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salin said:
Also of interest:
She confirmed that there will be an isatuximab trial.

(Wikipedia: "Chemically, isatuximab is similar in structure and reactivity to daratumumab; therefore, both drugs bind to CD38 in the same way. However, isatuximab exhibits greater inhibition of its ectoenzyme function. Isatuximab acts as an allosteric antagonist, inhibiting the enzymatic activity of CD38 in a dose-dependent manner.")

Unfortunately, this is only available to patients who have previously undergone immunadsorption.
I would have loved to have taken part...
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What? Why that?
That meants again, only fo aab positive people, which is only 30 percent of patients and a very different strategy than Daratumumab trial
 
MelbME said:
I wonder if someone will be game to do a CD19 CAR-T therapy on ME. That would be the ultimate test of the autoimmune hypothesis.
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I think last year during the Q+A after his dara presentation, Fluge said an American company was considering it, but Fluge thought it was too soon - iirc he said 'maybe in five years'.

Who knows, maybe that company will go ahead with it though. It would be really good to confirm for certain if it's a dead end, although of course there are patient safety issues to think about.

If dara works, it would also be interesting to see if dara non responders respond to CD38 CAR-T therapy. That would clear up whether there's a subset who need a different approach or whether it's just about drug action.
 
MelbME said:
I wonder if someone will be game to do a CD19 CAR-T therapy on ME. That would be the ultimate test of the autoimmune hypothesis.
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Jonathan talked about CAR-T being quite hyped on another thread..
Jonathan Edwards said:
Firstly, I can assure you from years from now experience that people treating autoimmune disease do not have a clue about how to use rituximab intelligently. Rheumatologist have no clue about B cell dynamics - which is presumably why I was almost the only person to think of using rituximab for RA, lupus etc.. Oncology is quite different.

But that isn't the point. I have not seen good evidence for CAR-T working where rituximab did not work. There have been dramatic claims about cures lasting for ages for CAR-T but whenever Maria Leandro an I see presentations on this the data are no different from her results in 2000 on lupus with ritux. We had people staying well for years even then.

We know that depletion with standard ritux is not always complete, although for some of our cases it seems likely that it was and that the return of disease was because of survival of 'educator' plasma cell clones. I don't know of evidence on how complete depletion is with CAR-T. I suspect it may be similar - complete for some but not all.
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Braganca said:
Jonathan talked about CAR-T being quite hyped on another thread..
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The theory around why CAR-T would be better than Ritux is based on the hypothesis that EBV has close to immortalised a plasma cell tucked away somewhere. Ritux killing circulating B cells and then waiting 6 month for natural plasma cell death wouldn't work.

That's a simplification of the hypothesis of why Ritux may not work as well as CAR-T.
 
MelbME said:
The theory around why CAR-T would be better than Ritux is based on the hypothesis that EBV has close to immortalised a plasma cell tucked away somewhere.
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I don't think EBV is particularly implicated. It just seems that plasma cells can last for decades. Antibodies to vaccines tend to remain at reasonable levels throughout childhood even in those who are EBV naive as far as I know.

You can of course keep people B cell depleted for five years or more by repeat use of rituximab every 5 months and I have done that in severe RA cases. Antibody levels to tetanus tended to remain much the same. I am not sure that anyone has done it in cases of diseases like scleroderma that tend not to initially respond.

CD19 (or CD20) CAR-T would not hit plasma cells much I think.
 
Jonathan Edwards said:
I don't think EBV is particularly implicated. It just seems that plasma cells can last for decades. Antibodies to vaccines tend to remain at reasonable levels throughout childhood even in those who are EBV naive as far as I know.

You can of course keep people B cell depleted for five years or more by repeat use of rituximab every 5 months and I have done that in severe RA cases. Antibody levels to tetanus tended to remain much the same. I am not sure that anyone has done it in cases of diseases like scleroderma that tend not to initially respond.

CD19 (or CD20) CAR-T would not hit plasma cells much I think.
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There is an upswell of people believing now that EBV is the multiplier of all autoimmune disease and they see the CART success in Lupus as evidence. Every reactivation is another opportunity for EBV to spread to a different B cell with a different repertoire.
 
MelbME said:
There is an upswell of people believing now that EBV is the multiplier of all autoimmune disease and they see the CART success in Lupus as evidence.
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Yes, I keep away from upswelling people!! We don't even have any evidence for any special CAR-T success in lupus. You should see Maria Leandro smile behind her hand when she sees these 'new' data repeating 25 year old results.
 
Murph said:
I can't help but think about ORS, an intervention which killed loads of patients before they dialled in the dose exactly and it is now considered the greatest medical achievement of the 20th century, saving almost 100 million lives: https://www.amjmed.com/article/S0002-9343(24)00752-6/fulltext

(if you give cholera patients water: they die, if you give them salty water: they die, if you give them sugar water: they die, if you give strong salty sugar water: they die. But if you give them lightly salty sugar water they sit up, recover, get out of the hospital bed and go home.)

