OMF Symposium keynote address-Oystein Fluge, MD, PhD

[Ben H]

Hi guys

We're pleased to share a video of the keynote address from the recent OMF-sponsored Second Annual Community Symposium on the Molecular Basis of ME/CFS at Stanford University: Oystein Fluge, MD, PhD, of the University of Bergen presented on Clinical trials and metabolic features of ME/CFS.

You can watch the presentation and also find a written transcript of it here: http://bit.ly/2BpmDIi

Thank you to our team of volunteers who are busily transcribing the Symposium videos! #MECFS18

Hope you enjoy,


B

 

[Moof]

Thank you – just worth adding, as it's not 100% obvious, that you click on Dr Fluge's name to access the transcript.

 

[used_to_race]

It seems like the implication here is that CycloME has been fairly successful. He also made the comment that most of the clinical cancer cases where they noticed an improvement before any trials were with Cyclophosphamide as well. I wonder what the next steps will be in terms of clinical trials. My ideal scenario would be to take this info and use it to design a set of larger trials with several different immunosuppressive protocols geared towards different patient subsets, stratified by symptom types, severity, and other potentially diagnostic findings such as metabolic markers. It would be nice if the T cell clonal expansion work were to move forward a little quicker, I think that will yield a big piece of evidence that symptoms in ME/CFS are immune-mediated. Why wouldn't immunosuppression ease the severity of some symptoms?

 

[frozenborderline]

It seems like the implication here is that CycloME has been fairly successful. He also made the comment that most of the clinical cancer cases where they noticed an improvement before any trials were with Cyclophosphamide as well. I wonder what the next steps will be in terms of clinical trials. My ideal scenario would be to take this info and use it to design a set of larger trials with several different immunosuppressive protocols geared towards different patient subsets, stratified by symptom types, severity, and other potentially diagnostic findings such as metabolic markers. It would be nice if the T cell clonal expansion work were to move forward a little quicker, I think that will yield a big piece of evidence that symptoms in ME/CFS are immune-mediated. Why wouldn't immunosuppression ease the severity of some symptoms?

It's my understanding that "immunosuppression" is pretty broad. There are many different cytokines, antibodies, etc, involved in immune activation and autoimmunity. Some people with ME/CFS have both low total IgG and high IgG bands... Some people have had relief from symptoms with corticosteroids but those also cause problems for a lot of people. If there are any active viruses, broad immunosuppression might be a bad idea. I wonder if IVIG at different doses could normalize an immune system that has both low total IgG and some bands of IgG that are high?

 

[used_to_race]

It's my understanding that "immunosuppression" is pretty broad. There are many different cytokines, antibodies, etc, involved in immune activation and autoimmunity.

It's my understanding that cyclophosphamide confers quite broad immunosuppression. Sure there are selective drugs like rituximab, but in general the DMARDs and 5-ASA drugs all act fairly broadly. There are the TNF inhibitors and newer gen biologics, but generally we don't have a ton of tools off the shelf for selective immunosuppression.

The first step in curing the disease will be to identify the specific parts of the immune system that are dysregulated and why this is the case. But until then people need treatment ASAP and if cycloME is any indication (as well as anecdotes about corticosteroids), then maybe the less severe patients will benefit from drugs like azathioprine, sulfasalazine, and plaquenil. Isn't Klimas doing a trial involving a TNF inhibitor at this time?

Some people with ME/CFS have both low total IgG and high IgG bands...

I'm just speculating here but as the immune system is a multivariate nonlinear system, it's possible the abnormal antibody production is a compensatory mechanism stemming from the underlying T cell pathology. This sort of thing has been suggested vis a vis pathogen-specific antibodies by Naviaux IIRC.

If there are any active viruses, broad immunosuppression might be a bad idea.

Speaking of viruses, I'm still skeptical of this angle. The triggers are so heterogeneous for so many people, and most of the recent evidence points to viral exposures being no different for ME/CFS patients vs controls. I saw the recent post on EBV proteins in ME/CFS patients but the researchers did not establish whether that's causal or downstream from the immune dysfunction. My guess is the latter.

I wonder if IVIG at different doses could normalize an immune system that has both low total IgG and some bands of IgG that are high?

It might, but there have been cases where people get all their IgG removed via plasmapheresis and then IVIG replacement, and their disease persists. I don't think B cell dysfunction is at the root of this illness. Studies on IVIG have been contradictory, and there seems to be a subset for which the treatment is beneficial, but it's rarely curative. Even mainstream cutting-edge immunologists don't know how IVIG works for certain things, but it magically seems to induce Tregs and apoptosis of cytotoxic T cells. It can also be antiviral. I support its use in ME/CFS and would try it myself if I could afford it, but in 10 years I doubt it will be a common treatment for this disease.

