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I don't think we have fully appreciated the significance of the new study comparing Calcitriol + Vitamin D3 to methylprednisolone which provides no sustained benefit.

While the study directly compared Calcitriol + D3 againt methylprednisolone and found it was far superior in terms of remission and the ability to remain relapse free, the study also looked at the literature for Tysabri, Interferon beta, and glatiramer acetate and shows how marked superior calcitriol + D3 is against all these standard DMDs.

Although this is a study in EAE mice which as we know is not MS, it is a comparison against how these drugs performed in EAE mice.

I would say there is considerable urgency to get this tested in humans because even if it only matches the performance of these drugs, it would mean savings of billions of dollars.

"Thus, in this direct comparison, only the calcitriol/+D treatment induced lasting remissions in all animals and significantly reversed EAE disability. We conclude that the calcitriol/+D protocol is markedly more effective than IFNβ, mAb to α4β1I, or GLAT in the rodent MS model."

I compiled this table comparing the drugs against Calcitriol + D3 from the data in the study. The table does not appear in the study.


Source URL: http://www.ncbi.nlm.nih.gov/pubmed/23968560
PMID: 23968560
DOI: http://dx.doi.org/10.1016/j.jneuroim.2013.07.016
Journal Title: Journal of neuroimmunology
Journal Date: 6 Aug 2013
Abstract URL: http://www.ncbi.nlm.nih.gov/pubmed/2396 ... t=abstract
Article Title: One calcitriol dose transiently increases Helios(+)FoxP3(+) T cells and ameliorates autoimmune demyelinating disease.
Article Authors: Faye E Nashold,Corwin D Nelson,Lauren M Brown,Colleen E Hayes

Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, United States.

Here is the relevant quote from the study:

3.6. Efficacy of the calcitriol/+D protocol compared to other MS treatments
It is instructive to compare the calcitriol/+D protocol with published EAE treatment data for three approved MS drugs, IFNβ (Yu et al., 1996), monoclonal antibodies to alpha4 integrin (mAb to α4I) (Kent et al., 1995), and GLAT (Teitelbaum et al., 1999). Data from these studies were compared to the data shown in Fig. 5A, expressing the disability scores as percentages of the maximum score to facilitate direct comparisons. As detailed above, the calcitriol/+D protocol, when administered to animals with partial to complete paralysis of both hind limbs, halted disease progression in all animals, gradually reduced the mean EAE disability score by 61% (from 2.3 to 0.9), and completely prevented relapses over a 60 day observation period (Fig. 5A and Suppl. Fig. 2A). For comparison, alternate day IFNβ treatments administered to animalswith first EAE signs (loss of tail tone) reduced the mean EAE disability score 14% (from 3.5 to 3.0), and reduced relapses/mouse from 2.2 to 1.2 over a 56 day observation period (Yu et al., 1996) (Suppl. Fig. 2B). Administering mAb to α4I to animals with first EAE signs and again 3 days later transiently reduced the EAE

Administering mAb to α4I [Tysabri] to animals with first EAE signs and again 3 days later transiently reduced the EAE disability score by 20%, before disease progression resumed and disability of the treated animals approached the placebo animals over a 42 day observation period (Kent et al., 1995) (Suppl. Fig. 2C). Alternate day GLAT treatments beginning one week before EAE disease induction delayed disease onset slightly but did not inhibit disease progression although the treatments decreased the final EAE disability score ~45% relative to the placebo group at the end of a 25 day observation period (Teitelbaum et al., 1999) (Suppl. Fig. 2D). Thus, in this direct comparison, only the calcitriol/+D treatment induced lasting remissions in all animals and significantly reversed EAE disability. We conclude that the calcitriol/+D protocol is markedly more effective than IFNβ mAb to α4β1I, or GLAT in the rodent MS model.

Morn Ed,
thought if you can call it that, does this mean that a trial would be requiring RRMS patients only and preferably ones who are in the very early relapse?
I was given IV steroids for 5 days to attempt to improve a peak in my symptoms. My disease has been progressive not RRMS and the outcome was a worsening of symptoms which took about 4-6 weeks to settle after the treatment. This was said to be a fail regarding steroid treatments.

I assume that the ideal trial PwMS would possibly be someone who is in early relapse that is driven by diet,stress,infection,injury that has enabled cytokine activation that has crossed the BBB?

The dampening of the cytokine production is the target of the treatment?


