Rituximab Phase III - Negative result

[andyguitar]

I get what many say about immune system defects. No doubts in my mind that unusal immune responses are common in both ME and CFS. But I just dont buy into the idea that sufferers are genetically predisposed to have those sort of problems. I think the problems with the immune system are acquired and are caused in most cases (of CFS) by an adverse drug reaction and, in some cases, adverse supplement reaction. The idea that because something can be bought from a health food store it must be "healthy" is cobblers. Supplement manufacturers in the UK get away with far to much when it comes to not having to prove the safety and effectiveness of their products.

 

[Gingergrrl]

Its a very easy to understand tutorial on the immune system and how autoimmunity can develop in people with immune system defects. Starting at around1:00 he discusses treatment, including high dose IVIG, Rituximab, Bortizimub, and plasmapherisis.

Thx @Learner1 and I bookmarked the video to watch it later. And enjoy your conference!

 

[Learner1]

Thanks, I did!

 

[Learner1]

I get what many say about immune system defects. No doubts in my mind that unusal immune responses are common in both ME and CFS. But I just dont buy into the idea that sufferers are genetically predisposed to have those sort of problems. I think the problems with the immune system are acquired and are caused in most cases (of CFS) by an adverse drug reaction and, in some cases, adverse supplement reaction. The idea that because something can be bought from a health food store it must be "healthy" is cobblers. Supplement manufacturers in the UK get away with far to much when it comes to not having to prove the safety and effectiveness of their products.

At the conference I went to, doctors from the University of Washington enumerated over 300 genetic defects leading to immune system irregularities, which seems to fit with what Neil McGegor had found in Australia. They are also piloting gene editing techniques in more severely ill patients.

No doubt there also are many of us who have had environmental factors like infections, toxins, or drugs trigger ME/CFS.

And, there are likely some of us that have all of the above.

 

[denlander]

Tough!

Maybe identifying the subgroups is much more important than I thought. Because: I don't think that a total remission in CFS due to RTX treatment (which occurred in Phase II) can be placebo.

Or they really messed up diagnostic criteria ;-)

 

[denlander]

That would be bad news. Because if they find sth. for one group..........
But I think that the underlying cause has to be the same since Dr. Davis nano-chip seems to work on all CFS patients...

You made an excellent point, the criteria for the diagnosis is important . We must compare the results of a clinical condition ME CFS , including non ME CFS patients will impact the results of a study. We can look to the Oxford Criteria (ugh) and see the unacceptable result of the PACE study.
It is sad that the Oslo study was not positive.

 

[denlander]

At the conference I went to, doctors from the University of Washington enumerated over 300 genetic defects leading to immune system irregularities, which seems to fit with what Neil McGegor had found in Australia. They are also piloting gene editing techniques in more severely ill patients.

No doubt there also are many of us who have had environmental factors like infections, toxins, or drugs trigger ME/CFS.

And, there are likely some of us that have all of the above.

The theory that there is a genetic abnormality or predisposition was suggested by a paper published by Jonarhan Kerr and myself several years ago. Maybe the genetic problem allows the "antigen" to gain a foothold and cause the immune abnormality in the methylation cycle or maturation of the NK (natural Killer) cells. What ifs the antigen? Still a mystery, thought by Ramsey in 1955 to be a virus, we are still searching for the answer.

 

[Learner1]

The theory that there is a genetic abnormality or predisposition was suggested by a paper published by Jonarhan Kerr and myself several years ago. Maybe the genetic problem allows the "antigen" to gain a foothold and cause the immune abnormality in the methylation cycle or maturation of the NK (natural Killer) cells. What ifs the antigen?

Very interesting. It would be really helpful to have a current analysis of all of the genes the various research groups have found to be involved in ME/CFS, a way to figure out if we have problems with how they are expressed due to the behavior of certain SNPs or reactions to environmental factors. And then, what treatment(s) might improve their expression.

 

[Gingergrrl]

Maybe identifying the subgroups is much more important than I thought. Because: I don't think that a total remission in CFS due to RTX treatment (which occurred in Phase II) can be placebo. Or they really messed up diagnostic criteria ;-)

I agree with this @denlander and find it so hard to imagine that all of the remissions, and improvements, in Phase II were due to placebo, unless they actually had a group of patients with autoimmunity who were misdiagnosed with ME/CFS.

Either way, I believe there is still a sub-group or a misdiagnosed group who benefit from Rituximab b/c I am in that group and I know that I cannot be the only one. (I was not part of any study and doing Ritux with my own doctors).

Sorry for stupid question but are you Dr. Enlander (@denlander)? If so, it is an honor to talk to you and hear your thoughts re: the Rituximab trial!

 

[FMMM1]

I agree with this @denlander and find it so hard to imagine that all of the remissions, and improvements, in Phase II were due to placebo, unless they actually had a group of patients with autoimmunity who were misdiagnosed with ME/CFS.

