How We Get Fooled

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How We Get Fooled

Postby mrhodes40 » Fri Mar 17, 2006 12:11 pm

Well, here I am going to talk only about how we get fooled by research on anything but for us specifically CRABS. I've wanted to do this for a long time. I am taking abx, but this is not related so if that's not your thing read on with confidence, it's about trials and how they work. People put huge faith in trials, less in personal experiences. This seems scientific and wise. But do we understand trials correctly? They've been sold to us as infallible, repeatedly people point to conflicting ones and are confused, how can both be true?

In this absract <shortened url> , we see that people correctly guess if they are taking a placebo or the active drug. This is related to the informed consent process:
People must be told what they might experience if they get the active drug. Flu like reactions? must be told. Large swelling of the injection site? must be told IT's an FDA requirement. So people go into the trial with a knowledge of how the active drug reacts. According to this study 70%of people guess correctly which one they got.

THis paper <shortened url> another on the reactions of participants to studies, indicates that participants tend to judge the "new" medication based on many factors not just what the trial authors are telling them which causes bias.

Oh please. You don't suppose that could be related to the extensive media campaign pre release that builds up expectations. Everything from national coverage to my local station "releasing" such "science" as this might be; 'today, researchers have discovered a new molecule that may mean the end to MS! (pan to people in wheelchairs) Researchers at (where ever) now say that they have discovered a peviously unknown part of the immune system, clinical trilas should start with in the year"

You sit with bated breath, Oh please let it be! You call the station -who's doing the trial?
Many of these little snippets come out causing you to nearly salivate with expectation! Oh if only I can hang on! They are really on to something!

months later you are offered a spot in the clinical trial and you are given your disclosure. After the first injection, you notice the marked side effect they disussed. You KNOW you are getting "IT". You relax. I'm getting the new drug! Whew! I'm going to be among the first to get this, not placebo. And you do better. You tell the doc, I'm getting the real drug, look at this swelling! He thinks also you are better, it's exciting.

Is this blind? No, it's not. My mom has been in three trials and she always knew.

So what, you might say? I tell you it's a big deal. In other studies on studies and how they work, it has been estimated that a considerable portion of the positive reaction to a drug in such 'blinded' studies are attributed to this knowledge, not to effectiveness of the drug. Essentially the blind study is often not and any slight positive reaction is added to this effective placebo effect being added.

Now think about the original beta interferon studies, is there any way the treated people did not have some knowledge of being treated? flu, sick.

Same for the copaxone trial any way they did not know they were being treated? (My leg on my first cop injection swelled from my thigh to my knee) the placebo guys were saying oh darn, I'm not on it, even if they thought they might have been at first, by the time they went to the clinic and saw jane doe over there with her huge red swelling, doubt crept in.

Now it is common knowledge that placebo effects overall are 35%. If you don't see a better response than that, you are not beating placebo. In public lecture from a local well known MS neuro, he admonished us many years ago that this 35% accounts for the "results" of fish oil etc. He chastized us to be very leery of such scams (this was '94 or so)

But wait, the CRABs barely beat this placebo, though in their trials, the placebo THEY got was much lower than the usual 35%, which is how they talk about the differences. (um gee, cause people figured it out?)

IF THERE WAS A VIRTUAL PLACEBO GROUP THAT EVERY TRIAL USED, IN OTHER WORDS THEY STOP GIVING PLACEBOS BUT USE THE 35% NUMBER, NEITHER COP OR BETA WOULD HAVE BEATEN THIS NUMBER EARLY ON.

Imagine this: so these drugs are shelved, and other approaches are tried. Looking for something that actually is better, maybe even in terms of disability. Has the "success" of these drugs cost us advancement of the research into more fruitful arenas?

Why would it matter you might say, the lesions decreased that can't be related to their thinking they were on the real drug....that's can't be a placebo...

OH YES, it can. Why? because the ones who figured out they were getting it were relieved, their HPA axis was influenced. They made endorphins. This has a profound effect on the body and immune system. This is also why counseling helps if it is successful in reducing the anxiety. The HPA axis is tied to our perceptions and feelings and is activated or not by them to a certain extent.

OK now look at the difference between the plabcebo group and the treated group. THE DIFFERENCE IS ABOUT 5% . It's not a reduciton of "35%" it's only a little tiny bit better than placebo.

if one believed that fish oil would do this for you, you'd get at least as good results, and many do. I have taken stuff like that for years because I think there is good research to support the notion it would be helpful in reducing at least inflammation, but as we've shown in so many threads, imflammation is probably a red herring anyway.

Anyway, I have wanted to post this for some time. We must not overvalue "blind" studies. We need research and people have to do their best to figure out what to treat us with, but equally important is how you react to a given treatment and what other research is out there. Problem is the neuro relies heavily on the blinded group studies and spends much less time reading about the theories behind what's really happening.

