Invest in ME/Prof Jonathan Edwards statement on UK Rituximab trial, 30 July

[Esther12]

I am interested in the frustration sensed by people within the ME community over funding.

I think that I, and perhaps other patients, were given unrealistic expectations as a result of how CFS is often treated. It is quite normal for doctors to take it upon themselves to treat CFS patients with 'positive' thinking, 'reassurance' and exaggerated claims about the understanding they have of CFS and the efficacy of treatments. It was only after being ill for half a decade that I realised none of the forms of graded exercise were leading to the recovery I was told to expect, and then another couple of years before I realised that ME/CFS could be a serious problem I might not recover from (which is still not something I've truly accepted to be honest).

The fact that people can be given reassuring claims about recovery, and then come to realise that these claims were not supported by the evidence but were actually psychosocial management performed without consent, makes it harder to then also accept that there is little money being spent on trying to really understanding the cause of one's health problems.

Also, funding for ME/CFS is low when compared to other conditions with equivalent economic impact or effect on QOL.

(Only a brief post on a complicated matter, but I don't want to take things too off topic.)

 

[Jill]

In these discussions, I'm not sure if Prof Edwards is aware of Snells research into the post exertional malaise and his test - retest protocols . Snell was trying to get a handle on metabolic data that shows, and it does show, that activity does exacerbate symptoms.
Would these tests be useful in selecting patients for the trial? I know it seems like punishment, but then atleast you would have a set of patients who all had (hopefully) the same metabolic defect.
Please watch this, if you are not familiar with the work of Snell et al.
Incidently , it looks like none of us would qualify for a heart transplant as results show we are sicker than patients that meet entry requirements for heart transplant.

 

[MeSci]

I think almost anything could fit with a B cell loop. Short lived autoimmunity sometimes occurs when B cells are returning after something like bone marrow transpantation. Some autoimmune diseases, like immune thrombocytopenia remit in quite a good proportion of cases spontaneously. Lupus quite often stops giving major problems after initial episodes have been controlled. All sorts of patterns seem to be possible. That is perhaps not too helpful for theorising because it doesn't narrow things down, but that's the way it is I think.

Have you any idea what is the longest duration of autoimmune disease known to have subsequently remitted spontaneously?

Yours,

Still an optimist after 18 years...

 

[Jonathan Edwards]

It is quite normal for doctors to take it upon themselves to treat CFS patients with 'positive' thinking, 'reassurance' and exaggerated claims about the understanding they have of CFS and the efficacy of treatments.... makes it harder to then also accept that there is little money being spent on trying to really understanding the cause of one's health problems.

Also, funding for ME/CFS is low when compared to other conditions with equivalent economic impact or effect on QOL.

Yes, I think there is every reason to be frustrated with the common practice of doctors assuming that they know all there is to know about a disease - that they 'understand' it when in fact they have no explanation available at all. That is worth trying to change, but maybe the interesting question is how you change it - how did other people make that sort of change for other diseases? - because the same problem applied to them once.

When I got interested in rheumatoid arthritis as a student (1973) I was the only one in my year remotely interested in the disease. RA was understood to be a chronic incurable illness - so it was incurable wasn't it? Even after I presented my first work on rituximab (2000) a colleague who probably considered himself eminent stood up and said he did not think we should be trying to cure RA. We still do not have a permanent cure but most patients are treated very effectively - the transformation, particularly for young adults and children, has been amazing.

There has never been any significant government funding for RA research in the UK. It is an illusion that our society has a system for paying people to research into diseases on a systematic basis. If anything we seem to be electing governments that feel that it is none of their business. But that may not matter. Research in RA in the UK was driven by two forces. One was originally called the Heberden Society, the other the Arthritis and Rheumatism Council. The Heberden Society was a group of interested doctors who had small meetings (I think there were just six 10 minute papers on original research at my first meeting, a smaller affair than the recent IiME meeting) and exchanged novel ideas. The ARC was a charity that encouraged universities to appoint such doctors to academic positions to do research. They paid for setting up almost everything although the universities took over a lot of funding because the academics were useful for teaching and also proved to be productive in research terms.

So I think what is needed is a small group of doctors and scientists genuinely interested in understanding the disease and charitable support - the two will feed off each other and grow. As I see it that has already started. The problem has in the past been not having a reproducible phenomenon, like an autoantibody, that encourages scientists to stick with the intellectual challenge of working out what is going on. I suspect we are quite close to getting something reproducible, so that's why I am optimistic.

 

[Jonathan Edwards]

Have you any idea what is the longest duration of autoimmune disease known to have subsequently remitted spontaneously?

Yours,

Still an optimist after 18 years...

Lupus can resolve after thirty years of being troublesome I would say. I have even seen RA disappear suddenly in someone I had looked after for twenty years.

 

[Sasha]

Jonathan Edwards - you mentioned in a post a while back (can't find it!) that these days, defining diseases by clusters of symptoms and expert consensus is a bit old-fashioned (I may be misrepresenting you there, but that's all I can remember!). ME of course has a big problem with definition and diagnosis. What's the modern way of doing things?

