Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME (2018) Scheibenbogen et al

[Jonathan Edwards]

Well this rings true to the flu type feelings I get. A good line of research to follow up methinks. Now where’s the substantial funding required?

I think people have to be aware that there are a number of gaps in the story.

Firstly, if a significant proportion of patients with ME had pathogenic autoantibodies one might expect there to be a noticeable response to rituximab and there was not at phase 3.

Perhaps most importantly there was no correlation between having autoantibodies and improving with rituximab at phase 2 either. Slightly more people with ME than normals seemed to have receptor autoantibodies but the difference was not big enough to suggest there was a causal link.

The immunoabsorption process removes all antibodies, not just the ones being tested for. So there is no evidence that it is the ones being tested for that are important.

We are let with the possibility that removing all antibodies and replacing them may make people with ME better for weeks or months. But it does not sound as if there was any clear pattern to this and there is no sham control. I think it is well worth while pursuing studies on immune cells but I am concerned about exposing people to potentially dangerous procedures without having a better rationale from the science.

 

[Gingergrrl]

I actually posted about Dr. Scheibenbogen's research on the other board tonight (great minds think alike @Mattie) but I am not sure why it is being dismissed over here? I understand it was a small preliminary study but it seems very solid to me that she has identified an autoimmune sub-group, or possibly a mis-diagnosed autoimmune disease group, and Simmaron feels the same and she was awarded two Ramsey Award Research Grants.

I totally 100 million percent understand why the BPS and PACE research is dangerous and pure nonsense. But I don't understand why the research of Dr. Ron Davis, Dr. Scheibenbogen, Cell Trend Lab, the recent study from Griffith University in Australia (re: Calcium Channels, Rituximab, and NK cells, etc), is all so quickly being dismissed? This forum is supposed to be focused on science but it seems like a lot of potential science and new research studies are dismissed or discussion is discouraged really quickly and I don't get it?

 

[adambeyoncelowe]

It's interesting to me that 30% had this finding. This number has appeared in other studies. Jared Younger has also said he's spotted three subgroups of roughly equal size (autoimmune, post-viral, metabolic).

Maybe it'll give us some clues about where to look next, at least? Or maybe we can start to split patients in trials a bit better?

 

[Adrian]

Firstly, if a significant proportion of patients with ME had pathogenic autoantibodies one might expect there to be a noticeable response to rituximab and there was not at phase 3.

Perhaps most importantly there was no correlation between having autoantibodies and improving with rituximab at phase 2 either. Slightly more people with ME than normals seemed to have receptor autoantibodies but the difference was not big enough to suggest there was a causal link.

Could there be a selection effect in these trials where they are looking for people with higher levels of auto-antibodies hence finding a smaller subset that wouldn't be found anywhere near as often at random?

 

[Jonathan Edwards]

I totally 100 million percent understand why the BPS and PACE research is dangerous and pure nonsense. But I don't understand why the research of Dr. Ron Davis, Dr. Scheibenbogen, Cell Trend Lab, the recent study from Griffith University in Australia (re: Calcium Channels, Rituximab, and NK cells, etc), is all so quickly being dismissed? This forum is supposed to be focused on science but it seems like a lot of potential science and new research studies are dismissed or discussion is discouraged really quickly and I don't get it?

I fully understand your feelings over this @Gingergrrl, but the whole point of science is that it has to be done properly. There is no difference between PACE being badly done and dangerous and antibody-targeting trials being badly done and dangerous. The idea that ME is due to antibodies rather than psychological factors sounds good but that has nothing to do with science. Science is about whether or not the evidence adds up.

Let me give you a common sense analogy. An advert for a household cleaner goes:
This is the best cleaner ever - the proof is that it even dissolves the bottle that it comes in!
The Griffith study suggests that rituximab interferes with the cells that the drug attaches to and uses to kill B cells. So what is the point of that? If the cells in PWME are more susceptible to rituximab that just means it is less likely to work. And as far as we know it doesn't work in ME anyway. So none of it seems to make any sense.