It matters that the research here says inflammation is a moot point.
http://www.msif.org/en/research/researc ... on_of.html

It matters that they outline that even severe suppression does not reduce disability.

Yet this kind of thinking based on scientific understanding of how things work is countered with these "blinded" studies. I asked my neuro about the research that Prineas did which showed MS is not autoimmune. He said he did not think anyone seriously thought MS was not autoimmune. His evidence? He cited the fact that CRABS work.
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Postby LifeontheIce » Sat Mar 18, 2006 7:41 am

Excellent point, Marie. Whatever I took so far made me stay in those 35%. I am so lucky!
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Postby Katman » Sat Mar 18, 2006 8:14 am

Marie

Thank you for posting this. I was somewhat aware of the nucleus or what you said but certainly could not begin to put it to paper, so to speak. Most people didn't have an inkling but what you said is so true that studies by their nature are distortions of reality. Thank you again and I hope everyone here reads this and gains understanding.

Rica
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Postby raven » Sat Mar 18, 2006 12:33 pm

No trial is perfect, this is true. However for those upon a blinded clinical trial there is an element of doubt.

For those taking an untrialled medication such as the ABX there is no doubt, also the reinforcement of belief exists.

Therefore every accusation made against the trials should also be levelled, perhaps even more stridently at anecdotal claims from untrialled regimens.

Prineas' research did not show that MS is not auto-immune. This is a common mis-representation of his work. The work of Luchinetti et. al. has highlighted distinct patterns of MS. One at least of these patterns is B cell / antibody mediated. Prineas noted extensive microglial activation in lesions that did not show gross inflammation / T cell responses. The microglia can be activated by antibodies and are CNS specific immune components. Given that fact where does Prineas' work discount auto-immunity?

I could make claims that supressing inflammation does indeed reduce disablity. I was EDSS 4.0, I am now around 1.5. For me supressing inflammation has had a profound beneficial effect but I do not have the hubris to claim that because a treatment has worked for me then it will work for others, or that I know better than those who have dedicated their careers to researching MS.

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Re: How We Get Fooled

Postby HarryZ » Sun Mar 19, 2006 7:33 am

Marie,

An absolutely excellent article!! Thanks for posting it.

I've been saying for a very long time that the current "approved" MS medications are over-rated and highly over-priced! I've been taken to task several times over those comments. But when you look closely at the very limited benefit that these drugs give MS patients, that 30-35% level has more or less remained constant over the years. What has improved, though, is the marketing/sales approach that these companies have done to keep or increase their market share of their product. And this has done nothing to get us any closer to a cure for this dreaded disease.

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Postby HarryZ » Sun Mar 19, 2006 7:43 am

Robin,

Prineas' research did not show that MS is not auto-immune. This is a common mis-representation of his work.


Nobody, after decades of MS research, has been able to scientifically prove that MS is an auto-immune disease. Prineas' autopsy on that young MS lady that died so suddenly from a massive exacerbation, indicated to us that there was something else involved in this disease. Of course, what that is remains unknown.

But at least it can perhaps give researchers a nudge to start looking in other areas as opposed to constantly trying to manipulate the MS patients' immune system. Because, so far, the focus of research has been locked into this area with no known cause and certainly nothing remotely close to any kind of cure for the disease.

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Postby raven » Sun Mar 19, 2006 8:37 am

I agree with you Harry. The work of Prineas and Barnett is complementary to the work of Claudia Luccinetti. The findings are a major step forward in MS research. They all point to MS having distinct patterns and it may be that MS is actually a cluster of related conditions with different causes.

However I do stand by my point, which was that the Prineas paper is not proof that MS is not auto-immune. This work is so often cited by those who wish to discredit the auto-immune theory and they are wrong in doing so.

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Postby bromley » Sun Mar 19, 2006 9:13 am

Robin / Harry,

I think most of the researchers are recognising that this is much more complicated than originally thought. In the Dr Steinman webcast which I posted he said that "And then there's the other issue that multiple sclerosis has different forms. Right now we've talked about a few defined forms, but as we look more deeply into the disease we realise that there may be a broader spectrum of MS than we're currently aware of".

I sometimes visit the Boston Cure Project site and they posted an article of a young man who went to the neuro with optic neuritis and within 8 months had progressed to 8.5 on the EDSS. The doctors tried interferon and then some heavy duty cancer therapies with little benefit. Rituximab stabilised him and he improved to EDSS 4. I wrote to BCP as I had never seen a case like this and asked whether we were talking about one disease. Hollie Schmit wrote back to me and said that BCP didn't believe MS was one disease and good evidence for this was that some pople saw good benefit from some treatments but others saw no benefit at all.

