Invest in ME/Prof Jonathan Edwards statement on UK Rituximab trial, 30 July

[Helen]

Jonathan Edwards . It would be very interesting if you would take your time to comment on Rich Van Konynenburgs hypothesis about Rituximab. I have followed his research for three years and so far I haven´t found anything that doesn´t fit in to his hypothesis about glutathione depletion due to one or more genetic defects in the methylation cycle ( primarily MTHFR and/or MTRR/MTR) as a necessary (but not sufficient) factor for ME. At least after that Rich made us aware of that when the methylation capacity is decreased, it is better to take mecobalamin than hydroxycobalamin (that doesn´t need to be methylated ). But I am not at all an expert in infections or immunology...

Best regards

Proposed mechanism for Rituximab in ME/CFS

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_me_kroniskt_trotthetssyndrom/${weburl}

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​

richvank, Oct 20, 2011​

#53​

​

 

[lansbergen]

Similarly, other HLA haplotypes such as HLA-DRB1*1301 are elevated in CFS patients (Carlo-Stella et al
., 2009)

http://cdn.intechopen.com/pdfs/28108/InTech-Gene_expression_in_chronic_fatigue_syndrome.pdf

 

[natasa778]

@Jonathan Edwards Could the world of HIV research and clinical practice teach us anything about autoimmune diseases in general, including ME (if indeed autoimmune)?

During frank loss of immunocompetence, autoimmune diseases that are predominantly T cell subtype CD8 driven predominate. There is evidence for B cell stimulation and many autoantibodies are reported in HIV patients. We propose a staging of autoimmune manifestations related to HIV/AIDS manifestations and the total CD4 count and viral load that may be beneficial in identifying the type of autoimmune disease and establishing the proper therapy. In stage I there is the acute HIV infection, and the immune system is intact. In this stage, autoimmune diseases may develop. Stage II describes the quiescent period without overt manifestations of AIDS. However, there is a declining CD4 count indicative of some immunosuppression. Autoimmune diseases are not found. During stage III there is immunosuppression with a low CD4 count and the development of AIDS. CD8 T cells predominant and diseases such as psoriasis and diffuse immune lymphocytic syndrome (similar to Sjogren's syndrome) may present or even be the initial manifestation of AIDS. Also during this stage no autoimmune diseases are found. In stage IV there is restoration of immune competence following highly active anti-retroviral therapy (HAART). In this setting, there is a resurgence of autoimmune diseases. The frequency of reported rheumatological syndromes in HIV-infected patients ranges from 1 to 60%. The list of reported autoimmune diseases in HIV/AIDS include systemic lupus erythematosus, anti-phospholipid syndrome, vasculitis, primary biliary cirrhosis, polymyosits, Graves' disease, and idiopathic thrombocytopenic purpura. Also, there is an array of autoantibodies reported in HIV/AIDS patients which include anti-cardiolipin, anti-beta2 GPI, anti-DNA, anti-small nuclear ribonucleoproteins (snRNP), anti-thyroglobulin, anti-thyroid peroxidase, anti-myosin, and anti-erythropoietin antibodies. The association of autoantibodies in HIV-infected patients to clinical autoimmune disease is yet to be established. With the upsurge of HAART, the incidence of autoimmune diseases in HIV-infected patients is increasing.

Is it possible that an acute infection, or immune stress through vaccination, could lead to a temporary dip in immune competence, to be followed by a sudden restoration of immune competence, which then leads to autoimmune disease? Same setting as above, but in the absence of HIV proper and happening in a shorter time span?


btw various autoimmune diseases, including RA, appear to be quite common in HTLV, another human retroviral infection, although unfortunately it is not clear from papers whether staging/phasing of autoimmune resurgence correlates to that seen in HIV patients.

