Hypogammaglobulinaemia after rituximab treatment—incidence and outcomes

[SaraEngland]

Thank you, professor.

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.


Interesting. Do we have any data on how much it goes down on average each time? I'd like to know average IgG after each infusion, and the standard deviation. I guess it depends on the dosage, but do we have any numbers regarding this at all?

And one last thing; it puzzles me that RTX would immediately lead to a drop in IgG. Why is that? Wouldn't one see a drop at a steady rate as IgG levels fall due to the fact that B-cells no longer transforms into antibodies? Why do one see an immediate decline?

Sarah

 

[SaraEngland]

Safety of rituximab in rheumatoid arthritis: a long-term prospective single-center study of gammaglobulinconcentrations and infections.

http://www.ncbi.nlm.nih.gov/pubmed/22285615

This gave me an idea.

 

[Jonathan Edwards]

Thank you, professor.

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.

Interesting. Do we have any data on how much it goes down on average each time? I'd like to know average IgG after each infusion, and the standard deviation. I guess it depends on the dosage, but do we have any numbers regarding this at all?

And one last thing; it puzzles me that RTX would immediately lead to a drop in IgG. Why is that? Wouldn't one see a drop at a steady rate as IgG levels fall due to the fact that B-cells no longer transforms into antibodies? Why do one see an immediate decline?

Sarah

That explains the dosage - and makes perfect sense.

I cannot remember all the papers but we put out several papers with Maria Leandro on Ig levels and they are recorded for all the major multicentre trials. We did one paper that looked at people who had had rituximab over up to seven years which detailed the falls in Igs. I would have to look through to find it. The figure in the post above is fairly typical but is a very small study on one practice. It is probably French and the French tend to give rituximab regularly without B cell recovery so the falls may be greater. As you can see the averages are in the normal range. The trouble is that plots like this do not tell you much about variation. Standard deviation is probably not much help because the distribution is not Gaussian. What you want to know is the chance of getting a level below about 5gm/L and it is pretty small. What may be rather more important than these levels anyway are titres of antibodies to common pathogens like tetanus and pneumococcus. Tetanus hardly falls at all and pneumococcus strangely often goes up (we think the anti-pneumococcal memory B cells are not killed).

There is no immediate drop in IgG with rituximab . It goes down slowly, as you would expect.

 

[Jonathan Edwards]

A good idea of the changes is given in the following paper:

http://rheumatology.oxfordjournals.org/content/46/4/626.long

After four cycles of treatment (which tends to be after 3-7 years of continued therapy) levels quite often go below the official lower limit of normal but the numbers going low enough to be a problem were small. It is easy to stop the treatment at any time. Hopefully in ME it may be possible to stop treatment after two years anyway. The problem is not trivial but for people with serious disability like RA or ME it seems to me that it is very manageable.

We did not think IgM and IgA levels were important. IgM often goes low right from the start but it bounces back very quickly once B cells return. Low IgA is common in the general population and does not seem to be a big problem.

We only really had reason to think that infection was related to low IgG in one patient who already had bronchiectasis. She moved on to another drug once something safe was available. (We could not use anti-TNF because that has a much worse reputation for infection.)

 

[SaraEngland]

Thank you!

What a brilliant paper. Very interesting.

I've read that for a IgG test, coefficients of total variation is 5.1% (analytic and biological variation). Wouldn't every individual receiving Rituximab expect a significant decline in IgG levels?

I can expect a significant decline in IgG, If I receive six infusions of Rituximab. The chances of dipping below 5 gm/L is low, if one stops there. Is that correct to believe?

A total variation of 5.1% does not sound much. I thought IgG numbers fluctuated more. Does that mean that levels of IgG are stable, and that every person has their own "value" that doesn't fluctuate significantly?

 

[Jonathan Edwards]

Thank you!

What a brilliant paper. Very interesting.

I've read that for a IgG test, coefficients of total variation is 5.1% (analytic and biological variation). Wouldn't every individual receiving Rituximab expect a significant decline in IgG levels?

