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

Valentijn

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Apparently the Nijmegen ME/CFS centre is starting a RCT to study Anakinra in 46 female ME/CFS patients. Maybe you're not that familiar with this centre, but they're very notorious for their biopsychosocial model. So seeing this study coming from them is pretty huge and suprising.
Other departments at Radboud (the uni in Nijmegen which the clinic is associated with) do real ME/CFS research from time to time. I think they'll often partner with the clinic, thinking that they're experts in the area. My guess would be that the clinic's involvement would be more peripheral in a study like this, and at most will result in a bad cohort and really stupid introductory statements about what they think CFS is, and a conclusion mentioning the efficacy of CBT in making patients think that they feel slightly better.

They certainly haven't changed their tune regarding ME/CFS. My doctor has never been able to get a response from them regarding my OI and norepinephrine issues, which I'd take as an indication that they're still trying to pretend that ME is a psychological problem.
 

Kate_UK

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FancyMyBlood

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Other departments at Radboud (the uni in Nijmegen which the clinic is associated with) do real ME/CFS research from time to time. I think they'll often partner with the clinic, thinking that they're experts in the area. My guess would be that the clinic's involvement would be more peripheral in a study like this, and at most will result in a bad cohort and really stupid introductory statements about what they think CFS is, and a conclusion mentioning the efficacy of CBT in making patients think that they feel slightly better.

They certainly haven't changed their tune regarding ME/CFS. My doctor has never been able to get a response from them regarding my OI and norepinephrine issues, which I'd take as an indication that they're still trying to pretend that ME is a psychological problem.
I always thought it was the other way around. Whenever the ME/CFS centre wanted to do a study they collaborated with a specific Radboud department. So whenever Van der Meer or Bleijenberg wanted to do a neurological study, they set up a study with Radboud's neurological department. I'm actually pretty sure it went this way because van der Meer and Bleijenberg are almost always head authors in these studies.

Regardless, as you said, the centre probably picks the cohort and has a big role in writing the manuscript.
 

Valentijn

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I always thought it was the other way around. Whenever the ME/CFS centre wanted to do a study they collaborated with a specific Radboud department.
That seems somewhat unlikely - the Nijmegen group are very hard-core supporters of a psychosomatic model, to the extent that they say some very nasty things. Worse than you'd find in any official documentation in the UK even. They don't believe any real physical problems exist, so I doubt they'd waste any time investigating them.
 
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Prof. Edwards,

Apparently the Nijmegen ME/CFS centre is starting a RCT to study Anakinra in 46 female ME/CFS patients.
Anyway, considering they picked a rather specific drug - a so called IL-1 receptor antagonist- do you envison a theoretical model for this drug to be effective in ME/CFS?
Anakinra has been used extensively in other conditions and is known to be an effective inhibitor of IL-1. There are some rare diseases that respond dramatically with resolution of severe symptoms. In rheumatoid arthritis the benefit was modest but we have reason to think TNF and IL-6 are more important there. To try it in ME/CFS is very sensible. IL-1 probably induces fatigue and other relevant symptoms in much the way that TNF does. TNF blockade I think has been tried with uncertain results (enbrel or remicade?) so far. Anakinra might do better - no reason why not. It is not the most practical of treatments but that may not matter. It would be very good to see a range of these sorts of drugs being tried in RCTs. Even if the result is negative we will have learnt something useful. And since IL-1 would be a rather broad spectrum mediator if it is involved (i.e common to many subgroups?) then patient selection might not be that critical here. Let's see.
 

Kati

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Prof @Jonathan Edwards we need more of your type in the world. Physicians forward thinking, believing patients when they say they're sick and willing to engage with us.

May i ask your opinion in how we can achieve change in physician populations and governments, foster cooperation and exchange in how to move forward?
 

Firestormm

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Prof. Edwards,

Apparently the Nijmegen ME/CFS centre is starting a RCT to study Anakinra in 46 female ME/CFS patients. Maybe you're not that familiar with this centre, but they're very notorious for their biopsychosocial model. So seeing this study coming from them is pretty huge and suprising.

