Geoengineering, Solar Radiation Management, Aerosol Clouds, Chemtrails
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Symptom orientation! Autism, Cancer, Fibromyalgia, Psoriasis, Multiple Sclerosis!


  • Symptom orientation! 
  • Autism!
  • Cancer!
  • Fibromyalgia!
  • Psoriasis!
  • Multiple Sclerosis!
  • Osteomalacia!
  • More about VitaminD!

Symptom orientation!

If the profit doesn't lie in a solution, but on the way of seeking, the profit becomes endless if the victim on meanders within a labyrinth. The labyrinth is build by keeping the victim preoccupied with the symptoms and distracted with "mitigation" of pain adaptation to suffering and feeding hope with fake solutions.

  • ClimateControl has already killed more life than the world wars!
  • ClimateControl is a war on all life forms!
  • ClimateControl kills at least since 1960, without any pause, extending its deadly tentacles all over the world!
  • ClimateControl kills globally. It is the real meaning of "globalization"!
  • ClimateControl is the ultimate method of "depopulation"!
  • ClimateControl is implementation of extinction of life!
  • ClimateControl is the ultimate tool of Psychopathocracy!
  • ClimateControl is the ultimate way of Corporatism/Fascism!
  • ClimateControl is the global earthquake machine!
  • ClimateControl is for fracking colonialism!
  • Climate Control mafia is Your enemy!
  • ClimateControl is the ultimate weapon of mass destruction!
  • ClimateControl kills by vitaminD deprivation!
  • ClimateControl is a global burka on all life!
  • ClimateControl death doesn't come with tanks and bombs, it is a creeping, slow death killing form inside by anti-immune reaction
  • ClimateControl is the ultimate attack on the ultimate freedom, which is the freedom on sunlight!
  • ClimateControl is already attacking You, so wake up!

Small or big, every fraud is implemented the same way.

Fake, even upside down correlations are part of the distraction, but finding the right correlation is the starting point of searching for reasons and some correlations are so compelling that we should not ignore them. Before diving into climate control relations, let us look at something else to prove that the scam is always working the same way. Epidemic autism and cancer are not the direct caused by climate control, but vitaminD deprivation prevents the self healing mechanisms.


Vaccines are propagated to protect us by controlled immunization against various pathogens. Since the invention of vaccination the amount of vaccines has grown and the materials have been modified. The idea of vaccinating children to give them a tough immune system at the start of their life may sound good, but what if the correlation indicates that at least some vaccines are more damaging than helping?

Or take this one! Why is the autism rate now about 1 of 50?

Should we ignore this correlation?

Should the pharma corporations ignore it, because else they would damage their revenues?

Should the governments ignore it, to protect the economy and workforce of the pharma industry?

Should the employees of pharma corporations accept having autistic children as a collateral damage of having income?

Should the medics and scientists observing this correlation prevent researching the reasons of this correlation?

There some studies which don't support the assumption of MMR (measles, mumps and rubella) vaccines would cause autism, but they don't deliver the explanation for the correlation or another reason of autism either! 

Vaccines and Autism: A Tale of Shifting Hypotheses Stanley Plotkin Jeffrey S. Gerber Paul A. Offit
Clinical Infectious Diseases, Volume 48, Issue 4, 15 February 2009, Pages 456–461, Published:15 February 2009

"Twenty epidemiologic studies have shown that neither thimerosal nor MMR vaccine causes autism. These studies have been performed in several countries by many different investigators who have employed a multitude of epidemiologic and statistical methods. The large size of the studied populations has afforded a level of statistical power sufficient to detect even rare associations. These studies, in concert with the biological implausibility that vaccines overwhelm a child's immune system, have effectively dismissed the notion that vaccines cause autism. Further studies on the cause or causes of autism should focus on more-promising leads."

They invest huge efforts to protect the market for MMR and thimerosal markets, but don't spend a cent in researching the causes of autism! Can we trust such guys, because they name their marketing paper "studies"?

If they don't know the real reason yet, why don't they stop using MMR and thimerosal for vaccination to go back to the former methods and materials and empirically rule out any involvement of MMR and thimerosal in the rise of autism?

There is only one answer to that question! 
They protect the investments in MMR and thimerosal!
They don't protect the health of the children!
They don't care about health, they only care for the business!

This conclusion alone should prevent any direct or indirect involvement of pharma corporations in research and development of medicine, particularly vaccines.

The best way of business protection is to blame the victims for their devastation!

What causes autism?

Whenever a collateral disease with epidemic scale has to be hidden from minds, the answers are always the same! They are made to blame the victims!


  • Autism’s genetic risk factors
  • Autism’s environmental risk factors
  • Advanced parent age (either parent)
  • Pregnancy and birth complications (e.g. extreme prematurity [before 26 weeks], low birth weight, multiple pregnancies [twin, triplet, etc.])
  • Pregnancies spaced less than one year apart
  • Differences in brain biology

Genetics, environment, parental age, pregnancy complications, different biology and all the other aspects existed also before the use of MMR and thimerosal! Why should all that be blamed?

But it is never what empirically correlates!
"No effect on risk:
Vaccines. Each family has a unique experience with an autism diagnosis, and for some it corresponds with the timing of their child’s vaccinations. At the same time, scientists have conducted extensive research over the last two decades to determine whether there is any link between childhood vaccinations and autism. The results of this research is clear: Vaccines do not cause autism. The American Academy of Pediatrics has compiled a comprehensive list of this research. You can view and download the list here.

These "studies" are not scientific evidence. They don't research the reaction of the vaccine materials in the body and verify or falsify the impact. They only play with statistics! Following a academic form doesn't make them scientific. Making the publication look scientific is the best working form of deceit. The notion "scientific" is abused like a religious dogma. You are expected to "believe in science" and accept and not resist the fraud!

Vaccines Cause Autism

"Firstly, vaccines contain both mercury and aluminum. See the Centers for Disease Control (CDC) additives chart."
"During the supposed 1999-2002 phase out mercury in vaccines. The Centers for disease control suggested that pregnant women in their first trimester receive a dosage of mercury labeled as a "flu vaccine." (CDC MMWR 205;54 (41):1050-52)"

"After the phase out, aluminum content was increased in vaccines in HEP A. Babies who follow the CDC immunization schedule recieve 5mg (5000 mcg) of aluminum by 18 months of age."

"When Mercury is Removed from the Body - Autism symptoms leave."


Truth Frequency Radio, Aug 26, 2014, Melissa Melton

"The rates of autism have skyrocketed and continue to get worse each year in this country. The CDC now estimates autism effects 1 in 68 children in the U.S., up a whopping 30% from 2012. For boys, the rate is now 1 in 42. The CDC continues to say genes play a role, but the agency readily admits it doesn’t know what is causing all this autism."

"The prevalence rate for autism before 1990 was only three children per 10,000. When the CDC began surveillance of the study population in 2000, it was one child in every 150. Look at the chart above. Autism just keeps going up."

"Back in 2009, when the autism rates first rocketed to 1 in 88, the Environmental Working Group suggested exposure to neurotoxic chemicals could definitely play a role: most notably, mercury."

All big crimes seem to begin with an "Act"!

"The federal Toxic Substances Control Act has allowed the chemical industry to flood the marketplace with toxic chemicals, including neurotoxins, with virtually no proof they are safe for people."

"Then again, the CDC is currently ignoring a whistleblower within its own ranks who came forward to admit that the agency knowingly manipulated data to hide a link in one of its major studies between the MMR vaccine and autism — a link which showed a 340% increase in autism specifically in African American boys given an MMR shot at age three or younger."

"Even if you pretend that isn’t happening, America has the most aggressive mandated vaccine schedule in the world. The CDC now recommends up to 37 shots of 14 different vaccinations by the age of two, prompting the National Vaccine Information Center to ask, “Is the atypical manipulation of the immune system with more and more vaccines in early life setting some children up for chronic disease and disability?”"

"Why not? The pediatric and adolescent vaccine market is set to be worth over $16 billion by 2016, and no one pushes those shots harder than the CDC, a well-known revolving door with Big Pharma."

"It isn’t hard to see where the mutually beneficial arrangement between CDC and Big Pharma would keep the agency pointing its finger at anything other than the products its pushing."

"Our children are being damaged en masse in this country, but none of these so-called medical experts running the show can seem to figure out why? The alarming rise in autism and developmental disabilities in this country are just such a great “mystery,” right?"


This is another example, where You can read a lot about the symptoms and mitigation and treatment, but the rate of cancer diseases grew, despite the huge oncology market!

Is oncology yet another marketing instrument of the pharma industry?

Growth of Cancer
Alternative Cancer Therapies | Natural Health Newsletter
Date: 02/21/2011 Written by: Jon Barron, © 1999-2017 The Baseline of Health Foundation

"And yet it is during the 20th Century that most of the suspect elements mentioned above became part of our lives. If cancer has gotten noticeably worse in the 20th Century, then the evidence is pretty clear that those elements play a role. If it has stayed the same or improved, then we can dismiss the alternative health POV as just another conspiracy theory."
"Look at the report "Cancer Trends" as published by the Competitive Enterprise Institute, and you learn that:"

"Every single day of your life your body produces anywhere from a few hundred to as many as 10,000 misprogrammed cells as part of normal metabolic processes. The trick is that if your immune system is healthy or not overwhelmed by too many rogue cells, it eliminates each and every one of those cells. What we call cancer results when the immune system fails to do its job and allows some of those rogue cells to survive long enough to begin to replicate and "establish a beachhead" in your body. Once the rogue cells develop a support network that allows them to feed themselves, they can start producing bio-chemicals that promote their own existence at the expense of healthy cells. That's cancer."

"And likewise, we know that certain dietary choices, chlorinated water, radon gas in our homes, and exposure to numerous toxins and xenoestrogens in our environment significantly increase our risk of cancer. It's a game of odds -- odds that we'd like to move in our favor."

"And how do you change those odds?

  • Minimize your exposure to toxins and foods that are likely to increase the number of misprogrammed cells in your body.
  • Clean out (detox) four times a year to get rid of any toxins that will inevitably make their way into your body.
  • Build up your immune system using immune boosters to maximize your body's ability to eliminate 100% of the rogue cells produced in your body.
  • Have regular checkups because even if you do everything right, it's still possible that one single cell made it through your body's defenses in a weak moment and took root. Caught early, your chances of defeating the cancer through natural or medical means are good. But remember, cancer is a game of odds, not guarantees.

