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Rituximab (I'm from Holland)

Thinktank

Senior Member
Messages
1,640
Location
Europe
If I remember correctly, the theory was that once you kill off the B cells with Rituximab, you still have high levels of various circulating auto-antibodies or whatever substance in the blood that is wreaking havoc with the mitochondria and immune system. Once you get rid of the B cells, the manufacturing of these auto-antibodies stops, but it will take a while before all the old auto-antibodies will clear off. Hence the delay.

Would plasmapheresis after rtx treatment be a viable option to reduce lingering antibodies and cytokines?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
To Jonathan Edwards...

Regarding this statement...

"Once one has started [tr]eating someone with rituximab there is no way of putting the clock back. The immune system is altered and permanently so, although in most cases it settles back to normal between treatments."

OK, but isn't this alteration desirable? Also, how is this alteration permanent if the B cells come back? And also, trying not to be cynical, or underestimate the need for specific expertise or patient monitoring, etc., but there are likely many treatments administered by many physicians, who don't understand the mechanisms behind the medications/treatments that they prescribe...they simply prescribe/treat based on the fact that it works.....

Thank you for your contribution to this forum.

No, I am afraid people simply have no idea how complicated this is.

The memory B cells that you accumulate throughout a lifetime somehow manage to ensure that you are protected against all the microbes you were immunised against as a child and also provide a rapid response to any new microbes without also producing autoantibodies. We have no idea exactly how a balanced repertoire is achieved. When we give rituximab we destroy B cells indiscriminately. It is remarkable that it does not seem to lead to much in the way of infection risk. But there is every reason to think that at least in a proportion of people we will be removing useful B cells that one day will be needed. For RA we take that risk because there are major benefits but we do not take the risk lightly. A small number of patients after one course of rituximab never seen to get B cells back at all - after ten years. They are well but we have no idea what the future holds. A small number of patients have a crash in antibody levels - down to less than 10% of normal, and need regular replacement.

So the alteration in B cells is desirable if we are sure there are autoantibodies that will go away. If as in scleroderma the autoantibodies do not budge then the effect is generally undesirable - just negative. If we do not know if there are any autoantibodies, as in ME the effect may be just negative.

And the bit about doctors often not understanding completely misses the point. For nearly all drugs doctors have a reasonable idea what the drug is supposed to do and why you either need to give it just for a week like an antibiotic or for years like insulin. Even the patient normally knows enough to understand why they take anti-hypertensives, hormones, cancer drugs, vitamins etc etc. But the mechanism of action of rituximab in terms of what it is doing to the B cell system is not understood by the vast majority of doctors using it for autoimmunity. Doctors understand why they use it in B cell cancer but not in autoimmunity. That is because immunology is complicated and most rheumatologists, despite dealing with immune diseases, are too lazy to learn enough immunology to understand it. They often think they do but really have no idea. In fact it only makes sense to use rituximab in autoimmunity if your working hypothesis about autoimmunity is the one I published in 1999. Most doctors have either not heard of that or think they know better and believe in something else - and then use rituximab despite it making no sense in terms of their theory.

So in short the chances of a doctor offering rituximab for a condition where autoimmunity is speculated, like ME, knowing what they are doing is close to zero. Fluge and Mella are exceptions because they have read the relevant literature and we have discussed all their findings in comparison with what we found in RA. They are also smart scientists.

It's bit like a comparison between removing a mole and open heart surgery. Most drugs are like removing a mole. Any doctor can do that. Using rituximab isn't.
 

IreneF

Senior Member
Messages
1,552
Location
San Francisco
I
No, I am afraid people simply have no idea how complicated this is.

The memory B cells that you accumulate throughout a lifetime somehow manage to ensure that you are protected against all the microbes you were immunised against as a child and also provide a rapid response to any new microbes without also producing autoantibodies. We have no idea exactly how a balanced repertoire is achieved. When we give rituximab we destroy B cells indiscriminately. It is remarkable that it does not seem to lead to much in the way of infection risk. But there is every reason to think that at least in a proportion of people we will be removing useful B cells that one day will be needed. For RA we take that risk because there are major benefits but we do not take the risk lightly. A small number of patients after one course of rituximab never seen to get B cells back at all - after ten years. They are well but we have no idea what the future holds. A small number of patients have a crash in antibody levels - down to less than 10% of normal, and need regular replacement.

So the alteration in B cells is desirable if we are sure there are autoantibodies that will go away. If as in scleroderma the autoantibodies do not budge then the effect is generally undesirable - just negative. If we do not know if there are any autoantibodies, as in ME the effect may be just negative.

And the bit about doctors often not understanding completely misses the point. For nearly all drugs doctors have a reasonable idea what the drug is supposed to do and why you either need to give it just for a week like an antibiotic or for years like insulin. Even the patient normally knows enough to understand why they take anti-hypertensives, hormones, cancer drugs, vitamins etc etc. But the mechanism of action of rituximab in terms of what it is doing to the B cell system is not understood by the vast majority of doctors using it for autoimmunity. Doctors understand why they use it in B cell cancer but not in autoimmunity. That is because immunology is complicated and most rheumatologists, despite dealing with immune diseases, are too lazy to learn enough immunology to understand it. They often think they do but really have no idea. In fact it only makes sense to use rituximab in autoimmunity if your working hypothesis about autoimmunity is the one I published in 1999. Most doctors have either not heard of that or think they know better and believe in something else - and then use rituximab despite it making no sense in terms of their theory.

