New Rituximab ME/CFS open-label phase II study with rituximab maintenance treatment

[Jonathan Edwards]

Thanks. Yes, I reminder the Bell scale from way back. Of course, the issue is that the illness is not stable,there are somewhat better hours and days and then horrific ones.

I have trouble understanding relapses. Does it mean B cells increase in those dreadful periods. I don't have a scientific background,so please overlook the naive questioning.

If the problem is autoimmune it means that unwanted B cells grow up again with relapse. The total number of B cells tells us nothing because 99.9% of them are ordinary useful ones.

 

[perrier]

If the problem is autoimmune it means that unwanted B cells grow up again with relapse. The total number of B cells tells us nothing because 99.9% of them are ordinary useful ones.

Thanks. So, if 99.9% is needed by the body, what constitutes a surfeit of B Cells? .1%% or is the body overwhelmed by the non stop manufacture of B cells? And this makes the person feel as if he or she is dying.

Do these B cells generate vasoconstriction, which Melle/ Fluge highlight as characteristic?

 

[Jonathan Edwards]

Thanks. So, if 99.9% is needed by the body, what constitutes a surfeit of B Cells? .1%% or is the body overwhelmed by the non stop manufacture of B cells? And this makes the person feel as if he or she is dying.

Do these B cells generate vasoconstriction, which Melle/ Fluge highlight as characteristic?

There is no such thing as a surfeit of B cells really. (Lymphoma is obviously different in that there is a large single clone of malignant cells.) In autoimmunity you have the same number of B cells but some of them are making pathogenic antibodies. It's a bit like having double agents in your intelligence services. You have the same number of staff but some are working against you.

One of the problems of popular ideas of immunology is that they tend to talk in terms of 'balances' or 'too much this' or 'too little that' but immune disease is more complicated than that - like double agents.

If B cells are involved in ME then they are involved because they make antibodies you don't want. What trouble the antibodies cause is anybody's guess, although it could be an effect on blood vessels.

 

[Kati]

There is no such thing as a surfeit of B cells really. (Lymphoma is obviously different in that there is a large single clone of malignant cells.) In autoimmunity you have the same number of B cells but some of them are making pathogenic antibodies. It's a bit like having double agents in your intelligence services. You have the same number of staff but some are working against you.

One of the problems of popular ideas of immunology is that they tend to talk in terms of 'balances' or 'too much this' or 'too little that' but immune disease is more complicated than that - like double agents.

If B cells are involved in ME then they are involved because they make antibodies you don't want. What trouble the antibodies cause is anybody's guess, although it could be an effect on blood vessels.

I like the analogy of double agent. Great way to explain it. Can we involve the CIA to identify the culprit?

 

[Jonathan Edwards]

I like the analogy of double agent. Great way to explain it. Can we involve the CIA to identify the culprit?

They are all double agents aren't they? Or at least sell to the highest bidder agents.

 

[perrier]

There is no such thing as a surfeit of B cells really. (Lymphoma is obviously different in that there is a large single clone of malignant cells.) In autoimmunity you have the same number of B cells but some of them are making pathogenic antibodies. It's a bit like having double agents in your intelligence services. You have the same number of staff but some are working against you.

One of the problems of popular ideas of immunology is that they tend to talk in terms of 'balances' or 'too much this' or 'too little that' but immune disease is more complicated than that - like double agents.

If B cells are involved in ME then they are involved because they make antibodies you don't want. What trouble the antibodies cause is anybody's guess, although it could be an effect on blood vessels.

So, if I understand: by ablating some B cells, with RTX, you have less double agents and thus feel better?

 

[perrier]

To ask further: if the role of B cells is to to produce antibodies, but some B cells are producing pathogenic antibodies, this means there is something really amiss with the functioning of the B cells? Caused by genetic problem?Or by some agent that has caused the B cells to malfunction?
Forgive my naive questions: I'm a heartbroken desperate mother of a very sick daughter.

 

[perrier]

In a telephone conversation with Dr Chia, he told me to think of B cells and T cells like on a see saw balancing, up and down, and he suggested that this balance was upset in this illness.

(Forgive me Dr Chia if I have not presented your point accurately.)

 

[Snow Leopard]

To ask further: if the role of B cells is to to produce antibodies, but some B cells are producing pathogenic antibodies, this means there is something really amiss with the functioning of the B cells? Caused by genetic problem?Or by some agent that has caused the B cells to malfunction?
Forgive my naive questions: I'm a heartbroken desperate mother of a very sick daughter.

In autoimmune disease, most of the B-Cells are behaving normally, or at least 'as expected' to the signals that they are receiving in their immediate environment.

The key factor in autoimmune disease is that a few B-Cells had auto-reactive B-Cell receptors to specific targets. This can occur simply due to 'random' permutations - stochastic factors, but the most important part is that the specificity of binding must be high. See: https://en.wikipedia.org/wiki/V(D)J_recombination
There is some discussion/speculation in the literature that mutations of the genes guiding VDJ recombination or MHC receptors (which present antigens to T Cells) could lead to higher risk of developing autoimmune diseases. but this is a risk factor, rather than a distinct cause and effect relationship.