"Is Cancer Mortality Increasing?
Wendell M. Strong, DOI: 10.1158/jcr.1921.251 Published July 1921
"In the registration of 1900, the cancer death rate per 100,000 population, which will hereafter be spoken of as the cancer death rate or cancer mortality, increased from 63 in 1900 to 79 in 1913, an increase of over 25 per cent. England and Wales for the same period showed an increase from 83 to 105 and most other European states showed a very considerable increase. Going back forty years, the rate in twenty large American cities was 49 for the period 1881–1885; for 1913 it had increased to 89. In twelve European countries the rate was 69 for the period 1896–1900; for the period 1906–1910, it had increased to 81."

United States Cancer Statistics: An interactive Cancer Atlas.

UK: Lung cancer mortality statistics

WHO: Cancer, Fact sheet
February 2017
"Key facts

  • Cancer is one of the leading causes of morbidity and mortality worldwide, with approximately 14 million new cases in 20121.
  • The number of new cases is expected to rise by about 70% over the next 2 decades.
  • Cancer is the second leading cause of death globally, and was responsible for 8.8 million deaths in 2015. Globally, nearly 1 in 6 deaths is due to cancer.
  • Approximately 70% of deaths from cancer occur in low- and middle-income countries.
  • Around one third of deaths from cancer are due to the 5 leading behavioral and dietary risks: high body mass index, low fruit and vegetable intake, lack of physical activity, tobacco use, and alcohol use.
  • Tobacco use is the most important risk factor for cancer and is responsible for approximately 22% of cancer deaths.2.
  • Cancer causing infections, such as hepatitis and human papilloma virus (HPV), are responsible for up to 25% of cancer cases in low- and middle-income countries3.
  • Late-stage presentation and inaccessible diagnosis and treatment are common. In 2015, only 35% of low-income countries reported having pathology services generally available in the public sector. More than 90% of high-income countries reported treatment services are available compared to less than 30% of low-income countries.
  • The economic impact of cancer is significant and is increasing. The total annual economic cost of cancer in 2010 was estimated at approximately US$ 1.16 trillion4.
  • Only 1 in 5 low- and middle-income countries have the necessary data to drive cancer policy5.

Here the distracting "official history" of cancer: 

Cancer Risk Factors:

  1. Risks of Tobacco
  2. Infection
  3. Diet, Body Mass, and Physical Activity
  4. Ultraviolet Radiation
  5. Reproductive and Hormonal Factors
  6. Environmental Pollutants and Occupational Exposures
  7. Human Carcinogens Identified by the IARC Monographs Program

All the above may facilitate cancer, but the oncology pharma business is fishing in murky waters. Decades of "research", billions from chemotherapy business don't deliver knowledge about the causes, so we have to look somewhere else.

What are the alternative explanations of cancer?
Could cancer be a reaction of the body on pathogens?
If true, why the cancer industry never talks about pathogens?

Following explanation is based on evidence and is not blaming the victims!

Radioactive radiation is the true cause of most cancer

"Cancer is often regarded as something that just occurs mainly naturally, a consequence of people living longer than they used to. But we can prove that this is untrue. We can prove that there is an exact year in history when cancer very suddenly became an ever growing worldwide problem, totally unrelated to average life expectancy. This year was the year when nuclear testing started and when the bombs on Hiroshima and Nagasaki were dropped. We think it can be proven that the great majority of cancer cases is caused by alpha radiation from radioactive fertilizer from mines that have natural Radium content, as well as alpha radiation from contaminated soil as a consequence of nuclear accidents and atmospheric nuclear detonations."

"We will also prove (with a link to another article of ours) that smoking causes cancer solely due to the alpha-radiation from the fertilizer used to grow the tobacco."

"It is easy to verify, using downloadable data from Sweden's Central Statistics Bureau that Swedes didn't suddenly start smoking much more in 1950 and that Sweden's population didn't rise sharply around that time or became significantly more elderly. Neither are their factors at play such as improvements in cancer detection rate in old age. The data is unequivocal: Starting in 1950, Swedes were getting more cancer. Ten years later, their cancer rate had doubled. Fifteen years after that, their cancer rate had doubled again. In 1990, their cancer rate was five times higher than that in 1950. And today their risk of getting cancer is six times higher than when it suddenly started to rise in 1950. And it's not that's it's just happening in Sweden: Cancer is getting out of control worldwide:"

"Drop in cancer coincides with closed nuke plants

Note how in 1990, UK cancer mortality rates saw a very sharp and very significant, sustained drop around 1998, 1999, 2000. What happened in the UK during that time? They closed a dozen ailing old nuclear reactors. Two Magnox reactors, an obsolete design used to produce Plutonium for nuclear weapons, were closed in the UK in 1989. The Dorset-Winfrith plant comprised of nine nuclear reactors and it was decommissioned in 1990. Do you see the leveling off of the cancer rate in 1981 and 1982? In 1981, the UK closed the Sellafield-Windscale plant.

This website delivers very valuable information and a clear 1:1 correlation with rise and decrease of cancer together with nuclear fallout from nuclear bombs and reactors. However, it doesn't really explain what cancer really is. The nuclear radiation is evidently an important trigger! The damaging of cells, the weakening of immune system seems to open the doors for cancer.

There is only one real source with clear evidence, repeatable testing, proving that cancer is caused by pathogens. 

It is the work of Dr. Alfons Weber!

What do we learn from Dr. Alfons Weber?

1. Cancer is caused by small pathogens, which mainly attack the red blood cells.
2. The pathogens grow to multi-cellular beings.
3. Unter threat the multi-cellular creature can separate itself into single cells.
4. The single cells can multiply by division.
5. Multi cells can breed sexually.
6. The pathogens can cross the blood vessels if they are damaged and attack other cells of the body.
7. Up to a limited capacity the attacked body cell can defend itself by neutralizing the pathogens by vesiculation.
8. If the capacity of vesiculation is reached the body cells divides itself to divide the pathogens on multiple cells for further vesiculation.
9. The exuberant growth of the tissue is the last defense method of the body cell.
10. The pathogens survive heat where body tissue is cooked and dead.
11. All cancer tumors contain the pathogens.


Researching for a cure against cancer pathogens, Dr. Weber detected that they have similarities with malaria pathogens. So he tried to fight them with quinine.

His own publication can be found here:
Über die Ursache der Krebskrankheit
Von Dr. med. ALFONS WEBER mit 130 vierfarbigen Abbildungen 1. Auflage 1969

Another private website about ...
Dr. Alfons Weber - Parasiten bei Krebs

Wikipedia article about Dr. Alfons Weber

Auf Grund der von Weber beobachteten Ähnlichkeit seiner Ca-Protozoen mit Plasmodien glaubte er auch an eine effektive Krebstherapie durch Medikamente die gegen Plasmodien wirken, wie Chinin, Resochin und Primaquin und berichtete von Zustandsbesserungen bei Patienten, bei denen er vorab einen hohen Protozoämiegrad festgestellt zu haben glaubte."

[Because of his observation about the similarities of his 'Ca-Protozoen" with plasmoids, he believed that a effective cancer therapy could be reached with with drugs against plasmoids liek quinine, resochin or primaquine and reported improvements of the condition of patiens, where he had confirmed a high level of protozomia.]

"Webers Therapie von Krebserkrankungen mit Anti-Malariamitteln stieß auf Ablehnung von Kollegen und Behörden und führte zu gerichtlichen Verfahren. Es kam in der Folge zu einer Auseinandersetzung mit den bayerischen Behörden und zu einer jahrelangen Schließung seiner Praxis und dem Entzug der Approbation im Jahre 1968."

[Weber's therapy of cancer with anti-malaria drugs was rejected by some colleagues and administration and lead to judicial proceedings. That was followed by a dispute with the Bavarian administration, resulted in the closure of his practice for many years and revocaton of his approbation in 1968.]

"1972 wurde Weber in das psychiatrische Krankenhaus Haar eingewiesen, wo jedoch keine psychiatrische Krankheit festgestellt werden konnte. Durch eine Spende von drei Millionen Mark durch eine Anhängerin konnte Weber trotz geschlossener Praxis privat weiterforschen. 1974 erhielt Weber seine Approbation zurück."

[In 1972, Weber was delivere to the psychiatric hospital in Haar, where no psychiatric disease could be detected. With a donation of 3 Million DM by a supporter, Weber could pursue his research privately, despite the closure of his practice. In 1974 Weber retained is approbation.]

By the way, compulsory hospitalization into psychiatry was and is still a feared method of administration and established criminals in Bavaria. A very famous case is the one of Gustl Ferdinand Mollath, who was jailed in psychiatry for exposing criminal money transfers to Switzerland by HypoVereinsBank, now part of Uni Credit!

Wikipedia article about Gustl Mollath:

His own website during internation:
Der Fall Gustl Mollath

[The case of Gustl Mollath]

Some excerpts from the same paper and also reference to Robert Picard is used here:
Mikroparasiten als Krebsauslöser

There we also find the list of all books of Dr. Alfons Weber:

  • Über die Ursache der Krebskrankheit“ (1969)
  • „Haben wir potentielle Krebserreger schon im Blut?“; 1983)
  • „Jahrhundertskandal Krebs“ (1987, bis zum Jahr 2003 zurückgehalten)
  • Dreisprachiger Farbatlas „Pathogene Protozoen im Blut-, Organ- und Tumorgewebe“ (1970)
  • „Krebsbankrott“ (2003) von Ernst Wollenberg und Thomas Blasig

Meanwhile for treating malaria, not quinine but artemisin is used. Artemisinin is a content of the herb Artemisia, which is name "Gemeiner Beifuß" in German and "Mugwort" or "Wormwood" in English.

Beifuss – uraltes Wissen gegen Krebs 

[Wormwood - aged knowledge against cancer]
[The secret of the effect of artemisinin]

"Das Geheimnis seiner Wirkung liegt in seiner Reaktion mit Eisen, das sich in hohen Konzentrationen in Malariaerregern findet."

[The secret of its effect lies in its reaction with iron, which is hugely available in malaria pathogens.]

"Gerät Artemisinin in Kontakt mit Eisen, kommt es zu einer chemischen Reaktion, durch die freie Radikale erzeugt werden, diese sind die eigentliche Waffe gegen die Malariaparasiten. Sie greifen die Zellmembrane an, reißen sie förmlich auseinander und vernichten so den Erreger.

