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

[Jonathan Edwards]

Do you remember which paper that was in? Sounds very interesting.

I heard about it at the IiME conference and have not looked into formal publications. It is mentioned in http://www.iacfsme.org/portals/0/pdf/brenu-pathomechanisms-spring2010-7-30.pdf
but I have a feeling that the work is in progress.

 

[Jonathan Edwards]

Prof Edwards

You wrote this in response to Legendrew's query about finding a 'consistent and measurable abnormality'.

This may not be directly relevant to autoimmunity per se (or it may be - who knows?) but there are an increasing number of published papers (including from Julia Newton's team) reporting current autonomic dysfunction in varying but pretty high proportions of ME/CFS patients.

I appreciate that autonomic dysfunction is far from specific but may provide some clues to the underlying problem - but - it can be a major contributor to the illness burden (POTS, tachycardia, gastrointestinal problems, exercise intolerance etc) and is treatable on an individual basis once testing confirms which arm (s) of the ANS are dysfunctional.

Given these ME/CFS research findings, the fact that autonomic dysfunction is treatable and the currently unknown etiology of ME/CFS (and indications from diabetic autonomic neuropathy that autonomic dysfunction if untreated can result in neuropathy), I wonder what you, having been a practicing clinician, think of this recommendation (made in the context of diabetic neuropathy but not intended to apply to that condition solely) :



https://www.google.co.uk/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&cad=rja&ved=0CDIQFjAA&url=http://wadepage.org/files/file/REDUCING%20RISKS/Autonomic%20Neuropathy.pdf&ei=xsAtUpTVKqS40QW_lID4CQ&usg=AFQjCNEI4h2axHa0sMLBjwDhq8SfyQFyBA

I am not sure that I can comment on this. The extrapolation would depend on a lot of things.

 

[Marco]

I am not sure that I can comment on this. The extrapolation would depend on a lot of things.

I guess what I'm asking is, if you had research evidence that a high proportion of your RA patients had autonomic dysfunction and you had no other effective treatment to offer (if that were the case) wouldn't you want your patients tested for autonomic dysfunction and treated appropriately?

 

[Jonathan Edwards]

Re: Encephalitis

In 2005, James Baraniuk et al. published an article in BMC Neurology titled:

A Chronic Fatigue Syndrome Related Proteome In Human Cerebrospinal Fluid
http://www.biomedcentral.com/1471-2377/5/22

In 2010, Dr. Anthony Komaroff characterized these findings as demonstrating "a low-grade inflammation going on in the brain."

The proteins found look to me to indicate something much more specific and interesting going on than just 'inflammation'. If they were confirmed they might be of considerable help. The trouble is that my information so far is that these sorts of findings tend to be one off and in science we have to get confirmation.

 

[Jonathan Edwards]

I guess what I'm asking is, if you had research evidence that a high proportion of your RA patients had autonomic dysfunction and you had no other effective treatment to offer (if that were the case) wouldn't you want your patients tested for autonomic dysfunction and treated appropriately?

I would if it were a situation of preventive treatment - which would be very relevant to diabetes, but might not be in other situations. I am not actually sure what one can do if one does not know the cause, other than treat symptomatically, as one would do anyway.

 

[Marco]

I would if it were a situation of preventive treatment - which would be very relevant to diabetes, but might not be in other situations. I am not actually sure what one can do if one does not know the cause, other than treat symptomatically, as one would do anyway.

Not to labour the point but the paper I linked to (where the authors claim to be experts in these things) suggests that early treatment of autonomic dysfunction is absolutely preventative in chronic conditions not limited to diabetes and that non-treatment not only risks dysfunction progressing to irreversible neuropathy (independently of the disease process of diabetes) but also greatly increased morbidity and increased mortality.

Finding autonomic dysfunction in childhood 'CFS' really should be a cause for concern.

