Got treatment in the EU and doing well starting remission

[Jonathan Edwards]

According to a lab I contacted, there is no one in Australia that does the auto antibody tests for the ones listed as being associated with the Rituximab response, published by Fluge/Mella

Perhaps I should repeat the point that, as far as I remember, the presence of these antibodies was NOT associated with response to rituximab. It was the FALL in the antibodies after treatment that correlated. Since you do not know if the antibodies are going to fall until you have had the treatment the test tells you nothing in advance.

 

[Gingergrrl]

Perhaps I should repeat the point that, as far as I remember, the presence of these antibodies was NOT associated with response to rituximab. It was the FALL in the antibodies after treatment that correlated. Since you do not know if the antibodies are going to fall until you have had the treatment the test tells you nothing in advance.

But wouldn't someone who has the autoantibodies (vs. someone who did not have the autoantibodies) be a potential candidate for the treatment even if there was no advanced guarantee that the autoantibodies would drop or that they would be a responder?

Wouldn't this be the same principle as with any other treatment which was based on someone having both autoantibodies and negative symptoms? If someone were not tested, then they would never know if they had the autoantibodies to begin with.

 

[justy]

There is a thread on PR if you do a Google site search that explains the entire protocol for how to send blood to Cell Trend in Germany (and it is actually easier and faster to send from Europe than the US). In the US, you are required that a doctor write a note for the blood draw since a patient cannot request a blood draw on their own (but am not sure how this part works in Europe). My main doc wrote a very simple note authorizing the blood draw which I brought to the specialty lab along with the instructions for Cell Trend and how to ship with Fedex International. I will try to find the thread and post the link here.

Edit: I found some of the threads and they are very long so am posting the direct website link for Cell Trend instead and hoping it has the info that you are looking for:

http://www.celltrend.de/

Thanks - yes sadly their website does not have the information.

 

[Gingergrrl]

Thanks - yes sadly their website does not have the information.

I am at my IVIG but once I am done w/this cycle, I have all the info at home and can send it to you via PM on Sun or next week. And please remind me if I forget!

 

[LivingwithFibro]

Shawn, you mentioned another drug that is safer than rtx in taking out "the bad guys", can you provide more info for that?

 

[Jonathan Edwards]

But wouldn't someone who has the autoantibodies (vs. someone who did not have the autoantibodies) be a potential candidate for the treatment even if there was no advanced guarantee that the autoantibodies would drop or that they would be a responder?

Wouldn't this be the same principle as with any other treatment which was based on someone having both autoantibodies and negative symptoms? If someone were not tested, then they would never know if they had the autoantibodies to begin with.

If we had no specific data it would be reasonable to suppose that someone with antibodies was more likely to respond than someone with no antibodies. However, in this case we actually have the evidence from the study and if my memory is correct the presence of antibodies did not predict a good response. So the actual evidence overrides what one might think on general principles. Just as you might think that a more expensive brand of chocolate ought in principle to taste better but it might turn out to be dull as ditchwater. If we know the test tells us nothing it tells us nothing.

 

[Gingergrrl]

@Jonathan Edwards But the responders had autoantibodies that went down after Ritux (meaning they had them to begin with) or is this incorrect? I know many had the autoantibodies and were not responders but the ones who were responders were the ones who had the auto-abs and had them go down post Ritux?

 

[Jonathan Edwards]

@Jonathan Edwards But the responders had autoantibodies that went down after Ritux (meaning they had them to begin with) or is this incorrect? I know many had the autoantibodies and were not responders but the ones who were responders were the ones who had the auto-abs and had them go down post Ritux?

No, the ones who were responders either had antibodies that went down or just did not have antibodies measurable. Having antibodies made people no more likely to respond than not having antibodies. That actually tends to make one think that these antibodies have nothing much to do with the illness (or the response in fact) but again that is speculation. The important thing is the facts and the facts were, as I remember them, that you are just as likely to respond if you do not have the antibodies. It is just that if you do have them and you respond they tend to go down. Results in science do not always work out the way that is easiest to understand but results are results.

 

[Gingergrrl]

Thank you and I need to re-read the study and had thought that the responders had the beta adrenergic & anti muscarinic auto-abs plus anti thyroid and positive ANA Titer.

 

[knackers323]

No, the ones who were responders either had antibodies that went down or just did not have antibodies measurable. Having antibodies made people no more likely to respond than not having antibodies. That actually tends to make one think that these antibodies have nothing much to do with the illness (or the response in fact) but again that is speculation. The important thing is the facts and the facts were, as I remember them, that you are just as likely to respond if you do not have the antibodies. It is just that if you do have them and you respond they tend to go down. Results in science do not always work out the way that is easiest to understand but results are results.

