Autoimmune RA, SLE, SSc, genes and Vitamin D – March 2023

Involvement of the secosteroid vitamin D in autoimmune rheumatic diseases and COVID-19
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Involvement of the secosteroid vitamin D in autoimmune rheumatic diseases and COVID-19

nature reviews rheumatology https://doi.org/10.1038/s41584-023-00944-2
Maurizio Cutolo®1 S, Vanessa Smith®2, Sabrina Paolino®1 & Emanuele Gotelli®1 Abstract
’Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology, Department of Internal Medicine and Specialties (DiMI), University of Genova-IRCCS San Martino Polyclinic Hospital, Genoa, Italy. 2Department of Internal Medicine, Department of Rheumatology, University Hospital Ghent, Ghent, Belgium. e-mail: tolo@unige.it

PDF Table of Contents

Vitamin D supplementation The vitamin D endocrine system
Synthesis and activation of vitamin D
Mediators of the effects of vitamin D Evidence of vitamin D interactions with the innate immune system
Evidence of vitamin D interactions with the adaptive immune system
Vitamin D interactions with steroidal hormones and immune response
Vitamin D and interconnections with autoimmune rheumatic diseases
Vitamin D and rheumatoid arthritis
Vitamin D and systemic lupus erythematosus -
Vitamin D and systemic sclerosis Vitamin D and seasonal rhythms of autoimmune rheumatic diseases
Vitamin D involvement in immune response and therapeutic effects in COVID-19
Conclusions Acknowledgements
Fig. 1 Metabolic pathways of vitamin D3-derived molecules, mineralocorticoids, glucocorticoids and sex hormones.
Fig. 2 The vitamin D3 endocrine system and the effects of vitamin D3 metabolites on innate and adaptive immunity.
Fig. 3 Seasonal trends in vitamin D status, expression of inflammatory mediators and incidence and severity of autoimmune rheumatic diseases.
Fig. 4 Effects of vitamin D in patients with COVID-19.
Table 1 Biological and clinical effects of vitamin D in RA in in vitro and in vivo studies.
Table 2 Biological and clinical effects of vitamin D in SLE in in vitro and in vivo studies.
Table 3 Biological and clinical effects of vitamin D in SSc in in vitro and in vivo studies.

Evidence supporting the extra-skeletal role of vitamin D in modulating immune responses is centred on the effects ofits final metabolite, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3, also known as calcitriol), which is regarded as a true steroid hormone. 1,25(OH)2D3, 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 D3 (25(OH)D3, 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)D3 is considered to be a risk factor for autoimmune rheumatic diseases and vitamin D3 supplementation seems to improve the prognosis; moreover, long-term vitamin D3 supplementation seems to reduce their incidence (i.e. rheumatoid arthritis). In the setting of COVID-19, 1,25(OH)2D3 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)D3 concentrations and for appropriate supplementation following clinical trial-based approaches.

Key points

Vitamin D3 (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 D3 is accomplished by sequential hydroxylations that produce 25(OH)D3 (calcidiol) in the liver and then the active metabolite 1,25(OH)2D3 (calcitriol) in the kidney and at extra-renal sites (including immune cells).
1,25(OH)2D3 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)D3 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)2D3 downregulates both the early viral phase of COVID-19, through the enhancement of innate antiviral effector mechanisms, and the later cytokine-mediated hyperinflammatory phase.

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