 

[heapsreal]

Is a drug like rituximab safe to use in people with immune defiencies like chronic neutropenia or low immunoglobulin sub classes etc.

 

[Jonathan Edwards]

Is a drug like rituximab safe to use in people with immune defiencies like chronic neutropenia or low immunoglobulin sub classes etc.

Low IgG is a problem but low IgA does not seem to matter. Significant neutropenia would be a worry although there may be no specific evidence it is a problem.

 

[Legendrew]

You appear to be approaching the problem for a more immunological standpoint, exploring what is measurably wrong in the immune system and specifically with the B-cells whereas Fluge and Mella seem to be concentrating more upon what effect the autoimmune response is having and how this develops into the plethora of symptoms. From my personal view this is good since your work likely complements one anothers and things progress faster along - i'm just hoping you meet in the middle as to what the immune response is targeting!

In a disease such as this where there is no measurable tissue damage do you feel the aberrant immune response is the best chance of finding a consistent and measurable abnormality? It's always difficult with something like this where there aren't many clues as to where the problem is whereas more systemic autoimmune problems have symptoms to help you along and work back from.

 

[Anne]

I am interested in the frustration sensed by people within the ME community over funding. Diseases do not in general 'not receive funding' because of some deliberate decision by anybody. Research is a free for all. If a researcher thinks he or she has a good idea they can ask for support. I am not sure that there is any particular bias against diseases.

Thank you so much Prof Edwards for being here on PR discussing with us!

About funding bias: Sadly I am aware of several cases where researchers of high quality and with cutting-edge technology are denied funding when they want to study ME/CFS, but are awarded large grants when applying to do the same kind of studies in for exemple MS.

After a few events of that sort, the researchers may realize that ME/CFS just isn't a great field for getting grants and making headway, and they turn their competence towards for example MS instead. I think we have lost a few promising leads this way, so it seems there indeed exists a bias against diseases.

 

[Jonathan Edwards]

In a disease such as this where there is no measurable tissue damage do you feel the aberrant immune response is the best chance of finding a consistent and measurable abnormality?

Not necessarily. There is a paper on NK receptor subtypes that I would like to see followed up. With narcolepsy the hard clue came from genetics (HLA-DR). A specific eye movement pattern might do. Confirmation of the effectiveness of rituximab would do. Reproducible specific muscle function abnormalities would do if they could clearly be distinguished from detraining. An autoantibody would do. As you say, though, if we found a change in B cell behaviour and the effects of rituximab were confirmed we would have not just a consistent finding but joined up consistent findings.

 

[Sasha]

I'm wondering why it has taken cancer patients who also happened to have ME being treated with rituximab to notice the effects of rituximab on ME. RA and other autoimmune diseases exclude a diagnosis of ME but I would have thought that there would have been people with ME who went on to develop RA, Sjorgren's, etc. who might also have been treated with rituximab and have seen their longstanding ME symptoms resolve as well.

I wonder if their ME symptoms might have been attributed post-hoc to their RA, etc. or whether lower doses or a different dosing schedule for autoimmune patients as opposed to cancer patients might not have been sufficient to affect their ME.

Jonathan Edwards, what do you think?

 

[MeSci]

Lupus can resolve after thirty years of being troublesome I would say. I have even seen RA disappear suddenly in someone I had looked after for twenty years.

I like this very much! Hopefully there is no reason to suppose that it can't happen in ME? Some people are sure that once you have had it for about 10 years or more you are stuck with it.

 

[Jonathan Edwards]

Thank you so much Prof Edwards for being here on PR discussing with us!

About funding bias: Sadly I am aware of several cases where researchers of high quality and with cutting-edge technology are denied funding when they want to study ME/CFS, but are awarded large grants when applying to do the same kind of studies in for exemple MS.

After a few events of that sort, the researchers may realize that ME/CFS just isn't a great field for getting grants and making headway, and they turn their competence towards for example MS instead. I think we have lost a few promising leads this way, so it seems there indeed exists a bias against diseases.

I am sure you are right to an extent. But I never managed to get any funding for anything actually original in RA - I just had to push on using money 'borrowed' from other projects. A certain amount of doggedness is needed!

 

[Jonathan Edwards]

I'm wondering why it has taken cancer patients who also happened to have ME being treated with rituximab to notice the effects of rituximab on ME. RA and other autoimmune diseases exclude a diagnosis of ME but I would have thought that there would have been people with ME who went on to develop RA, Sjorgren's, etc. who might also have been treated with rituximab and have seen their ME symptoms resolve as well.

I wonder if their ME symptoms might have been attributed post-hoc to their RA, etc. or whether lower doses or a different dosing schedule for autoimmune patients as opposed to cancer patients might not have been sufficient to affect their ME.

Jonathan Edwards, what do you think?

This is a very interesting point that had occurred to me too. It is puzzling. One would not expect there to be many people with ME who then get RA but there should have been some. The dosages are essentially the same. One interesting possibility is that ME is an autoimmune disease that you cannot have as well as RA - maybe they feed off opposite tendencies. A simpler answer is just that many more people with cancer have had rituximab than people with RA have and there may not be that many physicians as on the ball as Dr Fluge.

