Dimethylfumarates and Psoriasis

[Caroline]

Essential differences between fumarate and the well know immuno suppressors.

Ciclosporine and other medications out of the category of immuno suppressors, which in fact have been developed for different targets, do also work in favor of psoriasis. They do this by selectively suppressing the immune system. The idea that fumarates should also be seen as an immunosuppressor, adds to the cellular vision, stated by Virchow (some guy researcher) in earlier posts mentioned studies of Kiehl and Nibbering et al. are thereby left out of consideration.
However the original author of these posts remarks that by using cyclosporine, nowhere there is a mention of "flushing" or a higher body temperature. This also holds for the newer immuno suppressors under the name of 'biological's' and recently are often used in the battle against psoriasis.
This important difference in symptoms should have been remarked by the researchers, but it seems to be overlooked by them. Perhaps because this does not fit in the paradigm of the immune-modulation. This is perhaps why the Fumarate therapy is only used by exception, which means only by psoriasis patients where no solution exists and under regular measurement of several parameters in the blood before and during the therapy. In the medical/dermatological literature there is no mentioning of measurement and comparison of body temperature before and during the treatment, mentioning the "flushing" phenomenon and/or a description of specific local skin reactions due to the fumarate treatment.

[Caroline]

Side effects are in fact the desired effect which is a bit too strong

It is the question why the stimulating effect of fumarate on the citric acid cycle is seen as an obsolete theory in the literature (Caroline comment: Indeed very strange, nothing happens without a reason in our bodies, so that is a stupid consideration). Possibly the idea has taken hold that the attempts to treat psoriasis with fumaric acid (DMF) did not show results but only gastro-intestinal complaints. A publication on this subject is missing.
What is a fixed result is that Schweckendieck really did get good results with the fumaric acid treatments and only later stepped over to the use of fumarates.
The arguments given for this and the publications on it do plead for the stimulating effect/action of fumarates on the citric acid cycle and against the feared long term effects, that are common with immuno suppression (this is where many dermatologists are afraid of, but they just don't have enough knowledge on this subject).
The years of practical experience of the (original) author and of internal disease specialist dr. F. van Loon, support this vision.
There are only transient 'negative' effects, like mucosal irritations, "flushing" and slight deviations of the normal blood picture, which immediately return to normal when stopping the treatment. This also happens when the treatment is continued, though slowly. The side effect is in this case a wished effect that is a bit too strong. With a controlled accompaniment this can be caught.
When there is a large occurrence of diarrhoea, there is an indication to execute a bacteriological and parasitic faeces examination. A pre-existent, masked intestine infection might have become manifest under the DMF treatment and should of course be treated.

[Caroline]

DMF stimulates the citric acid cycle.

In the British Journal of Clinical Pharmacology results were published by Litjens of the serum concentration of MMF after orally taking DMF with healthy volunteers. MMF appears to be only shortly detectable in the blood. The concentration in that time has a peak-formed curve.
Citate: “The present results are in agreement with our observation that dimethylfumarate is rapidly hydrolysed to monomethylfumarate at pH 8.5, but not in acidic environment ….Further hydrolysis of this metabolite to fumaric acid occurs inside cells, thus fueling their citric acid cycle, as indicated by increased CO2 concentrations in the expired air of dogs injected with fumarates”.
This research clearly shows the effect of the fumarate treatment on the citric acid cycle and therefore supports the vision that psoriasis is a mitochondrial disease. Up to now this publication has had very little attention.
Research in this direction deserves repeating and extension.

Publicized in: Litjens H N R et al. Pharmakinetics of oral fumarates in healthy subjects; B J Clin Pharm:58 issue 4, page 429 Oct 2004.

