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Attack on Lipkin/Hornig and Fluge in a medical magazine

deleder2k

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The Swedish pediatric doctor Mads Reimer has published this in the Norwegian medical Magazine Dagens Medisin - literally "Today's Medicine":



Experimental tests and treatments for CFS / ME

Doctors in Bergen will now examine whether the chemo cyclophosphamide works on CFS / ME. The ethical approval approval for such a risky treatment, seem strange when there is no evidence that there is anything wrong with patients immune system.


THE BIG Swedish newspaper Dagens Nyheter (1) recently reported that "Scientists have found clear changes in the immune system in people with chronic fatigue syndrome (CFS / ME)." The scientific article "Distinct plasma immune signatures in ME / CFS are presented early in the course of illness" (2) is published in the newly established journal Science Advances.

I am a paediatrician and have no detailed knowledge of cytokines, but as far as I understand, this is an exploratory study that measured levels of over 50 different cytokines on about 300 patients with CFS / ME. Patients were then compared with 350 healthy control subjects to see if a changed immune response was seen. It was not.

MATHEMATICS? But when they chose to analyse only those patients who had been sick for a maximum of three years, they found up regulation of many different cytokines (3), both pro-inflammatory and anti-inflammatory - if one can make such a simplification.

Those who had been sick for more than three years, had instead lower levels, so it must be mathematically since there was no difference for the whole group, which should not be surprising. “We were surprised to find that the levels of so many cytokines were higher in short-duration cases than in healthy controls. Equally surprising was the observation that these same cytokines were lower in long-duration cases than in healthy controls”.


HOW? One should be critical of studies that do not test a previously stated hypothesis, especially if the material must be broken down into subgroups, to look at the p value sky. Some call this type of study a type of fish expedition. How did they come to the conclusion that three-year disease was an appropriate cut-off to break up the material?

The researchers write that they did not engage in recruiting, and that it obviously can be difficult to find patients early in the disease. They also claim that the timing is based on how the immune system is affected by chronic viral infections: "A 3-year cutoff for early ME / CFS cases was used on the basis of feasibility of recruitment and longitudinal changes in immune profiles in persistent infections with West Nile virus, HCV and HIV. " But a 3 year cut off (or change) in these infections do not seem to exist.

BIOMARKERS? It is difficult to liberty oneself from the suspicion that the material possibly were analysed several times, with different cut-offs, and found a point where they found measurable change. In addition, the time when the disease actually began, is not clearly defined: Illness onset was defined as the date when a patient reported the onset of the clinical features that led to a later diagnosis of ME/CFS illness, rather than the date when a physician made the diagnosis of ME/CFS. Discrepancies were resolved by clinician consensus ratings after review of all available data”.
One can at best look at this as a study in which hypotheses are generated, and then using those hypotheses be tested on a new group of patients and controls. My guess is that this is unlikely to lead to any useful biomarkers for CFS / ME diagnosis, but obviously I can be wrong.

Problematic. It is possibly also problematic that many of the authors of this study already treat CFS / ME patients with various drugs. Three of them; José G. Montoya, Nancy G. Klimas and Lucinda Bateman, is involved in a treatment study, where patients receive supplements and ADHD drug Ritalin (4).

More common is that CFS / ME patients are treated with antivirals or antibiotics, although this does not have any proven effect today. Martin Lerner, who along with Klimas and Bateman was coauthor of the new IOM report that will rename CFS (5), looking for CMV, EBV and HHV-6, but also the parasite Babesia and bacteria Mycoplasma, Borrelia, Anaplasma and streptococci.

WEIRD. In Norway, researchers in Bergen use treatment that weakens the immune system. They believe that rheumatism medication rituximab, which removes B cells, has helped CFS / ME patients, and is now used in a proper double-blind study in Norway.

The same researchers wanted to test TNF-alpha inhibitor Enbrel on CFS / ME patients who did not respond to rituximab. This experiment was stopped after two of the four initial pilot patients were deteriorating (6). Rituximab is expensive, and doctors at Haukeland University Hospital will now examine whether the much cheaper chemo cyclophosphamide works on CFS / ME. Being given ethical approval (7) for such a risky treatment, seem strange when there is no evidence that patients have something wrong with immune system.

No conflicts of interest

Reference List:
1) http://www.dn.se/nyheter/vetenskap/ny-forskning-ger-hopp-for-de-kroniskt-trotta/
2) http://advances.sciencemag.org/content/1/1/e1400121
3) http://advances.sciencemag.org/content/advances/1/1/e1400121/F1.large.jpg
4) http://thesynergytrial.org/study-treatment.html
5)
http://www.dagensmedicin.se/blogg/m...traning-hjalper-mot-kroniskt-trotthetssyndrom
6) https://www.clinicaltrials.gov/ct2/show/study/NCT01730495
7)https://helseforskning.etikkom.no/i...rosjektregister/prosjekt?p_document_id=525361


Mads Reimer
Translation conducted by Google and myself.