I really hope they use strict inclusion criteria though. In the past many studies from this group conflicted with other studies and I suspect many of these discrepancies were caused by using different study populations.

Anyway, considering they picked a rather specific drug - a so called IL-1 receptor antagonist- do you envison a theoretical model for this drug to be effective in ME/CFS?
I can't seem to find any reference to a pending trial. Can you provide more detail, please? A bit of information follows in relation to the expertise at Nijmegan that might be of interest:

Jos van der Meer

In 1984, van der Meer published the first paper about hyper-immunoglobulinemia D (HIDS), the new "periodic fever" syndrome he had discovered.[1]

This was the start of his research on interleukin-1 (IL-1) and his collaboration with Dr. Charles A. Dinarello, to find out whether this was an IL-1 disease.

In the early 1990s together with his former PhD student Joost PH Drenth, he collected data on HIDS patients in the Netherlands and abroad and characterised the inflammatory response in HIDS (increased IL-1β production of the white blood cells).

In 1999, Drenth and van der Meer could establish – together with the group of Dr. Marc Delpech in Paris – that the syndrome was due to mutations of the gene encoding for mevalonate kinase, an enzyme in the cholesterol synthesis pathway.[2] Independently – and at the same time – the group of Professor Ronald Wanders (Amsterdam), also found this genetic defect.

Together with Anna Simon and Joost Drenth he established that HIDS should be considered an auto-inflammatory syndrome. Some 5 years ago, his group discovered that recombinant interleukin-1 receptor antagonist (IL-1RA, anakinra) is effective as a treatment for HIDS.

This finding not only provides patients with an effective therapy, but also provides further proof that HIDS is an interleukin-1 disease.[3]
 

Firestormm

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That's OK @FancyMyBlood I found it via Tom on Co-cure. Presumably 'CVS' is the same as 'CFS' and was lost in translation...

From Tom Kindlon on Co-Cure

[This is a translation by Bing Translator. There is a flow chart in Dutch at the site. The original in Dutch is copied below. I don't accept any responsibility with regard to the accuracy of the information (or translation), or with regard to any other matter relating to this drug trial. I just thought people might be interested as there aren't that many drug trials in ME/CFS, particularly in Europe Tom (@TomKindlon)]

-----------------

http://www.me-cvs-stichting.nl/?pid=news&id=2240

Participate in drug research

We would like to ask your attention for a medication research that in the short term will start in the Radboud UMC in Nijmegen. For this research is the CiCFS study team looking for women with CVS. In the research of light immune suppression can provide reduction in severe chronic fatigue ...

What is the purpose of the research?
CVS is still a condition for which no obvious cause is found. There is evidence that CFS is caused by an overactive immune system. The aim of this study is to see if suppressing the immune system can reduce your fatigue. This involves Interleukin-1 (IL-1), IL-1 inhibited is a cytokine. Cytokines are part of the immune system.

The immune system
The immune system (immune system) defends the body both against intruders from outside (e.g. bacteria and viruses), as against certain harmful cells already present in our body. Cytokines are proteins and have a boodschapperfunctie between the different cells. There are cytokines that ontstekingsbevorderend work, but there are also
anti-inflammatory cytokines that are active.

Cytokines at CVS
From a scientific research there are indication that people with CFS have a cytokine disturbance in the brain. This is not measurable in the blood. There is, for example, an increase of certain cytokines found in the cerebrospinal fluid (CSF) of people with CFS. Ontstekingsbevorderend is an important cytokine IL-1. IL-1 can be inhibited without creating a risk of serious side effects.

Which medicines are examined?
In the research we compare treatment with placebo with treatment with Anakinra. These medications are injected subcutaneously daily. (Participants are instructed to administer the Center at home.) Anakinra is an anti-inflammatory medication. It inhibits IL-1. It is currently used in patients with for example rheumatism or gout.
Placebo is a medium in which no active substances. Placebos are often used in research. A placebo looks like on the real drug. In this way can be tested or an investigational drug really works.