[Caroline]

Persistant misconception,

As long as the scientific research for the influence of fumarate on the citric acid cycle and for the influence of it on the body temperature, c.q. of the basic metabolism is not done, the application of fumarates will hardly be done in the normal dermatological practice, as it is seen by dermatologists as an immunosuppressor, with the accompanying chance on damaging side effects (C:which there aren't).
The conclusion from the research of Litjens that there is hardly any evidence of damaging side effects, will therefore be ignored.
The years old misconception will continue to exist and, as is mentioned on the leaflet of the fumarate marketed version by Tiofarma, that says that the medication should only be used if all other medications have failed and then it should be only used under specialized monitoring. (C: This is what I really heard from the rheumatologist   )
Additional disadvantage of this way of working is, that serious liver- or kidney function disruptions can have been caused by these "usual" therapies that have harmed the health of the patient in such a serious way that the treatment with fumarates is too late.

Ciclosporine cannot be used for longer than a year because of the nefrotoxical action and cumulative toxicity; that is an absolute rule. With long term use there is a risk of the genesis of malignant neoplasm. These risks can also appear in relation to the 'biologicals', though there is large progress made over there. (C: this is the opinion of the original author.)
For many well-informed patients with psoriasis, this could be a reason never to start at those medications (C: I mean like cyclosporine over here).
However in the dermatological practice, ciclosporine is still often prescribed, anyway much more often than fumarates. The costly 'biologicals' are being pushed by the strong industrial lobby, withhout much attention for this important shadowside. (C: this is the opinion of the original author.)

Important signals when using medication that is exclusively developed for the suppression of the immune system can be found in repeated respiratory infections and badly  healing wounds. The increased incidence of Borrelia infection and the alarming spreading of the MRSA bacteria via pig to human, do make the use of immune suppressors in this time not very attractive.
Increased vulnerability for infections with the many hundreds Psorinovo (DMF) users however, has never shown up in the past 30 years.

[Caroline]

Auto-immunity primary or secondary.

If we look at the literature that has been incorporated in the prevalent posts, we can see that it is plausible that the auto immune reaction that is seen with psoriasis, is secondary to a not optimal functioning citric acid cycle. Not only in the skin and in the joints, but also, as we have seen, in the blood cells en possibly even in all tissue.
With an insufficient biological oxidation the forming of free radicals increases resulting in damage of the celmembranes (oxidation of lipoprotein). It has been shown that with psoriasis there is an increased concentration of free radicals in the blood. Anti bodies against, as well as T cell reactions on oxidized lipoproteins and proteins are in these circumstances known with mankind and animal.
How there reactions exactly elapse and how T-cell recognize normal body components and antigenes, when these have been changed by free radicals, is still not sufficiently known. Any way an auto immune reaction following on oxidative membrane damage is a well known phenomena. Adding fumarate repairs the physiological oxidative energyproduction, whereby the substrate for the auto immune reactions, the lipoproteins that were changed by the free radicals, will disappear. This information is of course very interesting, not only for the understanding of the etiology of psoriasis, but also of the etiology of other so-called auto-immune diseases, and of course for the treatment of them. Not to forget the total aging process, which is also powered by free radicals.
Exclusively based on the ground of the immunopathogenic equation with psoriasis on cellular level, dermatologist H.B. The (C: Leading dermatologist in the Netherlands) posited in his thesis that fumarate could possible be effective in the treatment of multiple scleroses. (C: Think of the new medication of Biogen against MS)
One could also connect the relation between fumarate and MS on the basis of another similarity between psoriasis and multiple sclerose, namely that between climate and incidence of both diseases. As in prevalent posts has been tried to show that both diseases have a mitochondrial source, that is also a point of similarity. In the mean time, research has shown that there is a connection concerning the treatment. Schimrigk S et al, told in 2006 about the results of fumarate treatment with ten patients with MS. Seen the positive results of this research, further research on the treatment of MS with fumarate should be done. In the mean time this resulted in new medication.
Kreuter A et al. publicized in 2005 on positive results of fumarate treatment with necrobiosis lipoidica and Venten l et al, had success with fumarate treatment with alopecia areata. Fumarate also has shown its value with some cases of Lichen Sclerosus, CDLE, MCTD and the M. Hailey & Hailey.

