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

[Legendrew]

In the context of previous discussions about inflammation (or lack of) I found the CSF findings interesting given that these were much more consistent than the serum ones :

Quote taken from this transcript :

http://www.mecfsforums.com/wiki/Lipkin_presentation,_CDC_Conference_Call_9/10/2013

Interesting - not surprising really that plasma levels of cytokines deviate more than CSF levels. I'm hoping that the plasma ones prove more reliable over time as I certainly think blood samples are much easier for both patients and doctors in a clinical setting. Can't say the prospect of CSF collection excites me to be honest!

Interesting to see IL13 there considering its action in muscus hypersecretion - could explain the common flu type symptoms some people complain of. Also interesting to see increased IL17 yet reported lower TNF given that IL17 is thought to induce production of TNF - this could say something about the unusual loops the immune system in ME appears to be taking. IL5 would seem to correspond to the reported increase in eosinophils It seems some of these findings are somewhat contradictory - I assume that some of them will prove non-reproducible but I suppose it could also speak to the generalised dysregulation going on.

 

[Marco]

Interesting - not surprising really that plasma levels of cytokines deviate more than CSF levels. I'm hoping that the plasma ones prove more reliable over time as I certainly think blood samples are much easier for both patients and doctors in a clinical setting. Can't say the prospect of CSF collection excites me to be honest!

Interesting to see IL13 there considering its action in muscus hypersecretion - could explain the common flu type symptoms some people complain of. Also interesting to see increased IL17 yet reported lower TNF given that IL17 is thought to induce production of TNF - this could say something about the unusual loops the immune system in ME appears to be taking. IL5 would seem to correspond to the reported increase in eosinophils It seems some of these findings are somewhat contradictory - I assume that some of them will prove non-reproducible but I suppose it could also speak to the generalised dysregulation going on.

I'm rather encouraged by the CSF results as serum cytokines seem to be all over the place at the best of times. The elevated presence of (generally) anti-inflammatory IL-10 and 1L-13 seem somewhat at odds with pro-inflammatory IL-1b, IL-17 and TNF-a (I'll park IL-5 for the meantime) but ying and yang - for every action there's a reaction etc applies. IL-13 is elevated in parallel with IL-1b and TNF-a in rat models of Alzheimer's for example.

This to me signifies neuroinflammation which is implicated in a wide range of mood and neurodenegerative disorders which may or may not be accompanied by gross tissue damage. Perhaps we need to define what constitutes 'inflammation'?

 

[Legendrew]

I'm rather encouraged by the CSF results as serum cytokines seem to be all over the place at the best of times. The elevated presence of (generally) anti-inflammatory IL-10 and 1L-13 seem somewhat at odds with pro-inflammatory IL-1b, IL-17 and TNF-a (I'll park IL-5 for the meantime) but ying and yang - for every action there's a reaction etc applies. IL-13 is elevated in parallel with IL-1b and TNF-a in rat models of Alzheimer's for example.

This to me signifies neuroinflammation which is implicated in a wide range of mood and neurodenegerative disorders which may or may not be accompanied by gross tissue damage. Perhaps we need to define what constitutes 'inflammation'?

Certainly as I understand it; generalised inflammation and neuroinflammation are different in many aspects and while from a personal view I doubt either are involved to any great degree, neuroinflammation appears as a much more likely possibility that generalised does. Certainly though the decreases in Interleukin’s IL-17, IL-2, IL-8 and in TNF-alpha would appear to imply that inflammation is not the major disease driving force - assuming these prove repeatable obviously!

One thing which I originally had overlooked is the upregulation of leptin, given its role in metabolism it's fairly easy to make the links with the dysfunctional mitochondria and ATP production that have been observed in ME - along with the increased lactate buildup in the muscles following overexertion. I doubt this is a primary part of the disease but it certainly provides further evidence of the problems in respiration for those with ME.

