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Astounding Norwegian research breakthrough with Rituximab can solve CFS mystery!!!

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
furture study?

No Currer they will enroll functional somatic disorder patients, depressed, amd the like to a special Rituximab study. :D

The Lancet, special edition, 2015

Rituximab is Less Effective Than CBT and GET for CFS
Whitely et. al.

100 CFS patients were selected using the Oxford definition. Half were treated with Rituximab, half with CBT/GET. Only three of the patients treated with Rituximab showed any improvement, but 16 of the patients treated with CBT/GET showed significant improvement.


Online commentary to this article: Analysis of the data showed that the CBT/GET patient responders only improved a small amount, while the Rituximab responders are near recovery. One has to wonder just how many patients in this study really had CFS?

---------------------------------------------------------------------------------------

The biopsychosocial researchers are not going to like this study. Expect more spin.

Bye
Alex
 

WillowJ

คภภเє ɠรค๓թєl
Messages
4,940
Location
WA, USA
Continuing on with what Rich mentioned, the question is about the root cause and how the clinical effects are mediated. I agree that the clinical effects are likely due to the reduction of proinflammatory cytokines and reduction of oxidative stress. However the root cause may still be an autoimmune disorder, at least in a subset of patients.

There has never been an autoantibody profiling study done on CFS, with the aim of discovering novel autoantibodies. This study justifies such an investigation in my opinion.

That's true, and such a study would be really neat.
 

Boule de feu

Senior Member
Messages
1,118
Location
Ottawa, Canada
Benadryl prior to infustion? That's not good, a significant number of ME/CFS patients can't take that as it is metabolized by Cytochrome P450 2D6. There is a test though to find out if you have a problem with that enzyme, I know I do.

OMG, Kurt! :eek:
Are you telling me that the crazy reaction I got after my GP gave me a shot of Benadryl could have been avoided if I would have known this???
 

acer2000

Senior Member
Messages
818
Rich, whether your glutathione theory is correct or not, I think this points out that there may be more than one way to interpret their results. They are saying that this suggests that ME/CFS is an autoimmune disorder, but I think that's a pretty big leap of logic. We know that parts of the immune system are activated above normal. We also know that some of the over-activated parts are what turn on the so-called "sickness behavior" in the brain: that is, the signals that tell us we're sick and make us feel lousy. It stands to reason that if you shut down those parts of the immune system, we'll feel better. But it doesn't really tell us WHY those parts of the immune response are up-regulated. If they are up-regulated in response to a persistant pathogen (or combination of pathogens), shutting down the immune system could make us feel better in the short-term, but leave us less able to fight the pathogen.

I'm not saying that's what's happening, just that it's another possible explanation.

The results of this trial are intriguing, but I would be very hesitant to take a drug to shut down parts of the immune system without a lot more evidence of what's going on. I think that their autoimmune theory is just one of several plausible explanations for the results they got. It doesn't explain things like why ME/CFS patients don't have an abnormal antinuclear antibody (ANA) test.

I think that this one will be trumpeted as a big breakthrough because it is a drug that they own the patent to, so they could make a lot of money if it works. But because drug companies' job is to make money, they don't always look too closely at the long-term effects of their drugs on patients. I think we need to approach this one very cautiously.

I agree, the results of this study could have multiple explanations. I think its premature to say that because Rituxan has been used in other auto-immune illnesses that it makes ME/CFS necessarily auto-immune. After all, if that logic held (which it doesn't), then we could also claim cancer must be auto-immune because it also responds to Rituxan. We all know that isn't the case.

I hope this study spurs more research to find out exactly what is going on here. I think we can all agree that this study overwhelmingly shows that ME/CFS has biological causes. I seriously doubt if "inappropriate illness belief disorder" would respond to chemotherapy. Then again, when ME/CFS responded to Ampligen it didn't shut up the psychs. *shrug*
 

richvank

Senior Member
Messages
2,732
Rich, whether your glutathione theory is correct or not, I think this points out that there may be more than one way to interpret their results. They are saying that this suggests that ME/CFS is an autoimmune disorder, but I think that's a pretty big leap of logic. We know that parts of the immune system are activated above normal. We also know that some of the over-activated parts are what turn on the so-called "sickness behavior" in the brain: that is, the signals that tell us we're sick and make us feel lousy. It stands to reason that if you shut down those parts of the immune system, we'll feel better. But it doesn't really tell us WHY those parts of the immune response are up-regulated. If they are up-regulated in response to a persistant pathogen (or combination of pathogens), shutting down the immune system could make us feel better in the short-term, but leave us less able to fight the pathogen.

