Extended B-cell phenotype in patients with ME/CFS: A cross-sectional study

[A.B.]

Not to make too much or it but I have wondered lately why certain parties haven't tried to set up a 'ritux debunking' study as happpened in the past and there has been little overt criticism apart from some off target comments suggesting that the late response was evidence against autoimmunity.

If one looks at diseases that were claimed to be psychosomatic, the impression is that most of them are autoimmune or otherwise closely connected to immune system activity.

Maybe they are reluctant to explore the autoimmune angle because they are well aware of history and have a good idea of what's likely to happen.

 

[BurnA]

Has anyone noticed that ME researchers in Europe are looking at autoimmunity, and those in the USA (along with KDM in Europe) are looking at infections? I wonder why it has worked out like this - Prof. Edwards, any ideas? Do Europeans love a nice autoimmune disease? Do Americans prefer a good old infection?

Is it just a case that the European researchers are involved and looking at autoimmunity because of rituximab. If the rtx trials hadn't happened maybe they wouldn't be involved at all ? I assume this is the case for UCL.

The researchers in US do appear to be focused more on viral infection - perhaps because they have been involved longer and autoimmunity wasn't as valid a theory when they got involved ? Also the outbreak in Tahoe would have pointed towards a virus perhaps.
It's surprising though that they haven't recruited more immunologists into the fold, or that none have joined.
I think there will be a whole lot more once the phase 3 results are out and hopefully demonstrate efficacy.

 

[deleder2k]

I suspect because it would require a very large amount of money and non-psychiatric manpower to run a "debunk rituximab" trial whereas with the XMRV thing it was very easy to run tests on their fatigue clinic convenience blood samples.



I'd be curious to know what Fluge and Mella thought of ME/CFS (if they even knew about it) before their accidental discovery.

Olav Mella had some sort of relative with ME, but she died many years ago. He said that he didn't know anything about ME (like most doctors) before their discovery.

 

[Marco]

I'd hazard it has something do with them lacking the necessary skill set

And also lacking the supporters with the necessary skill set. They tend to target neurologists pretty heavily with the psychogenic theories, but not so much rheumatologists or oncologists. Who would they find with the credentials to run the debunking study?

I don't know. There seemed to be no problem recruiting some top retrovirologists (at one stage they seemed to be queuing up to sudy it). Maybe we got the wrong end of the stick and the debunking impetus was coming from the retrovirologists?

 

[A.B.]

I didn't follow the XMRV story but it could very well be that retrovirologists quickly understood that something was wrong and wanted to debunk the claims.

 

[alex3619]

Unless you have ME in which case I'm sure it sucked every bit as much as the UK does.

Yes, and no. I know of a Norwegian pwme who gets to go to regular health camps, funded by the state, where she is looked after and taught things that might help. The big down in Norway is the same as in much of Europe, far too many doctors are considering that ME is primarily psychological.

One thing we have to consider is that aside from psychs (in Europe at least) there are not many researchers for ME and CFS, and not much funding. People tend to have their own research programs, based on their own expertise and history, and with limited funding they don't get to do very much of that either, certainly not all the studies I am sure they want.

With a small number of researchers, and very limited funding, there is not as much diversity in research as we need. Some of the people new to ME research are being brought in as part of collaborations, so they are joining an existing research program.

If ME, a quite common disease, and CFS, a quite common diagnosis, did not get such limited funding that in the history of the entire illness there has probably been less funding than many other diseases get in a single year, then we would be seeing a very different situation.

 

[alex3619]

I didn't follow the XMRV story but it could very well be that retrovirologists quickly understood that something was wrong and wanted to debunk the claims.

Trying to debunk scientific claims is normal in science. Its expected. The problem with those jumping on the XMRV-debunking-bandwagon was that many of them were running limited studies and making hyperbolic claims they debunked the XMRV finding. Only some of the studies against XMRV were of sufficient quality to take seriously, including the Lipkin, Mikovits et. al. study that put the XMRV theory to rest.

 

[M Paine]

It's surely within the realms of possibility that a Virus, particularly one which infects immune cells, could be responsible for host autoimmunity. Viral gene products could be interfering with host immune function, or perhaps other mechanisms.

Perhaps autoimmunity and infection go hand in hand, being two sides of the same coin.

 

[SOC]

Has anyone noticed that ME researchers in Europe are looking at autoimmunity, and those in the USA (along with KDM in Europe) are looking at infections?

Aren't there several US physician/researchers giving Ritux as part of small studies? I know some US patients are getting it and I thought they had to meet certain research requirements. Or are the doctors simply using it off-label not as part of a research program, which seems a bit unlikely, but possible.