[Artemisinin getting in contact with iron, the chemical reaction results in production of free radicals. These are the real weapons against malaria parasites. They attack the cell membrane, destroy the cell and extinguish the pathogens.]

"Da Krebszellen große Mengen an Eisen verbrauchen, um bei der Zellteilung ihre DNS zu reproduzieren, finden sich darin auch wesentlich höhere Konzentrationen als in normalen Zellen."

[As cancer cells consume huge amounts of iron, to produce their DNS during cell division, more higher concentrations of iron can be found there, compared to healthy cells.]

"Die Krebszellen können deshalb mehr Eisen aufnehmen, weil sich an ihrer Oberfläche viele Transferrin-Rezeptoren befinden."

[The cancer cells can absorb more iron, because the surface contains more transferrin-receptors.]

"Diese binden die Eisenteilchen und schleusen sie in das Zellinnere. Krebszellen werden mit so viel Eisen wie möglich vollgepumpt."

[These (trasferrin-receptors) bind the iron particles and transfer them into the cell. Cancer cells are filled up with iron.]

"Gibt man Artemisinin, wird die gleiche Reaktion wie bei Malaria in Gang gesetzt, es kommt zur massiven Freisetzung von Sauerstoffradiakalen in der Krebszelle, so dass dies zu ihrem Untergang führt: sie werden vernichtet."

[Giving artemisinin, the same reaction like with malaria is triggered. Oxygen radicals are set free in the cancer cell, which leads to their doom: to be demolished.]

"Bestätigt wurden diese Befunde an Brustkrebszellkulturen. Acht Stunden nach Exposition gegen Artemisinin waren 75 Prozent der Zellen vernichtet, nach 16 Stunden lebten so gut wie keine mehr. Noch beeindruckender waren Tests mit Leukämiezellen. Diese waren bereits nach acht Stunden völlig zerstört."

[These findings were confirmed on breast cancer cell cultures. Eight hours after exposition to artemisinin, 75% of the cells were destroyed, after 16 hours nearly none were alive. More impressive were the tests with leukemia cells. They were all destroyed within 8 hours.]

"Neben seiner hohen Effektivität hat Artemisin 
viele Vorteile: Es ist selektiv.Es wirkt auf Krebszellen toxisch, doch auf normale Zellen hat es fast keinen negativen Effekt."

[In addition to its efficiency, artemisinin has many preferences: It is selective. Acting toxic on cancer cells, it nearly no negative effect on healthy cells.]

"Auch Krebszellen, die gegenüber Zytostatika resistent sind, reagieren bzw. werden abgetötet. Alle Krebsarten reagieren und sind empfindlich!"

[Also cancer cells which are resistant against cytostatica react accordingl and are killed. All kinds of cancer react and are very sensitive.]

The explanations in this article are very promising, but there is one point which is not clearly mentioned! The intention should not be just to kill the cancer cells, but the pathogens. At least the pathogens are not mentioned or any knowledge about the work of Dr. Alfons Weber. According the evidence from his documentation, killing a cancer cell would release the pathogens, which would swarm out and attack other healthy cells, building the known metastases.

Why is the established clerical science ignoring the important research of Dr. Alfons Weber and has done everything to degrade is work and deprive him from all means to continue?

Why is the established clerical science assuming the parasites would be organelles of the cell?

Why are the patients pushed into the expensive and deadly chemotherapy, which fully destroys the immune system, instead of supporting it to fight the pathogens?

Talked enough about autism and cancer to indicate the method of big fraud on the society we come now to the diseases which correlate with climate control!

Vitamin D deficiency increases risk of cancer

Dr. David Jockers +


Let us begin with some basics.

Fibromyalgia Syndrome

"Fibromyalgia is a chronic illness that causes immense physical pain and debilitating fatigue. Classified as a syndrome, fibromyalgia is not a disease. Instead it is a condition that causes many different symptoms. These symptoms affect all systems in the body. Fibromyalgia plagues up to 5% of the population, with 6 million sufferers in the United States alone. The name fibromyalgia comes from \"fibro\" meaning fibrous tissue (such as tendons and ligaments), \"my\" meaning muscles, and \"algia\" meaning pain."

"Many Other Symptoms
Although pain is the foremost symptom of fibromyalgia, it is by no means the only symptom. Among other symptoms, fibromyalgia sufferers often experience:

  • sleep disorders
  • fatigue
  • morning stiffness
  • irritable bowel syndrome

The so called "research" is again prepoccupied with the symptoms and doesn't really deliver any reason!

What Is The Latest Fibromyalgia Research?
  • Processing Pain
  • Genetics
  • Stress
  • Reproductive Hormones
  • Sleep Problems
  • Psychiatric Disorders
  • Understanding Different Reactions To Fibromyalgia

Vitamin D May Ease Fibro Pain
By Randy Dotinga, HealthDay Reporter

"In the study, researchers led by Dr. Florian Wepner, of Orthopedic Hospital Vienna Speising, sought to discover whether there is a link between a patient's vitamin D levels and the chronic pain of fibromyalgia."

"Wepner's team launched a randomized, controlled trial in 30 women withfibromyalgia who also had low levels of vitamin D. Some of the women took supplements for 25 weeks and then were tracked for another 24 weeks."

"Reporting in the February issue of the journal Pain, the researchers said those who took supplements reported less pain and morning fatigue over time than those who did not receive the supplements."

"[Vitamin D] may be regarded as a relatively safe and economical treatment and an extremely cost-effective alternative or adjunct to expensive pharmacological treatment," Wepner said in a journal news release."

"Vitamin D levels should be monitored in fibromyalgia patients -- especially in the winter when levels can be lower due to less sun exposure -- and adjusted as necessary, Wepner said."

"Although the study was able to find an association between vitamin D supplementation and an easing of fibromyalgia pain, it did not prove a cause-and-effect link."

"Fibromyalgia patients and those with chronic pain should certainly have their vitamin D blood levels checked and, if low, consider supplementation under the guidance of a physician," said Dr. Kiran Patel, a pain medicine specialist at Lenox Hill Hospital in New York City who often treats people with fibromyalgia."

"Dr. Houman Danesh, director of integrative pain management at Mount Sinai Hospital in New York City, agreed. "Vitamin D deficiency has been linked to chronic pain, and this study further strengthens the argument to [replenish] vitamin D in deficient individuals," he said."

""It is important to note that these patients were under the care of a physician during the [vitamin] repletion, and that it took months for the benefits to be shown," Danesh said. "This is expected, as vitamin D is a fat-soluble vitamin and is stored in fat cells. When a patient has low levels, those stores need to be [replenished], and this takes weeks or months to occur.""

Here is a more mixed view on VitaminD and fibromyalgia!

Fibromyalgia: Vitamin D and fibromyalgia

"Vitamin D levels

Several studies report that people with fibromyalgia have lower vitamin D levels:

In the United Kingdom, 43% of females with fibromyalgia had very low vitamin D levels compared to 19% without fibromyalgia.
In Belfast, Northern Ireland, people with fibromyalgia frequently had low vitamin D levels. The study also linked anxiety and depression to low vitamin D levels.

However, other studies have different observations:

In Israel and Brazil, vitamin D levels did not vary in people with or without fibromyalgia. In the same Brazilian study, there was no connection between vitamin D levels and pain intensity.
In Turkey, neither vitamin D levels nor bone mineral density varied in people with or without fibromyalgia.

In all of the above studies, vitamin D levels could be the result of disease condition rather than the cause of the disease. Thus, the evidence that vitamin D plays a role in fibromyalgia is weak at best.

"How vitamin D works

Some studies have reported that vitamin D may reduce the risk or symptoms of fibromyalgia by lowering inflammation. Vitamin D reduces cytokine production. This protein causes inflammation. However, one study found that fibromyalgia pain was not directly affected by these compounds."


There is no evidence that vitamin D reduces the risk of fibromyalgia. However, it may reduce inflammation. Based on studies of other diseases, it might be worthwhile to keep vitamin D blood levels above 30–40 ng/mL (75–100 nmol/L).


Vitamin D has been used to treat fibromyalgia in several studies and observations:

In the United Arab Emirates, people diagnosed with fibromyalgia or muscle pain benefited from vitamin D. However, it was unclear whether those with muscle pain actually had fibromyalgia.

People in Minnesota with fibromyalgia who initially had low vitamin D levels (10–25 ng/mL [25–63 nmol/L]) participated in a clinical trial. Some people received placebos. Others took 7000 international units (IU)/day of vitamin D3 (cholecalciferol). Vitamin D3 is the type of vitamin D made in the body.

After 8 weeks, those receiving placebos showed no improvement. The vitamin D3 group showed significant improvement in fibromyalgia assessment scores. However, they did not show significant improvement in most musculoskeletal symptoms or in activities of daily living. In addition, those with severe vitamin D deficiency had no symptom improvement during the trial nor one year later."

"Diffuse back pain related to vitamin D deficiency is often diagnosed as fibromyalgia. Raising vitamin D blood levels reduces that type of pain."

"Vitamin D may reduce fibromyalgia pain. Those with fibromyalgia should consider increasing their vitamin D levels above 30–40 ng/mL (75–100 nmol/L)."

Does anyone ask why the people suffer vitaminD-deficiency and how long?

Which impact would long term vitaminD-deficiency have on human body?

Aren't women more dependent on vitaminD because of monthly menstruation?

Just look here! It touches the explanation of cancer again, but more is told about the requirement of vitaminD for a healthy life, particularly for the pregnant mother and her growing baby.

Journal of Reproductive Medicine and Endocrinology
Vitamin D: What Gynecologists Need to Know.

"Vitamin D is classically known to protect against rickets and is a standard treatment for osteoporosis patients. Vitamin D receptors (VDR) have, however, been discovered in almost all human cells and recent studies suggest an important role of the vitamin D endocrine system for several extraskeletal diseases."

"In detail, we discuss that vitamin D deficiency is associated with increased risk of adverse pregnancy outcomes, reduced fertility and polycystic ovary syndrome (PCOS), as well as cancer."

The rest is in German and will be directly translated here!

