Symptom orientation: Multiple Sclerosis, Osteamalacia - A collection of scientific studies!

CONTENT

1. Symptom orientation!
2. Autism!
3. Cancer!
4. Fibromyalgia!
5. Psoriasis!
6. Multiple Sclerosis!
7. Osteomalacia!
8. More about VitaminD!

1. Symptom orientation!

General view on distraction from solutions by declaring the symptoms of the diseases to be their reasons.

https://geoarchitektur.blogspot.com/p/symptom-orientation-autism-cancer.html

Chapters of this article have been put into separate pages, but the content list and numbering of the chapters ist kept as original.

2. Autism!

Symptom orientation: Autism - A collection of scientific studies!

https://geoarchitektur.blogspot.com/p/symptom-orientation-autism-collection.html

3. Cancer

Symptom orientation: Cancer - A collection of scientific studies!

https://geoarchitektur.blogspot.com/p/symptom-orientation-cancer-collection.html

4. Fibromyalgia

Symptom orientation: Fibromyalgia - A collection of scientific studies!

https://geoarchitektur.blogspot.com/p/symptom-orientation-fibromyalgia.html

5. Psoriasis

Symptom orientation: Psoriasis - A collection of scientific studies!

https://geoarchitektur.blogspot.com/p/symptom-orientation-psoriasis.html

6. Multiple Sklerosis!

Iranian consensus on use of vitamin D in patients with multiple sclerosis
BMC Neurol. 2016; 16: 76. Published online 2016 May 21. doi: 10.1186/s12883-016-0586-3 PMCID: PMC4875642
Soodeh Razeghi Jahromi, Mohammad Ali Sahraian, Mansoureh Togha, Behnaz Sedighi, Vahid Shayegannejad, Alireza Nickseresht, Shahriar Nafissi, Niayesh Mohebbi, Nastran Majdinasab, Mohsen Foroughipour, Masoud Etemadifar, Nahid Beladi Moghadam, Hormoz Ayramlou, Fereshteh Ashtari, andShekoofe Alaie
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4875642/

"Conclusions

Considering the mounting evidences presented here, the consensus recommends:

1. Vitamin D assessment for all MS patients, especially after diagnosis and in the first demyelinating attack.
2. Vitamin D supplementation in case of 25(OH)D level below 40 ng/ml.
3. In patients with vitamin D insufficiency or deficiency, a large replacing dose is proposed in initial phase (e.g. 50,000 IU capsules of D per week for 8–12 week).
4. Checking the serum vitamin D level and patients compliance after initial phase. If the level of vitamin D does not reach normal level by repeating the replacing period for another 8–12 weeks is recommended.
5. Checking serum calcium level at base line and after replacing dose (3 months).
6. A maintenance treatment of 1500–2000 IU daily or equivalent intermittent (weekly, biweekly or monthly) Dose. Biweekly or monthly dose might have better compliance.
7. When D3 is available, supplementation with D3 is preferred.
8. Routine check of serum vitamin D level at least two times a year especially at the beginning of spring and autumn is advised for all treated and untreated patients.
9. Serum vitamin D evaluation for first degree relatives of MS patients at high risk age. Supplementation is recommended in case of insufficiency (25(OH)D less than 40 ng/ml). The panel recommends maintenance dose for family members with normal vitamin D level.
10. The panel suggests the correction of vitamin D deficiency and insufficiency before pregnancy. During pregnancy, the panel suggested a daily dose of 1500–2000 IU or equivalent biweekly intake in 2nd and 3rd trimesters. The panel also suggested 25(OH)D check every 3 months. In case of serum levels greater than 100 ng/ml, the supplementation should be ceased.
11. The panel suggests 1000 IU/d or its intermittent equivalents in MS patients with limited physical activity.
12. The panel suggests vitamin D level check and 8–12 weeks of supplementation in case of serum 25(OH)D level below 40 ng/ml for all CIS patients.

The data of national comprehensive study on household food consumption pattern and nutritional status, Iran, 2001–2003 revealed that average per capita consumption of dairy products in Iran was 0.1–0.18 of western societies (139 g/d compared to 769–1369 g/d) [56]. Also Iranians have limited access to oily fishes as one of the main sources of vitamin D [57]. Considering low intake and high prevalence of vitamin D deficiency, it seems plausible to recommend government and authorities for starting national surveys on vitamin D fortification or supplementation."

Gestational Vitamin D and the Risk of Multiple Sclerosis in the Offspring
Ann Neurol. Author manuscript; available in PMC 2012 Jul 1.
Published in final edited form as: Ann Neurol. 2011 Jul; 70(1): 30–40. doi: 10.1002/ana.22456 PMCID: PMC3205990 NIHMSID: NIHMS288253
Fariba Mirzaei, M.D., MPH, ScD,1,2 Karin B. Michels, ScD, Ph.D.,2,4,7 Kassandra Munger, ScD,1 Eilis O’Reilly, ScD,1 Tanuja Chitnis, M.D.,5 Michele R. Forman, Ph.D., M.S.,6 Edward Giovannucci, M.D., ScD,1,2,7 Bernard Rosner, Ph.D.,3,7 and Alberto Ascherio, M.D., DPH1,
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205990/

"Results

MS was diagnosed in 199 women. The relative risk (RR) of MS was lower among women born to mothers with high milk or vitamin D intake during pregnancy. The multivariate adjusted RR of MS was 0.62 (95% CI: 0.40– 0.95; p trend=0.001) for nurses whose mothers consumed 2–3 glasses of milk per day compared with those whose mothers consumed fewer than 3 glasses per month, and 0.57 (95% CI: 0.35–0.91; p trend=0.002) for nurses with mothers in the highest quintile of dietary vitamin D intake compared with those in the lowest. The predicted 25(OH) vitamin D level in the pregnant mothers was also inversely associated with the risk of MS in their daughters. Comparing extreme quintiles the adjusted RR was 0.59; (95% CI: 0.37–0.92; p trend =0.002)."

"Conclusion

Higher maternal milk and vitamin D intake during pregnancy may be associated with a lower risk of developing MS in the offspring."

Can we prevent or treat multiple sclerosis by individualised vitamin D supply?
EPMA J. 2013; 4(1): 4. Published online 2013 Jan 29. doi:10.1186/1878-5085-4-4 PMCID: PMC3564873
Jan Dörr,1,2 Andrea Döring,1,2,3 and Friedemann Paul1,2
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564873/

"Multiple sclerosis: background information

Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system (CNS) in young adults in Western countries and often leads to early disability and retirement [1]. Typical clinical manifestations are optic neuritis, central paralysis, sensory disturbances, and difficulties in coordination and balance, as well as cognitive dysfunction, fatigue, and sleep disorders [1-3]. The initial course is usually relapsing-remitting, but after several years, the disease tends to convert into a secondary progressive form. A primary progressive course also exists but is much less common.

It is estimated that 2.5 million people suffer from MS worldwide, and as in most autoimmune disorders, there is an obvious female preponderance of approximately 3 to 4:1. Importantly, most female patients are affected in their child-bearing age which may have fundamental consequences for family planning. The cause of MS is not yet clear. Several genetic and environmental factors have been isolated to contribute to the risk of MS, among them vitamin D (VD) status, but the individual significance of each factor is not yet clear. From the pathophysiological point of view, dysregulated encephalitogenic T cells are thought to initiate and to orchestrate in concert with abundant other immune cells an autoimmune multifocal CNS inflammation."

