Neuromyelitis optica spectrum disorder (a rare nerve inflammation) 24X more likely to be vitamin D deficient – meta-analysis Dec 2023

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Vitamin D status and the risk of neuromyelitis optica spectrum disorders: A systematic review and meta-analysis

J Clin Neurosci . 2023 Dec 18:119:185-192. doi: 10.1016/j.jocn.2023.12.010
Shuangxi Liu 1, Bichun Tan 2, Jun Zhou 1, Liqian Xiao 3, Minxia Li 1, Junjie Yin 4

Background: Previous studies have linked vitamin D deficiency with autoimmune diseases, and recent research has found low vitamin D levels in neuromyelitis optica spectrum disorder (NMOSD) patients. We aimed to determine the variances in serum 25(OH)D levels between NMOSD patients and healthy controls.

Methods: We searched English and Chinese databases (PubMed, Embase, Cochrane Library, Web of Science, CBM, CNKI, WanFang Med, VIP) for observational studies related to serum 25(OH)D levels in NMOSD patients published up to August 24, 2023. We included studies with healthy controls and compared serum 25(OH)D levels between NMOSD patients and controls. We computed the mean difference (MD) and 95% confidence interval (CI) for continuous variables to evaluate serum 25(OH)D levels and combined odds ratios (ORs) and 95% CIs for dichotomized 25(OH)D data.

Results: Six papers were selected for meta-analysis, including 794 participants (347 in the NMOSD group and 447 in the healthy control group). Meta-analysis showed significantly lower serum 25(OH)D levels in the NMOSD group (MD: -7.83, 95 % CI: -10.99 to -4.68). The risk of 25(OH)D deficiency was 23.36 times higher in the NMOSD group (OR: 23.36, 95 % CI: 0.85 to 640.76, p = 0.06>0.05), with a 94 % occurrence rate.

There was no significant difference in the risk of having sufficient 25(OH)D between the groups (p = 0.12>0.05).

Conclusion: NMOSD patients have lower serum 25(OH)D levels than healthy controls. However, the current research results do not provide evidence for a causal relationship between serum 25(OH)D levels and the onset of NMOSD. Routine vitamin D supplementation may be advantageous for patients with NMOSD.

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The Potential Immunoregulatory Roles of Vitamin D in Neuromyelitis Optica Spectrum Disorder – 2020

Multiple Sclerosis and Related Disorders Volume 43, August 2020, https://doi.org/10.1016/j.msard.2020.102156
Yifan Wu a, Yu Cai a, Mingyuan Liu b, Desheng Zhu a, Yangtai Guan a

Neuromyelitis optica spectrum disorder (NMOSD) is an autoantibody-mediated disease affecting the central nervous system (CNS). Its pathogenesis involves both innate and acquired immune reactions; specific antibody (Aquaporin-4 antibody) and inflammatory cells cause direct damage on lesion sites, while B cell-T cell interactions facilitate the demyelination. However, its etiology is still not fully understood.

Vitamin D deficiency is present in numerous autoimmune diseases, including NMOSD. Evidence suggests that low vitamin D levels mayassociate with disease activity and relapse rate in NMOSD, indicating the participation in the pathogenesis of NMOSD. The immunoregulatory roles of vitamin D in both numerous autoimmune diseases and experimental autoimmune encephalomyelitis (EAE) models are increasingly recognized. Recent studies have revealed vitamin D modulation in cytokine production, immune cell development and differentiation, as well as antibody production. By enhancing an anti-inflammatory environment and suppressing the overactivated autoimmune process, vitamin D shows its potential immunoregulatory roles in NMOSD, which could possibly introduce a new therapy for NMOSD patients.
 Download the PDF from VitaminDWiki