Either way, I believe there is still a sub-group or a misdiagnosed group who benefit from Rituximab b/c I am in that group and I know that I cannot be the only one. (I was not part of any study and doing Ritux with my own doctors).

Sorry for stupid question but are you Dr. Enlander (@denlander)? If so, it is an honor to talk to you and hear your thoughts re: the Rituximab trial!

There's been a school of thought that some people with ME/CFS have an autoimmune (B-cell) disease; I have an interest in that. Among the problems are the fact that not all autoantibodies can be detected with off the shelf diagnostic tests, and the off the shelf tests can give false positives/negatives. The problem with false positives/negatives can be addressed by changing to tests which use this technique (by Ron Davis) https://www.omf.ngo/2018/02/12/tweak-assay-bolster-disease-detection-stanford-medicine-news-center/.

Possibly a small percentage of people may have an autoimmune (B-cell) disease; this may explain why Rituximab didn't work. However, if you could find autoimmune antibodies in a small percentage of people (i.e. which cause ME/CFS) then you would have made significant progress for all of those with ME/CFS. I.e. you'd know what causes the disease, target, mechanism etc. Ron Davis has been keen on trying to find the underlying cause. Some research into the underlying cause is focused on genetics e.g. if a particular mutation has a very high incidence of ME/CFS then I assume that gives clues to mechanism. Ron Davis's group at the OMF are due to publish a paper on genetics in ME/CFS later in the year. You may have seen Dr. Phair's (OMF) request for people with ME/CFS to provide their genetic data.

I'm a lay person with an interest i.e. not a scientist.

Many people have diseases which cannot currently be diagnosed; e.g. diseases which are not purely genetic but have a genetic component and an environmental trigger (ME/CFS?). I find some (Kafkaesque?) humour in your statement "I believe there is still a sub-group or a misdiagnosed group who benefit from Rituximab". I also agree with it i.e. some people may have an autoimmune (B-cell) disease which is undiagnosed and which will respond to immuno-suppressants etc.

The European Union [Horizon 2020] has funded the development of a test for Lyme disease (40 million dollars/euros of research on Lyme). How do we get them to fund research for autoimmune antibodies in ME/CFS, or other research into ME.CFS?

 

[Learner1]

Many people have diseases which cannot currently be diagnosed; e.g. diseases which are not purely genetic but have a genetic component and an environmental trigger (ME/CFS?). I find some (Kafkaesque?) humour in your statement "I believe there is still a sub-group or a misdiagnosed group who benefit from Rituximab". I also agree with it i.e. some people may have an autoimmune (B-cell) disease which is undiagnosed and which will respond to immuno-suppressants etc.

Many of us have low NK cell function - could this be an example of having an underlying genetic component triggered by environmental factors? There are several recent articles talking about the role of NK cells being functionally impaired in cancer, like this one:

https://www.researchgate.net/public..._the_balance_NK_cells_in_anti-cancer_immunity

 

[FMMM1]

Many of us have low NK cell function - could this be an example of having an underlying genetic component triggered by environmental factors? There are several recent articles talking about the role of NK cells being functionally impaired in cancer, like this one:

https://www.researchgate.net/public..._the_balance_NK_cells_in_anti-cancer_immunity

Yea, we haven't been getting significant funding for ME/CFS research but we may benefit from research into other diseases which can e.g. cancer or Alzheimers. I had hopes the interest in immunity in cancer might help us. Haven't been able to access the full paper but the abstract looks interesting.

 

[Learner1]

Here it is:

 

[wastwater]

I liked the video posted by learner1 on unspecified immunodeficiency
There was a bit on a drug that blocked overactive T cells
It’s hard to find places in the U.K. with such knowledge

 

[Gingergrrl]

I find some (Kafkaesque?) humour in your statement "I believe there is still a sub-group or a misdiagnosed group who benefit from Rituximab". I also agree with it i.e. some people may have an autoimmune (B-cell) disease which is undiagnosed and which will respond to immuno-suppressants etc.

@FMMM1 I wasn’t sure what you meant re: my statement being Kafkaesque humor? (I know what the phrase means re: Kafka’s writing style but not sure how that pertained to what I said)?!

I was being totally serious that I believe there is a sub-group (or entire misdiagnosed group) that are responders to Rituximab. I truly believe the Ritux research should continue further.

 

[FMMM1]

First of all I think there may be a group of people with ME/CFS who have a B-cell autoimmune disease (autoimmune antibodies) i.e. who would respond to Rituximab or other immunosuppressant treatments. I've spent some time contacting members of the European Parliament etc. to try to get support for research to identify further (new) autoantibodies and for improved autoantibody tests for this known autoantibodies (fewer false positives/negatives). The European Union has done this for Lymes disease i.e. funded the development of an improved diagnostic test under Horizon 2020.

