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What might remissions mean?

Jonathan Edwards

"Gibberish"
Messages
5,256
I understand that Rituximab is not being touted as a cure. However, I'm hoping you can tell me why, after undertaking the rtx protocol, one wouldn't assume that the body will rapidly return to a state of producing "bad" b-cells in response to a particular antigen thereby resulting in a relatively quick relapse. If you have already answered this question in a previous post(s), please feel free to point me in that direction.

Antibody production is a chain reaction. A B cell makes antibody to an antigen X if it comes into contact with antigen X attached to an antibody. (It is much more complicated but this is an important part of the signal system.) You might say that you could never start an immune response then. But that is probably why mothers pass antibody to babies through the placenta and milk. You start off with some antibody. And you also constantly make small amounts of antibody to anything that is not self and does not get vetoed. So there is a lttle bit of antibody to prime making more.

For self antigens no antibody should be made at all. But if you by chance make an anti-self antibody that has some extra signalling property that it shouldn't then once you have made that you are more likely to make more and get a chain reaction going. (In the main autoimmune diseases we know about there are extra signalling options fairly easily identifiable in most cases.) So the idea with using rituximab was not just to get rid of the rogue B cells but hopefully to wash all their antibodies out of the system so that there was nothing to restart a chain reaction. Unfortunately the antibodies are mostly made by plasma cells, which are not killed by rituximab directly. When I first tried rituximab I did not really know what to expect but now that we have experience it looks as if one probably needs to keep the system free of new B cells for maybe five years to have a reasonable chance of breaking the loop completely - may be ten. But that is a bit long. So at the moment there is a big debate about how long to keep B cells away for. Fluge and Mella have taken a very intelligent approach of keeping them away for two years rather than just six months. For a condition that looks as if it might flip out into normality in some cases that looks a good place to start. The other approach would be to try to clear out plasma cells too but that has some other problems.

More work needs to be done but at least for the major autoimmune diseases I think we have a good idea what it is we want to achieve - not so good on how to do it yet.[/user]
 

Jonathan Edwards

"Gibberish"
Messages
5,256
That is interesting. Any idea what the foreign antigens are?

For many of the autoimmune rheumatic diseases we have a reasonable idea what they are - it is in the review article referred to. For ME we have no clue but it could easily be something totally non-specific - even degraded self material. There is plenty of non-specific non-self material floating about.
 

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,231
Location
Cornwall, UK
I think the idea that gut flora regulae our immune response is hype to be honest. It comes mostly from experiments with mice put in environments with no bacteria.

I agree that animal-derived evidence like that to which you refer is not worth bothering with (I tend to avoid all animal-derived findings as they are so poorly predictive), but I think I have come across human-based evidence too. Trouble is - I can't remember where! Don't have time to search right now.
 

lansbergen

Senior Member
Messages
2,512
For many of the autoimmune rheumatic diseases we have a reasonable idea what they are - it is in the review article referred to. For ME we have no clue but it could easily be something totally non-specific - even degraded self material. There is plenty of non-specific non-self material floating about.

I am interested in this because there was some talk B cells spread the pathogen I suspect through the body 'It was thought without Bcells it should be prevented but later it showed it could also spread without Bcells.
 

deleder2k

Senior Member
Messages
1,129
@Jonathan Edwards, do you think infusions of 500mg every 3 months is a wise choice in ME? If you had to pay out of your own pocket for off label treatment would you consider stretching this to 4 or 5 month intervals?

I've noticed that in their open phase 2 study they gave maintenance treatment after 3, 6, 9 and 15 months. In the new study they have swapped 15 out with 12. In the blinded phase 2 study the last maintenance dose was given at 12 months follow up.

Can we speculate whether it would be beneficial to delay infusions until a patient is experiencing relapse? Or wait 6 months rather than 3 after a year of infusions? That would be more cost effective, but since Rtx works quite slow it could lead to a total relapse, couldn't it?

I know the discussion is premature, but it is nevertheless interesting. At least for patients being treated in San Francisco. Infusions there aren't exactly cheap.
 

trails

Senior Member
Messages
114
Location
New Hampshire
Antibody production is a chain reaction. A B cell makes antibody to an antigen X if it comes into contact with antigen X attached to an antibody. (It is much more complicated but this is an important part of the signal system.) You might say that you could never start an immune response then. But that is probably why mothers pass antibody to babies through the placenta and milk. You start off with some antibody. And you also constantly make small amounts of antibody to anything that is not self and does not get vetoed. So there is a lttle bit of antibody to prime making more.