If this is the case then unfortunately the test would be pretty pointless, as you say. Damn

 

[Gingergrrl]

If this is the case then unfortunately the test would be pretty pointless, as you say. Damn

For me it was not pointless b/c it confirmed to my doctor that I have autoimmune POTS and autoantibodies that are contributing to my muscle weakness.

He's tested many patients and I am the winner (sarcasm!) with seven of the nine autoantibodies being positive. I seem to match w/the subgroup in the study (no idea why) and the positive autoantibodies (all of them, not just Cell Trend) confirmed that it was worth trying IVIG and now fighting to get Ritux (still fighting but closer than before)!

Without knowing I have the autoantibodies, I would have taken a different path. So even if all we know is that Ritux might help 30% of patients, I think the study and the autoantibodies help to narrow down who might be in that 30% and who it is worth it to try IVIG or Ritux (vs. a complete shot in the dark).

 

[knackers323]

@Gingergrrl yes true

 

[Kenny Banya]

Perhaps I should repeat the point that, as far as I remember, the presence of these antibodies was NOT associated with response to rituximab. It was the FALL in the antibodies after treatment that correlated. Since you do not know if the antibodies are going to fall until you have had the treatment the test tells you nothing in advance.

I don't infer this from the abstract - it states "Antibodies against β2, M3 and M4 receptors were significantly elevated in CFS patients compared to controls." This implies 'everyone' has these antibodies, but they are higher in CFS patients.
Then those who responded to RTX had their antibodies against β2 and M4 receptors (not M3) drop.
I am now going to read the entire paper - being someone of statistics background, I am interested in the results section

 

[Kenny Banya]

First mistake - in the Statistical Analysis section is stated:
Correlation analysis was performed by nonparametric Spearman coefficient r

Spearman's coefficient is rho (Greek letter ρ). r is the coefficient used for Pearson's parametric test.

I know I am being picky.....

 

[Kenny Banya]

For me it was not pointless b/c it confirmed to my doctor that I have autoimmune POTS and autoantibodies that are contributing to my muscle weakness.

He's tested many patients and I am the winner (sarcasm!) with seven of the nine autoantibodies being positive. I seem to match w/the subgroup in the study (no idea why) and the positive autoantibodies (all of them, not just Cell Trend) confirmed that it was worth trying IVIG and now fighting to get Ritux (still fighting but closer than before)!

Without knowing I have the autoantibodies, I would have taken a different path. So even if all we know is that Ritux might help 30% of patients, I think the study and the autoantibodies help to narrow down who might be in that 30% and who it is worth it to try IVIG or Ritux (vs. a complete shot in the dark).

Yes, as I am educating myself about biology, I am learning that POTS (subset of dysautonomia) seems to be a neuronal signalling issue. It may well be that RTX prevents the 'blocking' of neuronal receptors, so that they can get the correct signal to the heart to 'pump harder'!

That I have become more aware of my lightheadedness & head spins on standing up, adds to my own 'anecdata' related to POTS
Pertinently, the end of the noted paper's conclusion state:
It is conceivable that various symptoms of CFS including cognitive deficits, autonomic dysregulation and immune activation could be partly mediated by autoantibodies against these receptors in a subset of patients.

 

[Kenny Banya]

As I don't have a background in tertiary biology, I did not understand this:
1) CellTrend GmbH holds a patent on the use of b adrenergic receptor antibodies in diagnosis of CFS.
- I could understand them patenting a test for these, but not the use of. Maybe someone can elaborate.

2) Haukeland University Hospital has patents and pending patent applications on the issue of B-cell depletion therapy for Myalgic Encephalopathy/Chronic Fatigue Syndrome
- Roche holds the RTX patent, which results in B-cell depletion. Again can't understand what HUH can patent here - is it the 15 month treatment, quantity & rate per infusion?

I agree with this statement from the Conclusion:

...the association of b2 AdR and M AChR antibodies with immune activation markers and their decline in CFS patients responding to B-cell depletion may support a pathogenic role and warrants their testing as potential biomarkers in clinical trials of B-cell/antibody depleting therapy

 

[Jonathan Edwards]

I don't infer this from the abstract - it states "Antibodies against β2, M3 and M4 receptors were significantly elevated in CFS patients compared to controls." This implies 'everyone' has these antibodies, but they are higher in CFS patients.
Then those who responded to RTX had their antibodies against β2 and M4 receptors (not M3) drop.
I am now going to read the entire paper - being someone of statistics background, I am interested in the results section

I agree that what I suggested does not seem to add up. However, having spent years trawling through studies like this - including my own data - I have come to see that there are all sorts of ways it can eem there is a useful result when there is not.