"Vitamin D: background information

Research on VD started around 1915, stimulated by the quest for an effective treatment of rickets. By the end of the 19th century, up to 90% of the children living in large cities throughout Northern Europe and the United States suffered from rickets, and the most common cause was the insufficient supply of VD due to low sun exposure as a side effect of increasing industrialisation. The transformation to an industrialised economy radically changed the living conditions for large parts of the population. Children often had to work many hours a day in factories or mines, being completely shielded from the sun. When VD deficiency was recognised as the main cause of rickets, a significant reduction of cases was achieved by preventive measures like radiation from ultraviolet lamps, greater amount of time spent outdoors, or fortification of food with VD."

"The VD supply of the human organism is generally accomplished via two different routes: first, endogenous synthesis of VD3 (cholecalciferol) from its precursor 7-dehydrocholesterol in an ultraviolet (UV) B radiation-dependent process in the skin (wave length 290 to 315 nm); second, exogenous supply with VD3 or VD2 (ergocalciferol) by food, fortified food products, or supplements. About 90% to 100% of the VD requirement of a human body is covered by sun exposure-dependent endogenous production. The amount of UVB-radiation dependent VD production depends on numerous factors including individual factors like duration and frequency of sun exposure, the area of skin exposed to the sun, use of sun protection, skin pigmentation, age, sex, genetic factors, amounts of 7-dehydrocholesterol in the skin; geographic factors like latitude and altitude; as well as seasonal and meteorological factors like clouding and ozone levels. The magnitude of endogenous VD synthesis is referenced to the minimum erythema dose (MED) which describes the minimum individual dose of UVB radiation needed for the development of a transient skin irritation. One MED of the entire body equals the release of 10,000 to 20,000 IU (250 to 500 μg) of VD3 [1]. Compared to the endogenous production of VD3, the food-related intake of VD2/3 is usually of inferior importance since only few food products contain significant amounts of VD."

"Dietary sources of vitamin D

Both VD2 and VD3 are biologically inactive. After intradermal synthesis or intestinal uptake, VD2 and VD3 are bound mainly to vitamin-D-binding-protein and transported to the liver, where they are enzymatically hydroxylated to 25(OH)VD (calcidiol). As this step is not tightly regulated and because of the relatively long half-life, serum levels of 25(OH)VD integrate both the endogenous and exogenous supply and provide a good estimate of an organism's VD status. The enzyme 1α-hydroxylase (CYP27B1), which is located mainly in the kidneys but also in other tissues, converts 25(OH)VD in a second hydroxylation step into the biologically active 1,25 dihydroxyvitamin D (1,25(OH)2VD; calcitriol) . Unlike the first hydroxylation, this second step is tightly regulated, among others by parathormone and calcium/phosphate levels. Calcitriol effects are mainly mediated via the intracellular VD receptor (VDR) which functions as a transcription factor and controls the expression of numerous genes. In its membrane-bound form, VDR mediates additional non-genomic functions including several signal transduction pathways [39,40]."

"An ongoing debate addresses the optimal serum levels of 25(OH)VD. Currently, most experts consider 25(OH)VD levels above 30 ng/ml (75 nmol/l) as adequate [41-43], which is supported by the observations that serum levels of parathormone start plateauing at serum 25(OH)VD of 30 to 40 ng/ml and that immunological effects need serum levels around 30 ng/ml [35,44]. Levels below 20 ng/ml (50 nmol/l) are considered deficient. Less clear are the upper limits since substantial variability occurs in naturally occurring 25(OH)VD levels. According to the literature, levels of up to 150 to 200 ng/ml (375 to 500 nmol/l) can be considered safe [41]. Against this background, a significant proportion of the human population worldwide shows an alarming VD inadequacy [35,44-46]."

"Since VD homeostasis is linked on multiple levels to the risk of not only various diseases such as cancer and autoimmune diseases, but also metabolic, cardiovascular, and psychiatric disorders [35,42,47,48], the question arises whether improvement of VD supply may prevent or even treat respective diseases. Indeed, recent estimations indicate that yearly, >110,000 deaths could be prevented by adequate VD supply [49]."

"Linking vitamin D and MS: immunoregulatory functions of vitamin D

Apart from its fundamental role in calcium homeostasis and bone metabolism, increasing evidence suggests that VD has additional, particularly immunoregulatory functions which renders VD a promising candidate in both pathogenesis and treatment of autoimmune diseases such as MS. The capability of VD to modulate both innate and adaptive immune responses has been summarised in several comprehensive and excellent reviews [47,50-52]. With respect to the autoimmune MS pathophysiology [11,12], the following effects of VD on the immune system might be of particular interest: the ability to modulate the differentiation and function of antigen presenting cells which results in a reduced activation of potentially auto-aggressive T cells [53-55], the capacity to inhibit B cell and T cell proliferation and differentiation [56-58], the ability to shift the cytokine milieu from a pro-inflammatory, Th1/Th17-cell-mediated to a rather anti-inflammatory Th2-cell-mediated state [47,59], and finally, to facilitate the differentiation of regulatory T cells and function of natural killer cells [60,61]. Data on the VD effect on CD8 cells are still controversial. Figure ​Figure11 summarises the potential immunoregulatory effects of VD that might be pathophysiologically relevant in MS."


"Possible effects of vitamin D on immune cells. APC, antigen presenting cell; Th, T helper cell; Treg, regulatory T cell; BC, B cell; PC, plasma cell; NKC, natural killer cell. Figure was first published in [62] ."

"The presence of 1α-hydroxylase activity in neurons and microglia, and the presence of VD receptor in the CNS suggest local-, paracrine-, or autocrine-mediated effects of VD in the CNS [63,64]. Interestingly, data from in vitro or animal studies suggest that neurotrophic factors such as nerve growth factor, neurotrophin 3, and glial cell line-derived neurotrophic factor are regulated by VD which might indicate additional, possibly neuroprotective effects of VD [65]. Whether VD has clinically relevant neuroprotective properties still remains a subject of discussion."

"Linking vitamin D and MS: how do genes contribute?

... Second, loss of function variants in the CYP27B1 gene which encodes the enzyme that converts 25(OH)VD into its active form were shown to be associated with an increased MS risk [69]. In the same direction points a possible association between MS and VD-dependent rickets type I, which is a rare hereditary condition caused by a mutation in CYP27B1[70,71]."

"Linking vitamin D and MS: what do animal models tell us?

... Likewise, the therapeutic VD application (starting at onset of symptoms) lead to a significant reduction of disease severity [72-74]. Interestingly, some studies suggested gender-specific efficacy of VD only in female mice [75]. In a recent study, continuous treatment of mice with UVR dramatically suppressed clinical signs of EAE. Interestingly, the therapeutic effect was paralleled by only a moderate and transient increase of serum 25(OH)VD levels, which suggests that directly UVR-mediated effects which were at least partly independent of VD contributed to this observation [76]. ..."

"Linking vitamin D and MS: the clue to geographic and seasonal associations?

