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

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(I don't know how to do the @ quote thingy - duh will have to read up I guess)

Sasha:
This is what I had understood also from the Invest in ME conference of May this year. I was under the impression that the results presented were to be published at the end of your summer ie end of our winter - which is about now??

Professor:
I hope to see Peter shortly and will pass on your regards. He is still working (google Middlemore and his name and you'll find him - or let me know and I'll find his email for you) , although is semi retired. He has always had an interest in ME - I think more because people got sent to him - not that he knew much about it. He advocated a lot for arthritis patients when rituxan wasn't approved by our drug buying agency. I think *he * basically got Rituxan approved eventually , he was on the case and in the papers supporting the patient lobby. Hilarious you know him, but I thought you might because wasn't he involved in the worldwide rituxan arthritis trials?
Yes, I think the open label study will be ready for publication quite soon. The response rate is a little higher than in the controlled trial but fairly similar. It provides more information about repeated treatments and general safety and tolerability but being an open study will not be seen as moving the key question of proof of efficacy forward. The big multicentre study will be the gold standard for that and hopefully we will have more evidence from a UK study not too far down the line.

Peter may have been involved in rituximab studies in RA after I left that to the company to work up for a license. There was certainly a lot of interest in the Antipodes in the idea of using rituximab even before I got started on it. I was asked to talk about it at the big OZ/NZ meeting in 1998 just before we treated patients.
 
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He has always had an interest in ME - I think more because people got sent to him - not that he knew much about it. He advocated a lot for arthritis patients when rituxan wasn't approved by our drug buying agency. I think *he * basically got Rituxan approved eventually , he was on the case and in the papers supporting the patient lobby.
Hmm, NZ in general seems quite stingy when it comes to useful drugs. :(
http://www.stuff.co.nz/sunday-star-times/features/740504/A-bitter-pill-10-drugs-you-can-t-have
 

aimossy

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this man sounds useful then jill???
we have a weird bulk buying system that annoys big pharmaceuticals.... that is in my memory but that could be inaccurate...
I think we are behind with new drugs snow leopard you are right!....that I am pretty positive about.:)
 

Legendrew

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This was recently brought to my attention through facebook and I thought it worthwhile posting it here to get your opinions Jonathan Edwards. This research relates to a potentially promising hypothesis for the pathology of fibromyalgia however given the commonality between ME and FM it seems it could be of limited use in ME research - especially given that it ties together both the cardiovascular and nervous system, both of which appear to play roles within the pathology of ME.

Paper: http://onlinelibrary.wiley.com/doi/10.1111/pme.12139/abstract
Article: http://communities.washingtontimes....ct/17/fibromyalgia-solved-pathology-not-mind/

That aside I've recently been diagnosed with primary hyperparathyroidism as opposed to ME, so hopefully that can be sorted quite soon. I'm hoping to still play an active part both here on Phoenix Rising and hoping to return to university next year studying biomedical sciences, perhaps with a focus on immunity and autoimmunity - I guess I've been inspired. I'd like to personally thank Prof. Edwards for all the responses you've been making here.
 

Bob

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This was recently brought to my attention through facebook and I thought it worthwhile posting it here to get your opinions Jonathan Edwards. This research relates to a potentially promising hypothesis for the pathology of fibromyalgia however given the commonality between ME and FM it seems it could be of limited use in ME research - especially given that it ties together both the cardiovascular and nervous system, both of which appear to play roles within the pathology of ME.

Paper: http://onlinelibrary.wiley.com/doi/10.1111/pme.12139/abstract
Article: http://communities.washingtontimes....ct/17/fibromyalgia-solved-pathology-not-mind/
There's a thread about this, with links to the journal editorials/commentaries etc, in case anyone is interested:
http://forums.phoenixrising.me/inde...d-a-pathology-not-in-the-mind-research.25944/
 
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I had a quick look at the abstract of this study. The main paper was not open access which I think is bad form these days. The abstract is a bit thin on scientific hard currency - data numbers and statistics and key points on methodology. (I used to do quantitative histology and it is fraught with technical problems.) I also find it a bit hard to believe that a consistent physiological finding would be seen in 'fibromyalgia' which I have always assumed was far more of a rag bag even than ME. I am ready to believe this is interesting but the authors would have done better to present it in a more convincing format!
 

aimossy

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In the new research section there is a thread, emerging role of autoimmunity in ME/CFS that I have found interesting I am trying to get my head around the information in this.
 

