participants (men aged ≥50 years; women aged ≥55 years; NCT 01169259). Aggregate incident autoimmune disease was a prespecified endpoint of a funded ancillary study started before trial recruitment (NCT01351805). Trial protocol, oversight, and CONSORT diagram (consolidated standards of reporting trials; supplementary fig 1), as adhered to in this study, have been previously published.18 This trial did not intend to examine vitamin D supplementation in a population that was vitamin D deficient, but in participants representative of vitamin D levels in other large trials and in the general older adult population in the United States.
Eligible participants, recruited throughout the US, were required to limit vitamin D use from outside sources to no more than 800 IU/day, and to forego the use of fish oil supplements. At trial entry, those with a history of renal failure or dialysis, cirrhosis, hypercalcemia, cancer (except non-melanoma skin cancer), cardiovascular disease, or other serious illness were ineligible. A total of 25 871 people consented to enrollment; 5106 were black and 2152 were other racial and ethnic groups (non-white). These participants successfully completed a three month placebo run-in period and were randomized to treatment (vitamin D, n=12 927; omega 3 fatty acids, n=12 933) or placebo arms (vitamin D placebo, n=12 944; omega 3 fatty acid placebo, n=12 938) within sex, race, and five year age groups in blocks of eight. Randomization occurred between November 2011 and March 2014, and the intervention was completed as prespecified after five years of randomized assignment in December 2017.19

Baseline questionnaires collected data on clinical and lifestyle risk factors, and queried vitamin D supplement use and fish and dairy intake (supplement 1). Blood samples, obtained at baseline from all willing participants (n=16 956), were assayed for 25-hydroxyvitamin D and plasma omega 3 index (eicosapentaenoic acid plus docosahexaenoic acid as percentage of total fatty acids; Quest Diagnostics, liquid chromatography tandem mass spectrometry). Questionnaires were completed six months and one year after randomization, and then annually. These questionnaires asked about trial supplement adherence, new doctor diagnosed diseases, potential side effects of trial agents, and new cancer or cardiovascular disease risk factors. Calendar packs containing trial capsules (similar in appearance) were mailed to participants with the questionnaires. The vitamin D pill and its matching placebo, which contained soybean oil, were prepared by Pharmavite LLC (Northridge, California, USA). The omega 3 fatty acid pill and its matching placebo, which contained olive oil, were prepared by Pronova BioPharma (Norway).

The questionnaire response rate averaged 93.1%, and follow-up about mortality was greater than 98%.20 Adherence to the trial regimen (percentage of participants who took at least two thirds of trial capsules) averaged 81%. Blood samples from a subgroup at one year found mean 25-hydroxyvitamin D levels (n=1644) increased by 40% (from 29.8 ng/ml at baseline to 41.8 ng/ml at one year) in the vitamin D group and changed minimally in the placebo group; the mean omega 3 index (n=1583) increased 54.7% (to 4.1% at one year in the omega 3 group) and changed by less than 2% in the placebo group. The trial was approved by the institutional review board of Partners’ HealthCare and was monitored by an external data and safety monitoring board.
Autoimmune disease endpointsThe primary endpoint was total confirmed autoimmune disease incidence. Annual questionnaires inquired about new onset doctor diagnosed rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, psoriasis, and inflammatory bowel disease, with space to write in all other new onset autoimmune diseases. Participants who reported a new incident autoimmune disease were asked to sign a release for medical records. Two trained physicians (including a board certified rheumatologist, endocrinologist, and gastroenterologist), blinded to treatment assignment, reviewed each record and confirmed or disconfirmed the autoimmune disease according to classification criteria when available. For autoimmune thyroid disease in particular, insufficient medical record documentation, often consisting of a doctor’s diagnosis of Hashimoto’s thyroiditis or Graves’ disease and abnormal thyroid function tests without confirmatory studies, led to an inability to classify these participants as having confirmed disease according to our rigorous criteria. We classified participants with evidence of incident autoimmune disease, but insufficient documentation for certainty, as having probable autoimmune disease; these participants were added to those with confirmed autoimmune disease for secondary endpoints.
Date of first symptoms attributed to the autoimmune disease and date of doctor’s diagnosis were recorded from the medical records. New onset autoimmune disease was not confirmed if the disease was diagnosed or onset of its first symptoms occurred before randomization. Deaths were confirmed by review of medical records and death certificates, as previously reported.18

