Rich Konynenburg sobre el Rituximab

[EndSFC]

Octubre 2011

Rich V K on Rituximab for CFS, GSH, autoimmunity, etc.
http://forums.phoenixrising.me/showthre ... FS-mystery" onclick="window.open(this.href);return false;


Hi, all.

I think this is a very interesting development, and I want to suggest what I think is going on when Rituximab is used to treat ME/CFS.

It will probably come as no surprise to those familiar with my history here that I will propose a mechanism that fits with the GD-MCB hypothesis for the pathophysiology of ME/CFS.

O.K., here it goes:

Based on the body of immunological studies that have been done in ME/CFS over quite a few years, we know that the immune system is dysfunctional in this disorder. In particular, it has a pronounced shift to the Th2 type of response, away from cell-mediated immunity.

The NK cells and the cytotoxic (CD8) killer-T cells are ineffective, partly because they are unable to produce enough perforin to punch holes in cells that are infected with viruses. Since this is the main mechanism normally used to knock out viral infections, these infections cannot be knocked out.

The immune system is forced to use its fall-back mechanisms, which are the humoral immune response (antibodies produced in Th2 by the B cells, which become plasma cells), and the interferon-induced mechanisms, including RNase-L.

These are less effective and are not able to completely knock out viral infections (The cell-mediated cavalry never arrives). This is the reason for the ongoing guerrilla war in the person's body, with both the reactivated viruses which have been in the body in the latent state, and with new ones that come along and infect the person after the onset of ME/CFS

As has been noted, the B cells do produce proinflammatory cytokines, which of course promote inflammation. Because most PWCs also have a dysfunctional HPA axis, cortisol tends to be low, and the inflammation is allowed to intensify to a higher level than normal.

Note that one of the main features of inflammation is oxidative stress, because cells of the immune system produce oxidizing species to attack the body's enemies. Oxidative stress is well-documented in ME/CFS, with perhaps 20 published papers reporting evidence of it now.

And those familiar with the body's antioxidant system will know that when a state of oxidative stress is present, the antioxidant system is losing the battle between oxidants and antioxidants.

Those familiar will also know that glutathione is the basis of the antioxidant enzyme system in the body. So now we come to realize that in the subset of PWMEs/PWCs in whose bodies infection is a major aspect of their illness, we can expect that a major part of the oxidative stress, and hence a major part of the demand on glutathione, will be due to inflammation, which is being stimulated by the B cells in the overactive Th2 immune response.

O.K., so now we put in Rituximab, which kills the B cells. What happens?

Well, the inflammatory cytokines drop down, as does inflammation. This lowers the oxidative stress, taking a big demand off glutathione, which is then able to rise to at least some degree.

Aficionados of the GD-MCB hypothesis will immediately suspect that a big part of the symptomatology of ME/CFS will diminish, since the causes of a large fraction, perhaps the majority, of ME/CFS symptoms can be traced directly to the depletion of glutathione.

So voila! The patient feels better, until her/his B cells grow back, and the whole process repeats itself, making her/him miserable again. So we hit the patient with another dose of Rituximab, and she/he bounces back up, and so on. If we do succeed in permanently devastating the B cells, what happens in the longer term? Certainly they were there for a purpose. Will the body be adequately defended against its enemies in the future? I think that's a big question.

The main point I want to make is that this treatment, like many others that have been used or proposed for ME/CFS, addresses a down-stream issue in the pathophysiology, and does not get to the root of the problem, which I believe (and have evidence to support this belief) is a vicious circle mechanism that includes glutathione depletion, a functional deficiency of vitamin B12, a partial block of methionine synthase in the methylation cycle, and draining of folates from the cells. So far, the only way it seems to be possible to break this vicious cycle is to lift the partial block in the methylation cycle with appropriate treatment that includes simultaneous use of active forms of folate and high dosage of forms of vitamin B12. Among other effects, this should rebalance the immune system, so that the B cells as well as the other components of the immune system will return to their normal functions. I do need to add that some other things will likely need to be done as well to help this process along, and which things will depend on the details of each case. But lifting the partial methylation cycle block is the fundamental thing that needs to be done.

I would welcome any criticisms of this proposed mechanism. As far as I can tell, everything fits together well.

If anyone wants to get more information on the GD-MCB hypothesis, I recommend watching the video at

http://iaomt.media.fnf.nu/2/skovde_2011 ... Bweburl%7D" onclick="window.open(this.href);return false;

The slides from the talk are available there too, if you don't want to hang in for the whole 3-plus hours.

Best regards,

Rich

Hi, all.