 

[Gingergrrl]

I wonder if IVIG at different doses could normalize an immune system that has both low total IgG and some bands of IgG that are high?

My understanding from talking to my doctor and the nurses at my infusion center (where I got IVIG for 2 yrs) is that it can. It is more of an immune modulator (not an immune suppressant) and in low doses, it helps with immune deficiency and at higher doses, it helps regulate autoimmunity. I've known people who have benefited from IVIG who had both ID and AI (vs. I had only autoimmunity).

Sure there are selective drugs like rituximab

I think this is why I benefitted from Rituximab so much (b/c it is targeted so specifically for B-cells and I had B-cell driven autoantibodies at the core of my illness). I do not think I would have benefitted from (or even tolerated) broad immunosuppressants (but that does not mean that others wouldn't).

Interesting thread (and hoping what I wrote is coherent)!

 

[tiredowl]

Why wouldn't immunosuppression ease the severity of some symptoms?

Interesting. This could point to ME being some kind of autoimmune disease.
Could Azathioprine be therapeutic as well?

¨Azathioprine and 6-MP are purine antagonist antimetabolites.¨
Anyone know what that means exactly?

 

[used_to_race]

Interesting. This could point to ME being some kind of autoimmune disease.
Could Azathioprine be therapeutic as well?

¨Azathioprine and 6-MP are purine antagonist antimetabolites.¨
Anyone know what that means exactly?

I spent a lot of time reading about these medications a couple months ago when my doctors and I thought I might have Crohn's disease. But the mechanism of action here is pretty well-known. From wikipedia:

Azathioprine inhibits purine synthesis. Purines are needed to produce DNA and RNA. By inhibiting purine synthesis, less DNA and RNA are produced for the synthesis of white blood cells, thus causing immunosuppression.

This drug has lots of side effects and people are pretty miserable while taking it, so it's not exactly a suitable long-term treatment unless it helps people with moderate to severe ME/CFS. Plaquenil and Methotrexate are other immune suppressing drugs commonly used in Undifferentiated Connective Tissue Disease (UCTD), which can be indistinguishable from ME/CFS in many cases.

 

[Gingergrrl]

Interesting. This could point to ME being some kind of autoimmune disease. Could Azathioprine be therapeutic as well?

Azathioprine or "Imuran" was recommended to me by one Neuro in early 2016 but my main doctor thought it was not the right med for me, and was much too dangerous. He felt that IVIG and Rituximab were right in my case (and he was right). If I remember correctly Azaprine/Imuran wipes out the entire immune system (vs. Ritux only targets the B-cells).

 

[tiredowl]

.

Youre right, I see that it is commonly used for Chrons disease and other immune disorders, which I would guess also weakens the immune system in some ways, but they use a much lower dosage. So maybe a lower dosage wont be so dangerous? Though I read something about it having a higher risk of cancer, so maybe not for long term use.

 

[pattismith]

Plaquenil and Methotrexate are other immune suppressing drugs commonly used in Undifferentiated Connective Tissue Disease (UCTD), which can be indistinguishable from ME/CFS in many cases.

In this 2017 Cort article,

Not all the chemotherapy drugs Fluge has tried have produced positive results. Methotrexate, another chemotherapy and autoimmune drug, produced what Fluge, who has probably seen it all over the years, called “a horrible reaction” in ME/CFS patients.

.. Methotrexate is known for its neurologic toxicity by building up adenosine in the brain, (and by B9 induced deficiency)

.. Adenosine blockers are the known drugs to reverse the adenosine toxicity (caffeine, theophylline, Aminophylline)

.. Folic acid or folinic acid are commonly coadministrated with MTX to improve adherence to the treatment but adenosine blockers are not included because it is believed it would block MTX efficiency. (studies about this are very scarce)

I tried a tiny dose of MTX and got sleepiness and muscle weakness two days after the intake, tobether with tinglings, despite adding folinic acid to the regimen.
My bad trip was mostly reversed with caffeine which I switched then to Theophylline (+ inosine).

I feel that I may be able to stick to MTX if I keep the current regimen, let's see if it can produce some positive result that way... or not.

Methotrexate-Induced Leukoencephalopathy Reversed by Aminophylline and High-Dose Folinic Acid

Aminophylline for methotrexate-induced neurotoxicity​

High-Dose Aminophylline for Methotrexate-Induced Neurotoxicity in a Patient With Brain Metastasis​

Methotrexate Induced Acute Encephalopathy-Occurrence on Re-challenge and Response to Aminophylline​

https://www.healthrising.org/blog/2...me-mecfs-iacfsme-conference-overviews-part-v/