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Dr Bieger and Dr Mikovits discuss treating ME patients with Rituximab

Sherlock

Boswellia for lungs and MC stabllizing
Messages
1,287
Location
k8518704 USA
Dr. Bieber said that the patient who got very sick (Bodden) has been very sick for 1.5 years. I wonder if they have eliminated the possibility that he had a pre-existing rodent allergy.

Also, since all fog lifted completely and very quickly, what's the supposed mechanism?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
This is what I think she's saying as her main contention:

Some CD20+ cells become deranged from DNA changes due to a retrovirus. The deranged CD20+ cells then begin producing and emitting autoantibodies, even though the deranged CD20+ cells have not differentiated into plasma cells as is usual.

At this point I'd ask @Jonathan Edwards: ITP can occur as secondary to lymphoma (I've seen exactly that). When such humoral autoimmunity develops, is that the way it happens? Do deranged CD20+ B cells produce antibodies while staying CD20+ (and not differentiating in the normal way into plasma cells)? The 2ndary ITP case that I'd seen did resolve after ~8 weeks of RTX.

No, the antibodies are produced by plasma cells. However, it seems that many autoimmune plasma cells only last a few months, maybe even a few weeks. So they must be constantly replenished from CD20+ memory B cells. If you give rituximab the memory B cells are cleared out and the plasma cells disappear over a period of weeks or months. ITP is a bit atypical in that it can get better spontaneously and quite rapidly suggesting that the plasma cells in this case are very short lived indeed. But there are other complex kinetic issues relating to what the threshold is above which platelets get destroyed. Nobody really understands it.

This emphasises the point that markers like CD20 are just markers of maturity. And what people are measuring are proportions of cells of different maturity in the blood. It is very unlikely that these proportions have anything to dowith proportions in bone marrow or lymph node. This is where Mikovits's story is a trivialisation of the immunology. You do not build a theory of autoimmunity on the numbers of cells that happen to be passing through the bloodstream.

Further guessing about her contentions: the deranged CD20+ cells proliferate because of other DNA derangements, crowding out production of normal CD20+ cells (in the marrow). So, while the total number of CD20+ cells does not increase, the deranged CD20+ cells become a greater and greater percentage of the total CD20+ population, as the normal CD20+ cells become a lesser percentage of the total CD20+ population.

Those are the CFS cases that she thinks should be treated with RTX. But why does she think that low dose RTX will help kill off the deranged CD20+ cells but not the normal CD20+ cells?

Right.

I also don't recall that she addressed proliferation of B cells in lymph nodes or lymphoid tissue, which is where lymphoma usually develops. That's also where you'd expect the humoral response to develop in the short period after RTX dosing anyway - not the marrow.

Exactly right.
 

Strawberry

Senior Member
Messages
2,107
Location
Seattle, WA USA
Dr. Bieber said that the patient who got very sick (Bodden) has been very sick for 1.5 years. I wonder if they have eliminated the possibility that he had a pre-existing rodent allergy.

I was wondering that also. I am in the rodent allergy club too. But I would think that the reaction would have reduced over the last year and a half if it was rodent allergy?
 

heapsreal

iherb 10% discount code OPA989,
Messages
10,089
Location
australia (brisbane)
They were @Jacque and @Kati


In the larger world, a bone marrow transplant is far more dangerous than RTX,

I mentioned this as a matter of interest not safety. At the moment the stem cell/rituximab has a better for and against for MS than rituximab alone for ME, because at the moment the only criteria used is an ME criteria, no immune profiling is used to my knowledge, so its really a guess.

I actually saw this on an MS documentary on tv and what struck a cord was they were using rituximab prior to the bone marrow transplant and seem to have a very high success rate. The bone marrow transplant was dependent on the rituximab treatment. But i think the doctors carefully selected the patients to see if they were suitable, maybe through blood tests, not alot of info was given. Maybe their selection criteria could be useful for developing one for cfs for rituximab?

