Rituximab and placebo response

[Guest 2176]

I remain unconvinced that step counts could be kept up for a long time in ME/CFS just from placebo. Maybe for a few days, sure, depending on the severity.

A) it just doesn't help with anything I know about severe ME. And not only placebo but regression to the mean also doesn't make sense with the experience of people with severe ME , because they rarely get better on their own

B) if it's possible for placebos to produce long term functional improvements including raised step counts why did the pace trial abandon step counts and any measures of increased activity? It seems that all the psych interventions have failed to produce impressive increases in step counts , especially long term. I'm not talking about for a day or two.
If the argument is just that the psych interventions are bad placebos and that a caring doctor supposedly administering a strong drug or surgical intervention is a much better placebo, that's one thing, but we don't have recorded evidence of improvements in exercise capacity or step counts from any intervention as far as I know. And I would actually expect the cbt/lightning process thing to work as well as a placebo as the other stuff, especially given patient selection. Pace took a pretty broad group of people with moderate fatigue and who must have not had much of a negative view of the intervention and wanted to believe it would work ... I remember the mild to moderate stage when I first got sick I tried to exercise myself to health,I would have done anything and was desperate and super subject to placebo ... And then told them all this stuff about how this could work if they believe in it etc. And yet despite all these perfect environments for a placebo they couldnt produce functional improvements on things like step counts or even return to work.
Maybe step count isn't "objective" enough as a measure but if we start with the assumption that there's some real impairment in exercise physiology in this illness it should follow that that's a bettermarker than self reported fatigue , and not entirely subjective although something like doing an invasive cpet might be better.

The point is if it was easy to produce improvements in functional capacity with placebo in this illness we'd see it happen more in the literature. Y

 

[Saz94]

I remain unconvinced that step counts could be kept up for a long time in ME/CFS just from placebo. Maybe for a few days, sure, depending on the severity.

A) it just doesn't help with anything I know about severe ME. And not only placebo but regression to the mean also doesn't make sense with the experience of people with severe ME , because they rarely get better on their own

B) if it's possible for placebos to produce long term functional improvements including raised step counts why did the pace trial abandon step counts and any measures of increased activity? It seems that all the psych interventions have failed to produce impressive increases in step counts , especially long term. I'm not talking about for a day or two.
If the argument is just that the psych interventions are bad placebos and that a caring doctor supposedly administering a strong drug or surgical intervention is a much better placebo, that's one thing, but we don't have recorded evidence of improvements in exercise capacity or step counts from any intervention as far as I know. And I would actually expect the cbt/lightning process thing to work as well as a placebo as the other stuff, especially given patient selection. Pace took a pretty broad group of people with moderate fatigue and who must have not had much of a negative view of the intervention and wanted to believe it would work ... I remember the mild to moderate stage when I first got sick I tried to exercise myself to health,I would have done anything and was desperate and super subject to placebo ... And then told them all this stuff about how this could work if they believe in it etc. And yet despite all these perfect environments for a placebo they couldnt produce functional improvements on things like step counts or even return to work.
Maybe step count isn't "objective" enough as a measure but if we start with the assumption that there's some real impairment in exercise physiology in this illness it should follow that that's a bettermarker than self reported fatigue , and not entirely subjective although something like doing an invasive cpet might be better.

The point is if it was easy to produce improvements in functional capacity with placebo in this illness we'd see it happen more in the literature. Y

And frankly, if it was easy to produce improvements in functional capacity with placebo in this illness, then ME wouldn't be such a serious, life-ruining illness. (Since it is the impact upon functional capacity which makes this illness life-ruining.)

 

[Jonathan Edwards]

In a PWME, a placebo is not going to produce a persistent improvement in step count.

I don't think it is anything like as simple as that.

If someone increased their activity because a placebo made them think they were better, then PEM would come to bite them on the ass after a while

For some, yes, but you have to remember that trials are carried out on people at all stages of going in and out of bad phases of an illness. And we have no way of knowing whether in fact there is not a subgroup who are highly placebo-responsive and may return to normal. There is no way we can assume that the set of people with ME is homogeneous.

Didn't we criticise the PACE trial for not using measures of physical activity.

Measures of physical activity have advantages over questionnaires but they are still subjective at another level in the context of placebo effects. Moreover, as I mentioned, any sort of measure is of little value unless you have a prospective study with controls.

Even if some people after CCI surgery showed a change in a blood test we would need to compare that to how many not having the surgery showed the same.

We have to have a level playing field for assessing evidence quality. We cannot be more lenient with treatments that sound attractive to some.

 

[Jonathan Edwards]

The problem is that in the open label follow on study with rituximab people repeatedly showed major improvement in a time frame that matched expectations of how long the drug's effect would last. Then it became clear that in fact this was a placebo response. I don't know if altimetry or step counts were done but there is little doubt that at least some of these people had major improvements associated with a major increase in activity.

I can understand that PWME find it hard to believe that ME might respond long term to placebo but we have pretty good evidence that at least a subset of patients do. Maybe there are two illnesses, one that respond and one that does not.

 

[duncan]

I can understand that PWME find it hard to believe that ME might respond long term to placebo but we have pretty good evidence that at least a subset of patients do. Maybe there are two illnesses, one that respond and one that does not.

Doubtful.

 

[duncan]

Then it became clear that in fact this was a placebo response.

This is an inference that may not be accurate.

 

[Saz94]

I don't think it is anything like as simple as that.



For some, yes, but you have to remember that trials are carried out on people at all stages of going in and out of bad phases of an illness. And we have no way of knowing whether in fact there is not a subgroup who are highly placebo-responsive and may return to normal. There is no way we can assume that the set of people with ME is homogeneous.