 

[Jonathan Edwards]

Jonathan Edwards . It would be very interesting if you would take your time to comment on Rich Van Konynenburgs hypothesis about Rituximab. I have followed his research for three years and so far I haven´t found anything that doesn´t fit in to his hypothesis about glutathione depletion due to one or more genetic defects in the methylation cycle ( primarily MTHFR and/or MTRR/MTR) as a necessary (but not sufficient) factor for ME. At least after that Rich made us aware of that when the methylation capacity is decreased, it is better to take mecobalamin than hydroxycobalamin (that doesn´t need to be methylated ). But I am not at all an expert in infections or immunology...

Best regards

The problem I see with that explanation is the time course. If rituximab stopped B cells making inflammatory cytokines then people should get better in a few days because B cells are removed more or less overnight. The other point on cytokines is that B cells do not actually occur at inflammatory sites, with the exception of very gross types of inflammation like in RA (even then they are not always around). Unlike T cells they are not inflammatory effector cells per se. B cells hang out in lymph node and spleen. The cytokines they make are involved in talking to other cells getting educated - like T cells. These are likely to operate at very short range so not very likely to make you feel ill I guess. And if the idea is that T cells are not doing much anyway that does not seem a good line to pursue.

If on the other hand rituximab reduced inflammation by reducing antibodies to viruses - which can indeed contribute to inflammation at virus infected sites - you would expect the effect to occur when antibody levels reduced. We have no specific evidence on anti-virus antibodies but what we know about antibodies to foreign organisms (and just the total level) is that in most people they do not really go down at all, even after many months. It is only autoantibodies that go down significantly.

So it does not seem to fit the kinetics so far.

 

[lansbergen]

Excess of activating killer cell immunoglobulin‑like receptors and lack of HLA-Bw4 ligands: a two‑edged weapon in chronic fatigue syndrome.

I would be very interested to know if anyone else had found something similar to the above.

Sorry, no luck. Anybody else found something?

 

[lansbergen]

Would it not be a good idea to test this in the Rituximab trial?

Something I forgot to add to the last post is that one sort of genetic difference that might allow certain types of B cell error to occur would be a difference in NK cell, or more generally cytotoxic cell, function. I was interested to see the paper:
Mol Med Rep. 2011 May-Jun;4(3):535-40. doi: 10.3892/mmr.2011.447. Epub 2011 Mar 4.
Excess of activating killer cell immunoglobulin‑like receptors and lack of HLA-Bw4 ligands: a two‑edged weapon in chronic fatigue syndrome.

Pasi A, Bozzini S, Carlo-Stella N, Martinetti M, Bombardieri S, De Silvestri A, Salvaneschi L, Cuccia M.
NK receptors are strange. I am not convinced that poor killing of K562 target cells as reported in ME should be considered a 'defect' but it may indicate a difference. The above authors think in terms of clearing cells infected with pathogens but killer cells are involved in getting rid of unwanted B cells with no pathogen involved. I would be very interested to know if anyone else had found something similar to the above.

 

[olliec]

Prof Edwards, thank you so much for your interest, curiosity and support. If you don't mind I wanted to ask a few broader questions.

What do you think is required in order for this illness to get much more funding, from governments, pharma, and charitable organisations, and do you think a (successful) Rituximab trial could move things a little way down that path? Is a biomarker the ideal?

Do you see a space for so-called "Big Data" in ME research? e.g. some patients have accounts with 23andme so a little of their DNA has been sequenced, and others carry Fitbits that measure their activity and sleep. There are also web sites like CureTogether and PatientLikeMe that have quite a lot of patient data. Perhaps 23andme provides a lower cost way to acquire more data, and trial participants carrying Fitbits provides additional objective activity data at a low cost. There are also low-energy Bluetooth heart rate, HRV and breathing monitors that collect data and send it to a mobile (e.g. the Zephyr BioHarness).

What can patients do to help, aside from fundraising? Are there any successful models we can learn from?

 

[Jonathan Edwards]

Would it not be a good idea to test this in the Rituximab trial?