First hypotheses on a possible link between MS risk and VD deficiency were derived from the observation that the risk of MS is associated with latitude [78,79] which in turn shows a strong inverse correlation with UVB exposure. Furthermore, migrating from high to low latitude appears to reduce the MS risk [80]. This link was further corroborated by the observation of a MS risk lower than one would expect from the latitude in regions with a high consume of fatty VD-rich fish [81]. More recent investigations, however, suggest that this latitude gradient is fading which might be explained by several possible reasons, including better MS recognition, changes in lifestyle, and improvement of sanitary circumstances [34]. More indirect though not unambiguous support for a beneficial effect of VD comes from the observation that both MS risk and disease activity show a seasonal association. As shown in several studies including a very recent meta-analysis, humans born in spring have a significant higher risk to develop MS later in life than people born in autumn [82-85] which might be at least partially explained by longer in utero VD insufficiency due to lower motherly VD levels in winter/spring as compared to summer/autumn. Likewise, several methodically high quality studies showed an inverse association between sun exposure or outdoor activities during childhood and adolescence, and the risk of developing MS during adulthood [86-90]. In line with these reports is the recent observation that low sun exposure in fall/winter before disease onset was associated with a less favourable outcome [91]. Yet, all these studies have two major intrinsic limitations: first, despite a reported reasonable validity and reliability [92], the retrospective determination of sun exposure years or even decades in the past is inevitably subjected to recall bias [34], and prospective studies are hardly available. The determination of actinic damage as a surrogate parameter for cumulative sun exposition might be a viable loophole [34,86]. Second, sun exposure itself may have intrinsic immunomodulatory effects, independent of VD [76,93,94]. Also, not easy to harmonise with sun exposure or VD synthesis is the seasonal dependency of disease activity in already established MS. Several studies including a meta-analysis showed an excess of clinical exacerbations and MRI activity in spring/summer and a nadir in autumn/winter in the northern hemisphere [95-98]. Correspondingly, a reverse situation was observed in the southern hemisphere [99]. While a peak of disease activity in spring and a nadir in autumn in the northern hemisphere could be explained with a few-month lag in the course of serum VD levels, the situation in summer and winter does not easily fit with a protective role of VD. In conclusion, VD might contribute to some but cannot sufficiently explain all geographic and seasonal associations observed in MS."

"Linking vitamin D and MS: the impact of vitamin D intake and serum level

The rather indirect impact of predictors of 25(OH)VD levels on MS has been discussed above. But, how does the 25(OH)VD serum level itself sway the risk and course of MS? Generally, if VD had a beneficial effect on MS risk, one would demand an inverse relation between VD intake or serum levels and MS incidence. Indeed, various studies demonstrated such a relation. Most data on this issue, however, are derived from epidemiologic or observational studies, meaning, that methodical limitations like selection bias, retrospective survey, and interference with various confounders should be kept in mind. One recent study suggests that already in utero levels of VD, which are completely dependent on the mother's VD status, impact the risk to develop MS later in life [100]. In a Canadian cohort study on children presenting with a first demyelinating event, the risk to develop definite MS within the following 3 years was inversely and independently correlated with the 25(OH)VD serum level [101]. Furthermore, data from a nested case–control study involving more than seven million individuals of the US military suggest that in healthy young white adults, higher 25(OH)VD levels are predictive of a significantly lower risk of developing MS (62% lower odds in the top quintile of 25(OH)VD serum levels compared to the bottom quintile), independent from latitude of residency in childhood [102]. Another study by the same group addressed the relation between VD intake and MS risk in a cohort of approximately 200,000 US women and reported a 33% reduction of MS incidence over a follow-up period of 30 years when comparing the top quintile and the bottom quintile of VD intake. Moreover, in women taking daily supplements containing at least 400 IU VD, a 41% lower MS incidence was observed when compared to women who did not take supplements [103]. Likewise, in another survey, intake of cod liver oil was associated with a 4-year delay of MS onset [90]. In summary, substantial evidence exists for an inverse association between VD and the risk of developing MS."

"But, how does the situation look in already established MS? A number of studies consistently suggest that higher VD serum levels are associated with a more favourable disease course. In a small Finnish study, lower summer 25(OH)VD concentrations were measured in patients with a first MS relapse compared to healthy controls, and 25(OH)VD concentrations were significantly lower during relapses than in remission phases which may point to a regulative role of VD for MS activity [104]. Compelling support for this hypothesis comes from four independent recent reports, all showing a close relationship between clinical disease activity and 25(OH)VD concentrations: Two studies demonstrated that every 10 nmol/l increase of the VD serum level is correlated with a reduction of relapse occurrence of 11% and 13.7%, respectively [105,106]. A third study demonstrated a log linear association between serum VD concentration and MS relapse rate in that every doubling of serum levels reduced relapse rate by 27% [107]. The fourth study finally revealed a 34% reduction of relapse rate by every 10 ng/ml increase in paediatric onset MS [108]. In line with these clinical data, an inverse association between VD concentrations and disease activity on cranial MRI was recently demonstrated, but may possibly be restricted to patients without additional immunomodulatory treatment [109,110]. Of note, in studies addressing the relation between clinical disease activity and VD levels, a reverse association (low VD concentrations as a consequence rather than a cause of a relapse) cannot be completely ruled out. In contrast to the serum concentrations, a statistical difference in cerebrospinal fluid VD levels was neither observed between MS patients and healthy controls or in MS patients between phases of disease activity or in remission [111]."

"In conclusion, cumulating evidence quite consistently argues for a relationship between VD status and both risk and activity of MS. Of note, however, all these studies are methodically prone to bias and are therefore not suited to definitely proof such a relation."

"Linking vitamin D and MS: what do interventional trials tell us?

The compelling evidence for the beneficial impact of higher VD serum concentrations on disease activity leads directly to two questions:

(a) do patients with already established MS benefit from a therapeutic elevation of their VD levels and

(b) if so, which 25(OH)VD serum levels should be strived for in MS patients?

... An early uncontrolled study involving 16 MS patients (evidence level IIb) showed that regular intake of cod liver oil (equivalent to 5,000 IU VD/day) for a period of up to 2 years lead to a lower relapse rate as would have been expected from the participants' medical histories [112]. From today's point of view, design and sample size of this study are however not appropriate to address a therapeutic effect of VD.

Another small and uncontrolled study with a primary focus on safety aspects (evidence level IIb) provided evidence that escalating VD doses up to 280,000 IU/week over a rather short period of 28 weeks are safe in MS patients. No significant effects on clinical parameters were observed, but there was a possible effect on MRI activity [113].

In a successive randomised controlled but open label study, the same group applied cholecalciferol (up to 40,000 or 4,000 IU/d) continuously for 52 weeks in 49 MS patients (evidence level Ib). Patients in the high dose arm showed a significant reduction of the annualised relapse rate [114].

In another randomised double blind and placebo-controlled study focusing on serological markers of disease activity (evidence level IIb), administration of 1,000 IE cholecalciferol for a period of 6 months lead to a significant increase of the anti-inflammatory cytokine transforming growth factor-β and to a partial reduction of the IL-2 level [115].
....

Two recently published studies from Finland and Norway, both applying 20,000 IU/week in a randomised, double blind and placebo-controlled design (evidence level Ib), yielded partly contradictory results with respect to clinical and MRI parameters.

