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

[Bob]

Jonathan Edwards, it is important to patients that the most useful and meaningful criteria are used to define patients for research studies.

The Oxford criteria and the NICE guidelines criteria are the two most inclusive and heterogeneous diagnostic criteria in use, and i don't consider them useful for most research purposes because of their heterogeneity. For Oxford, only fatigue is required for at least six months, with no other symptoms required. NICE requires fatigue as well as one extra symptom or two, from a list, if my memory serves me correctly, but does not require post-exertional malaise. The CDC's Fukuda criteria also does not require post-exertional malaise (it's optional): Fukuda requires fatigue and four other symptoms from a list of eight.

So, Oxford, NICE, and the CDC's Fukuda definitions do not require post-exertional malaise: it is an optional secondary symptom for NICE and Fukuda.

I would not want to see either Oxford or NICE criteria used for an important study like this, as the sole diagnostic criteria, and Fukuda is little better in terms of heterogeneity. It could possibly be a waste of resources, if no other criteria were used, as it would be a heterogeneous patient cohort.

I think it is very important that a more selective criteria is used, at least in addition to a more heterogeneous selection criteria.

The Canadian Consensus Criteria (CCC) are being used more frequently in CFS/ME research these days, usually alongside Fukuda (so patients are tested against both Fukuda and CCC, creating subgroups). For example, a CFS/ME biobank, which is a joint project between various patient charities (including the ME Association and Action for ME) use the CCC alongside another criteria (possibly Fukuda).

CCC requires post exertional malaise (a delayed and prolonged symptomatic flare up in reaction to minimal exertion, which isn't relieved by rest), which many patients consider to be an essential feature of ME. ('ME' as opposed to a broadly defined fatiguing illness of unknown etiology.)

I hope that a CCC cohort can be defined for this study, or if not, then patients are at least subgrouped into patients who experience (delayed, prolonged) post exertional malaise, and those who don't.

So if you have any influence in this area, could you perhaps consider that patients are assessed by the CCC, in addition to any other recruitment criteria that you are using. And please don't use Oxford, because it is the most inclusive heterogeneous set of criteria in existence, and simple defines chronic fatigue, the symptom.

Hope you don't mind me bringing these issues to your attention.


Here are the most widely used definitions, in case helpful...

Canadian Consensus Criteria 2003:
http://www.cfids-cab.org/MESA/ccpccd.pdf

International Consensus Criteria 2011 (ICC superseded the CCC, but it hasn't gained widespread traction yet):
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02428.x/pdf

CDC Fukuda 1994 (CDC's current definition):
http://www.cdc.gov/cfs/case-definition/1994.html (CDC's website - simplified version)
http://www.ncf-net.org/patents/pdf/Fukuda_Definition.pdf (PDF version of full research paper)

Oxford 1990 (defines little more than chronic fatigue, the symptom):
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1293107/?page=1
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1293107/pdf/jrsocmed00127-0072.pdf (downloadable PDF version)

 

[Jonathan Edwards]

I think that Firestormm was refering to the diagnostic criteria published in the NICE guidelines. They are some of the least strict of the available criteria.

Yes, I think they may be more to do with who to give CBT than looking for causes of diseases!

 

[Ember]

I presume they will start with the Fluge and Mella choice but might want to narrow it down a bit further.

Do you know whether the Fluge and Mella choice will be narrowed down a bit further in their upcoming study?

 

[heapsreal]

heapsreal have Peterson or Klimas published any studies that would support the claims you are making, out of interest? Just wondering if it isn't a case of doctors finding patients improve on X drug, think it has something to do with XX; and are making conclusions without proper scientific scrutiny? Not saying it is - not saying it isn't. But life in a surgery is often different to life under a microscope or clinical trial

Edit:

I found this review from Klimas in 2007. Of course I have no way of knowing what she (or Dr Peterson) and indeed others specifically look for in their tests, or upon which they base any specific treatments; anyway in relation to NK cells:



I also have no idea if the theory expressed above is still something that is behind treatment with specific drugs in their clinics today. I suspect the studies above have never been replicated, but as science 'surges' forward perhaps we will see these smaller studies replaced with larger ones - and some of these theories replaced also - or at least confirmed.

Appreciate any more recent publications from Klimas and/or Peterson supporting any theory they may have about NK cells and specific drug treatment - as well as the theory behind it. Do you happen to know if any drug trials are planned on the back of any of their theories?

