Rituximab Phase III - Negative result

[justy]

Is it weird that I meet Fukuda, CCC, and ICC? Am I an outlier?

I took part in a Lenny Jason study a few years back and was found to meet ALL definitions of M.E. I dont think it's unusual, it hink it shows we really do have M.E (possibly, becuase without extensive testing we can never really know).

 

[Bedshaped]

Absolutely terrible news, this. I clung to the hope of a cure, so this really sucks. What now? Just give up? Or is there anyone out there getting somewhere?

 

[FMMM1]

CFS, definitely. ME might be like that, but it is not clear. The clearest example you can use to show this problem is depression. Depression, fatigue and pain are symptoms of disease, not diseases. Any diagnosis based mainly on one of these three, or any combination of these three, is problematic. Depression can be caused by many things, and its a category mistake to think its a discrete diagnostic entity. One can diagnose the symptom, but cannot diagnose the disorder or disease without making this error.

We also need to be careful about confusing a kludged disease category with any underlying disorder. ME may be many disorders, or one, but if its kludged with other diseases to create a bogus category it is not evidence that ME is not a discrete disease category, or several.

A similar mistake is made in medicine when they find nothing wrong with us using standard tests designed for other problems. Its also a problem when they have no test for ME and yet conclude there is nothing wrong with patients. They have to pay attention to the science, and most don't know the latest science, and test for what is testable. The first test that is proven to be useful dates from 1940, and that is the tilt table test. We can show specific problems even if we cannot diagnose ME using a test. So anyone making these claims that nothing can be found is about 77 years out of date. To be fair though, detecting OI in ME was not validated till 1995. But even if you use this date then doctors are still 22 years out of date.

There's a PET scan study which indicated activated microglia in ME/CFS "Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An ¹¹C-(R)-PK11195 PET Study. Y Nakatomi - ‎2014".

There's Mark Davis's data showing activated T-cells [Community Symposium on the Molecular Basis of ME/CFS - YouTube].

Hanson's leaky gut study [Community Symposium]

Baraniuk's leaky blood-cerebrospinal fluid (CSF) barrier ["Exercise – induced changes in cerebrospinal fluid miRNAs in Gulf War Illness, Chronic Fatigue Syndrome and sedentary control subjects"]

Chris Armstrong's hypothesis that leaky gut changes metabolism with drives the gut bacteria towards pathogenic micrbiome (webinar)

So maybe the suggestion that ME/CFS is chronic encephalitis, fits. There may be a number of ways to get there but the outcome is the same -- fatigue, neurological symptoms (noise sensitivity etc.).

Baraniuk is looking for participants with ME/CFS for an MRI study. I think he found orthostatic intolerance in one of the two Gulf War subgroups; he was able to identify this group with MRI. Maybe the new MRI study will turn up something in ME/CFS.

Not sure where I'm going with this but maybe this is an immune disease with a number of different triggers but the same outcome.

We need support for scientists Mark Davis (and others) that way we may get some more pieces of the puzzle.

How do we get the science funded?

 

[charles shepherd]

ME Association Statement:

Negative phase III clinical trial result from Norway for Rituximab in ME/CFS >>

http://www.meassociation.org.uk/201...rway-for-rituximab-in-mecfs-27-november-2017/

Dr Charles Shepherd
Hon Medical Adviser, MEA

Senior Consultant Øystein Fluge and Professor Olav Mella supervise the ME/CFS research group at the Dept. of Oncology and Medical Physics at Haukeland University Hospital. The coordinator for the clinical trials is study nurse Kari Sørland. The research group consists of doctors and scientists, nurses, research technicians, molecular biologists and health and exercise therapists. The purpose of the research group is the investigation of possible medical treatments for ME/CFS and biological mechanisms involved in the disease.

 

[JaimeS]

Could anyone around here post a Metabolomics sample to see what kind of info would be available? @JaimeS is such a thing available? Or is it just too detailed for a person to absorb and begs a computer analysis?

Generally speaking, these companies wouldn't make much money if they didn't make the data consumable.

Before working at Stanford, another patient offered me a peek at their data. Totally understandable, just a list of things and a list of standards beside them. I'm sure the accuracy of the standards has improved since then, too.

Sorry, a bit behind on this thread, someone may have already addressed this.