In the Finish study, mean 25(OH)VD serum levels in patients receiving VD over 1 year in addition to IFN-β increased to 110 nmol/l, and patients in the verum group showed significantly fewer gadolinium-enhancing lesions and a tendency to reduced disability accumulation and improved ambulation parameters. The annualised relapse rate was not different in both arms [119]. In an active subgroup of this study, an additional beneficial effect of VD on new/enlarging T2 hyperintense brain lesions was observed [120].

In the 96-week Norwegian trial, no significant differences were observed in annualised relapse rate, EDSS, MSFC, grip strength, or fatigue although the median 25(OH)VD serum concentration in the verum group raised to 121 nmol/l [121]."

"In summary, due to their ambiguous results, the so-far published interventional trials do not answer the question whether VD would be a treatment option in MS. The reasons for these heterogeneous results remain unclear. Given the substantial increase in serum concentration to greater 100 nmol/l in the two most recent trials [119,121], insufficient dosing is probably not a likely explanation. Further, well-designed interventional high-dose trials, which are at least partly better powered, are currently underway (Table ​(Table2)2) [122,123] and will hopefully contribute to elucidate the efficacy aspects."

"With respect to safety, more clinical data already exist. Generally, (iatrogenic) VD excess can result in life-threatening hypercalcaemia and has been occasionally reported on the basis of single cases [124]. However, unlike supplementation with high dose calcitriol, which indeed seems to bear a significant risk of symptomatic hypercalcaemia [125], treatment of MS patients with even very high doses of cholecalciferol or ergocalciferol was repeatedly demonstrated to be safe [113,114,116,119,121]. While a Cochrane report published in 2010 concludes that available data are not yet sufficient to draw the right conclusions regarding safety of VD supplementation [126], another recent meta-analysis suggests that daily doses of 10,000 IE cholecalciferol can be considered safe [127]."

"Conclusions
...
From a pragmatical point of view and considering available data on efficacy, safety, tolerability, and last but not least costs, it seems to be reasonable to regularly control 25(OH)VD levels in MS patients, especially during winter months. In patients with inadequate VD, levels should be raised to at least 30–40 ng/ml (75–100 mmol/l), either by appropriate sun exposure and/or adequate VD supplementation. As a rule of thumb, supplementary 1 μg (40 IU) cholecalciferol will increase 25(OH)VD levels by 1 ng/ml (2.5 nmol/l)."

Illuminating vitamin D effects on B cells – the multiple sclerosis perspective
Immunology. 2016 Mar; 147(3): 275–284. Published online 2016 Feb 2. doi: 10.1111/imm.12572 PMCID: PMC4754614
Linda Rolf, 1 , 2 Anne‐Hilde Muris, 1 , 2 Raymond Hupperts, 1 , 2 and Jan Damoiseaux 3
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754614/

"CONCLUSION

Vitamin D, as an immunoregulator, is an interesting component for research in autoimmune disorders, such as MS. Its anti‐inflammatory or regulatory effects within the T‐cell and dendritic cell compartment have been widely accepted. T cells gained most attention within MS research over the last decades. However, B cells have clearly made a comeback. The data referred to in this review indicate that vitamin D can have several effects on B cells, at least in vitro, which may be beneficial in MS: inhibition of plasma cell generation, inhibition of T‐cell co‐stimulation and enhancement of Breg cell activity. Taking into account the results of B‐cell‐depleting drugs, the production of autoantibodies as the driving force in MS pathology has become less likely, while particularly the ‘innate’ B‐cell functions can be considered relevant. As yet, vitamin D effects on these B‐cell functions have been poorly investigated, the more so with respect to in vivo effects. Therefore, this area offers many opportunities for further research.

It is apparent that vitamin D effects in vivo are less clear. We have speculated on the importance of germinal centres in secondary lymphoid tissue. Alternatively, it is of importance to look at B cells from a broader perspective. The role of EBV in B‐cell actions in MS has to be further elucidated first, but it would be interesting to also study vitamin D effects on EBV‐infected B cells.

Moreover, molecules that are functionally comparable to 1,25(OH)2D present in the microenvironment of B cells might interact with each other, either having competitive, additive or synergistic effects. Candidate molecules for this are other steroid hormones such as the sex hormones (oestrogens and progestogens) and corticosteroids (cortisol), which, like vitamin D, can influence immune responses, are thought to ameliorate MS and play a role in autoimmune (or immune‐driven) disorders in general.119 Moreover, they are derived from cholesterol metabolites and target nuclear receptors. Therefore, they can directly influence gene transcription.121 In EAE, these steroid hormones have been shown to prevent or ameliorate disease and to suppress inflammatory processes.121, 122 Interestingly, synergistic effects of vitamin D and oestrogen have been shown in EAE.123

Another candidate for interacting with vitamin D is retinoic acid, better known as vitamin A. Retinoic acid, like vitamin D, balances Th1 and Th2 immune responses and induces iTreg cells and IL‐10‐producing Breg cells.124, 125 Typically, retinoic acid binds nuclear retinoic acid receptors that heterodimerize with retinoid X receptors, which also form heterodimers with the vitamin D receptor.126 Therefore, vitamin A and vitamin D might be competitive in their actions. It will be necessary to have insights into the interactions of these immune modulatory molecules, to create a more holistic view of the effects of vitamin D on B cells.

Altogether, the abnormal B‐cell activation in MS seems to be an augmenting factor in the inflammatory loop. Vitamin D may influence some B‐cell functions, but in the complexity of the human body these effects may be difficult to unravel. It is intriguing that two important environmental risk factors in MS, EBV and vitamin D, may influence B‐cell actions in MS. This leads to the question of whether there might be an interplay, which particularly asks for new ways to explore their actions at sites of local inflammation."

Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis
Ther Adv Neurol Disord. 2013 Mar; 6(2): 81–116. doi: 10.1177/1756285612473513 PMCID: PMC3582312
Charles Pierrot-Deseilligny and Jean-Claude Souberbielle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3582312/

"Rationale for the involvement of vitamin D in multiple sclerosis

Vitamin D metabolism
The main steps of vitamin D metabolism are well known and will not be detailed here [Lips, 2006; Holick et al. 2007; Norman and Bouillon, 2010] (Figure 1).

After transformation of 7-dehydrocholesterol into cholecalciferol (vitamin D3) in the skin through the action of ultraviolet B radiation (UVB) or after direct oral intake of vitamin D3 (or D2), there is a first hydroxylation in the liver catalyzed by several vitamin D-25-hydroxylase enzymes, the most important being CYP2R1 [Prosser and Jones, 2004]: this results in 25-OH-D, which is the metabolite measured in the blood to evaluate the vitamin D status (see below).

Then, a second hydroxylation takes place in the proximal tubule of the kidney, catalysed by the enzyme 1α-hydroxylase (CYP27B1) [Prosser and Jones, 2004], resulting in 1,25-OH-2D (calcitriol), which is the active metabolite of vitamin D. Low calcium intake and the parathyroid hormone (PTH) stimulate this renal hydroxylation and increase the calcitriol level in the blood, whereas the phosphaturic hormone fibroblast growth factor 23 (FGF23) and a high level of calcitriol have the opposite effect.