Patients with ME in the study had, on average, rather higher antibody levels. However, there was huge overlap so one would not be able to conclude anything much from an individual patient's result. Even for the highest antibody levels there were people in the control group at that level.

But the crucial point is that amongst the patients those with high antibody levels showed no statistically significant increase in likelihood of responding to rituximab. That is counterintuitive if the antibodies are causing disease in a subset of patients but it is what they found.

What was found was that amongst those who responded to rituximab there was a greater fall in their antibodies. Now, this does not give us any evidence for those particular antibodies being relevant, because it might just be a sign that in these patients B cells were depleted more efficiently. And any benefit might be due to reducing some other antibodies that have not been measured and we know nothing about. If anything this piece of information supports the Norwegian idea that rituximab can benefit ME by reducing antibodies. However, since responses did not seem to be more common in patients with the specific antibodies tested it rather suggests that these are the wrong antibodies to look at. But there are further arguments about antibody populations and how tests reflect them that could counter that. It all becomes too speculative.

The bottom line remains, though, that if my memory is right the study indicates that antibody levels pre-treatment tell you nothing about likely response.

 

[BurnA]

I explicitly asked Carmen Scheibenbogen about this at iime conference last year -

@Jonathan Edwards conclusions seem to make the most sense but Dr. Scheibenbogen did say to me that you were more likely to respond if you had the autoantibodies. I don't know what this is based on.
Maybe she just told me what she thought I wanted to hear ( or what she wanted to believe)
I don't know, now I'm speculating.
But she definitely said that to me.

 

[Jonathan Edwards]

As I don't have a background in tertiary biology, I did not understand this:
1) CellTrend GmbH holds a patent on the use of b adrenergic receptor antibodies in diagnosis of CFS.
- I could understand them patenting a test for these, but not the use of. Maybe someone can elaborate.

2) Haukeland University Hospital has patents and pending patent applications on the issue of B-cell depletion therapy for Myalgic Encephalopathy/Chronic Fatigue Syndrome
- Roche holds the RTX patent, which results in B-cell depletion. Again can't understand what HUH can patent here - is it the 15 month treatment, quantity & rate per infusion?

I agree with this statement from the Conclusion:

...the association of b2 AdR and M AChR antibodies with immune activation markers and their decline in CFS patients responding to B-cell depletion may support a pathogenic role and warrants their testing as potential biomarkers in clinical trials of B-cell/antibody depleting therapy

These are very good points. I am currently acting as adviser on four patent cases rather of this sort and I am astonished by what you can patent. Often it seems to make no sense, but once you get deep into the infighting you begin to see what the rationale is. Very often people patent something that seems ridiculous only to stop someone else patenting something equally ridiculous that constrains what the first people can then sell.

I agree that in practice it would seem impossible to patent the use of a test for diagnosis. Some one else could just sell a similar test on the grounds that doctors might find the results interesting. Or that it diagnosed 'antibody-positive fatigue syndrome' which might be what we call it in five years time. But regulatory authorities stipulate that tests have to be validated for certain diagnostic purposes and the test will be seen as being sold as a diagnostic tool so there is commercial competition out there.

When you get to court you realise that there are in fact no facts about what is legitimate or not - people just try to argue one way or another and the judge tries to work out who is being reasonable. It is quite common for companies to claim patents simply to make it too expensive for other companies to try to challenge them. When the profits to be made shift the other side raises the money and the claim is shown to be ridiculous.

With regard to Haukeland, it is now becoming common for companies to patent treatment regimens. This is rather new and has a lot to do with complicated catch 22 situations for biosimilar approval. My feeling is that it is groundless, but that is not what the lawyers think. I think part of the reason for a hospital taking out a patentee of this sort is that it establishes that they had the concept of the treatment and had tried it. That removes the carpet from under any company that comes along saying they thought of it later. That protects government healthcare systems from being preyed on by industry. At present government run systems are being ripped off by biologic therapy manufacturers to the tune of tens of billions a year because they were slow to do this in the 1990s.

 

[Jonathan Edwards]

I explicitly asked Carmen Scheibenbogen about this at iime conference last year -

@Jonathan Edwards conclusions seem to make the most sense but Dr. Scheibenbogen did say to me that you were more likely to respond if you had the autoantibodies. I don't know what this is based on.
Maybe she just told me what she thought I wanted to hear ( or what she wanted to believe)
I don't know, now I'm speculating.
But she definitely said that to me.

I may be wrong but I do remember sitting down with the data and coming to this conclusion. Normally if I get something wrong someone on PR always puts me right! That's what I think is so great about it.