Anyway, in rare cases these autoreactive B-Cells manage to evade the normal checks to prevent auto-reactivity and ultimately differentiate into antibody producing plasma cells (this itself can happen due to random chance - a few will manage to make it through in spite of everything). https://en.wikipedia.org/wiki/Plasma_cell

Normally this isn't a big deal, because there are so few of them and these cells will soon die anyway. It becomes a problem however when these autoreactive B-Cells and plasma cells themselves interfere with immune signalling and basically set up a feedback loop that makes it favorable for these autoreactive B-Cells to continue to be generated. This is an oversimplification,
@Jonathan Edwards mentions models that have over 50 individual steps, but you get the idea.

 

[Jonathan Edwards]

To ask further: if the role of B cells is to to produce antibodies, but some B cells are producing pathogenic antibodies, this means there is something really amiss with the functioning of the B cells? Caused by genetic problem?Or by some agent that has caused the B cells to malfunction?
Forgive my naive questions: I'm a heartbroken desperate mother of a very sick daughter.

It is quite hard to understand the way it works. Most immunologists do not understand, although that is partly because they want to stick to old ideas I think. There is nothing wrong with the B cells in general. Every B cell makes a different antibody and it chooses its antibody at random. All it needs is for a B cell to make the mistake of choosing an autoantibody that happens to tell the B cell to grow and make more, because it just happens to bind to a receptor it shouldn't bind to or something like that. There need not be any genetic problem, although autoimmunity is more common with certain gene sets. Nothing needs to cause the B cell to malfunction because the malfunction is simply a random event that should be quite harmless and normal but in this case 'crashes the programme'.

If it is of any comfort, the implication of such a mechanism for ME is that there is nothing genetically wrong and there was no exposure to some toxic event or infection that could have been avoided, and certainly no psychological cause. It is simply a matter of bad luck. Moreover, if the bad B cells can be cleared out, as it seems they can for immune thrombocytopenia, then in theory you are back to being completely normal and healthy with no reason to relapse. In reality at present we tend to see relapse in a lot autoimmune diseases after rituximab but we know that we are not clearing out the B cells completely. Better drugs are coming along but it takes time.

 

[BurnA]

Moreover, if the bad B cells can be cleared out, as it seems they can for immune thrombocytopenia, then in theory you are back to being completely normal and healthy with no reason to relapse. In reality at present we tend to see relapse in a lot autoimmune diseases after rituximab but we know that we are not clearing out the B cells completely. Better drugs are coming along but it takes time.

Maybe this has already been discussed, but for the people who relapse, can they continue taking rituximab or what options would they have ?
Do you know what these better drugs are or what stage they are at?
Thanks.

 

[Jonathan Edwards]

Maybe this has already been discussed, but for the people who relapse, can they continue taking rituximab or what options would they have ?
Do you know what these better drugs are or what stage they are at?
Thanks.

Repeated rituximab treatments is standard for those autoimmune diseases that do not switch off completely - like RA. Long term usage is not always possible because of falling immnoglobulin levels but for most patients it seems to be practical.
There are several newer monoclonal antibody drugs with clever handles on to increase efficacy. These are mostly in trials for lymphoma at present but there is every reason to think they will be relevant for autoimmunity. In general they are not licensed yet so not available for off label usage.

 

[jimells]

I like the analogy of double agent. Great way to explain it. Can we involve the CIA to identify the culprit?

That would give a new meaning to the concept of "torturing the data".

 

[BurnA]

I don't doubt it might work, but I wouldn't want to put my money on any one particular mechanism>

Just curious, if the response to Cyclo is much sooner as it appears to be in some patients, and if this therefore implies a different mechanism, is this something you can learn from ? In other words, when you are attempting to validate or dispute your theories is this information useful or considered ? Or does it just suggest an alternative totally independant mechanism and maybe even a subgroup ?

 

[BurnA]

Kogelnik is still offering RTX treatment. I guess he wouldn't do that if the results were very poor.
I am sure that he said somewhere that he saw the same results as the Norwegians.. I just can't remember where and when.

Since the German pilot study and Kogelnik's experiences with RTX isn't published, it is impossible to confirm or validate what they say. We have two real studies from Norway now that shows a major effect on 2/3 of people treated. I am sure the phase 3 result will be somewhat lower, but if 50%+ responds to the drug it is still fantastic.

One interesting anecdote: I know about a patient in the new cyclo trial which was a non responder to RTX. That patient has now responded greatly to cyclophosphamide.
Stuff like that gives me hope! Maybe there is a cure for all of us.

Yes, having watched the DVD of the investinme conference Olav Mella says he "expects ...a 50% clinical response" with <20% response in placebo.