Event Related Potentials in Japanese Childhood Chronic Fatigue Syndrome

Abstract

The aim of this study was to investigate cognitive functions such as allocation and information processing in patients with childhood type chronic fatigue syndrome (CCFS) using event-related potentials. A total of 190 healthy children as controls and 414 patients with CCFS participated in this study. Both patients and controls had (i) event-related potentials (including P300, P100, N150 and P200 measurements); (ii) component analysis of electrocardiographic R-R interval to evaluate autonomic function; and (iii) KANA-Pick-out test to evaluate frontal lobe function. The cutoff threshold defining abnormal P300 latency to target stimuli and amplitude to non-target stimuli was set at two standard deviations above the mean values of controls. Forty patients (classified as Type-I) had an abnormally-prolonged P300 latency to target stimuli, and 49 patients (classified as Type-II) had an abnormally-exaggerated P300 amplitude, and the remaining 325 patients whose P300 latency and amplitude ranged below the above-mentioned threshold were classified as Type-III. All patient groups had normal P100, N150 and P200 measurements. Component analysis of electrocardiographic R-R intervals revealed that the power of high-frequency components was lower in all patient groups, compared to controls. The score in KANA-Pick-out test was worse in all patient groups compared to controls; Type-I Group had the worst score and Type-II Group had the best score among the patients. Taken together, we speculate that abnormally-prolonged P300 latency to target stimuli might be associated with learning disability and abnormally-exaggerated P300 amplitude to non-target stimuli might be associated with hypersensitivity such as phobia in patients with CCFS. Psychosomatic symptoms in patients with CCFS might be associated with higher-order level cognitive dysfunction.

http://iospress.metapress.com/content/w14pg23t125337q8/

The bolded text is interpreted in the full paper as showing that these children (aged between 9 and 18) had 'low' or 'very low' parasympathetic activity.

 

[Jonathan Edwards]

Not to labour the point but the paper I linked to (where the authors claim to be experts in these things) suggests that early treatment of autonomic dysfunction is absolutely preventative in chronic conditions not limited to diabetes and that non-treatment not only risks dysfunction progressing to irreversible neuropathy (independently of the disease process of diabetes) but also greatly increased morbidity and increased mortality.

I coudn't see anything in that article that says treatment has any long term or preventative effect. It might sound like that but the drugs used will all just have a temporary effect on transmitter levels as far as I can see. To prevent long term changes in diabetes you would need to get the insulin levels right, I think, and for other conditions you might not know what the equivalent was - certainly we would have no idea for ME. I think this is maybe a bit outside what I can usefully address to be honest.

 

[Sasha]

Jonathan Edwards - a lot of people with ME over the years have been referred to rheumatologists (as well as immunologists, cardiologists, infectious disease specialists, etc., depending on which symptoms seemed uppermost, perhaps). I expect a lot of rheumatologists have been frustrated at being unable to help their ME patients. Are rheumatologists now talking about Rituximab in relation to ME, as far as you know? I'm curious about how this all looks from the point of view of clinicians and how well known the Fluge and Mella work is among them.

 

[Marco]

I coudn't see anything in that article that says treatment has any long term or preventative effect. It might sound like that but the drugs used will all just have a temporary effect on transmitter levels as far as I can see. To prevent long term changes in diabetes you would need to get the insulin levels right, I think, and for other conditions you might not know what the equivalent was - certainly we would have no idea for ME. I think this is maybe a bit outside what I can usefully address to be honest.

I don't think for a minute that they were suggesting that treating autonomic dysfunction had any preventative effect on diabetes progression, more that autonomic dysfunction was associated with diabetes perhaps as a downstream effect or that both 'conditions' may have a common root cause. Julia Newton has found similar autonomic dysfunction in primary biliary cirrhosis, Sjogren's and ME/CFS. Regardless of whether they share any underlying pathology or are directly related to the disease process, treating autonomic dysfunction must have a positive impact on patients' function and quality of life. Personally I feel there's a clue there but its probably outside the bounds of this discussion.