 

[fingers2022]

Could someone explain why there has recently been more interest in an autoimmune theory than a retroviral theory? The former is probably an effect, the latter possibly a cause.

 

[Martin aka paused||M.E.]

Interesting. As a German speaker myself I understood whole parts of sentences as if straight out of a German dialect. Therefore I too wondered. Thanks.

As if a Dutch booked an English course and a German course at the same time and then something went terribly wrong... sorry beloved Belgians, just kidding!

 

[Learner1]

Could someone explain why there has recently been more interest in an autoimmune theory than a retroviral theory? The former is probably an effect, the latter possibly a cause.

As my doctor and the researchers at the OMF Symposium have explained, infections can promote autoimmune antibodies, especially if one has a genetic tendency to autoimmunity.

 

[gregh286]

There's a PET scan study which indicated activated microglia in ME/CFS "Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An ¹¹C-(R)-PK11195 PET Study. Y Nakatomi - ‎2014".

There's Mark Davis's data showing activated T-cells [Community Symposium on the Molecular Basis of ME/CFS - YouTube].

Hanson's leaky gut study [Community Symposium]

Baraniuk's leaky blood-cerebrospinal fluid (CSF) barrier ["Exercise – induced changes in cerebrospinal fluid miRNAs in Gulf War Illness, Chronic Fatigue Syndrome and sedentary control subjects"]

Chris Armstrong's hypothesis that leaky gut changes metabolism with drives the gut bacteria towards pathogenic micrbiome (webinar)

So maybe the suggestion that ME/CFS is chronic encephalitis, fits. There may be a number of ways to get there but the outcome is the same -- fatigue, neurological symptoms (noise sensitivity etc.).

Baraniuk is looking for participants with ME/CFS for an MRI study. I think he found orthostatic intolerance in one of the two Gulf War subgroups; he was able to identify this group with MRI. Maybe the new MRI study will turn up something in ME/CFS.

Not sure where I'm going with this but maybe this is an immune disease with a number of different triggers but the same outcome.

We need support for scientists Mark Davis (and others) that way we may get some more pieces of the puzzle.

How do we get the science funded?

So much to get through and so little time.
I had 2 full remissions in laat 6 year both after extended h-pylori treatment that probably wiped out my microbiome.....or some other hidden bacteria...who knows.

For around 4 weeks both times was bliss. After that i guess body finds its own natural biome again as natural gut flora repopulates. Then cfs begins all over again.
No amount of probiotics seem to sway it. Maybe its is lower GI.
Bizarrely i never had any GI issues during my cfs.

 

[Learner1]

after extended h-pylori treatment that probably wiped out my microbiome.....or some other hidden bacteria...who knows.

....

For around 4 weeks both times was bliss. After that i guess body finds its own natural biome again as natural gut flora repopulates. Then cfs begins all over again.
No amount of probiotics seem to sway it. Maybe its is lower GI.

Having been at this gut stuff for several years, its more than just probiotics. Its ensuring gut lining is good, having the right sort of terrain (targeted foods and insoluble fiber) for the bacteria you want to grow available, and have hospitable bacteria yo encourage the hard to grow ones, while not having bacteria that kill the ones that are helpful, and avoiding candida.

With all of the above in mind and occasional high quality DNA stool testing it is possible to purposefully manipulate the microbiome to get to a better state by rotating targeted probiotic strains paired with appropriate terrain.

Unfortunately no one knows what a perfect microbiome is...we're just guessing at this point, but one can make some educated guesses to decrease bad actors and increase "normal" citizens.

 

[gregh286]

Having been at this gut stuff for several years, its more than just probiotics. Its ensuring gut lining is good, having the right sort of terrain (targeted foods and insoluble fiber) for the bacteria you want to grow available, and have hospitable bacteria yo encourage the hard to grow ones, while not having bacteria that kill the ones that are helpful, and avoiding candida.

With all of the above in mind and occasional high quality DNA stool testing it is possible to purposefully manipulate the microbiome to get to a better state by rotating targeted probiotic strains paired with appropriate terrain.

Unfortunately no one knows what a perfect microbiome is...we're just guessing at this point, but one can make some educated guesses to decrease bad actors and increase "normal" citizens.