 

[Firestormm]

In the context of previous discussions about inflammation (or lack of) I found the CSF findings interesting given that these were much more consistent than the serum ones :

Quote taken from this transcript :

http://www.mecfsforums.com/wiki/Lipkin_presentation,_CDC_Conference_Call_9/10/2013

Now, Marco, you really should use our very own transcript tut tut tut

It's in the new article: Lipkin finds biomarkers not bugs

 

[Marco]

Certainly as I understand it; generalised inflammation and neuroinflammation are different in many aspects .

That's the reason I feel we need to parse what we mean when talking about 'inflammation'.

 

[Marco]

Now, Marco, you really should use our very own transcript tut tut tut

It's in the new article: Lipkin finds biomarkers not bugs

Sheitzen!

Sorry

(PS - I can invent words in any language)

 

[lansbergen]

Interesting to see IL13 there considering its action in muscus hypersecretion - could explain the common flu type symptoms some people complain of. .

Flu like symptoms do not necessarily mean hypersecretion. I for one have lack of mucous membrane secretion.

 

[Forbin]

Jonathan Edwards, an often unappreciated aspect of CFS is the fact that many, dare I say most patients can no longer fully tolerate foods that they were formerly able to eat.

Yes, this would have been something of an understatement in my case. Just days after sudden onset following the flu, I noticed I would get a pounding heart very quickly after eating anything sweet.

Then, about a year later, I drank a Coke on an empty stomach. Within 20 minutes, I was sweating, had a pounding heart, pulse of 130, fully flushed face and torso and was producing a LOT of urine. I had to lie down and pretty much felt like I was going to die. This lasted for the better part of an hour. In retrospect, it seems like something had triggered a large release of adrenalin.

By unintended trial and error, I came to discover that I had become particularly sensitive to the sweetener known as “high fructose corn syrup,” which was a component that had replaced sugar in many soft drinks (including Coke) in the early 1980’s. Throughout the 80’s and 90’s I found out the hard way that HFCS was being introduced into LOTS of processed foods, including baked goods.

Oddly, perhaps, I was not nearly so sensitive to just plain "corn syrup." Over time, my sensitivity to HFCS seems to have decreased, but I still stay clear of it as much as possible.

This only began after I came down with CFS. I’ve had several “normal” glucose tolerance tests, although some produced similar, though much milder symptoms.

I don’t know what mechanism might cause this, but an allergist scoffed at the idea that it was a “food allergy.”

 

[Snow Leopard]

I'm rather encouraged by the CSF results as serum cytokines seem to be all over the place at the best of times. The elevated presence of (generally) anti-inflammatory IL-10 and 1L-13 seem somewhat at odds with pro-inflammatory IL-1b, IL-17 and TNF-a (I'll park IL-5 for the meantime) but ying and yang - for every action there's a reaction etc applies. IL-13 is elevated in parallel with IL-1b and TNF-a in rat models of Alzheimer's for example.?

This is one of the reasons why some people (myself included) believe the whole fitting to patterns of TH1/TH2 etc to mostly be a fiction. The whole patterns are much more complicated and specific to the individual, including any disease states.

 

[Marco]

This is one of the reasons why some people (myself included) believe the whole fitting to patterns of TH1/TH2 etc to mostly be a fiction. The whole patterns are much more complicated and specific to the individual, including any disease states.

You might like this then. I'm sure you're familiar with the inflammatory model of depression which has been gaining ground and is generally assumed to mean that those with depression have high levels of inflammation and inflammation causes depression.

This appears to be so to an extent but the elevation of markers of inflammation for depressed groups is modest at best (not that this is necessarily a problem for the theory) and not all those with depression have inflammation. In fact in some circumstances low level inflammation may be protective.

Well worth a read and not too heavy going :

Do cytokines really sing the blues?

http://www.bna.org.uk/news/view.php?permalink=EHY6MK0AKN

It does though highlight the problem of simple group comparisons. It wouldn't be the first time that sub-groups within ME/CFS trended in different directions on certain measures so it would be useful to know the degree to which these markers were elevated or lower and if these patterns applied to all patients or just trended that way as a group..

