Chris Armstrong - Melbourne ME/CFS researcher, research updates and general chat

Thank you for responding.

Cyclophosphamide from the study by Fluge’s group. The hypothesis that cyclo is an effective treatment for MECFS has not been falsified.

https://www.s4me.info/threads/intra...-study-2020-rekeland-mella-fluge-et-al.14925/

Dara also from the Fluge Norwegian group
https://www.s4me.info/threads/pilot-study-in-norway-daratumumab-in-me-cfs.28098/

Campath suggested by Jo Edwards from UCL, an expert on immune modulation treatments.

https://www.s4me.info/threads/myalg...anisms-2024-rekeland.38262/page-2#post-529083

https://www.s4me.info/threads/prof-...lism-in-me-cfs-lecture.2097/page-2#post-41712

Lots of people, myself included have had short term remissions from steroids, which suppress the immune system.

Hope this helps.

 

Also disastrous crashes, resulting from accidental ingestion of small amounts of topical steroids.

My sudden relapses from able-to-work to in-need-of-care were caused by them. The relapses persisted for months because I was assured these meds couldn't cause a response like that, so I carried on taking them until the labyrinthitis or asthma had settled (not usually a quick job). But they were the problem, and it was plain enough in my records when we looked.

So all in all a pretty typical response to medication: beneficial, no effect, severe ill-effects.

 

That's great thank you.

Rituximab and Cyclo both used infusion as mode of delivery, I think they're aware of the problems with volume expansion in the placebo. Interestingly Dara uses subcutaneous injection. I am interested to see if Dara proved to be impactful.

I do recall Campath and Arzerra were 2 of the other B cell depletion drugs being discussed around the time Rituximab kicked off. They could be interesting.

I wonder how you could build up enough rationale to justify a human trial of these drugs to an ethics board without actually having access to patients that had it in combination with another disease like Fluge+Mella did. Especially in a post-pandemic world.

We're having some difficulties just trying to get Saline as an intervention through, something relatively low risk. We're new to the clinical trial area though.

 

You are correct, trying to get the immune modulators and cytotoxic drugs approved by a research ethics board would be next to impossible particularly when the rest of the world including the researchers at large, the peer reviewers only view Me/cfs as a simple fatigue problem with no biomarker. Finding objective endpoints can be hard too.

This said I would be very willing to try the big guns drugs for a simple chance of recovering my life as I knew it. But ethics boards do not look at it this way.

So very sorry you are also encountering difficulties getting approved for the saline intervention. It sounds to me like a logical next step that is very worthy of trying particularly for those who are more severe on the spectrum.

We as a disease (said it before and will say it again) are facing barriers of access to health care, research funding, government and insurance benefits and legitimacy. It’s still going on.

 

This may be a bit off topic but if you (or collaborators) are looking for research leads, I know of many, too many pwME that have a sensitivity to epinephrine. Understanding why would be a good study, because you can inject (just a bit ) epinephrine and observe the effects both as the patient experience them and at the cellular/cell signalling/ biological level.

Epinephrine that is administered for dental anesthetic is how patients typically find out something wrong. In my case I had a horrible reaction (like a bed-ridden type of crash that lasted 3 weeks, on top of other short term new symptoms) which did not occur hen I returned to the dentist one month later and got frozen without the epinephrine in the freezing.

What happened for me was immediate and exaggerated tachycardia, sweat, feeling horrible. Then 3 days of migraine type of headache (I very seldom get headaches) a very sore body, and a major 3 weeks long crash.

Dentists don’t understand, think it’s a preservative issue, but it’s not. It is inherent in my opinion to ME.

of course there would be research ethics issues in terms of injecting epinephrine into patients but a prospective study (patients with ME with unknown epinephrine sensitivity status) undergoing dental work could be valuable.

My 2 cents. I understand this may not be your field or interest, limited funds, limited time, but there are very few researchers visiting the forums and I thought I’d put it out there for you!