Thanks for the comments.

 

[Jonathan Edwards]

Jonathan Edwards - a lot of people with ME over the years have been referred to rheumatologists (as well as immunologists, cardiologists, infectious disease specialists, etc., depending on which symptoms seemed uppermost, perhaps). I expect a lot of rheumatologists have been frustrated at being unable to help their ME patients. Are rheumatologists now talking about Rituximab in relation to ME, as far as you know? I'm curious about how this all looks from the point of view of clinicians and how well known the Fluge and Mella work is among them.

As far as I know, rheumatologists are completely ignorant of all this, maybe with one or two exceptions I guess. They are quite a conservative lot.

 

[Kati]

As far as I know, rheumatologists are completely ignorant of all this, maybe with one or two exceptions I guess. They are quite a conservative lot.

Following the publication of the first Fluge/Mella paper, I sent the paper to 14 canadian rheumatologists asking them to consider a replication and/or compassionate access to Rituximab for patients with ME. I received 3 answers back, the main one from a rheumy heavily involved with Rituxan and clinical trials, saying he had no time nor interest to deal with patients with chronic fatigue syndrome.

Dr Klimas's (and Mary-Ann Fletcher's) cytokine testing showed lots of inflammation with some of the cytokine being over 20 times the normal. My ESR has been creeping up as of late, to 38. We know that exercise increases expressions of certain genes which will create exagerated inflammation. Pain along spinal, from head to sacrum after exertion gives me clues something is wrong in that area. Dr Byron Hyde's work shows abnormal spect scans and white lesions on MRI's of patients with ME.

There is lots of abnormalities, and no medical speciality to care for us. I am very convinced it is all too complicated for GPs.

 

[Sasha]

Fllowing the publication of the first Fluge/Mella paper, I sent the paper to 14 canadian rheumatologists asking them to consider a replication and/or compassionate access to patients with ME. Received 3amswers back, the main one from a rheumy heavily involved with Rituxan and clinical trials, saying he had no time nor interest to deal with patients with chronic fatigue syndrome.

Good for you for trying, Kati. That's a disappointing response but maybe things will change as more Rituximan/ME work gets published. The new Fluge & Mella paper should be out soon, we hope, and then there'll be the preliminary study that Prof. Edwards is planning, and then the UCL 30-patient RCT, and then the new Fluge & Mella 140-patient trial... The first two, at least, I hope we might expect to be published within a year (?).

I am very convinced it is all too complicated for GPs.

I think it needs a coordinated team of specialists. I think all GPs can do is help manage symptoms, at this point, and refer on.

 

[Jonathan Edwards]

Fllowing the publication of the first Fluge/Mella paper, I sent the paper to 14 canadian rheumatologists asking them to consider a replication and/or compassionate access to patients with ME. Received 3amswers back, the main one from a rheumy heavily involved with Rituxan and clinical trials, saying he had no time nor interest to deal with patients with chronic fatigue syndrome.

Dr Klimas's (and MaryAnn Fletcher's) cytokine testing showed lots of inflammation with some of the cytokine being over 20 times the normal. My ESR has been creeping up as of late, to 38. We know that exercise increases expressions of certain genes which will create exagerated inflammation. Pain along spinal, from head to sacrum after exertion gives me clues something is wrong in that area. Dr Byron Hyde's work shows abnormal spect scans and white lesions on MRI's of patients with ME.

There is lots of abnormalities, and no medical speciality to care for us. I am very convinced it is all too complicated for GPs.

Yes, I am sure it is too complicated for GPs. And probably too complicated for rheumies. I am seriously wondering if maybe ME comes in 57 varieties and the reason why nobody can find any consistent marker if simply that there are 57 markers sprinkled around and so nothing is consistent. There does seem to be some common pathway, but it seems to be the bit without the marker - unless some of these muscle tests will do it. Some people have thyroid antibodies, some have a raised ESR or CRP, some have inflammatory bowel disease, some have changes on MRI etc etc etc. And it may be a mistake to try to bundle all these into one disease. Both doctors and patients want to put things in pigeon holes more than is helpful very often I think. But there still ought to be ways to pin down some common factor that allows sense to be made of it all. It needs a bit of thinking time, which doctors tend not to get much of these days.