Furthermore, the vitamin D 24-hydroxylase, another enzyme located in the renal tubule and encoded by the CYP24A1 gene, is also able to induce an inactivating pathway for vitamin D metabolites. This enzyme is tightly regulated by FGF23 and the level of calcitriol.

The importance of this inactivating pathway has recently been highlighted in the literature with the demonstration that inactivating mutations of the CYP24A1 gene induced severe neonatal hypercalcaemia [Schlingman et al. 2011]. Vitamin D and its diverse metabolites, including calcitriol, are transported in the blood by the vitamin D-binding protein (DBP) (which is a serum globulin mainly produced in the liver) and to a lesser extent by albumin. The calcitriol dissociates from DBP when entering a target cell and first binds to a specific receptor of vitamin D (VDR) within the cytoplasm (Figure 1).

Then, this complex enters the nucleus and forms a heterodimer by connecting to a nuclear receptor, that is, the retinoid X receptor (RXR). The heterodimer calcitriol–VDR–RXR finally binds to vitamin D-responsive elements (VDREs), which constitute a specific sequence of DNA within the promoter region of the target genes, the whole regulating (by activation or suppression) gene transcription and expression and finally protein synthesis (e.g. cytokines, etc.) in approximately 5–10% of the genome [Wanget al. 2005; Niino et al. 2008; Norman and Bouillon, 2010; Pike and Meyer, 2010] (Figure 1). Thus, calcitriol, secreted into the bloodstream by the kidney and exerting its actions in various other tissues by binding to a specific receptor, can be considered as a hormone."


"Schematic representation of vitamin D metabolism." "...
Besides its role in calcium physiology and bone health, vitamin D also has numerous potential extra-bone actions: protective for the cardiovascular system, antiproliferative (in certain cancers), anti-infectious (innate immunity) and anti-inflammatory and immunomodulatory (adaptive immunity), an effect which could be involved in autoimmune diseases such as type 1 diabetes, Crohn’s disease, rheumatoid arthritis and MS [Holick, 2004, 2007; Vieth, 2007;Vieth et al. 2007; Borradale and Kimlin, 2009; Hewison, 2012]. The specific role of calcitriol within CNS cells remains to be clarified [Smolders et al. 2011b]: it may have potential actions in neuronal functioning, neuroprotection and myelination [Wergeland et al. 2011], but also in innate and adaptive immunity of the CNS, through the invading lymphocytes. Accordingly, the presence of VDRs and CYP27B1 in the different immune and nervous cells constitutes a first indication for potential actions of vitamin D in MS. The immunodulatory action of vitamin D through the general immune system, likely important for MS pathogenesis, is specifically reviewed in the following sections."



"Schematic representation of one of the hypothetical immunomodulatory effects of vitamin D (through calcitriol).
Tr, regulatory T lymphocyte; Th1, lymphocyte T helper 1 (‘aggressive’); Th2, lymphocyte T helper 2 (‘protective’)."

"General immunodulatory effect of vitamin D in humans
The general immunodulatory effect of vitamin D in humans (for a review, see Hewison [2012]), that is, outside the CNS, is currently the best known mechanism through which vitamin D appears to influence MS risk and course. Furthermore, vitamin D could enhance innate immunity via its actions on macrophages and monocytes and regulate adaptive immunity in multiple ways [Adorini and Penna, 2008]. The presence of VDRs in human T lymphocytes [Provvedini et al. 1983; Baekeet al. 2010], in greater number in CD8 than in CD4 lymphocytes [Vedman et al. 2000], as well as in B lymphocytes [Provvedini et al. 1983; Chen et al. 2007], and the expression of CYP27B1 in lymph nodes [Zehdner et al. 2001] and T lymphocytes [Sigmundsdottir et al. 2007] constitute important indications of a potential role of vitamin D in adaptive immunity.

Furthermore, a number of mechanisms by which vitamin D and calcitriol could favourably influence immunity have been reported in the past 30 years: it has been shown that vitamin D (through calcitriol)

reduces differentiation of monocytes to DCs and differentiation and proliferation of DCs, thus decreasing T-cell stimulation [Griffin et al. 2001];

controls T-cell activation [von Essen et al. 2010] and

inhibits T-cell proliferation [Rigby et al. 1990; Lemireet al. 1984];

reduces the production of interleukin (IL)-2 (growth factor for T cells) [Müller et al. 1993];

suppresses in vitro and in vivo production of proinflammatory Th1 cell-derived IFNγ and tumour necrosis factor α [Reichel et al. 1987; Lemire et al. 1995; Baeke et al. 2010;Zhang et al. 2012];

reduces proinflammatory Th17 activity and IL-17 production [Tang et al. 2009; Ikeda et al. 2010; Bruce et al. 2011; Joshi et al. 2011; Allen et al. 2012];

enhances the production of the anti-inflammatory cytokine IL-10 [Heine et al. 2008; Baeke et al. 2010;Allen et al. 2012];

promotes in vitro and in vivo the development of Tregs expressing cytotoxic T lymphocyte antigen 4 and forkhead box P3, resulting in an anti-inflammatory effect [Jeffery et al. 2009; Prietl et al. 2010; Khoo et al. 2012; Urry et al. 2012];

enhances the transformation of CD4 T lymphocytes into a Th2 phenotype (with a protective role) [Boonstra et al. 2001; van Etten and Mathieu, 2005; Sloka et al. 2011b]; and furthermore,

inhibits B-cell differentiation [Chen et al. 2007].

Accordingly, vitamin D has general immunomodulatory and anti-inflammatory effects not only by reducing DCs, Th1, Th17, B-cell proliferation and proinflammatory cytokines but also by promoting Th2 phenotype, Treg activity and anti-inflammatory cytokines. The vitamin D action on Tregs, as mentioned above in the context of EAE, could itself reduce Th1 activity and re-equilibrate the balance between Th1 and Th2 cells, resulting in a reduction of inflammation [Cantorna, 2006; Smolders et al. 2008a] (Figure 2).

Such an action profile of vitamin D (through calcitriol) strongly suggests that an insufficiency of this vitamin could play a role in the pathophysiology of autoimmune diseases, including MS, and may constitute one of the risk factors involved in these diseases."

"Immunomodulatory effect of vitamin D in patients with multiple sclerosis

The multiple immunological studies on patients with MS reported recently have shown that the general immunomodulatory actions of vitamin D on T and B cells already described in animals and normal humans likely also exist in this disease.

One of the first studies dealing with the immunological action of vitamin D in patients with MS was a controlled trial in which it was observed that vitamin D supplementation (1000 IU/day for 6 months) significantly increased tumour growth factor β1, a cytokine inhibiting T cells and secreted by different types of cells, including Tregs [Mahon et al. 2003].

More recently, it has been shown in patients with MS that calcitriol inhibits in vitro T-cell proliferation, inhibits the development of IL-6- and IL-17-producing cells, enhances IL-10 production and the number of Tregs [Correale et al. 2009] and stimulates CD 46 and IL-10 [Kickler et al. 2012], all these mechanisms contributing to an anti-inflammatory action.

Furthermore, a correlation was found between the vitamin D and calcitriol serum levels and the Treg number [Royal et al. 2009], or only between the vitamin D serum level and the inhibitory action of Tregs on Th1 cells, with a beneficial effect in IFNβ users [Smolders et al. 2009] and without correlation with calcitriol, PTH and calcium [Smolders et al. 2010a].

