Klimas/NOVA gene expression, treatment avenues

mariovitali

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I am finding hard to imagine severely ill patients -who can hardly tolerate supplements- taking immunosuppresive medications. Do we have any knowledge on this subject ? (=whether severely ill ME/CFS patients tolerating any kind of medication)
 

used_to_race

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Thanks for sharing that, and I've seen the talks in which Klimas describes her methodology. I can't comment on its validity for GWI, but it sounds like we will know if she is successful treating humans with GWI in a year or less, right? Before posting this reply, my impression was that her group has sort of just decided to use etanercept on a whim, and that the evidence linking ME/CFS to any cytokine, let alone TNF-alpha, isn't really there. However, she has a few publications in the last few years that seem to indicate TNF-alpha, IL-6, and IL-1B are all upregulated in ME/CFS, at least among some patients. I guess it's hard to really interpret because cytokine levels are always fluctuating and the ranges for "normal" are really wide. I don't know what the deal is with the mifepristone as the other component of her treatment, and can't claim to have the background to evaluate it.

After briefly looking into it, I'm still a little skeptical because of the number of cytokines that are dysregulated (why not use prednisone to reduce more circulating cytokines?) but excited at the prospect of human trials in ME/CFS. Ultimately it will be good if we can get trials going on a number of therapeutic targets and see which ones work for which patient groups.
 

Wishful

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After briefly looking into it, I'm still a little skeptical because of the number of cytokines that are dysregulated (why not use prednisone to reduce more circulating cytokines?) but excited at the prospect of human trials in ME/CFS.
If the chaotic theory for the immune system is valid (still just a hypothesis I think), then lowering all cytokines wouldn't help. It would need a disturbance of the ratios between cytokines to disrupt the feedback loop. Think of water on a surface with hills and valleys: increasing gravity won't change the pattern; you have to add water to or remove it from a specific valley, or pump it from one to another.

For me, prednisone did work the first two courses, but then stopped having any effect on my symptoms. Other immunosuppressants didn't work at all. Some immunostimulants do make my symptoms worse, but I'm not sure what they're doing in regards to cytokine levels.

It's too bad that the drugstore doesn't have suppressants and stimulants for specific cytokines. I'd experiment with those. Maybe a multi-pack, with several pills for each cytokine...
 

used_to_race

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If the chaotic theory for the immune system is valid (still just a hypothesis I think), then lowering all cytokines wouldn't help. It would need a disturbance of the ratios between cytokines to disrupt the feedback loop. Think of water on a surface with hills and valleys: increasing gravity won't change the pattern; you have to add water to or remove it from a specific valley, or pump it from one to another.
To me this feels too metaphorical an explanation. The ratios of cytokines are surely fluctuating all the time. If CFS is just caused by a certain ratio of TNF-a to IL-6, for example, then many more people would get it, but it would be a transient condition.

For me, prednisone did work the first two courses, but then stopped having any effect on my symptoms. Other immunosuppressants didn't work at all. Some immunostimulants do make my symptoms worse, but I'm not sure what they're doing in regards to cytokine levels.
Then maybe you had some inflammatory process at the time but no longer do. I have a friend who is diagnosed with ME/CFS and he had very high levels of IL6, IFNg, and TNFa early on in his illness. These resolved with IVIG and another treatment (and he improved greatly) but still has symptoms all the time. You tried prednisone, but what were the other immunosuppressants you tried? Azathioprine? Methotrexate? I've heard people in the UCTD facebook group (I am convinced there is massive overlap between UCTD and ME/CFS) say they had poor responses to plaquenil and methotrexate, but are doing well on Humira or Actemra. It's just that most people either don't get access to those medications, or like me, have access but are too afraid to try them. If you're talking herbal immunostimulants, a lot of those can cause liver enzymes to elevate which alludes to an underlying toxicity. So that's there in addition to any issues with stimulating an already dysfunctional immune system. I felt terrible on Equilibrant.

