Questions Answered by Dr. Naviaux

[Learner1]

Sorry, I've been under the weather the last couple of days after IVIG and IV antibiotics for my ME/CFS... spent last night in the ER. I tend to believe there's an infectious component...

Can we go back to this from @duncan 's post above?

Basilico said: ↑

Actually, Ron Davis did prove that CFS is not the result of an infection in the blood. He searched for viral DNA (which is much more precise and accurate than looking for antibodies as most CFS docs are currently doing) and he couldn't find anything significant - the healthy controls actually had slightly more evidence of viral infection than severe CFS patients.

Duncan said: ↑
This does not prove ME/CFS is not the result of an infection in the blood. Obvious exceptions could be - and I emphasize could - Borrelia and certain enteroviruses.

Basilico said: ↑

While it is possible that there's an infection that can only be detected in the tissues (or maybe hiding in the vagal nerve), after listening to what he's learned so far, an infection seems unlikely. When he took cells from a severe CFS person and put them in the plasma of a healthy person, those cells behaved like a perfectly healthy cell. So he knows there's a problem with something in the plasma but not in the cells - I don't think this is consistent with a viral infection (which highjacking cells).

Duncan said: ↑
I think this is a very valid point, and I think it strongly supports an autoimmune etiology. But I fear it may not be a slam dunk, especially if there is a paucity of truly investigative efforts for some potential infectious culprits.

I like Davis's and Naviaux's positions, and I think they may be right. But I still am concerned that they have not disproven an infectious agent is at play for at least a significant subset of pwME.

I'm seeing a top ME/CFS specialist who also diagnosed me with multiple chronic infections, low immune function AND the adrenergic and muscarinic antibodies linked to POTS and ME/CFS.

Given this, I had an interesting chat with Jarred Younger at the OMF Symposium...he's the researcher who found 2 subsets - infectious and autoimmune:

I shared my test results and said, "can there be a third group of us with BOTH infections and autoimmunity?" He said that there definitely could be.

Given what is out there, I tend to believe that Naviaux is right and it doesn't matter what the triggers are, some will be infectious, some toxicity, some autoimmunity, and others from his list of cell dangers. And a lot of us will have multiple triggers.

Both my doctor and Mark Davis indicated that these infections can stress cells to provoke the production of autoimmune antibodies. Sometimes the infections go away and just the antibodies remain, but others are left with both. Though its pretty hard, if not impossible for viruses to be gone for good. They can reactivate at any time, and they attack different areas of the body - the heart, the liver, the brain, the stomach, etc.

Seems like the things that are important are removing the cell dangers, calming inflammatory and autoimmune processes and fixing collateral damage, not excluding people from the group because they don't have the same exact triggers... we're all individuals with unique environmental exposures and genetics... though we share the same symptoms.

 

[nandixon]

I think there's a decent possibility that suramin may be working in Dr Naviaux’ autism studies by inhibiting IL-6 (explained later below). This possibility needs to be explored in ME/CFS as well since suramin appears to have a normalizing effect in Dr Ron Davis’ cellular impedance testing device.

So while we wait for any future suramin trial results for ME/CFS, which may take a number of years, I’m hoping that Dr Davis (@Janet Dafoe (Rose49)) will use his device to test at least one possibility for why suramin could be working in that device, namely IL-6 inhibition.

Suramin actually has potentially quite a few different actions in the human body. Some of these are mediated by suramin’s non-selective purinergic (P2) receptor antagonism and some are not. Since the impedance testing device potentially provides a convenient in vitro proxy for the energy impairment in ME/CFS, it would be desirable to try to narrow down how suramin might be working. This might allow us to come up with a more readily available alternative drug treatment or even a better treatment than suramin, and hopefully much more quickly.

Suramin is able to inhibit IL-6 in a variety of different cell types both by reducing IL-6 production and/or by preventing its binding to the IL-6 receptor (IL-6R). This inhibition may occur via suramin’s antagonism of various P2Y and/or P2X receptors. (Non-exhaustive PubMed search string)

(Suramin also inhibits other cytokines, including TGF-beta, which interestingly is mostly found to be high in the blood of ME/CFS patients but low in autism. It also inhibits other non-cytokine receptors as well, including NMDA glutamate receptors, and has additional diverse actions.)

So I think the first thing to test with Dr Davis’ impedance device, relative to suramin, is the IL-6 receptor (IL-6R) monoclonal antibody tocilizumab (Actemra). This drug is used in rheumatoid arthritis (RA) and has been found to significantly improve fatigue (i.e., energy impairment) in RA patients. Interestingly, in a single patient study, pyruvate dehydrogenase (PDH) was increased with tocilizumab. (Fluge & Mella found the PDH complex to be impaired in ME/CFS.) There's also one anecdotal report of a possibly successful use of tocilizumab on this forum.