"Solch ein Mangel an Vitamin D findet sich bei ca. der Hälfte der deutschen und österreichischen Allgemeinbevölkerung, wobei dies zu ausgeprägten gesundheitlichen Folgen führen kann, da der Vitamin-D-Rezeptor (VDR) in fast allen Zellen des menschlichen Körpers exprimiert wird und das Vitamin D und seine Metaboliten ca. 3 % der menschlichen Genoms regulieren."

[Such a deficiency of vitaminD can be found at about the half of German and Austrian population, where this can lead to distinct health issues, as the vitaminD receptor (VDR) is shown in nearly all cell types of human body and vitaminD and its metabolites regulate about 3% of human genome.]

"Daher ist es nicht verwunderlich, dass Vitamin D bei sehr vielen Erkrankungen eine Rolle spielt, wobei Vitamin D schon seit Jahren eine Standardtherapie bei Osteoporose-Patienten ist, da Vitamin-D-Supplementierung die Häufigkeit von Stürzen und Knochenbrüchen signifikant reduziert."

[Therefore it doesn't surprise that vitaminD has a role in many diseases, where vitaminD is already a therapy for osteoporosis, as supplementing vitaminD significantly reduces the frequency of tumbling and broken bones.]

"Zahlreiche Studien weisen auch daraufhin, dass Vitamin D bei diversen anderen Erkrankungen wie z. B. Herz-Kreislauferkrankungen, Infektions- oder Autoimmunerkrankungen sowie Krebs eine positive Rolle spielen könnte."

[Many studies also indicate that vitaminD has positive role in many other diseases, like heart-blood-circulation, infections or auto immune disorders as well as cancer.]

"Dies wird auch dadurch unterstrichen, dass eine Meta-Analyse von randomisierten, placebokontrollierten Studien zeigen konnte, dass Personen, welche Vitamin D einnehmen, statistisch signifikant länger leben."

[This is also emphasized, as show by a meta analysis of randomized, placebo controlled studies, that people taking vitaminD live statistically longer.]

"Das im Serum zirkulierende 25(OH)D scheint die entscheidende Determinante für die lokale 1,25(OH)2D Bildung in den extra-renalen Geweben zu sein, während die 1,25(OH)2D Bildung in der Niere vor allem durch den Kalzium-Phosphathaushalt beeinflusst wird."

[The 25(OH)D circulating in the serum, seems to be the decisive determinant for the local bildup of 1.25(OH)2D in the extra-renal tissues, where the 1.25(OH)2D buildup is influenced in the kindeys, mainly by calcium-phosphate balance.]

"Gerade in der Schwangerschaft scheint ein suffizienter Vitamin-D-Status von besonderer Bedeutung für Mutter und Kind zu sein, wobei hier das 25(OH)D von der Mutter in den kindlichen Kreislauf gelangt."

[Particularly during pregnancy, a sufficient vitaminD condition seems to be very important for mother and child, where the 25(OH)D is transferred from the mother to the circulation of the child.]

"Die offiziellen Empfehlungen für die Vitamin-D-Einnahme bei Schwangeren schwanken zwischen Minimalmengen von 200–400 IE pro Tag bis hin zu etwa 2000 IE tgl. (z. B. in Kanada)."

[The minimal recommended amount of vitaminD supplementation varies between 200 and 400 IU per day up to about 2000 IU daily (e.g. in Canada).]

"Eine bereits auf diversen Kongressen präsentierte Studie von Bruce Hollis (USA) konnte zeigen, dass die Einnahme von 4000 IE während der Schwangerschaft nicht nur absolut nebenwirkungsfrei ist, sondern auch die Rate an Frühgeburten bzw. Schwangerschaftskomplikationen reduziert."

[A study presented in various conferences  by Bruce Hollis (USA) could show that taking of 4000 IU during pregnancy is not only free of side effects, but also reduces the rate of premature birth and complications during pregnancy.]

"Hier hat neben der „Endocrine Society Practice Guideline“ z. B. Ende 2010 das „Institute of Medicine“ (IOM) in den USA eine tägliche Einnahme von zumindest 600 IE Vitamin D (vormals waren es nur 200 IE) und einen 25(OH)D-Spiegel von zumindest 20 ng/mL (50 nmol/L) für schwangere Frauen empfohlen, mit dem Hinweis, dass bis zu 4000 IE tgl. in der Schwangerschaft (entsprechend der von Bruce Hollis empfohlenen Dosis, welche jedoch derzeit von keiner großen Fachgesellschaft unterstützt wird) als sicher zu werten sind."

[Parallel to the 'Endocrine Society Practice Guideline' the 'Institute of Medicine' (IOM) in the USA has recommended a daily take of 600 IU vitaminD (before it was 200 IU) and a 25(OH)D level of minimum 20nq/mL (50 nmol/L) for pregnant women, with a notice about 4000 IU daily during pregnancy (according the dose recommended by Bruce Hollis, which is not supported by any medical association yet) would be considered as safe.]

"Weiters wurde beobachtet, dass weibliche VDR-Knock-out-Mäuse eine uterine Hypoplasie, eine gestörte ovarielle Follikulogenese sowie eine um 75 % reduzierte Fertilität aufwiesen."

[Further it was observed that female VDR knockout mice develop an uterine hypoplasia, a disordered ovarial folliculagenesis as well as 75% reduction of fertilitiy.]

"Interessanterweise zeigen auch männliche VDR-Knockout-Mäuse eine reduzierte Fertilität mit Hypogonadismus und gestörter Spermiogenese [4]. Klinische Studien beim Menschen zeigen bei Männern in manchen, aber nicht allen Studien einen Zusammenhang zwischen höheren 25(OH)D-Spiegeln und besserer Spermienqualität sowie höheren Testosteronwerten."

[Interestingly, also the male VDR knockout mice show a reduced fertility with hypogonadism and disordered spermiogenesia. Clinicial studies with people show by men, in some but not all studies, a correlation between higher 25(OH)D level and improved quality of sperms and higher testosterone degrees.]

"Bereits Anfang des 20. Jahrhunderts wurde beobachtet, dass Patienten mit Hautkrebs bzw. starker Sonneneinstrahlung ein signifikant reduziertes Risiko für Krebsmortalität bzw. Krebsinzidenz aufwiesen"

[Already at the beginning of 20th century it was observed, that patients with skin cancer and higher sunlight radiation have a significantly reduced risk for cancer mortality and cancer incidence.]

"Garland & Garland zeigten einen inversen Zusammenhang zwischen KolonkrebsMortalität und Sonneneinstrahlung und sie stellten die Hypothese auf, dass dieser Zusammenhang eine antikarzinogene Wirkung von Vitamin D reflektiert"

[Garland & Garland showed a inverse relation between colon cancer mortality and sunlight exposure and the developed the hypothesis, that this relation would reflect the anti-carcinogene effect of vitaminD.]

[Short] History of Fibromyalgia

1981The first scientific study confirmed that symptoms and tender points could be found in the body.

1990The American College of Rheumatology wrote the first set of guidelines to help diagnose fibromyalgia.

2005The first guidelines for treating fibromyalgia pain were published by the American Pain Society.

2007The first prescription medication was FDA-approved to manage fibromyalgia.

History of Fibromyalgia

"The condition has been known to mankind since the 1800’s when physicians wrote about a condition that leads to pain, fatigue and disturbed sleep. They called it muscular rheumatism and found no joint involvement."

"The disease was described clearly by Smythe in 1972 with the descriptions of the widespread pain and tender points."

Fibromyalgia Medications

"Fibromyalgia is a widespread pain disorder that affects females more than males. The condition as of now has no cure and is mainly treated symptomatically."

"Several medications, however, have been found to be useful in fibromyalgia. Some of these include:

  • Pain relievers
  • Antidepressants
  • Tranquillizers and sedatives
  • Muscle relaxing agents
  • Anti-seizure medications
  • Neuroleptics

No healing, only syptomatic "treatment" brings the big profit!

You can also dumb Yourself by looking at the results of "studies" and detect which one serves the interest of pharma and which one is honestly scientific! Who really needs that system of 
"perfect" dumbification?

Serum 25-OH vitamin D levels in patients with fibromyalgia.
We found no association between fibromyalgia and low 25OHD levels as previously suggested in other studies.

The relation between vitamin D deficiency and fibromyalgia syndrome in women.
Matthana MH1. Saudi Med J. 2011 Sep;32(9):925-9.

Vitamin D deficiency has to be considered in the management of fibromyalgia syndrome.

The Relationship Between Balance and Vitamin 25(OH)D in Fibromyalgia Patients

M Kasapoğlu Aksoy et al. Mod Rheumatol 1-7. 2016 Dec 09.

"CONCLUSION: It was observed that low vitamin D levels affected balance in both FMS group and healthy control group. It should be kept in mind that vitamin D level is likely to negatively affect balance and VAS values in FMS."

Abstracts Accepted for Publication
Fibromyalgia and pain in rheumatic diseases

D. Solmaz1, O. Avci2, B.C. Yalcin2, S.P. Kara2, M. Oran2

Vitamin D deficiency may contribute disease severity, fatigue and disturbances in health quality in FMS patients. Based on this, in FMS screening the level of vitamin D and correction may be helpful in symptom control."

From the same trash bin of NCBI You can find some pearls. :-)

Consider, that no one talks about the reasons of the epidemic vitaminD deficiency. No one has any hint about SRM, TAI, Tropospheric Water Grabbing, global climate control and geophysical warfare. They behave like hamsters in their cages.

Vitamin D and the Immune System
J Investig Med. 2011 Aug; 59(6): 881–886. doi: 10.231/JIM.0b013e31821b8755
Cynthia Aranow, MD, Investigator

Vitamin D has important functions beyond those of calcium and bone homeostasis which include modulation of the innate and adaptive immune responses. Vitamin D deficiency is prevalent in autoimmune disease. Cells of the immune system are capable of synthesizing and responding to vitamin D. Immune cells in autoimmune diseases are responsive to the ameliorative effects of vitamin D suggesting that the beneficial effects of supplementing vitamin D deficient individuals with autoimmune disease may extend beyond effects on bone and calcium homeostasis.

