Fun in the Sun: The Benefits of Vitamin D

WASHINGTON, D.C.—Vitamin D has gotten a lot of press over the years. But is it actually worth the hype, especially when it comes to autoimmunity? Does it prevent the onset of autoimmune disease? Does it have a role in treatment?

Dr. Karen Costenbader

At ACR Convergence 2024, Karen Costenbader, MD, MPH, Michael Weinblatt, MD Distinguished Chair of Rheumatology and director, Lupus Program, Brigham and Women’s Hospital, and professor of medicine, Harvard Medical School, Boston, shared updates in the world of vitamin D and autoimmunity.

Reduction in Autoimmunity

Cross-sectional case-control studies have shown that people with many different rheumatic diseases (and perhaps chronic inflammatory diseases in general) have lower levels of serum 25-hydroxy-vitamin D (25-OH-D). What’s more, some autoimmune diseases (like multiple sclerosis) are more prevalent at northern latitudes, where less ultraviolet light exposure leads to lower 25-OH-D levels.¹

As for the risk of developing rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE), evidence is conflicting. Some studies show a decreased risk with higher baseline 25-OH-D levels, and some show no association. A systematic review performed by Dr. Costenbader and colleagues confirmed that few small studies had been done, both with positive and negative results.² On the other hand, much hypothesizing had taken place in the literature, which was rife with review articles and editorials.

“There hadn’t been a prospective randomized trial yet that tested the effects of high dose vitamin D supplementation on the incidence of autoimmune disease over time, so we took advantage of the VITamin D and OmegA-3 TriaL (VITAL) trial that was already enrolling patients,” Dr. Costenbader said.³

VITAL was a large trial with over 25,000 participants who were randomized to receive vitamin D3 2,000 IU daily, omega-3 fatty acids 1g daily, both, or placebo. Primary outcomes examined incident cancer and cardiovascular disease diagnoses. The secondary outcome was the incidence of all autoimmune diseases. Dr. Costenbader explained, “We followed these people for five years, and we saw a small but significant reduction in the incidence of all autoimmune disease. We also saw an interaction of vitamin D with body mass index (BMI), with a stronger effect noted in people with low or normal BMIs.” Importantly, there were no significant differences in adverse effects in intervention vs. placebo arms.⁴

Over a follow-up of five years, the hazard ratio for confirmed incident autoimmune diseases was 0.78 (95% CI 0.61-1.00, P=0.045). Of note, the effect of vitamin D was not instantaneous. “It took two to three years for the curves to separate. It’s not the first day you pop the vitamin d into your mouth. It takes awhile for the effects to be seen,” Dr. Costenbader noted.

So how long does the small, protective effect of vitamin D last? Or as our patients often ask, “Do I have to take this for the rest of my life?” Data show that the answer is yes. “After you stop taking it, the effect dissipates pretty quickly unfortunately,” she said.⁵

As with all studies, there are limitations. Dr. Costenbader explained, “Since this was just one big trial, it can’t answer all the questions we have about vitamin D for our diseases. This wasn’t a high-risk or vitamin D deficient population, where the effect may be even greater. We only studied older adults (men 50 years of age or older and women 55 years of age or older), so the effect in younger populations remains to be proven. And, we did have difficulty confirming incident autoimmune thyroid disease in particular since this diagnosis is often made without testing for autoantibodies.”

As for strengths, Dr. Costenbader noted, “This was the first large, nationwide, double-blind randomized controlled trial for the prevention of autoimmune disease in the general population. Vitamin D is a well-tolerated, non-toxic supplement, and nothing else has been shown to reduce the overall incidence of autoimmune disease yet. It was safe without an increase in adverse events, and two-year extension assessed prolonged effects. I think it has high clinical importance.”

Treatment Effects in Rheumatic Disease

Some recent meta-analyses speak to the potential effect of vitamin D supplementation in RA and SLE.^6,7 Varying doses and durations of vitamin D supplementation have been tested. “There were no strong or consistent effects observed, though there may possibly be small benefits on pain and DAS-CRP. The evidence isn’t strong,” Dr. Costenbader said.

Conclusion

To summarize, vitamin D deficiency is very common in most all inflammatory conditions. Long-term use of vitamin D3 2,000 IU daily was safe and reduced the incidence of all autoimmune diseases by 22% after two to three years, but the effect dissipates quickly after cessation of vitamin D.⁴ Varying doses and durations of vitamin D have been tested for the treatment of SLE and RA, but no strong or consistent effect has been observed. And last but not least, supplementation for patients with vitamin D deficiency to prevent bone loss is still recommended.