Here's why I think suramin might be working in Dr Naviaux’ mouse and human autism studies by IL-6 inhibition:

In Dr Naviaux’ first (2013) mouse study he used the maternal immune activation (MIA)/poly(IC) mouse model. This is essentially an environmental exposure model for autism. This (2015) review article on inflammatory cytokines in autism states that:

Several groups have found that the developing fetus’s exposure to maternal cytokines precipitates neurological, immunological, and behavioral abnormalities in the offspring [35, 36]. These effects require a key mediator, IL-6. Maternal injection with IL-6 alone is sufficient to cause abnormal behavior in the offspring following maternal poly-(I:C) injection or respiratory infection. Conversely, IL-6 inhibition was sufficient to attenuate the behavioral deficits caused by MIA [35, 37].

(My bolding.)

Thus IL-6 is sufficient for poly(IC) to have its effect, and IL-6 knockout mice do not develop several of the autism-like behavioral features upon exposure to poly(IC).

Related arguments can be made for Naviaux’ remaining suramin autism studies, including use of the genetic Fragile X (Fmr1 knockout) mouse model and also the human study. For example, expression of Fmr1 is greatly reduced (by 50%) in the MIA model suggesting that IL-6 may be involved in the Fragile X model as well. And IL-6 has been found to be elevated in both autistic-like mice brains and autistic human brains alike.

So I think the possibility then has to be considered that suramin might be acting through an IL-6 dependent mechanism in Dr Davis' impedance testing device and Actemra may be the simplest and potentially most useful way to test for this.

Of course, there are many permutations for outcomes here. These are just a few:

If Actemra works in the impedance device this may or may not mean that Dr Naviaux’ cell danger response (CDR) theory is correct. If it is correct then Actemra might not be as effective as suramin (e.g., not as likely to correct as many problems and/or not as likely to effect a cure versus be an ongoing treatment). (A positive outcome also doesn't necessarily mean suramin would be working via an IL-6 mechanism in autism.)

If Actemra doesn't work in the impedance testing device, that doesn't necessarily mean it might not work in vivo. It also doesn't mean Actemra might not work in autism (where it obviously should be tested, it seems to me). This is because if the CDR theory is correct, then the degree to which a given pathway (e.g., IL-6) is affected is likely to vary considerably between diseases depending on what combination of factors in addition to the CDR underlies each disease.

Anyway, Actemra might be a promising potential alternative to suramin and/or might at least help narrow down some possible modes of action for how suramin could be working.

 

[Jesse2233]

Excellent post @nandixon, might be good to email Dr Naviaux with your theory as well. Given all this do you think Actemra would still be useful in patients whose IL-6 levels are normal?

Tagging @dreampop as he's quite interested in Actemra

Edit: there are also the rumored clinical trial of Actemra being planned for ME in Japan

 

[Janet Dafoe]

I think there's a decent possibility that suramin may be working in Dr Naviaux’ autism studies by inhibiting IL-6 (explained later below). This possibility needs to be explored in ME/CFS as well since suramin appears to have a normalizing effect in Dr Ron Davis’ cellular impedance testing device.

So while we wait for any future suramin trial results for ME/CFS, which may take a number of years, I’m hoping that Dr Davis (@Janet Dafoe (Rose49)) will use his device to test at least one possibility for why suramin could be working in that device, namely IL-6 inhibition.

Suramin actually has potentially quite a few different actions in the human body. Some of these are mediated by suramin’s non-selective purinergic (P2) receptor antagonism and some are not. Since the impedance testing device potentially provides a convenient in vitro proxy for the energy impairment in ME/CFS, it would be desirable to try to narrow down how suramin might be working. This might allow us to come up with a more readily available alternative drug treatment or even a better treatment than suramin, and hopefully much more quickly.

Suramin is able to inhibit IL-6 in a variety of different cell types both by reducing IL-6 production and/or by preventing its binding to the IL-6 receptor (IL-6R). This inhibition may occur via suramin’s antagonism of various P2Y and/or P2X receptors. (Non-exhaustive PubMed search string)

(Suramin also inhibits other cytokines, including TGF-beta, which interestingly is mostly found to be high in the blood of ME/CFS patients but low in autism. It also inhibits other non-cytokine receptors as well, including NMDA glutamate receptors, and has additional diverse actions.)

