De Meirleir is using Rituximab?

[Jonathan Edwards]

@Jonathan Edwards is the original autoimmune dose that you developed a total of two infusions being one week apart?

That is the regimen I used. The licensed regimen is two weeks apart based on my studies but that was a hang over from the early days when we used cyclophosphamide two weeks apart. For the last ten years or so the department has used one week apart. We also do not use the mg/metre squared formula the oncologists use but some of the time we adjusted the dose in much the same way for people who are very big or small.

 

[msf]

So what happened here then?

http://www.blackwellpublishing.com/acrmeeting/abstract.asp?MeetingID=761&id=80137

This seems to be part two: http://ard.bmj.com/content/72/12/2048.extract

 

[msf]

I also found this: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2474694/

Is cytokine production by effector B cells controversial then?

There seems to be quite a lot of evidence for it:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2745290/

 

[Jonathan Edwards]

So what happened here then?

http://www.blackwellpublishing.com/acrmeeting/abstract.asp?MeetingID=761&id=80137

This seems to be part two: http://ard.bmj.com/content/72/12/2048.extract

The rituximab depleted the B cells and the inflammatory process due to autoantibodies (that presumably declined) decreased along with the mediating cytokines just as I said. Sjogren's is actually a rather aberrant example here because one of the features is a non specific polyclonal expansion of B cells that is probably beyond just autoantibody producing cells (maybe another example like MS where there are too many antibodies in a particular place but not necessarily auto-).

I'm not sure what you are gettin at to be honest.

Note that the most striking decrease was in IL-10, which is regarded as an anti-inflammatory cytokine! So you would expect any direct result to be pro-inflammatory. There aren't actually any numbders in the abstract either so I am not that impressed. Fifteen years ago ACR abstracts were not even accepted unless they had numerical data in them. These days anything seems to get through.

 

[msf]

It seems to me that if B cells produce cytokines, both inflammatory and anti-inflammatory, which there seems to be quite a lot of evidence for, then getting rid of them should affect cytokine levels.

The second part of the study I quoted said that the effect was primarily on pro-inflammatory cytokines. There are also some numbers.

Edit: Something very weird happened when I went back to the second part - the table had dissappeared! Either that or I was so desperate for evidence to back up my theory that I imagined a table!

 

[msf]

From the article I posted above: The cytokine profile of B cells can also be altered by disease, leading to an imbalance of proinflammatory and anti-inflammatory cytokines. However, this proinflammatory bias can be reversed in at least some patients treated with Rituximab.

Now I don´t know who to believe, Frances E. Lund or Prof. J. Edwards.

 

[Jonathan Edwards]

I also found this: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2474694/

Is cytokine production by effector B cells controversial then?

It depends on what level you are talking about. Sadly it is very popular, but amongst people who have no direct experience of B cell depletion who write in trash journals like 'Current opinion in immunology, or cooking with spinach or how to improve your eye brows...' Sorry to be flippant but journals whose titles start like that are at the level of magazines in dentists' waiting rooms. What I call immunobabble. In science these days popular ideas are very often wrong - they are the ideas that even the dumbest researchers can think they understand. And they are lining the pockets of someone manipulating grant committees. Amongst the people who I respect in the field the idea is a joke.

Even in RA, which is very unusual in having B cells actually at sites of inflammation for complex reasons I spend several years working out, most gross inflammatory lesions have few or no B cells in them. B cells live in lymph nodes and spleen. In fact one pathologist made his career out of showing a negative correlation between the presence of B cells in RA joints and the level of damage.

I am afraid it would take hours to go through all the reasons why this stuff is drivel.

 

[msf]

I´ve just checked and she has her own laboratory, which I guess could either be a plus or a minus for her.

 

[msf]

It still seems to me that there is evidence out there that B cells produce cytokines, and that therefore depleting B cells should deplete cytokines, both pro-inflammatory and anti-inflammatory.

 

[Jonathan Edwards]

From the article I posted above: The cytokine profile of B cells can also be altered by disease, leading to an imbalance of proinflammatory and anti-inflammatory cytokines. However, this proinflammatory bias can be reversed in at least some patients treated with Rituximab.

Now I don´t know who to believe, Francis E. Lund or Prof. J. Edwards.

Of course B cells produce cytokines, but they do so in order to send signals to cells a few microns away in a lymph node. You will pick that up in a cell culture but it has nothing to do with inflammation for the reasons I have given. OK, I am simplifying, becuase in advanced RA and Sjogren's glands you do get B cells present, but there is no reason to think they are what are sending the intimal macrophages in RA crazy - that has to be antibody because they go just as crazy with no B cells (or even T cells) there. The people who write this stuff do not understand that you need to think of immunology in the context of tissue microenvironment. B cell cytokines are involved in T cell help, which is an important stage towards antibody production but has nothing significant to do with inflammation, despite the fact that the same cytokines may be involved.

The business about 'balance' of pro-inflammatory and anti-inflammatory cytokines is drivel that has been around since the 1980s and has never had a shred of evidence to back it up. I used to have a slide to indicate the importance of this balance - with Noddy on one side outbalanced by Big Ears on the other - an indication of the intellectual level I thought had been reached. I got quite a lot of laughs but decided to move on once the joke got worn.

 

[Jonathan Edwards]

I´ve just checked and she has her own laboratory, which I guess could either be a plus or a minus for her.