For self antigens no antibody should be made at all. But if you by chance make an anti-self antibody that has some extra signalling property that it shouldn't then once you have made that you are more likely to make more and get a chain reaction going. (In the main autoimmune diseases we know about there are extra signalling options fairly easily identifiable in most cases.) So the idea with using rituximab was not just to get rid of the rogue B cells but hopefully to wash all their antibodies out of the system so that there was nothing to restart a chain reaction. Unfortunately the antibodies are mostly made by plasma cells, which are not killed by rituximab directly. When I first tried rituximab I did not really know what to expect but now that we have experience it looks as if one probably needs to keep the system free of new B cells for maybe five years to have a reasonable chance of breaking the loop completely - may be ten. But that is a bit long. So at the moment there is a big debate about how long to keep B cells away for. Fluge and Mella have taken a very intelligent approach of keeping them away for two years rather than just six months. For a condition that looks as if it might flip out into normality in some cases that looks a good place to start. The other approach would be to try to clear out plasma cells too but that has some other problems.

More work needs to be done but at least for the major autoimmune diseases I think we have a good idea what it is we want to achieve - not so good on how to do it yet.[/user]

@Jonathan Edwards - thank you very much for this answer to my question. You adressed my question perfectly!
 

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,231
Location
Cornwall, UK
I'm trying to find studies on humans that suggest a causal role for gut microbiota in autoimmunity.

Here are a couple:

Bacteroides dorei dominates gut microbiome prior to autoimmunity in Finnish children at high risk for type 1 diabetes

Gut microbiome and the risk factors in central nervous system autoimmunity - the link doesn't seem to have worked here so I will paste it now: http://www.ncbi.nlm.nih.gov/pubmed/25286403

I think this is still on-topic, as it does suggest a way that remission could be brought about - correction of dysbiosis - and how re-emergent dysbiosis could lead to relapse - at least for some of us.


Perhaps we have a genetic predisposition which is then 'fulfilled' by dysbiosis or some other trigger that makes us susceptible to dysbiosis causing autoimmunity.

I have read at least one post where someone has said that their remission included the ability to eat foods that were previously not tolerated.

Hope that makes sense - brain a bit fuzzy at the moment.
 
Last edited:

Marky90

Science breeds knowledge, opinion breeds ignorance
Messages
1,253
I'm trying to find studies on humans that suggest a causal role for gut microbiota in autoimmunity.

Here are a couple:

Bacteroides dorei dominates gut microbiome prior to autoimmunity in Finnish children at high risk for type 1 diabetes

Gut microbiome and the risk factors in central nervous system autoimmunity - the link doesn't seem to have worked here so I will paste it now: http://www.ncbi.nlm.nih.gov/pubmed/25286403

I think this is still on-topic, as it does suggest a way that remission could be brought about - correction of dysbiosis - and how re-emergent dysbiosis could lead to relapse - at least for some of us.


Perhaps we have a genetic predisposition which is then 'fulfilled' by dysbiosis or some other trigger that makes us susceptible to dysbiosis causing autoimmunity.

I have read at least one post where someone has said that their remission included the ability to eat foods that were previously not tolerated.

Hope that makes sense - brain a bit fuzzy at the moment.

A subset does seem to get better after eating e.g. paleo, but how that potentially has anything to do with autoimmunity seems like a really complex investigation.. :)
 

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,231
Location
Cornwall, UK

Jonathan Edwards

"Gibberish"
Messages
5,256
@Jonathan Edwards, do you think infusions of 500mg every 3 months is a wise choice in ME? If you had to pay out of your own pocket for off label treatment would you consider stretching this to 4 or 5 month intervals?

I've noticed that in their open phase 2 study they gave maintenance treatment after 3, 6, 9 and 15 months. In the new study they have swapped 15 out with 12. In the blinded phase 2 study the last maintenance dose was given at 12 months follow up.

Can we speculate whether it would be beneficial to delay infusions until a patient is experiencing relapse? Or wait 6 months rather than 3 after a year of infusions? That would be more cost effective, but since Rtx works quite slow it could lead to a total relapse, couldn't it?

I know the discussion is premature, but it is nevertheless interesting. At least for patients being treated in San Francisco. Infusions there aren't exactly cheap.

I don't think we know the answers at present. If I was paying out of my pocket I would probably leave it to Dr Fluge to decide!
 

Jonathan Edwards

"Gibberish"
Messages
5,256
I'm trying to find studies on humans that suggest a causal role for gut microbiota in autoimmunity.

Here are a couple:

Bacteroides dorei dominates gut microbiome prior to autoimmunity in Finnish children at high risk for type 1 diabetes

Gut microbiome and the risk factors in central nervous system autoimmunity - the link doesn't seem to have worked here so I will paste it now: http://www.ncbi.nlm.nih.gov/pubmed/25286403

I think this is still on-topic, as it does suggest a way that remission could be brought about - correction of dysbiosis - and how re-emergent dysbiosis could lead to relapse - at least for some of us.