I'm not saying that's what's happening, just that it's another possible explanation.

The results of this trial are intriguing, but I would be very hesitant to take a drug to shut down parts of the immune system without a lot more evidence of what's going on. I think that their autoimmune theory is just one of several plausible explanations for the results they got. It doesn't explain things like why ME/CFS patients don't have an abnormal antinuclear antibody (ANA) test.

I think that this one will be trumpeted as a big breakthrough because it is a drug that they own the patent to, so they could make a lot of money if it works. But because drug companies' job is to make money, they don't always look too closely at the long-term effects of their drugs on patients. I think we need to approach this one very cautiously.

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
 

Snow Leopard

Hibernating
Messages
5,902
Location
South Australia
There are currently over a thousand Rituximab studies on the clinicaltrials.gov register. i can guarranty you that every one of them is paid by the pharma company.

For those that look at the cost of the vial, you need to know this is not a drug you can inject at home. it needs to be done in the safety of the hospital. Not at your dr's office either. It needs to be titers to only a few cc forthe first hour first as there are chances of infusion reaction that can be serious. ( that is why you need tylenol and benadryl prior to the infusiin, and can stil have reactions).

Personally I feel we need to show rheumatologists and for the countries like Canada that have socialized medicine, request compassionate access to the drug. Ask your government about clinical trials on a larger number of patients. We need to validate these findings.

Some good advice.


By the way, the drug costs (full price in Australia) $2400 per dose and you need two doses every six months or so (at least that is the clinical course for Arthritis).
 

WillowJ

คภภเє ɠรค๓թєl
Messages
4,940
Location
WA, USA
The results of this trial are intriguing, but I would be very hesitant to take a drug to shut down parts of the immune system without a lot more evidence of what's going on. I think that their autoimmune theory is just one of several plausible explanations for the results they got. It doesn't explain things like why ME/CFS patients don't have an abnormal antinuclear antibody (ANA) test.

60% of Fukuda-CFS does have + ANA. I can't find the full text just now, but I think it's in Sorensen et al.'s Complement activation study. A Japanese review says some studies find less, but without being able to read the text, I suspect 15-25% is Oxford-CFS.

Some Japanese scientists say some Autoimmune Fatigue Syndrome patients develop CFS.
 

Snow Leopard

Hibernating
Messages
5,902
Location
South Australia
Also note,
Retrospectively, we checked the 30 patients according to the Clinical Working Case Definition (Canadian criteria) [8]. Two patients in the placebo group did not fulfil these criteria, and it could therefore be argued that they might not have CFS. One of these had almost no pain, and one had only slight cognitive symptoms and also reported marked mood disturbances. The latter patient reported major improvement after intervention with saline and was recorded as one of the two responders in the Placebo group.
 

WillowJ

คภภเє ɠรค๓թєl
Messages
4,940
Location
WA, USA
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, Rich, how high is "a little higher than normal"?

thanks,
willow
 

ixchelkali

Senior Member
Messages
1,107
Location
Long Beach, CA
I wasnt aware it claimed to say anything about the cause of ME, it's just a possible treatment. I'm failry sure there are lots of treatments out there that dont lay claim to understadning or explaining the condition they are treating.


From the Discussion part of the paper:
The associations between B-cell depletion and clinical responses, and the time frames for clinical responses delayed 27 months after the initial and rapid B-cell depletion, indicate that CFS may be an autoimmune disease, often preceded by an infection, and targeting specific parts of the nervous system. We speculate that the responses occurring late after intervention could be explained by the elimination of disease-associated autoantibodies, while the early response pattern could be related to interaction of B-cells with T-cells in antigen presentation, as suggested in systemic lupus erythematosus [9]. Work is in progress in our laboratory to elucidate the localization and nature of a putative target for an autoimmune process.