In a small controlled trial, MS-associated abnormal T reactivities were suppressed in vivo by vitamin D supplementation at serum 25-OH-D concentrations higher than 100 nmol/liter [Kimball et al. 2011b].

In another small study, in which patients with relapsing–remitting MS (RRMS) were supplemented with high doses of vitamin D (20,000 IU/day) for 3 months, Tregs were unchanged but the proportion of IL-10+ CD4+ T cells was increased [Smolders et al. 2010b].

Furthermore, in patients with MS, a low vitamin D serum level was associated with T-cell proliferation [Grau-Lopez et al. 2012], vitamin D inhibited in vitro the differentiation and maturation of DCs [Bartosik-Psujek et al. 2010] and enhanced in vivo anti-inflammatory cytokines [Moysayebi et al. 2011], and calcitriol reducedin vitro proinflammatory cytokines and enhanced anti-inflammatory cytokines [Lysandropoulos et al. 2011]. However, there was no substantial effect on phenotypic markers of B-cell differentiation in circulating B cells in a study using supplementation with high doses of vitamin D3 [Knippenberg et al. 2011].

Lastly, the immunomodulatory and anti-inflammatory effects of vitamin D appear to be more marked in women than in men in patients with MS as well as in healthy subjects, maybe due to synergic effects between calcitriol and 17-β estradiol [Correale et al. 2010].

Altogether, these different studies show that vitamin D has potentially beneficial immunomodulatory and anti-inflammatory effects in patients with MS, though their actual impact on the course of the disease remains to be accurately evaluated by randomized, controlled trials (RCTs) using vitamin D supplementation."

"Vitamin D requirements and insufficiency

Optimal vitamin D serum level

25-OH-D is the vitamin D metabolite usually measured in the blood since it is representative of the vitamin D store in the organism [Heaney, 2000;Zerwekh, 2008]. The limits usually recommended are between 75 and 200 nmol/liter (i.e. 30 and 80 ng/mL) [Dawson-Hughes et al. 2005; Binkley and Krueger, 2008; Souberbielle et al. 2010].

The question of the lower cut-off (75 nmol/liter) is a key point to understand the whole vitamin D problem. This limit has not been determined from classical control groups of ‘normal’ adults (i.e. with the 2.5th or 5th percentile found in an apparently healthy population) since vitamin D insufficiency is widespread in general populations (see below), but it has not been empirically fixed either.

Defining vitamin D insufficiency corresponds to determining the 25-OH-D serum level below which adverse outcomes may occur or above which beneficial effects of vitamin D may be observed.

Ideally, this supposes that RCTs demonstrating positive effects of vitamin D compared with placebo on clinical (‘hard’) outcomes are available and that the 25-OH-D concentrations in the ‘vitamin D groups’ of theses RCTs have been evaluated. It must be emphasized that, with the exception of the effect on the risk of falls, the many lines of evidence concerning the various potential extra-skeletal effects of vitamin D are mostly based on observational and mechanistic studies. Although numerous prospective studies have shown that subjects in the highest quantile of 25-OH-D serum concentrations (usually >70–80 nmol/liter) have a lower relative risk for many diseases than those in the lowest quantile (usually Munger et al. 2006; Bodnar et al. 2007; Leu and Giovannucci, 2011; Ma et al. 2011], the observational nature of these studies precludes any conclusion regarding a causal relationship between low vitamin D status and these diseases, and there are consequently no clear clinical cutoff(s) to optimize the potential vitamin D effects. It must be acknowledged that the 75 nmol/liter cutoff is only ‘reasonably’ evidence based (i.e. based on RCTs) for the musculoskeletal effects of vitamin D: in the RCTs that have shown positive effects of vitamin D on nonvertebral fractures [Bischoff-Ferrari et al. 2009b] and falls [Bischoff-Ferrari et al. 2009a], subjects in the ‘vitamin D groups’ generally had 25-OH-D levels of more than 75 nmol/liter, whereas those in the ‘placebo groups’ had levels mostly in the 30–60 nmol/liter range. Consistent with these RCTs, bone biopsy data showed that histomorphometric signs of defect in the mineralization of bone were not detected in subjects with a 25-OH-D serum level of more than 75 nmol/liter whereas they were present, as defined by the most conservative threshold of the osteoid volume/bone volume ratio of 2%, in approximately 20% of subjects with a 25-OH-D serum level between 50 and 75 nmol/liter [Bischoff-Ferrari et al. 2004; Priemel et al. 2010]. Furthermore, patients with a basal 25-OH-D serum level of up to 70 nmo/liter decreased their PTH serum concentration when they were given vitamin D (without calcium) [Okazaki et al. 2011], whereas it has been reported that the PTH serum concentration may increase when the 25-OH-D serum level is below 75–80 nmol/liter [Chapuy et al. 1996; Holick, 2007; Durazo-Arvizu et al. 2010]. It has also been shown that calcium absorption was improved in menopausal women when the 25-OH-D serum level increased to approximately 80 nmol/liter [Heaney et al. 2003b] and calcium excretion was no longer directly dependent on 25-OH-D serum concentrations below the level of 75 nmol/liter [Kimball et al. 2011a]. Lastly, recent data indicate that a 25-OH-D serum level of at least 82 nmol/liter is required to optimize the antifracture efficacy of bisphosphonates [Carmel et al. 2012].

Due to the convergence of the findings provided by all of these different approaches on the 75 nmol/liter level, most medical laboratories in the world have now adopted this level as the lower normal limit, even if this point is not yet consensual [Ross et al. 2011; Heaney and Holick, 2011; Holick et al. 2011]. Furthermore, it should be noted that the ‘physiological’ zone between the 75 and 200 nmol/liter 25-OH-D serum levels grossly corresponds to the serum levels observed in outdoor workers [Haddad and Chyu, 1971; Haddock et al., 1982;Barger-Lux and Heaney, 2002; Azizi et al. 2012], as well as in traditionally living populations in East Africa [Luxwolda et al. 2012]. This zone is far below the toxic zone, which appears to be located above the 400 nmol/liter serum level [Hathcock et al. 2007; Burton et al. 2010]."