Statistical analysesAnalyses were based on the intention-to-treat principle. In a priori power calculations based on the log rank test, we calculated that the trial sample size would have at least 80% power to detect a 30% rate reduction using the projected incidence of validated composite autoimmune disease over five years. We conducted t tests or χ2 tests to compare baseline characteristics of participants randomized to supplementation or placebo. For our primary analyses, we compared the separate main effects of vitamin D or omega 3 fatty acid supplement assignment on autoimmune disease incidence by using Cox regression models. To account for randomization stratification and study design,21 we additionally adjusted for age, sex, self-reported race, and randomization to the other supplement. Person time was counted until diagnosis of a new confirmed autoimmune disease, death, or the end of the trial. Because autoimmune diseases develop slowly over time,22 we examined our a priori interest in whether effects varied over time by using cumulative incidence plots; we also ran models including linear and quadratic interactions with time and conducted analyses of the primary outcomes excluding events that occurred during the first two years. Additionally, we assessed hazard ratio by year of study (supplementary table 1).

To assess for synergistic effects of supplementation with omega 3 fatty acids and vitamin D, specified a priori, we examined four group cumulative incidence curves, added an interaction term for treatment with vitamin D and omega 3 fatty acids to models, and repeated Cox models with the vitamin D placebo/omega 3 fatty acid placebo group as the reference arm compared with the three intervention arms.

We assessed the effects of treatment on individual disease endpoints (rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, and psoriasis) and grouped all other autoimmune diseases as an additional endpoint of other autoimmune diseases (supplementary table 2). Because people with an existing autoimmune disease are at high genetic risk of developing a new autoimmune disease, for each autoimmune disease endpoint we included validated reports of diagnoses of another autoimmune disease (eg, those with autoimmune thyroid disease at baseline were followed for other incident autoimmune disease). We ran models including interaction terms between treatment and the variable of interest to test whether the effect of treatment on incident autoimmune disease varied by age, sex, race, randomization to the other arm of the trial, baseline body mass index, family history of autoimmune disease, baseline blood levels of 25-hydroxyvitamin D or vitamin D intake (for the vitamin D arm), or baseline blood levels of eicosapentaenoic acid plus docosahexaenoic acid (omega 3 fatty acid arm). In addition to prespecified dichotomized subgroup analyses, for the continuous variables, such as age and body mass index, we ran models including linear and quadratic interaction terms between treatment and the variable of interest. To test the sensitivity of results to our strict definition of autoimmune disease, we ran models with all probable and definite autoimmune disease as an endpoint. In other preplanned sensitivity analyses, we ran models in which we excluded all participants who reported any autoimmune disease at baseline. Data analyses were performed using SAS 9.2 (SAS Institute, Cary, North Carolina, USA).

Patient and public involvementThis was a randomized controlled trial inspired by physicians’ awareness of limited choices for treating patients with autoimmune disease, and desire by patients for effective treatments. Patients and the public were not further involved in the design or conduct of this double blind trial.

ResultsBaseline characteristics of the 25 871 participants were balanced between treatment and placebo groups (table 1; details of the cohort given by Manson and colleagues20). Fifty one per cent were women; mean age was 67.1 years. The racially diverse cohort consisted of 71% who self-identified as non-Hispanic white, 20% black, and 9% other racial or ethnic groups. A total of 4555 participants (18%) reported at least one autoimmune disease before randomization. Numbers of deaths and participants who reported side effects were low, as previously reported.19

Table 1 Characteristics of VITAL trial participants at baseline according to randomized assignment to active supplementation (vitamin D or omega 3 fatty acids) or placebo. Data are numbers (%) unless indicated otherwise



Preplanned analyses excluding the first two years of follow-up (n=25 499) to test the latency of treatment effects revealed a significantly lower incidence of confirmed autoimmune disease in the vitamin D group compared with the placebo group (0.61, 0.43 to 0.86, P=0.005; table 2); this was not observed in the omega 3 group (table 3). When hazard ratios were calculated for each year of the trial (supplementary table 1), although the numbers of participants with confirmed autoimmune disease in a given year were small, hazard ratios for vitamin D treatment were consistently lower in the last three years than in the first two years of the trial. However, when modeled as a linear association over the five years of the study, there was no clear statistical evidence that treatment effects varied by time for vitamin D (P for interaction=0.14) or omega 3 fatty acids (P for interaction=0.57). The nonlinear effects of time were similarly non-significant (P for interaction=0.34 for vitamin D, 0.59 for omega 3 fatty acids).
Secondary analysesWe investigated the effects across the four subgroups of this trial’s two-by-two factorial design. The cumulative incidence of confirmed autoimmune disease over the five years of the trial (fig 1) was lower in all three of the groups receiving supplementation (vitamin D and omega 3 fatty acid; vitamin D and omega 3 fatty acid placebo; vitamin D placebo and omega 3 fatty acid) than in the group receiving vitamin D placebo and omega 3 fatty acid placebo (log rank P=0.08). In a Cox model adjusted for age, sex, and race, with a separate term for each group (vitamin D placebo and omega 3 fatty acid placebo as the reference group), the incidence of confirmed autoimmune disease was lower among those randomized to vitamin D with omega 3 fatty acids (hazard ratio 0.69, 95% confidence interval 0.49 to 0.96) or without omega 3 fatty acids (0.68, 0.48 to 0.94) compared with those who received only placebo (table 4). For omega 3 fatty acids alone, the benefit was marginally significant (0.74, 0.54 to 1.03). A test of multiplicative interaction between the two treatments was not statistically significant (P=0.20).