Introduction
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system (CNS), characterized by recurrent longitudinally extensive transverse myelitis (LETM) and optic neuritis (ON) (Marignier et al., 2017; Patterson and Goglin, 2017). There are 80-90% patients having a remission-relapse course and developing permanent sequelae in CNS in result (Wingerchuk et al., 2007). Neuromyelitis optica (NMO) is once thought to be a variant of multiple sclerosis. Since the identification of immunoglobulin against aquaporin-4 (AQP4-IgG, also known as NMO-lgG), a water channel mainly located on astrocytes in the brain, in 2004. The term NMOSD was introduced in 2007 to include mainly AQP4-lgG seropositive patients (Wingerchuk et al., 2007) and has an extensive define in 2015 to include seronegative patients (Wingerchuk et al., 2015).Therefore, there are two kinds of NMOSD patients, AQP4-IgG NMOSD and seronegative NMOSD, accounting for 10-25%patients (Lennon et al., 2004). NMOSD now has six core symptoms: optic neuritis (ON); acute myelitis; area postrema syndrome (APS); acute brainstem syndrome; symptomatic narcolepsy or acute diencephalic clinical syndrome and symptomatic cerebral syndrome (Wingerchuk et al., 2015). For AQP4-IgG NMOSD patients, they only need to meet at least one of six core syndromes, but seronegative patients should meet at least two core syndromes and at least one symptom is one of ON, acute optic neuritis and APS (Wingerchuk et al., 2015).These findings not only confirmed NMOSD as a distinct entity, but also led to the concept that NMOSD may be an antibody-mediated inflammatory disorder (Weinshenker and Wingerchuk, 2017; Wu et al., 2019).

The prevalence of NMOSD meeting 2015 diagnostic criteria varies from 0.37/100,000 to 10/100,000, and the age of onset is from 25 to 45.7 (Etemadifar et al., 2015; Mori et al., 2018; Pandit et al., 2015). Recognized differences are seen ethnicity, geography, and sex. NMOSD is more prevalent among non-European populations, such as East Asia and Africa (Hor et al., 2018; Houzen et al., 2017; Mori et al., 2018; Papp et al., 2018). Higher susceptibility and disease severity are observed in nonwhite races compared to the white population (Cabrera-Gomez et al., 2009; Flanagan et al., 2016). Additionally, females show higher disease prevalence compared to males by almost 2-10 times (Etemadifar et al., 2015; Gold et al., 2019; Pandit et al., 2015). According to the latest diagnostic criteria in 2015, more patients have been included. Epidemiological studies showed new criteria made the rate of incidence and prevalence 1.5-2 times higher, compared with the criteria published in 2006 (Papp et al., 2018; Sepulveda et al., 2017).

Vitamin D, whose function is now established far beyond the regulation of bone metabolism, has been reported to have immune-modulatory properties through inhibiting pro-inflammatory reactions and enhancing anti-inflammatory processes. Vitamin D deficiency is found in various autoimmune diseases, and NMOSD is no exception. Numerous studies have suggested that a low level of vitamin D is likely to correlate with disease activity in experimental autoimmune encephalomyelitis (EAE) mice, an animal model for multiple sclerosis(MS) and NMOSD (Min et al., 2014; Shan et al., 2016; Sintzel et al., 2018), and in MS patients. Additionally, vitamin D supplementation showed therapeutic effectiveness in both animal models and patients. However, although vitamin D deficiency is revealed to associate with higher Expanded Disability Status Score (EDSS) and annual relapse rate (ARR) in both MS and NMOSD (Ascherio et al., 2014; Shan et al., 2016), the efficacy of vitamin D as an immunoregulator for disease development and relapse is not yet understood.

This review focuses on the immunomodulatory effects of vitamin D based on the pathogenesis of NMOSD and discusses its role in the disease course.

__Section snippets))
Vitamin D: its metabolism and physiology
Vitamin D, a lipid-soluble vitamin, can be synthesized by the human body with exposure to sunlight or absorbed from the diet. Endogenous and exogenous vitamin D, also called cholecalciferol (vitamin D3 synthesized endogenously) or ergocalciferol (vitamin D2 originating in plants). Both vitamin D3 and vitamin D2 undergo a transformation to 25(OH)D (calcidiol) by 25-hydroxylase in the liver. Vitamin D3 is more potent than vitamin D2 at increasing the 25(OH)D level (Tripkovic et al., 2012). The . . . .

Vitamin D and immune system
The immunomodulatory effect of vitamin D was confirmed both in acquired immunity and innate immunity. 1,25(OH)2D3 and VDR signaling exert an anti-inflammatory effect to various kinds of immune cells (Pierrot-Deseilligny and Souberbielle, 2017). . . .