Marco

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This was recently brought to my attention through facebook and I thought it worthwhile posting it here to get your opinions Jonathan Edwards. This research relates to a potentially promising hypothesis for the pathology of fibromyalgia however given the commonality between ME and FM it seems it could be of limited use in ME research - especially given that it ties together both the cardiovascular and nervous system, both of which appear to play roles within the pathology of ME.

Paper: http://onlinelibrary.wiley.com/doi/10.1111/pme.12139/abstract
Article: http://communities.washingtontimes....ct/17/fibromyalgia-solved-pathology-not-mind/

That aside I've recently been diagnosed with primary hyperparathyroidism as opposed to ME, so hopefully that can be sorted quite soon. I'm hoping to still play an active part both here on Phoenix Rising and hoping to return to university next year studying biomedical sciences, perhaps with a focus on immunity and autoimmunity - I guess I've been inspired. I'd like to personally thank Prof. Edwards for all the responses you've been making here.

First off congratulations on your alternative diagnosis Andrew of course I do hope you stick around - both here and around the subject area :)

Intrigued by some claims that AV shunt dysregulation may be 'diagnostic' for FMS I did a quick google around and found that its also common in type II diabetes and something called 'complex regional pain syndrome'.

Warning : the linked articles are a long read - but very worthwhile I believe for anyone interested.

The latter condition is particularly interesting. Not only are many of the clinical signs and symptoms (and physiological findings) similar to the wide range of multi-organ symptoms found in ME/CFS (and fibro) but many of the symptoms respond to ketamine (a nod to my ongoing fixation on glutamate as a symptom mediator) :

http://www.rsds.org/pdfsall/Systemic-Complications-of-CRPS.pdf

More importantly, while frequently considered a psychogenic illness, recent research now suggest a neuroinflammatory model of complex regional pain syndrome that may be of autoimmune origin and ticks many of the boxes as a potential model of ME/CFS (or fibro) onset and progression.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661922/

Some key points of the model :

While a peripheral injury/trauma is often the initial trigger for CRPS, it needn't be. CRPS is also known with no apparent injury or even following psychological stress;

The model provides a mechanism whereby peripheral inflammation (potentially caused by autoantibodies - to either the beta(2)-adrenergic receptor (β2AR) or the muscarinic acetylcholine receptor (M2R) in CRPS) can propagate from the peripheral injury site to higher levelc of the nervous system and eventually impact on higher cognitive functions (avoiding the blood brain barrier issue by propagating via the parenchyma of the CNS e.g. glial cells);

This 'spreading neuroinflammation' can impact on many bodily systems/functions far from the original (if any) injury;

The condition becomes chronic;

Neuroinflammation leads to loss of sensory gating, excessive sensory gain and 'central sensitization' of the nervous system;

Symptoms may be subject to rapid deterioration and remission. etc.

Some excerpts :

The key concept here is that the development of autoimmunity to specific neuroautoantigens may be the initiating event for many cases of CRPS. Psychological stressors, physical trauma, infectious agents, and/or genetic susceptibility could all play a role in the breakdown of self-tolerance, and the onset of an autoimmune response. This set of etiological linkages fits well with documented clinical experience with CRPS (Mitchell 1872; Birklein et al. 2000). Psychological stressors and immunologic priming have been linked to the enhanced activation of microglia to nervous system injury (Frank et al. 2007; Hains et al. 2010).
Spreading neuroinflammation provides a non-psychogenic etiology to plausibly explain the progression and chronicity of certain disease states, as well as the migration of symptoms to different portions of the body. This mechanistic concept of spreading neuroinflammation within the CNS needs to be incorporated into differential diagnosis of neurological and neuropsychiatric disorders, as well as into the standard use of the Diagnostic and Statistical Manual for Mental Disorders (DSM). This would substantially advance the recognition and diagnosis of neuroinflammatory-mediated functional disorders within the biomedical community.

