Coimbra ProtocolMultiple SclerosisUncategorizedVitamin D

The fallacy of the absence of evidence from the Coimbra Protocol

For the last 4 years I had the privilege of being part of the more than 100 worldwide doctors who have been prescribing vitamin D to fight autoimmune conditions, like multiple sclerosis, lupus or rheumatoid arthritis. Despite quite extensive in Europe, my experience is very small taking into consideration that the Coimbra Protocol has been developed for the last 18 years by Professor Cícero Coimbra. Globally, more than 20.000 people are being treated with this vitamin and were able to achieve a wide range of success and, also, failure. Thankfully, the former are overwhelmingly more than the later and improvement in this diseases are a daily occurrence in our practice.
It is not a conventional treatment, turning it into a huge target for attacks and criticism. Some of them are reasonable: saying that high-vitamin D intake is highly dangerous and can potentially be catastrophic is an understatement. It is 100% true that, under very specific conditions, the Coimbra Protocol can lead to hypercalcemia – high blood calcium. This high concentration is very dangerous and a lot of health problems can come from it, from nefrocalcinosis to cardiovascular disturbances. But there is a “but” and it is a big “but”: the patient is totally able to avoid it. By following the diet and hydration prescribed, all potential side effects of this treatment can be prevented.
However, the main attack this treatment suffers is not the potential harm but the “lack of scientific evidence supporting the use of vitamin D to treat autoimmune conditions”. It is the most common argument used to persuade patients from fighting for their health on a non-conventional way.
I am glad to said that this argument is false! The evidence exists and justifies its use.

The Science behind the Coimbra Protocol

Let me start from what the Coimbra Protocol does not have, trying to set aside the most used argument: there isn’t any paper published showing the results of the treatment with high dosages of vitamin D. It is false, it exists. In 2014, the DermatoEndocrinology published the results of a 6-month-long  study where patients with Vitiligo and Psoriasis were given 35.000IU of vitamin D. The results were quite fantastic: more than 85% of the vitiligo patients got between 25 and 75% of the lesions improved. The number jumped to 100% of the patients with psoriasis. Incredible numbers! However, the study had some technical limitations: it was not an randomized clinical trial (RCT), the number of patients was small and the diseases can be considered “minor autoimmune conditions” (even though there isn’t any minor in the emotional suffering of people with these skin conditions). So, following the medical reasoning in which “only treatments backed by RCTs should be prescribed”, the Coimbra Protocol could fall short on it.
The “counter-argument” is brought to us by some of the most respected medical journals in the world.
Let’s start with this:
In 2003, the British Medical Journal published a paper which concluded the use of parachutes could not be prescribed because there wasn’t a single RCT published supporting its use. Their goal was simple: show that a blind following of the evidence-based medicine doutrine could create some ludicrous situations. In their words:
 “(…) advocates of evidence based medicine have criticised the adoption of interventions evaluated by using only observational data. We think that everyone might benefit if the most radical protagonists of evidence based medicine organised and participated in a double blind, randomised, placebo controlled, crossover trial of the parachute”.
Other “counter-argument” that can be raised is the existence of double standards when comparing similar therapies: the existent evidence supporting the use of insulin and levotiroxine in patients with insulin-dependent diabetes and hypothyroidism, respectively, is about the same compared to the the vitamin D evidence. Surprised? RCTs aren’t needed in these situations, as insulin and levotiroxine are treatments needed and physiologically make sense: they give the body what it needs and cannot produce on this own.
So, giving the body what is needs is quite logical, right? Of course. Specially when we are talking of something which is mandatory to a healthy human system. They are
  • Hormones
  • With pleiotropic effects
  • Without a ideal-for-all therapeutic dosage; it needs to be adjusted by analytical follow-up;
  • Underdosage has no clinic or therapeutic level;
  • Overdosage can be life-threatening.
Having in consideration that vitamin D is also an pleiotropic hormone with need for careful titration to have clinical effect without side effects, not accepting its use while accepting insulin or levotiroxine shows quite clear double standards!
Before focusing on the science supporting the vitamin D in the treatment of autoimmune diseases, it is important to shed some light on its physiopathology.