The crucial piece of evidence relating to the receptor autoantibodies is whether or not they are at a level in ME that suggests they are important and whether it is the people with the antibodies who get better with rituximab. Neither is the case. So we do not have any evidence for an autoimmune subset based on these antibodies. They are antibodies that are pretty common in normal people.

So yes we are focussed on science. And it is worth remembering that the scientific method consists of disproving things, of showing that ideas don't add up. That was the definition of science from Karl Popper that we all recognise to be true, even if in a rather subtle way. Science has nothing to do with physical rather than mental. It has to do with things turning out to fit with explanations. Unfortunately, 95% of biomedical science is pretty makeshift, so, sadly, we have to spend a lot of time picking things apart.

 

[Trish]

Hi @Gingergrrl, I don't agree that research is dismissed on this forum. What we aim to do is examine all research and try to understand whether it is scientifically sound, and whether it provides useful progress in understanding the mechanisms and possible treatments of ME.

I am very grateful that we have people like @Jonathan Edwards and others with professional experience of medical research in the relevant areas who can point out to us the problems and flaws in some research or, in many cases, in the way non-experts are writing about that research.

It is all too easy for those of us without the necessary depth of understanding to get overexcited by articles written by non-experts that sometimes exaggerate the findings of what is often very preliminary research. It is important that this is pointed out clearly so we don't get our hopes falsely raised.

I am delighted that the scientists you mention are digging deep into ME/CFS biology which seems to be immensely complex. I am sure those scientists would the the first to agree that their findings so far are very preliminary and we shouldn't get overexcited when they are sometimes hyped up by others into more than they are.

This doesn't mean we think the research is bad, or that we reject it. It means we take a realistic view that it is very early days and we still have no clear idea about the cause or underlying biology of ME/CFS, though we have some tantalising clues.

 

[Jonathan Edwards]

Could there be a selection effect in these trials where they are looking for people with higher levels of auto-antibodies hence finding a smaller subset that wouldn't be found anywhere near as often at random?

The antibody scatter plots for normals and PWME look very similar. The range is much the same and the upper tail to the distribution is much the same. There was a statistical difference in levels but in conditions where autoantibodies are known to be important you do not need any statistics. it is like comparing a bed of geraniums with a bed of delphiniums.

 

[Mattie]

Thank you for your input @Jonathan Edwards , much appreciated.
I added a questionmark at the end of this thread title.

 

[Sunshine3]

I actually posted about Dr. Scheibenbogen's research on the other board tonight (great minds think alike @Mattie) but I am not sure why it is being dismissed over here? I understand it was a small preliminary study but it seems very solid to me that she has identified an autoimmune sub-group, or possibly a mis-diagnosed autoimmune disease group, and Simmaron feels the same and she was awarded two Ramsey Award Research Grants.

I totally 100 million percent understand why the BPS and PACE research is dangerous and pure nonsense. But I don't understand why the research of Dr. Ron Davis, Dr. Scheibenbogen, Cell Trend Lab, the recent study from Griffith University in Australia (re: Calcium Channels, Rituximab, and NK cells, etc), is all so quickly being dismissed? This forum is supposed to be focused on science but it seems like a lot of potential science and new research studies are dismissed or discussion is discouraged really quickly and I don't get it?

Agree, we have to start somewhere

 

[Andy]

I assume Cort's, I assume it's Cort, article is based on this study, https://www.s4me.info/threads/immun...ndrome-cfs-me-2018-scheibenbogen-et-al.3020/?

 

[Esther12]

This forum is supposed to be focused on science but it seems like a lot of potential science and new research studies are dismissed or discussion is discouraged really quickly and I don't get it?

I didn't see people discouraging discussion.

Sometimes headlines can seem over-hyped in a way that encourages a more cynical 'here-we-go-again' response, and there probably is a desire to avoid a cycle of over-excitement and disappointment that can follow results from small studies. I'm sure we've all seen how it can make it more difficult to have concerns about work like PACE taken seriously if there are also some patients making strong claims about the biology of ME/CFS based on really preliminary findings (even just a few people doing this can be used to try to discredit patients' concerns about unfounded psychosocial claims). It's helpful for all of us to try to keep our feet in the ground until we get stronger evidence to help us understand ME/CFS.