Nigel

NZer1 wrote:Morn Ed,
thought if you can call it that, does this mean that a trial would be requiring RRMS patients only and preferably ones who are in the very early relapse?
I was given IV steroids for 5 days to attempt to improve a peak in my symptoms. My disease has been progressive not RRMS and the outcome was a worsening of symptoms which took about 4-6 weeks to settle after the treatment. This was said to be a fail regarding steroid treatments.

I assume that the ideal trial PwMS would possibly be someone who is in early relapse that is driven by diet,stress,infection,injury that has enabled cytokine activation that has crossed the BBB?

The dampening of the cytokine production is the target of the treatment?


Nigel

Nigel,
Many questions and I'm afraid there may not be answers for all of them.

Whether this will only work in RRMS is a question that I think can only be answered by trying it.

There isn't going to be a big clinical trial of this. No one can get rich selling D3 or calcitriol which has been around for more than 20 years in human medicine. And, if word gets out that is more effective than current DMDs, I think we can expect a major pharmaceutical effort to block its use!

The annual cost of a single dose of calcitriol plus some D3 is such a tiny fraction of the cost of today's DMDs (likely $100 or so) and at least for those compared in Professor Hayes' study, calcitriol + D3 was significantly superior. (Tysabri, Interferon beta, and Glatiramer acetate, plus methylprednisolone.)

I think the only way to see whether it provides benefit to people with PPMS is to try it. The risks are well known, manageable and minimal.

Prof Hayes will probably cringe at my lay explanation of what it does, but that's all I can do since I only have a lay understanding of it.

As we've discussed here often, vitamin D controls the adaptive, local immune system. It is what activates all those T-cells, B-cells and other immune actors to deal with a problem.

The immune system is pretty aggressive. It produces stuff like hydrogen peroxide to dissolve things it wants to get rid of like infectious agent, defective cells and so on.

Given the destructive power of these components of the immune system, the regulatory hormone vitamin D, calcitriol, also has ways to tell them to stop, to commit suicide, programmed cell death or apoptosis.

That cell death is not happening fast enough in MS, most cancers and other diseases. The whole theory behind using calcitriol to treat a number of these diseases is that if there isn't enough calcitriol being made in the cells to activate or deactivate the immune system, maybe the solution is to take a big dose of it.

The body can make calcitriol in the cells and degrade it through two enzymes CYP27B1, the gene that produces calcitriol or CYP24A1, the gene that activates the enzyme that degrades. These genes are not working in MS, cancer, IBD and so on so there is insufficient calcitriol to manage the immune system.

There can be many reason they aren't working. If there isn't enough D3, then the cells can't make calcitriol. Maybe your chlamydia pneumonia are blocking these genes. Whatever the reason, taking a big dose of calcitriol should make enough to kill off the T-cells that are causing problems.

An important point here is that calcitriol doesn't just kill off these T-cells, it activates the immune system and produces useful T-cells, B-cells, macrophages and so on. The immune suppression drugs just kill things. Calcitriol both kills and produces things.

So the basic way this works is a mega dose of calcitriol stops the disease and then moderate doses of D3 keep it under control. The calcitriol instructs the T-cells to kill themselves, but it also activates immune system actors to deal with whatever triggered it in the first place.

Hope that makes sense and is reasonably accurate.

Squeakycat wrote:

NZer1 wrote:Morn Ed,
thought if you can call it that, does this mean that a trial would be requiring RRMS patients only and preferably ones who are in the very early relapse?
I was given IV steroids for 5 days to attempt to improve a peak in my symptoms. My disease has been progressive not RRMS and the outcome was a worsening of symptoms which took about 4-6 weeks to settle after the treatment. This was said to be a fail regarding steroid treatments.

I assume that the ideal trial PwMS would possibly be someone who is in early relapse that is driven by diet,stress,infection,injury that has enabled cytokine activation that has crossed the BBB?

The dampening of the cytokine production is the target of the treatment?


Nigel

Nigel,
Many questions and I'm afraid there may not be answers for all of them.



There can be many reason they aren't working. If there isn't enough D3, then the cells can't make calcitriol. Maybe your chlamydia pneumonia are blocking these genes. Whatever the reason, taking a big dose of calcitriol should make enough to kill off the T-cells that are causing problems.

An important point here is that calcitriol doesn't just kill off these T-cells, it activates the immune system and produces useful T-cells, B-cells, macrophages and so on. The immune suppression drugs just kill things. Calcitriol both kills and produces things.