So I think the first thing to test with Dr Davis’ impedance device, relative to suramin, is the IL-6 receptor (IL-6R) monoclonal antibody tocilizumab (Actemra). This drug is used in rheumatoid arthritis (RA) and has been found to significantly improve fatigue (i.e., energy impairment) in RA patients. Interestingly, in a single patient study, pyruvate dehydrogenase (PDH) was increased with tocilizumab. (Fluge & Mella found the PDH complex to be impaired in ME/CFS.) There's also one anecdotal report of a possibly successful use of tocilizumab on this forum.

Here's why I think suramin might be working in Dr Naviaux’ mouse and human autism studies by IL-6 inhibition:

In Dr Naviaux’ first (2013) mouse study he used the maternal immune activation (MIA)/poly(IC) mouse model. This is essentially an environmental exposure model for autism. This (2015) review article on inflammatory cytokines in autism states that:


(My bolding.)

Thus IL-6 is sufficient for poly(IC) to have its effect, and IL-6 knockout mice do not develop several of the autism-like behavioral features upon exposure to poly(IC).

Related arguments can be made for Naviaux’ remaining suramin autism studies, including use of the genetic Fragile X (Fmr1 knockout) mouse model and also the human study. For example, expression of Fmr1 is greatly reduced (by 50%) in the MIA model suggesting that IL-6 may be involved in the Fragile X model as well. And IL-6 has been found to be elevated in both autistic-like mice brains and autistic human brains alike.

So I think the possibility then has to be considered that suramin might be acting through an IL-6 dependent mechanism in Dr Davis' impedance testing device and Actemra may be the simplest and potentially most useful way to test for this.

Of course, there are many permutations for outcomes here. These are just a few:

If Actemra works in the impedance device this may or may not mean that Dr Naviaux’ cell danger response (CDR) theory is correct. If it is correct then Actemra might not be as effective as suramin (e.g., not as likely to correct as many problems and/or not as likely to effect a cure versus be an ongoing treatment). (A positive outcome also doesn't necessarily mean suramin would be working via an IL-6 mechanism in autism.)

If Actemra doesn't work in the impedance testing device, that doesn't necessarily mean it might not work in vivo. It also doesn't mean Actemra might not work in autism (where it obviously should be tested, it seems to me). This is because if the CDR theory is correct, then the degree to which a given pathway (e.g., IL-6) is affected is likely to vary considerably between diseases depending on what combination of factors in addition to the CDR underlies each disease.

Anyway, Actemra might be a promising potential alternative to suramin and/or might at least help narrow down some possible modes of action for how suramin could be working.

I forwarded this to Ron and I will also ask him about it. Thank you. He Ioves getting ideas from people!

 

[A.B.]

@nandixon in the recent Montoya paper on cytokines IL-6 did not stand out particularly (it did increase with severity but less so than many other cytokines. See table 1). http://www.pnas.org/content/114/34/E7150.full

TGF-β on the other hand was clearly increased at all levels of severity. As far as we know the impedance test works at all levels of severity.

The TGF-β pathway is involved in Dauer state initiation and maintenance in C. elegans, via insulin signalling (there is the connection to glucose metabolism, which may explain why adding pyruvate to cells undergoing the impedance test helps). https://www.ncbi.nlm.nih.gov/pubmed/17900898

 

[nandixon]

Given all this do you think Actemra would still be useful in patients whose IL-6 levels are normal?

The IL-6 blood level may not matter. I believe it's mostly normal in the blood of autism patients, too. IL-6 may be normal from every aspect but it still might be useful to down-regulate it. Or perhaps it's normal in the blood, but there's over-expression of the IL-6 receptor (IL-6R). There might be other possibilities including downstream effects of over-expression of IL-6R (or IL-6) at the mRNA level as well.

Edited to add: "(or IL-6)" [because the mRNA level of IL-6 could be high but the translated protein level of IL-6 normal]

 

[dreampop]

I think there's a decent possibility that suramin may be working in Dr Naviaux’ autism studies by inhibiting IL-6 (explained later below). This possibility needs to be explored in ME/CFS as well since suramin appears to have a normalizing effect in Dr Ron Davis’ cellular impedance testing device.

Very interesting theory (to my simple mind). I'm very interested in it but here are some sobering observations. One question I have is how strong the anti-Il-6 properties of Suramin are? I looked at it briefly in June in Jesse's Suramin alternatives thread and it was strong relative to it's other inhibitions but I don't know what that means practically.

