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Hypogammaglobulinaemia after rituximab treatment—incidence and outcomes

Jonathan Edwards

"Gibberish"
Messages
5,256
Prof. Edwards, earlier in the thread you said that the reason that IVIG is used is not to replenish IgG levels, but to replace the patient's IgG with a healthy person's IgG. I don't fully understand what you mean by this. IVIG was used in those Ritux patients with Hypogammaglobulinaemia - this would seem to be replenishing, since the aim is to get the patient's IgG levels to where they were before they were treated.

I also find it difficult to understand how diminished IgM and IgA levels are not important. I can sort of see why IgM might not be important, if the body is still able to produce IgM in response to a new infection (the question then is whether the B-cell depletion would significantly reduce this), but surely IgA is important, since this is the major immunoglobulin in the gut, and diminished levels would have an immediate impact on the immune system's regulation of the gut, wouldn't they?

IVIG is given for ME as a primary treatment, presumably tried because IVIG seems to help certain autoimmune conditions like immune thrombocytopenia and dermatomyositis. Nobody knows the mechanism in any of the autoimmune diseases it has been used for and nobody really knows if it works much, except perhaps for immune thrombocytopenia. Since the patients given IVIG in this context have normal Ig levels then the treatment is not a replenishing one. It seems that it has to be something to do with other people's Ig being better for the patient than their own - or maybe mopping up the patient's bad Ig. It will not depress Ig production much because the feedback mechanism does not seem to be through Ig itself (again nobody really understands this).

After rituximab the reason for giving IVIG is completely different. It is not a treatment for the ME, but simply a way of keeping up antibody immunity to common infections. It is not a matter of getting back to what it was before so much as getting up to a baseline immune level - about 6gm/L or so.

All that one can say about IgA and IgM levels is that they do not seem to matter much in practice. Genetically determined IgA deficiency is very common in the general population and does not seem to matter on its own. The reason for thinking that low IgM does not matter much is that it often falls after rituximab but without any associated problems.

It might seem as if these antibodies are terribly important to immunity and health but it is worth remembering that there are reasons to think this is too simple. When you meet an potentially serious infection in almost all cases you will fight off the infection within two weeks - or at least get it under control. Antibody production has hardly started by then. So making new antibodies probably has rather little to do with fighting off infections in the normal situation. In fact people with no antibodies (Bruton's kinase deficiency or agammaglobulinemia) manage reasonably well a lot of the time. Eventually they run into chronic infection problems but that may have quite a bit to do with not having antibodies to help antigen presentation to T cells (i.e. presentation by B cells).

One way of looking at antibodies is that they are really mostly for newborn babies, for priming responses by other cells and for pre-emptively knocking out infections a second time around. Newborn babies need antibody to prime their systems so that they can develop T cell immunity to all the common pathogens. They have to get it from mother through the placenta. Once things are primed you can run pretty well on macrophages and T cells and some old stock antibody you have from long lived plasma cells.

Things are clearly not quite as simple as that because there probably is an increased risk of infection if you develop secondary hypogammaglobulinemia after rituximab. However, the vast proportion of problems occur in cases where there are other reasons for low resistance, like lymphoma and multiple chemotherapy.
 

msf

Senior Member
Messages
3,650
Thanks for the explanation, Prof. Edwards, it was very interesting as usual - I had no idea some people managed to live without any antibodies! I guess it's not so surprising then that people seem to do okay after Ritux has depleted their antibody levels.
 

msf

Senior Member
Messages
3,650
https://en.wikipedia.org/wiki/X-linked_agammaglobulinemia

Wow, they need IVIG every 3-4 weeks for their entire lives! That must be one of the most expensive treatment regimens around.

It's also interesting to note that they are particularly susceptible to Enteroviruses and vaccines, both of which have been implicated in ME.

Has anyone done any research on the rate of hypogammaglobulinaemia in ME patients?

And they are immune to EBV because they don't have any B cells! If you found one with ME you could put the EBV causes ME hypothesis to rest!
 

Marky90

Science breeds knowledge, opinion breeds ignorance
Messages
1,253
Thanks Jonathan, awesome to receive your insight on these matters!
 

Marky90

Science breeds knowledge, opinion breeds ignorance
Messages
1,253
That is a very complicated question and the answers are not fully known. Most B cells probably die within days through lack of antigen to meet up with. Memory B cells may last for years in follicles but it is not clear exactly how long. Successful B cells turn into more B cells, which may undergo further mutation, and into plasma cells, which may live for at least ten years.