The Equation of Autoimmunity

The base equation of autoimmunity can be described as

    AI= Treg – Th17

Meaning the onset of autoimmune diseases happens when Treg cells (the maestro of the immune system) and Th17 cells (besides a small role of fighting bacterial infections, they are the immunological basis of autoimmunity) get out of balance. While Treg cells can control the magnitude of Th17 cells’ function and keep it under control, the chances of developing an autoimmune condition are very slim. That is also the Holy Graal every autoimmune treatment aims: being able to rebalance the Treg / Th17 scale would mean treating the root cause of these diseases.
The first argument in favor of the vitamin D is the effect it has been showing on immunity. For the last decade, hundreds of papers have been published in different medical magazines. In this study published in the Clinical Reviews of Allergy and Immunology magazine it was concluded that
     It has been shown to inhibit Th17 cytokine production, enhance Treg activity, induce NKT cell functions, suppress Th1, and promote Th2 cytokine production, and thus skew T cells toward Th2 polarization
In this other, published in the Journal of Neuroimmunology, it is stated that
    “ (…) the results indicate that the active form of vitamin D added to polyclonally-activated T cells from MS patients is able to reduce the proportion of pathogenic T cells, defined by the ability to produce IL-17 with or without IFN-γ cytokines
By all means, these are not the only ones! There is mounting evidence relating low levels of blood concentration of vitamin D with higher numbers of Th17 cells over Treg cells, leading to autoimmunity. Also, the conclusions we just shared are quite clear: by increasing the biological effect of the vitamin D we may be able to limit the production of Th17 cells and increase the maestro Treg! Please, let me repeat: the biological effect of these vitamin is able to accomplish the ideal therapeutic effect: more Treg, less Th17. Therefore, more vitamin D might mean less autoimmunity!
Very different observational studies have been published during the last years linking low vitamin D with increased incidence or severity of several autoimmune conditions, such as multiple sclerosislupusrheumatoid arthritisCrohn’s diseaseHashimoto’s thyroiditis,  vitiligo or psoriasis. That relationship seems to be less and less questionable.

How much vitamin D is needed?

Among the existing evidence, the question we should ask is “which vitamin D level is needed for the body to achieve the optimum biological goal and optimize its function?”.
Truth be told, our body has the ability of producing vitamin D. For that to happen, we need to have a great area of skin exposed to the sun for long enough so it can kickstart the pathway leading to the active vitamin D form, calcitriol. It is estimated that we need between 20 and 30 min of sun exposure to accomplish it. Unfortunately, our modern way of living leaves very little chance for that to happen, leading to the pandemic low vitamin D levels worldwide .
Current recommendations for the supplementation of vitamin D of 600 to 800 IU per day have already been considered statistically inaccurate in a paper published in 2014 by Nutrients magazine.
Does it mean this “high-dosage” is enough to control autoimmunity and accomplish the so-needed immune balance? Unfortunately, not always. There are some published papers suggesting that higher than 800IU of vitamin D taken daily don’t affect symptoms of multiple sclerosis (here or here). It can also be said that normal blood vitamin D level may not have real clinical impact in autoimmunity. However, on the other hand, papers have been published showing the opposite. In this paper, published in the Immunology Research magazine, not-so-high intake of this hormone led to quite significant analytic and clinical results in SLE patients!
How can this dissociation be explained? Why is vitamin D showing results on the Treg / Th17 balance in lab but isn’t in clinical settings? Allow me a small detour, trying to explain it.

The Story of the Perfect Factory and the Real Factory

Imagine you visit the best table factory in the country, with high profitability and quality. Let’s call it the Perfect Factory. You are so impressed with it that you want to emulate it, aiming the same good results. After studying all the details of its production line, you came to the conclusion that 100 tables are produce each day made from 1000 kg of wood, entering the factory on a daily basis. You also got the design of the production line’s machinery and, with that, you feel comfortable on starting your own. Let’s call it the Real Factory.
While trying to set everything up, you are able to get in touch with the wood supplier and got a good deal on it. However, the production line is not that easy: you are informed the old models are not available anymore, but this new one is almost the same and also do a good job. You have to settle with it. Unfortunately, when the Real Factory started producing, the results are catastrophic: despite using the same 1000 kg of wood, it can only produce roughly 50 tables per day.
In order to save your company, you have to find out what is going on, where the problem is located and what would be the solution for it. You start tinkering and the first hypothesis is the wood might not be good enough. However, you drop it: as the wood is exactly the same as the one used in the Perfect Factory, it doesn’t make sense that it is the reason of the bad performance. The other hypothesis that you come up with is the machinery quality in the production line. When you payed attention to it, you notice one of the main piece of equipment in the factory is under-performing because of its differences when compared with the Perfect Factory.
A solution is now needed. After trying different solutions, you realized that raising the amount of wood in the beginning of the production can overcome the lack of performance and increase the number of tables produced. So you decided to keep raising it until you achieve your ultimate goal of more than 100 tables produced daily and profitability.
This metaphor tries to explain that dissociation between lab results and clinical results.
Just like in the Perfect Factory, when physiology is under a rigorous control, vitamin D is able to balance the Th17 / Treg responses, reducing the severity and prevalence of these diseases. However, as it happens in the Real Factory, due to malfunction of our machinery, the real clinical effect under real world conditions seems to fall short: the same amount of vitamin D does not create the same effect. This is what have been shown by most of the published data. Facing this differences, we may jump into the conclusion that “vitamin D does not perform in real world conditions”. Following the example of the factories, it would not be fair or accurate. Next step is then try to find out if and which “machinery” is working poorly and conditioning the vitamin D results.
Several different research teams have been looking into it from this point of view, asking the question “where is the pitfall? What is limiting the biologic effect of vitamin D?”. The most obvious place to look is our “production code” which determines everything we produce: the DNA.

