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

[Jill]

Where did you read this Jill? I can't seem to find anything on IiME website or Facebook. Is it a recent announcement? Thanks.

This was on another forum site - looks like its come from facebook.

I'v just gone back in the thread and realised you've discussed the fibro study - sorry

https://www.facebook.com/groups/2379871070/10151971491711071/Current and Planned Research Studies

MICROBIOME - A role for a leaky gut and the intestinal microbiota in the pathophysiology of myalgic encephalomyelitis. This has been fully funded already and begins in autumn 2013.

RITUXIMAB - Invest in ME have now initiated a UK rituximab project with UCL. A specific web site has been set up to document this project - see www.ukrituximabtrial.org.

Autoimmunity and ME:
HYPOTHALAMUS - Invest in ME are working with researchers, as part of the examinations facility proposal and to support the rituximab trial, on a more comprehensive and detailed analysis of antibodies binding the hypothalamus. This is important as these are more likely to explain various ME symptoms. This, along with a search for anti-cytokine antibodies, will form the first the part of work on autoimmunity in ME. This project will take between 15 and 18 months with a further 3 months for data analysis and publication.

EDUCATION
This is a scheme which Invest in ME will fund whereby medical students will be enrolled in a Masters degree course whilst performing their medical training. The MA course would be related to research into ME and be performed at UEA. In the first instance we are looking at funding two students - at a cost of up to £10000 each. The knowledge gained and the publicity obtained by these courses will be beneficial for future research and awareness, as well as influencing medical colleges. The funding of these medical students will be via the Invest in ME Biomedical Research Fund.

 

[Jonathan Edwards]

@Jonathan Edwards, question for you. In RA there must be patients for whom Rituximab is not working for them. How do you explain that, since logically Rituximab kills auto-antibodies?

And have responders vs non-responders have been researched in term of what is similar and what is different?

Thank you

A proportion of people who are diagnosed with RA have no autoantibodies. In general they do not respond to rituximab, which makes sense. We have always known that it is not always possible to distinguish RA from other sorts of inflammatory arthritis like psoriatic arthritis, especially when there is no psoriasis to see so it seems likely that a proportion of 'RA non-responders' do not have a B cell related disease.

Then there are people whose joints are so badly damaged that they do not get much benefit from any drugs.

Of the remainder with autoantibodies most respond well but there also seems to be a small group with a lot of inflammation whose disease responds very slowly and is hard to get fully under control. This is not actually that surprising. Remember that rituximab does not kill the cells that actually make the autoantibodies (i.e. plasma cells), it kills younger B cells that might one day become plasma cells, so there is a lag in the effect. If the plasma cells making autoantibodies live long enough, and we know that some can live for up to ten years, then repeated courses of rituximab for several years may not reduce antibody levels enough to control inflammation. We tend to see rheumatoid factor levels dropping to about a half the original level in responders, which often seems to be enough, but clearly it might not always be. Even for B cells we have reason to think that some can hide away in lymph nodes and survive rituximab.

So it is not that difficult to explain non-responses. What is needed is a something that actually kills all autoantibody producing plasma cells. The problem with that is that it needs to be specific for autoantibody producing plasma cells rather than useful plasma cells and we do not know how to do that.

 

[Kati]

Thank you so much for your answer.

 

[Firestormm]

@Jill thank you. I missed those

 

[Bob]

A new update re funding for the Norwegian Rituximab trial (not the UK trial).
It seems that they've got all the funding they needed, and more:
http://mariasmetode.no/2013/11/update-haukeland-english/

 

[Marco]

For those of you who like to speculate (like me ) I've written up a little something on an autoimmune mechanism that 'may' be relevant to ME/CFS :

FROM CHRONIC REGIONAL PAIN SYNDROME TO FIBROMYALGIA TO ME/CFS? THE ‘SPREADING NEUROINFLAMMATION’ MODEL

http://www.cortjohnson.org/blog/201...lgia-mecfs-spreading-neuroinflammation-model/

 

[Bob]

@Jonathan Edwards

I wonder if you have seen this paper, and if you think it has any merit, and if you think it might have any potential as a plausible hypothesis for ME?

Immunological trigger events have often been associated with ME. Reported trigger events have included: receiving vaccinations (e.g. Hep B); travel abroad esp after vaccination; and having an illness or infection.

The full paper is accessible.


Self-Organized Criticality Theory of Autoimmunity
Tsumiyama K, Miyazaki Y, Shiozawa S
Published: December 31, 2009
PLoS ONE 4(12): e8382.
doi:10.1371/journal.pone.0008382
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008382

PDF format:
http://www.plosone.org/article/fetchObject.action?uri=info:doi/10.1371/journal.pone.0008382&representation=PDF

Abstract

Background

The cause of autoimmunity, which is unknown, is investigated from a different angle, i.e., the defect in immune ‘system’, to explain the cause of autoimmunity.