Totally with you there. There.is no perfect mona lisa gut.
But when a nuclear attack on gut cfs relieves temporarily.....has be questions about connection.
Its so difficult to maintain the homeostatic gut bacteria state post abx apocalypse

 

[FMMM1]

Could someone explain why there has recently been more interest in an autoimmune theory than a retroviral theory? The former is probably an effect, the latter possibly a cause.

Mark Davis's, and Ron Davis's, YouTube talks on the OMF Community Symposium go through this.

Yea because I don't understand this it's hugely complicated.

In a B cell autoimmune disease you've got an autoimmune antibody targeting a self antigen. Relatively simple except finding the antibody/antigen seems to be frustratingly difficult.

Mark Davis looked at T-cells which were activated against an antigen (clonal expansion) in ME/CFS. Problem is you've got to find the antigen; you know what a section of the peptide sequence is but you don't know the whole parent protein or whatever. Also, I guess that you don't know whether the antigen is the cause or the consequence.

There's been some talk that the immunologist who got the NIH research centre funding must have found something but so far I haven't heard what that might be.

Viruses seem to be fading from the picture; see Ron Davis's talk. Ron doesn't rule out viruses entirely but today he reckons you could identify an new virus in 2 days (he compares this with AIDS which took years). Therefore, if there was a lot of virus floating around he reckons you'd find it. He reckons that possibly there could be something hiding somewhere; presumably that something would be degraded and it's constituent peptides identified by T- cells and yes you've guessed you'd get clonal expansion targeting the degraded viral protein or whatever.

I'm guessing that many of us have a high incidence of immune diseases such as asthma in our families. So this may not necessarily be the virus from the black lagoon it may be the way our immune systems work.

Others are getting interested in immunology, e.g. cancer, so we may just get lucky with what they find.

Funding for scientists would be good and a dollop of luck please.

 

[fingers2022]

I'm guessing that many of us have a high incidence of immune diseases such as asthma in our families. So this may not necessarily be the virus from the black lagoon it may be the way our immune systems work.

Interestingly, none of that in my siblings/parents/ancestors nor myself, although could that be because these are relatively recent developments (I'm 60 and youngest sibling)? Then again, my son has hayfever and partner has IBD and coeliac. Could the latter point more to infectious agent?

All anecdotal of course, but such epidemiological data on a large scale might be very illuminating.

 

[justy]

Interesting. As a German speaker myself I understood whole parts of sentences as if straight out of a German dialect. Therefore I too wondered. Thanks.

As an English speaker i also can understand a fair amount!

 

[FMMM1]

Interestingly, none of that in my siblings/parents/ancestors nor myself, although could that be because these are relatively recent developments (I'm 60 and youngest sibling)? Then again, my son has hayfever and partner has IBD and coeliac. Could the latter point more to infectious agent?

All anecdotal of course, but such epidemiological data on a large scale might be very illuminating.

Hi first of all on reflection my comment re "virus from the black lagoon" may have been misjudged.

Re the way our immune system works, if you haven't already done so then possibly check out Neil McGregor's presentation at the symposium and the transcript which is on the Melbourne University website. E.g. the following "Dendritic cells are found on those parts of the body which have contact with the external environment (skin, and mucosa like nose, throat, gut). They serve to alert the immune system to the presence of pathogens. The CD207 gene codes for Langerin, which is a protein found in dendritic cells. If there is a problem with the CD207 gene, then the body will likely have problems detecting certain viruses."

I think the latter bit highlights that it may not be a case of a virus that is good at avoiding the immune system etc.; it's potentially just that our immune systems aren't functioning properly.

Neil's presentation is worth viewing for the last slide alone. Much of the science goes over my head.

I think the problems re finding autoimmune antibodies are illustrated by recently publicised study at Angela Vincent's laboratory in Oxford (your part of the world). The study found that some of those who tested negative for the known antibodies (to the NMDA receptor) responded positively to immuno-suppressive treatments. I think this group tried unsuccessfully to get funding for a study looking at autoimmune antibodies in ME/CFS. Maybe there is a group of people (with ME/CFS) with causal autoimmune antibodies; if there is then I'm not clear whether they can be diagnosed using a specific test for the antibody or if there's anyone looking for same.

To me Mark Davis's T-cell activation work stands out at this point (symposium); it may be high risk but I can't see anything better.

I seem to recall something about incidence of ME/CFS and occurrence of asthma etc. in siblings but I haven't found it.

