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Cytokine inhibition - a randomized placebo-controlled, double-blind trial

Gijs

Senior Member
Messages
691
I am not sure I agree about that. IL-1 might well be acting locally, with nothing to find in the blood. Doing blood levels would be sensible and I expect they will do them, but they certainly should not be the primary outcome measure. If you think about it showing that an IL-1 inhibitor inhibits IL-1 in PWME tells you nothing whatsoever about ME - just that you put the right drug in the bottle. The end point is designed to show that in PWME the inhibitor benefits symptoms - i.e. fatigue, so fatigue is precisely the right endpoint!

I am sorry but it sounds more like speculation rather than science. It is also inconsistent with the findings of Lipkin. If they use patiënts who are longer sick then 3 years beacause only in the first three years cytokines are elevated.
 

user9876

Senior Member
Messages
4,556
I am not sure I agree about that. IL-1 might well be acting locally, with nothing to find in the blood. Doing blood levels would be sensible and I expect they will do them, but they certainly should not be the primary outcome measure. If you think about it showing that an IL-1 inhibitor inhibits IL-1 in PWME tells you nothing whatsoever about ME - just that you put the right drug in the bottle. The end point is designed to show that in PWME the inhibitor benefits symptoms - i.e. fatigue, so fatigue is precisely the right endpoint!

Would an IL-1 inhibitor work all over the body hence stop the pathways if it is locally acting or does it just work in certain areas and hence reduce overall levels?
The other thing I was wondering its what the half-life of cytokines such as IL-1 is hence how quickly it would fade from the system if an inhibitor stops new production? In which case should a dynamic behavior pattern be observed?

I'm assuming with a placebo controlled trial not aimed at changing peoples views on their symptoms then subjective questionnaires are more reliable then when applied to things like CBT. However, I would worry about small effects due to the lack of linearity and a 'feeling well enough to know how ill you are' effect. So it would be nice to have some form of activity monitoring as well as correlation measures between different outcomes (including IL-1 reductions).
 

Jonathan Edwards

"Gibberish"
Messages
5,256
I am sorry but it sounds more like speculation rather than science. It is also inconsistent with the findings of Lipkin. If they use patiënts who are longer sick then 3 years beacause only in the first three years cytokines are elevated.

I think you missed the point that cytokines can mediate illness without being elevated in the serum - if they are secreted locally around neural tissue for instance.

Pretty much all science is testing of speculations. This seems to me to be a sensible speculation at least worth proving wrong so that we do not miss a useful treatment. IL-1 inhibitors turn out not to be very good for most of the diseases people thought logically they would be good for but are absolutely brilliant for some rare diseases where they might easily not even have been thought of.
 
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Jonathan Edwards

"Gibberish"
Messages
5,256
Would an IL-1 inhibitor work all over the body hence stop the pathways if it is locally acting or does it just work in certain areas and hence reduce overall levels?
The other thing I was wondering its what the half-life of cytokines such as IL-1 is hence how quickly it would fade from the system if an inhibitor stops new production? In which case should a dynamic behavior pattern be observed?

I'm assuming with a placebo controlled trial not aimed at changing peoples views on their symptoms then subjective questionnaires are more reliable then when applied to things like CBT. However, I would worry about small effects due to the lack of linearity and a 'feeling well enough to know how ill you are' effect. So it would be nice to have some form of activity monitoring as well as correlation measures between different outcomes (including IL-1 reductions).

An IL-1 inhibitor would work everywhere, except maybe inside the blood brain barrier - which might be relevant.
This particular inhibitor does not stop production, it neutralises what is produced. I think it may be given weekly and for IL-1 mediated disease it blocks IL-1 activity continuously and very effectively.

I agree that some activity measures would help - as we have discussed before in terms of some sort of composite measure that showed that symptom changes had functional significance.
 

jimells

Senior Member
Messages
2,009
Location
northern Maine
The end point is designed to show that in PWME the inhibitor benefits symptoms - i.e. fatigue, so fatigue is precisely the right endpoint!

Except "fatigue" is subjective and not the worst symptom by far for most of us. How about objective measures that show improvement in functioning? I mean, that's what I want - to go to the grocery without causing a crash. It sounds like this is another questionnaire-based outcome measure. We all know how "great" they are!
 

Gijs

Senior Member
Messages
691
Edwards wrote:''The end point is designed to show that in PWME the inhibitor benefits symptoms - i.e. fatigue, so fatigue is precisely the right endpoint!''.

This is not the right endpoint at all. Describe fatique? ME is not a ''fatique'' disease it is much, much more. What about tachycardia, breathing-, bloodflow-, oxygen problems, losing weight etc... you can measure this.
 