 

[voner]

Jonathan Edwards,

I would like to know if you are aware of the work of Dr. John Chia? He is a infectious disease clinician located in the Los Angeles area. This basic theory is the ME/CFS is a Chronic Enterovirus infection that is residing in the tissues of ME/CFS patients. He maintains that you are not going to find any evidence of these infections by analyzing blood samples rather you have to take tissue samples from the stomach. I do not know of anybody having replicated his study.

Here's a link to his most relevant publication (I think),

http://www.ncbi.nlm.nih.gov/pubmed/17872383

Here is a slew of other information from Cort Johnson's (The founder of the Phoenix Rising website) site,

http://www.cortjohnson.org/chronic-fatigue-syndrome-mecfs-doctor-resource-center/dr-john-chia/

here is The website of his foundation he founded to do research on enteroviruses,

http://www.enterovirusfoundation.org

I would be very interested in your comments..... is Dr. Chias study information significant?

 

[Jonathan Edwards]

Jonathan Edwards,

I would like to know if you are aware of the work of Dr. John Chia? He is a infectious disease clinician located in the Los Angeles area. This basic theory is the ME/CFS is a Chronic Enterovirus infection that is residing in the tissues of ME/CFS patients. He maintains that you are not going to find any evidence of these infections by analyzing blood samples rather you have to take tissue samples from the stomach. I do not know of anybody having replicated his study.

Here's a link to his most relevant publication (I think),

http://www.ncbi.nlm.nih.gov/pubmed/17872383

Here is a slew of other information from Cort Johnson's (The founder of the Phoenix Rising website) site,

http://www.cortjohnson.org/chronic-fatigue-syndrome-mecfs-doctor-resource-center/dr-john-chia/

here is The website of his foundation he founded to do research on enteroviruses,

http://www.enterovirusfoundation.org

I would be very interested in your comments..... is Dr. Chias study information significant?

I think these are the sort of data that need verification in independent studies.

 

[Legendrew]

I've been frequenting the other thread that seems popular at the moment discussing Prof. Lipkin's word and one argument appears to be cropping up quite frequently. It regards the idea the idea of infections, whether they be viral, bacterial or otherwise and how they relate to autoimmunity. The general argument that many people appear to hold is the following.

"I refuse to believe the immune system attacks self for no reason. I always have and likely always will"

certainly I think it is difficult to understand sometimes and wondered whether there is a general process that the immune system takes in autoimmune diseases to arrive from a state of being healthy to the development of the symptoms. Do infections have a role to play somewhere or are are genetics and chance the driving forces? I suspect it will be difficult to answer as I believe autoimmunity, similar to cancer, is something of an umbrella term with a whole spectrum of immune related diseases.

 

[Jonathan Edwards]

I've been frequenting the other thread that seems popular at the moment discussing Prof. Lipkin's word and one argument appears to be cropping up quite frequently. It regards the idea the idea of infections, whether they be viral, bacterial or otherwise and how they relate to autoimmunity. The general argument that many people appear to hold is the following.

"I refuse to believe the immune system attacks self for no reason. I always have and likely always will"

certainly I think it is difficult to understand sometimes and wondered whether there is a general process that the immune system takes in autoimmune diseases to arrive from a state of being healthy to the development of the symptoms. Do infections have a role to play somewhere or are are genetics and chance the driving forces? I suspect it will be difficult to answer as I believe autoimmunity, similar to cancer, is something of an umbrella term with a whole spectrum of immune related diseases.

The immune system produces millions of B cells reactive against self every day. The amazing thing is that almost always all of these are re-educated or killed off. The immune system makes self-reactive cells for a good reason - the only way it can guarantee to make cells reactive to the infective you meet tomorrow is to make cells reactive against absolutely everything and then discard the bad ones. Infections may give a little extra stimulus to the immune system that in theory could tip it in to clinical autoimmunity but the reality is that 90% of autoimmunity seems to have nothing to do with infection. If infection was important identical twins living together would get autoimmune disease within a fortnight of each other and this I have never heard of. Maybe in one in four cases where one gets an autoimmune disease the other does too but it may be years apart. Someone has quoted a paper referring to vaccination but this is a vanishingly small number of cases and I am not sure it is more than co-incidence, with a few significant exceptions. We have mentioned narcolepsy after flu vaccination and it may be that some ME has a similar relation to some infections. I am not sure that knowing that will lead to useful treatment though. It may do and it may be worth researching, but I would invest in other approaches myself. Studying gut flora may well be useful though, because it may tell us useful things for other reasons.