Thanks

Theres enough stuff on the internet done by klimas and peterson with petersons latest being the ihhv6.
I suppose we wait for the 2 pathogen studies to be done, the one by Stanford with dr montoya and the other pathogen study by lipkin.

I still think there going to have to put people into the right subsets first. Im not anti ritux, i think its going to do good things for the right sub set. I think we are slowly working out sub groups by which patients respond to certain treatments. Theres definately a antiviral/herpes subset and it looks like they haved found an auto immune subset. Are these people that respond to ritux have any other biomarkers, maybe higher inflammatory markers or ANA.

I think there is alot of interesting things about to unfold, its just not happening quick enough.

cheers!!!

 

[voner]

Jonathan Edwards, it is important to patients that the most useful and meaningful criteria are used to define patients for research studies.

The Oxford criteria and the NICE guidelines criteria are the two most inclusive and heterogeneous diagnostic criteria in use, and i don't consider them useful for most research purposes because of their heterogeneity. For Oxford, only fatigue is required for at least six months, with no other symptoms required. NICE requires fatigue as well as one extra symptom or two, from a list, if my memory serves me correctly, but does not require post-exertional malaise. The CDC's Fukuda criteria also does not require post-exertional malaise (it's optional): Fukuda requires fatigue and four other symptoms from a list of eight.

So, Oxford, NICE, and the CDC's Fukuda definitions do not require post-exertional malaise: it is an optional secondary symptom for NICE and Fukuda.

I would not want to see either Oxford or NICE criteria used for an important study like this, as the sole diagnostic criteria, and Fukuda is little better in terms of heterogeneity. It could possibly be a waste of resources, if no other criteria were used, as it would be a heterogeneous patient cohort.

I think it is very important that a more selective criteria is used, at least in addition to a more heterogeneous selection criteria.

The Canadian Consensus Criteria (CCC) are being used more frequently in CFS/ME research these days, usually alongside Fukuda (so patients are tested against both Fukuda and CCC, creating subgroups). For example, a CFS/ME biobank, which is a joint project between various patient charities (including the ME Association and Action for ME) use the CCC alongside another criteria (possibly Fukuda).

CCC requires post exertional malaise (a delayed and prolonged symptomatic flare up in reaction to minimal exertion, which isn't relieved by rest), which many patients consider to be an essential feature of ME. ('ME' as opposed to a broadly defined fatiguing illness of unknown etiology.)

I hope that a CCC cohort can be defined for this study, or if not, then patients are at least subgrouped into patients who experience (delayed, prolonged) post exertional malaise, and those who don't.

So if you have any influence in this area, could you perhaps consider that patients are assessed by the CCC, in addition to any other recruitment criteria that you are using. And please don't use Oxford, because it is the most inclusive heterogeneous set of criteria in existence, and simple defines chronic fatigue, the symptom.

Hope you don't mind me bringing these issues to your attention.


Here are the most widely used definitions, in case helpful...

Canadian Consensus Criteria 2003:
http://www.cfids-cab.org/MESA/ccpccd.pdf

International Consensus Criteria 2011 (ICC superseded the CCC, but it hasn't gained widespread traction yet):
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02428.x/pdf

CDC Fukuda 1994 (CDC's current definition):
http://www.cdc.gov/cfs/case-definition/1994.html (CDC's website - simplified version)
http://www.ncf-net.org/patents/pdf/Fukuda_Definition.pdf (PDF version of full research paper)

Oxford 1990 (defines little more than chronic fatigue, the symptom):
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1293107/?page=1
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1293107/pdf/jrsocmed00127-0072.pdf (downloadable PDF version)

bob,

I took a look at the Invest in ME Website and they have a Description of their trial That Dr. Edwards is advising. Here is it's web address:

http://www.ukrituximabtrial.org/IIMEUKRT Summary.htm#1


here are 3 Interesting points:

- Invest in ME have arranged for Professor Edwards to visit Dr Fluge and Professor Mella in Bergen, Norway to discuss the clinical trial in detail - thus enhancing cooperation and research.

• Invest in ME have agreed to fully fund the preliminary study by UCL which is a pre-requisite to the full clinical trial. This will begin shortly.

• The preliminary study will be a small study which will confirm the earlier work of Dr Amolak Bansal [1] on B-cells but using a different cohort of ME patients.

If you look at the reference cited in the work of Dr Amolak Bansal [1], You will see that Dr Amolak Bansal Used patients that the criteria for the Canadian and Fukuda Definition.