"Vitamin D requirements

On the basis of these new metabolic and pathological findings, the daily requirement of vitamin D has recently been reassessed and is now thought to be far higher than the 200–400 IU/day dose that, until a few years ago, was generally estimated to be sufficient. The previously held belief regarding the optimal requirement was principally based on the results of experiments in the rat almost one century ago in the context of studies on rickets prevention. Nowadays, it is more readily accepted that humans are different from rats, as a species as well as in terms of weight for determining treatment doses, and that rickets prevention is not the only vitamin D action to be taken into account. The daily requirement does of course depend on what the optimal target 25-OH-D serum level is considered to be: for a 25-OH-D serum level of 50 nmol/liter, 800-1000 IU/day of vitamin D appears sufficient, but to bring most people above the 75 nmol/liter level, a dosage of between 1000 and 4000 IU/day (depending on the individual, but on average 2000 IU/day) is required [Heaney et al. 2003a, 2009; Grant and Holick, 2005; Hollis, 2005; Bischoff-Ferrariet al. 2006, 2009b, 2012; Vieth, 2006; Hall et al. 2010; Schwalfenberg et al. 2010; Whiting and Calvo, 2010; Cashman et al. 2011; Garrett-Mayer et al. 2012; Holick, 2011, 2012]. However, vitamin D intake via (unfortified) food is very marginal in normal Western diets, even in those considered well balanced, and generally provides less than 100–200 IU/day, rarely reaching little more than 400 IU/day with fortified food [Calvo et al. 2004; Moore et al. 2005; Välimäki et al. 2007; O’Donnell et al. 2008; Vatanparast et al. 2010; von Geldern and Mowry, 2012]. Sunshine therefore remains the principal natural source of vitamin D, providing 80–90% of the requirement in the absence of fortified food. However, in temperate and Nordic countries, vitamin D may be synthesized in the skin via UVB only a few months per year (around summer), that is, when the sun is seasonally sufficiently high in the sky for UVB to penetrate all the layers of the atmosphere, and vitamin D stocks disappear in a few weeks after exposure to the sun (or oral intake) if they are not regularly replenished [Holick, 2007]. It should also be noted that modern lifestyles have tended to reduce most people’s outdoor activities and exposure to the sun. Moreover, exposure to the sun is often avoided due to dermatological concerns and people with dark skins and older people synthesize vitamin D less easily than people with light skins and the young [Vieth, 1999; Armas et al. 2007;Binkley et al. 2007]. Lastly, in people who are overweight, (liposoluble) vitamin D is partly sequestered in adipocytes, which may contribute to a worsening of insufficiency [Earthman et al. 2012]."

"Widespread vitamin D insufficiency

The characteristics of vitamin D physiology, the effects of latitude and climate and multiple societal factors related to vitamin D synthesis result in an insufficiency in this vitamin in most people living beyond the 40th parallels, that is, in Europe, the northen half of the United States, Canada and the former Soviet Union for the northen hemisphere, and New Zealand and Tasmania for the southern hemisphere [Holick, 2007; Pierrot-Deseilligny and Souberbielle, 2011; van der Mei et al. 2012b]. In these countries (for a review, see Pierrot-Deseilligny and Souberbielle [Pierrot-Deseilligny and Souberbielle, 2010]), 25-OH-D serum levels in ‘normal’ adults are between 40 and 70 nmol/liter on average, with generally only slight differences depending upon the season and consequently, at least for a large part of the year, 75% of people are in a state of insufficiency with a 25-OH-D serum level cut-off of 75 nmol/liter and still almost half of the population is in a state of insufficiency if one considers that the cutoff should be 50 nmol/liter. In tropical or subtropical countries, vitamin D serum levels are generally higher, at least for people not systematically avoiding sun exposure, and a correlation exists between latitude and vitamin D serum levels in white people at the world scale [Hagenau et al. 2009]. Such a correlation has also been observed in France, a relatively small country [Chapuy et al. 1996]."

"Vitamin D insufficiency in patients with multiple sclerosis

In patients with MS living in temperate and Nordic countries, as in the general populations of these countries, vitamin D insufficiency is widespread, whatever the cutoff (50 or 75 nmol/liter) for the lower limit of the 25-OH-D serum level (Figure 3): indeed, as early as the earliest stages of the disease, that is, in patients with clinically isolated syndrome (CIS) or with RRMS, average serum levels are between 42 and 74 nmol/liter, depending on the studies and the seasons, with a general mean close to 60 nmol/liter [Soilu-Hänninen et al. 2005, 2012; Smolders et al. 2008b;Hiremath et al. 2009; Kragt et al. 2009; Mowry et al. 2010; Pierrot-Deseilligny and Souberbielle, 2010, 2012; Simpson et al. 2010; Banwell et al. 2011; Dabbaghmanesh and Yousefipour, 2011; Lonergan et al. 2011; Neau et al. 2011; Steffensen et al. 2011; Yildiz et al. 2011; Bäärnhielm et al. 2012; Kampman et al. 2012; Kirbas et al. 2012; Løken-Amsrud et al. 2012; Moen et al. 2012; Runia et al. 2012; Soilu- Hänninen et al. 2012; Šaltyte. Benth et al. 2012; Triantafyllou et al. 2012] (Table 1).

In some of these studies, there was a control group in addition to the patient group and there was not always a significant difference in vitamin D serum levels between the two groups. However, this point may be considered secondary since we now know that most control ‘normal’ subjects are also in a state of more or less marked vitamin D insufficiency. Thus, the possible role of vitamin D status in any disease, including in MS, must always be interpreted in conjunction with the actions of multiple other environmental and genetic risk factors interacting with this status (see below). In this context, vitamin D insufficiency appears to be only one risk factor favouring the disease, interacting in concert with multiple other risk factors, which may explain a significant deleterious effect on MS risk of this widespread vitamin insufficiency at a population scale but does not account for the totality of individual situations of patients with MS, in whom the cumulative effects of several other risk factors may have at times a crucial role, independently of vitamin D status. In particular, in the relatively rare cases of patients with MS in whom normal spontaneous vitamin D serum levels are observed throughout the year, it may be hypothesized that, in these patients, either other environmental (infectious, toxic, etc.) and genetic risk factors play a determinant role or (genetic) errors in the metabolism and actions of vitamin D exist downstream to the 25-OH-D serum level determination. Conversely, the fact that the great majority of ‘normal’ subjects who are in a state of vitamin D insufficiency (on the same basis as patients with MS) do not eventually develop MS may be explained by the existence, in these subjects, of other protective environmental or genetic factors."



"Schematic representation of the evolution of 25-OH-D serum level according to multiple sclerosis stage."

"Note that there are so far no data in patients with RIS and siblings of patients with MS but it may be inferred that their 25-OH-D serum concentrations are not very different from those of ‘normal’ populations. CIS, clinically isolated syndrome; MS, multiple sclerosis; RIS, radiologically isolated syndrome."

  "Modulation of multiple sclerosis risk from conception to the time of disease triggering."

"Note that
(a) risk factors for MS are multiple, genetic and environmental (lower part of the figure),
(b) opposite conditions or other factors may be protective from MS occurrence (upper part of the figure),
(c) interactions are numerous between all these risk and protective factors and
(d) may occur throughout the first part of life, from conception until MS triggering."

"Note also that the period from conception to adolescence is crucial for the maturation of the immune system and thymus and could be particularly important for the interactions of the different protective and risk factors. In these successive events or situations, the likely risk factors are (see text):

(1) unfavourable genetics, (1’) including HLA-DRB1*1501;
(2) EBV infection, which may be a crucial event for subsequent MS (years later), with particularly an increase in MS risk if (2’) the primo-infection occurs late and (2”) is followed by a high anti-EBNA1 level;
(3) vitamin D insufficiency, also increasing MS risk, (3’) including conditions likely related to this insufficiency or to insufficient exposure to sun; and
(4) smoking, also contributing to this risk, even if (4’) it is only passive in childhood (however, with only one study having been reported so far). Reverse or other conditions could be protective: (1p) favourable genetics, (1p’) including HLA-A*0201; (2p) absence of EBV infection; (3p) vitamin D sufficiency, (3p’) including conditions likely related to a normal vitamin D status or sufficient exposure to sun; and (4p) numerous infections during childhood (hygienic hypothesis), possibly protective from subsequent auto-immune diseases. EBV, Epstein–Barr virus; HLA, human leukocyte antigen system; MS, multiple sclerosis."