 

[currer]

Dear Dr Edwards,

The immune modulator Immunovir (inosine pranobex) has a good record in improving ME patient symptoms.
Perhaps studying its effects in the body and looking for biomarkers in patients who respond/don't respond to this drug would help understand what is going wrong in ME and maybe also cast light on Rituximab's therapeutic impact in ME.

After all, they are both drugs which affect the immune system but immunovir is very safe and easy to prescribe, hence easier to study than rituximab. Given the complexity of the immune system, perhaps looking at how another drug impacts the immune system in this disease may advance our understanding of the immune system abnormalities?

Professor Anthony Pinching Immunologist at St Barts (now retired) wanted to get funding for an RCT of this drug as his clinical experience showed that two thirds of his ME patients improved on immunovir. I told Dr Fluge about this when I met him and gave him some information. He seemed quite interested at the time as he already had had some contact with Prof Pinching during the design of the original rituximab study.

Just my two cents.

 

[Gemini]

Low IgG is a problem but low IgA does not seem to matter.

Professor Edwards, in autoimmune patients with high IgG does that tend to normalize after rituximab therapy? And, I apologize if this has already been asked, in my re-reading of Eng Tan's paper in Arthritis & Rheumatism which notes: "Since the autoantigens were targeted by autoantibodies of the IgG class and autoantibodies of IgM or IgA were rare, the ongoing immune response in CFS might be due to antigen-driven maturation of memory B lymphocytes and release of IgG from plasma cells" I'm most interested in your assessment of Tan's 1996-97 findings of autoantibodies to insoluble cellular antigens and whether his work might inform current research in any way? Reason for asking I was fascinated by how in your description of your RA discovery you went back to an observation you had made many years prior and am wondering if something like that could happen with ME/CFS?

http://www.ncbi.nlm.nih.gov/pubmed/9041942

http://www.ncbi.nlm.nih.gov/pubmed/8878441 Open Access

 

[Jonathan Edwards]

The immune modulator Immunovir (inosine pranobex) has a good record in improving ME patient symptoms.

From what I can see on the net it does not look as if inosine pranobex has reproducible effects. Others may know more but the rationale for its usage looks a bit simplistic too. I am very keen to learn about all sorts of possibilities but this one doesn't grab me I'm afraid.

 

[Jonathan Edwards]

Professor Edwards, in autoimmune patients with high IgG does that tend to normalize after rituximab therapy? And, I apologize if this has already been asked, in my re-reading of Eng Tan's paper in Arthritis & Rheumatism which notes: "Since the autoantigens were targeted by autoantibodies of the IgG class and autoantibodies of IgM or IgA were rare, the ongoing immune response in CFS might be due to antigen-driven maturation of memory B lymphocytes and release of IgG from plasma cells" I'm most interested in your assessment of Tan's 1996-97 findings of autoantibodies to insoluble cellular antigens and whether his work might inform current research in any way? Reason for asking I was fascinated by how in your description of your RA discovery you went back to an observation you had made many years prior and am wondering if something like that could happen with ME/CFS?

http://www.ncbi.nlm.nih.gov/pubmed/9041942

http://www.ncbi.nlm.nih.gov/pubmed/8878441 Open Access

In most autoimmune diseases the IgG autoantibodies will only be a small proportion of total IgG (the rest is to bugs). We see autoantibodies fall but the total IgG level stays fairly stable - we think because quite a lot of autoantibodies are made by short lived plasma cells, whereas most IgG is made by long lived plasma cells. On the other hand in patients with grossly high IgG levels as part of their autoimmune response the level may normalise completely. Strangely, in patients with low IgG as part of their autoimmunity this sometimes comes up to normal.

I had not seen the Tan paper before. The question is why it was never followed up. Presumably it did not prove repeatable? There are various features of the data that look a bit 'non-specific' - the low antibody levels and the patterns on staining. But I would like to know from immunologists who have tried to repeat this why it has not been widely accepted as the situation. I have a rather strong feeling that there are in fact quite a lot of autoantibodies around in CFS patients that are getting ignored because there are lots of different ones. I am not sure that is a good reason to ignore them. We have already talked about thyroid antibodies. Researchers often take a rather simple minded view of data of this sort and I think they may be underestimated. However, it is essential that we stick to results that can be confirmed in at least three different laboratories (and not just commercial institutions selling their wares!).

 

[cornwall13]

Professor Edwards

This is the imunovir sheet, which Professor Pinching gave to me about 4 years ago , when I tried imunovir. I am not allowed to take it now because my new specialist won't prescribe. However, I found that when I first took the drug it seemed to have really positive effects. But I found that the effect was almost immediate to me. And I actually went up to 6 tablets a day, which he allowed. I can't really go into too much detail here, but I did do a graph of pre 6 months and post 6 months of imunovir of how my health was, and there was what I would describe a dramatic improvement.

Regards