So the basic way this works is a mega dose of calcitriol stops the disease and then moderate doses of D3 keep it under control. The calcitriol instructs the T-cells to kill themselves, but it also activates immune system actors to deal with whatever triggered it in the first place.

Hope that makes sense and is reasonably accurate.

I think that with all the reading you and I are doing we have come to a similar base line other than we are both lay men!

The immune system is defective and most likely from an outside influence rather than an inside dysfunction or genetic or similar.

I get the feeling many ill people have the same reason for these diseases that have no known cause. The basic problem is that the immune system has been manipulated in various ways and it has been cleverly done by centuries of evolution by things such as bacteria/pathogens which evolve within our life span as individuals and modify us each generation.

We haven't evolved fast enough or far enough to avert the mutations of our immune system by the bacteria/pathogens.

Big Pharma may already know this if we laymen can work it out, so yes there will be opposition to the Empire.

The Australian Vit D study for instance is 'possibly' less influenced by Big Pharma, but they have to work with Neuro's often.
If a person on the Aussie team can be 'influenced' by the knowledge you have Ed, I believe there is a chance of running your trial alongside theirs. The cost 'may' be less in countries like Aussie and NZ compared to the other Capitalist Nations and less strung up with pointless red tape and rules.

There must be a way a person thinking outside the box ;) can 'use' another similar trial to advantage and create a Win/Win outcome.

There are Institutes that sponsor Medical trials etc down under which show promise, one I was told about years ago is the Mulligan Institute, and they have shown support in Brain disorders and de-generative diseases many times. A couple of Mill may be possible. ;)

;)
Nigel

Nigel,

I'll have to check out the Mulligan institute. With my Irish ancestry, surely they will be happy to offer a few million. :>)

Here's the interesting thing that that I didn't realize until I read Prof Hayes' study.

If you have genes blocking the metabolism of vitamin D to calcitriol, then you can take vitD until the cows come home and it isn't going to change anything.

You may be born with these genes, or their action may be blocked epigenetically by something like a virus or bacteria.

But calcitriol is the bioactive form of vit D so most of these problems go away. There still could be issues with VDRs being blocked genetically or epigenetically by some process other than our DNA.

Even so, I can now see for the first time why a mega dose of calcitriol might get the whole system back on track and then, with sufficient, though relatively modest amounts of vitD, be able to prevent relapses.

It is doing this in EAE mice. It is doing it much better than the methylpred or the DMDs that it has been compared with.

This really could work in humans. And at a cost that is likely under $100 for the first year and $30 in subsequent years.

It might prove necessary to repeat the calcitriol periodically. Testing has only been for 60 days in mice. They remained disease free for that time, but who knows what will happen in humans.

At this point, I think I can safely say that all the vitamin D trials are going to fail. D alone did not work in EAE. MS or the genes of MS patients are not allowing enough of it to be converted to calcitriol and it is that bioactive form that does the magic, not D3.

Mark,

In light of this, the D3 recommendation may be a disservice unless it is paired with a dose of calcitriol.

It is still a good idea to achieve and maintain a 25(OH)D level of 125 nmol/L (50 ng/ml), but without a shot of calcitriol, it now seems crystal clear that it probably isn't going to have much benefit.

Not that I don't like talking to you Nigel, but this new study is a MAJOR breakthrough in MS and vitamin D.

Isn't anyone interested in something that might halt progression and sustain remission?

Okay, so it has only been shown in EAE mice. But that is true of every shipping MS drug. And the data show that is more effective than any of these, at least in EAE.

Come on folks. This is EXCITING. We have to figure out a way to get this tested in humans!

My ancestry wasn't Irish and my time at school was about eating lunch etc, rather than spelling lessons;

http://www.malaghan.org.nz/

I also think that whether a person has RR or PP MS there is going to be a connection to dis-regulation of the Vit D processes that link into the general immune system functions/ VDR system/ secondary porphyria malfunction/ mitochondria production of ATP/ mitochondrial dysfunction caused by intracellular infections/ endothelial dysfunction caused by intracellular infections and the apoptosis dysfunction caused by intracellular infection/ cytokine cells infected (B & T and marcophages, etc) . True stealth!!

All of these things the body has not been able to evolve enough to fix the actions of bacterial manipulations at a DNA, RNA and basic cellular level.