These were russian doctors who have been using this technique for like 20years and they were treating an australian girl who couldnt get this treatment in australia for some political reason.
 

user9876

Senior Member
Messages
4,556
Quite the opposite. If severe adverse events are rare, then studies of the sort that have been published to date are no good for detecting them. An N=3 case series of patients with ME/CFS + lymphoma and a 30 person RCT in which 15 persons received the drug is the extent of the published literature to date. The statistical probability of capturing a rare severe negative reaction like Mr Bodden's (if the rate of such an event is low in the population) in such small samples is minuscule. The current evidence base thus tells you absolutely nothing about the incidence of adverse events in the population of ME/CFS patients. Even a well-designed phase III trial will tell you little.

You generally don't find out how often a drug is harmful or kills people until it's unleashed on the general population after regulatory approval. Think black box warnings on antidepressants etc.

In thinking through adverse effects with ME we need to look at the whole treatment path and not just the drug. I remember a time when my child went to see a consultant at the hospital and required x-rays, scans with a lot of waiting in a noisy environment. She had quite a severe relapse after that for at least 6 months and I don't think she has recovered her level of function after a couple of years. No drugs involved just the process of going to a hospital. But then a relapse following too much exertion should not surprise anyone.

I remember reading blogs of people in the US who were being treated with Rituximab who were travelling quite large distances (from the perspective of someone in the UK). So I wonder if when thinking through adverse incidents in treatment we need to think about the exertion involved in getting treatment as well as the treatment itself - particularly for the more severely effected.

I wonder if Fluge and Mella's clinics (as oncology clinics) are better set up for dealing with people with limited function in comparison to other clinics?
 
Messages
38
Well what we can say is that cases like Bodden is probably extremely rare, based on the sole fact that something likewise has not occured in the norwegian ritux-studies.
I think so too, and I'd happily take the risk, but from the preliminary results from the open phase 2 study (posted by @deleder2k in another thread) it looks like one of those patients also got considerably worse.

It would be great if the treatment differences between the norwegians and germans could be explained somehow. It might just be chance, or it might be due to dosage. Or disease severity etc etc
This is a total mystery to me. I don't think disease severity would explain the differences, and I was always under the impression that the same dosage was used. But I don't know how the 10 German patients were picked out.

I know hypogammaglobulinemia is.
You can read more about the exclusion criterias here: https://clinicaltrials.gov/ct2/show/NCT02229942
Thanks, I had actually read them but forgot that hypogammaglobulinemia was mentioned. Would that mean that everyone with a subclass defect was excluded? I read somewhere that only 1:25000 people (in the general population) have hypogammaglobulinemia, that sounds very few to me?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Thanks, I had actually read them but forgot that hypogammaglobulinemia was mentioned. Would that mean that everyone with a subclass defect was excluded? I read somewhere that only 1:25000 people (in the general population) have hypogammaglobulinemia, that sounds very few to me?

IgA deficiency is unlikely to be a problem since it is common and does not seem to be a major health issue. I have treated at least one patient with low IgA. IgG is what matters most and a significantly low IgG1 would be an issue. I am not sure that the others matter so much. Generally speaking one does not bother to look at subclasses unless the total IgG is low. I would not start treatment with someone with a total IgG of below 6Gm/L anyway. In the RA studies and routine practice nobody measures subclasses.
 
Messages
38
IgG is what matters most and a significantly low IgG1 would be an issue. I am not sure that the others matter so much. Generally speaking one does not bother to look at subclasses unless the total IgG is low. I would not start treatment with someone with a total IgG of below 6Gm/L anyway. In the RA studies and routine practice nobody measures subclasses.
I know Fluge/Mella are looking at both IgG and subclasses, but I don't know for sure what would be an exclusion criterion. What are the risks with low IgG1? Risk for infections? Would that also apply for patients who normally don't have problems with recurrent infections?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
I know Fluge/Mella are looking at both IgG and subclasses, but I don't know for sure what would be an exclusion criterion. What are the risks with low IgG1? Risk for infections? Would that also apply for patients who normally don't have problems with recurrent infections?

Low IgG increases risk of infection, although most people will not get problems unless it well below 6. With rituximab treatments there is a slight fall each time, so after four successive treatments over two years a level of 8 might drop to 6 and a level of 6 might possibly drop to 4. The only person I have treated who started below 7 got down to about 4.5 before we decided we had better use something else for a while, but she had rituximab on and off for about ten years.