Methodology/Principal Findings

Repeated immunization with antigen causes systemic autoimmunity in mice otherwise not prone to spontaneous autoimmune diseases. Overstimulation of CD4+ T cells led to the development of autoantibody-inducing CD4+ T (aiCD4+ T) cell which had undergone T cell receptor (TCR) revision and was capable of inducing autoantibodies. The aiCD4+ T cell was induced by de novo TCR revision but not by cross-reaction, and subsequently overstimulated CD8+ T cells, driving them to become antigen-specific cytotoxic T lymphocytes (CTL). These CTLs could be further matured by antigen cross-presentation, after which they caused autoimmune tissue injury akin to systemic lupus erythematosus (SLE).

Conclusions/Significance

Systemic autoimmunity appears to be the inevitable consequence of over-stimulating the host's immune ‘system’ by repeated immunization with antigen, to the levels that surpass system's self-organized criticality.

 

[Jonathan Edwards]

@Jonathan Edwards

I wonder if you have seen this paper, and if you think it has any merit, and if you think it might have any potential as a plausible hypothesis for ME?

I am afraid that I can say from the abstract that this is a very bad piece of science. The conclusion is totally unjustified. The experiments are just irrelevant. As I mentioned a while ago, the cause of a disease in mice caused by researchers injecting masses of foreign material is not the cause of human autoimmunity - it is researchers injecting antigens. This sort of nonsense has been going on since the 1960s and looks as if it will not change. We have a pretty good idea of how autoimmunity comes about. It is not through being a small rodent in a cage in a lab! It occurs very unpredictably over a period of decades in Homo sapiens. maybe sometimes there is a trigger but not the sort they are describing. What is worrying is that this sort of work, with this sort of lazy conclusion, is now taken as being respectable. Science has been dumbed down by the commercialisation of journals and various other things.

In other words: 'Nul points' as they say on Eurovision.

maybe I'm getting old, but I don't think so yet.

 

[Bob]

What is worrying is that this sort of work, with this sort of lazy conclusion, is now taken as being respectable. Science has been dumbed down by the commercialisation of journals and various other things.

Thanks for your views. We patients have noticed that a lot of dodgy stuff gets published, despite it being allegedly peer reviewed.

 

[Bob]

I thought this article might be of interest to folk following this thread, and to Prof Edwards:
http://www.theguardian.com/society/2013/nov/17/alzheimers-arthritis-drug-new-weapon

It describes how they are going to test etanercept for Alzheimer's.
Etanercept is a drug widely used for rheumatoid arthritis, and is also being tested by Fluge and Mella for patients who are not responsive to Rituximab.

There's a separate forum thread for this, here:
http://forums.phoenixrising.me/index.php?threads/arthritis-drug-for-alzheimers.26525/

 

[Jill]

Here is an Opinion piece which I thought brought together a lot of ideas that Prof Edwards might appreciate. Similarities and diffs between ME vrs MS

http://www.biomedcentral.com/1741-7015/11/205

 

[Jonathan Edwards]

Here is an Opinion piece which I thought brought together a lot of ideas that Prof Edwards might appreciate. Similarities and diffs between ME vrs MS

http://www.biomedcentral.com/1741-7015/11/205

Thanks Jill,
Bob flagged this paper up in September and I ducked out of commenting. Some other relevant comments have been made so I feel a bit more comfortable about doing so now. It is written as if by a rather overenthusiastic student on one of the non-clinical biomedical science courses. Full marks for reading references but not so many marks for critical analysis. Not up for the course medal. The stuff on rituximab is mostly nonsense I am afraid. I am slightly surprised that a senior academic has put his name to it.

I may sound stuffy at times, but, as you may have noticed, I am about as subversive as you can get in terms of received dogma. The truth is that this is not how science gets done, even if, in this era of publishing as commercial advertising (both for the publishing company and the authors), a lot of people in science have come to think it is. The secret is to look for things that DON'T fit, not for things that fit, to see why ideas do not quite work and move on to ones that do. Similarities are two a penny. Important inconsistencies are not.

Still, it is worth looking at everything that comes along. Other people's attempts to piece things together can be very useful for making one realise why one idea does not quite work and another does.

 

[Marco]

@Jonathan Edwards

While you're on the subject, a critical appraisal of this just published (full) paper would be very welcome :

Epitopes of Microbial and Human Heat Shock Protein 60 and Their Recognition in Myalgic Encephalomyelitis

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081155

 

[Simon]

..The secret is to look for things that DON'T fit, not for things that fit, to see why ideas do not quite work and move on to ones that do. Similarities are two a penny. Important inconsistencies are not.