Perhaps we have a genetic predisposition which is then 'fulfilled' by dysbiosis or some other trigger that makes us susceptible to dysbiosis causing autoimmunity.

I have read at least one post where someone has said that their remission included the ability to eat foods that were previously not tolerated.

Hope that makes sense - brain a bit fuzzy at the moment.

Looks a bit like clutching at straws to me. There is no indication that the bacteria actually caused anything in the first paper - just correlated. With all these wandbagon groups studying microbiota there are bound to be papers claiming to have found things - that is the way they will justify the next grant. If this is the best people can do so far there does not seem to be much of a smoking gun to my mind.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
There have been lots of studies of starving people with RA or feeding them elemental diets of glucose and amino acids and suchlike - which is about as much exclusion as you can get - and not much happened. People tend to feel better to begin with but the disease itself does not seem to change.
 

Marky90

Science breeds knowledge, opinion breeds ignorance
Messages
1,253

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,231
Location
Cornwall, UK
But how could it lead to autoimmunity? (not expecting a scientific answer, I just havent seen this explained before when people hypophesise around the role of the microbiome in the gut in ME)

This thread talks about it.

As I have learned more, I have become a little more sceptical about some of it. When one has been unable to achieve improvement for many years, one can be too willing to clutch at straws.

But on the other hand, adopting a leaky gut diet and supplements has provided significant improvement, as I report both in that thread and in my profile. Nothing else has provided such improvement. But, to return to the subject of this thread, the near-remission I had initially has not persisted, although several symptoms are still quite consistently better than before I started the intervention, and I do get some good periods - hours or days - when energy is also good.

So I am glad that I clutched at that straw. I can't be sure how it works, but it does!

Now I just want to make it permanent.

Can @Jonathan Edwards help us by explaining how we develop resistance to some treatments? It often seems as though the body just doesn't want to be well, and reverts to a pathological state after an initial improvement. This appears to be common in cancer too. I have a friend with chronic lymphocytic leukaemia (CLL), who previously responded to chemotherapy but then became resistant (or the leukaemia progressed?), then moved on to biologicals, including rituximab, then ibrutinib, but these too stopped working and she is on yet another trial of a new biological drug.

I understand antibiotic resistance, but am more hazy about other kinds.
 

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,231
Location
Cornwall, UK
There have been lots of studies of starving people with RA or feeding them elemental diets of glucose and amino acids and suchlike - which is about as much exclusion as you can get - and not much happened. People tend to feel better to begin with but the disease itself does not seem to change.

Glucose seems a bad idea to me, if RA patients are anything like us (and even if they're not!). My father had RA and Type 2 diabetes at the same time, and many pwme find that they are a lot better if they drastically reduce sugar intake. This may be at least partly due to adverse effects of sugars on the gut microbiome. Some of us seem prone to excess acidity in the lower bowel, which I think sugar can cause.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Can @Jonathan Edwards help us by explaining how we develop resistance to some treatments? It often seems as though the body just doesn't want to be well, and reverts to a pathological state after an initial improvement. This appears to be common in cancer too. I have a friend with chronic lymphocytic leukaemia (CLL), who previously responded to chemotherapy but then became resistant (or the leukaemia progressed?), then moved on to biologicals, including rituximab, then ibrutinib, but these too stopped working and she is on yet another trial of a new biological drug.

I understand antibiotic resistance, but am more hazy about other kinds.

There are several reasons why treatments lose their effect. Common ones involve adjusting of receptor sensitivity or hormonal balance - like loss of effect of airway dilators in asthma or steroids for inflammation. But I think what you are interested in here relates to diseases where there is a 'survival of the fittest' process going on in either host cells or microbes. For antibiotic resistance the few resistant microbes survive and take over. For cancer the few cancer cells that have mutated a bit more and so similarly become resistant to control take over. In autoimmunity B cells that are resistant to particular therapies may take over. however, fortunately there is not much evidence for rituximab resistance. The annoying thing is that there are some resistant cells right from the start.

When it comes to benefit from treatments in ME there may be all sorts of reasons of these different types I guess.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
What about "leaky gut" ?
Would be curious as to your thoughts on this sort of thing:
http://www.ncbi.nlm.nih.gov/pubmed/22109896

Not much. I think the evidence for gut barrier function having anything to do with human autoimmunity is close to zero. Unfortunately this sort of speculative idea that would once be had over a glass of beer is now being used to make money by review journals and they don't mind how little evidence there is.

As far as I know the gut barrier has nothing to do with self tolerance at all.