 

[msf]

Hmm, I know Prof. Edwards was weaning himself off the forum, but it seems we unfortunately probably don´t need him anymore anyway to explain how Rituximab may work.

On the subject of the last post, that quote from MacGregor is intriguing given the recent KDM paper where they mention the failure of PDCs to prime the immune response against gut bacteria.

 

[JES]

To me Mark Davis's T-cell activation work stands out at this point (symposium); it may be high risk but I can't see anything better.

There is also Chia's long standing work on enteroviruses, it's just a shame it hasn't caught more interest in the scientific community, because it would at least be worth investigating to get a definite answer on whether enteroviruses play a part or not.

One problem with treating enterovirus infections is that there are no good antivirals today that achieve high enough in vivo concentrations, but this might change in the near future. Dr. Chia has been in contact with Belgian researchers who are working on a new drug against CVB4, which would be order of magnitude more efficient than anything we have today. This drug was not intended for CFS/ME originally, but I can see no reason why it couldn't be trialed in CFS/ME patients as soon as it gets approved.

 

[FMMM1]

There is also Chia's long standing work on enteroviruses, it's just a shame it hasn't caught more interest in the scientific community, because it would at least be worth investigating to get a definite answer on whether enteroviruses play a part or not.

One problem with treating enterovirus infections is that there are no good antivirals today that achieve high enough in vivo concentrations, but this might change in the near future. Dr. Chia has been in contact with Belgian researchers who are working on a new drug against CVB4, which would be order of magnitude more efficient than anything we have today. This drug was not intended for CFS/ME originally, but I can see no reason why it couldn't be trialed in CFS/ME patients as soon as it gets approved.

Yea I agree there are a lot of research areas, see community symposium etc.

If you had causal enterovirus what would be the consequence? An activated immune system? Check out Mark Davis's video (about 3 minutes in). I assume that the enterovirus would get broken down into it's constituent parts (peptides) and the foreign bit (enterovirus peptides) would be identified as not self i.e. you'd get an immune response. So possibly the striking activated immune system (clonal expansion in T-cells) is due to enterovirus.

Why did the current study fail? I haven't read the above but I read elsewhere that one option is that the disease has a number of causes. Therefore, there's a possibility that there is a sub-group where the disease is caused by autoimmune antibodies i.e. should have responded positively to rituximab. Possibly the same applies re enterovirus i.e. if only a subgroup will benefit then you need to identify the sub-group otherwise the treatment fails the stage 3 trial.

I think you're right re picking up on already licensed drugs. Here's an extract from a paper "Repurposing Food and Drug Administration approved drugs offers a cost-effective solution with a significantly abbreviated timeline." [From "Using gene expression signatures to identify novel treatment strategies in gulf war illness"].

NIH had a call for suggestions for possible research areas a year ago (ish); the European's have about 80 billion dollars under Horizon 2020 science research program [you can make suggestions]; and practically laughably (after PACE) the UK has NICE [you can make suggestions]. Guess where I live! The Europeans have a fair but of bumf re there funding for Lyme's (diagnostic tests -----) but I couldn't tell you anything they've done for ME/CFS. If you know an interested Member of the European Parliament then pass on the details to OMF etc.

 

[FMMM1]

Hmm, I know Prof. Edwards was weaning himself off the forum, but it seems we unfortunately probably don´t need him anymore anyway to explain how Rituximab may work.

On the subject of the last post, that quote from MacGregor is intriguing given the recent KDM paper where they mention the failure of PDCs to prime the immune response against gut bacteria.

Re "recent KDM paper" could you give the title, I'm interested in having a brief look. Thanks

I have an interest in autoimmune antibodies and can think of one scientist who reckons there's potentially a subgroup of people with ME/CFS where this could be relevant. I'd like to think Prof. Edwards would be around.

 

[Aroa]

There is also Chia's long standing work on enteroviruses, it's just a shame it hasn't caught more interest in the scientific community, because it would at least be worth investigating to get a definite answer on whether enteroviruses play a part or not

I believe Dr. Chia will play an important role in Maureen Hanson`s CCR. This will probably mean they will look into it.

You can find it at the end of this link :
http://news.cornell.edu/stories/2017/09/94m-nih-grant-funds-chronic-fatigue-syndrome-center