Cytokine production is a central part of the overlapping and interlocking mechanisms that produce neuroinflammatory disorders, including CRPS. Neuroendocrine alterations and disturbances in the metabolism of monoamines have been correlated with cytokine-induced mood and cognitive symptoms (Capuron et al. 2002; Dantzer et al. 2008; Doorduin et al. 2009; Engler et al. 2012). In addition, neuroimaging studies have revealed alterations in specific brain regions during cytokine treatment (Kullmann et al. 2012; Schneider et al. 2012). These changes could contribute to the development of fatigue, depression, and cognitive alterations in patients with neuroinflammation (Raedlera 2011; Schedlowski 2012). In CRPS patients, fatigue, paresis, depression, anxiety, and cognitive impairments are well documented (Mitchell 1872; Birklein et al. 2000; Apkarian et al. 2004).
 

user9876

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I noticed that Roche has just got a new drug approved for RA which targets IL-6. Is this of interest given a autoimmune theory for ME?

ACTEMRA, originally approved by the FDA as an IV medicine in 2010, is the first and only humanised interleukin-6 (IL-6) receptor-antagonist monoclonal antibody approved by the FDA for both SC and IV administration.
http://www.roche.com/media/media_releases/med-cor-2013-10-22.htm
 
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@Jonathan Edwards

I was wondering if you had read the recent Meyer/Light et al. post-exercise gene expression study and had any input.
http://www.tandfonline.com/doi/abs/10.1080/21641846.2013.838444#preview

I think that it brings a key insight to the model of functioning of the HPA-axis. Rather than 'hypoactivity' (which was rather speculative), I believe it reflects a clear shift in functioning, with the Glucocorticoid receptor function being shifted from Transactivation to Transrepression. I would say this reflects a more direct approach at triggering an anti-inflammitory response, while minimising the effect on insulin production, especially when considering that the cortisol response is normal or slightly low (therefore not increasing gluconeogenesis) and but the Alpha-2A receptors expression is increased so the overall insulin/glucose balance is maintained.

I am wondering whether this shift has been observed in any other illness? Perhaps it is a beneficial response to underlying problems (increased oxidative stress, or an autoimmune condition), the body deliberately choosing not to increase glucocorticoid levels, in favour of a different response? Or could it be a response to 'Glucocorticoid resistance' discussed in various literature?

Glucocorticoid resistance in inflammatory diseases (Lancet 2009) said:
Some studies have reported increased expression of glucocorticoid receptor β in glucocorticoid-resistant patients of several diseases, including asthma, rheumatoid arthritis, and inflammatory bowel disease,72, 73, 74 and 75 but other studies do not support this finding.76 and 77
(Ref 76/77 are about Asthma)
http://www.ncbi.nlm.nih.gov/pubmed/19482216

I guess it could be unique to CFS, but I'm not so sure.

Edit/Additional:

On a related note, Jammes from France has published multiple post exercise studies showing strong evidence of increased oxidative stress and interestingly, low serum levels of HSP post-exercise.

Two of the most recent studies:
http://www.ncbi.nlm.nih.gov/pubmed/19457057
http://www.ncbi.nlm.nih.gov/pubmed/22112145

and a study by another group:
http://cimonline.ca/index.php/cim/article/viewArticle/4917

But low serum levels of HSP could simply be explained by the HSP forming complexes with the GC receptors.
 