Fingers crossed some of these small studies do lead on to more promising findings, but we've seen from the past how many will not.

 

[Wonko]

Fingers crossed some of these small studies do lead on to more promising findings, but we've seen from the past how many will not.

Indeed, so far I am not cured, and I am not in danger of being cured. I have no official management strategy either.

So.....100% of studies so far have failed to help me, or, as far as I know, anyone else, with ME. In fact many, many studies have actively harmed me, my QoL, and prospects for the future.

So if I'm not leaping around with joy over every, or any, provisional study results, I ask people to look again at the track record, isn't boundless optimism every time a new study is published, or reported, irrational, even delusional?

We need more studies, as it appears only by weight of research will anyone get anywhere, this is not the same thing as needing to be excited about every unreplicated study that comes out......and I don't consider looking, evaluating and discussing, to be anti scientific, no matter what the conclusions reached by individuals, or the forum.

 

[Keela Too]

I agree that we shouldn't expect every avenue explored to lead to a result.

Certainly, I don't expect any psycho-social avenue to lead to anything more useful than the "counselling to cope" type of help. That, in part, is due to my lived experience of having ME - the idea doesn't fit with my first hand experience.

But I also suspect that some avenues are too readily discounted as potential areas for study. Sure, results may not be superb, sure we don't have all the answers, but I also feel that sometimes it is reasonable for patients to comment about the plausibility of a concept based on how the illness "feels" to us.

I haven't yet read the paper linked, so I don't know clearly enough how the detail of the finding stacks up, perhaps (as @JonathanEdwards says) it is not such a good hypothesis, but I still can't help feeling that immunity is going to play a big part in the eventual answer. I often feel flu-ish, not perfectly like 'flu, but similar enough for me to think my immune system is playing up..

Yet part of that flu-feeling also changed after my treatment with the ARV Tenofovir. Not only did I have a distinct improvement in my functioning after T, but the PEM changed flavour - it's still there, but somehow different. I have no real explanation as to why I responded to T whilst others didn't, nor a reason that it didn't give me total recovery. I'm still ill. So many questions.

What we really need is plenty of researchers seeking answers, formulating hypotheses, trying them out & trying again in the light of what turns up. And the more people we have attempting to find those answers (and getting funding to do so) the better chance we have of finding our way through this complex maze of understanding - towards some sort of real answer.

LOL and that's my mini-rant for this evening. xx
As you were!

 

[Jonathan Edwards]

I haven't yet read the paper linked, so I don't know clearly enough how the detail of the finding stacks up, perhaps (as @JonathanEdwards says) it is not such a good hypothesis, but I still can't help feeling that immunity is going to play a big part in the eventual answer.

What we really need is plenty of researchers seeking answers, formulating hypotheses, trying them out & trying again in the light of what turns up. And the more people we have attempting to find those answers (and getting funding to do so) the better chance we have of finding our way through this complex maze of understanding - towards some sort of real answer.

I don't think anyone is suggesting we do not study immune cells. I am absolutely in favour of that. The issue is whether or not a piece of work tells us anything that makes sense in the context of what we already know. What I think is hard for people not involved in science to realise is that so often researchers get in a complete muddle about what theory their data proves or disproves.

And I agree that we want lots of researchers looking for answers. Very often answers turn up unexpectedly. The downside is that if researchers are only looking for results that they think confirm a theory but in fact tell us nothing then they are likely to miss something interesting. I well remember in the lab when at a social event a technician admitted she had thrown out a set of results that showed no response because she thought they did not fit with the theory when in fact they told us the most interesting thing we had seen for months.

 

[Skycloud]

I do agree that research is critically picked apart on this forum but that in my opinion is a good thing. I think those who dismiss some research have reasonable reasons for doing so, which is fair enough, and views do differ.