 

I would really like more work to be done on orthostatic issues. For me this is one area where I think progress can be made with just a few well designed studies. And while it won't necessarily help everyone, I think it would help bring more researchers to the disease and uncover some of the mechanisms at play. Studies looking at blood flow, and blood pooling I think could be very useful. Its the one area where we can demonstrate a clear issue, so why not do more work to figure out exactly what is causing that problem.

 

Yeah they are aware of this. I spoke to them about it several years ago. At the end of the day the Rituximab trial failed to show enough improvement over placebo. They probably know as well as anyone.

It's not more difficult than other medications. It's just that it's a lot more complicated than an observational study.

 

It certainly is interesting. Do you have POTS? The tachycardia in POTS is driven by epinephrine.

 

I do have POTS. I assume I was already on Atenolol at the time it happened, early in my disease onset. POTS came in the package deal.

 

I don't have POTS (though I do have OH) but also react in much the same way as Milo with epinephrine in dental anaesthesia.

 

Campath depletes T cells as well as B cells.


“Alemtuzumab is a humanized monoclonal antibody targeting CD52 expressed on the surface of most white blood cells (6). Upon binding, alemtuzumab induces antibody and complement-mediated cytolysis of targeted cells. Cells of the adaptive immune system express the highest level of CD52 and the lowest level of complement inhibitory proteins, and likely as a consequence of this they are the cells most sensitive to alemtuzumab-induced depletion (6). After depletion, the adaptive immune system reconstitutes from precursor cells or mature cells that have escaped depletion. B cells repopulate within 3-6 month reaching or overshooting baseline levels, followed by a delayed T cell reappearance after 1-3 years but with circulating cell counts significantly lower than at baseline (7–9). Furthermore, the reconstitution dynamics of T cell subtypes differ, with regulatory T cells repopulating faster than effector T cells (7, 10). The reconstituted immune system with a higher proportion of regulatory cells has therefore been proposed to contribute to the long-lasting effect of alemtuzumab therapy (10).”

 

Yes, Campath can produce years of profound T cell depletion at doses that produce very brief B cell depletion. I think I suggested it as a way of targeting T cells in relation to a T cell theory for ME/CFS.

 

(I think maybe I've said this before, so apologies if I'm repeating myself.)

LDN has been quite common among Swedish pwME for a few years, because ME Center in Stockholm used to prescribe it to many of their patients (ME Center has since closed). This means that lots of Swedish pwME have had a chance to try it, so lots of lived experience has been shared over time in the Swedish ME and POTS/OI discussion groups.

LDN obviously doesn't help everyone, we already know that, but judging by the comments in these groups over time I would say that it genuinely seems to help some/many pwME in a meaningful way -- including pwME and pwLC with POTS, OH, IST and other kinds of dysautonomia. It also seems that it's very tricky to get the dosage right, requiring a very slow increase over a very long period of time.

I have read lots of credible reports from ME patients over the years, including friends of mine, who have been helped by LDN in a concrete and meaningful way though improvement of what Branganca calls "primary ME symptoms", which has also increased their ability to function and to be active. For some pwME, especially some of the severely/very severely ill who have been very ill for a very long time, LDN has been life-changing. (Very different than the newly ill people who celebrate their "recovery" every other month after trying some new miracle cure...)

However, for political reasons pwME in Stockholm are suddenly no longer being prescribed medication. The improvement gained from LDN does seem to disappear when they stop taking LDN, and we will soon start to see the consequences in the group at large. It's absolutely heartbreaking.

In Sweden mestinon seems to be more common among pwLC and POTS/OI/IST than among pwME. At least one of the long covid clinics [EDIT: and/or one of the cardiology specialist clinics they are referring their patients to] is prescribing it to some/many of their patients, many of whom have gotten an ME diagnosis after coming down with long covid and POTS. This means that there has been plenty of reports from patients in the Swedish discussion groups about mestinon as well. Lots of pwPEM are reporting that mestinon is improving symptoms such as PEM and PEM threshold, muscle weakness etc.

Bragée ME Center claimed that they did a lot of scientific research, but I haven't even seen any ethical approval applications for these rumoured studies, so it doesn't look likely at this point in time that ME Center will publish anything about their findings?