Vitamin D: The “sunshine” vitamin
J Pharmacol Pharmacother. 2012 Apr-Jun; 3(2): 118–126.
doi: 10.4103/0976-500X.95506 PMCID: PMC3356951 Rathish Nair and Arun Maseeh

Numbers of people with VDD are continuously increasing; the importance of this hormone in overall health and the prevention of chronic diseases are at the forefront of research. VDD is very common in all age groups. Very few foods contain vitamin D therefore guidelines recommended supplementation of vitamin D at tolerable UL levels. It is also suggested to measure the serum 25-hydroxyvitamin D level as the initial diagnostic test in patients at risk for deficiency. Treatment with either vitamin D2 or vitamin D3 is recommended for the deficient patients.

Vitamin D deficiency: a worldwide problem with health consequences.

Am J Clin Nutr. 2008 Apr;87(4):1080S-6S. Holick MF1, Chen TC.

Vitamin D deficiency is now recognized as a pandemic. The major cause of vitamin D deficiency is the lack of appreciation that sun exposure in moderation is the major source of vitamin D for most humans. Very few foods naturally contain vitamin D, and foods that are fortified with vitamin D are often inadequate to satisfy either a child's or an adult's vitamin D requirement. Vitamin D deficiency causes rickets in children and will precipitate and exacerbate osteopenia, osteoporosis, and fractures in adults. Vitamin D deficiency has been associated with increased risk of common cancers, autoimmune diseases, hypertension, and infectious diseases. A circulating level of 25-hydroxyvitamin D of >75 nmol/L, or 30 ng/mL, is required to maximize vitamin D's beneficial effects for health. In the absence of adequate sun exposure, at least 800-1000 IU vitamin D3/d may be needed to achieve this in children and adults. Vitamin D2 may be equally effective for maintaining circulating concentrations of 25-hydroxyvitamin D when given in physiologic concentrations.

Vitamin D deficiency is associated with anxiety and depression in fibromyalgia.

Armstrong DJ1, Meenagh GK, Bickle I, Lee AS, Curran ES, Finch MB.
Clin Rheumatol. 2007 Apr;26(4):551-4. Epub 2006 Jul 19.

Fibromyalgia is a complex problem in which symptoms of anxiety and depression feature prominently. Low levels of vitamin D have been frequently reported in fibromyalgia, but no relationship was demonstrated with anxiety and depression. ...Vitamin D deficiency is common in fibromyalgia and occurs more frequently in patients with anxiety and depression. The nature and direction of the causal relationship remains unclear, but there are definite implications for long-term bone health.

Vitamin D deficiency in women with fibromyalgia in Saudi Arabia.
Abokrysha NT1. Pain Med. 2012 Mar;13(3):452-8. doi: 10.1111/j.1526-4637.2011.01304.x. Epub 2012 Jan 5. Department of Neurology, Cairo University, Kaser Al-Aini Hospital, Al-Manyal, Cairo, Egypt.

Vitamin D deficiency is often seen in patients diagnosed with fibromyalgia in our population. This was equally true in veiled and nonveiled, but conservatively dressed populations. Effective treatment with high-dose vitamin D could lead to resolution of almost all symptoms. Further study of these populations and fortification of foods with vitamin D may be essential.

Vitamin D deficiency in Fibromyalgia
Shaheen Ayuob Bhatty, Niaz Ahmed Shaikh, Muhammad Irfan, Syed Muhammad Kashif, Aneel Sham Vaswani, Aneel Sumbhai, Gunpat ( Medical Unit One, Civil Hospital Karachi. ) November, 2010 >>

Vitamin D Deficiency is frequently seen in patients diagnosed as fibromyalgia and nonspecific musculoskeletal pain in our population. Although the sample size of the study is small, but the figures are so alarming that it is an eye opener towards the need of a population based study , including normal population as well as those presenting with musculoskeletal pain. There is also a need to look into the factors contributing to vitamin D deficiency in our younger population as now it is not only considered as a culprit to bone disease but also common diseases like Diabetes, Hypertension and Heart disease which is already a burden on our health projects. More studies are needed to see the optimum levels of vitamin D in our population to prevent the different health consequences.



"Psoriasis is a common chronic inflammatory skin disease with a spectrum of clinical phenotypes and results from the interplay of genetic, environmental, and immunological factors. Four decades of clinical and basic research on psoriasis have elucidated many of the pathogenic mechanisms underlying disease and paved the way to effective targeted therapies. Here, we review this progress and identify future directions of study that are supported by a more integrative research approach and aim at further improving the patients' life."

"Psoriasis affects 2%–4% of the population in Western countries, with prevalence rates influenced by age, geographic location, and genetic background (Chandran and Raychaudhuri 2010)."

"Prevalence is higher in adults (from 0.91% to 8.5%) as compared with children (from 0% to 2.1%) with a dual peak of incidence: ∼30–39 years and ∼60 years of age. Disease prevalence is different across countries, with a geographical pattern suggesting less prevalence in those closer to the equator as compared with the more distant ones, in line with the beneficial effects of UV radiation exposure and clinical amelioration of psoriasis (Hart et al. 2011). Prevalence in Europe varies from 0.73% to 2.9%, similar to the Unites States (0.7%–2.6%) and higher than Latin America, Africa, and Asia ..."

"Plaque-Type Psoriasis

Plaque-type psoriasis, occurring in 85%–90% of affected patients, is the most common form of psoriasis and is characterized by oval or irregularly shaped, red, sharply demarcated, raised plaques covered by silvery scales (Fig. 1A–C) (van de Kerkhof and Nestle 2012).

"Guttate Psoriasis

Guttate psoriasis, from the Latin “gutta” for tear drop, is characterized by multiple small scaly plaques usually occurring around the trunk and upper arms and thighs. The rash has often sudden onset, usually within 2–4 wk after a bacterial infection of the upper ways, notably streptococcal pharyngitis in children and young adults, and is therefore associated with type I psoriasis (Griffiths et al. 2007).

"Generalized Pustular Psoriasis

GPP, also known as von Zumbush psoriasis, is a rare but potentially life-threatening disease characterized by episodic, widespread skin and systemic inflammation.

"Erythrodermic Psoriasis

Erythrodermic psoriasis, one of the rarest forms of psoriasis (1%–2.25% of patients with psoriasis), represents the most severe phenotype; it carries substantial morbidity and can be potentially life threatening (Boyd and Menter 1989).


About 20%–30% of psoriasis patients develop a seronegative, chronic inflammatory muscoskeletal disorder named psoriatic arthritis (PsA), which occurs, in most cases, about a decade after the appearance of psoriasis (Gladman et al. 2005).

"PsA can affect different tissues (synovium, cartilage, bone, entheses, tendons); it presents common involvement of distal joints, asymmetric articular distribution, erythema over-affected joints, spinal involvement, and enthesitis (Gladman et al. 2005) and eventually leads to erosion and loss of function of the affected areas."

"Because ∼80% of the patients develop PsA following psoriasis (Ellinghaus et al. 2012b), PsA is sometime considered as a disease within a disease (Eder et al. 2011)."

"Nevertheless, PsA shares several key cellular and molecular mediators with psoriasis, such as lymphocytes infiltrating the inflamed skin or joint (Pitzalis et al. 1996; Shen et al. 2006) and critical cytokines such as tumor necrosis factor (TNF), IL-23, and IL-17 (Gullick et al. 2010). Genetic association with class I HLA molecules and clinical evidence supports an important role of CD8 T cells in PsA, with the presence of oligoclonally expanded CD8 T cells in the joint fluids of individuals with active PsA (Costello et al. 2001). TNF is a critical disease player as it is in psoriasis and ∼70% of patients successfully respond to anti-TNF therapy in terms of signs and symptoms improvement, and, in some cases, also by radiographic progression (Anandarajah and Ritchlin 2009)."

"The systemic manifestation of the disease results in comorbidities including, but not limited to, metabolic syndrome, cardiovascular disease (CVD), diabetes, depression, and cancer (Griffiths and Barker 2007)."

"Finally, psoriasis carries a severe psychosocial burden with anxiety, depression, and perceived stress appearing at a higher rate in psoriasis patients (O’Leary et al. 2004)."


In contrast to the fast-growing list of psoriasis susceptibility genes, the environmental factors concurring in initiating the disease are still ill-defined. Among known environmental triggers of psoriasis, there are drugs, infections, physical trauma, smoking, alcohol, and stress.

"Disease Initiation

One of the best-characterized initiation mechanisms, leading to dysregulated skin immune responses, involves KCs releasing the cationic antimicrobial peptide (AMP) LL-37 following physical trauma (Koebner phenomenon) or infection. LL-37 binds to self-DNA/RNA fragments (Lande et al. 2007; Ganguly et al. 2009) also released by damaged skin cells (Ganguly et al. 2009; Lin et al. 2011), forming LL-37/self-DNA/RNA complexes found in psoriasis lesions.


In common with other immune-mediated complex diseases, there is no definitive cure for psoriasis, and available treatment is only to decrease disease activity and improve symptoms."

"Therapies are administered according to disease severity and assessed by the Psoriasis Area and Severity Index (PASI, ranging from 0 to 72), which takes into account appearance and extension of the lesions.

Why only vitamin D "analogs", not real vitamin D?

Why not UVA/UFB phototherapy from the beginning?

"Classic therapies span from topical treatments (emollients, topical corticosteroids, vitamin D analogs) used in mild-to-moderate psoriasis, to UVA/UVB phototherapy or systemic therapies reserved to moderate-to-severe cases.

Among systemic therapies, which include retinoids, methotrexate, and cyclosporine, the folic acid antagonist methotrexate, which has immunosuppressive, cytostatic, and anti-inflammatory activity and is rather inexpensive, is often used as first line of treatment. However, classic therapy has not completely met patients’ needs, especially in the most severe cases.

In the past decade, a better understanding of disease immunopathogenesis has been successfully translated into new drugs, known as “biologics,” targeting key inflammatory mediators and currently representing an effective third-line therapy in moderate-to-severe psoriasis patients, unresponsive to nonbiologic systemic agents."

"Anti-T-Cell Therapies

The first biologic to be approved was Alefacept in 2003, a lymphocyte function-associated antigen (LFA)-3/IgG1 fusion protein binding CD2 on T cells and, thus, selectively inducing apoptosis of CD2+ human memory-effector T cells in vivo (da Silva et al. 2002), although further studies suggested a broader immunomodulatory effect (Chamian et al. 2005; Haider et al. 2007). Clinical efficacy was shown in phase III studies with 40% of patients achieving a PASI75 response (75% reduction of the PASI) (Krueger et al. 2002) and more that 50% achieving PASI 50 (50% reduction of the PASI) (Lebwohl et al. 2003a).