Do you know if any drug is in the works which can target these plasma cells specifically, in the manner rituximab targets b-cells?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Do you know if any drug is in the works which can target these plasma cells specifically, in the manner rituximab targets b-cells?

There are similar antibody drugs that target plasma cells that are being investigated but it has taken twenty years to get near anything promising. Plasma cells are much more difficult to persuade to die than B cells, but once the right drug is available it should be possible to remove them. There is still the problem that we cannot so far target bad plasma cells without targeting good plasma cells as well. But in time that may prove feasible.
 
Messages
2,087
We have very detailed information about this. IgG levels tend to go down only a small amount after a dose of rituximab. If B cells are allowed to come back then IgG comes back to normal. If further doses of rituximab are given the IgG goes down about the same amount each time (not usually to make any difference) but it may go down a bit more as time goes by. If rituximab doses are repeated without allowing B cells to return - which is one way of using it and what the Norwegians have done over a 18 month to 2 year period then IgG will tend to go down more each dose. Even so, for most people it remains within the normal range but maybe 10-20% of people may have to give their B cells a rest after three or more doses.

You say that you are due to get six doses of rituxmab and that puzzles me because I cannot see any particular reason why anyone should recommend six doses - unless this is a pair of induction infusions and maintenance doses at 3-4 month intervals after that to prevent B cell return. More often than that is probably a waste of time since there are no B cells to target.

Has this paper been discussed - seems to imply 39% of rituximab patients had low levels of immunoglobulin G.

Incidence of Hypogammaglobulinemia in Patients Receiving Rituximab and the Use of Intravenous Immunoglobulin for Recurrent Infections
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4035033/

You say if B cells are allowed to come back then IgG comes back to Normal. But isnt the idea of the dose in the norwegian trial to keep the B cells away for as long as possible ? Or have i misunderstood - if so could you clarify.?
You mention in another thread that B cells can be kept away for 4-5 years - would this mean continued RTX which would lead ( inevitably ) to hypogammaglobulinemia ?
 
Last edited:

Jonathan Edwards

"Gibberish"
Messages
5,256
Has this paper been discussed - seems to imply 39% of rituximab patients had low levels of immunoglobulin G.

Incidence of Hypogammaglobulinemia in Patients Receiving Rituximab and the Use of Intravenous Immunoglobulin for Recurrent Infections
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4035033/

You say if B cells are allowed to come back then IgG comes back to Normal. But isnt the idea of the dose in the norwegian trial to keep the B cells away for as long as possible ? Or have i misunderstood - if so could you clarify.?
You mention in another thread that B cells can be kept away for 4-5 years - would this mean continued RTX which would lead ( inevitably ) to hypogammaglobulinemia ?

That paper relates to cancer usage as far as I can see - which is a quite different situation. There are all sorts of other reasons for hypogammaglobulinaemia for lymphoma cases - bone marrow infiltration and other chemotherapy etc.. It is also a rather doubtfully designed retrospective study. We have prospectively studied several hundred patients with autoimmune disease and hypogammaglobulinaemia only occurs in a very small proportion. When I retired we had only needed to use IVIG in two or three patients out of 200.

The idea of the Norwegian trial is to keep B cells away continuously for about 18 months. In most cases IgG will not fall significantly as a result. And if IgG does go down it is always possible to delay a maintenance dose. The ideal management for each patient can involve a degree of compromise on timing of treatments but for most repeated dosing with continuously low B cells is not a problem for at least two years. In some patients a single dose of rituximab will produce 5 years B cell depletion, but this is very uncommon. In those cases we did not need to give Ig as levels did not fall. (A potential disadvantage of the Norwegian protocol is that some patients will get more frequent rituximab than they need, but in reality there is a good case for doing things the way they are doing it in my opinion.)
 
Messages
2,087
The idea of the Norwegian trial is to keep B cells away continuously for about 18 months. In most cases IgG will not fall significantly as a result. And if IgG does go down it is always possible to delay a maintenance dose. The ideal management for each patient can involve a degree of compromise on timing of treatments but for most repeated dosing with continuously low B cells is not a problem for at least two years. In some patients a single dose of rituximab will produce 5 years B cell depletion, but this is very uncommon. In those cases we did not need to give Ig as levels did not fall. (A potential disadvantage of the Norwegian protocol is that some patients will get more frequent rituximab than they need, but in reality there is a good case for doing things the way they are doing it in my opinion.)