"Furthermore, it should be noted that the vitamin D serum level usually tends to decrease throughout the course of MS because of the conjugate actions of three worsening factors for vitamin D insufficiency, successively intervening and accumulating during this course (Figure 3): as early as the beginning of MS, Uhtoff’s phenomenon (heat sensitivity) may lead some patients to spontaneously avoid sun exposure and the associated heat, an attitude that until recently was often encouraged by neurologists, leading to an accelerated decline in vitamin D synthesis; in the mid course of the disease, disability reduces outdoor activities and, consequently, sun exposure; in older patients, vitamin D synthesis is physiologically reduced by age. These different factors contributing to the deterioration of vitamin D status likely partly explain why vitamin D serum levels are lower in secondary progressive MS (SPMS) than at the earliest stages of the disease, with concentrations usually close to 40 nmol/liter [Nieves et al. 1994; Ozgocmen et al. 2005; Smolders et al. 2008b; Pierrot-Deseilligny and Souberbielle, 2010; Neau et al. 2011].

These associated factors might also contribute to ‘reverse causality’ (i.e. with the disease worsening the initial insufficiency in vitamin D), at least in mid and advanced stages of MS. However, it should not be ignored that a marked hypovitaminosis D is observed as early as the earliest stages of MS (i.e. before these associated factors can be exerted) and consequently may contribute to triggering the disease (see below). From a preventive point of view, it would also be of particular interest to study the vitamin D status of subjects with radiologically isolated syndromes and in siblings of patients with MS (Figure 3), since they all have an increased risk for MS."

"Vitamin D insufficiency is likely one of the risk factors for multiple sclerosis"

"It is nowadays commonly accepted that MS is a multifactorial disease that appears in subjects who are genetically predisposed and who encounter one or more deleterious environmental factors [Goodin, 2009]."

"Relapses

Since vitamin D has general immunomodulatory and anti-inflammatory actions, and furthermore, since some already documented immunological effects of this vitamin have been reported in patients with MS, most of whom are in a state of vitamin D insufficiency (see the first section), a potential influence of vitamin D status may be expected on the inflammatory component of MS, in particular on relapses during the initial stage of the disease.

Vitamin D supplementation was associated with a decrease of about 50% in the number of relapses in a pioneering uncontrolled small study using 5000 IU/day of vitamin D for 2 years in 10 patients with RRMS [Goldberg et al. 1986].

There was also a decrease in relapses, albeit nonsignificant (–41% in the vitamin D arm versus –17% in controls), in a more recent controlled study using high doses of vitamin D (14,000 IU/day on average) for 1 year in patients with RRMS, with 25 treated versus 25 control patients [Burton et al. 2010], which is too small a sample and too short a follow up to draw definite conclusions about clinical outcomes. Furthermore, the very high vitamin D doses used in this study eventually resulted in high, supraphysiological vitamin D serum levels (i.e. close to 400 nmol/liter), which were well tolerated but may not be required to obtain a vitamin D effect (see below)."
...

"In contrast to these inconclusive small controlled studies, several recent association studies found a significant relationship between the vitamin D status and the relapse rate in patients with RRMS [Smolders et al. 2008b; Runia et al. 2012], with possible variable positive or negative interactions with IFNβ depending upon the vitamin D serum level, higher or lower than 50 nmol/liter respectively [Stewart et al. 2012].

In another recent association study, preliminary results provided evidence that low serum 25-OH-D levels are an important risk factor for conversion from CIS to MS, suggesting that vitamin D supplementation in combination with IFNβ-1b may improve outcomes in CIS [Ascherio et al. 2012b]. 

Interestingly, three other association studies, one in a paediatric cohort of patients with CIS or RRMS at the very beginning of the disease [Mowry et al. 2010] and the other two in adult cohorts of patients with RRMS [Simpson et al. 2010; Pierrot-Deseilligny et al. 2012], were comparable for sample size and follow up (Table 2). Furthermore, similar statistical models were used in these studies and predicted an analogous quantitative vitamin D effect on the relapse rate since an increase of 50 nmol/liter in the 25-OH-D serum level was associated with a marked decrease in the relapse rate (−50% to −68%), independently of the use of vitamin D supplementation or an association with a first-line immunomodulatory therapy (IMT) (Table 2).

These quantitative predictions made by statistical models on the vitamin D effect may appear high, with a therapeutic action potentially similar to that of the best active treatments used in MS. However, such predictions are global and there are, of course, limits in the possibilities for a decrease in relapses (i.e. necessarily between 0% and 100%). It should also be noted that most of the patients in these three studies had relatively low vitamin D serum levels, close to 50 nmol/liter on average, including in our patients before supplementation [Pierrot-Deseilligny et al. 2012].

Furthermore, the patients in our study were systematically supplemented with moderate doses of vitamin D (3010 IU/day) for 2.5 years on average and their serum level passed from 49 ± 22 to 110 ± 26 nmol/liter with this supplementation. This resulted in a relatively wide range of vitamin D serum levels (before and under supplementation) and led us to observe a plateau effect of vitamin D action on the relapse rate beyond 110 nmol/liter (Figure 5), which might thus indicate an upper limit for vitamin D efficacy.

Therefore, at least in our study, there appeared to be a marked vitamin D effect mainly within a relatively limited range of vitamin D serum levels, between 60 and 110 nmol/liter (Figure 5). It should be noted that this range extends from a lower limit approximately equivalent to the spontaneous level found in most patients in temperate countries to an upper limit reached by most of them if supplementation uses physiological doses of vitamin D, thus providing an almost maximal advantage of the potential vitamin D effect.

Reverse causality, that is, the disease itself worsening the vitamin D insufficiency by limiting sunshine exposure, has been invoked to try to account for the correlations found between the spontaneous vitamin D serum level and the relapse rate of patients with RRMS in association studies. However, such an argument becomes very unlikely when patients are at the very beginning of the disease [Mowry et al. 2010] or are supplemented with vitamin D [Pierrot-Deseilligny et al. 2012].

Altogether, even if no definite conclusion can be drawn from simple association or observational studies, the fact that a similar marked vitamin D effect on the relapse rate has been found in three different cohorts of patients with RRMS of all ages, with or without associated IMT and with or without vitamin D supplementation, already strongly suggests that the vitamin D status significantly influence relapses. Of course, RCTs have to confirm this effect and accurately calibrate it."


"Example of evolution of relapse incidence rate ratio according to the 25-OH-D serum level in patients with MS."


7. Osteamalacia! 

 Osteomalacia is a condition in which bones become soft and there is aching, throbbing bone pain. This is a result of impaired bone metabolism due to inadequate levels of phosphate, calcium, and vitamin D. Another symptom is muscle weakness.
- Type 1 diabetes,
- cardiovascular disease,
- certain cancers,
- cognitive decline,
- depression,
- pregnancy complications,
- autoimmunity,
- allergy
- low levels of vitamin D during pregnancy and infancy appear to increase susceptibility to schizophrenia, type 1 diabetes, and multiple sclerosis (MS) in later life.
- Osteoporosis