There is one study (a British one!) that looked at Il-6, and Sil-6R at rest and post-exercise and found no difference in Il-6 levels, number of Il-6R and [I thought also Il-6R expression but I can't find the full paper atm so maybe I'm wrong about that] after exercise or at rest from healthy controls. Il-6 levels in the brain are generally normal as well asfai. CRP is normal. If that is the case, I don't see how it could be impacting the mitochondria significantly.

The one account we have on PR was a response a little staggered from what is seen with Actemra in RA where the dramatic reduction in inflammation comes in 2-4 weeks, and the account had a slower response from about 2-8 weeks. It was suggested that the patient had RA, although I think through the language barrier they were quite confident in the CFS diagnosis. That it wasn't a miraculous remission, however, adds credence to the account in my mind.

I'm still curious about it, and would be interested to see Ron test Actemra in his impedance testing and have some other ideas about it that I'm still trying to coalesce.

 

[Janet Dafoe]

I forwarded this to Ron and I will also ask him about it. Thank you. He Ioves getting ideas from people!

Ron says thank you, it's interesting, and he's sent it to the CFS research group so they can discuss it. "Interesting idea".

 

[nandixon]

Ron says thank you, it's interesting, and he's sent it to the CFS research group so they can discuss it. "Interesting idea".

Thank you Janet!

One question I have is how strong the anti-Il-6 properties of Suramin are?

Suramin’s ability to inhibit the binding of IL-6 to its receptor (IL-6R) appears to be of a similar magnitude to its ability to inhibit various purinergic (P2) receptors.

For example, I saw one reference give an IC50 of 30 micromolar for suramin’s inhibition of IL-6R and another give 48 micromolar for its inhibition of P2Y2.

I think that even if suramin’s ability to inhibit the different P2Y and P2X purinergic receptors were on average actually closer to 10 micromolar overall, and it's ability to inhibit IL-6R were closer to 50, that IL-6 inhibition is still likely to be very comparable to the P2 inhibition because suramin not only inhibits the binding of IL-6 but also inhibits production of IL-6 in the first place (and by multiple mechanisms).

So I think that to whatever degree suramin inhibits purinergic signaling, chances are that it will inhibit IL-6 signaling to a similar degree. (This is probably going to be true for a lot of the other actions of suramin as well.)

There is one study (a British one!) that looked at Il-6, and Sil-6R at rest and post-exercise and found no difference in Il-6 levels, number of Il-6R and [I thought also Il-6R expression but I can't find the full paper atm so maybe I'm wrong about that] after exercise or at rest from healthy controls.

That 2010 study (full text) was done using Fukuda criteria for patient diagnosis and only 6 patients participated in the exercise portion of the study, but I’m guessing the results are correct, namely that IL-6 is not elevated following exercise in ME/CFS.

The authors have made an oversight, though, and mistakenly believe they are the first to measure exercise-related IL-6:

Moreover, no studies have measured IL-6 levels during exercise in CFS patients, which is known to exacerbate symptoms.

Actually, that had been done previously in a 1999 study (full text). The 1999 study also found that IL-6 was not elevated during exercise in ME/CFS.

However, the authors found instead that:

These data demonstrate a correlation between the secretion of IL-6 by lymphocytes and monocytes and 'natural fatigue' in CFS patients, therefore, IL-6 may play a role in the clinical manifestations of CFS. Furthermore, experimentally induced fatigue does not appear to be a good model for studying in vivo changes in immune response during the natural course of CFS. Finally, longitudinal studies are required to study the pathogenic role of altered immune responses, including cytokine production in CFS.

This is saying that while IL-6 is not elevated during exercise, the authors did find IL-6 to be elevated when tested when the patient actually experiences “fatigue” (presumably including PEM) and suggests that arbitrary time points (such as were used in the 2010 study) may not be useful for determining IL-6 levels in ME/CFS.

 

[junkcrap50]

I think there's a decent possibility that suramin may be working in Dr Naviaux’ autism studies by inhibiting IL-6 (explained later below). This possibility needs to be explored in ME/CFS as well since suramin appears to have a normalizing effect in Dr Ron Davis’ cellular impedance testing device.

....

Anyway, Actemra might be a promising potential alternative to suramin and/or might at least help narrow down some possible modes of action for how suramin could be working.

Excellent post @nandixon, might be good to email Dr Naviaux with your theory as well. Given all this do you think Actemra would still be useful in patients whose IL-6 levels are normal?

Tagging @dreampop as he's quite interested in Actemra

Edit: there are also the rumored clinical trial of Actemra being planned for ME in Japan

I second forwarding this to Dr. Davis and Dr. Naviaux. I'm surprised you got a response from Dr. Davis already so quickly.