Measures of physical activity have advantages over questionnaires but they are still subjective at another level in the context of placebo effects. Moreover, as I mentioned, any sort of measure is of little value unless you have a prospective study with controls.

Even if some people after CCI surgery showed a change in a blood test we would need to compare that to how many not having the surgery showed the same.

We have to have a level playing field for assessing evidence quality. We cannot be more lenient with treatments that sound attractive to some.

I see your points here.

 

[Barry]

For some, yes, but you have to remember that trials are carried out on people at all stages of going in and out of bad phases of an illness.

It makes me think there is probably a serious oversight with regard to sampling theory in a lot of this. In essence your sampling frequency must be at least high enough to not miss signal information that later analysis will assume would not have been lost.

 

[Saz94]

I can understand that PWME find it hard to believe that ME might respond long term to placebo but we have pretty good evidence that at least a subset of patients do. Maybe there are two illnesses, one that respond and one that does not.

If you want to be an ally to PWME, please don't go round saying that ME can respond long-term to placebo. That is exactly the sort of thing that the psych brigade will lap up. Ooh look it's all in their heads, they just need to believe that they're receiving a treatment that works!

 

[Jonathan Edwards]

Doubtful.

How can anyone tell? If we have strongly suggestive evidence of a long lasting placebo response in some cases then it has to be on the cards.

 

[Barry]

If you want to be an ally to PWME, please don't go round saying that ME can respond long-term to placebo. That is exactly the sort of thing that the psych brigade will lap up. Ooh look it's all in their heads, they just need to believe that they're receiving a treatment that works!

I think @Jonathan Edwards is primarily an ally to the truth, wherever it may be found. It is what we all have to be. Why is it not possible that there may be different subgroups?

 

[duncan]

How can anyone tell?

How can anyone tell that God didn't decree it? Or that the repressed emotions that caused these people to be sick were released, and they grew well? Similar logic.

If we have strongly suggestive evidence of a long lasting placebo response in some cases then it has to be on the cards.

Placebo effect cannot be sustained. There is no precedent. This requires a leap of faith that cannot be justified.

 

[Jonathan Edwards]

If you want to be an ally to PWME, please don't go round saying that ME can respond long-term to placebo.

I can only be a genuine ally of PWME if I stick to the truth and all possibilities that need exploring.

Medical science does not allow us to pick and choose the truth. The truth comes out as what it is. What the psychiatric fraternity use most powerfully as ammunition is the claim that PWME do not want to know the truth.

 

[duncan]

Medical science does not allow us to pick and choose the truth.

Well, it shouldn't. But the reality is that it happens more frequently than I am comfortable with.

 

[Snow Leopard]

The problem is that in the open label follow on study with rituximab people repeatedly showed major improvement in a time frame that matched expectations of how long the drug's effect would last. Then it became clear that in fact this was a placebo response.

Placebo response or reporting bias?

The only known biological placebo responses are acute responses to short term pain and nausea, which just results from behavioural conditioning of evolutionary preserved responses to help us escape danger despite illness/poisoning or injury.

 

[chrisb]

What is "the truth"? Could even a true statement necessarily reveal "the truth"?

 

[Jonathan Edwards]

Placebo response or reporting bias?

The only known biological placebo responses are acute responses to short term pain and nausea, which just results from behavioural conditioning of evolutionary preserved responses to help us escape danger despite illness/poisoning or injury.

Reporting bias is theoretically possible but having looked at the data I find it very hard to believe that in these cases people did not think they were having a very significant response to the drug.

Known placebo responses may be limited but I don't think that means we know they are always short term. Prior to the development of more than a tiny handful of effective remedies medicine survived on the basis of the placebo response for centuries.

 

[Snow Leopard]

Reporting bias is theoretically possible but having looked at the data I find it very hard to believe that in these cases people did not think they were having a very significant response to the drug.

Yes, they thought they were responding to the drug, hence reporting biases...

 

[duncan]

Known placebo responses may be limited but I don't think that means we know they are always short term.

Please cite one that wasn't short term.

 

[rvallee]

Placebo response or reporting bias?

The only known biological placebo responses are acute responses to short term pain and nausea, which just results from behavioural conditioning of evolutionary preserved responses to help us escape danger despite illness/poisoning or injury.

In addition to the obvious misdiagnoses, more likely just random timing. Like many I had several remissions, 3 that I would count as real and tangible.

Had some treatment been used during that time, it would likely have been at least correlated with remission (though incorrectly as recovery). If a placebo had been used at the time, it likely would have been correlated to have played a role. Same reason why some people swear that [weird treatment X] did something to cure their cold, which would have cured itself anyway. Same principle, except this same mistake is done by the incompetent people who hijacked this disease.

The most significant failure in dealing with this disease remains to properly account for wild fluctuations over time. On the BPS side out of sheer incompetence. On the real science side mostly because the logistics of doing that require much larger budgets. A serious effort in researching this disease would have to include some live-in facility where patients are followed around the clock in an appropriate environment for sustained long-term presence. I would sign for this in a nanosecond. Doesn't even matter how long. But that's very expensive.

A foundation of proper science is "all other things being equal", of being able to accurately measure the thing you want to measure and not some other thing. The BPS side explicitly makes no effort doing this, doesn't care one bit, and as such produces nothing but cold garbage. On the biomedical side, the problem is that there clearly seems to be differences in what we can observe in vivo vs in a lab, the processes being dynamic and cannot be reduced down to a single snapshot in time from one factor only, the blood.

Of course there is also the addition that this is a spectrum disease that features many false diagnoses. Those factors pile on and very likely account for the failure in making significant progress, that it takes a much more organized and rigorous effort to account for all the factors than usual, something that medicine usually doesn't have to deal with and so is ill-equipped to take the necessary, expensive, steps.