MarkW wrote:Refined Target for D3 is 125nmol/L (50ng/ml) as that put pwMS on the plateau for reducing relapses. Before anyone says there is no proven link between relapses and MS progression, I know but are relapses an enjoyable experience or best avoided ?
Mark, I should really read through this whole thread and look at your logic and calculations for a target level, but I'm going to shoot from the lip on this one since it caught my eye and will return with citations later.
The body allows you to produce 20,000 IU a day, more if you have special needs. People with full sun exposure plateau at 25(OH)D levels above 220 nmol/L (88 ng/ml). Perhaps not coincidentally, this is the approximate normal level for our evolutionary cousins, the ape.
These are levels absent special needs! There is a special need in pwMS which I think points to a need for even higher levels to have effect.
I would contend this is the starting point and that daily equivalents (pulsed weekly) above 10,000 IU are likely necessary to have real effect in MS.
This raises the second question which you point to, what effect should we expect?
What stands out in the pivotal study of vitamin D in EAE mice is that it stopped active encephalitis cold. 100% of the treated mice did not develop encephalitis and 100% of those treated after encephalitis had developed were able to stop it. And they showed that stopping vitamin D supplementation reversed these positive effects.
What this tells me is that the most immediate and dramatic effect of gaining vitamin D sufficiency is that it allows vitamin D to find a way to maintain the integrity of the blood brain barrier.
One of the main functions of regulatory hormone VitD is to manage the cell replacement cycle when a cell is damaged, whatever the cause, turbulent blood flow, hypoxia, EBV, Dr. Wheldon's c. pneumonia.
It almost doesn't matter what causes the breech in the blood brain barrier, it is Vitamin D's job to restore its integrity.
It does this by managing cell replication and apoptosis as well as by marshaling the immune system to clean up the mess and attempt to deal with any pathogens that are attacking the endothelium.
As such, the principle benefit of vitamin D supplementation should be to quickly repair any injury to the bbb and set off the process to dispose of the injured cells by apoptosis and ward off any pathogens threatening the bbb.
I suspect that in the EAE mice, it was vitamin D's role in protecting the bbb that made it so effective.
In humanMS, where I would expect to see the most immediate effect would be in stopping active lesions (gadolinium enhanced lesions) which are an indication of a breech in the bbb.
The second end point would be to reduce the number of relapses, especially to the extent that these are caused by injury to the endothelium. By maintaining vitamin D sufficiency appropriate for pwMS, the blood brain barrier integrity should be protected.
Were I designing clinical trials of vitamin D, I would do several things:
1. Limit enrollment to those with gadolinium-enhanced lesions (or have a group large enough to have significance).
2. Set my primary endpoint as the reduction in gadolinium-enhanced lesions and the secondary endpoint as a reduction in the number of relapses.
3. Set a target 25(OH)D level of 220 nmol/L (88 ng/ml) and achieve that quickly with a loading dose that would attain this level quick time.
(Loading Dose = 40 x (Target 25(OH)D level/nmol/L - Serum 25(OH)D level nmol/L) x BodyWeight(Kg))
4. Set a maintenance dose that is escalated until the 25(OH)D level reaches an equilibrium and does not rise further. I think that dose is likely to be above 10,000 IU per day, pulsed weekly to avoid hypercalcemia.
I don't know if Vitamin D plays a role in remyelination. I do know that there is a very promising drug, LKE, that stimulates remyelination apparently through CRMP-2 and has shown remarkable progress in halting and reversing several neurodegenerative diseases such as MS, ALS, and Alzheimers in animal models.
I would not expect to see any short term change in EDSS which is linked to the demyelination. But once the bbb integrity is attained, there are likely natural processes, or new drugs, that can trigger remyelination.
I think the simple fact of all this is that MS would not exist if the bbb integrity were maintained and once it has been injured, adequate levels of Vitamin D should restore its integrity and minimize damage as it did in the EAE mice. What is central is the BBB. All the immune reaction to that is secondary. Put a thumb in that leak and you can manage MS.
Should note that I don't think Vitamin D is a panacea. It acts on many things which have to be fully functioning for it to have effect. There are many co-factors involved from adequate calcium levels to the integrity of the innate immune system. Constant pounding on the endothelium from turbulent blood flows, associated hypoxia and local hypertension, have to be fixed.
The immune system grew up in a very hostile environment and may well be over-reacting to some things. There is some basis in evolutionary biology to consider that neuroinflammation is a type of "disposable soma" consequence to evolving in a pathogen-rich world.
That may mean that there is still a role for some limited interventions with immune suppresives while you try to attain an equilibrium by restoring the integrity of the BBB.
Sorry for the length. I have a very serious genetic disorder: An Irish heritage where the quantity of words is highly prized, even when they don't add much.