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Why do the Fluge/Mella trials seem to be more successful than off/trial reports?

msf

Senior Member
Messages
3,650
If the body creates b-cells which turns into autoantibodies that attacks an enzyme that is required for the metabolic system to function properly then Rituximab is surely a very interesting drug to consider using. If the phase 3 trial shows a response rate of 50% for patients treated with rituximab, compared to say 10-20% for placebo group, that would be a fantastic result.




Most absurd thing I've read in 2017. Where do you get your information? I don't want to be rude, but I think you have read up on why immunomodulatory drugs like rituximab works in diseases. It is 100% certain that all of us wont benefit from rituximab, but I think we know from a fact that quite a few of us would. We don't know how many before the study is published in early 2018, but the researchers are confident that a group of patients with ME respond to the drug. It would be great if they actually could link B-cell depletion to the believed metabolic dysfunction, but if they are on the wrong that it doesn't really make any difference for the rituximab study. We use many drugs that we don't know exactly why they work. The important thing with respect to treatment is that patients that receive the drug improves more than the placebo group, and that side effects are not an issue. Even why we don't know why it helps, if we're certain that rituximab does alleviate symptoms for ME patients, then we have something that can help many of us.

I would also have a look at their latest presentation in Norwich which is available here:

I think it would be fairer to say that, apart from Kogelnik and the German one (sorry, I can´t spell German names), none of the other researchers seem very keen on looking at Rituximab as a treatment before we have actually determined what the problem is, which is exactly how I feel. Others (particularly those who are more ill tan me) may feel quite differently.
 

msf

Senior Member
Messages
3,650
This is the final slide from Fluges recent presentation in Norwich, part of the video that Delder linked above.
16667107_1250994638302816_1163896336_o.png


Rituximab stage 2 trials showed 65% of patients responded positively to the treatment, stage 3 results will be out in 2018. Earlier in the talk cyclophosphamide was discussed, results will be out later this year so all they would say was that they were getting positive results with that too.

In the diagram, Fluge is illustrating their theory on how these treatments may work, in that the drugs impact on what is causing the upregulating of PDKs and SIRT4, which they believe are the reason that PDH function is down regulated and which then causes our problems in glucose conversion. Also note that the diagram indicates two potential areas for new treatments, first, alternatives to rituximab and cyclophosphamide and secondly, at the point of PDK-PDH interaction. I took many things from the talk, and one of them is that if they can find an alternative and better treatment to use then they will use it.

And it seems that Fluge and Mella are looking at alternatives too.
 

msf

Senior Member
Messages
3,650
I haven´t watched it all yet, but in a recent Mella talk on YouTube he seems to be suggesting that they now think it is less likely that this is a typical autoimmune disease vs some other type of immunological disease, so perhaps this is reflected in their interest in other treatments.
 

jpcv

Senior Member
Messages
386
Location
SE coast, Brazil
I haven´t watched it all yet, but in a recent Mella talk on YouTube he seems to be suggesting that they now think it is less likely that this is a typical autoimmune disease vs some other type of immunological disease, so perhaps this is reflected in their interest in other treatments.

Do you have the link?
 

deleder2k

Senior Member
Messages
1,129
Not sure if I follow you. It is extremely difficult to fund a rituximab trial, and I think the researchers in the field are waiting for the results of the current study. Fluge and Mella has emphasised that we need more research into treatment. One may think that figuring out what this disease is really about and then finding a treatment is the way to go, but in many diseases it happens the other way around. The rituximab story is a rather common example of how medicine develops. A patient is treated with a drug for disease A, and then miraculously it leads to an improvement for disease B.

They have previously stated that they are pretty confident that they are looking at a response rate of >50%. That would be nothing else than spectacular. Remember that 10-20 million suffer from this disease. We need viable treatment options now. The news about the cyclo trial also very promising. I don't think Haukeland has changed their hypothesis about ME in the last year. My understanding is that they believe there are some sort of autoimmune component in the disease.

To my understanding more studies will follow. That is also promising. We will know much more when the current phase 3 study will be published. If the study is positive I think we can all agree that that will be a game changer for all of us - even though we turn out to be non-responders. It will pave the way for more research, and it will also make it more difficult for the psychobabblers. Many of them has made som rather extraordinary comments about the rituximab trial. They all seem to think that the study will turn out with a negative result. I can't wait to see them explain why a drug that depletes B-cells would benefit a disease where the patient can recover if he/she really wants to by "getting out of bed". One would assume the placebo group wants to get out of bed just as much as the group that receives and improves with rituximab, given that both groups are blinded. Must be difficult to explain for ms. C.
 
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Jesse2233

Senior Member
Messages
1,942
Location
Southern California
Had another thought on this topic

What if an infectious trigger in Norway is more prevalent to that region (climate?), and is not as widley reflected in warmer southern latitudes. Or what if a more common warmer climate pathogen is not as prevalent in cold climates

Has there been any research on EBV preferring colder climates? And perhaps enteroviruses preferring warmer ones?

I mention EBV, because it is more closely associated with B-cells, so may play a role in their causality in a subset

@Hip you might have thoughts on this
 

heapsreal

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10,079
Location
australia (brisbane)
Had another thought on this topic

What if an infectious trigger in Norway is more prevalent to that region (climate?), and is not as widley reflected in warmer southern latitudes. Or what if a more common warmer climate pathogen is not as prevalent in cold climates

Has there been any research on EBV preferring colder climates? And perhaps enteroviruses preferring warmer ones?