"A second anti-T-cell strategy was approved in 2003 and consisted of a humanized antibody (Efalizumab) binding and blocking CD11a, a key molecule for T-cell activation and migration through the circulation into the skin (Jullien et al. 2004)."

"Despite a good efficacy profile, efalizumab (Gordon et al. 2003; Lebwohl et al. 2003b;Leonardi et al. 2005, 2008a; Menter et al. 2005; Gottlieb et al. 2006; Papp et al. 2006) has been withdrawn from the market in 2009 because of three cases of progressive multifocal leukoencephalopathy (Tan and Koralnik 2010), highlighting the importance of carefully monitoring the long-term safety of immunomodulatory therapies."

"Anticytokine Therapies

An alternative strategy to anti-T-cell targeting aims at interfering with the psoriasis cytokine network (Nickoloff 1991) by using anticytokine biologic drugs.

TNF blockade, using etanercept, a human p75 TNF receptor fusion protein (approved in 2004), infliximab, a humanized chimeric anti-TNF monoclonal antibody (approved in 2006), or adalimumab, a fully human monoclonal antibody (approved in 2008) is another effective therapeutic strategy. 

[Adaalimumab is sold as HUMIRA:]
[Etanercept is sold as ENBREL:]

Etanercept efficacy have been shown in three phase III trials with about 50% of patients achieving PASI75 at week 12 in the high-dose group (Leonardi et al. 2003;Papp et al. 2005, 2011d; Tyring et al. 2006). TNF neutralization causes early down-modulation of myeloid cell-related genes, with decrease of Th17 cell products and downstream molecules in just 2 wk after commencing therapy (Gottlieb et al. 2005; Zaba et al. 2007; Johansen et al. 2010). Interestingly, only patients who downregulate the expression of Th17 pathway genes successfully respond to etanercept treatment (Zaba et al. 2007; Zaba et al. 2009c)."

[Ustekinmab is sold as STELARA:]

"The latest biologic to be approved for psoriasis in 2009, ustekinumab, is a monoclonal antibody simultaneously blocking the heterodimeric proteins IL-12 and IL- 23 via its biding to the shared subunit p40. Its efficacy is quite high, with 67% of patients achieving PASI75 at 12 wk of treatment (Leonardi et al. 2008b; Papp et al. 2008)."

"Some serious adverse events, such as opportunistic infections and reactivation of latent tubercolosis, have been reported for these monoclonal antibodies (Sivamani et al. 2013). Long-term safety data (up to 4 and 5 yr treatment) are now available for etanercept and ustekinumab (Leonardi et al. 2003; Papp et al. 2005, 2012d, 2013a; Tyring et al. 2006), suggesting a safe use of these drugs."

"A number of other biologic drugs is currently (mid-2013) being investigated in clinical trials. In line with the prominent role of IL-23/IL-17 axis in psoriasis, two antibodies (guselkumab [formerly CNTO1959] and MK-3222) targeting the specific IL-23p19 subunit are in phase II and III, respectively (Janssen 2013; Merck 2013a,b)."

"Monoclonal antibodies blocking either IL-17A (ixekizumab and secukinumab) (Leonardi et al. 2012; Papp et al. 2013b; Rich et al. 2013) or IL-17R brodalumab (Papp et al. 2012b) have shown striking efficacy in phase II clinical trials with >70% of patients achieving PASI75 and more than half receiving a remarkable PASI90. Although phase III clinical trials are currently ongoing (Amgen 2013a,b,c; Eli Lilly 2013a,c,d,e,f; Novartis 2013b), initial molecular data showed that the effect of IL-17 blockade on expression of genes synergistically regulated by IL-17 and TNF-α is greater than in previous studies with anti-TNF therapy (Krueger et al. 2012)."

"Notwithstanding the efficacy of the biologic drug currently available in the clinic, at least one third of patients do not respond to biologic therapy (Gudjonsson et al. 2012) or lose initial responsiveness because of the development of antidrug antibodies (ADA), which causes decreased drug efficacy and/or induction of adverse events (Sathish et al. 2013; Vincent et al. 2013). Moreover, biologic drugs pose a considerable economical burden because of their costs (Poulin et al. 2009; Liu et al. 2012). Finally, a sizable number of patients with mild-to-moderate psoriasis still rely on traditional topical treatments."

Influence of Vitamin D Status and Vitamin D3 Supplementation on Genome Wide Expression of White Blood Cells: A Randomized Double-Blind Clinical Trial

PLoS One. 2013; 8(3): e58725.
Published online 2013 Mar 20. doi: 10.1371/journal.pone.0058725
PMCID: PMC3604145
Arash Hossein-nezhad,1 Avrum Spira,2 and Michael F. Holick1,*
Moray Campbell, Editor


Our data suggest that any improvement in vitamin D status will significantly affect expression of genes that have a wide variety of biologic functions of more than 160 pathways linked to cancer, autoimmune disorders and cardiovascular disease with have been associated with vitamin D deficiency. This study reveals for the first time molecular finger prints that help explain the nonskeletal health benefits of vitamin D.

"These results suggest that to maximize vitamin D's effect on gene expression may require even higher doses than 2000 IUs of vitamin D3 daily."

"Vitamin D supplementation has proven skeletal health benefits [3],[4], particularly in individuals at risk for vitamin D deficiency. "

Vitamin D and its role in psoriasis: An overview of the dermatologist and nutritionist
Rev Endocr Metab Disord. 2017; 18(2): 195–205.
Published online 2017 Feb 7. doi: 10.1007/s11154-017-9411-6
PMCID: PMC5486909
Luigi Barrea,1 Maria Cristina Savanelli,1 Carolina Di Somma,2 Maddalena Napolitano,3 Matteo Megna,4Annamaria Colao,5 and Silvia Savastano

"The dermatologist’s point of view

Patients suffering from psoriasis present a broad range of clinical phenotypes. Psoriatic lesions are classified into plaque, guttate, pustular, and erythrodermic types according to clinical features, especially regarding lesions size and distribution [1]. Disease onset may occur at any age, including childhood, with two peak age ranges, 16 to 22 and 57 to 60 years [2, 3]. Psoriasis lesions are characterized by hyper-proliferation with incomplete differentiation of epidermal keratinocytes and decreased keratinocyte apoptosis, associated with inflammatory cellular infiltrate in both dermis and epidermis [12]. Psoriasis Area and Severity Index (PASI) score is currently the preferred method for the assessment of the disease severity and extent [13].

"Effects of vitamin D on skin biology

The role of vitamin D as main regulator of skin physiology is very complex (Table ​(Table1).1). 

The epidermis is composed of four layers: 

  • basal layer (stratum basale), 
  • spinous layer (stratum spinosum), 
  • stratum granulosum and stratum corneum. 

The stem cells within the basal layer, which contact the basement membrane, continually divide during the lifetime of the organism, providing a source of cells which progressively migrate upwards through the epidermis, differentiating and stratifying to form the barrier layer of the skin [11, 14].

The process of epidermal differentiation is complex, sequential, and tightly controlled [11]. 

The precursor of vitamin D, 7-dehydrocholesterol, is located in the membranes of keratonocytes of the basal and spinous layer of epidermis [10]. 

By the action of UVB (wavelength between 290 and 315 nm), via a photochemical reaction, the B ring of 7-dehydrocholesterol is broken to form pre-vitamin D3 or cholecalciferol, which is subsequently converted first to 25-hydroxyvitamin D (25OHD) by the enzymes CYP27A1 and CYP2R1 and then to 1,25-hydroxyvitamin D (1,25(OH)D or calcitriol) the active form of vitamin D, by CYP27B1 [15].

Physiologically, the active form of vitamin D and its receptor regulate the differentiation and proliferation of keratinocytes, the balance of the cutaneous immune system and the process of apoptosis.

The 1,25(OH)D has been shown to exert anti-proliferative effects on keratinocytes [16]. Numerous in vitro and in vivo studies have demonstrated dose-dependent effects of vitamin D on proliferation and differentiation of keratinocytes. Of interest, low concentration of vitamin D promotes keratinocyte proliferation in vitro, while at higher pharmacological doses a clear inhibitory effect became apparent [14, 17].

Moreover, 1,25(OH)D and analogs reduce S100A7 levels, generally up-regulated in psoriatic skin, in the reconstituted human epidermis stimulated by IL-22 [18], in interleukin (IL)-17-stimulated keratinocytes and in skin of patients with psoriasis [19]. 

Indeed, 1,25(OH)D regulates the cell proliferation in the stratum basale and increases the synthesis of keratins (K1 and K10), involucrin, transglutaminase, loricrin, and filaggrin, in the stratum spinosum [11, 14, 15]. 

Furthermore, vitamin D helps to regulate the synthesis of glycosylceramides needful for the barrier integrity and permeability in the stratum corneum [11, 14, 17]. These actions are due to the capacity of vitamin D to regulate intracellular calcium level, through induction of the calcium receptor, and the phospholipase C enzymes [19, 20].

A decrease or deficiency in 1,25(OH)D or a loss-of-function of its receptor has been shown to disrupt the differentiation of the epidermis, with reduced levels of involucrin and loricrin and loss of keratohyalin granules, resulting in hyperproliferation of the basal layer [11, 2123]."

"Vitamin D regulation of apoptosis in keratinocytes

Calcitriol stimulates the synthesis of ceramide by inducing the neutral Mg2+-dependent sphingomyelinase (thereby increasing the conversion of sphingomyelin to ceramide) and in return, ceramide enhances the pro-differentiating effect of calcitriol on keratinocytes in a feedback loop [10, 24]. It has been demonstrated that physiological concentrations of calcitriol do not initiate apoptosis in cultured keratinocytes but, in contrast, pharmacological concentrations of calcitriol exert a pro-apoptotic effect on keratinocytes [25].

"Effects of vitamin D on the cutaneous immune system

Psoriasis pathogenesis implicates the innate and adaptive segments of the immune system. In particular, it is centrally controlled by T cells, in which an important role is played by T-helper (Th)1, Th17 and Th22, interplaying with numerous cell types via different cytokines, including tumour-necrosis factor-α (TNF-α), IL-6 and IL-17 [26]. The activity of these cells is modulated by specific T lymphocytes, named regulatory T cells (Treg) [9]. Regulatory T cells (Tregs) are able to inhibit the immunological response and to preserve the cutaneous immunological homeostasis, preventing autoimmune response against self-antigens [27].