I checked out her home page. She is one of a hundred eager young immunologists who claims to have discovered that B cels do more than make antibody and send signals to other cells to stimulate immune responses.

Pity she did not read the papers produced in the 1980s when she was at school when we discovered this! The ability of B cells to stimulate T cells by presentation of antigen with other signals, now known to be cytokines, was known when I was a registrar. The problem is that these people have never done any tissue pathology and looked at the histological architecture.

One thing you can be sure of is that the reinvention of this wheel was not her idea - that honour goes to Mark Shlomchik in 1994.

 

[msf]

Well, like most things in medicine, there seem to be two points of view on this, and I haven´t read enough about it to have my own opinion, so I will just wait and see who turns out to have the correct interpretation.

 

[BurnA]

Well, like most things in medicine, there seem to be two points of view on this, and I haven´t read enough about it to have my own opinion, so I will just wait and see who turns out to have the correct interpretation.

I don't know the first thing about immunology, but i know who i'd be putting my money on

 

[msf]

If you don´t know the first thing about immunology (like me), I would suggest not putting money on any immunologist.

 

[Gingergrrl]

That is the regimen I used. The licensed regimen is two weeks apart based on my studies but that was a hang over from the early days when we used cyclophosphamide two weeks apart. For the last ten years or so the department has used one week apart. We also do not use the mg/metre squared formula the oncologists use but some of the time we adjusted the dose in much the same way for people who are very big or small.

Thank you @Jonathan Edwards and I assume if you were administering it today for an autoimmune issue, this is still the protocol that you would use? (Two doses total and one week apart.)

ETA: Also, have you seen cases where after this protocol, the B cells re-grew healthy without the pathogenic auto-antibodies?

 

[Jonathan Edwards]

Thank you @Jonathan Edwards and I assume if you were administering it today for an autoimmune issue, this is still the protocol that you would use? (Two doses total and one week apart.)

ETA: Also, have you seen cases where after this protocol, the B cells re-grew healthy without the pathogenic auto-antibodies?

Yes. In RA we see B cells regrow without a rise in autoantibodies in about half of patients but the autoantibodies more or less always creep back eventually, even if in some cases it takes five years for that to happen after a single course of treatment. But not all the autoantibodies necessarily come back and quite often patients with severe disease complications lose these and move into a milder form of disease. In other conditions treated wit this regimen, such as immune thrombocytopenia the autoantibodies seem to disappear for good in a proportion of cases - no further treatments are needed.

 

[Jonathan Edwards]

Well, like most things in medicine, there seem to be two points of view on this, and I haven´t read enough about it to have my own opinion, so I will just wait and see who turns out to have the correct interpretation.

Fair enough. Unfortunately you may wait for ever. Despite Freud being debinked fifty years ago his theory is still the popular one in psychiatry. Despite the idea that nephrotic syndrome oedema is due to low serum protein being disproven in the 1970s it is still taught to all medical students. The dumbed down theories tend to go on for ever it seems, untouched by evidence. The difference between my view and that of Dr Lund is evidence, including my New England Journal paper, but I appreciate that you are not in a position to assess that.

 

[user9876]

In order to break a cycle of autoantibody production even for a period of months you need complete depletion - both on theoretical grounds and based on experience in particular in lupus. Anything less than about 90% depletion tends to have no clinical benefit at all, as one would theoretically expect. The reasons are to do with complicated immunology. However, it is not too difficult to follow. If a self-controlling system has got into a vicious cycle then gentle actions are more likely to interfere with the remaining good functions of the system than hit the vicious cycle. If you blow gently at a snowball rolling down a hill you do not stop the snowball getting bigger, you just blow away the snow around it.

I guess your point is that most of the B-Cells are sitting around waiting to react and as long as some are there then there are sufficient resources to keep the cycle going.

If someone had treated a number of people with ME with smaller doses of Rituximab and measured b-cell depletion and any improvements would the lack of improvements help confirm a autoimmune theory as opposed to something else happening with b-cells?

 

[Jonathan Edwards]

I guess your point is that most of the B-Cells are sitting around waiting to react and as long as some are there then there are sufficient resources to keep the cycle going.

If someone had treated a number of people with ME with smaller doses of Rituximab and measured b-cell depletion and any improvements would the lack of improvements help confirm a autoimmune theory as opposed to something else happening with b-cells?

I think it probably would point in that direction but it might depend on what alternative mechanism is being considered. All antibody production involves a positive feedback loop so 'bad' but not 'auto' antibody production might not be distinguishable in this way. I think what would be surprising and therefore very interesting would be if in fact subdepleting doses of rituximab produced improvement. I find it hard to see why they should, through any mechanism, but biology often turns out to be unexpected.

 

[msf]

Fair enough. Unfortunately you may wait for ever. Despite Freud being debinked fifty years ago his theory is still the popular one in psychiatry. Despite the idea that nephrotic syndrome oedema is due to low serum protein being disproven in the 1970s it is still taught to all medical students. The dumbed down theories tend to go on for ever it seems, untouched by evidence. The difference between my view and that of Dr Lund is evidence, including my New England Journal paper, but I appreciate that you are not in a position to assess that.

My problem is that there seems to be evidence that supports both sides interpretations. If it was just a question of being ´in a position to assess it,´ then surely all the immunologists would agree with you?