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I noticed that Roche has just got a new drug approved for RA which targets IL-6. Is this of interest given a autoimmune theory for ME?



http://www.roche.com/media/media_releases/med-cor-2013-10-22.htm
The anti-IL6 receptor antibody has been around for RA for some years now and works very well. Part of the action is on the inflammation in the joints themselves and benefit comes on quite quickly. Since CRP levels are not raised, at least not very much, in ME, it seems unlikely that there is much IL-6 inflammation drive in ME (IL-6 stimulates CRP). However, IL-6 is also involved in B cell growth and function and the longer term effect of the drug may include a B cell 'cooling off' effect. This might be relevant to ME subsets if they are autoimmune. Anti-TNF has been tried in ME and does not seem to be very helpful. There might be a case for trying an IL-6 inhibitor but it might take several months to work even if it did. My feeling would be to try to firm up on the evidence for B cells being involved in other ways first, but it would be interesting to know if anyone with ME had had the IL-6 inhibitor having developed RA subsequently.
 
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@Jonathan Edwards

I was wondering if you had read the recent Meyer/Light et al. post-exercise gene expression study and had any input.
http://www.tandfonline.com/doi/abs/10.1080/21641846.2013.838444#preview
I could only see the abstract and the data are not presented there in a way I find easy to interpret. I think researchers these days have a certain responsibility to be more explicit if they can - and if possible publish open access. I am not quite sure what to make of changes in white blood cell protein synthesis after excercise. White blood cell populations can shift rapidly so there might be lots of resons. On the other hand if there is a consistent difference from controls it suggests that something is happening to endocrine control. I would be interested to know more but I doubt I can get hold of this particular journal!
 
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Hm! And rheumatoid arthritis may cause you to have gut bacteria? I don't know quite what to make of this. It may be useful to note that mice do not get rheumatoid arthritis - only the sorts of arthritis that researchers give them. There is no particular reason to think that the cause of those sorts of arthritis have anything to do with RA - since the cause is being given arthritis by a researcher, not being human, being born with a particular gene make-up, living for half a century etc. and developing autoantibodies up to ten years before you have arthritis. And IL-17 blockade did not have much effect on RA as I remember. (I don't think there was a link to an IL-17 gene polymorphism either.)

I can see that it might fit that if you have been brewing autoantibodies for five years and get a big dose of a particular bug your RA might decide now is the time to show itself. But it looks as if you can get RA without the bug and getting rid of the bug later in RA is no help - you still have RA.

I like a theory to fit together all ways around and I am not seeing that here. Still it will be interesting to see if anyone can get the same result.
 

Jill

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Just incase this is of any relevence.
I just recently read that Invest in ME are funding a study on antibodies to the hypothalamus. I think it is the study that is going to happen pre Rituxan trial??? . That sounds fascinating and I'm wondering if anyone knows anymore?. I then remembered reading about a fibro study about AV shunts and that being to do with core temperature/hypothalamus and wonder if anyone has made the connection that most people with ME also have fibro (or who knows its all one disease??). Anyway, the Washington Times article is below . If the Invest in ME study is looking for antibodies, I guess that the supposition is that Rituxan is depleting those, maybe??

This fibro study may have no relevance in terms of the Invest in ME study, but maybe it might?? and its getting late for me, so forgive me if this is a goose chase, but others may want to check it out. It seemed v big news in the fibro world.

http://communities.washingtontimes....ct/17/fibromyalgia-solved-pathology-not-mind/

I'm sure more competent people than me can get the full paper.
 

Firestormm

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I just recently read that Invest in ME are funding a study on antibodies to the hypothalamus. I think it is the study that is going to happen pre Rituxan trial??? . That sounds fascinating and I'm wondering if anyone knows anymore?.
Where did you read this Jill? I can't seem to find anything on IiME website or Facebook. Is it a recent announcement? Thanks.
 
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I just recently read that Invest in ME are funding a study on antibodies to the hypothalamus. I think it is the study that is going to happen pre Rituxan trial??? .
This is not directly linked to plans to set up a rituximab trial. However, if autoantibodies are found that would clearly make the argument for using rituximab much more straightforward.

A number of groups have been interested in vascular physiology and the potential role of neuropeptides in ME, which could link hypothalamus to peripheral vascular changes perhaps. (I am not sure that I see fibromyalgia as being a useful term as a disease category rather than just a symptom complex that might be associated with several sorts of problem.)

The hope is, clearly, that all these different aspects will fit together. Something must fit together!
 

Kati

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@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