To be honest it is a very uncommon problem. Of about 200 patients we treated I think there were 3 who had low enough IgG to worry. The only one who ran into infection problems had chronic lung disease from smoking to start with and also had rheumatoid bronchiectasis, which got superinfected. But she had so many other problems that everybody still thought it was worth having used rituximab.
 

Kati

Patient in training
Messages
5,497
Low IgG increases risk of infection, although most people will not get problems unless it well below 6. With rituximab treatments there is a slight fall each time, so after four successive treatments over two years a level of 8 might drop to 6 and a level of 6 might possibly drop to 4. The only person I have treated who started below 7 got down to about 4.5 before we decided we had better use something else for a while, but she had rituximab on and off for about ten years.

To be honest it is a very uncommon problem. Of about 200 patients we treated I think there were 3 who had low enough IgG to worry. The only one who ran into infection problems had chronic lung disease from smoking to start with and also had rheumatoid bronchiectasis, which got superinfected. But she had so many other problems that everybody still thought it was worth having used rituximab.
My IgG levels have remained within normal range even after 6 doses of Rituxan. I have never had an IgG or A or M defficiency. I believe it is a subset of <name of the disease here> who has that.
 
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3
Low IgG increases risk of infection, although most people will not get problems unless it well below 6. With rituximab treatments there is a slight fall each time, so after four successive treatments over two years a level of 8 might drop to 6 and a level of 6 might possibly drop to 4. The only person I have treated who started below 7 got down to about 4.5 before we decided we had better use something else for a while, but she had rituximab on and off for about ten years.

To be honest it is a very uncommon problem. Of about 200 patients we treated I think there were 3 who had low enough IgG to worry. The only one who ran into infection problems had chronic lung disease from smoking to start with and also had rheumatoid bronchiectasis, which got superinfected. But she had so many other problems that everybody still thought it was worth having used rituximab.

I'm interested in this as I was diagnosed immune deficient in 2012 which probably accounts for most of my infective symptoms and debility and not ME/CFS - but I am keeping an open mind and I'm interested in Rituximab et al.

I have IgG subgroup 1 & 3 deficiencies along with inability to make antibodies against pneumococcus. Also, IgA, NK cell and mannose binding lecithin deficiency and b cell deficiency (v rare I understand). All my deficiencies are just out of spec so nothing drastic and as I responded well to the pneumovax vaccine I don't fall under the CVID diagnosis. I'm responding well to daily Cotrimoxazole and hope to be back in work in a few months, though I am still struggling quite a bit, I'm not now in a wheelchair every 4-6 weeks with a sinus infection (caused by pneumococcus and coliforms). My total IgG is about 8 - so I disagree with you regarding not getting problems till this is below 6. It's caused me a decade of grief and lost life....

I've shared this experience with other patients who are members of ME groups and several - not many - who have specific evidence of on-going opportunistic infective type symptoms (sinusitis, tonsillitis, ear infections etc) have been seen by immunologists and several have come back with t cells deficiencies - all of unknown cause. No one else has anything like me though..... I suspect there are a few of us out there misdiagnosed under the "ME/CFS" banner so its good to read that a details view of patients immunological status is being carried out.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
I'm interested in this as I was diagnosed immune deficient in 2012 which probably accounts for most of my infective symptoms and debility and not ME/CFS - but I am keeping an open mind and I'm interested in Rituximab et al.

I have IgG subgroup 1 & 3 deficiencies along with inability to make antibodies against pneumococcus. Also, IgA, NK cell and mannose binding lecithin deficiency and b cell deficiency (v rare I understand). All my deficiencies are just out of spec so nothing drastic and as I responded well to the pneumovax vaccine I don't fall under the CVID diagnosis. I'm responding well to daily Cotrimoxazole and hope to be back in work in a few months, though I am still struggling quite a bit, I'm not now in a wheelchair every 4-6 weeks with a sinus infection (caused by pneumococcus and coliforms). My total IgG is about 8 - so I disagree with you regarding not getting problems till this is below 6. It's caused me a decade of grief and lost life....