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In preplanned secondary analyses of individual autoimmune diseases, for both vitamin D and omega 3 supplementation, hazard ratios were less than 1 (favoring supplementation) for almost all diseases; however, none of the differences was statistically significant for the individual disorders (table 2, table 3). When participants with probable autoimmune disease were also included, 210 in the vitamin D arm and 247 in the vitamin D placebo arm developed definite or probable autoimmune disease (0.85, 0.70 to 1.02, P=0.09); while 208 in the omega 3 fatty acid arm and 249 in the omega 3 fatty acid placebo arm developed confirmed or probable autoimmune disease (0.82, 0.68 to 0.99, P=0.04). When participants with probable autoimmune disease were included, there was a significant interaction of omega 3 fatty acid treatment with time (P for interaction=0.04), with an apparent increase in effect over time as seen in figure 1. When participants who had reported any other autoimmune disease at baseline were excluded, hazard ratios changed only slightly (table 2, table 3).
Results of prespecified subgroup analyses for confirmed autoimmune disease suggested that people with lower body mass index seem to benefit more from vitamin D treatment (P for interaction=0.02). For example, when we modeled body mass index as a continuous linear term because we found no evidence for nonlinear interactions, for vitamin D treatment versus placebo the hazard ratio was 0.47 (95% confidence interval 0.29 to 0.77) for those with a body mass index of 18, 0.69 (0.52 to 0.90) for those with a body mass index of 25, and 0.90 (0.69 to 1.19) for those with a body mass index of 30. When we stratified by categories of body mass index, for vitamin D treatment versus placebo the hazard ratio was 0.62 (0.42 to 0.93) for body mass index <25, 0.92 (0.61 to 1.38) for body mass index 25-30, and 0.88 (0.54 to 1.44) for body mass index ≥30. The beneficial effect of omega 3 fatty acids on autoimmune disease prevention was greater among those with a family history of autoimmune disease (0.66, 0.43 to 0.99) compared with those with no family history (1.14, 0.82 to 1.58; P for interaction 0.03; supplementary fig 3). All other tested interactions were statistically non-significant (supplementary figs 2 and 3; supplementary table 3).
Discussion
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Principal findings

In this large primary prevention trial in diverse older Americans, supplementation with vitamin D at a dose of 2000 IU/day for approximately five years, alone or in combination with 1 g/day of omega 3 fatty acids (460 mg eicosapentaenoic acid and 380 mg docosahexaenoic acid) led to a lower incidence of confirmed autoimmune disease than placebo. Supplementation with omega 3 fatty acids alone did not significantly lower incidence of autoimmune disease. However, when participants with probable autoimmune disease were included, omega 3 fatty acid supplementation did reduce the rate by 18% compared with placebo and a significant interaction was found with time, pointing to an increased effect after longer duration of supplementation. When only the last three years of the intervention were considered, the vitamin D group had 39% fewer participants with confirmed autoimmune disease than the placebo group (P=0.005); while the omega 3 fatty acid group had 10% fewer participants with confirmed autoimmune disease than the placebo group (P=0.54). In this two-by-two trial, supplementation with both vitamin D and omega 3 fatty acids decreased autoimmune disease by about 30% versus placebo alone. Numbers of participants with individual autoimmune diseases were generally fewer in the treatment groups than in the placebo groups; autoimmune thyroid disease (the most challenging to confirm using medical records) and psoriasis were exceptions to this pattern. These individual differences were not statistically significant, perhaps because of the small numbers of participants with individual diseases. Rheumatoid arthritis incidence was approximately 40% lower in the supplementation groups than in the placebo groups, although <40 participants were reported to have definite disease. Following trial participants for a longer period of time will clarify whether these rate reductions persist.