The high rate of CFS in women compared to men is a suggestion of an underlying autoimmune process. On-going autoimmune phenomena in CFS have been discussed [10] perhaps triggered by infections through molecular mimicry, through structural similarity between a pathogen component and self-structures [11]. Several autoantibodies have been reported in CFS, but their pathogenic roles have not been established, for a review see [10]. In the present study, 23% of the patients had a previous known autoimmune disease, and 40% had first-degree relatives with an autoimmune disease. However, there were low frequencies of positive known common autoantibodies, none had elevated anti-nuclear antibodies, and two had elevated anti-thyroid peroxidase antibodies (data not shown). A possible or established clinical infection before CFS onset was identified in 21 out of 30 patients included (70%).
 

ixchelkali

Senior Member
Messages
1,107
Location
Long Beach, CA
60% of Fukuda-CFS does have + ANA. I can't find the full text just now, but I think it's in Sorensen et al.'s Complement activation study. A Japanese review says some studies find less, but without being able to read the text, I suspect 15-25% is Oxford-CFS.

Some Japanese scientists say some Autoimmune Fatigue Syndrome patients develop CFS.


I thought that a positive ANA was considered an exclusion for ME/CFS?
 

biophile

Places I'd rather be.
Messages
8,977
So 60% had a "major" clinical response. I have not yet looked into what this means exactly (there appears to be multiple criteria for that), but dealing with the PACE Trial has left me generally more suspicious about how symptoms and "improvements" are defined. Also, it seems that some measures were not sustained after the cessation of the drug? Their reasoning behind the speculation about auto-immune disease was intriguing. I found it interesting that this study also looked for XMRV and MLV using several methods, but why was there no mention of MLV in the coculture test?:

"We have not been able to demonstrate XMRV or MLV infection in any of the 30 patients included in this study, despite multiple different approaches including four different highly sensitive Taqman qPCR and four nested PCR approaches, and using both genomic DNA and cDNA as templates. We also performed coculture of patient peripheral blood mononuclear cells with LNCaP prostate cancer cells for biological virus amplification prior to PCR, also with no XMRV positive cases."

It is encouraging that Canadian criteria is getting more and more attention, even if it isn't perfect:

"Retrospectively, we checked the 30 patients according to the Clinical Working Case Definition ('Canadian criteria')[8]."

Add this important study to the several others on CFS which have garnered attention despite being published in PLoS ONE. This reminds me of Mikovits' assertion IIRC that she had several papers that no one would publish. So PLoS ONE wouldn't even publish them, or is she too good for PLoS ONE? This isn't an attack, it just doesn't make sense to me when her career is on the line and it would be helpful to have some more crucial data from her out there.

I didn't read all of richvank's post or this thread for that matter but I do take an interest in the inflammatory oxidative stress angle. I recently resumed a combined version of the richvank/Freddd methylation protocol (without all the co-factors though, just folates and B12, still have to add aB12) after questioning the role of FolaPro (methyl-THF) in my situation for various reasons and stopping it. In addition I've started taking Jarrow Formulas sustained release NAC for both glutathione synthesis and immune system assistance(?), I was concerned about reports of "NAC flu" and supplement/drug-sensitive patients rapidly crashing but so far after a few weeks of 2 x 300mg/day and sometimes more I haven't noticed anything obviously negative from the NAC, and it is cheap so I will continue. I just starting taking vitamin D too, without obvious effects. I've also been researching for supplements for tackling the (simplistically stated) Th2 dominance over Th1 response and the reported elevations of NFKb/TNFa , F2-isoprostanes, and malondialdehyde (MDA) in CFS.

[currer] wrote: We should all get a copy of this paper and KEEP IT ON US AT ALL TIMES for use in a tight spot. It is OUR PASSPORT TO HUMAN RIGHTS. It should stop the psyches dead in their tracks.

Good luck with that. It would only be a matter of time before one of those "psychs" would read this single sentence from the paper and start banging on again about chronic stress causing or perpetuating or contributing to CFS: "Although poorly understood, immune system alterations seen in stress-related diseases such as post-traumatic stress disorder could also be relevant for the effects of B-cell depletion seen in CFS [20]." As Alex said, "The biopsychosocial researchers are not going to like this study. Expect more spin."

[alex3619] wrote:

The Lancet, special edition, 2015

Rituximab is Less Effective Than CBT and GET for CFS

Whitely et. al.