I can expect a significant decline in IgG, If I receive six infusions of Rituximab. The chances of dipping below 5 gm/L is low, if one stops there. Is that correct to believe?

A total variation of 5.1% does not sound much. I thought IgG numbers fluctuated more. Does that mean that levels of IgG are stable, and that every person has their own "value" that doesn't fluctuate significantly?

Your six doses are not equivalent to six cycles (12 doses) and because they are over only 12 months they will be more like one and a bit cycles.

There is a measurable drop in IgG in almost everyone but for many it is trivial for the first two cycles. The chances of you getting down to 5gm with that is pretty tiny, unless you start at 6- 6.5 gm and I am not sure I would recommend going ahead then.

Normal levels of IgG range from about 7 to 15gm per litre. Each person tends to have their own pretty constant level. We know very little about homeostasis of antibody levels. There are suggestions that there is no negative feedback per se but that there is simply a 'dissipative' constancy. that is to say that we all have about the smae amount of space in marrow for plasma cells and the same half life for IgG so the dynamic equilibrium level is fairly similar but not that similar. The story is that IgG production is limited by space for plasma cells which jostle for survival but it is not well undrestood.

 

[SaraEngland]

Thank you so much. I asked my immunologist about this, and he couldn't tell me much about it without reading up on the subject. He charged me 200 pounds.

On the contrary you explain it in depth - instantly! Thank you very much.

I owe you a book about birds (if you haven't got them all)

This is a book for you if you're going to Bergen:

Have a good evening, dr.

 

[Marky90]

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?

 

[Jonathan Edwards]

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?

That does not really make sense to me. Maybe she was meaning something I haven't quite grasped.

 

[Marky90]

That does not really make sense to me. Maybe she was meaning something I haven't quite grasped.

Ok i looked it up and its about future virus-related vaccines

 

[Jonathan Edwards]

Ok i looked it up and its about future virus-related vaccines

All I can find relates to infants who need their basic virus vaccinations, and I have not yet found any explanation that really makes sense of this. I cannot see that it would be likely to be an issue for an adult but would be interested to know where the story comes from.

 

[SaraEngland]

A good idea of the changes is given in the following paper:

We did not think IgM and IgA levels were important. IgM often goes low right from the start but it bounces back very quickly once B cells return. Low IgA is common in the general population and does not seem to be a big problem.

That means that one will experience low IgA levels after the first RTX infusion until B-cells come back? I imagine that can be a few years! And what about IgE - does it influence it?

Found an article about IgE here - Rituximab did not significantly lowered IgE. While it seems to that IGE in serum is slightly lower after RTX. But if it is not significant it won't matter...

What about lymphopenia? This paper says the following:

Although rituximab therapy is known to cause prolonged B-lymphopenia and may decrease immunoglobulin levels in some patients,2 it has not been clearly associated with increased infections either as monotherapy2 or in combination with alkylating agents.

Wouldn't Rituximab lead to a sharp decline in B-cells which also lead to a decline in Lymphocytes that could cause instant lymphopenia?

 

[SaraEngland]

I found a graph in your article that dazzled me:

Changes in immunoglobulin levels associated with repeated cycles of B-lymphocyte depletion with rituximab. (A) IgM (B) IgG (C) IgA. Number of patients is given above each plot. Median, range, 25th and 75th percentile charted.

Can't get my head around how long a cycle is, do you know professor @Jonathan Edwards? Does it vary for each patient based on clinical response?

And one last question: What are the dotted lines? I had this in statistics, but I can't recall what the dotted lines are.
EDIT: Are they the range?? Must be the reference range!

 

[Jonathan Edwards]

That means that one will experience low IgA levels after the first RTX infusion until B-cells come back? I imagine that can be a few years! And what about IgE - does it influence it?

Found an article about IgE here - Rituximab did not significantly lowered IgE. While it seems to that IGE in serum is slightly lower after RTX. But if it is not significant it won't matter...

What about lymphopenia? This paper says the following:

Wouldn't Rituximab lead to a sharp decline in B-cells which also lead to a decline in Lymphocytes that could cause instant lymphopenia?