Thanks. Would there be the possibility to predict when maintenance doses are required per patient based on B cell levels to avoid unnecessary rituximab doses ?
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Thanks. Would there be the possibility to predict when maintenance doses are required per patient based on B cell levels to avoid unnecessary rituximab doses ?
B cell numbers can readily be measured in blood. The issue is determining what is the optimal level at which they need another dose of Rituximab.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Thanks. Would there be the possibility to predict when maintenance doses are required per patient based on B cell levels to avoid unnecessary rituximab doses ?
B cell numbers can readily be measured in blood. The issue is determining what is the optimal level at which they need another dose of Rituximab.

Actually, no, the need for another dose of rituximab has nothing to do with the B cell level because it has to do with the re-emergence of pathogenic plasma cell clones. The B cell level cannot tell you anything about need for re-treatment, other than if there are no B cells there is no point. Rheumatologists have made this mistake and assumed that when B cells rise you need another treatment, but this is not the case. Patients with autoimmune disease can go for years after B cells have become normal with no symptoms. Then may then relapse at any time from a few months to five years later. All one can do is allow patients to regain B cells and wait for relapse and retreat and then next time around retreat at a slightly shorter time interval, because patients tend to remit for the same period each time. But the Norwegians have opted to pre-emptively re-treat to begin with, which is another way of doing things that has certain theoretical advantages.
 
Messages
2,087
Actually, no, the need for another dose of rituximab has nothing to do with the B cell level because it has to do with the re-emergence of pathogenic plasma cell clones. The B cell level cannot tell you anything about need for re-treatment, other than if there are no B cells there is no point. Rheumatologists have made this mistake and assumed that when B cells rise you need another treatment, but this is not the case. Patients with autoimmune disease can go for years after B cells have become normal with no symptoms. Then may then relapse at any time from a few months to five years later. All one can do is allow patients to regain B cells and wait for relapse and retreat and then next time around retreat at a slightly shorter time interval, because patients tend to remit for the same period each time. But the Norwegians have opted to pre-emptively re-treat to begin with, which is another way of doing things that has certain theoretical advantages.

Thanks for explaining this.
Could the pre-emptive retreatment in theory extend periods until relapse or can you shed any light on the theoretical advantages ?
Is it just a matter of time for all patients to relapse or can some break the cycle indefinitely ?
 
Messages
2,087
From the paper linked previously it states :

B-lymphocyte depletion in RA was initiated on the basis that, if successful, it might be expected to induce sustained remission such that re-treatment might not be required more than once every several years. For those patients in whom improvement lasts for two or more years following B-lymphocyte repopulation, such that their immune systems are fully reconstituted most of the time, B-lymphocyte depletion is an extremely attractive form of therapy. The single-most significant drawback is that patients have to accept that relapse will eventually occur, and that at present there is no clear strategy for preventing this with pre-emptive re-treatment. The dilemma faced is that pre-emptive treatment will by definition reduce the period during which immunological competence is restored.

For patients who relapse at the time of B-lymphocyte repopulation, B-lymphocyte depletion is theoretically less attractive since continued immunosuppression is involved. Continued B-lymphocyte depletion may be unsuitable for such cases, but where no alternative therapy is available it may still be justified.


Would you speculate the above might be true for ME also or are there any reasons to think otherwise ?
 

deleder2k

Senior Member
Messages
1,129
@Jonathan Edwards, at what threshold for IgG would you consider IVIG therapy after Rituximab for a patient with ME?

Would you consider it if this was a real patient? Say this was on an exam in Immunology 101:


"Patient XYZ":

The patient has received 5 infusions. The first infusion was 10 months ago.
1000mg at day 0 and day 14. Then 500mg after 3 months, 6 months and 9 months.


Current IgG 5.97 (Reference range 6.8-14.5)
IgG level pre Rituximab 6.3.
IgA post Rituximab 0.81 (reference 0.83-4.6)
IgM post Rituximab 0.39 (reference 0.47-2.5)

Question 1: Should the patient receive IgG?

Question 2: Is the patient more prone to infections after Rituximab therapy because of a significant fall in IgG?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
@Jonathan Edwards, at what threshold for IgG would you consider IVIG therapy after Rituximab for a patient with ME?

Would you consider it if this was a real patient?


"Patient XYZ":

The patient has received 5 infusions. The first infusion was 10 months ago.
1000mg at day 0 and day 14. Then 500mg after 3 months, 6 months and 9 months.