Originally posted here: Eksperimentelle tester og behandlinger for CFS/ME



What is your take on this @Jonathan Edwards? Am I right to classify this as some sort of Immunobabbling? :)

A wise friend of mine, @DanME, points out that:

- Lipkin is one of the most famous immunologist on the planet and his group probably knows, how to handle data properly...
- There are a lot more studies, showing abnormalities. Like 2DayCPET, abnormalities in NK cell function, abnormalities in the brain etc.
- Haukeland didn't only conduct only one study with RTX, but four. A pilot, two phase II and one phase III. There have a lot of experience and wouldn't go on, if they didn't see any benefit or serious side effects.


I can comment on the article, but the best would be to write an article back. If someone wants to respond and knows immunology in some way or are a doctor professor I could help translating it to Norwegian. Fluge usually don't engage in these debates, and it would be good if someone could write back. Mads Reimer has written a lot of critical articles over the years where he supports CBT, GET. Some would say he is the definition of a "psychobabbler".
 
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A.B.

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Seems like a poorly informed person picking out parts that support his prejudices.

The Lipkin study has nothing to do with what Fluge and Mella are doing, other than confirming that there are immune system abnormalities. As for the accusation of fishing for correlations, that is in principle justified, but in this case, it seems rather unlikely that 24 out of 51 cytokines would follow a certain pattern merely be chance. The p value of the INF-gamma finding was extremely good.

The idea that it's problematic that some of the authors are already treating CFS patients with drugs is a matter of opinion.

The author ignores the previous results and observations concerning the use of Rituximab in CFS patients. Perhaps because that would make things appear less dramatic and irresponsible, or perhaps he's simply unaware. Neither is good journalism.
 
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deleder2k

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The first thing that hit me about RTX is that they have had several patients responding from immunosuppressive drugs. MTX, Cyclo, RTX. With the unpublished phase 2 study they have probably been involved with around 40 patients that have tried either of them. When the ethical committee approved their latest cyclo study I guess they knew that the results from the open phase 2 were positive.

Why wouldn't it be OK to try out Cyclo in a cancer department at a hospital when two patients first said they got better during cancer chemo for breast cancer, and then 3 more in a pilot study? In addition we have two RTX studies, and MTX that was used on a few patients.
 

Helen

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A well respected doctor friend said to me "Who cares about M...s R.....s opinion" when he once earlier attacked ME/CFS. I wouldn´t care about this article either, as his job as a columnist is to provoke people. Very few doctors comment on his articles. I wouldn´t spend any more time on this.
 
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Sidereal

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This essay reads like a high school child's idea of science. It's not how things happen in practice.

It is difficult to liberty oneself from the suspicion that the material possibly were analysed several times, with different cut-offs, and found a point where they found measurable change.
A perfectly reasonable approach for an exploratory, hypothesis-generating study which isn't trying to make any definitive statements, it's just setting the stage for future hypothesis-driven replications.
 

waiting

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In the 1st paragraph, he says there is NO EVIDENCE there is anything wrong with patients' immune systems.

In the last paragraph, he says there IS EVIDENCE there is something wrong with patients' immune systems.

???
 

deleder2k

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In the 1st paragraph, he says there is NO EVIDENCE there is anything wrong with patients' immune systems.

In the last paragraph, he says there IS EVIDENCE there is something wrong with patients' immune systems.

???
Sorry. My bad. I have corrected it now. He says two times that we have no proof of immune abnormalities.
 

Sherlock

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It is difficult to liberty oneself from the suspicion that the material possibly were analysed several times, with different cut-offs, and found a point where they found measurable change.
A perfectly reasonable approach for an exploratory, hypothesis-generating study which isn't trying to make any definitive statements, it's just setting the stage for future hypothesis-driven replications.
Exactly! It's the perfectly right thing to do.

But I also can't help thinking how good it would be if they released their data and let the world at large look for patterns, amateurs included. I am reminded that amateur astronomers found many comets, including the famous Shoemaker-Levy that crashed into Jupiter. It can help to have a lot of eyes looking for things.
 
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In some diseases, it was the treatment that gave hints as to the underlying pathology, rather than the other way around. This seems to be a fact this doctor seems to have forgotten.

If these drugs demonstrate continued efficacy, then it gives a big "pay attention" message to the scientific community in general.

This guy isn't a scientist, so that probably explains why he doesn't seem to understand where scientific insights come from.
 
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I feel sorry for this paediatrician that his potty training should have left him with such an anal view of the world.

Discovering drugs through chance observations in unrelated situations is probably more common than trying them because you have a good reason.

I guess he has to be a paediatrician since adult patients are not going to go and see someone with such a negative and ill-inofrmed attitude to their disease.
 

deleder2k

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I feel sorry for this paediatrician that his potty training should have left him with such an anal view of the world.

Discovering drugs through chance observations in unrelated situations is probably more common than trying them because you have a good reason.

I guess he has to be a paediatrician since adult patients are not going to go and see someone with such a negative and ill-inofrmed attitude to their disease.
I agree. Do you think one shouldn't reply to this "babble" at all? I feel like this s### should be answered. He writes technical so that is hard for those with non-medical expertise to answer. Fluge doesn't engage in public debate. At least he hasnt for a while so I guess he won't write back.
 
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deleder2k

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The problem is that many will believe in this crap if no one responds to it... Maybe I at least should comment under his article. He actually responds to comments on the article he writes, so that can be interesting.