Anyway. I just wanted to add this, as a counterpoint to Braganca's observations.

 

Any treatment trial in ME/CFS would receive pushback from many people and for good reason. All sorts of treatments only seem to work in certain individuals, and it may be the case that non of them are effective for a majority of the community.

Personally, I believe there isn't good evidence to suggest that any specific treatment will be successful, especially without an understanding of the cause of ME/CFS. The only thing we have to go off right now is anecdotal evidence. And while there many be some biases, the clinicians surely would be in the best place to asses this evidence. I think its fair to push back and say we don't want any treatment trials until we know more, but I don't think it is fair to suggest they should have trialed some other drug instead.

 

So you are happy for the Lightning Process to be tried on everyone with ME/CFS based on reports of cure from Dr Garner's friends? You are happy for another hundred thousand people to be forced to do GET because clinicians are so sure it works? And for the psychologists to make a comfortable living handing out and teaching CBT because they KNOW it works. And for surgeons to stick nails in people's necks because they can see it works?

Clinicians are probably the least reliable people in this. We were all taught what works and we used it and we saw it work - we didn't even need to check that patients were better, it was part of the job seeing the treatment worked. After a few year some of us physicians began to thin twice and realised that we had no idea whether half the stuff worked. Most therapists never ever question it.

And of course clinicians in private practice will sell whatever people buy and sell it with a neat sales pitch.

If people with ME/CFS want to pushback against trials that actually tell us if there is any noticeable effect then I suspect the only people who are likely to be able to help in the long term will walk away like all the others. I continue to take an interest in ME/CFS because I can see that some people genuinely want to take evidence seriously. I am not going to be the person to find the breakthrough but at least I seem to be having some success in encouraging some people who might - including people on this forum who are making invaluable contributions to research progress.

 

yes to all your post above but this certainly rings true here unfortunately.

 

Well CBT and GET has been tested and shown not to work. If we had no data on these treatments at all I would be fine with a study being run. But I understand your argument.

I only wanted to point out that we have no inclination beside anecdotal evidence that any of these treatments work. We have to start somewhere and because doctors are biased that's why we run the trials. I think the LDN study is useful because clearly some of these clinicians have heard that LDN helps and I want to know if this treatment is actually effective. I never meant to say that anecdotal evidence is good enough, just that there aren't any treatments that warrant a clinical trial in ME/CFS based of more than anecdotal evidence right now.

I just don't understand how people can say: OMF shouldn't trial LDN but instead some dangerous immunomodulating drug when we have no more evidence that this other drug would work.

 

I know I'm quoting selectively from your post. @Jonathan Edwards was part of the MRC group which was asked to identify research opportunities for ME/CFS - this led to DecodeME [common genetic variants]. Hopefully DecodeME will identify drug targets (genes & pathways):

• I've been surprised to find (BBC Radio 4*) that generally making a new drug is straightforward (you just need to know the target!).
• possibly there are drugs which could be repurposed.

I'm hoping that NIH will fund a:

• rare variant study (e.g. families with more than 1 member affected & one severe);
• large metabolomics study (possibly focused by DecodeME results);

those are also potential routes to find drug targets.

For all of the above - I'm still not confident that there will be a drug to help my family member i.e. in the short term --- but there are opportunities!

*BBC Radio 4 - The Bottom Line - Blockbuster drugs
"How to come up with a billion-dollar medicine, and who pays for it."
https://www.s4me.info/threads/how-t...dicine-and-who-pays-for-it.36186/#post-504257

 

I think clinicians provide the first layer of evidence this is how trialling Rituximab and Ampligen came about. Then it comes down to a design placebo-controlled trial to test the treatment. We all remember what a disaster the PACE trial was.

As you say, we want objective evidence.of treatment effectiveness.

 

An aside, but the funny thing is that when we find something really works the evidence will be hard to capture in graphable form.

Years ago I had ME remissions, and if I'd been attending a clinic the doctor wouldn't have recognised me at the next annual review. I'd resumed work, friendships, interests, dating, and exercise, and started training in a new field...it would have taken half a day to write it up.