 

[Wolfiness]

Dr Naviaux, please can you explain to my dad why I can't meditate or otherwise desensitize/defocus myself neurologically from distressing stimuli such as noise?

Like e.g.

 

[Jesse2233]

@nandixon any thoughts on how to balance IL6R inhibition with the necessary immunological defense role IL6 plays?

 

[soti]

cytokine madness

I want this on a t-shirt!

 

[JES]

In bold - you sure? If so, that in itself could yield some useful data.
Coud we test your (bold) statement with a poll or series of polls? Is that still possible here?
My anecdotal experience, for example with ART, is that many sufferers are (possibly rightly) wary of trying it, whilst others have tried but got worse on it, whilst others have tried and subjectively (although with some objective outcomes) claim some improvement. 'Cured' would certainly be a strong claim, and we'd all be skeptical I'm sure. Perhaps it's the wrong term anyway, perhaps such a state is impssible with ME, only remission or improvement.

I cannot be 100% sure about the "most people on this forum" part, fair enough. What I can be sure of is that I've seen many users here, for example Hip and Jesse2233, that regularly test every new drug or therapy they can access, and many have been doing so for several years. There has been no time in history where information wasn't as accessible as it is today thanks to Internet, so with so many people sick with CFS/ME worldwide, you'd imagine information about a "cure" would spread quickly if there was one. Naturally certain drugs like suramin are not feasible for us to test due to availability, and others due to price. But price and availability would restrict some treatments anyway, even if they are found to be working.

Regarding "cured", I agree it may not be possible to achieve. But the way I would accept "cured" would be for example as in the Rituximab phase 2 study results, where some patients went from an SF-36 score of around 30 to a score of 100 post treatment (chart).

 

[fingers2022]

I cannot be 100% sure about the "most people on this forum" part, fair enough. What I can be sure of is that I've seen many users here, for example Hip and Jesse2233, that regularly test every new drug or therapy they can access, and many have been doing so for several years. There has been no time in history where information wasn't as accessible as it is today thanks to Internet, so with so many people sick with CFS/ME worldwide, you'd imagine information about a "cure" would spread quickly if there was one. Naturally certain drugs like suramin are not feasible for us to test due to availability, and others due to price. But price and availability would restrict some treatments anyway, even if they are found to be working.

Regarding "cured", I agree it may not be possible to achieve. But the way I would accept "cured" would be for example as in the Rituximab phase 2 study results, where some patients went from an SF-36 score of around 30 to a score of 100 post treatment (chart).

Good points, JES.
One point I'd make is that it seems from the anecdotal evidence that ART takes 2 or 3 years or more to be effective, maybe longer if condition is chronically established.
I will have to research what SF-36 means, sorry I'm ignorant, but will do it now. 30 to 100 is possibly subjective or maybe not. I'll have to research that too.
Generally, my own experience of ME is that it is an immune system not working enough rather than working too much. Anyway, if the immune system is (over) stimulated, something is stimulating it. Don't we need to find out what it is and address that rather than address the effects?

 

[fingers2022]

Good points, JES.
One point I'd make is that it seems from the anecdotal evidence that ART takes 2 or 3 years or more to be effective, maybe longer if condition is chronically established.
I will have to research what SF-36 means, sorry I'm ignorant, but will do it now. 30 to 100 is possibly subjective or maybe not. I'll have to research that too.
Generally, my own experience of ME is that it is an immune system not working enough rather than working too much. Anyway, if the immune system is (over) stimulated, something is stimulating it. Don't we need to find out what it is and address that rather than address the effects?

Ah, got it, SF-36 is psychology, subjective.
If Rituximab trial outcomes are based on that...oh dear...back to the drawing board folks.

Give me some objective physiological tests please???
Please???????
WTF is running these rituximab trials anyway?
Seems like yet another can of worms.
Help!!!!!!!

 

[Jesse2233]

@fingers rest assured on the rituximab trials. They are using objective pedometers, and it is being run by two excellent Norwegian scientists

 

[Wonko]

Ultimately everything is subjective, even objectivity

 

[Hajnalka]

@fingers rest assured on the rituximab trials. They are using objective pedometers, and it is being run by two excellent Norwegian scientists

In addition to the pedometers they are also using the 2 day CPET (but this test only for those who are able), gastrological and phlebological testing (source: Invest in ME talk on DVD).

 

[PinkPanda]

Does anyone know what the next steps would be to be able to test suramin in a human ME/CFS trial or how far we are from that?