What do you want to ask Fluge and Mella?

[Maria Gjerpe]

Hi there,

Is there anything that you would like to ask Drs.Fluge and Mella, if you could?

I´m visting Haukeland Hospital next week, and might have time for a short interview. If so, I´m writing an article for Phoenix Rising which might answer some of your questions, if you have some. I do not know what you wonder about.

Today is sunday. I will come back and look in this section for questions from you on Tuesday. Shoot!


(Who am I? I´m a pilotpatient at Haukeland Hospital and a major responder to Rituxan. I am also an educated medical doctor.

I know that my time as well and healthy is limited, and use all my regained health to make sure the science and the search for knowledge continue.

I started the initiativ MEandYou, which has a goal to crowdfund 7 million NOK, for financing 140 ME-patients for The Haukeland Study, phase 3, in 90 days. We can to this. Together. MEandYou. This is only about money.

Please watch the movie I made about the initiativ.
Thank you.

MEandYou at YouTube
MEandYou on Facebook
MEandYou English site

I´ll tell you more about the MEandYou-initiativ in an article later.

High Five!)

And, dear ME-fellows - I´m sorry. I do not have the capacity of answering questions about my treatment and health right now. I´m 100% focused on MEandYou 24/7. I hope you understand, even though I fully understand your need for info.

 

[Sushi]

Maria Gjerpe

Thanks you for doing this!

Sushi

 

[snowathlete]

I'd like to know more about their thoughts on autoimmunity. How they think it might come about.

 

[Daisymay]

I'd like to know if they think it is possible that autoimmune diseases could be caused by hitherto unknown infections in those diseases.
Thanks.

 

[Helen]

Hi Maria,

It is a fantastic story you tell about the effect you have had of the treatment. Thank you for sharing with us.

Maybe you think I am too critical, but I just have to ask you what your comment is on Rich Van Konyneburgs theory why the treatment works, and the risks with it. We are many who have had gene defects confirmed in the methylation cycle and in the Phase I and Phase II liver detoxification. Some of us have also had the methylation capacity evaluated in a lab panel from Vitamin Diagnostics. Low reduced glutathione, low folates ...

Of course it would be very interesting to get a comment from the researchers on Rich´s theory too. Do they test for anything like what is in a methylation panel as reduced glutathione before and after treatment e g?

Wish you all the best from your next treatment!
Helen

[

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Proposed mechanism for Rituximab in ME/CFS​

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Hi, all.​

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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.​

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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.​

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O.K., here it goes:​

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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. ​

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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. ​

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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. ​

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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 ​

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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. ​

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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. ​

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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. ​

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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.​

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

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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. ​

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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. ​

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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.​

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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.​

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

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

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http://iaomt.media.fnf.nu/2/skovde_2011_me_kroniskt_trotthetssyndrom/${weburl}​

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

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Best regards, ​

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Rich​

 

[ukxmrv]

I would love to know

1. Does Rituxan show any signs of being more or less effective in patients with an acute viral onset to their disease

2. Does Rituxan show any signs of being more effective in patients with a EBV onset

3. Have you made an changes to the protocol you reported in your initial papers (and would you like to)

Thank you Maria!, very good of you. Wonderful work and I'm really grateful.

 

[SOC]

Thanks for doing this, Maria!

I don't have any specific questions at this time, but I would be pleased if you would pass on my immense appreciation for their work and their dedication to helping us.

 

[heapsreal]

The relevance they see in natural killer cell function in cfs/me as well as other autoimmune conditions as well as chronic viral infections and the impact rituxin has on nk function??

cheers!!

 

[Blue]

I would be interested to know if Mella and Fluge can already say s.th. about maintenance regimen (how often, how long, which dosis) after having finished the 15 month protocol. Could this be for example similar to patients with rheumatism?

Many thanks for what you are doing!

 

[Purple]

1. Does Rituxan show any signs of being more or less effective in patients with an acute viral onset to their disease

2. Does Rituxan show any signs of being more effective in patients with a EBV onset

These are some of the things that interest me a lot too. Especially seeing there are links between EBV and Lymphoma and Rituximab being used in Lymphoma,

Some other things I would like to know:
- is autoimmunity the only explanation for responding to Rituximab
- if autoimmunity is supposed as the explanation, any ideas what the autoantibodies are directed against (and is there a search for these?)

 

[Waverunner]

Thank you, Maria. Two very important questions in my eyes would be:

1. Do they have any marker that predicts, if a patient is more likely to respond?
2. Is CFS an autoimmune or an infectious disease?

 

[lycaena]

Thank you for your great fundraising initiative!

My question is, if objective assessments like pedometers will be used in the trial?

And I would like to know more about the ongoing trial in very severe ME.

 

[Sasha]

Hi Maria - thanks so much for doing this! I'm very glad you've had such a good response to Rituximab and I hope you might be one of the patients who stay well.