Having now read the full paper, I note that it was reported that two of the patients who received Rituximab, and one who received the placebo (saline solution) were still going strong a year later and were back at full-time work (and by then their B cells had come back up). So how do I explain that? Well, I'm guessing that shutting down the inflammation and the concomitant oxidative stress in the patients who received Rituximab must have given glutathione such a big boost that it was able to break the vicious circle and restore the methylation cycle and the immune system to normal operation by the time the B cells came back up. In the past, I don't know of anyone who was able to turn things around by boosting glutathione, but maybe the inflammation prevented it from going high enough. How about the one who recovered after receiving only saline? I don't know. That's pretty amazing. It's well-known that many PWMEs/PWCs have what has been called a "mild" case of diabetes insipidus (not to be confused with diabetes mellitus), and that involves low blood volume. Putting in some saline has helped a lot of patients temporarily. I don't know how it could produce a permanent fix. So that's a puzzle.

I sure wish these researchers had monitored glutathione in these patients! Note that they write, "Thus, we believe that B-cell depletion targets a central player in the pathogenesis of the CFS disease, directly or indirectly." I suggest that this central player is glutathione.

Best regards,

Rich

Hi, ix.

I agree. Shutting down cytokine production will impact the brain. I don't think there has been much evidence for autoimmunity in ME/CFS, except for Hashimoto's, and I have offered an explanation for that that is based on glutathione depletion in the thyroid. Some patients do have ANA a little higher than normal, but that may just result from die-off of cells.

Best regards,

Rich

Hi, justy.

Thanks for hanging in there for my whole talk! I appreciate knowing what the researches said about the patient on placebo who recovered. All of us suffer from lack of an agreed-upon, solid case definition that is tight enough to give a very homogeneous cohort. It is hard to believe that a person who is seriously ill from ME/CFS could be cured by salt water!

With regard to IV infusion of glutathione, this has been done and is being done by quite a few practitioners. The general experience is that in most cases it brings temporary relief of symptoms (for about a day or two), but in a subset it actually makes the symptom picture worse. When glutathione is given by I.V., about 80% is taken out of the blood by the kidneys. It is initially broken down, and then some is reformed. Some cysteine is put back into the blood. About 10% is taken by the lungs. The rest goes to a variety of tissues. The problem with I.V. application is that it is apparently not able to raise the glutathione level inside the cells very much, in general. Probably the intracellular levels are raised more by use of liposomal glutathione, or possibly the acetylglutathione that is now being offered. But I think it is still likely that the vicious circle mechanism will prevail unless glutathione comes up a lot, on a sustained basis, and lifting the partial methylation cycle block is the only way I have found that will do that on a more permanent basis. But perhaps in the two patients in this study who recovered after Rituximab treatment, just lowering the inflammation was enough to break the vicious cycle, so that glutathione came up enough to restore the B12 function to normal and lift the partial methylation cycle block.

As you know, the methylation treatment alone has not brought total recovery to very many PWMEs/PWCs, though it brings significant improvement to most. One of the possible reasons why it has not brought complete recovery in many of the cases may be that there is some condition in the body that is still placing a big demand on glutathione, and just lifting the partial methylation cycle block is not able to overcome it. Inflammation-related oxidative stress seems like one good possibility. If Rituximab lowers the oxidative stress, at least temporarily, this might be enough to help break the vicious circle. Perhaps the methylation treatment combined with one course of rituximab would push more people into recovery. This is just speculation at this point. It does seem to be true that the few people who have recovered apparently completely after the methylation treatment was given had had other types of treatment before that, some of them directed at knocking down infectious diseases, and hence, inflammation. Maybe that's how all of this fits together. Note also that there were some people in the Rituximab study who were not helped by the treatment. Perhaps the dominant glutathione demand in these people was due to toxins rather than to infections. If this was the case, knocking out the B cells would not have lowered the demand on glutathione, and that could explain why there was no improvement. There are many factors that can place demands on glutathione, and not everyone with ME/CFS shares the same ones.

I'm hopeful that as time goes on more researchers will begin to believe that glutathione is an important actor in this drama, and will begin measuring it in an accurate way. I think that could help to pull all of this together.

Thanks for your comments.

Best regards,

Rich

Hi, Willow.

Sorry, I don't have numbers to give you. The abstracts just say that the titers were low. I think they mean low compared to what happens in a recognized autoimmune disease, such as systemic lupus erythmatosis. I think docs use ANA to help with their differential diagnosis between ME/CFS and lupus sometimes.

Personally, I don't think ME/CFS is an autoimmune disease, though some autoantibodies can be found in it, especially the thyroid ones, if a person has Hashimoto's as part of ME/CFS. Wikland reported that 40% did in his study, and Byron Hyde also finds a lot of Hashimoto's in his ME cases.