The relationship between vitamin D, genes and autoimmunity

When they looked which genetical features were common among autoimmune patients and could influence the vitamin D pathways, researchers found a relationship between single nucleotide polymorphisms (SNP) in key genes, such as the vitamin D receptor (VDR), and different autoimmune conditions. These relationships have been published already: multiple sclerosis, rheumatoid arthritis, Crohn’s disease, Hashimoto’s thyroiditis or lupus.
This specific article stating the association between genetical features and SLE deserves a deeper look into it because:
  1. It was published by a Portuguese team;
  2. The patients were Portuguese;
  3. Its conclusions are quite clear:
    1. Our study confirms a possible role of VDR gene polymorphisms in SLE.
    2. A positive association was found between VDR polymorphisms and SLE severity (chronic damage).
    3. The presence of CT genotype of FokI and TT genotype of TaqI seems to confer a worse prognosis and may constitute a risk factor for higher long-term cumulative damage in SLE patients.
Let’s repeat it so it can sink in: having certain genetic features seems to confer a worse prognosis and may constitute a risk factor for higher long-term cumulative damage in those patients! In other words, it is the underperforming machine responsible for lower than ideal efficiency!
Obviously further explanations are needed, specifically in terms of specific mechanism by which these genetic changes change the outcome. Some data have already been published: it seems that each gene codes for a different 3D configuration impairing the link between active vitamin D and the docking place in the VDR. When this connection is other than perfect, the message cannot go through easily and the function will not be perfect. The same way a bad contact between wood and machine led to lower performance, a worse vitamin D – receptor pair create the conditions for changes in immune function.
So, the explanation of the dissociation is, in a way, quite simple: because of the genetical changes existent in patients with autoimmune conditions, the intake of normal or “high” vitamin D (but still under the safe dosage of 10.000IU) is not enough to enable its biological effect, needed to balance the Th17/Treg responses and controlling autoimmunity. Now, is it the same as concluding that vitamin D has no role to play or ineffective? Or should we find out a way to overcome this resistance? I believe you would agree that the later is quite the right option!
What we need to do is to find a way to emulate lab results in the real life.
Several tried. A paper published by the same Portuguese team used higher than the standard vitamin D recommended dosage in SLE patients and studied its analytical and clinical effect. And it was quite good: reduced Th17 cells and improvement in the Th17/Treg ratio, with clinical changes as well. In the last remarks of the conclusion, here is what the authors had to say:
“In spite of displaying optimal circulating vitamin D levels, the ability to metabolize vitamin D may vary between individuals’ genetics and may therefore contribute to the risk of developing immune abnormalities. These situations are illustrated by the presence of certain gene polymorphisms in the vitamin D metabolizing enzymes, such as CYP2R1 (hydroxylates vitamin D3 to 25(OH)D in the liver) or CYP27B1 (activated by PTH and hydroxylates 25(OH)D to 1,25(OH)2D3 in the kidney). Even if all these steps are properly functioning, the vitamin D active metabolite (1,25(OH)2D3) must be recognized, bound and activated by its receptor (VDR). Polymorphisms in the VDR gene may also play a role in this mechanism“.
Professor Coimbra tried to go further and deeper in his quest to achieve maximum biologic effects of our vitamin. He figured we needed to measure the actual real effect, the physiologic end-result, a barometer of sorts that could help us having a better window into it. The ideal scenario would be measuring the Th17 cells or response. Even though analysis like IL17 concentration exist, they are not easily available to clinical use or its price reduce their potential use. Professor Coimbra needed another molecule.

PTH: the barometer of vitamin D effect

Probably the easiest and simpler way to assess the real action of our vitamin is by using the balance of calcium because vitamin D is deeply involved in it. Its effect changes inversely with another hormone: parathormone (PTH). Vitamin D and PTH are controlled by strict biofeedback mechanisms and one of them comes very handy: the former suppresses the production of the later. To achieve it, it has to go through all the same steps involved in the control of the immune responses, meaning that when PTH is low, the biologic effect needed is high.
The blood level of the PTH becomes the “number of tables produced in a day”, if we want to use the example of the Factories: the lower it gets, the higher the efficacy of the vitamin D. Therefore, by keeping it very low (in targeted therapeutic and safe levels) we ensure maximum biologic effect and, as science has been showing, better Th17/Treg ratio. That leads into improved immune, reduced auto-attack against different cells and tissues, which means controlling the magnitude and progression of diseases like multiple sclerosis, SLE, rheumatoid arthritis or Crohn’s.
I hope I was able to share a clear view into the science behind the use of vitamin D in the treatment of autoimmune conditions and why the Coimbra Protocol is a evidence-supported option to achieve the ultimate goal: helping millions of patients in their quest to a better health.

One thought on “The fallacy of the absence of evidence from the Coimbra Protocol

  1. Thank you so very much for authoring this article. I have been in significant discussion with the physician at our site regarding the Coimbra Protocol and you have addressed all the major points of our discussion. Hoping you will be coming through Chicago soon, as we would love to meet with you.

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