I 'assume' that the rapid bacterial evolving compared with the slower human evolving has given the bacteria the edge which has meant that the human immune system is overlooking the steps that have occurred and is instead looking for the 'wrong' targets in all of these 'auto-immune system' blamed diseases.
The bacteria have 'aced' or outsmarted the immune system to the degree that the immune system does not suspect the bacteria as the problem until the bacteria are dead and re-cycled in separate pieces as an endo-toxin.

Very clever ploy, to clever for Humans, eh!


Nigel

Squeakycat wrote:Not that I don't like talking to you Nigel, but this new study is a MAJOR breakthrough in MS and vitamin D.

Isn't anyone interested in something that might halt progression and sustain remission?

Come on folks. This is EXCITING. We have to figure out a way to get this tested in humans!

Well Ed, you MAY not have noticed that I'm doing my Happy Dance here, because my gait makes it look a bit more like a Frankenstein stagger. But note the big smile on my face while I'm doing it!

Thanks, Ed. I truly am excited about this development.

euphoniaa wrote:Well Ed, you MAY not have noticed that I'm doing my Happy Dance here, because my gait makes it look a bit more like a Frankenstein stagger. But note the big smile on my face while I'm doing it!

Thanks, Ed. I truly am excited about this development.

Well I guess it is time to rain on that parade and deflate a little of your euphoria. Happy Dance indeed.

There are some good reasons this may not work in humans in spite of how well it is working in mice.

The main caveat is that it is only working as a bypass to problems in converting D3 to calcitriol, problems that seem to go away after treatment with calcitriol suggesting they are epigenetic and reversible.

If there is a congenital genetic or an epigenetic problems with the expression of Vitamin D Receptors, then this may not work.

And there are other reasons that it may not work at least for some people even though it works in the EAE mice. I don't know what these are, but do know that humans are quite heterogeneous in terms of genetics and lab mice are likely very homogeneous. To the extent that a particular human is genetically different from the mice, then the process may well not work for that person.

Until this is tested in humans, I don't think there is any way to know how this will all shake out.

Squeakycat: Just perused a very interesting article tying Lyme (Borrelia burgdorferi), Epstein-Barre virus (EBV), some cancers, calcitriol, and VDR's together. I intend to read it more in depth, but at first blush it appears to suggest that MS has etiologies with geneses in Lyme, EBV, Cpn, and perhaps a host of other bio-pathogens. Perhaps the "one dose calcitriol plus D" would work to, as Hayes believes, "cause the autoimmune cells attacking the nerve cells' myelin coating to die, while the vitamin D prevents new autoimmune cells from taking their place," no matter the original trigger. And while I understand eradicating the trigger would definitely be advantageous, perhaps it's not absolutely necessary to do so to stop the damage. After all, our immune system handles reinfections; once "reset," it may now be able to handle the persistent infection.
http://mpkb.org/home/pathogenesis/vitamind/metabolism

grandsons4 wrote:Squeakycat: Just perused a very interesting article tying Lyme (Borrelia burgdorferi), Epstein-Barre virus (EBV), some cancers, calcitriol, and VDR's together. I intend to read it more in depth, but at first blush it appears to suggest that MS has etiologies with geneses in Lyme, EBV, Cpn, and perhaps a host of other bio-pathogens. Perhaps the "one dose calcitriol plus D" would work to, as Hayes believes, "cause the autoimmune cells attacking the nerve cells' myelin coating to die, while the vitamin D prevents new autoimmune cells from taking their place," no matter the original trigger. And while I understand eradicating the trigger would definitely be advantageous, perhaps it's not absolutely necessary to do so to stop the damage. After all, our immune system handles reinfections; once "reset," it may now be able to handle the persistent infection.
http://mpkb.org/home/pathogenesis/vitamind/metabolism

I think if you view MS as a disease that results from a breakdown of the blood brain barrier, then any or some combination of these pathogens, or the injury caused by turbulent CCSVI blood flow, explains the etiology.

The immune system evolved in a hostile world and is sometimes more aggressive than it should be. The adaptive, local part of the immune system, is controlled by regulatory hormone vitamin D in the form of calcitriol and it acts through Vitamin D Receptors. So everything that provokes an immune response is highly related to vitamin D and VDRs. And that is as true of the gut as the CNS.

Squeakycat wrote:Not that I don't like talking to you Nigel, but this new study is a MAJOR breakthrough in MS and vitamin D.
Isn't anyone interested in something that might halt progression and sustain remission?
Okay, so it has only been shown in EAE mice. But that is true of every shipping MS drug. And the data show that is more effective than any of these, at least in EAE.
Come on folks. This is EXCITING. We have to figure out a way to get this tested in humans!