@ Jonathan Edwards, Have you gotten a chance to get that trip over to Norway yet? Nice chance to chance to collaborate and learn from others.... for both you and the Norway Contingent.

 

[Gemini]

My information so far about the literature is that there are no consistent findings of active infections.

Professor Edwards thank you for discussing infections. This may be a bit off that topic but maybe not, I've heard many ME/CFS patients describe not catching common colds or flu since becoming ill with ME/CFS noting that before ME/CFS they would experience several in the course of a year. Might this point to an overactive upregulated immune system and perhaps that loop you refer to earlier in the thread?

 

[rosie26]

Perhaps we should have a poll on another thread for that Gemini regarding colds. I have had severe ME and I still get the usual amount of colds. But interesting that some ME'ers don't get colds.

 

[Firestormm]

Morning all

Re: criteria and my own previous call for NICE to be used as a minimum in terms of both criteria and methodological assessment.

In order for Rituximab to become licensed for use in CFS/ME both NICE would need to endorse and (I understand) the MRHA - Medicines and Healthcare Regulatory Products Agency would need to approve.

Now, albeit it was waaayyy back in 2007, when NICE published their Guideline (though it remains in force and has not been changed) they did review, incorporate aspects of, and reject other criteria as were then available for review: though it wasn't so much NICE in isolation if I recall but NCCPC and RCGP.

You can read all about it still in the Full Guideline from I think (interactive index btw) pp. 124 that is section 5.1. including the review of the then other and existing criteria (such as the Canadian - rejected I recall because of it's deemed poor methodology) and each of the reviewed criteria pro's and con's - at least in the opine of these expert advisers.

Now, I will concede at this juncture that I am rather confused by the difference between 'clinical' and 'research' in terms of criteria for a condition defined by symptoms and exclusion; and it may be that if NICE were considering a 'research definition' they would have more more favourable of the Canadian: but I can't honestly think it would have made a difference.

Jonathan Edwards I guess you don't want to get drawn in to this debate much - but what is the difference really between 'research' and 'clinical' definitions/criteria in your opinion? Thanks

I think that Firestormm was refering to the diagnostic criteria published in the NICE guidelines. They are some of the least strict of the available criteria.

I was but also the methodology used to determine a diagnosis including tests and exclusions etc.

...NICE requires fatigue as well as one extra symptom or two, from a list, if my memory serves me correctly, but does not require post-exertional malaise....

Bit of a wonky memory there Bob me old mate

Funny really as we have spent so long discussing NICE over the years, but only to be expected of course.

NICE Clinical Guideline - abridged version of the Full Guideline but it is the official recommendation:

1.2. Presentation pp. 14

1.2.1.2 Healthcare professionals should consider the possibility of CFS/ME if a person has:

fatigue with ALL of the following features:

• new or had a specific onset (that is, it is not lifelong)
• persistent and/or recurrent
• unexplained by other conditions
• has resulted in a substantial reduction in activity level
• characterised by post-exertional malaise and/or fatigue (typically delayed, for example by at least 24 hours, with slow recovery over several days)

and one or more of the following symptoms:

• difficulty with sleeping such as insomnia, hypersomnia, unrefreshing sleep, a disturbed sleep–wake cycle
• muscle and/or joint pain that is multi-site and without evidence of inflammation
• headaches
• painful lymph nodes without pathological enlargement
• sore throat
• cognitive dysfunction, such as difficulty thinking, inability to concentrate, impairment of short-term memory, and difficulties with word-finding, planning/organising thoughts and information processing
• physical or mental exertion makes symptoms worse
• general malaise or ‘flu-like’ symptoms
• dizziness and/or nausea
• palpitations in the absence of identified cardiac pathology

1.3.1 Making a diagnosis

1.3.1.1 A diagnosis should be made after other possible diagnoses have been excluded and the symptoms have persisted for:

• 4 months in an adult
• 3 months in a child or young person; the diagnosis should be made or confirmed by a paediatrician

pp.17

1.3.1.3 The diagnosis of CFS/ME should be reconsidered if NONE of the following key features are present

• post-exertional fatigue or malaise
• cognitive difficulties
• sleep disturbance
• chronic pain.

 

[Marco]

Morning all

difficulty with sleeping such as insomnia, hypersomnia, unrefreshing sleep, a disturbed sleep–wake cycle

Hi Firestorm

You're up early!

 

[Firestormm]

Hi Firestorm

You're up early!