I certainly think it would be worth looking at other populations for NK receptor ligands. I am not sure how it would be linked to a rituximab trial. Rituximab kills B cells through several mechanisms, including NK killing but I think it would be a mistake to think this has any relevance to the relation of NK function to ME. In the doses rituximab is given in it basically kills all B cells, at least in circulation, and there is no evidence that it matters what NK receptor types you have. The experiments recently reported on the killing mechanism are of technical interest to those making antibody-based drugs but not much else I think.

 

[Jonathan Edwards]

@Jonathan Edwards Could the world of HIV research and clinical practice teach us anything about autoimmune diseases in general, including ME (if indeed autoimmune)?

Is it possible that an acute infection, or immune stress through vaccination, could lead to a temporary dip in immune competence, to be followed by a sudden restoration of immune competence, which then leads to autoimmune disease? Same setting as above, but in the absence of HIV proper and happening in a shorter time span?

btw various autoimmune diseases, including RA, appear to be quite common in HTLV, another human retroviral infection, although unfortunately it is not clear from papers whether staging/phasing of autoimmune resurgence correlates to that seen in HIV patients.

I am a bit doubtful that HIV research will tell as much. There has been a history of anecdotal reports related to HIV but as far as I know there is no real link to autoimmunity proper (with autoantibodies). There is a link to things like psoriasis, which are probably best called something else. As indicated before, I doubt that infections trigger autoimmunity because there isn't actually a mechanism that makes sense that would work like that, even if for fifty years immunologists have assumed there was!

I am intrigued by the constant interest in viruses. I have a theory as to why this should be and may comment on it when I have time, but I suspect virus-hunting is a blind alley. The idea that XMRV might have explained ME seems to me as a scientist completely bonkers - a bit like Benveniste saying homeopathic remedies left a memory in the water or Wakefield's MMR story - they just don't stand up to common sense. I am intrigued but not surprised that it got published in a 'respectable' journal. I know I need to justify these prejudices and will try to soon, but paradoxically I think the virus fixation may be telling us something quite important about the biology of ME - to do with why it is not 'caused by viruses'!!!

 

[Jonathan Edwards]

What do you think is required in order for this illness to get much more funding, from governments, pharma, and charitable organisations, and do you think a (successful) Rituximab trial could move things a little way down that path? Is a biomarker the ideal?

To the first question the answer is willpower, but willpower seasoned with clear thinking. I think keeping the momentum on the rituximab lead until we know which way it will go is well worth while - enough for me to put my retirement pursuits to one side and try and get something moving. And, yup, the biomarker is the Holy Grail. Once ME has a biomarker the whole game changes. I am hoping there is a whiff of a lead but I am not going to speculate until I have seen something more solid. It would be good to use a rituximab trial to move this forward but I am still trying to get a clear view of this.

Do you see a space for so-called "Big Data" in ME research? e.g. some patients have accounts with 23andme so a little of their DNA has been sequenced, and others carry Fitbits that measure their activity and sleep. There are also web sites like CureTogether and PatientLikeMe that have quite a lot of patient data. Perhaps 23andme provides a lower cost way to acquire more data, and trial participants carrying Fitbits provides additional objective activity data at a low cost. There are also low-energy Bluetooth heart rate, HRV and breathing monitors that collect data and send it to a mobile (e.g. the Zephyr BioHarness).

To be honest I never found Big Data much use. When I needed some data to test an idea I had to take the samples afresh and I have a feeling that unless samples are taken afresh in a way carefully suited to the study being done you tend to get a lemon.

What can patients do to help, aside from fundraising? Are there any successful models we can learn from?

Use your brains. Try to work out what is going on. Be critical. Keep nagging the scientific community, but from a well informed position. Ask me some really tough questions. Don't take my word for it - nullis in verba.

 

[Firestormm]

...
I am intrigued by the constant interest in viruses. I have a theory as to why this should be and may comment on it when I have time, but I suspect virus-hunting is a blind alley. The idea that XMRV might have explained ME seems to me as a scientist completely bonkers - a bit like Benveniste saying homeopathic remedies left a memory in the water or Wakefield's MMR story - they just don't stand up to common sense. I am intrigued but not surprised that it got published in a 'respectable' journal. I know I need to justify these prejudices and will try to soon, but paradoxically I think the virus fixation may be telling us something quite important about the biology of ME - to do with why it is not 'caused by viruses'!!!