I mention EBV, because it is more closely associated with B-cells, so may play a role in their causality in a subset

@Hip you might have thoughts on this

Was a possible theory that the Norwegian mecfsers had an autoimmune disease only found in Norway, maybe genetic related. The thought was they werent actually ME patients but had an autoimmune disease confined to that area. I guess we wont really know until they can diagnose ME with 100% accuracy.
 

Hip

Senior Member
Messages
17,802
@Hip you might have thoughts on this

I had thoughts along these lines: there was a major outbreak of giardiasis (Giardia lamblia infection) in Bergen, Norway in 2004 (an estimated 2500 cases), so this lingering pathogen may now be common in the intestines of a subset of people in Bergen. Giardia lamblia is linked to ME/CFS, as well as autoimmune diseases. Fluge and Mella are based in Bergen, so it occurred to me that their cohort may contain lots of people who developed ME/CFS as a result of Giardia lamblia. More in this post.
 
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Gingergrrl

Senior Member
Messages
16,171
Jesse or Hip, even if there were regional autoimmune diseases (and I don't know if there are?) wouldn't Ritux still work on all B cell driven autoantibodies regardless of which region of the world someone lived in?
 

Manganus

Senior Member
Messages
166
Location
Canary islands
@Hip

Interesting. Do we know if enteroviruses prefer warmer latitudes?

@heapsreal

It's maybe more a question of which habitate we humans are evolutionary adapted to?

Norway (Bergen) is not that far away north. It's the same latitude as the former Russian capital Sankt Petersburg, aswell as Helsinki, Stockholm and Oslo.

The crucial difference may turn out to be more about day-light than temperature.
The temperatures are (sort of) human on that latitude. But the winter-darkness is not.
 

Manganus

Senior Member
Messages
166
Location
Canary islands
@Manganus say more about that... do you mean in terms of endogenous Vitamin D production, something relating to pathogens, or autoimmune prevalence?

I don't really know what to say. :confused:

No, not pathogens. Not primarily. Rather, maybe, interaction between immune system and Vitamin D.

I don't know in what way we humans might be badly adapted to the (long) dark winters. But that's the direction of my suspicions, rather than temperature. And this despite I myself having improved after moving from the 55th to the 27th latitude (the same as Tampa, Florida, Brisbane in Australia or Johannesburg in South Africa).

If one looks at climate tables, then temperature and humidity in (the populated parts of) Scandinavia are not drastically different from what's found in the US, UK or the European continent. This is thanks to the North Atlantic Current (a.k.a. the Gulf Stream).

Drastic differences are to be found in the day length and, maybe more importantly, the sun altitude (a.k.a. the sun angle).
 
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Jesse2233

Senior Member
Messages
1,942
Location
Southern California
Yes they do. This is why there is a seasonal variance with highest incidence in the summer months in temperate climates. In tropical areas they are hyperendemic.

Interesting, then how to explain Dr Hyde's findings that ME tends to appear in the Fall / early Winter? Link to double immune hit from seasonal influenza / certain vaccines?
 

Manganus

Senior Member
Messages
166
Location
Canary islands
With regard to Vitamin D, take a look at this figure:
G9Rda0w
(Nope - the figure at http://i.imgur.com/G9Rda0w.png seems to hide itself... )

This I found in a (somewhat lengthy) wiki-text about MS, which I think is a good disease to compare with.

There it's argued, among other things, quote:
Northern Europeans or people with Northern European ancestry have a much higher risk of developing MS compared to other ethnicities, including ethnicities found in similar latitude regions. MS susceptibility is very low in people who are Chinese, Japanese and Mongolian, even if they live outside of their respective countries. For example, Japanese in Japan and Japanese Americans both have MS prevalence rates of 5 per 100,000 people. African Americans have a MS prevalence rate roughly half that of Americans of Northern European backgrounds. A number of factors may cause these prevalence rates amongst races including genetic, environmental and lifestyle factors.

However, various studies have shown that it may not be genetic susceptibility that causes the variations in MS rates amongst races, but mainly environmental factors. MS prevalence rates in West Africans are fairly low in comparison to places of high prevalence and incidence, such as Northern Ireland. However, the children of West African immigrants in the UK have MS prevalence and incidence rates similar to those of Northern Ireland. Another study showed that British immigrants in South America who came to South America as adults had an MS prevalence rate of 60 per 100,000 people, while British immigrants who came to South America as children had a prevalence rate of only 15 per 100,000 people, and local populations had a rate of less than 5 per 100,000 people. This study showed that ethnicity is a factor, but age differences also play an important role in prevalence, as well as the effect of environmental factors before and after adolescence.

The rather fresh understanding of epigenetics may be useful. There are a bunch of papers published on MS. Se for instance this abstract from 2014 by Küçükali & al, or this Canadian review article, also from 2014.

Major environmental risk factors for MS, vitamin D deficiency, smoking and Ebstein-Barr virus are all known to exert epigenetic changes. In the last few decades, compelling evidence implicating the role of epigenetics in MS has accumulated.
 
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