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

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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 at 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.

 Download the PDF from Vitamin D Life

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Vitamin D Life – Rheumatoid Arthritis category:

115 RA items     See also Overview Rheumatoid Arthritis   Autoimmune  Inflammation   Pain - Chronic

    Highlights of RA studies in Vitamin D Life
RA worse if low Vitamin D

• Rheumatoid Arthritis is more severe if low vitamin D – July 2023
• Rheumatoid arthritis pain was 5.8 X more likely if low vitamin D – Aug 2017
• Adaptive and innate immune system, vitamin D genes, and Rheumatoid Arthritis – June 2019
• Every patient with rheumatoid arthritis had low vitamin D, severity was proportional to degree of deficiency – June 2014
• Active Rheumatologic disease was 5X more likely with low vitamin D – June 2013
• Rheumatoid Arthritis strongly associated with low vitamin D – meta-analysis April 2016
• Rheumatoid Arthritis associated with lower vitamin D and higher latitude – meta-analysis Jan 2016

10 RA and Vitamin D Receptor (auto-updated)

RA Treated by Vitamin D

• Rheumatoid Arthritis pain reduced by monthly 100,000 IU of Vitamin D – Oct 2018
• Rheumatoid arthritis reduced by 440,000 IU of Vitamin D over 4 months – Oct 2015
• Connective tissue disorders (Lupus, RA, etc) treated by vitamin D – May 2016
• 43 percent of Rheumatoid Arthritis patients have Vitamin D prescriptions (15 countries) – June 2017
• Big increase in vitamin D supplementation in just 2 years after Swiss rheumatology report – Dec 2013
• High dose vitamin reduced pain of fibromyalgia, osteoarthritis, and rheumatoid arthritis - July 2015
  • Note: Vitamin D receptor problems (such as RA) are best treated by infrequent large doses of Vitamin D

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Vitamin D Life – Lupus category:

74 items in LUPUS category

Some of the studies in Vitamin D Life

• Every aspect of Lupus is associated with low viramin D – Oct 2021
• It is time to routinely give vitamin D to Lupus patients – Dec 2016
• 93 pcnt of these Lupus patients supplemented with Vitamin D - Nov 2020
• Lupus patients are 5 X more likely to have low vitamin D – many meta-analyses
• Lupus fought by Vitamin D in all trials longer than 12 weeks - review Sept 2017

See also Autoimmune: 196 items    Rheumatoid Arthritis: 115 items

Autoimmune disease, mainly in 50 per 100,000 women, no cure, many parts of body Wikipedia

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Vitamin D Life – Low Vitamin D strongly associated with Systemic Sclerosis - many studies

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Vitamin D Life – Autoimmune category:

• 196 items in Autoimmune category
• Vitamin D and   MS    Asthma    RA    Diabetes    Gut   Allergy    Hay Fever    Lupus    Psoriasis
• Predicted 95% autoimmune cured by HIGH-DOSE vitamin D - 2014
• 10% of the UK have Autoimmune Diseases - Lancet May 2023 PDF is behind a paywall
  • Increase in 20 years : coeliac disease 2.19 X. Sjogren's syndrome 2.09, and Graves' disease 2.07
  • All 43 references are FREE on-line
• Autoimmune diseases fought by Vitamin D, especially if have more than 40 ng – Sept 2022
• The BEST Nutrient for Autoimmune Conditions (Vitamin D) - video May 2022
• The number 1 Deficiency behind All Autoimmune Diseases (Vitamin D) video - Dec 2023
• Autoimmune disease clusters run in families having low D
• How Vitamin D reduces inflammation, improves immunity and fights autoimmunity – review Dec 2018
• 120 doctors and 20,000 MS patients using high dose Vitamin D Dec 2018
• Vitamin D has treated Multiple Sclerosis and autoimmune diseases for 16 years – Coimbra April 2018
• Vitamin D Receptor is associated in over 58 autoimmune studies
• More autoimmune disease if higher pollution or lower UVB - Feb 2023
• Many autoimmune diseases associated with low vitamin D or poor Vit D genes – July 2019
  

See also web: consensus that ~50 diseases are autoimmune, ~50 more are suspected:

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19 Vitamin D Life studies in both Autoimmune and VDR categories

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VitaminDwiki – Cholesterol category contains

51 items below in the Vitamin D Life category = Cholesterol

see also Overview Hypertension and Vitamin D
Search HLD OR LDL   Overview Cardiovascular and vitamin D
Overview Cholesterol and vitamin D

• Less cholesterol in diet resulted in less vitamin D in blood (in mice) – Feb 2016
• Vitamin D levels are (again) associated with HDL cholesterol levels – Feb 2018
• More cholesterol is associated with more vitamin D – June 2013
• Cholesterol, Vitamins D3 and K2, heart disease, sulfates, LDL, – Masterjohn Interview Jan 2013
• Most Profitable Pill in Medical History Is Based on Flawed Science (Statins) May 2019
• Kids have recently reduced both cholesterol and vitamin D – Aug 2012
• Cholesterol is needed to produce both Vitamin D and Cortisol 2011?
• Cholesterol reduced by Vitamin D plus Calcium – RCT March 2014
• Eating less cholesterol is harmless other than it causes vitamin D deficiency – June 2011
• Vitamin D bioavailability is associated with cholesterol – Jan 2011
• Vitamin D increases HDL
• Overview Cholesterol and vitamin D
• Cholesterol and vitamin D book - 2009