Hello Ed,
Yes this is exciting. Giving 5000 IU of Vit D3 to pwMS would cost around 20 USD per person per year but on one is to driving using D3 in everyone at risk of MS, very sad.
My contribution is to remind everyone to include Vit D3 in their vein health program. Affording Balloon Venoplasty by an expert is not cheap (but worth it). However, D3 is cheap and most neuros and pwMS ignore it.
Please keep posting on D3,
Kind regards,
MarkW

MarkW wrote:

Squeakycat wrote:Not that I don't like talking to you Nigel, but this new study is a MAJOR breakthrough in MS and vitamin D.
Isn't anyone interested in something that might halt progression and sustain remission?
Okay, so it has only been shown in EAE mice. But that is true of every shipping MS drug. And the data show that is more effective than any of these, at least in EAE.
Come on folks. This is EXCITING. We have to figure out a way to get this tested in humans!

Hello Ed,
Yes this is exciting. Giving 5000 IU of Vit D3 to pwMS would cost around 20 USD per person per year but on one is to driving using D3 in everyone at risk of MS, very sad.
My contribution is to remind everyone to include Vit D3 in their vein health program. Affording Balloon Venoplasty by an expert is not cheap (but worth it). However, D3 is cheap and most neuros and pwMS ignore it.
Please keep posting on D3,
Kind regards,
MarkW

One thing of HUGE importance here, note what Ed is highlighting!!

The dose of Vit D on it's own is not the key to this!!

The "one dose calcitriol plus D" Is the point!!

It is the one pulse of calcitriol that is enabling the Vit D dose to be of benefit, how or why is unknown BTW !!

It's the devil in the detail that is the straw to break the camels back!!

;)
Nigel

NZer1 wrote:It is the one pulse of calcitriol that is enabling the Vit D dose to be of benefit, how or why is unknown BTW !!!
Nigel

Nigel,
This is KNOWN until proven otherwise.

The Hayes study is very clear. Let me go through it step by step.

1. Something in the disease process is blocking the full functionality of the CYP27B1 gene which converts D3 to the bioactive form of vitamin D, calcitriol.

2. When she gives the mice a high dose of calcitriol, it goes directly to the cells that need it without the need for it to be converted from D3 to calcitriol.

3. When that happens, it is as if the immune system has been rebooted. It begins to operate normally and then, maintaining adequate levels of D3 is enough to keep the EAE mice in remission.

Of course, we have no way of knowing whether this approach will work in humans, with MS without testing, but what happens in EAE is very clear and measured in detail in Prof Hayes' study.

So the how and why are well established. It is true that we don't yet know all the details about this and we can only really find out if it works in MS by testing it in humans.

To the extent that this EAE study is applicable to humans, we can draw two conclusions:

1. D3 alone will provide little benefit because it is not being converted to the bioactive form.

2. A one time high dose of calcitriol by acting directly on the immune system halts the disease in 100% of Prof Hayes' mice and 100% stay in remission with D3 alone.

If this works in humans as it has in EAE, then it is a major, revolutionary discovery.

Squeakycat wrote:

NZer1 wrote:It is the one pulse of calcitriol that is enabling the Vit D dose to be of benefit, how or why is unknown BTW !!!
Nigel

Nigel,
This is KNOWN until proven otherwise.
The Hayes study is very clear. Let me go through it step by step.
1. Something in the disease process is blocking the full functionality of the CYP27B1 gene which converts D3 to the bioactive form of vitamin D, calcitriol.
2. When she gives the mice a high dose of calcitriol, it goes directly to the cells that need it without the need for it to be converted from D3 to calcitriol.
3. When that happens, it is as if the immune system has been rebooted. It begins to operate normally and then, maintaining adequate levels of D3 is enough to keep the EAE mice in remission.

Hello Guys,
I read this as theory not known facts. Does the gene CYP27B1 do this is all pwMS? To what degree? Is there evidence? Does D3 from sunlight need this gene? It would be great if a pulse of calcitrol then D3 reboots the MS immune system and keeps it operating normally. If the dose for a 70kg human (me) was a reasonable risk I would try this in the coming weeks. I need to study the paper and supporting papers in detail. We need to keep in mind that there is a D3 blood level/disease activity level relationship so there are more variables to consider. Like Ed says the costs of taking calcitrol/D3 is very low so funding research will be a problem.
kind regards,
Markw