You buggar! A LOL caused yet another caffeine spillage

Yeah I know. Got fed up with the 'issues' at 3am and thought 'sod it'. You know how it goes my friend. Still, I'll probably slide back into the sack a little bit later.

Have yourself a NICE day on the other side of la Manche

 

[Forbin]

Professor Edwards thank you for discussing infections. This may be a bit off that topic but maybe not, I've heard many ME/CFS patients describe not catching common colds or flu since becoming ill with ME/CFS noting that before ME/CFS they would experience several in the course of a year. Might this point to an overactive upregulated immune system and perhaps that loop you refer to earlier in the thread?

This interests me as well. Following the intense flu which seemed to trigger the sudden onset of ME, I didn't get a cold or flu for a decade. This sort of observation is sometimes written off as an effect of ME induced "isolation" from infection opportunities, but I had a lot of contact during that decade and was not housebound for most of it. I only came down with the flu again after my symptoms had improved somewhat.

I was frankly surprised when I saw the same thing being reported by others. I think there was a poll on it here a while ago. While some people seem to become more susceptible to infection, others seem to become more resistant.

 

[Jonathan Edwards]

Do you know whether the Fluge and Mella choice will be narrowed down a bit further in their upcoming study?

No, that has not been decided.

 

[Jonathan Edwards]

Professor Edwards thank you for discussing infections. This may be a bit off that topic but maybe not, I've heard many ME/CFS patients describe not catching common colds or flu since becoming ill with ME/CFS noting that before ME/CFS they would experience several in the course of a year. Might this point to an overactive upregulated immune system and perhaps that loop you refer to earlier in the thread?

I don't think it really works to talk of an overactive or underactive immune system. Autoimmune loops do not necessarily have any effect on responses to infections. Remember that most of our symptoms of infections are due to the immune systems's response.

 

[Jonathan Edwards]

Jonathan Edwards,
CCC requires post exertional malaise (a delayed and prolonged symptomatic flare up in reaction to minimal exertion, which isn't relieved by rest), which many patients consider to be an essential feature of ME. ('ME' as opposed to a broadly defined fatiguing illness of unknown etiology.)

I think ME/CFS physicians are in favour of the CCC for something more tightly defined. However, we have to follow the evidence so far. We do not know that CCC would better define rituximab response. It is possible that post exertional malaise is a specific feature of the sort of ME that is not B cell related - then we would really mess up if we insisted on it in a trial. We can only work methodically from one step to the next. Also the CCC is worded in a way that does not lend itself well to drawing logical conclusions from findings on such a group - because there is a lot of 'some of this or some of that' in it. Complex sets of diagnostic criteria like this are rather archaic from a scientific point of view - like the Duckett Jones criteria for rheumatic fever. Once we have a foothold on mechanism I would throw them all in the bin, but for the moment the priority is to make sure that studies can be compared where it is useful to do so.

 

[lansbergen]

This interests me as well. Following the intense flu which seemed to trigger the sudden onset of ME, I didn't get a cold or flu for a decade. This sort of observation is sometimes written off as an effect of ME induced "isolation" from infection opportunities, but I had a lot of contact during that decade and was not housebound for most of it. I only came down with the flu again after my symptoms had improved somewhat.

I think it is not as much not getting a cold but the normal symptoms do not show because the immunesystem reacts different.

For many many years I wished to get a good flu to get the immunsystem go back on track but that did not happen.

Something is changing for the better now. Nose mucous membrane becomes more moist and rapid turnover occurs. Lungs are working better and none productive dry cough has changed to productive cough.

 

[Jonathan Edwards]

In order for Rituximab to become licensed for use in CFS/ME both NICE would need to endorse and (I understand) the MRHA - Medicines and Healthcare Regulatory Products Agency would need to approve.

I have long experience of these bodies! NICE is just a place where various different chaps at different times get together to try and decide what is most sensible clinical practice. They change their minds all the time. It is a bit like the Court of Appeal - any time another lot of judges can come along and say something different. And there is no particular reason why NICE guidelines for using rituximab in chronic fatigue should have to mention NICE diagnostic criteria for CFS. Guidelines for drug usage call on all sorts of criteria other than diagnostic ones. NICE diagnostic criteria might indeed be good but I don't think one would choose them for licensing reasons.

Jonathan Edwards I guess you don't want to get drawn in to this debate much - but what is the difference really between 'research' and 'clinical' definitions/criteria in your opinion?