SOC

Senior Member
Messages
7,849
...the absence of raised CRP in ME...
I don't think the evidence exists to support the conclusion that CRP is not raised in ME. Very few PWME have had CRP tested, and most research studies in ME/CFS do not use well-characterized patient cohorts. We don't know whether or not CRP is raised in ME. The evidence simply doesn't exist one way or the other.

Different people claim many different "absences" in ME, but there is very, very little solid research using a patient cohort that is not so sloppy that any evidence of absence could be attributed to the inclusion of non-ME patients in the study cohort. Until we eliminate Oxford- and Fukuda-based research, the best we can say is "In the generally fatigued population, there is not a statistically significant number of patients with XYZ to conclude that XYZ is a factor in all fatiguing conditions." That doesn't say much of anything about ME in particular.

Given the sloppiness of the inclusion criteria used in most ME/CFS research, only evidence of presence can be considered somewhat legitimate. If a significant majority of mild Fukuda patients (the cohort in most non-UK ME/CFS research) have PQR, then it's probable (not certain) that the minority group of ME patients included in the study also have PQR. If a significant majority of mild Fukuda patients do NOT have PQR, it is still very possible that the majority of the minority group of ME patients has PQR.

Attempting to prove a negative is logically weak.

Absence of evidence is not evidence of absence.
 

medfeb

Senior Member
Messages
491
My son did a trial of Kineret because of high IL-1 levels and it did help with functioning (e.g. level of activity) although not as much as Rituxan has.

This video by Klimas discusses some system biology modeling of cytokines that discusses IL-1 cytokine inhibition - she's been trying to get funding for it and hasn't been able to.
- minute 41 or so.

If I remember correctly, this system biology work was originally presented at the SOK in 2011 by Broderick but I don't see a video for that
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Edwards wrote:''The end point is designed to show that in PWME the inhibitor benefits symptoms - i.e. fatigue, so fatigue is precisely the right endpoint!''.

This is not the right endpoint at all. Describe fatique? ME is not a ''fatique'' disease it is much, much more. What about tachycardia, breathing-, bloodflow-, oxygen problems, losing weight etc... you can measure this.

Being abe to measure things is not what matters. If you are treating pain, which you cannot measure, then what matters is that the person reports less pain, not some biochemical marker. If all the patients in the trial reported that they felt completely healthy after IL-1 inhibition, had no difficulty getting up in the morning and going for a jog or doing their tax returns, but the measurements you suggests showed no change (I am not sure that most of them are even recognised as abnormal in ME) should we say the drug is useless? And if all the measurements improved but the patients felt absolutely no better should we say it is great treatment?

We have discussed how it may be useful to generate composite measures of improvement including both symptomatic and functional factors on a thread devoted to that. I agree that functional measurements can be important but patients are not going to be impressed if they are offered a treatment that does not make them feel better - nor should they.
 

Valentijn

Senior Member
Messages
15,786
If all the patients in the trial reported that they felt completely healthy after IL-1 inhibition, had no difficulty getting up in the morning and going for a jog or doing their tax returns, but the measurements you suggests showed no change (I am not sure that most of them are even recognised as abnormal in ME) should we say the drug is useless?
Except the questionnaire being used isn't about feeling healthy, and certainly not about being healthy and able to do more. It's a questionnaire about fatigue, designed by verified psychobabblers who believe that ME/CFS == fatigue.

The SF36 Physical Functioning subscale would be far more appropriate than the CIS fatigue subscale in determining reduction in disability. And even better still would be a nice actometer. But since ME/CFS == fatigue to them, disability is irrelevant.

I'm glad the SF36-PF is being used, but as a secondary measure they will easily find a way to bury it if they don't like the results. The drug will fail or succeed based on fatigue, with an illness where fatigue is not a primary symptom (albeit useful in starting the diagnostic process).

And if @Effi 's source is correct about CBT also being offered to participants, that will also warp the fatigue-based primary outcome measurement. The sort of CBT used there is designed to change the way patients respond to the primary outcome questionnaire.
 

