Rituximab and placebo response

their is also semantics at play the word fatigue means different things to different people . I e muscles rapid fatigueability or simple tiredness.

 

So to be clear, there were no objective measures of activity in the rituximab trial?

 

To me it means the administrative arm had higher ADRs. The dose was too high.

5 mg of Rituximab without premedication can lower B-cells below detection.

Because the barrier to entry of having CFS in Scandinavia is saying to a doctor "I am tired sometimes" and then receiving living wage benefits. They have cases of severely, severely ill people no doubt. But the spectrum is much wider.[/QUOTE]

 

Couldn't be further from the truth. Actually receiving a CFS diagnosis and especially any wage benefits from CFS is almost impossible, at least in Finland and Sweden (and Denmark didn't even consider CFS a disease until the recent parliament decision). The situation became so absurd in Finland that some doctors now recommend CFS patients to apply for disability or wage benefits by a diagnosis of depression, since depression somehow is looked at with different lenses here.

 

Patients in the United States do that as well... bipolar, narcolepsy etc.

You are correct, that is an unfair characterization, I am sorry. So change the word to depression then.

People in the United States have been denied disability with an accident causing double-amputation and full body burns to electrocution in the United States. We are talking four levels of appeal, and it stood. That's the point I am making, surely you know the litmus test differs and that would have the downstream effect on subsequent patient populations.

 

This may be off topic but transient responses to some drug or supplement seem to be typically interpreted as placebo effect.

It's important to realize that this interpretation is not based on actually observing a "placebo effect" but merely a transient self reported response. It seems plausible that there is a real improvement that just does not last because the body quickly adapts to the drug or supplement.

We have talked about this before, it's the idea that the illness persists because homeostasis does not work. If you try to push the body towards better health, which could be easily done with many different interventions, it will just result in the body pushing back towards illness even harder.

 

Could it be that the private patients were paying for their treatment and so were more likely to 'expect' a significant improvement i.e. 'I want what I've paid for'. Whereas the patients in the study were getting it free and so were more likely to report an improvement out of gratitude for their 'free' treatment even if that improvement was small.

 

I think this is very likely, and a well known phenomena already.

When i did ritux privately, I remember feeling better around the second to third month.. I wondered if it was real, or just a mix of summer and hope. Well since I`m kind of a self destructive person I decided to go out and bike until the ME-fatigue came. After a while it came hard, and I struggled to get back home. Had i not done this, if I were in a study, i might have put myself on a 6 instead of a 4 in physical function at this time. If I wanted the study to be as success would I even have reported a 7?

 

It is arguable that the question of benefits or compensation has always biased the views of psychiatrists. Even when they think it irrelevant to the facts of the casethey bring it up just to prejudice the innocent reader:

In our patients, there is the possibility that potential financial compensation played a role in the persistence of symptoms. However, we have no direct evidence of this. It is apparent that this factor alone is certainly insufficient, since all the patients, including the recovered persons,would be eligible for disability compensation.

Imboden, Canter and Cluff in the Brucellosis 111 paper from 1959. As this was the sacred text for the BPS school, the harm cannot now be escaped.

 

Same here. As I remember it quite a few of us who did it privately had that experience, but were later disappointed to find it didn't last or wasn't real. My improvement at the 2 month mark also coincided with what I now know to be my annual, partial remission that comes every spring.

I have also wondered like someone further up the thread if we might have seen some sort of temporary effect, from the immune system being calmed down or distracted in some way for a little while, like I experience in the days before a serious cold comes on. I think it's also worth considering if the frequent follow up from medical staff in the first three months had an effect. I was seen, treated with respect and given treatment first for the consultation, then two and four weeks later the first doses, with checkups by phone between then and the third dose three months later. That's the most medical attention I've seen in such a short timespan ever.

 

Generally not true.

But more importantly, all patients in the trial had to fulfill the Canadian consensus criteria, and they re-screened participants before entering them in the trial.

 

They did use 'activity tracker armbands' (not sure what they are called in english...?) as secondary outcomes.

Not read the trial in detail yet, but this table compaires the different results:

https://acp.silverchair-cdn.com/acp...bk6lSnzYMQ__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA

 

Even the patients doing it privately had to have a formal diagnosis after the CCC. We were even reevaluated for other dxs before being offered the treatment.

 

@Jonathan Edwards Speculation about this seems like a waste of time and is fundamentally second-guessing the purpose of a blinded control trial in the first place.

Participating in trials leads to altered symptom reporting and some people by pure chance might be lucky enough to improve on their own - this phenomena is beyond dispute. This is why we do controlled studies.

 

I thought private patients would tend to justify the high costs. The 2 anecdotes of people I remember who got the costs covered were not better.

I am puzzled by the open phase 2 trial, too. I don't think it is a good example to help our case. It's to easy to wrongly interpret it as placebo effect was a real mind over matter thing and helpful and all what we need.

The bigger blinded trial shows little difference of steps between baseline and follow up and is a much better example to explain that we need controlled blinded trials and objective outcomes especially if you can't blind it.

 

The discussion so far seems to me of interest. I may not have worded the opening post perfectly but I was sort of being devil's advocate.

Clearly we are talking about the wider phenomenon of systematic expectation bias plus all the other factors that make people seem to improve in trials like regression to mean rather than a classic placebo phenomenon. But it is worth rehearsing the plausibility of all the factors.

It may be relevant that people in trials tend to improve a bit gradually over two to three years as in the control groups in PACE.

Another factor that might be relevant is the expectation of maybe needing top ups of rituximab every 6 months. That might produce a very peculiar sort of bias.

 

I'm not sure how it could be isolated, but I don't think we should discount the impact of basic socialization. Most of us are terribly isolated in real life and talking to real human beings who actually understand our suffering is a very rare experience. That impact is well-known in geriatric populations and I don't understand how it is simply ignored with us. The same can likely be said of cheap trials for self-help stuff where there is clearly a feel-good effect to talking to other patients and just being away from the same damn four walls that confine most of our existence.

Actually I think it could probably be tested but I don't know who would pay for that. Literally just an occasional meeting in an extra quiet and cozy room with the opportunity to interact with other patients, maybe have some snacks or other comfortable things. Right now most of those will be support groups run by patients so organisation is far from ideal. I wouldn't be surprised if it had an even greater questionnaire effect than any of the usual active therapy. It would be small and purely subjective but then that's already what there is.

Even for introverts like me this isolation is crushing. Obviously alleviating that should have subjective benefit. This is usually noted as being the product of group therapy but I'm pretty sure the therapist is completely superfluous.

 

ChrisB, I received Rituximab. I am not a BPS proponent.

Canadian Consensus, just like all CFS criteria, is all subjective report. Someone asked why the results were that poor, I speculated it was because it was not a multi-centered trial in a country with a higher degree of incentivization than normal. Does it matter?

I said 10 years ago the results would be confounded anyways with frequent glucocorticoid administration, when no one else did. The placebo effect being that high is new.

The main point is patient classification. If you have a lower threshold for entry, you are going to have more room for patient improvement, and with a higher one they would be more treatment resistant.

 

@Jonathan Edwards , there were only improvements on subjective measures, in the placebo groups, not any kind of measurement of activity ? This seems sort of important to the point you are trying to make. Its not surprising that a placebo (in addition to corticosteroids and antihistamines) may reduce self reported fatigue , but to actually increase activity significantly and in a sustained way is not something I would expect a placebo or psychological treatment to do. So it's important to clarify this.

 

I don't think there were objective measures in this trial because it was controlled and blinded, so they were less essential.