In NMOSD (85% AQP4-IgG NMOSD), neutrophils show an activated phenotype and dysfunction (Hertwig et al., 2016). Intracerebral administration of the neutrophil protease inhibitors could reduce the lesion in NMOSD mice, a model of NMOSD in mice, analogous to . . .

Immunomodulatory effects of Vitamin D supplementation in clinical applications
Vitamin D has already been applied in clinical studies in many other autoimmune diseases, such as MS (Dörr et al., 2012; Muris et al., 2016). Vitamin D therapy at various dosages shows immunomodulatory effects, and both cellular and humoral immunity are involved (Ashtari et al., 2015; Haas et al., 2016; Mosayebi et al., 2011). More importantly, these findings indicate that the effect might be dose-dependent.. . .

After the supplementation of vitamin D3 for 12 weeks (20,000 IU/day), no difference was . . .

Vitamin D deficiency in NMOSD patients
Few studies have been done on vitamin D levels in patients with NMOSD (Table 1). According to current studies, unlike in MS, the role of vitamin D in NMOSD is not well understood. It is commonly accepted that higher MS risk correlates with higher latitude (Olsson et al., 2017). Vitamin D insufficiency, which may be a result of lack of solar radiation due to a high latitude, is reported to contributed to MS susceptibility (Kočovská et al., 2017; Pierrot-Deseilligny and Souberbielle, 2017). . . .

Conclusion
NMOSD is thought to develop by an antibody-mediated immune response, and the discovery of its immunopathogenesis has facilitated treatment strategies for NMOSD attacks. Abundant evidence shows numerous immune cells participate in this process including myeloid cells, T cell, and B cells (Michael et al., 2013; Mitsdoerffer et al., 2013). Therapeutic targets focus on these pathogenic cells and their interactions. As the pathological mechanism of NMOSD is not fully understood, vitamin D is showing . . .

135 references include:

T. Akaishi et al.
Serum AQP4-IgG level is associated with the phenotype of the first attack in neuromyelitis optica spectrum disorders
Journal of neuroimmunology
(2020)
P. Bhargava et al.
The vitamin D to ameliorate multiple sclerosis (VIDAMS) trial: study design for a multicenter, randomized, double-blind controlled trial of vitamin D in multiple sclerosis
Contemp Clin Trials
(2014)
L. Brill et al.
Foxp3+ regulatory T cells expression in neuromyelitis optica spectrum disorders
Mult Scler Relat Disord
(2019)
M.T. Cantorna et al.
In vivo upregulation of interleukin-4 is one mechanism underlying the immunoregulatory effects of 1,25-dihydroxyvitamin D(3)
Archives of biochemistry and biophysics
(2000)
J. Correale et al.
Vitamin D-mediated immune regulation in multiple sclerosis
Journal of the neurological sciences
(2011)
D.S. da Costa et al.
Vitamin D modulates different IL-17-secreting T cell subsets in multiple sclerosis patients
Journal of neuroimmunology
(2016)
M. Gao et al.
Low levels of vitamin D and the relationship between vitamin D and Th2 axis-related cytokines in neuromyelitis optica spectrum disorders
Journal of clinical neuroscience: official journal of the Neurosurgical Society of Australasia
(2019)
J. Haas et al.
Hypovitaminosis D upscales B-cell immunoreactivity in multiple sclerosis
Journal of neuroimmunology
(2016)
J.Y. Hor et al.
Prevalence of neuromyelitis optica spectrum disorder in the multi-ethnic Penang Island, Malaysia, and a review of worldwide prevalence
Multiple sclerosis and related disorders
(2018)
J. Jitprapaikulsan et al.
Vitamin D level status in Thai neuromyelitis optica patients
Journal of neuroimmunology
(2016)
View more references
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Lack of vitamin D in adults can lead to problems such as osteoporosis (Holick, 2010). In addition, insufficient vitamin D intake often affects the endocrine pancreas and immune system, leading to a variety of diseases (Arabi, Bahrami, Ranjbar, Tabesh, & Norouzy, 2020; Leuven, 2020; Wu, Cai, Liu, Zhu, & Guan, 2020). More recently, many studies have linked vitamin D deficiency to non-skeletal diseases, such as cancer (Carlberg & Muñoz, 2020), heart disease (Mokhtar, Fawzy, Allam, Amer, & Hamed, 2019), arterial stiffness (Chen et al., 2019), neuropsychiatric disorders (Kim et al., 2020), diabetes (Mirzavandi et al., 2020; Zhang, Wu, Lu, & Fei, 2020) and other chronic illnesses.