Marky90

Science breeds knowledge, opinion breeds ignorance
Messages
1,253
I agree @Valentijn, SF36 PFS is more suited to pick up eventual physical improvements through a questionnaire.
SF36measurementmodel.jpg
 

Bob

Senior Member
Messages
16,455
Location
England (south coast)
This video by Klimas discusses some system biology modeling of cytokines that discusses IL-1 cytokine inhibition - she's been trying to get funding for it and hasn't been able to.
- minute 41 or so.
I love what Nancy Klimas and her colleagues are doing. That video is very interesting, and worth watching. There's a thread about it here:
http://forums.phoenixrising.me/index.php?threads/nancy-klimas-webinar-hosted-by-pandora.35834/

If I remember correctly, this system biology work was originally presented at the SOK in 2011 by Broderick but I don't see a video for that
In case of interest, there are a number of 2015 presentations by Broderick and others on the Institute of Neuro-Immune Medicine (INIM) website, here (scroll down):
http://www.nova.edu/nim/past-events.html
 
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Bob

Senior Member
Messages
16,455
Location
England (south coast)
Another issue with the subjective experience of fatigue is that many of us can manage fatigue, to a degree, with symptom management techniques i.e. by pacing and resting etc. So, for example, if I rest for extended periods then my fatigue/exhaustion improves, but if I push against my symptoms then my experience of fatigue/exhaustion worsens. i.e. my fatigue can worsen when I increase my activity levels, and my fatigue can improve when I decrease my activity levels. So an improvement in fatigue can actually indicate worse incapacity. So that's another reason why fatigue is a crap measure of the overall illness. My own preference is to have reduced symptoms by reducing my activity; that's how I choose to manage, and live with, my illness. But if my symptoms improve and I'm less active then my overall health has not improved; it's just a better subjective experience for me but with worse incapacity. I think most of us would agree that a measure of overall physical function is a better indicator of changes in the underlying illness, than a snapshot measure of subjective fatigue. Although, physical function can also be misleading if the increased activity is at the expense of symptoms and quality of life.
 
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Valentijn

Senior Member
Messages
15,786
For those who are wondering, the primary outcome of fatigue severity on the Checklist Individual Strength is scored based on the responses to the following statements:
I feel tired.
Physically I feel exhausted.
I feel fit.
I feel powerless.
I am rested.
Physically I feel I am in bad form.
I tire easily.
Physically I feel I am in an excellent condition.
I'm not sure if that's even useful in assessing fatigue, assuming fatigue were actually relevant in the first place.

They are also omitting the token items relevant to physical activity:
I am physically very active.
I am physically not very active.
My level of physical activity is low.
 

Effi

Senior Member
Messages
1,496
Location
Europe
And if @Effi 's source is correct about CBT also being offered to participants, that will also warp the fatigue-based primary outcome measurement. The sort of CBT used there is designed to change the way patients respond to the primary outcome questionnaire.
I only know it was offered, but I would suspect it to be carried out AFTER the entire anakirna trial + questionaire/evaluation was finished. Otherwise the whole trial would be fraudulous to begin with. From a rational point of view they probably thought of offering CBT as an incentive for patients, as 'CBT is the only evidence based treatment for cfs'. A bit like how in other new medication trials after it is finished they offer a different, already tested and approved medicine to the patients in the placebo group, so everybody gets something out of it. Offering CBT along the same lines is a pretty hilarious concept, but let's try to be positive and imagine they offered this with the best intentions. :rolleyes:
 

Gijs

Senior Member
Messages
691
CONCLUSIONS:
The findings show that ME/CFS is characterized by low-grade inflammation and activation of CMI. The results suggest that characteristic symptoms of ME/CFS, such as fatigue, autonomic symptoms and a flu-like malaise, may be caused by inflammatory mediators, e.g. IL-1 and TNFα.

http://www.ncbi.nlm.nih.gov/pubmed/21975140
 

Jonathan Edwards

"Gibberish"
Messages
5,256
I don't think the evidence exists to support the conclusion that CRP is not raised in ME. We don't know whether or not CRP is raised in ME. The evidence simply doesn't exist one way or the other.

So if I were to say to Mady Hornig 'Hi Mady, you know that complicated cytokine stuff you did last year? Well my friend SOC says you needn't have bothered to do any of that 'cos nobody has measured the CRP and that would have proved ME was a biological disease just the same.' would she have
(a) said 'Doh! How silly of me not to think of that.'
(b) tossed her curls and laughed.

In fact she might have done the first but with even more of a twinkle in her eye than usual.

If the CRP was at a similar level to diseases that are known to be cytokine driven then ME would have been recognised as a biological illness years ago, like polymyalgia - where there was in most cases only symptoms of pain and stiffness and a raised ESR/CRP to go on.

Maybe you can show me the 25 peer reviewed papers that studied the medical records of hundreds of randomly selected ME patients and found that 68% had never had a CRP tested? Or maybe...

What was that phrase ... absence of evidence is not evidence of absence ...?

Seems a bit logically weak to me. [/QUOTE]