I think this is a great approach to interviewing ME researchers - to ask other patients what they would like to know, as well as having your own questions. I think that's a very good model for interviews!

I have a question. As I expect you know, the Open Medicine Institute have a priority list of ME research projects that they would like done (Drs Fluge and Mella are signatories) and the first on their list is this one:

http://openmedicineinstitute.org/research-initiatives/mecfs-merit/

OMI-MERIT Priority Projects

1. Treatment: Phase 1: A Large-scale, Randomized, Placebo-controlled Trial of Rituximab and Valgancyclovir
   • Goal: This rigorous, four-armed study will examine and further validate two of the most promising therapies in the field by comparing placebo, rituximab alone, valgancyclovir alone, and combination therapy of valgancyclovir plus rituximab. Measurements of physiologic, genomic, virologic, and immunologic markers will be made throughout the course of the trial.
   • Importance: A large-scale, rigorous trial is needed to confirm the initial findings of earlier smaller studies and move ME/CFS to a molecularly trackable disease. Success of such a trial could move ME/CFS to a mainstream process for additional diagnostic and treatment trials.

In the US, Valganciclovir (Valcyte) is being used by Drs Montoya, Lerner, and Kogelnik and others for the treatment of people with ME who have high titres of HHV-6 (and/or EBV?). I could understand a trial with placebo, Valcyte only and Rituximab only but I'm wondering about the logic of the fourth arm with both Valcyte and Rituximab. I thought that Rituximab wiped out B cells (?) and that its success in people with ME maybe indicated some kind of autoimmune disease, whereas Valcyte prevents replication of humanherpes viruses and might work because people with ME have high levels or reactivated virus.
It seems like a strange collision of two therapies in a single trial. Is there some reason for thinking that it would be a good idea to use these two drugs together?
I'm wondering if Drs Fluge and Mella think that viruses such as HHV-6 are strongly implicated as causing part of the symptomatology of ME as well as there being an auto-immune component.
I'm not at all knowledgeable about biology so if my question is rubbish and you think you can put a better version of it to Drs Fluge and Mella, please feel free!

 

[Mark]

I'm just starting collating these questions for Maria to take to Fluge and Mella tomorrow. So if you have any further questions, you have less than 3 hours to post them. And please note there is no guarantee that they will have time to answer our questions, we are just hoping they will be able to do so.

 

[Gemini]

I'm just starting collating these questions for Maria to take to Fluge and Mella tomorrow. So if you have any further questions, you have less than 3 hours to post them. And please note there is no guarantee that they will have time to answer our questions, we are just hoping they will be able to do so.

Just saw the post, hope its not too late for questions:
1. In Rituxan responders which immune system markers normalize?
2. Do you test for hypogammaglobulinemia and hypergammaglobulinemia?

 

[rebar]

I may be too late but, what are the biological markers for responders?

 

[Mark]

Too late for these last two, I'm afraid. Sorry about the short notice on this, but it couldn't be helped. Rebar, I think your question may already be covered. We may conceivably have another chance to ask further questions, but at the moment there's no guarantee that Fluge and Mella will even have time to answer the first group of questions.

 

[meg_pollock]

I'm aware I'm too late, but will post anyway, just in case it's something you can bring up later. There are two issues on my mind just now: 1) Hashimoto's thyrioditis has links to atypical coeliac (e.g. Hadithi et al., 2007, World Journal of Gastroenterology, 11, 1715-1722). Do Fluge and Mella reccomend patients with CFS and Hashimoto's try going gluten-free before looking at more invasive options? And 2) maybe the Rituximab non-responders have a problem with T-cells, not with B-cells? Many thanks...

 

[Maria Gjerpe]

Thank you for your overwhelming interest!
Mark suggested I would try to make an interview with Fluge/Mella, if that was possibly.

I spoke to Fluge today. I sent him all your warm regards and appreciation, but due to a lot of interest from the media in the MEandYou-initiative and meetings for the Drs, we did not have time to an interview this time, unfortunately. They are both Drs with a little time to spare. Remember; besides doing clinical trials on ME, they have both full-time job at the cancer-ward, and they have been doing this for years - just because they are curious. Impressing! I´think that what the doctors would like to do, at the time being, is use all their possible time to focus on their work - and that is in our benefit-in the end.
But your questions are here, for me to find them, if there will be any opportunity next time I meet them. Thank you!

What I do know, is that Fluge/Mella are always looking for new traces and change in directions, or add some, along the path. This is what science is about, as you of course know. Questions-answers-questions-answers and so on. I, myself, do not want to dedicate myself to discuss hypotheses anymore. I just want us to start here, at this promising, but small, trial, because I think its important to continue looking in this direction.

I´ll write you an article about the MEandYou Association, if you like, later.

 

[ukxmrv]

Thanks Maria. We'll have the list of question for maybe some later date. Quite understand how the pressure of work and media would be using all of their time.
The important thing is that you thanked them.
Will look forward to your blog.