A sidebar by Physician Editor Bharat Kumar, MD, MME, FACP, FAAAAI, RhMSUS

Calcium Absorption

Sylvia Christakos, PhD, professor in the Department of Biochemistry and Molecular Biology, Rutgers New Jersey Medical School, Newark, discussed calcium absorption and homeostasis in the aging individual. She noted that in mouse models, vitamin D receptor (VDR)–knockout mice developed hypocalcemia and rickets, but when given a rescue diet high in calcium, rickets can be prevented. This suggests that the decreased effect of vitamin D (and its active form, 1,25-dihydroxy-vitamin D) is largely in the absorption of calcium for the gut.

Interestingly, Dr. Christakos noted that 1,25-dihydroxy-vitamin D suppresses diabetes, experimental autoimmune encephalomyelitis (EAE)—the multiple sclerosis (MS) equivalent in mice—and inflammatory bowel disease (IBD) in mouse models. The mechanisms by which vitamin D ameliorates these diseases remain quite unknown, as well as whether this can reverse the effects of EAE. However, there are tantalizing hints that interleukin 17 (IL-17) may be downregulated by vitamin D treatment, which may be contributory. A separate in vitro study combining 1,25-dihydroxy-vitamin D with interferon-beta also showed a cooperative effect of decreasing IL-17. Unfortunately, human studies have not shown a utility for IL-17 inhibitors for multiple sclerosis.

Dr. Christakos noted that vitamin D and 1,25-dihydroxy-vitamin D can suppress colitis in a genetically predisposed mouse model of IBD. In genetically engineered mice lacking Rab11a, mice treated with 1,25-dihydroxy-vitamin D had restoration of pathologic chances as well as decreased IL-6 and IL-1-beta in the ileum. Although these are mouse models, human beings may have similar mechanisms.

Infection Reduction

Margherita Cantorna, PhD, distinguished professor of molecular immunology at Pennsylvania State University, University Park, also discussed how vitamin D affects immune responses to pathogens. In pregnant women, vitamin D deficiency and VDR deficiencies affect immune progenitors likely through vitamin D signaling. Moreover, vitamin D may have a regulatory effect on the microbiome in neonates. Vitamin D-sufficient animals tend to have more diverse microbes, greater epithelial barrier function and local immune responses. Indeed, vitamin D may help to “regulate the balance between anti- and pro-inflammatory responses” by supporting cells that create IL-10 and decreasing cells that produce IL-17 and interferon gamma.

On a more holistic level, clinical trials have not shown an effect of vitamin D replacement on reducing or preventing respiratory infections. However, raising 25-hydroxyvitamin D (25(OH)D) reduces inflammation, which may help protect the host from infection. In mice models, offspring born to mothers with lower vitamin D have lower VDR levels, which lead to increased susceptibility to influenza. Importantly, supplementation with vitamin D restores vitamin D status but susceptibility to influenza remains.

Altogether, it suggests that vitamin D is a fine-tuner of the immune system, not a hammer.

Samantha C. Shapiro, MD

Samantha C. Shapiro, MD, is a clinician educator who is passionate about the care and education of rheumatology patients. She writes for both medical and lay audiences and practices telerheumatology.

References

1. Beretich BD, Beretich TM. Explaining multiple sclerosis prevalence by ultraviolet exposure: A geospatial analysis. Multiple Sclerosis. 2009;15(8).
2. Kriegel MA, Manson JAE, Costenbader KH. Does vitamin D affect risk of developing autoimmune disease? A systematic review. Semin Arthritis Rheum. 2011;40(6).
3. Manson JE, Cook NR, Lee IM, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med. 2019;380(1).
4. Hahn J, Cook NR, Alexander EK, et al. Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial. The BMJ. 2022;376.
5. Costenbader KH, Cook NR, Lee IM, et al. Vitamin D and marine n-3 fatty acids for autoimmune disease prevention: Outcomes two years after completion of a double-blind, placebo-controlled trial. Arthritis Rheumatol. 2024;76(6).
6. Zheng R, Gonzalez A, Yue J, et al. Efficacy and safety of vitamin D supplementation in patients with systemic lupus erythematosus: A meta-analysis of randomized controlled trials. Am J Med Sci. 2019;358(2).
7. Al-Saoodi H, Kolahdooz F, Andersen JR, Jalili M. Effect of vitamin D on inflammatory and clinical outcomes in patients with rheumatoid arthritis: A systematic review and dose–response meta-analysis of randomized controlled trials. Nutr Rev. 2024;82(5).