FWIW, prednisone didn't work for me at all and made me feel really sick. But there are people with obvious inflammatory markers and more conventional rheumatic diagnoses who report the same thing. Just furthers my belief that there is a whole component to the immune system (or at least its function) that just hasn't been discovered.
 

Wishful

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The ratios of cytokines do fluctuate all the time. However, they might not be fluctuating enough to change the pattern: for the example, sloshing a bit but not enough to cut new channels. Hopefully someone will model the immune system from the chaos theory perspective, and see if it can explain ME.

I tried prednisone, methotrexate, and cyclosporine, plus various herbs. Only prednisone had an effect, and that was temporary.
 

nandixon

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Hopefully someone will model the immune system from the chaos theory perspective, and see if it can explain ME.
It’s basically been done for our purposes. See this post:

https://forums.phoenixrising.me/threads/chaotic-immune-system.62945/post-1026632

Klimas/Broderick found, in effect, that the immune system alone can't explain ME/CFS, because they found no conditions under which a single intervention (treatment) directed at the immune alone was able to re-establish normal health in their chaos theory-based computer modeling. To “achieve” the unfortunate state of our disease requires, under their model, a new (bad) homeostasis to exist between a dysregulated immune system AND a dysregulated HPA axis (and potentially the HPG axis as well).

This is why in the current clinical trials that Klimas is running for the specific subgroups of GWI men with high cortisol and ME/CFS post-menopausal women, that she's using a two-stage treatment protocol of etanercept first to target the immune system followed by mifepristone to reset the HPA axis. (Note that while mifepristone may end up being useful for a number of different subgroups, etanercept on the other hand would only be suitable where a TH1 immune system shift of some kind had occurred. Premenopausal women, for example, are apparently needing to knock down TH2 cytokines, and from what I could glean from the study in the OP, Klimas/Broderick haven't yet found a suitable drug for this purpose. This is partly why they talk about the possibility of an anti-TGF beta drug - and there's currently not one that's been FDA approved yet… despite decades of research, although it should happen soon.)
 

used_to_race

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Klimas/Broderick found, in effect, that the immune system alone can't explain ME/CFS, because they found no conditions under which a single intervention (treatment) directed at the immune alone was able to re-establish normal health in their chaos theory-based computer modeling. To “achieve” the unfortunate state of our disease requires, under their model, a new (bad) homeostasis to exist between a dysregulated immune system AND a dysregulated HPA axis (and potentially the HPG axis as well).
Do you have a link to their paper on this topic? To me it seems like they are talking about these exhaustive computer models, but the underlying mechanisms of ME/CFS are so poorly-understood that I don't see how their models could be valid. It seems like a big contradiction and for some reason I've never seen that addressed.
 

nandixon

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Do you have a link to their paper on this topic? To me it seems like they are talking about these exhaustive computer models, but the underlying mechanisms of ME/CFS are so poorly-understood that I don't see how their models could be valid. It seems like a big contradiction and for some reason I've never seen that addressed.
This 2014 paper describes what they're doing, but there are also a number of related papers both before and after that:

A Role for Homeostatic Drive in the Perpetuation of Complex Chronic Illness: Gulf War Illness and Chronic Fatigue Syndrome
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885655/

If I remember correctly, in that study they collected blood samples from the patients at only 3 time points (something like pre-exercise, peak exertion, and post-exercise) and each blood sample was analyzed for a large array of different hormones and cytokines, etc.

Subsequently, and this is so far unpublished, they reran the study using 9 different time points relative to the exercise challenge (including 24 hours later) because the computational biologists said they needed more data points to obtain a valid result. Klimas said they lost some number of years because of that.

I believe Klimas also said in one of her video presentations that they ended up with over 1 million data points, and that they used about 2 weeks worth of US Dept of Defense supercomputing time analyzing the data.

They're actually not needing to understand the underlying mechanisms that are specific to ME/CFS. The computer algorithms go in the various directions that the data leads them, and that's possible because of the changes that have occurred in the collected data relative to the exercise challenge along a timeline. (The data is reflecting the early development of PEM in the patients.) They wouldn't be able to do anything with data collected at only a single time point because most of the data will have the appearance of being rather random, I think.