Thanks for the critique: I think that philosophy would have saved more than a few dead ends in mecfs research.

 

[Jonathan Edwards]

@Jonathan Edwards

While you're on the subject, a critical appraisal of this just published (full) paper would be very welcome :

Epitopes of Microbial and Human Heat Shock Protein 60 and Their Recognition in Myalgic Encephalomyelitis
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081155

I think these results are quite interesting but I think the most useful sentence in the paper may be:
"Although we find relatively high levels of antibodies to specific HSP60 epitopes in ME, the high frequency of anti-HSP60 antibodies in control samples, and the high conservation and many functions of HSP60, argue against simplistic conclusions regarding its etiological role(s) and possible therapeutic implications."

Heat shock proteins (HSPs), especially HSP60 have fascinated research workers since about 1985 and antibodies to HSP60 have been looked for in lots of diseases. They have often been found, but this is really the problem, there does not seem to be a lot of specificity about them. The authors come up with sentences like "HSP60 is a central autoantigen." but I am not sure they are entitled to. Antibodies to HSP60 are trendy in labs but for someone like me working with autoimmune disease in the clinic they were never more than a sort of vague non-secific suggestion that kept coming up and dying down - a sort of pervasive low level noise. You cannot really talk of a 'central autoantigen' because for the antigens that correlate closely with clinical disease, each disease has a different autoantigen. If you are looking for an explanation for ME, and specifically ME, then HSP60 seems rather unlikely to help, simply because it does turn up so often.

There are also technical aspects to the paper that I am not sure help much. Antibodies react with whole proteins and I am not sure what antibody binding to peptides (fragments) tells us. To me what is relevant is whether or not there are antibodies to the whole human protein. Again, the authors bring in the story about cross reactivity between bacterial and human proteins but this story has never had much (?any) evidence for it and the data do not tell us one way or another. There is a touch of the usual looking for what everyone thinks one should find and finding it.

Nevertheless, if the ME patient had more autoantibodies to human HSP60 than controls that does seem to fit with the more general idea that those patients may have one or more autoimmune diseases (or ME subtypes if you like). What does seem to be true about antibodies to HSP60 is that they are more common in people with autoimmunity of various sorts. The downside is that this could be just another rather vague bit of circumstantial evidence for an idea already supported by some rather better evidence (from response to rituximab). But if, say, three other labs could show that three other unselected ME cohorts had comparable increases in antibodies to HSP60 I think that would be something pretty impressive, as support for an autoimmune basis in general terms. The evidence may be circumstantial but it may be at this stage that just systematically repeating this sort of observation will allow a much higher level of confidence in an autoimmune theory. That is not trivial because once that confidence gets to a certain level trying treatments like rituximab becomes easier to justify not just in formal trials but on a single patient basis.

 

[Marco]

Nevertheless, if the ME patient had more autoantibodies to human HSP60 than controls that does seem to fit with the more general idea that those patients may have one or more autoimmune diseases (or ME subtypes if you like). What does seem to be true about antibodies to HSP60 is that they are more common in people with autoimmunity of various sorts.

Many thanks. That was very useful. I've just finished (my first) reading of the paper and it does seem (including file S1 - the supplementary material) quite a considered and careful paper whose conclusions (your own concerns excepted) don't go too far beyond the findings.

They did appear to go to some convoluted lengths though to establish significant differences between the ME group and controls and as, par for the course, most significant differences obtained in the initial cohort tend to disappear when applied to a new cohort.

I was also struck by their observation that immunoreactivity in healthy blood donors may vary by year or season. I wonder how often this has been a confounding factor.

Getting back to your quote above, the lack of specificity I find comforting. Despite what some would claim, none of the symptoms of ME/CFS are specific to that diagnosis and the most common symptoms (fatigue, neurocognitive symptoms, sleep disturbances) are quite common in other autoimmune diseases.

 

[Jonathan Edwards]

... it does seem (including file S1 - the supplementary material) quite a considered and careful paper whose conclusions (your own concerns excepted) don't go too far beyond the findings.

They did appear to go to some convoluted lengths though to establish significant differences between the ME group and controls and as, par for the course, most significant differences obtained in the initial cohort tend to disappear when applied to a new cohort.

... the lack of specificity I find comforting. Despite what some would claim, none of the symptoms of ME/CFS are specific to that diagnosis and the most common symptoms (fatigue, neurocognitive symptoms, sleep disturbances) are quite common in other autoimmune diseases.