It will be interesting to see whether Prineas and Barnett contribute to the Australian MS Society conference at the end of the month.

I haven't followed Dr Luchinetti's work closely but understand that she has identified four lesions types and that an indivdual only gets one type (although this has been questioned). It will therefore be important, in the future, to be able to identify which 'type' an individual has and how best to treat.

The work being done by Dr Freedman in Canada should also start shedding some light on the role of the immune system and whether killing it off and starting again can stop the disease. The Rituximab trials should throw light on the role of B cells in the pathogenesis of the disease.

One would hope that in the next 2-3 years there will be some big leaps forward in the understanding of this disease/s. But for now I like many are stuck with the current CRABs. The MS neuro who suggested that I start something was honest enough to admit that the efficacy was not great but also that his research had suggested a slow down in atrophy. I'll take that anyday until something better is available.

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Postby HarryZ » Sun Mar 19, 2006 10:13 am

Robin,

However I do stand by my point, which was that the Prineas paper is not proof that MS is not auto-immune. This work is so often cited by those who wish to discredit the auto-immune theory and they are wrong in doing so.


I think the most important aspect of the Prineas paper is to show that "other factors" are involved with MS and not just the immune system going after inflammation taking place in the brain. The immune system is doing its job by trying to stop inflammation but many researchers state that this is a "reaction to" as opposed to "cause of" for MS.

But until someone discovers what is causing this disease, I fear the majority of research is going to be spent on trying more potent immune system altering drugs. And that approach hasn't worked so far. Monoclonal antibody work appears to be the new "buzz" word for the pharmas.....and we are already seeing what kind of disastrous results that can bring on!!

Take care.

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Postby Rita » Sun Mar 19, 2006 12:41 pm

I think Prineas tried to show that immune system is not in the cause of MS, something else is there before immune system is implicated, and shoot the mechanism doing all going wrong. Until the cure question does not have any response, MS wouldn’t be cured.

And as Harry says all kind of potent drugs are going to be tried to MS suffers with all the terrible consequences that may involve. Good assist us!

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Postby SarahLonglands » Sun Mar 19, 2006 4:22 pm

Rita, having read the whole paper, I'm damned sure that this was what they were trying to show.

Sarah
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Postby raven » Mon Mar 20, 2006 2:16 am

In the paper Prineas and Barnett selected tissue samples from 13 MS patients. These samples were selected from a tissue bank of 307 MS cases. They actively went looking for a new lesion type that they called the 'apoptopic' lesion.

Tissue from 11 other patients with early MS (6 with new lesions similar to the fatal lesion in Case 1 [Table 1] and 5 without such lesions) and 6 patients with long-standing MS selected from an archival bank of 307 MS cases also was examined.


In the 7 cases with 'apoptopic' lesions all 7 patients died from MS very shortly after contracting the disease which is hardly the normal MS pattern.

Nine additional lesions similar to the 17-hour lesion in Case 1 were identified in six other cases with clinically active disease who died shortly after onset of the disease (Cases 2–7, see Table 1). These lesions formed a very small fraction of the total number of actively demyelinating
lesions examined. No “apoptotic” lesions were found in the six patients with chronic MS included in the study


Out of 307 patients they found this new lesion type in 7, all of whom died shortly after disease onset. In the six chronic MS (the normal pattern) patients, no evidence of the 'apoptopic' lesion was found.

The findings are important and interesting but certainly do not disprove the auto-immune theory.

Despite this, until the true cause (or causes) of MS is known this paper will continue to be cited by those who believe that they know better than the massed ranks of scientists who are dedicating their careers to end this curse.

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Postby HarryZ » Mon Mar 20, 2006 6:55 am

Robin,

The findings are important and interesting but certainly do not disprove the auto-immune theory.


I suppose one might turn this around and say that after decades of research, nobody has been able to prove the auto-immune theory....despite almost the entire focus of research being done in this area. You would think that if the immune theory was correct, someone, somewhere would have been able to do this. And despite all the immune system altering drugs that have been used so far, none of them have any real impact on the natural progression of the disease.

The 7 very different lesions discovered by Prineas and Barnett obviously indicate something outside of the normal thinking box with this disease. Is it another sign that MS is more than just one kind of disease which manifests itself differently in its victims?

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Postby raven » Mon Mar 20, 2006 8:40 am

Absolutely Harry

The fact that this paper is not proof that MS is not auto-immune is not proof that it is.

I suspect that when the answers come it will be that some flavours of MS are, some aren't.

It is worth remembering that arthritis is an auto-immune condition and despite many years of research no cure or proven DMD exists for it either.

Stay strong, the answers will come.

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Postby mrhodes40 » Mon Mar 20, 2006 12:18 pm

RObin, Hubris ? 8O How utterly rude.