The reality is that there are an infinite number of sensible ways of dividing clinical problems up, depending on the situation and criteria have never seemed to me to be very helpful in most of them. As an example one might want clinical criteria for 'quite likely lupus' which meant that it was sensible to check blood pressure and a blood count for the patient every three months. This would not be the same as criteria for entry into a lupus trial of rituximab which would exclude patients who had no current problems or just had damage from old disease. It may be that the distinction between clinical and research criteria is the wrong way to look at it. It perhaps should be a distinction between criteria for practical decisions and criteria for testing scientific theories. To be honest the whole thing is a mess and as complicated as there are numbers of questions you might want to ask. We could do a rituximab trial just in people with post exercise malaise, maybe excluding people who have known active infection like TB or flu. That might test some interesting theories about PEM, but not about other aspects of ME.

Standardised criteria are junk really - each question has its sensible choice of patients.

 

[Ember]

We do not know that CCC would better define rituximab response. It is possible that post exertional malaise is a specific feature of the sort of ME that is not B cell related - then we would really mess up if we insisted on it in a trial.

All but two of the subjects in the 2011 study did meet the CCC, however:

After the trial, the investigators compared all 30 patients’ symptoms to the Canadian clinical definition for ME/CFS. All but two met these criteria as well as the broader Fukuda criteria....

One of the individuals who responded to placebo was also one of the two subjects who did not fulfill Canadian criteria for ME/CFS.

In this interview, an early intention is reported to again use the “so-called Canadian criteria:"

If we have a study in which we are sure to get the result we must be very clear about the criteria. They must be crystal clear, says Mella.

This is particularly important as it will be different doctors at different centers to take care of patients. Fluge Mella and therefore want to use the so-called Canadian criteria.

- We will go for the strict criteria. It shall be the greatest possible chance that the patients included really have ME and general exhaustion, said Fluge.

He also points out that all will benefit from a careful selection process.

- If it then would be a study that is positive and shows a clear effect and are not experiencing severe, unexpected side effects, so we begin to approach that this may be an approved treatment. It will benefit many patients, says the Fluge tv2.no.

 

[MeSci]

I think it is not as much not getting a cold but the normal symptoms do not show because the immunesystem reacts different.

For many many years I wished to get a good flu to get the immunsystem go back on track but that did not happen.

Something is changing for the better now. Nose mucous membrane becomes more moist and rapid turnover occurs. Lungs are working better and none productive dry cough has changed to productive cough.

In the early days of ME my symptoms became much milder when I caught a cold or flu (or seemed to catch a cold or flu). But then I seemed to stop getting colds and flu altogether, despite interacting with others, including those who were probably infectious. If a friend says that she is worried about coming over in case she gives me the cold or flu she or her children have, I laugh and tell her not to worry as nothing seems to get past my immune system!

Your changes do sound positive, by the way, lansbergen.

 

[Firestormm]

I have long experience of these bodies! NICE is just a place where various different chaps at different times get together to try and decide what is most sensible clinical practice. They change their minds all the time. It is a bit like the Court of Appeal - any time another lot of judges can come along and say something different. And there is no particular reason why NICE guidelines for using rituximab in chronic fatigue should have to mention NICE diagnostic criteria for CFS. Guidelines for drug usage call on all sorts of criteria other than diagnostic ones. NICE diagnostic criteria might indeed be good but I don't think one would choose them for licensing reasons....

I swear that much more of this spitting of my coffee due to unexpected laughter, and I shall be requiring a new computer monitor! Faceless bureaucracy 'tis everywhere but some hurdles you gotta leap - unfortunately...

 

[Legendrew]

In the early days of ME my symptoms became much milder when I caught a cold or flu (or seemed to catch a cold or flu). But then I seemed to stop getting colds and flu altogether, despite interacting with others, including those who were probably infectious. If a friend says that she is worried about coming over in case she gives me the cold or flu she or her children have, I laugh and tell her not to worry as nothing seems to get past my immune system!

Your changes do sound positive, by the way, lansbergen.

I've read about these immune system things before and they always seem strange - perhaps it is the immune system just acting differently when presented with a challenge, I for one know the last time I got a cold - a few months back - it made me feel so incredibly ill, i'm never usually bed-bound but I spent the entire week on the sofa feeling congested, nauseous and dizzy. Perhaps it was just the cold on top of the standard ME symptoms that made me feel so bad.

I believe Fluge and Mella had noted this difference that patients describe and seemed to think from early trials that it didn't seem to effect patient outcome with rituximab. I'll see if I can find the interview where I read that.