Current IgG 5.97 (Reference range 6.8-14.5)
IgG level pre Rituximab 6.3.
IgA post Rituximab 0.81 (reference 0.83-4.6)
IgM post Rituximab 0.39 (reference 0.47-2.5)

Those figures do not in my view indicate any consideration of IVIG. A drop of 0.33 in IgG is trivial - smaller than average after 5 doses I suspect. I do not think IgA levels are critical and this is close to normal. IgM often falls much lower without any evidence of a problem. In my own practice I would have started thinking that something might need doing if IgG fell to 5.0. Any occurrence of infection might influence that but I would be unlikely to suggest IVIG until below 5.0. In the first instance I would probably simply hold off further rituximab and monitor.
 

deleder2k

Senior Member
Messages
1,129
Thank you so much, @Jonathan Edwards. Would your answer on the exam be to hold off with IVIG and to suspend a final Rituximab infusion which is planned at month 12 because of the current IgG levels?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Thank you so much, @Jonathan Edwards. Would your answer on the exam be to hold off with IVIG and to suspend a final Rituximab infusion which is planned at month 12 because of the current IgG levels?

That is a difficult question. If I thought it was important to give the full set of infusions I would probably continue. If I thought the evidence for needing a full set was uncertain I would probably hold off, but it would depend on a full analysis of the case.
 

Gingergrrl

Senior Member
Messages
16,171
I just discovered this thread which is very interesting and have a few questions for @Jonathan Edwards (and anyone else)!

IVIG has been found to help in trials over quite a long period, it is just that the trials are a bit small. I would be in favour of further IVIG trials.... And nobody knows whether it is safer than rituximab.

I was curious re: the words that I bolded above: "over quite a long period", did you mean that someone could end up benefitting from IVIG quite a bit after they have finished the treatment vs. during the treatment? And when you said no one knows if it is safer than RTX, I was curious in which ways you meant? (allergic reactions, other side effects, long term effects, etc)?

but its probably great for the immune system taken together with Rituximab..

Is this your overall feeling, @Jonathan Edwards, that IVIG with RTX is the ideal scenario (if feasible and if the patient tolerated it)?

"I have heard one single recovery story which involved treatment with Gammanorm only, but I am not sure how long that recovery lasted".

Is Gammanorm comparable to Gamunex? @Joolz, I was curious if you know any other details re: the recovery story?

But if your own IgG is generally bad for some reason then giving IVIG with rituximab makes perfect sense because you would be reducing your own IgG and have more of other people's. The only problem is that both are very expensive so using the two together is likely to break the bank.

This was basically my question-- if clinically the ideal scenario is to give IVIG with RTX (separate from whether it is financially an option) and am just interested clinically. (There is a program in which someone could get RTX for free from Genentech if they qualify and I know of several people who have done this but not posted about it).

Does IgG decline after every RTX infusion? Or does it not reduce IgG for everyone? Do we have any numbers on this? I am considering treatment at OMI, in S.F. Could 6 RTX infusions could lead to a decline IgG? Not sure if one should worry about a slight decrease though. Probably not.

I was also curious if IgG declines after every RTX infusion for everyone or if this is greatly variable? Also, @SaraEngland did you end up doing the RTX at OMI and if so, how did it go? If not comfortable posting this publicly, you can PM me if you happen to see this. Am hoping if you did it that it went well.

You say that you are due to get six doses of rituxmab and that puzzles me because I cannot see any particular reason why anyone should recommend six doses

I believe if I do it, it will only be two doses (the autoimmune dosing vs. ME/CFS protocol) but I am nowhere even close to that point.

I haven't been told by dr. Kogelnik that I will get 6 doses, I heard that they used the same dosing schedule as the Norwegians. 2x infusions (1 gram max) over 14 days, and then maintenance therapy for at 3, 6, 9, and 12 months.

I believe this is correct if they are following the Norwegian schedule but I think for me it would be the autoimmune dosing.

IgM often goes low right from the start but it bounces back very quickly once B cells return.

I have always tested high in IgM so I assume this would not end up being a problem for me?

Today i went to my general practioner and brought up IVIG, she was positive, but reluctant due to some internet site saying that it can make vaccines redundant (bringing back measles etc). Is this an actual risk @Jonathan Edwards?

I have now had three IVIG's with 4th in October and I have never been told this by any doctor. I know that you cannot get a vaccine while doing IVIG (which I would never be doing anyway) but I have never heard that it could bring back measles or something a person was vaccinated against as a child.

That was a study of high dose IVIG as an immunomodulator, which is quite different from replacement. The replacement dose is whatever is needed to get the levels up to something near normal.

My goal is for it to be an immunomodulator vs. a replacement or immune deficiency dose (even though I am still in the ID dose range at present).

Recommended start dose is often 28-56 grams of IgG with IV for primary immunodeficiency.

It depends on the person's weight and I am doing 24 grams and this is solidly in the immunodeficiency dosing for my weight but is no where close to the autoimmune dosing which would start in the mid 50's.

Thanks in advance to any responses on these questions!