I think it's Kafkaesque to suggest that someone with an autoimmune (autoantibody) disease doesn't have ME/CFS i.e. if the causal autoantibody has been identified. If you know what's wrong with you you aint got ME/CFS.

I was unsure about trying to be humorous; obviously I should have acted on that. I was not trying to be humourous at your expense.I was just trying to reflect the problems those of us who feel our family member/we may have an autoimmune (autoantibody) disease. I.e. no tests available/poor quality tests. How do we address that problem?

 

[Gingergrrl]

Thank you for your reply and I want to clarify that everything I am asking is in complete seriousness and good faith so I can learn. It is not my intention or style to joke about this topic or minimize anything. I will have my 5th infusion of Rituximab next week and it has been life changing. I have had amazing improvements and I am very fearful what happens when I stop these treatments (most likely after the 6th infusion). My other treatment is IVIG and that will come to an end soon, too. I cannot imagine going back to my life pre-treatment which is why I want to learn as much as I can. I hope that makes more sense now.

First of all I think there may be a group of people with ME/CFS who have a B-cell autoimmune disease (autoimmune antibodies) i.e. who would respond to Rituximab or other immunosuppressant treatments.

I absolutely 100% agree with you (which is what I was trying to explain in an earlier post but did not do a good job)!

I think it's Kafkaesque to suggest that someone with an autoimmune (autoantibody) disease doesn't have ME/CFS i.e. if the causal autoantibody has been identified. If you know what's wrong with you you aint got ME/CFS.

This is the part that I don't understand b/c I actually was not suggesting that someone with an autoimmune (or autoantibody) disease doesn't have ME/CFS. I actually think there is a sub-group that does have an autoimmune mediated disease (even if this has not yet been proven or identified). I was not trying to be humorous or Kafkaesque or anything but totally serious. I think it is so hard with the written word when you cannot hear someone's tone.

I was unsure about trying to be humorous; obviously I should have acted on that. I was not trying to be humourous at your expense.

I promise I was not trying to be humorous and still not sure what you mean when you said it was obvious that you should have acted on it at my expense. I didn't even get that you were trying to be humorous at my expense! I think I am so laser-focused on trying to understand the mechanism of action behind these treatments and wish that the research into the Rituximab responder group was not over (b/c I believe that I am a part of that group).

I was just trying to reflect the problems those of us who feel our family member/we may have an autoimmune (autoantibody) disease. I.e. no tests available/poor quality tests. How do we address that problem?

I agree that the tests are not widely available, many are poor quality, or even money-making scams. I don't know how to address that problem and wish I did. I truly did not know if I would be a responder to IVIG and Ritux but felt it was worth the risk and it was. I wish I knew which sub-group I was in or if I have a different disease? It torments me b/c without knowing, I do not know if my remission will go away when I stop the treatments. I hope I am explaining this well but I feel that I might not be.

 

[Learner1]

If you know what's wrong with you you aint got ME/CFS.

This is not at all true. The IOM ME/CFS Clinician's Guide, prepared after reviewing thousands of pages of research, says,

"Comorbidities such as fibromyalgia and irritable bowel syndrome are common in
ME/CFS (SEID) patients. These comorbidities should be diagnosed and treated
when caring for patients. The presence of other illnesses should not preclude pa-
tients from receiving a diagnosis of ME/CFS (SEID) except in the unlikely event that
all symptoms can be accounted for by these other illnesses."

I agree that the tests are not widely available, many are poor quality, or even money-making scams. I don't know how to address that problem and wish I did. I truly did not know if I would be a responder to IVIG and Ritux but felt it was worth the risk and it was. I wish I knew which sub-group I was in or if I have a different disease? It torments me b/c without knowing, I do not know if my remission will go away when I stop the treatments. I hope I am explain

@Gingergrrl , from everything I've read, you have every chance of success at this point. You had a plethora of awful antibodies and a history of EBV and mold. Getting rid of the triggering conditions (as much as one can get rid of EBV), and attacking the antibodues, first with IVIG and then with Rituximab should clean them out of your system. As long as you steer clear of future triggers, you should have every chance of success. Which is wonderful!

Unfortunately, we are a mixed bag of patients, sharing symptoms but having a diverse group of genetic and environmental factors, so there's no one identical to you. So, we can each just to the best we can to get through our individual situations.

 

[FMMM1]

IVIG

Thank you for your reply. That treatment doesn't sound like a whole lot of fun. I'm glad you're feeling better. I think they (researchers) should study those who respond to immunosuppressants e.g. to see if they can identify autoimmune antibodies. Mark Davis (OMF), and Dr Unutmaz (NIH Research Centre), among others, are looking at the immune system; hopefully we will see some significant progress in the near future.

 

[Learner1]

I think they (researchers) should study those who respond to immunosuppressants e.g. to see if they can identify autoimmune antibodies.

Immunosuppressants are a great way to end up with cancer or sepsis.

Figuring out how to reverse autoimmunity vs. suppressing the immune system seems wiser.