How is the research carried out?
The research consists of several parts. A screening phase, the treatment phase and a follow-up phase. The examination takes a total of six months. During this period, participants will visit the RadboudUMC three times. At the beginning of the study participants treated with the medicine daily for a month. In the period afterwards,
on multiple moments, blood, saliva, hair, stools, and questionnaires. In the flow chart is showing how the research looks like.

CiCFS Flow Chart

CiCFS Flow Chart

Neighborhood Control
For example, certain values in the blood in a reliable way to be able to compare with persons without fatigue, we ask that people participating in the research once someone of roughly the same age (+/-5 years) and the same sex.

You can take part in?
You have CVS You are a woman You are between the ages of 18 and 59 years old You use, with the exception of paracetamol and birth control, no medications When the above criteria, you may be able to participate in the research.

Are you interested in participating?
If you are interested in participating in the research we kindly ask the CiCFS form. The CiCFS study team are watching if you qualify for participation. It is expected that the first people in May this year. Your application will be sent directly to doctor-researcher M.E. Rafiei, you can sign up here.
 

FancyMyBlood

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That's OK @FancyMyBlood I found it via Tom on Co-cure. Presumably 'CVS' is the same as 'CFS' and was lost in translation...
This is it indeed- quick find!

This picture got lost in the translation though:



A rough translation for the non-Dutch speakers since it can't translated by digital software:

46 ME/CFS patients
|
Collection of blood, salvia, hair and stool samples -> measuring cytokines
|
23 patients daily Anakinra injections for 4 weeks ---- 23 patients daily placebo injections for 4 weeks
|
Repeat measurements
|
Questionnaires till 6 months post-treatment
 
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Prof Jonathan Edwards. I am very happy to see you here!

Today I called the University Hospital in Bergen to ask them when Mella and Fluge will start with the big Rituximab trial. I was told they have all the resources they needs included the funding (an expencive one) and there will be 140 participants in this study. Now they will use the time that`s needed to find the right candidates. (more than 900 wants to participate in this study, and I`m one of them, crossing my fingers.)
They will start up in the end of May 2014 and the selection process is underway.
I`ve been told they will use strict criteria and the CCC, and the participants will receive a letter from their MD. within a month or so. I am just so happy to know that they`re finally ready! :)

Mr. Edwards. The UK rituximab trial wil start in the end of July and I feel pleased that there are enough Financial resorces and necessary logistics to conduct this study, and together with the Norwegian stydy this will be powerful and hopefully confirmed that the b-cells are indeed involved in this disease. I really feel we`ll get an anwear and deeper insight into the pathophysiology; what causing the immune activation. And I feel so pleased to know you`ll be there as an advicer for the uk trial. Thanks a lot!

Greetings from Oslo
Wilhelm
 
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Firestormm

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Prof Jonathan Edwards. I am very happy to see you here!

Today I called the University Hospital in Bergen to ask them when Mella and Fluge will start with the big Rituximab trial. I was told they have all the resources they needs included the funding (an expencive one) and there will be 140 participants in this study. Now they will use the time that`s needed to find the right candidates. (more than 900 wants to participate in this study, and I`m one of them, crossing my fingers.)
They will start up in the end of May 2014 and the selection process is underway.
I`ve been told they will use strict criteria and the CCC, and the participants will receive a letter from their MD. within a month or so. I am just so happy to know that they`re finally ready! :)

Mr. Edwards. The UK rituximab trial wil start in the end of July and I feel pleased that there are enough Financial resorces and necessary logistics to conduct this study, and together with the Norwegian stydy this will be powerful and hopefully confirmed that the b-cells are indeed involved in this disease. I really feel we`ll get an anwear and deeper insight into the pathophysiology; what causing the immune activation. And I feel so pleased to know you`ll be there as an advicer for the uk trial. Thanks a lot!