"Vitamin D and psoriasis linkage

In psoriasis, vitamin D is involved in the maintenance of cutaneous barrier homeostasis. Several studies identified an association between polymorphisms of vitamin D receptor (VDR) and psoriasis susceptibility [9]. Richetta et al., have found that the A-1012G promoter polymorphism of the VDR gene is associated with psoriasis risk through a lower expression of VDR mRNA, favoring conditions that may alter cutaneous barrier and the development of psoriatic lesions [31]. In addition, in psoriatic skin a decreased expression of VDR and reduced tight-junction proteins is associated [32]. Tight junctions are fundamental to regulate adhesion and permeability of keratinocytes, and to polarize cutaneous cell differentiation, to regulate extracellular calcium gradient, interacting with nuclear and cytoplasmic proteins and influencing the regulation of specific genes involved in keratinocytes differentiation and proliferation [32, 33]. Different studies have focused on the possible role of low vitamin D status in the pathogenesis of psoriasis [3436].

"Indeed, several studies reported that vitamin D is a key modulator of inflammation function [37, 38]. The active metabolite of vitamin D exert an anti-inflammatory effect on the inflammatory profile of human monocytes/macrophage [3942], down-regulating the expression and production of several pro-inflammatory cytokines including TNF-α, IL-1β, IL-6, and IL-8 [43]. Moreover, dendritic cells differentiation, maturation, chemotaxis and antigen presentation seem to be dampened, and hydrogen peroxide secretion in human monocytes is also activated by 1,25(OH)D resulting in an increased oxidative burst potential [9, 44]. These anti-inflammatory effects support a role a low vitamin D status in the pathogenesis of psoriasis. Recent studies have shown that 1,25(OH)D values are significantly lower in psoriatic patients than in control subjects, even after adjusting for confounding factors in a multivariate analysis [11, 35]. In another study, vitamin D levels were lower in women with psoriasis in comparison with men, a difference not observed among controls [45]. Therefore, low levels of vitamin D are negatively associated with markers of inflammatory activation (C-reactive protein, CRP) and obesity [35]. Moreover, other studies showed that serum vitamin D levels were also reduced in patients with psoriatic arthritis and being inversely linked to disease activity [46, 47]."

"Topical vitamin D in psoriasis treatment

The beneficial effects of vitamin D induced by exposure to sunlight in the treatment of psoriasis have been known for decades. The effectiveness on psoriasis of vitamin D and its derivatives (calcitriol, calcipotriol, tacalcitol, hexafluoro-1,25(OH)D and maxacalcitol) have been known since 1985, being confirmed in numerous trials [45, 48]. The therapy with vitamin D, is one of the most popularly prescribed topical medications for this disease as the first-line, singly or in combination with topical corticosteroids, and numerous studies documented the efficacy and safety of using topical calcipotriol in the treatment of cases of localized plaque psoriasis [4954]. Vitamin D analogs are particularly helpful for hard-to-treat areas such as the face or inguinal regions that are sensitive to steroid-induced atrophy [55]. Vitamin D analogs do not exhibit tachyphylaxis, as seen with corticosteroids, and topical treatment can be continued indefinitely without serious adverse side effects [9, 55]. Additionally, they are effective in the treatment of psoriatic skin lesions in children and elderly population [5658]. A recent meta-analysis on the effectiveness of topical vitamin D therapies evidenced not only comparable efficacies to corticosteroids when used as monotherapy, but also superior effects when vitamin D used in combination with a potent topical steroid. According to these results, as topical vitamin D derivatives demonstrated a favorable safety profile, with “steroid-sparing” effects, and should be considered an indispensable component of the current physician’s arsenal in the treatment of psoriasis [11].

The therapeutic effects of topical vitamin D occur via a VDR mediated genomic mechanism resulting in inhibition of keratinocyte proliferation and mediated non-genomic mechanisms inducing keratinocyte differentiation by increasing intracellular calcium levels [59]. The anti-inflammatory effects may also result from inhibition of production of IL-2, IL-6, and interferon-gamma (IFN-γ). Further, topical calcipotriol inhibits human beta defensin and proinflammatory cytokines which are found in increased levels in psoriatic lesions [60]. Allelic variations in individual VDR genes may determine a different response to treatment: the isoform A of VDR is associated with a greater therapeutic response in psoriatic patients [61]

"The nutritionist’s point of view

Severe psoriasis has been associated with nutritional deficiencies because of an accelerated loss of nutrients, in particular of vitamin D, from the hyperproliferation and desquamation of the epidermal layer of skin [6264]. Vitamin D supplementation is of particular interest to Nutritionists for two important reasons. First, besides its topical use, oral vitamin D supplementation represents an important adjunctive treatment option for psoriatic patients [9]; second, vitamin D supplementation might be very important for the prevention of psoriasis-related comorbidity [65], hypertension [66] and metabolic syndrome [67].

"Food and vitamin D

There are two ways to meet vitamin D requirements in mammals: via nutrition and via synthesis in skin by from the sun or other UVB source [8]. Several recommendations were published regarding the dietary intake of vitamin D [6870]. In particular, these recommendations they refer to dietary reference intakes for calcium and vitamin D updated by the Institute of Medicine (IOM) in 2010 [71]. To date, as the evidence for extra-skelatal effects of vitamin D are inconsistent and insufficient, the intake recommendations were based on beneficial effects of vitamin D only on skeletal health. The Recommended Dietary Allowances (RDAs) covering requirements of ≥97.5% of the population are shown in Table ​Table2.2. Other organizations recommended different RDAs: the Endocrine Society suggested that adults aged 19–50 years require at least 600 international unit (IU) of vitamin D daily to maintain bone and muscular function [72]. However, the task force further annotated that 1500–2000 IU per day are necessary to consistently raise the serum level of 25(OH)D above 30 ng/mL. Finally, for older adults aged 60 and above, the International Osteoporosis Foundation (IOF) recommended a RDA of 800–1000 IU in order to reach a serum 25(OH)D level of 30 ng/mL [73].

"The diet is an important determinant of vitamin D status [71, 74]. Some studies have calculated that the amount of vitamin D intake that would ensure that the majority of the population (97.5%) maintains plasma 25(OH)D concentrations >25 nmol/l throughout the year is 8.7 mg/d [75]. Only few foods contain naturally vitamin D, and these foodstuffs are mainly of animal origin. The vitamin D status is the sum from the combination of synthesis in the skin after sun exposure and intake of the two main dietary forms of vitamin D: ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) [76]."

"The fish (especially fatty fish and fish liver) have the highest natural content of vitamin D [80] Also egg yolk has a high vitamin D3 content [80], which strongly correlates with the content of vitamin D3 of the hen’s feed [77]. Depending on the hen’s diet [81] and UVB exposure [82], the vitamin D3 and 25(OH)D3 were transferred from the hen to the egg yolk. Regarding of meat products, the content of vitamin D depends on the contents of vitamin D in the fodder, the fat content of the meat product, and latitude where the animals have grazed [83]. Finally, the vitamin D3 is also available through dietary supplements, and is the form present in vitamin D-fortified foods such as milk, orange juice, and cereals. The fortification of food with vitamin D has been considered to be the most promising strategy with the broadest reach and impact [8486]. In fact, in countries where this strategy was adopted proved to have a significant influence on the daily vitamin D intake in the average adult [87]. The food sources of vitamin D are listed in Table ​Table33 [88]."

"Bioavailability and influence of processing and cooking

The vitamin D, like other fat-soluble vitamins (A, E, K), is absorbed incorporated in mixed micelles from the intestine into the enterocytes by non-saturable passive diffusion. Subsequently, the vitamin D is transported in the chylomicrons via lymph to the circulation [89]. The more polar metabolite 25(OH)D is absorbed better and faster than vitamin D because it is also taken up directly from the proximal jejunum into the portal vein [79]. There are few data on its availability from natural sources. The absorption of vitamin D from supplements may differ depending on the used vehicle substance, such as oils, powders, ethanol [90]. For example, it has been reported that the bioavailability of vitamin D from fortified hard cheese is equivalent to supplements [91] and that vitamin D bioavailability is not influenced by the fat content of the fortified milk [92].

"The cooking does not much influence the vitamin D content of animal foods. Mattila et al. [93] found that, in eggs boiled for 10 min, the vitamin D3 concentration was 1–6% lower and 25(OH)-D-3 content was 6–11% lower compared with raw eggs. In addition, also in fish, the cooking effect was moderate: baking various kinds of fish (e.g., perch, rainbow trout, Baltic herring) in the oven at 172 °C or 200 °C for 20 min induced a vitamin D3 loss of 93]. The stability of vitamin D3 and 25(OH)D and vitamin D2 in foodstuffs during cooking has been shown to vary widely with heating process and foodstuffs, with reported retentions in eggs, margarine and bread after boiling, frying and baking of between 40% and 88% [94]."

"The nutritionist and vitamin D supplementations

Supplements are the most important determinant of variation in vitamin D intake [85, 86, 95] A number of studies showed that the daily intake of vitamin D was higher in adults using vitamin D supplements than in those without vitamin D supplementations (348 IU vs 84 IU of vitamin D) [86]. Most nutritionists recommend the use of vitamin D3 to treat and prevent vitamin D deficiency, because several studies indicating a higher efficacy for vitamin D3 in raising serum 25(OH)D concentrations when compared to vitamin D2 [96]. Although a significant inter-individual variation exists, due to different variables including body weight, sunlight exposure and calcium intake, it has been calculated that supplementation of 1000 IU of vitamin D3 daily leads to an approximate increase in 25(OH)D levels by 10–20 ng/mL (25–50 mmol/L), [9799]. Findings from randomised placebo-controlled trials conducted during the winter have shown that each 1 mg of supplemental vitamin D is associated with an increase in serum 25(OH)D of between 0.7 nmol/L [100] and 2 nmol/L [75].