OK. So now I gone and spat coffee at my computer screen whilst laughing and choking at the same time

I for one will be most interested to read your further comments in relation to the above. Damn just when I'm all nice and relaxed, you throw another corker at me!

Thanks Professor

 

[voner]

And, yup, the biomarker is the Holy Grail. Once ME has a biomarker the whole game changes.

Prof. Edwards,

Can you give some examples of possible biomarkers? Shouldn't they be simple and usable in a clinical setting and hopefully inexpensive? I am especially interested in examples that are not blood tests.

Here's to hoping that your interest is sparked enough to keep you from pursuing those retirement thoughts...

 

[lansbergen]

I thought memory B cells have CD20. According to this scheme I am right.

Is this scheme correct?

http://arthritis-research.com/content/15/S1/S3/figure/F1

 

[lansbergen]

Would you in a Rituximab trial include patients with known low to no seroconversion after vaccination?

 

[garcia]

What I think is more likely and more promising as something we could treat is that the immune system is behaving as if there is a serious infection when there is no more than the usual harmless bugs around - that is more or less what autoimmunity is about, at least in many cases. So at present I have no idea what to advise I am afraid.

Jonathan Edwards
If as you say the immune system is behaving as though there is a serious infection, but there is no serious infection, then surely things like hydrocortisone would make us feel better (by shutting down an aberrant immune response)? However my experience, and the experience of most patients, is that hydrocortisone makes us feel worse, not better. If it were just a runaway immune response (without a pathogen) then surely shutting down the immune response would make patients universally feel better? (it seems to have the opposite effect).

 

[Legendrew]

I thought memory B cells have CD20. According to this scheme I am right.

Is this scheme correct?

http://arthritis-research.com/content/15/S1/S3/figure/F1

This is something which I'm also interested in, i've heard many people refuse to believe rituximab will prove a good treatment due to the loss of these memory cells and people being unwilling to have this happen. As i understand it, these memory B cells so provide a form of lasting protection to previously encountered disease however i've also heard of people implying that long-lived plasma cells are also somewhat capable of doing this and since they don't express CD20 (as far as i'm aware anyway!) the risks from losing this supply of circulating memory B-cells isn't as extreme as many people seem to believe. It does however at least concern me given the long length of treatments that could be involved.

Jonathan Edwards
If as you say the immune system is behaving as though there is a serious infection, but there is no serious infection, then surely things like hydrocortisone would make us feel better (by shutting down an aberrant immune response)? However my experience, and the experience of most patients, is that hydrocortisone makes us feel worse, not better. If it were just a runaway immune response (without a pathogen) then surely shutting down the immune response would make patients universally feel better? (it seems to have the opposite effect).

As far as i'm aware hydrocortisone is a corticosteroid and therefore acts by reducing inflammation - in a few previous posts it has been discussed as to whether there is any inflammation involved in ME with the conclusions that there's little evidence of, at least standard, inflammation. I believe there's some debate about whether neuro-inflammation follows the same pathways/course and then there's also the possibility that any autoantibody acts by directly blocking or at least changing the normal function of receptor sites in neurones or other organs, meaning no inflammation need be involved!

I have to say I'm glad someone is sticking their neck out and saying that they doubt any pathogens such as viruses are involved - in the past 6 months or reading into ME research the sheer number of pathogen studies claiming different viruses, bacteria and fungi present in chronic forms in patient sub-sets is so vast that it is self defeating in the respect that it muddies the waters for anyone looking in from the outside wanting to enter the field and isn't furthering the understanding at all. I don't deny studies which rule out things are just as important as those with prove ideas but after so many years of emphasis on viruses surely it's getting to the point where people should embrace research in a different direction. The number of different infectious and non-infectious triggers implies something amiss in the immune system. I honestly believe that chasing these pathogens is the wrong line entirely; i'm sure if these pathogen studies were done on a general population you'd find the same levels of pathogens anyway!