So in short the chances of a doctor offering rituximab for a condition where autoimmunity is speculated, like ME, knowing what they are doing is close to zero. Fluge and Mella are exceptions because they have read the relevant literature and we have discussed all their findings in comparison with what we found in RA. They are also smart scientists.

It's bit like a comparison between removing a mole and open heart surgery. Most drugs are like removing a mole. Any doctor can do that. Using rituximab isn't.
When I had rtx I felt that I had nothing to lose. I was willing to take risks. It didn't do me much good, but it doesn't seem to have done any harm.
 

frederic83

Senior Member
Messages
296
Location
France
Once you get rid of the B cells, the manufacturing of these auto-antibodies stops, but it will take a while before all the old auto-antibodies will clear off. Hence the delay.

Thanks, Fluge and Mella discussed it in the conclusion here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2711959/

I was taking a look at @Jonathan Edwards ' publication "Efficacy of B-Cell–Targeted Therapy with Rituximab in Patients with Rheumatoid Arthritis" and I don't understand why the CD19+ B cells are increasing during the first 2 weeks, in the methotrexate only group, figure 3.A. Shouldn't the number be decreasing, or constant, at least ?
 
Last edited:

Jonathan Edwards

"Gibberish"
Messages
5,256

Thanks, Fluge and Mella discussed it in the conclusion here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2711959/

I was taking a look at @Jonathan Edwards ' publication "Efficacy of B-Cell–Targeted Therapy with Rituximab in Patients with Rheumatoid Arthritis" and I don't understand why the CD19+ B cells are increasing during the first 2 weeks, in the methotrexate only group, figure 3.A. Shouldn't the number be decreasing, or constant, at least ?

I don't think that small change means anything.
 

greeneagledown

Senior Member
Messages
213
A small number of patients after one course of rituximab never seen to get B cells back at all - after ten years. They are well but we have no idea what the future holds.

Do you know roughly what percentage of Rituxan-treated patients never get back to a normal B-cell population, even after several years? Are we talking less than 1%?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Did you ever speculate as to why this happens?

Yes. The B cell niche in the bone marrow competes with a plasma cell niche. If pro-B cells are wiped out for a period of months the nurse cells that future B cell development may die off. When B cells come back there may be nowhere for them to grow. There are other possibilities but this seemed the most likely. But the longest term B cell aplasia I saw was in a patient with lupus and in lupus the bone marrow is disordered i a more complex way. It also is possible that failure of regeneration of B cells is itself due to an autoimmune problem, although it would be hard to work out just how that worked.
 

Persimmon

Senior Member
Messages
135
A small number of patients after one course of rituximab never seen to get B cells back at all - after ten years. They are well but we have no idea what the future holds. A small number of patients have a crash in antibody levels - down to less than 10% of normal, and need regular replacement.

@Jonathan Edwards, do you know roughly what percentage of Rituxan-treated patients have a crash in antibody levels?

Also, over what sort of time period do these patients need regular replacement? Are we talking 1-2 years; 5-10 years; indefinitely?

Also, where B cells don't return or there is a crash in antibody levels, do you think these side effects mostly occur in patients who have some complicating autoimmune problem (such as the disordering of bone marrow in lupus)?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
@Jonathan Edwards, do you know roughly what percentage of Rituxan-treated patients have a crash in antibody levels?

Also, over what sort of time period do these patients need regular replacement? Are we talking 1-2 years; 5-10 years; indefinitely?

Also, where B cells don't return or there is a crash in antibody levels, do you think these side effects mostly occur in patients who have some complicating autoimmune problem (such as the disordering of bone marrow in lupus)?

I cannot give precise figures on any of these things.The problems are uncommon but not trivial. Problems are definitely more common in lupus patients.
 

ebethc

Senior Member
Messages
1,901
No, I am afraid people simply have no idea how complicated this is.

The memory B cells that you accumulate throughout a lifetime somehow manage to ensure that you are protected against all the microbes you were immunised against as a child and also provide a rapid response to any new microbes without also producing autoantibodies.

So, after RTX, do you have to be re-innoculated w all the childhood vaccines? (MMR, polio, DTaP, etc.)
 

IreneF

Senior Member
Messages
1,552
Location
San Francisco
So, after RTX, do you have to be re-innoculated w all the childhood vaccines? (MMR, polio, DTaP, etc.)
Under normal conditions you are still making B cells after treatment with rituximab. If you weren't making any I don't think immunizations would do you any good, because you couldn't make antibodies.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
So, after RTX, do you have to be re-innoculated w all the childhood vaccines? (MMR, polio, DTaP, etc.)

Nobody really knows because exposure to these viruses is very low in most communities. Physicians who use rituximab tend to re-inoculate for the ones that normally need boosters like tetanus. T cell responses to others may be good enough to prevent clinical infection. We do not have enough information yet.
 

ebethc

Senior Member
Messages
1,901
Nobody really knows because exposure to these viruses is very low in most communities. Physicians who use rituximab tend to re-inoculate for the ones that normally need boosters like tetanus. T cell responses to others may be good enough to prevent clinical infection. We do not have enough information yet.

How long does a CFS remission last after tx w RTX? do we know?