[Caroline]

Summary

That fumarates are effective with psoriasis is with researchers already a fact. There is still some distress and nescience about which fumarates are usable and which are not. Also the working principle is in discussion. Because of that, there is a difference in view on the possible harmful side effects of the diverse fumarates, about the indication area and about the type of doctors who should prescribe this treatment.
This appears also from the report of the Commission Pharmaceutical Help from 2004 (Dutch), where a) Monoethyl as well as dimethylesters of fumaric acid are mentioned as usable medications, where b) Immuno suppression is seen as a sufficient explanation for the treatment result and where c) fumarate treatment, because of possible harmful side effects is limited to psoriasis patients where all other medications have failed, under the additional limit that this may only be prescribed by a dermatologist (C: in the mean time there is more space in the prescription possibilities, at least in the Netherlands. The report has been rewritten)
The conclusions on this report however are missing a scientific basis (C: yeah, written by a Committee can never be scientific.... ) At first, based on literature research in prevalent posts we have shown that monoethylfumarates do not work with psoriasis and that they pose more risk for the health than dimethylfumarate.
Secondly there is still no proof that immunomodulation, as well as suppression is the definitive explanation for the positive effect of fumarate with psoriasis. Sunlight is also very favorable for the skin with psorisis, but nobody will state that this has to do with immunosuppression. On the contrary, sunlight means an addition of energy in the form of photons and normally stimulates the immune system. Also the reduction of stress has a positive influence on psoriasis and that also has nothing to do with immunosuppression.
According to the original author of this information, it cannot be ruled out that psoriasis is based on a mitochondrial disfunction which is normalized by the use of the fumarate treatment. Because of the fact that above that the indication area of fumarate is much broader than solely the treatment of psoriasis, the use of fumarates ought not to be limited the specialistical, dermatological practice, as the mentioned report states (C: the committee report).
The original author points in this situation to the fact that according to US patent 6858750 (2005) the medical use of fumarate, based on extensive literature study is claimed for the treatment of all possible mitochondrial diseases.
Finally the harmless side effects and the favourable long term effects of fumarates, as shown by Litjens, are strong arguments to use fumarates as a first choice treatment of manifest psoriasis, specifically as dimethylfumarate in slow release form.
A solid medical supervision with the treatment is necessary, that is obvious, but there is no scientifically based reason why this supervision could not be done by a GP.

   ====  end of this series of posts on dimethylfumates ====

There is a lot of research literature. I don't have that, but I can give references if necessary.

[Caroline]

Some more clarity on the subject of DMF in the form of combination preparation with MEF and DMF.
Nicolle Litjens, is writing in her thesis on page 14: “Monomethylfumarate (MMF) is considered the most active metabolite and is formed in the circulation following the hydrolysis of DMF”. As can be seen under this sentence a schema is following, which shows what hydrolysis means (if you did not know that): and that is that a methyl group (CH3) is replaced by a hydrogen molecule (H).



Everyone who has passed a high school with a little chemistry can conclude from the picture, that from MonoEthylFumarate you can never form MonoMethylFumarate (MMF). Leading doctors, any doctor/dermatologist, should know that, together with the knowledge that the real working factor is MMF, this is the effective molecule. Still doctors are prescribing the combination preparation, of which one component not only does not have any anti-psoriasis effect, but even appears to be toxic.
In the Netherlands this would mean that a even a comparison between the two preparations is senseless as the difference so easily can be seen.

Litjens consciously has examined if there was a difference in activity between the several forms of fumarates concerning their influence on the citric acid cycle. DMF, MMF and MEF were compared. The effect of MEF appeared to be negligible (last line on page 20).



In the rest of the thesis MEF does not play a role anymore. Statements 2 and 3 belonging to the thesis, do speak a clear language (unfortunately I don’t have them). MMF is the most active metabolite (and this can only be originated from DMF). Litjens has written a thesis called: "Immunomodulatory effect of fumarates in psoriasis", and did for this thesis quite some practical research and a lot of theoretical research.