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Mendelian randomization study updates the effect of 25-hydroxyvitamin D levels on the risk of multiple sclerosis
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Serum levels of interleukin-6 and Vitamin D at the onset of multiple sclerosis and neuromyelitis optica: A pilot study
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Chronic Urticaria: Advances in Understanding of the Disease and Clinical Management
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Comparison of Ergosterol and Vitamin D<inf>2</inf>in Mushrooms Agaricus bisporus and Cordyceps militaris Using Ultraviolet Irradiation Directly on Dry Powder or in Ethanol Suspension
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Dysbiosis of gut microbiota in patients with neuromyelitis optica spectrum disorders: A cross sectional study – Feb 2020

Journal of Neuroimmunology Volume 339, 15 February 2020 https://doi.org/10.1016/j.jneuroim.2019.577126
Ziyan Shi a 1, Yuhan Qiu a 1, Jiancheng Wang a, Yihuan Fang b, Ying Zhang a, Hongxi Chen a, Qin Du a, Zhengyang Zhao a, Chao Yan a, Mu Yang c, Hongyu Zhou a

Gut microbiota vs healthy controls

Background
Accumulating evidence points to an association of alternations in the gut microbiota with health and disease, including the development of neurological diseases. However, there are relatively scarce studies of the role of the gut microbiota in neuromyelitis optica spectrum disorders (NMOSD). Therefore, the aim of the present study was to evaluate the differences in the intestinal microbiota composition between patients with NMOSD and healthy control subjects.

Methods
This was a cross-sectional study. Stool samples were obtained from 20 patients with NMOSD and 20 healthy family members of the patients as controls (HC). The bacterial 16S rRNA gene amplification sequencing (V3-V4 region) was used to detect the composition and structure of the intestinal microbiota community in the two groups.

Results
The gut microbiota compositions clearly differed between the NMOSD and HC groups, although there was no significant difference in the overall microbial community structure. In detail, patients with NMOSD had an increased abundance of the pathogenic genera Flavonifractor (P = .004) and Streptococcus (P = .007) compared with the HC. In addition, several intestinal commensal bacteria were detected at significantly lower abundance in the NMOSD patients compared to the controls, including Faecalibacterium, Lachnospiracea_incertae_sedis, Prevotella, Blautia, Roseburia, Romboutsia, Coprococcus, and Fusicatenibacter (all P < .05). ROC curve analysis suggested that gut microbiota genera had potential to distinguish NMOSD from controls. Functional analysis further indicated that the gut microbiome of NMOSD patients was associated with three significantly downregulated metabolic pathways: “Photosynthesis” (P < .001), “Photosynthesis proteins” (P < .001), and “Thiamine metabolism” (P = .007). These differences remained significant even after correction for multiple comparisons (all PFDR < 0.05).

Conclusion
Our results reveal the dysbiosis of intestinal bacteria and regarding metabolic abnormalities in patients with NMOSD. Further studies are warranted to elucidate the potential mechanism by which dysbiosis of microbiota contributes to the onset and progression of NMOSD. Download the PDF from VitaminDWiki

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NMOSD is an autoimmune inflammation disorder with similar symptoms to Multiple Sclerosis

NMOSD prevalence is between 0.07 and 10 per 100,000 people. ( 10 ==> 1 in 10,000)
MS prevalence: 1 in 333 (30 to 300X more common)

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VitaminDWiki – Autoimmune category contains

• 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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VitaminDWiki – Vitamin D Receptor is associated in over 58 autoimmune studies

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VitaminDWiki - 6 studies in both categories Autoimmune and GUT

This list is automatically updated