Yes, I tend to agree. But there may be subtleties. In RA there are HSP60 antibodies but I doubt they cause fatigue in RA - I think that comes from the specific antibodies - rheumatoid factor or anti-citrulline - and TNF release. HSP60 antibodies look to be a bit like the 'smoke with a fire' - an epiphenomenon maybe. As another example, in scleroderma you get more or less the same symptoms from one of three quite different autoantibodies. Everyone with scleroderma has an autoantibody but each person only has one of the three options. So, despite some sceptical remarks from some quarters, I am a believer in each autoimmune ME patient having their own specific autoantibodies (maybe twenty options?) as well as anti-HSP60 smoke. The difficulty with twenty different autoantibodies is that none of them might each show up in enough cases for anyone to take notice, so we may learn more from looking for the smoke at the moment. But I could be wrong.

 

[Marco]

Yes, I tend to agree. But there may be subtleties. In RA there are HSP60 antibodies but I doubt they cause fatigue in RA - I think that comes from the specific antibodies - rheumatoid factor or anti-citrulline - and TNF release. HSP60 antibodies look to be a bit like the 'smoke with a fire' - an epiphenomenon maybe. As another example, in scleroderma you get more or less the same symptoms from one of three quite different autoantibodies. Everyone with scleroderma has an autoantibody but each person only has one of the three options. So, despite some sceptical remarks from some quarters, I am a believer in each autoimmune ME patient having their own specific autoantibodies (maybe twenty options?) as well as anti-HSP60 smoke. The difficulty with twenty different autoantibodies is that none of them might each show up in enough cases for anyone to take notice, so we may learn more from looking for the smoke at the moment. But I could be wrong.

A major problem.

So what 'smoke' should we be looking for? Cardinal symptoms that are non speciifc?; atypical symptoms that overlap with other disorders, a particular cytokine signature that probably isn't specific?

What is it that is common about autoimmunity potentially arising from up to twenty autoantibodies that would result in a diagnosis by exclusion of ME/CFS rather than another autoimmune disease or non autoimmune condition that shares similar symptoms?

I'll stick my neck out and suggest that ME/CFS is not a discrete clinical condition but a particular constellation of symptoms (perhaps of autoimmune origin) that doesn't neatly fit into an alternative diagnosis.

 

[Jill]

Prof , said : "The secret is to look for things that DON'T fit, not for things that fit, to see why ideas do not quite work and move on to ones that do. Similarities are two a penny. Important inconsistencies are not."

Thinking on this angle, one thing that strikes me about ME is that the severe people also have the strangest reactions to medications. I've always thought this should "tell" us something. For example, recently a friend had all his pain helped by SR voltaren 75mg, BUT he is now so weak he can't walk unaided ( the weakness comes from puffing like a 120 yr old with obstructive heart failure) . He hates the thought of the pain back ( it appears like joint pain, even has some redness), but I suspect thats what will have to happen as he is possibly reacting to the voltaren.
He may of course, have also now developed some form of arthritis that doesn't show up in RF, ANA , CRP or sed rate. If that is the case he will have to be tried on a different type of med, but the question is , which sort do we punt for? Do folk with arthritis have this sensitivity to meds?

 

[Jonathan Edwards]

A major problem.

So what 'smoke' should we be looking for? Cardinal symptoms that are non speciifc?; atypical symptoms that overlap with other disorders, a particular cytokine signature that probably isn't specific?

What is it that is common about autoimmunity potentially arising from up to twenty autoantibodies that would result in a diagnosis by exclusion of ME/CFS rather than another autoimmune disease or non autoimmune condition that shares similar symptoms?

I'll stick my neck out and suggest that ME/CFS is not a discrete clinical condition but a particular constellation of symptoms (perhaps of autoimmune origin) that doesn't neatly fit into an alternative diagnosis.

I am not sure it is such a big problem. Non-specificity in relation to 'disease' pigeonholes does not matter if the feature of interest indicates a sort of mechanism to which one can target a rational treatment. Anti-HSP antibodies may not be specific for any pigeonhole but they are pretty good evidence for a disturbance in B cell function. The fact that they do not distinguish ME from other autoimmune diseases is OK if the treatment is the same.

What would make sense to me would be for the research community to systematically repeat all the studies of this sort to see whether the results really are consistent. If they are confirmed then the long haul of looking for specific antibodies is more clearly justified. Some sort of specificity of the process ought to be there to explain why ME does not include glomerulonephritis, for instance. But even within disease groups where the antibodies are well documented there are lots of fine detail differences between cases that we cannot account for. That is not surprising because for any one antigen target (like thyroid peroxidase or DNA) you can make thousands of slightly different sorts of antibodies.