Klimas said their computer models successfully predicted a treatment course for the GWI mouse model (which is apparently a very good model for GWI) on the first go around, i.e., the computer figured out what treatment would likely cure the mice, and they were indeed cured with the treatment. So I have some optimism for this approach.
 

Wishful

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Klimas said their computer models successfully predicted a treatment course for the GWI mouse model (which is apparently a very good model for GWI) on the first go around, i.e., the computer figured out what treatment would likely cure the mice, and they were indeed cured with the treatment. So I have some optimism for this approach.
Squeak squeak! Gimme treatment! :)

I don't feel like digging through more research papers just now. Did the treatments for mice involve only approved drugs? That would save the time frame for approval for new drugs. We'd still need a set of biomarkers for official diagnosis to justify the prescriptions, but that might not take long. Approval for a treatment for GWI would probably come first, (more funding), but that would lay the groundwork for us.

Definitely optimistic news. :thumbsup:
 

nandixon

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Did the treatments for mice involve only approved drugs?
I'm pretty sure that the same drug combination I previously mentioned (etanercept + mifepristone) that Klimas is currently using in her two clinical trials for GWI men and postmenopausal ME/CFS women is what worked in the GWI mice.

And again, the etanercept would be replaced with an (still to be determined) anti-TH2 drug for ME/CFS premenopausal women.

And unfortunately we don't know what Klimas is considering for ME/CFS men (still hoping @Belbyr might be able to find out something for us in that regard). In one of Klimas's pilot studies that came out just prior to the 2014 study I cited earlier, it was found that IL-23 was elevated in (ten) ME/CFS men:

A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome [2013]
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3698072/
These subjects also expressed significantly higher levels of IL-23 both prior to and following exercise (p = 0.01, 0.01) but not at peak effort.

On the face of it this might suggest that an anti-IL23 monoclonal antibody drug (used for treating psoriasis, for example) might be useful for ME/CFS men to replace the etanercept, but this was a small study and, more importantly, it's what the computer determines is going to work after running everything through the algorithms.
 

perrier

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I'm pretty sure that the same drug combination I previously mentioned (etanercept + mifepristone) that Klimas is currently using in her two clinical trials for GWI men and postmenopausal ME/CFS women is what worked in the GWI mice.

And again, the etanercept would be replaced with an (still to be determined) anti-TH2 drug for ME/CFS premenopausal women.

And unfortunately we don't know what Klimas is considering for ME/CFS men (still hoping @Belbyr might be able to find out something for us in that regard). In one of Klimas's pilot studies that came out just prior to the 2014 study I cited earlier, it was found that IL-23 was elevated in (ten) ME/CFS men:

A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome [2013]
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3698072/



On the face of it this might suggest that an anti-IL23 monoclonal antibody drug (used for treating psoriasis, for example) might be useful for ME/CFS men to replace the etanercept, but this was a small study and, more importantly, it's what the computer determines is going to work after running everything through the algorithms.
Thanks for this information Nandixon; much appreciated. Is there no way to get a tiny clue as to if her protocol is having results? After all, the folks aren't going to be on these meds for long periods of time. And how many CFS patients are in her trial? Thanks.
 

nandixon

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@perrier, I'm not sure how many of the post-menopausal ME/CFS women there are in their trial. And I wouldn't think Klimas would want to give out any information at all until the trial is complete for fear of biasing the results with respect to the patients that haven't yet been administered the drugs, since the patients are likely running through the trial sequentially - one patient every two weeks, for example (as a guess). I'm thinking we probably won't hear anything for at least a year, unfortunately, unless there are dramatically good or dramatically bad results.
 

junkcrap50

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Thanks for this information Nandixon; much appreciated. Is there no way to get a tiny clue as to if her protocol is having results? After all, the folks aren't going to be on these meds for long periods of time. And how many CFS patients are in her trial? Thanks.
In some video of Klimas, she said 1 GWS patient has gone through her protocol and the patient has been seeing positive results.