I've shared this experience with other patients who are members of ME groups and several - not many - who have specific evidence of on-going opportunistic infective type symptoms (sinusitis, tonsillitis, ear infections etc) have been seen by immunologists and several have come back with t cells deficiencies - all of unknown cause. No one else has anything like me though..... I suspect there are a few of us out there misdiagnosed under the "ME/CFS" banner so its good to read that a details view of patients immunological status is being carried out.

Thanks Joanie. It is difficult to comment without clear numbers. A total IgG of 8 is very normal and I cannot see any reason to relate it to infections. The problem I have is that I can find no convincing evidence in the literature for an increased rate of immunodeficiency in ME/CFS patients. There is a lot of talk about it and in particular about abnormal in vitro NK results but there does not seem to be much consistency in the findings. The situation is clearly distorted by some researchers claiming immunological abnormalities way beyond anything that the data actually show. I suspect it is further clouded by unreliable results from commercial labs.

If there is immunodeficiency in ME/CFS I would very much like to nail that and show it reliably, but the ME/CFS immunologists that I have spoken to at scientific meetings all seem to think that there is nothing much replicable to find.
 

duncan

Senior Member
Messages
2,240
I would imagine it is challenging to capture meaningful immunological data when the population one is testing is heterogeneous and inclusive of individuals who don't have ME/CFS.

Refine the cohort, i.e., strengthen the inclusion criteria, and maybe the data will clarify a bit. Then, who knows how the immune dice may roll?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
I would imagine it is challenging to capture meaningful immunological data when the population one is testing is heterogeneous and inclusive of individuals who don't have ME/CFS.

Refine the cohort, i.e., strengthen the inclusion criteria, and maybe the data will clarify a bit. Then, who knows how the immune dice may roll?

Actually, I think immunodeficiency should stand out pretty clearly even if the cohort is diluted. Defects in immune function sufficient to be clinically relevant are quite uncommon. If immunodeficiency was a general factor in ME/CFS it ought to stick out like a sore thumb even with fivefold dilution with 'don't have ME/CFS'. It might be hard to pick up if say 5% of ME/CFS was related to immunodeficiency but if that were the case it is still hard to understand why that has not been flagged up by every jobbing clinical immunologist who gets referred everyone with low levels on immune tests. And it might be that the 5% of people who have immunodeficiencies don't actually fit the tighter criteria for ME/CFS.
 

duncan

Senior Member
Messages
2,240
Then maybe some researchers are just looking for - or at - the wrong markers.

We break the mold in many regards. Why should we expect it to be any different on the biomarker side of things, including immune markers?

Not that we don't have them: How many of us, what percentage who have been tested, have low NK levels? Or elevated titers across the board for supposedly latent or inactive viruses and bacteria? Are these not signs of immune deregulation, or, at the least, abnormalities?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Then maybe some researchers are just looking for - or at - the wrong markers.

We break the mold in many regards. Why should we expect it to be any different on the biomarker side of things, including immune markers?

Not that we don't have them: How many of us, what percentage who have been tested, have low NK levels? Or elevated titers across the board for supposedly latent or inactive viruses and bacteria? Are these not signs of immune deregulation, or, at the least, abnormalities?

For me the question is why we are looking for immunodeficiency in the first case, other than because some lab workers have speculated about it?

Finding the biomarkers in ME/CFS is certainly hard but we are talking here about well standardised tests of immune function and I am not aware that these are abnormal in ME/CFS. All I can gather from the research community about the NK results is that a recent attempt to reproduce the results failed. Unfortunately this sort of thing never gets published. And nobody really knows the significance of in vitro NK function tests at this level. If there are raised titres of antibodies to pathogens that would tend to be a sign of immune competence rather than deficiency. Again, I am not aware of replicated evidence that these titres really are different in ME/CFS. If they were consistently high it would be very easy for some junior scientists to churn out papers on it - but I have not seen that. My understanding is that Hornig and Lipkin found pretty little on their big trawl for evidence of viral infection.
 

duncan

Senior Member
Messages
2,240
With all due respect, Jonathan Edwards, it is YOU who are talking about "well standardised tests of immune function". I am looking at other metrics that may have merit; metrics that perhaps deserve further research.

Why look for immune issues? What's that old adage: Where there's smoke, there's fire?