@Gingergrrl - My current reservation eg. about Ron Davies is that he hasn't published yet; I understand that he is working towards that now - it's good he has funding. So he's made some interesting sounding presentations but I don't think a proper judgement can be made about what he's been doing just yet. That's not the same as being dismissive of his work. Similarly to want more replication and development of anyone's promising research before becoming excited is not being dismissive. As a patient I see it as keeping one's powder dry and avoiding an emotional roller coaster. Perhaps you and I are just different

 

[Esther12]

The issue is whether or not a piece of work tells us anything that makes sense in the context of what we already know.

Also, when so much around ME/CFS seems so tentative, it's worth staying open to evidence that doesn't seem to fit with it. At this stage I'd find it very difficult to make any guess as to which research groups with which ideas are most likely to turn up a substantial breakthrough.

 

[Ravn]

This forum is supposed to be focused on science but it seems like a lot of potential science and new research studies are dismissed or discussion is discouraged really quickly and I don't get it?

Do you think that maybe your impression is more due to the tone of the discussion rather than the substance? I, too, often get a first impression of instant dismissal in some of the threads here. Then, after taking a deep breath and reading more closely for substance, I find the critique is often justified. Note that I use the word critique, not criticism.

What can be missing though is some balance. Most studies contain a bit of all three of the good, the bad, and the ugly. And by acknowledging all three, rather than jumping straight to the ugly, any comment on a study becomes less of a dismissive criticism and more of a balanced and reasonable critique, all while still pointing out any problems.

Unfortunately, 95% of biomedical science is pretty makeshift, so, sadly, we have to spend a lot of time picking things apart.

Sadly not limited to biomedical research but seems to be a widespread issue in all fields of science.

Just how so much research unworthy of the name science gets funded and published is beyond me. But all the more reason to repeat and reiterate again and again the principles of good science – and to praise every glimpse of it when we see it.

And it is worth remembering that the scientific method consists of disproving things, of showing that ideas don't add up.

This may be one of the roots of the evil. We know we should be trying to demolish our own hypotheses to test how strong they really are but it's human to want to defend one's own ideas. And when we feel, rightly or wrongly, criticised we retreat further into our own position and become less open to alternative or even just more nuanced views. So to keep those researchers that are able and willing to change their views in light of new evidence we should acknowledge any good work they do as well as pointing out where we disagree.

 

[Gingergrrl]

It's interesting to me that 30% had this finding. This number has appeared in other studies. Jared Younger has also said he's spotted three subgroups of roughly equal size (autoimmune, post-viral, metabolic). Maybe it'll give us some clues about where to look next, at least? Or maybe we can start to split patients in trials a bit better?

This is my feeling as well, that there are distinct subgroups, and these researchers are working hard to figure it all out. They have to start somewhere and Dr. Scheibenbogen has no funding and is really a pioneer IMO. I have great respect for her and the fact that her study was small and preliminary does not make it wrong IMO. I hope she will do a lot more research on autoantibodies, IA, IVIG, Rituximab, all of it.

There is no difference between PACE being badly done and dangerous and antibody-targeting trials being badly

I don't understand this viewpoint but it might be because I am not in the UK. I try very hard not to comment on the UK threads since I do not live there and feel it is not my place to comment on something that I do not fully understand. But if you are comparing the PACE trial with Dr. Sheibenbogen's recent study on a true potential medical treatment and findings (immunoadsorption and autoantibodies), I don't see the connection?!

And it is worth remembering that the scientific method consists of disproving things, of showing that ideas don't add up.

But how can a single study be so immediately discounted? It might stop the researcher from doing further work. I think we need to be more open minded to different potential ideas.

I assume Cort's, I assume it's Cort, article is based on this study, https://www.s4me.info/threads/immun...ndrome-cfs-me-2018-scheibenbogen-et-al.3020/?

It is from Simmaron (and I truly do not know what Cort's connection to Simmaron is), but IMO, this should not matter b/c the research was done in Germany and is now being reported on by different articles and groups in different countries.

But I also suspect that some avenues are too readily discounted as potential areas for study. Sure, results may not be superb, sure we don't have all the answers, but I also feel that sometimes it is reasonable for patients to comment about the plausibility of a concept based on how the illness "feels" to us.

I agree @Keela Too and I think this will only help future areas of study (and I am talking about medical studies, not the BPS/PACE stuff).