In the mean time science has progressed. The immediate reaction after the reading of the thesis of Litjens would be to prescribe MMF. Unfortunately the law in the Netherlands (after Psorinovo had hit the market) has changed in such a way that it is virtually impossible to get MMF on the market.
The requirements that must be fulfilled for new medicines have been raised so enormously that the development of a new medicine costs billions and that development only is admitted if the research protocol follows a strict and extremely expensive route (Once again people who know nothing block the quality of life of lots of their fellow civilians, only in the sake of utter safety and money). This route can only be followed by a multi national and if the stuff is patentable. MMF is not patentable. So it will only be done if there somehow is a large financial reward. The chance is there, because DMF (in reality MMF) can be used for more and more purposes.
Because  what is happening…..:

Dr. B. Thomas, neuroscientists of the Department of Pharmacology and Toxicology and connected to the Medical College of Georgia (Augusta university) US, has published studies in the Journal of Neuroscience, which show that MMF and DMF stimulate the functioning of the mitochondria (the energy suppliers in every cell [we knew that already, read my thread]), but it appears that DMF initially slows down the working of the mitochondria for a short time, and only in second instance will stimulate, while MMF immediately stimulates the mitochondria.
This inconvenient and disadvantageous difference exists because DMF firstly retracts glutathione (an important anti oxidant) from the mitochondria. So they are working less efficiently and this explains according to dr. Thomas the unwanted side effects of DMF, that are not to be expected with MMF.
After the change of DMF into MMF, the so called hydrolysis, this disadvantage is again compensated and more than that. But this the explanation of the superiority of MMF as a medicine, which also were found by Litjens, without knowing the details.
 
By the way it is this essential effect on the mitochondria, which results in the fact that the body temperature is slightly rising and that people can get a red head (the well know flush), a point that dermatologists never mention, let it even be that they explain the effect on the cytric acid cycle, the biochemical proces that facilitates the production of energy in the mitochondria.
The role of the citric acid cycle I have earlier described in my thread Dimethylfumarates and Psoriasis, which is based on an article in the Dutch Magazine of Integral Medicine and written by my doctor.  

The observed side effects of MEF (a possible detoriation of the kidney function) is based on the same disadvantage that DMF has to a much lesser extent, that is the negative influence on the mitochondria. It is well known that damaging the mitochondrial function in the first place influences the heart, but in the second place the kidneys. This follows in that chronic kidney diseases are mainly based on damaged mitochondria. This is the reason that chronic kidney diseases nowadays are treated with anti oxidants, for example Cysteine ( Bill ! ) , glutamine and glycine  (J Nephrol 2015;42:318-319). MMF seen from this point could be a miracle medicine against heart muscle degradation and kidney degradation, but… also MMF has its lesser sides as it remains immunosuppressive.

By the way, the unwanted side effects of DMF (damaging the mitochondria) can be prevented by eating glutathione rich food and to avoid food with a lot of oxidants. Glutathion is available in raw vegetables and fruit, e.g. Asparagus, avocado and walnuts, fish and meat. You could also use a food supplement wich supplies you with glutathione  250-750 mg per day, depending on your DMF dose.
Schweckendiek prescibed (1981) with the use of fumarates, the anti oxidants cystine and glycine and extensively discussed the mitochondrial functioning in combination with the fumarate treatment.
 
It can be assumed that the dermatologists are too less aware of what is happening in the body. They may be too busy with the outside. The doctors who show the relation between psoriasis, mitochondria, the citric acid cycle and nutrition are not taken seriously.
The dermatologists are not aware what is happening and keep tight to therapies with MEF included. We do not know the effects of the biologicals on the mitochondria yet, but lets not be too negative on that. There is no research findable on that subject.

While neuro scientists have observed that MMF reduces the damage to the neurons with diseases as MS, Parkinson and other neurodegenerative diseases, in England a RCT has been started with Parkinson patients. The purpose is to stop the progress of this disease by this approach, the past has shown that giving anti oxidants to Parkinson patients is of no use.

We must be aware that the use of immunosuppressive medication increases the chance of dangerous infections, although we have seen in the last more than 30 years that this chance is low with the use of fumarates.
If you would want to lower your microbial “load” in order to reduce other immunosuppressive medication than there is another solution for that.
 
Literature.
Metabolite of oral DMF drug for multiple sclerosis appears to slow onset of Parkinson's disease; Medical Science News, June 9, 2016