Greetings from Oslo
Wilhelm
I did not realise it was starting in the UK at the end of July or that they had raised the £350,000 in their initial target. Is this correct please? Thanks :)
 

Mark

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This is quite a detailed study and the various components do seem to corroborate the idea that there may be antibodies binding to adrenergic receptors in these cases. My main worry is why they only apparently give an immunofluorescent result for one patient. If these were antibodies and they gave fluorescence of the sort indicated then it would seem obvious to screen the whole panel. I would also like to see more detailed images to confirm that the staining pattern was consistent with membrane receptors. It does look as if these patients have some sort of circulating factor that interferes with receptors but I would like to see it repeated by another group before I concluded that this was autoantibody.

If this finding can be confirmed I think it would add impetus to the search for autoantibodies in ME/CFS. The question would be what target receptor to set up your assays with to look for the antibodies.
Thanks Jonathan.

What piqued my interest was the mention I read somewhere (which I now can't find! :rolleyes:) that one of the autoantibodies targets a receptor that is present in (amongst other places) peripheral blood vessels - or at least, it has a role in controlling vasoconstriction. Because of my own symptoms, I'm particularly interested in the peripheral neuropathic symptoms present in a subset of ME/CFS patients, and I've heard it suggested a few times that some kind of impairment of the control of vasodilation and vasoconstriction could potentially explain a range of symptoms and observations noted in ME/CFS - not only POTS and OI symptoms, but low blood volume, peripheral neuropathy, headaches/migraines and more.

I also understood from the paper that two types of autoantibodies targeting two types of receptors are suggested by the paper, and each targets receptors present in a range of specific locations in the body. Add and combine just one or two more types of autoantibodies and consider the permutations, and overlapping symptom clusters and diverse symptomology in a range of inter-related syndromes seem to me eminently explicable by this kind of mechanism.

I've been warned before that biological plausibility and explanatory power are not a reliable guide to guessing at what the actual answer may be, and that lots of other possible explanations would also make sense, but this hypothesis does seem to me to fit some of the more curious aspects of the observed epidemiology rather well. Is my very rough layman's understanding of the biological mechanisms proposed here along the right lines, and is there anything else I've missed out that may be particularly significant?
 
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Thanks Jonathan.

What piqued my interest was the mention I read somewhere (which I now can't find! :rolleyes:) that one of the autoantibodies targets a receptor that is present in (amongst other places) peripheral blood vessels - or at least, it has a role in controlling vasoconstriction. Is my very rough layman's understanding of the biological mechanisms proposed here along the right lines, and is there anything else I've missed out that may be particularly significant?
Yes, I think there is a plausible story here, but you are right, it needs corroboration before we can know if it is the right story.
 

Kate_UK

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from http://www.investinme.eu/news.html

We are enormously pleased that Dr Oystein Fluge and Professor Olav Mella will be returning to London to present at the BRMEC4 research Colloquium organised by Invest in ME on 29th May.

Dr Fluge and Professor Mella are continuing their research and will shortly begin their phase 3 multicentre clinical trial of rituximab. Both will be attending the IIMEC9 conference on 30th May.
 
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Hi @Jonathan Edwards I was wondering what you made of the Griffiths paper if you had time to make sense of it?
I think the findings are interesting. How to interpret them in terms of a theory of disease is more difficult, although it does seem that there is something going on in terms of immune dysregulation. The key thing we need is comparable studies done in different units to try to get reproducibility. Hopefully that is something that will become a reality over the next fe years. I am hoping to meet up with members of a number of teams at the IiME meeting and probably other meetings later in the year.
 

aimossy

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Thanks @Jonathan Edwards Its good to hear. I figured they might be using some different techniques or tools for their findings as well, because I haven't come across other papers quite like this, with what they are analysing. Not that I know much about these things, it was instinctual more than anything. It's good to hear of collaboration with these things:).
 
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