I will reference everything so you can know how this thinking evolves. Please read this and the links

You overstate your understanding of what is in the Prineas paper. He DID mean to say that oligo's die first which is not autoimmune, that's the whole point of it.

You said "extensively activated microglia" and that is not what the paper says. In the abstract we see "extensive oligodendrocyte apoptosis in tissue exhibiting early microglial activation" .

The paper itself clarifies this, and I will quote for everyone the pertinent things as this paper is not free. The interesting point is that the oligo damage was extensive when the microglia were barely responding

Since oligodendrocyte damage ITSELF causes microglial activation and since when this was seen extensive oligo damage was already present, this early activation ( as opposed to late activation with ameboid microglia) is the whole point.

In this paper, extenive discussion of microglia is undertaken. http://cmr.asm.org/cgi/content/full/17/4/942

This makes it clear that ramified microglia are in a stable, resting state, not ameobic or yet altered . Ramified microglia are what was found in he area of apoptotic oligodendrocytes

You'll note from that paper that microglia are in a privileged area of the brain, b-cells are not there to activate them, that they act independantly and are able to call in immune cells from outside the BBB by detecting problems inside the CNS. Since this happens they send out a chemical signal to open the BBB to allow t-cells, b cells and other immune factors in to aid in the fight of pathogens or cleanup of damaged cells inside the CNS. When an oligo is damaged, it will cause this cascade.

You will note in this paper that many infective triggers (like LPS) can cause this microglial activation. It has been a long concerned problem of the autoimmune theory that the BBB lets these peripheral immune cells in because it should not. Seen in light of the fact that microglia can open the BBB on pupose to let in t-cells when they have need of help in infective states and when cleaning up dead tissue, it's easy to there is a good reason for peripheral t-cells etc to be there if there were issues of those kinds. Note the paper lists several kinds of infections that invade microglia and alter thier function.

It is autoimmune theory, which has never been proven and which remains a troublesome model, that contends that b-cells, t-cells and other immune factors go into a naive CNS and activate things there of their own accord. As I mentioned there were no b-cell, t-cells or any other immune cells there in the lesions Prineas reported on. Again this is why it is cited as support for non autoimmunity

Back to Prineas since your point is that I misused Prineas research, as have "others" in your view (though I presume you do not mean Chadhuri who uses Prineas to support his conclusion that MS is not autoimmune)

within hours, oligodendrocytes throughout the affected tissue appear apoptotic, myelin sheaths stain positively for activated compliment while immunoreactivity for CNP and MAG (refs given) is diminished and ramified microglia with thickened processes appear in increased numbers
it goes on to list the immune cells ordinarily thought to cause MS as absent or very rare

So at this point there is barely altered microglia, because they are ramified but with thickening process (just starting to change) migrating to the damaged area of many apoptotic oligo's. Since we know damaged oligo's will cause microglial activation, this is expected and since it is early activation, still migrating to the area,geee... a fully activated microglia is ameoboid. NO b cell came and started this situation or it'd be fully activated. By they way there was very little caspase 3, less than 2%. It's not apparently caused by that either.

There are reasons that anti inflammatories will help any process in the brain. IT's not mutually exclusive. But that does not mean it's autoimmune. Case in point, If you get herpes zoster in the cranial nerve 3 which impacts the eye, you must give an antiviral but also steroids to protect the delicate eye area from the inatural nflammatory action. It is perfectly plausible that the brain being equally delicate will need anti inflammatory actions even if the cause is an infection of some kind causing the damage to the oligo's and triggering the whole mess. Just because suppressive therapies help does not mean that autoimmunity and or inflammation is the cause, or that it corrects the cause. In fact it might make people seem better for some time but eventually the "cause" would get the upper hand and people will progress, just as most things used to date seem to do. All bets could be off tomorrow if they come out and disclose that all people on "something" after 5 years continue to improve and do better and better than they did early on. NO MED DOES THAT NOW.

Your point was that microglia are starting the process and you attributed it to Prineas. He does not say that. His whole point was that the oligo damage seems to come FIRST. The headlines when it was released to the press said this also. This was his point.

People who cite Prineas and Barnett to support non autoimmune models are correct in doing so. What he found was very damning for autoimmunity. Lucchinetti did different work and as you say by her findings one type was autoimmune. Science goes on. The final answer is not in and there are papers on both sides. We are all doing our best with this half finished research. Each decides based on her or his understanding what to do in their own case.

We are a huge experiment.

My point was people have to try things on themselves to know what helps them, not merely to rely on trial data, which can be biased. I am doing that with abx. I've said it before, but I am a trial of one, and this trial is the only one that matters. That is very congrunet with my post as you might infer that the point is that it's all, every approach, unknown before you personally try it. This fits nicely with Lucchinetti.

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