 

[RustyJ]

Only some of the studies against XMRV were of sufficient quality to take seriously, including the Lipkin, Mikovits et. al. study that put the XMRV theory to rest

Although I can't comment on the quality of the other studies, Mikovits would very much dispute your view of this study.

It's all about the funding. The debunking was coordinated between the UK and US which may indicate that the funding on both sides of the Atlantic was coming from the same sources.

What is clear is that the studies were undertaken to debunk the science or non science of XMRV, not to validate or investigate.

Perhaps the fact that Rituximab is not so targeted at any infectious cause or at a particular infectious cause is the reason it hasn't triggered a response.

 

[halcyon]

The previous findings of Bradley and Bansal were not replicated but there is a suggestion that there may be a subtle shift in early B cell trafficking that may be hard to pin down consistently with traditional cell sorting techniques but may still prove consistent if techniques are refined.

If I'm understanding correctly, CD24 (aka HSA) is an adhesion molecule that binds to P-selectin expressed on epithelial tissue, so these findings might indicate that we have a potential for increase in B lymphocyte recruitment into tissues? Also I assume CD24 expression is driven by cytokine exposure? Obviously not enough data in this research to make a jump like this but seems compatible at least.

 

[alex3619]

What is clear is that the studies were undertaken to debunk the science or non science of XMRV, not to validate or investigate.

That is normal scientific practice. Its also considered to be fairly solid evidence that if the author cannot replicate a study in blinded conditions then they were wrong. Its up to them to prove otherwise. The originators of the study that was tested often dispute the findings afterward. I have never heard of a case where a scientist has later proved they were right in these conditions, though Mikovits does deserve the chance to try. There will be funding issues though.

Its good scientific practice to try to break the findings from a study, aside from early validation studies. Its bad practice to just try to confirm a study, and nothing else, which is why too much psychiatry is psychobabble. The issue with XMRV is that many inadequate and underpowered studies to try to break the XMRV findings had exaggerated claims about what they showed. This was a failure to produce good contrary evidence, except for a very small number of studies.

Science is full of disproved findings. Its an essential feature of science. Something being disproved in science is not grounds, by itself, to consider anything bad about a researcher. Science goes down many false paths. That is normal.

 

[jimells]

Olav Mella had some sort of relative with ME, but she died many years ago. He said that he didn't know anything about ME (like most doctors) before their discovery.

So not only are they competent researchers, but they actually listen to their patients as well.

 

[deleder2k]

So not only are they competent researchers, but they actually listen to their patients as well.

He talks about it here (remember to turn on subtitles):

 

[CFS_for_19_years]

He talks about it here (remember to turn on subtitles):

Best comment posted on YouTube:

* stands up *
* applauds *
* has PEM for an hour *

 

[Forbin]

It's surely within the realms of possibility that a Virus, particularly one which infects immune cells, could be responsible for host autoimmunity. Viral gene products could be interfering with host immune function, or perhaps other mechanisms.

Perhaps autoimmunity and infection go hand in hand, being two sides of the same coin.

I don't know if the below are a dumb questions, but what the heck...

In autoimmunity, the immune system can start attacking cells of the body itself. Can the immune system also attack... the immune system?

Could this cause a perpetual war, with the body re-supplying both sides with new "soldiers"?

Or maybe there's only one side. Could defective immune cells actually be attacking other immune cells with the exact same defect?

Would any of this wind up looking like chronic immune activation?

 

[M Paine]

Autoimmune neutropenia is one autoimmune disease in which the immune system attacks neutrophils. Not sure of any others, but perhaps during Systemic lupus erythematosus it may also happen as well

 

[valentinelynx]

Hypergammaglobulemia? Mine has always been on the low side of normal. i.e. it was last like 900 in a range of 700 to 1600 with some subclasses also showing as borderline low.

My IgG is low, mid-400s.

 

[BurnA]

This paper is the initial study in the B-cell research prerequisite to a UK trial of rituximab, and meanwhile adding value to the Phase III Norwegian trial.

@Jonathan Edwards are you able to say where this leaves the prerequisite work for a rtx trial ? I realise you can't say much in terms of details but can you say if further work is now required or do the results of this paper steer you in a different direction ? Is it a case of back to the drawing board or are there several strands to this work. I know you have to be tight lipped on this subject so if you can't say anything that's ok.

 

[Jonathan Edwards]

@Jonathan Edwards are you able to say where this leaves the prerequisite work for a rtx trial ? I realise you can't say much in terms of details but can you say if further work is now required or do the results of this paper steer you in a different direction ? Is it a case of back to the drawing board or are there several strands to this work. I know you have to be tight lipped on this subject so if you can't say anything that's ok.

As you know, I have ben asked not to give a running commentary on this. All I can really say is that a lot of positive things have happened in the last year and that although getting a trial fixed is not one of them the idea is no less in frame than it ever was. Logistics have just been complicated.