Do you mind if i ask how you know about the cyclo responder who didnt respond to RTX ? This would indeed be fantastic news, but dont want to get too excited until its validated....

 

[Jonathan Edwards]

Just curious, if the response to Cyclo is much sooner as it appears to be in some patients, and if this therefore implies a different mechanism, is this something you can learn from ? In other words, when you are attempting to validate or dispute your theories is this information useful or considered ? Or does it just suggest an alternative totally independant mechanism and maybe even a subgroup ?

One would probably expect cyclo to work quickly however it worked so I am not sure one can drw any further conclusions. There are too many unknowns.

 

[BurnA]

One would probably expect cyclo to work quickly however it worked so I am not sure one can drw any further conclusions. There are too many unknowns.

Seems like there are too many unknowns everywhere around here !

 

[deleder2k]

@BurnA, the patients doctor told me about the significant response. It is only one patient though. We need to wait and see how other RTX non responders are doing.

 

[DanME]

It is quite hard to understand the way it works. Most immunologists do not understand, although that is partly because they want to stick to old ideas I think. There is nothing wrong with the B cells in general. Every B cell makes a different antibody and it chooses its antibody at random. All it needs is for a B cell to make the mistake of choosing an autoantibody that happens to tell the B cell to grow and make more, because it just happens to bind to a receptor it shouldn't bind to or something like that. There need not be any genetic problem, although autoimmunity is more common with certain gene sets. Nothing needs to cause the B cell to malfunction because the malfunction is simply a random event that should be quite harmless and normal but in this case 'crashes the programme'.

If it is of any comfort, the implication of such a mechanism for ME is that there is nothing genetically wrong and there was no exposure to some toxic event or infection that could have been avoided, and certainly no psychological cause. It is simply a matter of bad luck. Moreover, if the bad B cells can be cleared out, as it seems they can for immune thrombocytopenia, then in theory you are back to being completely normal and healthy with no reason to relapse. In reality at present we tend to see relapse in a lot autoimmune diseases after rituximab but we know that we are not clearing out the B cells completely. Better drugs are coming along but it takes time.

I had some immunology classes back in med school and there are still several things, I don't really get. Maybe you can help, Prof. Edwards?

Our Prof told us, that autoimmune diseases are often triggered by infections, psychological traumatic events, chronic stress or surgeries. Basically by anything, which stresses the immune system to a large enough amount. He mentioned, that the malfunctioning T and B cells are already there, but a random stressful event and the following immune and cytokine turmoil activates them. Is that just an nice theory, or do we have actual empirical data for this claim?

Also, the molecular mimicry theory was my Prof's favourite, but from what I got out of your posts is, that there isn't actually much evidence for molecular mimicry and much more evidence for random B or T cell events. Bad luck as you call it. Like in cancer (if I remember correctly 2/3 of all cancer mutations are also just bad luck). Is that correct?

If you eradicate almost any B cells, why isn't the body prone to more nasty opportunistic infections? I know, B cells aren't the only defence of the body, but shouldn't the loss of B cells be a larger problem for the immune system? The good plasma cells tend to live longer and continue to produce antibodies against old pathogens, right? But what about new pathogens? With no B cells, new plasma cells cannot develop against new pathogens and new antibodies cannot tag them. So is the rest of the immune defence enough to keep them in check?

 

[BurnA]

I had some immunology classes back in med school and there are still several things, I don't really get. Maybe you can help, Prof. Edwards?

Our Prof told us, that autoimmune diseases are often triggered by infections, psychological traumatic events, chronic stress or surgeries. Basically by anything, which stresses the immune system to a large enough amount. He mentioned, that the malfunctioning T and B cells are already there, but a random stressful event and the following immune and cytokine turmoil activates them. Is that just an nice theory, or do we have actual empirical data for this claim?

Also, the molecular mimicry theory was my Prof's favourite, but from what I got out of your posts is, that there isn't actually much evidence for molecular mimicry and much more evidence for random B or T cell events. Bad luck as you call it. Like in cancer (if I remember correctly 2/3 of all cancer mutations are also just bad luck). Is that correct?

If you eradicate almost any B cells, why isn't the body prone to more nasty opportunistic infections? I know, B cells aren't the only defence of the body, but shouldn't the loss of B cells be a larger problem for the immune system? The good plasma cells tend to live longer and continue to produce antibodies against old pathogens, right? But what about new pathogens? With no B cells, new plasma cells cannot develop against new pathogens and new antibodies cannot tag them. So is the rest of the immune defence enough to keep them in check?

I am also interested to know this....the following article states :
"Scientists at Queensland’s Griffith University have discovered that critical cell receptors that help regulate human cells can be damaged by an infection or severe physical or psychological trauma. - See more at: http://www.thecitizen.org.au/news/n...chronic-fatigue-syndrome#sthash.gyECJSAi.dpuf

Any thoughts ?