IgA often does not fall much but it can go down during the period of B cell depletion, which tends to be about 6 months for each cycle. It would be longer if maintenance doses were used. It does not seem to be a problem clinically. We did not measure IgE - people do not seem to think it is necessary, although I am not sure why.

Rituximab reduces B cells to 2% or less of what they were within 24hrs. Lymphopenia just means low lymphocytes so there is more or less total B lymphopenia but no T lymphopenia. B cells are usually in the minority but that is not really relevant since B cells and T cells do different jobs and are only lumped together for simplicity in standard blood counts.

 

[Jonathan Edwards]

I found a graph in your article that dazzled me:

Can't get my head around how long a cycle is, do you know professor @Jonathan Edwards? Does it vary for each patient based on clinical response?

And one last question: What are the dotted lines? I had this in statistics, but I can't recall what the dotted lines are.
EDIT: Are they the range?? Must be the reference range!

Cycles, or courses, can be anything from 6 months to eight years apart depending on patient needs. The dotted lines are the statistical reference range, which indicates what level range most people have but does not indicate anything much about what is 'healthy'.

 

[SaraEngland]

Rituximab reduces B cells to 2% or less of what they were within 24hrs. Lymphopenia just means low lymphocytes so there is more or less total B lymphopenia but no T lymphopenia. B cells are usually in the minority but that is not really relevant since B cells and T cells do different jobs and are only lumped together for simplicity in standard blood counts.

Aha, okey. So that means most patients experience a quick (24 hours) drop in lymphocytes count of approx. 23% (Range 18-47%) since B-cells vanish? I would assume that some could get Lymphopenia if one starts with low levels, but if it is just an instant thing related to B-cells and only B-cells one shouldn't worry.


Just checked IgG total levels and they are around 11!

 

[Joolz]

There is no reason for a difference in giving Ig IV or IM in terms of effect that I can think of but IM is pretty hard on the poor old muscle after a while and SC can produce local tissue reactions. I would prefer to have it IV I think

Oh, I was always under the impression that IVIG patients would be more prone to side effects.. I know that the people at the Charité are using SCIG on their immunodeficiency patients (since it can be administered at home via a pump or rapid push), and it seems to be uncomplicated. The effect should be the same?

There is a measurable drop in IgG in almost everyone but for many it is trivial for the first two cycles. The chances of you getting down to 5gm with that is pretty tiny, unless you start at 6- 6.5 gm and I am not sure I would recommend going ahead then.

What would be the risk? Serious infections? Is that also true for those who do NOT suffer from recurrent infections, but rather fit the "less infections since CFS onset" model?

Is there any way to calculate total IgG from the four subclasses btw?

 

[Jonathan Edwards]

Oh, I was always under the impression that IVIG patients would be more prone to side effects.. I know that the people at the Charité are using SCIG on their immunodeficiency patients (since it can be administered at home via a pump or rapid push), and it seems to be uncomplicated. The effect should be the same?

What would be the risk? Serious infections? Is that also true for those who do NOT suffer from recurrent infections, but rather fit the "less infections since CFS onset" model?

Is there any way to calculate total IgG from the four subclasses btw?

The real problem with IV is that you need a skilled technician to put up the IV. You may get phlebitis too but bottom ache from IM injections is likely to be worse. Sub cut is fine but you need to be reasonably well trained to do it without going in the wrong place.

Serious infections are in theory more likely the lower IgG goes below about 5gm but it depends a lot on other factors. The real problem is for people who make no IgG at all. The sorts of recurrent infections some people with ME have are probably not the sort of thing to worry about. There are more likely to be issues if the person already has some focus that can get chronically infected like an area of bronchiectatic lung or a blocked sinus.

 

[deleder2k]

Would it be okey to start RTX treatment at a low level of IgG (5-7) if one at the same time gives IVIG during the cycles?

 

[Jonathan Edwards]

Would it be okey to start RTX treatment at a low level of IgG (5-7) if one at the same time gives IVIG during the cycles?

Very difficult to weigh up the risks and benefits there. I guess it would be inappropriate as part of the current trial and beyond that things are rather hypothetical.