 

[medfeb]

I was thinking its quite a low risk since the drug is already developed. How would the cost of say giving the drug to trials and helping with licensing compare to a marketing campaign costs to find similar numbers of potential consumers. In other industries money is often spent to open up new markets and I was seeing it in those terms.

I get your point for already existing drugs - the risk is lower because there is a good understanding of the safety profile and the company already has the manufacturing/drug stability/etc issues worked out.

But even for already existing drugs, the company has to show efficacy in the new indication and there would be some risk in showing that. In the case of ME, I expect that risk is complicated by the lack of agreement on how to measure efficacy and the definitional issues that confound what patients you are even studying.

If I understand, companies may also have to do additional safety work depending on the previous safety studies. For instance, was the drug previously studied for a disease that is likely to be quickly fatal if not treated and that affects a small population? The safety proposition and the size of safety studies will be different for that patient population then for an indication that affects more people and has a lower mortality associated with it.

 

[Legendrew]

Studying gut flora may well be useful though, because it may tell us useful things for other reasons.

I'd be interested to hear where you think this will lead. I personally think it'll be interesting to look at but I'm not sure what I expect to be found.

 

[Jonathan Edwards]

I'd be interested to hear where you think this will lead. I personally think it'll be interesting to look at but I'm not sure what I expect to be found.

If a difference in gut flora was found my first thought would be that it would be likely to be due to a change in gut motility or secretory patterns from autonomic dysfunction or immunological changes in the gut wall. In scleroderma there is a change in gut flora because of reduced motility. My malabsorption is presumably associated with some sort of change in flora pattern as a hang over from functional changes due to some immunological reaction to tropical organisms ten years ago. So I was thinking that a shift in flora might be a useful marker of some specific gut dysfunction. If ME patients had bacteria present never found in normal people that would be different, but I suspect this is unlikely to be the case.

 

[lansbergen]

If a difference in gut flora was found my first thought would be that it would be likely to be due to a change in gut motility or secretory patterns from autonomic dysfunction or immunological changes in the gut wall. In scleroderma there is a change in gut flora because of reduced motility. My malabsorption is presumably associated with some sort of change in flora pattern as a hang over from functional changes due to some immunological reaction to tropical organisms ten years ago. So I was thinking that a shift in flora might be a useful marker of some specific gut dysfunction. If ME patients had bacteria present never found in normal people that would be different, but I suspect this is unlikely to be the case.

In animals stool chances are a sign to be alert. From animals I know gut flora changes during virus infections and should go back to normal after the infection is cleared.

I do not have big gut problems but there is a clear pattern. At the beginning of a flare up constipation starts, at the end of the flare up a bout of diaree occures and then it is back to normal.[/quote]

 

[Gemini]

. My malabsorption is presumably associated with some sort of change in flora pattern as a hang over from functional changes due to some immunological reaction to tropical organisms ten years ago.

Professor Edwards, along the lines of prior infections Dr. Lipkin plans to test not only the microbiome but for previous infections via antibodies. I'm interested in your thoughts about how the type of antibody testing he has in mind might help?

 

[Jonathan Edwards]

Professor Edwards, along the lines of prior infections Dr. Lipkin plans to test not only the microbiome but for previous infections via antibodies. I'm interested in your thoughts about how the type of antibody testing he has in mind might help?

I am not sure. I am not up to date on what can be done in this area. Antibodies to intracellular pathogens like shigella might be interesting because intracellular pathogens can cause Reiter's syndrome. Reiter's syndrome can produce severe fatigue and I can imagine that there might be 'bottom of the iceberg' cases with fatigue but none of the diagnostic features in joints or skin. I would expect these to be only a small subset but antibodies to shigella may not be common in the general population.