"Several studies have observed the safety concerns regarding the dosage of vitamin D supplementation. However, oral vitamin D intakes of up to 10,000 IU daily were not associated with any harmful effects [101], since this dose is comparable to the maximum cutaneous vitamin D production, and reports of vitamin D intoxication from cutaneous synthesis alone do not exist [101]. In this context, the IOM and the European Food and Safety Authority (EFSA) recommend a safe tolerable upper intake level of 4000 IU vitamin D perday for all adults, including pregnant and lactating women [102], although, to date, very few studies have investigated the long-term effects of a vitamin D intake above the suggested threshold of 4000 IU per day [103, 104]. To reach a steady state, after two to three consecutive months of treatment with vitamin D supplementation, it’s necessary a re-measurement of 25(OH)D serum levels [98]."

"Thus, the Nutritionists should consider a general vitamin D supplementation in populations at high risk for vitamin D deficiency, such as psoriatic patients [105]. The compounds of vitamin D commonly used in clinical trials varied from 1,25(OH)D, the physiologically active form of vitamin D, to 1αOHD, alfa-calcidol, requiring only liver metabolism to be converted to the active form to vitamin D or cholecalciferol, requiring both liver and kidney metabolism to become active. Perez et al. observed an overall 88% of clinical improvement of psoriasis with oral vitamin D with a decrease in mean PASI scores [61]. The results were confirmed in different studies on limited number of patients, reporting moderate or greater improvement in psoriasis in 25–50% of subjects [106109]. It has also been proposed the therapeutic use of systemic alpha-calcidol in patients with psoriatic arthritis [61]. Another study demonstrated that a combination of acitretin and oral calcitriol resulted in a faster reduction of PASI in patients of chronic plaque psoriasis [110]. A study on a large population sample including 70,437 US females over a period of 14 years, examined the vitamin D intake levels and the incidence of psoriasis in the population. After adjusting for confounding variables, the study found that there was no significant association between vitamin D intake (dietary, supplementary, and total vitamin D) and the risk of incident psoriasis. Thus, the authors proposed that there was no role of dietary or supplemental vitamin D intake to prevent the development of psoriasis [111]. However, current recommendations for dietary intake of vitamin D are based only on its effect on skeletal health, while no information is present as regards psoriasis. In addition, a discrepancy between recommended RDAs and actual daily vitamin D intake exists. Therefore, solutions like food fortification and personalized diet or vitamin D supplementation in psoriatic patients need to be developed. In addition, taking into account the common association among psoriasis, obesity and Mets of which will be discussed in the next chapter, the advantage of the potential use of oral vitamin D supplementations to treat psoriasis and metabolic syndrome concurrently through its anti-inflammatory effects was strongly supported by a comprehensive meta-analysis including the results of clinical trials using vitamin D supplementation in psoriasis [106]."


Due to its role in proliferation and maturation of keratinocytes, vitamin D has become an important local therapeutic option in the treatment of psoriasis. Indeed, significant associations between low vitamin D status and psoriasis have been systematically observed. Although the exact role of vitamin D in the pathogenesis of psoriasis is unclear, understanding the possible bi-directional relationships between low vitamin D status and psoriasis is also important for delineating the risk profile for co-morbidities that may result from psoriasis, such as obesity, type 2 diabetes, and MetS. To date, the successful treatment based on adequate dietary intake of vitamin D or oral vitamin D supplementation in psoriasis represent an unmet clinical need and the evidence of its beneficial effects remains still controversial. Nevertheless, the Nutritionists should consider a general vitamin D supplementation in populations at high risk for vitamin D deficiency, such as psoriatic patients. This information is important either for Dermatologists and Nutritionists to increase the knowledge on the potential usefulness of vitamin D in psoriasis with the aim to reduce not only its clinical severity, but also cardiac risk factors and psoriasis co-morbidities. Future well-designed dietary intervention trials with vitamin D supplementations on large population samples are needed to define the specific dose of vitamin D supplementations for psoriasis.

1,25(OH)D, 1,25-hydroxyvitamin D or calcitriol; 25OHD, 25-hydroxyvitamin D; BMI, body mass index; CRP, C -reactive protein; IL, interleukin; MetS, metabolic disease; PASI, psoriasis area and severity index; RDAs, recommended dietary allowances; TNF, tumor necrosis factor;VDR, vitamin D receptor.

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


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,


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).


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

"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.

An external file that holds a picture, illustration, etc.
Object name is 1878-5085-4-4-1.jpg
"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]."


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


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

"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."
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Object name is 10.1177_1756285612473513-fig1.jpg"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."

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"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. 1995Baeke 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. 2011Joshi 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."
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"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."

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"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]."


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."

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

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

More about VitaminD!

Further sources for own research!

A very easy explanation of vitaminD deficiency, in German!

Don't poison Your skin with chemicals!

Synthesis and metabolism of hormonal steroids.

"This figure illustrates the formation of the major hormone classes from cholesterol. Steroid names in conventional script are steroid hormones and precursors; those in italics are urinary metabolites of the aforementioned. The major transformative enzymes are in rectangular boxes, the cofactor (“facilitator”) enzymes in ovals. The pale blue area contains common intermediate steps; the yellow preliminary steps in glucocorticoid synthesis; the green mineralocorticoids; the orange, glucocorticoids; dark blue, androgens and pink, estrogens. Mitochondrial CYP type I enzymes requiring electron transfer via adrenodoxin reductase (ADR) and adrenodoxin (Adx) CYP11A1, CYP11B1, CYP11B2, are marked with a labelled box ADR/Adx. Microsomal CYP type II enzymes receive electrons from P450 oxidoreductase (POR), CYP17A1, CYP21A2, CYP19A1, are marked by circled POR. The 17,20-lyase reaction catalyzed by CYP17A1 requires in addition to POR also cytochrome b5 indicated by a circled b5. Similarly, hexose-6-phosphate dehydrogenase (H6PDH) is the cofactor-generating enzyme for 11β-HSD1. The asterisk (*) indicates the 11-hydroxylation of 17OHP to 21-deoxycortisol in 21-hydroxylase deficiency. The conversion of androstenedione to testosterone is catalyzed by HSD17B3 in the gonad and AKR1C3 (HSD17B5) in the adrenal. StAR, steroidogenic acute regulatory protein; CYP11A1, P450 side-chain cleavage enzyme; HSD3B2, 3β-hydroxysteroid dehydrogenase type 2; CYP17A1, 17α-hydroxylase; CYP21A2, 21-hydroxylase; CYP11B1, 11β-hydroxylase; CYP11B2, aldosterone synthase; HSD17B, 17β-hydroxysteroid dehydrogenase; CYP19A1, P450 aromatase; SRD5A2, 5α-reductase type 2; SULT2A1, sulfotransferase 2A1; PAPPS2, 3′-phosphoadenosine 5′-phosphosulfate synthase 2."

Vitamin D and Cardiovascular Disease

P.E. Norman, J.T. Powell

"... Vitamin D receptors have been found in all the major cardiovascular cell types including cardiomyocytes, arterial wall cells, and immune cells. Experimental studies have established a role for vitamin D metabolites in pathways that are integral to cardiovascular function and disease, including inflammation, thrombosis, and the renin–angiotensin system. Clinical studies have generally demonstrated an independent association between vitamin D deficiency and various manifestations of degenerative cardiovascular disease including vascular calcification. However, the role of vitamin D supplementation in the management of cardiovascular disease remains to be established. This review summarizes the clinical studies showing associations between vitamin D status and cardiovascular disease and the experimental studies that explore the mechanistic basis for these associations."

"Interview mit Dr Coimbra über hochdosiertes Vitamin D für Multiple Sklerose und andere Autoimmunerkrankungen: Das Coimbra Protokoll. Erfolgsquote 95 Prozent."

"Die tägliche Dosis, die heute international empfohlen wird, ist eine armselige Dosis, weit unter der physiologischen Dosis. Die physiologische Dosis beträgt – wie kürzlich belegt wurde – minimal 7.000 Tageseinheiten für Erwachsene mit einem normalen Body-Mass-Index, die gleiche Menge, die der Körper in nur 10 bis 20 Minuten der Exposition gegenüber der Sonne produzieren kann – abhängig vom Ausmaß der exponierten Körperoberfläche, der Körperposition (liegend oder stehend), der Pigmentierung der Haut, Alter und dem Sonnenstand."

"10.000 IE sind also eine physiologische Dosis, keine Super-Dosis."

"Beeindruckt von diesem ersten Ergebnis begann ich, die 10.000 Einheiten Vitamin D auch bei Patienten mit Multipler Sklerose zu geben. MS ist eine sehr häufige Autoimmunerkrankung in der Neurologie, mit sehr verheerenden Auswirkungen. Diese erste tägliche Dosis gaben wir auch bei anderen Autoimmunerkrankungen wie Psoriasis, Lupus, rheumatoider Arthritis. Wir waren erstaunt, zu sehen, wie viel besser es diesen Patienten ging, obwohl sie nicht völlig symptomfrei wurden. Aber das war der Ausgangspunkt: die Anerkennung des großen Wertes von Vitamin D bei der Behandlung von Autoimmunerkrankungen."

"Vitamin D ist der größte Regulator des Immunsystems und modifiziert die Funktion von Tausenden von Genen in jeder Zelle des Immunsystems. Es ist eine Substanz, zu der es keine vergleichbare Zweite gibt."

"Bei einem Vitamin-D-Mangel kann der Kranke die Aktivität von Tausenden von biologischen Funktionen innerhalb der Zellen des Immunsystems nicht mehr regulieren – also stimulieren oder reduzieren – ein Mangel an dieser einen Substanz resultiert also in einer Katastrophe für das Immunsystem!"

"Menschen mit Vitamin-D-Mangel sind darum anfällig für zahlreiche Autoimmunerkrankungen wie Multiple Sklerose, Autoimmune Polyneuropathie, Guillain-Barré-Syndrom, rheumatoide Arthritis, Psoriasis-Arthritis (und Schuppenflechte selbst), Myasthenia gravis, Polymyositis und systemischem Lupus erythematosus – um nur einige zu nennen."


  1. Replies
    1. Alles bedarf einer Entwicklung.
      Die Verknüpfung erscheint schwierig, bis sie völlig offensichtlich wird.
      Die wissenschaftlichen Studien untermauern die Aussagen. Viele Menschen denken nicht selbst, sondern brauchen stets irgendwelche "Studien", denen sie "vertrauen" können. Hoffe, dass der Artikel auch bei diesen Leuten wirkt.


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Geoengineering is never the solution against but the reason of killing and devastating changes!

This blog is absolutely not "peer reviewed" and not written by a "renown" scientiputa!


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