What we really need is plenty of researchers seeking answers, formulating hypotheses, trying them out & trying again in the light of what turns up. And the more people we have attempting to find those answers (and getting funding to do so) the better chance we have of finding our way through this complex maze of understanding - towards some sort of real answer.

I agree.

As a patient I see it as keeping one's powder dry and avoiding an emotional roller coaster. Perhaps you and I are just different

I am not sure what keeping ones's powder dry to avoid an emotional roller coaster means (so I have no idea if you and I are different!) and do not know most of the people on this board as well as on the other board. But I like everyone here and would love to discuss the positive merits of the article that could be used in a future study vs. just dismissing it outright.

Do you think that maybe your impression is more due to the tone of the discussion rather than the substance? I, too, often get a first impression of instant dismissal in some of the threads here.

That's a great question and for me I think the tone probably plays a role but it is also the content/substance as well. I often get the impression of "instant dismissal" to use your term and I find it frustrating b/c then if I have an alternate point of view, it feels less comfortable to share it (although I did it here anyway and usually speak my mind regardless if I am in the minority view)!

 

[Jonathan Edwards]

But how can a single study be so immediately discounted? It might stop the researcher from doing further work. I think we need to be more open minded to different potential ideas.

We are not talking about a single study. We are talking about a long series of observations from the US, the UK, Norway, Australia and Germany and wherever. Science only works if you check that everything fits together. It is very complicated but we have to make sure things make sense otherwise we waste vast amounts of time and money on blind alleys.

I don't understand this viewpoint but it might be because I am not in the UK. I try very hard not to comment on the UK threads since I do not live there and feel it is not my place to comment on something that I do not fully understand. But if you are comparing the PACE trial with Dr. Sheibenbogen's recent study on a true potential medical treatment and findings (immunoadsorption and autoantibodies), I don't see the connection?!

They are directly comparable. ME may be purely brain problem and it is not impossible that talking therapy might have helped. My wife had a physical brain illness from taking an anti-malarial and although in the end it was no good, talking to her for hours would sometimes get her brain to connect back to the person she used to be. The problem with PACE was not that it was a psychiatric trial but that the theory behind it was not very good and the methods were shoddy. If research into antibodies is based on a theory that we can see has already not worked out and the methods of study are poor it is exactly the same. And the dangers of immunological treatments are probably even greater.

The reason why the BPS crowd have managed to convince the medical community that they know about ME (at least until recently) is that they can point to the patients' criticisms and say 'well that certainly isn't rigorous science'. The way to wipe out the BPS myth is to point out that it is not science, and to do that one has to be careful to show that one is using an absolutely level playing field.

I am sorry to disappoint people but I don't think a lot people realise just how muddle-headed most of what gets published in scientific journals is. And it is not so difficult to see that - members here are brilliant at seeing flaws just on a common sense basis.

 

[Skycloud]

Sorry @Gingergrrl - you're right to pull me up on my use of colloquialisms as they're not always understandable to others from different places. I guess I lapsed into them because I was tired and foggy and had started a post and was determined to finish it but it wasn't helpful to you ( and probably others too). I also didn't mean anything disparaging, I know that we all have our own way of thinking, and that I shouldn't make assumptions.

I find all the research really really fascinating. It's good for me to know when more work needs to be done, or that there might be a better way that a researcher could/should approach something, because my science education was limited and I'm learning what robust research is. I can't always make sense of it all but I learn from the papers and the discussion. I appreciate the identification of weaknesses, or potential weaknesses in research because as a patient I don't want my hopes raised unnecessarily, or prematurely when there is more work to be done (that's me avoiding the 'emotional rollercoaster' of raised hopes being dashed). The XMRV saga was a learning curve for me.

I want my GP to respond well when I go to him with solid and useful and replicated things that come up in the research. It's useful to know what he might object to in a paper. Critique, and the criticisms that can be part of it, are useful to me and I don't see them as being dismissive.

I really can't write as well as I used to be able to so I hope this is clearer and not rambling.

Please don't feel put off commenting.

edited a few times for grammar