 

[Kati]

Yes, I am sure it is too complicated for GPs. And probably too complicated for rheumies. I am seriously wondering if maybe ME comes in 57 varieties and the reason why nobody can find any consistent marker if simply that there are 57 markers sprinkled around and so nothing is consistent. There does seem to be some common pathway, but it seems to be the bit without the marker - unless some of these muscle tests will do it. Some people have thyroid antibodies, some have a raised ESR or CRP, some have inflammatory bowel disease, some have changes on MRI etc etc etc. And it may be a mistake to try to bundle all these into one disease. Both doctors and patients want to put things in pigeon holes more than is helpful very often I think. But there still ought to be ways to pin down some common factor that allows sense to be made of it all. It needs a bit of thinking time, which doctors tend not to get much of these days.

Agreed, Jonathan Edwards, and that is why personalized medicine, medicine of the 'near' future will likely help us. However it is striking at how so many of us have common symptoms, disease features and common disease onsets. For instance I have a lab documented EBV IGM+ onset at age 39. Low natural killer cell function. Chronic immune activation. Chronic viral reactivation. Post exertional neuro-immune exhaustion. Exercise test abnormalities. Abnormal pathology on muscle biopsy ( smaller caliber low-twitch fibers, when I used to be an athlete). POTS (abnormal tilt test table) These are all pieces of a puzzle which hopefully can come together, somehow, one day. i really wish more researchers would engage here, I am thankful that you do.

 

[Marco]

Y I am seriously wondering if maybe ME comes in 57 varieties and the reason why nobody can find any consistent marker if simply that there are 57 markers sprinkled around and so nothing is consistent. There does seem to be some common pathway, but it seems to be the bit without the marker - unless some of these muscle tests will do it. Some people have thyroid antibodies, some have a raised ESR or CRP, some have inflammatory bowel disease, some have changes on MRI etc etc etc. And it may be a mistake to try to bundle all these into one disease. Both doctors and patients want to put things in pigeon holes more than is helpful very often I think. But there still ought to be ways to pin down some common factor that allows sense to be made of it all. It needs a bit of thinking time, which doctors tend not to get much of these days.

I've intruded too much on this conversation. Regarding 'what is ME/CFS?' I'd previously come down to this conclusion :

http://www.cortjohnson.org/blog/201...atory-view-of-chronic-fatigue-syndrome-pt-iv/

I'll butt out now but I do appreciate this statement :

Both doctors and patients want to put things in pigeon holes more than is helpful very often I think.

 

[FancyMyBlood]

Prof. Edwards,

I've noticed you mentioned interferon several times in your earlier posts. I find it quite interesting since there is some (circumstantial) evidence interferon might be implicated in this disease.
As you know, interferon-alpha therapy produces a lot of the same kind of "sickness symtpoms" as ME/CFS. In fact, CDC and UK researchers are currently studying the similarites between them. They already found that they both affect the basal ganglia in the same way. They've also found that the the only gene that was differentially expressed in patients with IFN-α-induced depression/fatigue was OAS2. Interestingly, OAS2 is also implicate in ME/CFS. Another interesting thing worth mentioning is that both ME/CFS and IFA-therapy induced fatigue and anxiety don't respond to antidepressants and stimulants.

A lot of the research is still ungoing but dr. Andrew Miller already reported some of the findings and his comments on them at the Ottawa conference in 2011. (http://phoenixrising.me/archives/8707)

Do you think there a way to connect the autoimmune hypothesis/rituximab findings with these findings?

