Involvement of the secosteroid vitamin D in autoimmune rheumatic diseases and COVID-19
Maurizio Cutolo, Vanessa Smith, Sabrina Paolino, Emanuele Gotelli
Nature Reviews Rheumatology, doi:10.1038/s41584-023-00944-2
Evidence supporting the extra-skeletal role of vitamin D in modulating immune responses is centred on the effects of its final m et ab ol ite, 1 ,2 5-di hy dr ox yvitamin D 3 (1,25(OH) 2 D 3 , also known as calcitriol), which is regarded as a t r u e s t e r o id h o r m o ne. 1,25(OH) 2 D 3 , the active form of vitamin D, can modulate the innate immune system in response to invading pathogens, downregulate inflammatory responses and support the adaptive arm of the immune system. Serum concentrations of its inactive precursor 25-hydroxyvitamin D 3 (25(OH)D 3 , also known as calcidiol) fluctuate seasonally (being lowest in winter) and correlate negatively with the activation of the immune system as well as with the incidence and severity of autoimmune rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis. Thus, a low serum concentration of 25(OH)D 3 is considered to be a risk factor for autoimmune rheumatic diseases and vitamin D 3 supplementation seems to improve the prognosis; moreover, long-term vitamin D 3 supplementation seems to reduce their incidence (i.e. rheumatoid arthritis). In the setting of COVID-19, 1,25(OH) 2 D 3 seems to downregulate the early viral phase (SARS-CoV-2 infection), by enhancing innate antiviral effector mechanisms, as well as the later cytokine-mediated hyperinflammatory phase. This Review provides an update of the latest scientific and clinical evidence concerning vitamin D and immune response in autoimmune rheumatic diseases and COVID-19, which justify the need for monitoring of serum 25(OH)D 3 concentrations and for appropriate supplementation following clinical trial-based approaches.
Sections Key points • Vitamin D 3 (cholecalciferol) is a prototypical secosteroid, a type of steroid with a 'broken' ring, which originates from cholesterol, as do all steroid hormones (including glucocorticoids, mineralocorticoids and sex hormones). • The activation of vitamin D 3 is accomplished by sequential hydroxylations that produce 25(OH)D 3 (calcidiol) in the liver and then the active metabolite 1,25(OH) 2 D 3 (calcitriol) in the kidney and at extra-renal sites (including immune cells). • 1,25(OH) 2 D 3 modulates the innate immune response against pathogens and invading microorganisms, downregulates the inflammatory response and supports the adaptive arm of the immune system. • Reduced serum concentrations of 25(OH)D 3 are detected in autoimmune rheumatic diseases such as rheumatoid, systemic lupus erythematosus and systemic sclerosis; vitamin D supplementation seems to improve at least the prognosis. • Serum concentrations of vitamin D fluctuate seasonally (being lowest in winter) and correlate negatively with the activation of the immune system and with the incidence and severity of autoimmune rheumatic diseases. • 1,25(OH) 2 D 3 downregulates both the early viral phase of COVID-19, through the enhancement of innate antiviral effector mechanisms, and the later..
Author contributions M.C. and E.G. researched data for the article. V.S. and S.P. made a substantial contribution to discussion of the content. M.C. and E.G. wrote the manuscript. All authors reviewed and/or edited the manuscript before submission.
Competing interests M.C. declares that his university laboratory has received funds for research from Amgen, Bristol-Myers Squibb, Boehringer Ingelheim and Pfizer. V.S. declares that she has received funds for research from Boehringer-Ingelheim and Janssen-Cilag. S.P. and E.G. declare no competing interests.
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