It's known that some cells die early in ME/CFS. Dr. Howard finds elevated levels of cell-free DNA due to this. Howard Urnovitz has suggested looking at this DNA to find retroviral DNA in it. This is the socalled "Next Generation Sequencing" that was reported on at the Ottawa conference. I think Judy Mikovits is moving in that direction, too.

Anyway, when cells die at a higher rate, I think that autoantibodies can rise, as the immune system responds to the fragments of these cells before they have been cleaned up by the macrophages. I think this is what accounts for the autoantibodies that have been observed in ME/CFS, except for the thyroid antibodies, and I have invoked Duthoit's mechanism for that, i.e. glutathione depletion causing higher hydrogen peroxide, which damages proteins there and provokes the autoimmune reaction.

Best regards,

Rich

Hi, all.

The more I read and hear from people, the more I believe that the role of Rituximab and other immune suppressants in ME/CFS is to lower the inflammation, and hence the oxidative stress, allowing glutathione to rise. If it rises enough to break the vicious circle involving the B12 functional deficiency, the partial methylation cycle block and the folate draining, the person recovers. If not, when the drug treatment wears off, down they go again. It has occurred to me, and some others have suggested this also, that doing methylation treatment while suppressing the immune system, at least somewhat, might help more people to achieve recovery. This is just a hypothesis, and would have to be entered upon very carefully, with supervision of a licensed physician. I would be leery of continuing to suppress such an important part of the immune system indefinitely.

I think that concluding from this study that ME/CFS is an autoimmune condition would be following a red herring. It could cause a lot of effort to be wasted in the wrong direction. That's just my opinion, and as always, I could be wrong.

Best regards,

Rich

Hi, Vitalic.

Yes, it's true that I'm skeptical about there being specific autoantibodies in ME/CFS. Of course, I could be wrong, but there have been efforts in the past to find them, and as far as I know, these efforts have not paid off. There is some elevation of ANA, there is some anticardiolipin antibody in some cases, and there are Hashimoto's antibodies in quite a few PWMEs, but I haven't heard of any specific ones in ME/CFS.

I think the ANA and the anticardiolipin antibodies are the immune system's response to fragments of cells that have had an early death.

I recall going to an NIH CFS workshop in Bethesda, MD, several years ago at which Prof. Dan Clauw, the rheumatologist from U. of Michigan, made the statement that one thing we don't see in these patients is autoimmune disease. I raised an objection: "What about Hashimoto's?" He essentially said that he did not consider Hashimoto's to be in the same category as autoimmune disorders such as rheumatoid arthritis or lupus. In my hypothesis, I have adopted the Duthoit model in which the thyroid's own hydrogen peroxide attacks its proteins in the absence of enough glutathione to protect them, and the immune system mounts an immune response to these altered proteins. Wikland found Hashimoto's in 41% of the patients he studied using fine needle biopsy.

I think it makes sense to think more generally about what would happen when there is a Th2-shifted person with a dysfunctional HPA axis who then has their B cells knocked out. I think the inflammation that was present will go down, taking down the oxidative stress, which is a major factor in the abnormal biochemistry of ME/CFS. I hope that people who do Rituximab trials will monitor glutathione. I expect that it would be very revealing.

I'm certainly open to other explanations, but so far I think this one fits pretty well, when we consider everything else we know about ME/CFS.

Best regards,

Rich

Hi, Vitalic, globalpilot and Snow Leopard.

I think all of you have made some good points. I also think that it is going to take more research to answer the issues that we have raised. I hope that glutathione measurements will be part of the ongoing studies in this area, because I think that would help to sort things out. I guess I've speculated about as far as I can at this point, and time will tell whether there is any validity to the speculations. I'm glad this study was done, because I think it is likely to stimulate progress in the ME/CFS field.

Best regards,

Rich

Hi, snowathlete.

Active EBV is definitely found in quite a few PWMEs. It does reside in its latent state in immortalized B cells. Rituximab does knock out B cells.

Based on the work of Palamara et al. at the University of Rome, a healthy ratio of reduced to oxidized glutathione is able to prevent proliferation of herpex simplex type 1 by preventing the formation of disulfide bonds in glycoprotein B. The other herpes family viruses, including EBV, also have glycoprotein B. I conclude from this that a healthy ratio of reduced to oxidized glutathione also suppresses proliferation of EBV.

As I've posted before, I suspect that the Rituximab treatment overcomes the inflammation that is being produced by the overactive B cells (due to the known Th2 shift in ME/CFS), and this allowed glutathione to normalize in the patients who experienced recovery from this treatment. Recovery of glutathione would suppress not only the herpes family viruses, but would also restore cell-mediated immunity, which is necessary to defeat other viruses as well as intracellular bacterial infections (mycoplasma, chlamydia and rickettsia) and fungi, including yeasts. All of these are found in various ME/CFS patients. EBV is not the only pathogen found.

Best regards,

Rich