PS. While inflammation in ME/CFS is a very controversial subject, I think it's worth mentioning that prof. Chaudhuri et al. found active inflammation in their peripheral nervous system or signs of a degenerative process in their spinal cord and brain in 4 autopsy reports.

I don't believe this has been published in a peer-reviewed journal but prof. Chaudhuri and prof. Perry discussed it with the Naked Scientist radio program. The episode and a transcript can be found here: http://forums.phoenixrising.me/inde...ntists-including-autopsy-reports-on-me.17463/

 

[Jonathan Edwards]

I've noticed you mentioned interferon several times in your earlier posts. I find it quite interesting since there is some (circumstantial) evidence interferon might be implicated in this disease.
As you know, interferon-alpha therapy produces a lot of the same kind of "sickness symtpoms" as ME/CFS. In fact, CDC and UK researchers are currently studying the similarites between them. They already found that they both affect the basal ganglia in the same way. They've also found that the the only gene that was differentially expressed in patients with IFN-α-induced depression/fatigue was OAS2. Interestingly, OAS2 is also implicate in ME/CFS. Another interesting thing worth mentioning is that both ME/CFS and IFA-therapy induced fatigue and anxiety don't respond to antidepressants and stimulants.

Do you think there a way to connect the autoimmune hypothesis/rituximab findings with these findings?

Yes, certainly, interferons are just the sort of mediators to get caught up in autoimmune knots, I would say. And interferons go with viruses and ME feels like having a bad virus so it's sort of a no-brainer, to use a rather doubtful phrase. The tricky part is that autoantibodies do not always shoot straight for goal. They may slip a pass to a team mate at the last minute. In myasthenia gravis the antibodies are to an acetyl choline receptor that does not immediately make sense, but there are AChR in thymus as well as muscle and that is where the B cells accumulate to make autoantibodies. In coeliac disease the antibodies are not to gluten but to an enzyme that binds gluten. To be consistent to my approach I would have to suggest that there are some autoantibodies to something that triggered overactivity of alpha interferon which in turn assisted in the production of more of the same antibodies. A loop of that sort has actually been talked about as a mechanism in lupus for some years but there are plenty of other ways to explain lupus so maybe it has more to do with ME. It's all speculation but it would fit very satisfactorily.

 

[lansbergen]

To be consistent to my approach I would have to suggest that there are some autoantibodies to something that triggered overactivity of alpha interferon which in turn assisted in the production of more of the same antibodies. A loop of that sort has actually been talked about as a mechanism in lupus for some years but there are plenty of other ways to explain lupus so maybe it has more to do with ME. It's all speculation but it would fit very satisfactorily.

I do not doubt interferon type1 is involved in the disease proces and I think one of the helpfull things levamisole does is making the immune system produce more interferon gamma.

 

[Forbin]

The proteins found look to me to indicate something much more specific and interesting going on than just 'inflammation'. If they were confirmed they might be of considerable help. The trouble is that my information so far is that these sorts of findings tend to be one off and in science we have to get confirmation.

I'm not sure if this qualifies as confirmation of the 2005 proteome study by Baraniuk, but Natelson, et al. published a paper in early 2011 in which they were able to distinguish the cerebrospinal fluid proteomes of CFS patients from those of both controls and Neurologic Post Treatment Lyme Syndrome patients (nPTLS).

Distinct Cerebrospinal Fluid Proteomes Differentiate Post-Treatment Lyme Disease from Chronic Fatigue Syndrome
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017287

​

 

[bambi]

Hallo Professor Edward,

I have four questions and a simple yes or no, plus number will suffice.

Would you treat patients diagnosed ME with Rituximab who have tested positive for:

1. Increased CD4+CD25+T cells (Treg) FoxP3,
2. active co-infections such as of the herpes family HH-V6, HH-V7, CMV, EBV


3. Prevalence of children diagnosed with autoimmune condition ?
4. What are the chances (statistically) that mother and child, or several children (vertical blood line) are diagnosed with the same autoimmune disease?

Thank you
Bambi