100 CFS patients were selected using the Oxford definition. Half were treated with Rituximab, half with CBT/GET. Only three of the patients treated with Rituximab showed any improvement, but 16 of the patients treated with CBT/GET showed significant improvement.

Online commentary to this article: Analysis of the data showed that the CBT/GET patient responders only improved a small amount, while the Rituximab responders are near recovery. One has to wonder just how many patients in this study really had CFS?

Cheeky. Maybe next time other ME/CFS researchers will speak up more publicly about it. Anyway, you forgot to add: Lancet swiftly dismisses commentary as biased and an unfair personal attack on the utterly impartial authors. Critics who pointed out said discrepancies also branded in news articles and skeptic forums as extreme fringe radicals who know nothing about science and who are hell bent on a hate campaign to discredit anything that remotely suggests cognitive behavioural factors in CFS!

[Snow Leopard] wrote: By the way, the drug costs (full price in Australia) $2400 per dose and you need two doses every six months or so (at least that is the clinical course for Arthritis).

So AU$9600 per year, hmmm, it better deliver for that cost!
 

Kati

Patient in training
Messages
5,497
Re: cost of Rituximab, well, Ampligen is approximately 20-30000 a year, so Rituximab is a cheaper choice, and I suspect that the side effects are milder than Ampligen.
 

redo

Senior Member
Messages
874
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/$%7Bweburl%7D

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

I think this fits perfectly well with the glutathione depletion and methylation theory. The way I see it these two things happen simultaniously:
(Pathogen which may or may not be present) -> Immuneproblems -> Methylation and glutathione depletion -> symptoms
(Pathogen which may or may not be present) -> Immuneproblems -> Symptoms

I am leaning towards the pathogen being active, and what the rituximab does mostly is get rid of most of the (auto)immune problems and thereby also the methylation and glutathione problems, and the symptoms get a whole lot better. And they also get symptom improvement as a direct effect of less autoimmunity.
 

currer

Senior Member
Messages
1,409
Yep, Bio,

I want to point out that Dr Bell was also at the conference where the Norwegians gave their presentation, and he talked about the follow-up of the Lyndonville cohort.

Now - there you had an infectious outbreak spreading thrrough a population leaving ME/CFS in its wake.

Dr Bell followed up the children for years, until adulthood. They had typical ME.

So what auto-immune disease follows infectious outbreaks? None are acknowledged as yet. Rheumatoid arthritis, Lupus etc dont come in infective outbreaks.

Drs Fluge and Mella were very excited by their findings at the conference, but they were there together with Judy Mikovits and Dr Bell, and the conference also had time set apart for the presenters to meet in private and share their findings and ideas.

The norwegians admitted they had come to this illness as oncologists. They admitted they were not familiar with ME. They have only treated individual sufferers late after onset. They have seen ME patients following lymphoma treatment and if I remember their first paper correctly, prostate cancer. (sound familiar?)

They have not looked at epidemiology.

To have infectious outbreaks you have to have a population primed in some way to responding to an infection with an abnormal immune response.

So the important question is Why?

I can think of two answers, both equally unacceptable to the establishment.
 

Enid

Senior Member
Messages
3,309
Location
UK
Just seems marvellous news to me (non-scientist) and thanks Rich and all for piecing the "mechanisms" together.

(All the psyches can now take indefinite holidays)
 

Sasha

Fine, thank you
Messages
17,863
Location
UK
All good news, this! Can only be good in stimulating research and squishing the psychosocial model even if it's early days for deciding if Rituximab is a good way to go for treatment (in terms of likelihood of response, side effects, stability of effect, etc.). In particular, I expect it to be a stimulus for forcing researchers to stick to the CCC or similar because it would be ridiculous to submit people with idiopathic fatigue to drugs like this one.

Huge step forward.
 

Enid

Senior Member
Messages
3,309
Location
UK
Now this is in the "biopsychosocials" should be sent on indefinite holidays - preferably cold.
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
Two patients in the placebo group did not fulfil these criteria, and it could therefore be argued that they might not have CFS. One of these had almost no pain, and one had only slight cognitive symptoms and also reported marked mood disturbances. The latter patient reported major improvement after intervention with saline and was recorded as one of the two responders in the Placebo group.

No doubt this would be reported in the UK press as 'saline solution cures fatigue'.

I'd report it as saline solution much more effective that CBT and GET for Oxford fatigue patients.:D