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

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

 

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.

 

on the edge of my seat waiting for publishing quite honestly! sigh!

 

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.

 

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/

 

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!

 

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.

 

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 :

 

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

 

@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?

(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.

 

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.

 

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!

 

We have the full paper here
Filled Paper Requests

 

Science Article:
4 November 2013
Gut Bacteria May Cause Rheumatoid Arthritis

 

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.

 

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.

 

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 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!

 

@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

 

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.