(In some people viruses may be the issue but I honestly believe this is not the case in the vast majority of people!)

 

[Forbin]

I wonder if the relationship of ME to infection could be somewhat indirect. The Dubbo study found that the sole predictor of developing CFS following an infection was not the particular infectious agent, but rather the severity of the infection.

If M.E. is caused by a random, stochastic and self-perpetuating error/mutation in immune cells, would such an error be statistically more likely to occur when the immune system is highly active, such as during or just after a viral infection? Might that explain the variety of “triggers?”

The triggers then would not “cause” the illness, per se, but a highly active immune system would increase the probability that the immune system itself would make a self-perpetuating mistake.

In other cases, the “error” might more rarely occur in a quiescent immune system, just as a matter of probability.

Perhaps, there might also be some other factor that sets up the immune system to be more likely to make this kind of mistake when it becomes highly active.

Just amateur speculation. I really don’t know if what I just said was either extremely naïve or extremely obvious.

[ I also wonder how quickly a single random error could propagate into something like the onset of M.E. I became ill a couple of weeks after a particularly severe case of the flu (and then continued to get worse), but I know that for many people the initial illness simply “becomes” M.E. with no apparent interval.]

 

[user9876]

I wonder if the relationship of ME to infection could be somewhat indirect. The Dubbo study found that the sole predictor of developing CFS following an infection was not the particular infectious agent, but rather the severity of the infection.

If M.E. is caused by a random, stochastic and self-perpetuating error/mutation in immune cells, would such an error be statistically more likely to occur when the immune system is highly active, such as during or just after a viral infection? Might that explain the variety of “triggers?”

The triggers then would not “cause” the illness, per se, but a highly active immune system would increase the probability that the immune system itself would make a self-perpetuating mistake.

In other cases, the “error” might more rarely occur in a quiescent immune system, just as a matter of probability.

Perhaps, there might also be some other factor that sets up the immune system to be more likely to make this kind of mistake when it becomes highly active.

Just amateur speculation. I really don’t know if what I just said was either extremely naïve or extremely obvious.

[ I also wonder how quickly a single random error could propagate into something like the onset of M.E. I became ill a couple of weeks after a particularly severe case of the flu (and then continued to get worse), but I know that for many people the initial illness simply “becomes” M.E. with no apparent interval.]

I was wondering something along similar lines. If an illness leads to increased antibody production then there would be more chance that some would be bad. However, I'm not convinced that the numbers add up. If there were a hundred fold increase in production then from a simple probablistic perspective then this would be equivalent to 100 normal days hence you would expect a greater mix of infection/non infection related illness. The other thing I was thinking was that maybe the filtering of bad antibodies could become overloaded and hence become less effective on increased antibody production.

The other thing I was wondering about is there appear to be several epidemics (royal free, LA, lake tahoe) and how do these fit into a model. Of course a population model could perhaps show that we should expect some apparant epidemics by chance?

 

[Sasha]

Jonathan Edwards - I think that ages ago I read something that said that about half of cases of ME were acute viral onset with a flu-like illness, plus there have been epidemic outbreaks, such as at Lake Tahoe or the Royal Free Hospital, which is why everyone thinks, 'virus'. A lot of us with acute viral onset could tell you what time on what day we got sick. The other cases were 'insidious onset'.

So any model would need to address why a virus would at least trigger the illness, even if it doesn't maintain it. In the US, patients with ME with high antibody titres to EBV, CMV and/or HHV-6 get treated with antivirals by specialists such as Peterson, Enlander, Klimas and so on and many have very significant improvement, though there haven't been any RCTs (lack of money) apart from one by Montoya that we're all waiting for to be published.

 

[rosie26]

I think whatever causes our ME, catching a virus like flu is like "the last straw". I had mild symptoms of ME for years before complete collapse into ME. It was a nasty flu that finally took me down completely. In my case.