Potential mechanisms and comparison with other studies

Preclinical studies provide several plausible mechanisms for how these supplements might reduce autoimmune disease incidence. Binding to the vitamin D receptor, the vitamin D metabolite 1,25-dihydroxyvitamin D regulates an array of genes, many involved in inflammation and acquired and innate immune responses.23 Vitamin D receptors are found at high density on dendritic cells, T and B lymphocytes and macrophages, whose functions are dramatically affected by activated 1,25-dihydroxyvitamin D binding.24 1,25-dihydroxyvitamin D inhibits expression of interleukin 2 (IL-2), an important growth factor for T lymphocytes, and suppresses T helper 1 cytokines IL-12, interferon γ, and tumor necrosis factor (TNF), while increasing IL-4, IL-5, and IL-10.23 The addition of 1,25-dihydroxyvitamin D to CD4+ T cells also inhibits inflammatory IL-6, an important factor stimulating T helper 17 cells, which play a role in autoimmune disease development.25 1,25-dihydroxyvitamin D inhibits B cell autoantibody production and promotes monocyte differentiation into macrophages, suppressing inflammatory cytokines and chemokines, and reducing antigen presentation capacity by decreasing major histocompatibility complex II expression.2627 1,25-dihydroxyvitamin D might also increase the production of anti-inflammatory regulatory T cells.28
Animal and in vitro studies indicate that increased dietary intake of eicosapentaenoic acid and docosahexaenoic acid inhibit production of C reactive protein and inflammatory cytokines such as TNFα, IL-1β, and IL-61529; decrease T cell proliferation and activation30; and serve as substrate for specialized pro-resolving lipid mediators, including resolvins, protectins, and maresins, which promote resolution of inflammation.313233 A substudy of 1561 VITAL participants assessing concentration changes in systemic inflammation biomarkers (IL-6, TNF receptor 2, and high sensitivity C reactive protein) from baseline to one year found no evidence of reductions over the first year.34 Results of other human studies of omega 3 fatty acids and inflammatory proteins are mixed.293536
The observation that people with lower body mass index seem to benefit more from vitamin D supplementation has been made before.37 One potential mechanism might be the dilution effects of body fat, in that vitamin D is fat soluble and can be sequestered in fat cells. However, the D2d study38 observed a major interaction of body mass index with treatment, which did not change when treatment was 4000 IU versus 2000 IU. This finding suggests the effect is not purely dilutional. Further study of how body mass index moderates the effect of vitamin D on autoimmune disease is warranted. Our finding in secondary exploratory analyses that those with a family history of autoimmune disease appear to benefit more from omega 3 fatty acid supplementation also warrants further study because this is a higher risk group.

Strengths and limitations of this study

The strengths of this trial include a large, diverse general population sample; high rates of follow-up and adherence to the trial regimen; validated biomarkers of regimen adherence; and rigorously defined autoimmune disease endpoints. The US population is aging and increased autoantibody and autoimmune disease prevalence is reported.39 Because participants were older adults, the results might not generalize to autoimmune diseases that primarily have their onset in younger people. However, the pathogenesis of many of the specific autoimmune diseases observed (eg, rheumatoid arthritis and psoriasis) is similar in younger adults. The trial tested only one dose and formulation of each supplement. The relatively low number of participants with a confirmed diagnosis of most individual diseases, and the challenge of confirming diagnosis of autoimmune thyroid disease based on medical records, limited statistical power to detect an effect on individual disease outcomes and subgroups of a priori interest. Given the latency of autoimmune disease onset, longer follow-up could be informative, and participants are being followed in an open label extension study.

Clinical implications

This study of more than 25 000 older adults in the US provides evidence that daily supplementation with 2000 IU/day vitamin D or a combination of vitamin D and omega 3 fatty acids for five years reduces autoimmune disease incidence, with more pronounced effects found after two years of supplementation. Autoimmune diseases are a group of heterogeneous conditions with similar underlying pathogenetic mechanisms and together are associated with considerable morbidity and mortality. The clinical importance of these findings is high because these are well tolerated, non-toxic supplements, and other effective treatments to reduce the incidence of autoimmune diseases are lacking. Additionally, we saw consistent results across autoimmune diseases and increasing effects with time. We are continuing to follow participants for two years in an extension study to test the time course of this autoimmune disease reduction effect. Further trials could test these interventions in younger populations, and those with high autoimmune disease risk.

https://www.bmj.com/content/376/bmj-2021-066452
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