It's frustrating but in biology details matter so if you fail on one dose, sometimes abandoning the drug altogether is the wrong call.
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That was a matter of getting the chemistry right. If I remember correctly from reading about ORS a long time ago, you need the sugar to get the salt out of the gut without going through the normal salt route, which in turn made the water get absorbed faster.

It was the same for HIV drugs, where you needed to come at it from multiple angles. But none of that was figured out before you had evidence of efficacy in isolation, and people then tried to combine them to see if it worked even better. And it was all guided by insights in the pathology.
 
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V.R.T. said:
Do you have a source for this? It may be relevant to something I'm (slowly) writing
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Before you do, can I just jump in and say this is something that is often described inaccurately. I have clarified what happened in these two posts: here and here. Basically, the plan was always to use actigraphy as a predictor, not an outcome, but they did consider using it or two other things as objective outcome measures. They decided not to use any of them as primary outcome measures. Their reasoning for that was heinous.

They did not originally plan for it to be an outcome measure and then reverse that decision.

Just tagging people who discussed this above @Robert 1973, @Sean, @rvallee.

I am reading Lucibee's blog now and will edit this if I am wrong!

Editing having read it: I don't think Lucibee's blog changes my stance. She writes:
In the original trial FAQs (now no longer available on the PACE trial website, for some reason) and in their response to Tom’s comments on the protocol, the investigators stated:
“Although we originally planned to use actigraphy as an outcome measure, as well as a baseline measure, we decided that a test that required participants to wear an actometer around their ankle for a week was too great a burden at the end of the trial. We will however test baseline actigraphy as a moderator of outcome.“
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I cannot verify that quote as it's not available. However, there's nothing in the Trial Management Group minutes or the protocol that supports that. It would be odd to say that on a public FAQ and not in private meetings, but I trust Lucibee that it is an accurate quote. It contradicts both the protocol and the minutes, though, so notwithstanding some contemporaneous evidence I haven't read yet, it's possible they got a bit confused there.

I have read Tom's letter on the protocol BMJ 2013;347:f5731. His mention of outcome measures is here:
One reason that the minutes are sought for the PACE (Pacing,Graded Activity, and Cognitive Behaviour Therapy—a Randomised Evaluation) trial, which looked at the effectiveness of treatments for chronic fatigue syndrome, is to find out why outcome measures were changed.1 None of the three primary outcomes were reported as in the protocol...
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And their response BMJ 2013;347:f5963 is here:
Kindlon states that access to the committee minutes of the PACE (Pacing, Graded Activity, and Cognitive Behaviour Therapy—a Randomised Evaluation) trial is needed “to find out why outcome measures were changed.”1 We disagree.Firstly, the primary outcome measures were the same as those described in the protocol—fatigue and physical disability.2
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Nothing else in their response is relevant.

So actigraphy is mentioned by neither, though I believe Tom has brought it up elsewhere.

It doesn't change the fact that their reasoning for not using actigraphy as an outcome measure was outrageous. That remains undeniably true.

From TMG minutes #11, 4 Nov 2004:
Actigraphy is to be given at baseline only, as a predictor. This is on the basis of research by the Dutch Nijmegen group who found it useful as a predictor (the more passive, the poorer outcome), but not useful for outcome.
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And TMG minutes #12, 10 Dec 2004:
The issue of using actigraphy as an outcome measure was raised. It was noted that the Dutch study by Bleijenberg and colleagues reported that actigraphy was not a good outcome measure since the majority of patients are reasonably active and there is no change in this in spite of improvement in fatigue. However, pervasively passive people at baseline may do worse on CBT and perhaps better on GET.

A final decision on using this as an outcome has been postponed until we see how much of a measurement load actigraphy is, and it was agreed that this may be changed later next year if desired.
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Happy to be corrected with other sources.
 
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I wasn't sure where I should post this but I believe it should be posted here, given the presentations of the conference.

I spoke yesterday to two LongCOVID patients who have PEM after exertion. One of them (a psychiatrist) told me that he is witnessing LongCOVID being turned to Fibromyalgia as time passes by. After discussions, we realised that both of them have Gilbert's syndrome, a benign (??) problem of the gene UGT1A1 which impairs Phase 2 detoxification of the liver. One of them (the Psychiatrist) has consistently elevated blood ammonia.

Another patient told me -10 days ago- she has the HFE Gene (Hereditary Hemochromatosis - cc @Chris Ponting )

I read about neurons, CRH, CAR-T therapies, ME/CFS being associated with the brain -which is fine- but OTOH I see no actions for going back to the basics and investigating whether key metabolic perturbations exist in patients. I sincerely hope I am not the only one being deeply concerned about this.
 
What was also really interesting about the presentation by Michelle James was that her hypothesis is basically the same as the one from Mitodicure and Klaus Wirth. It would be interesting to know whether she came to that conclusion independently or whether she adopted it from Wirth. In her presentation, she definitely also mentioned this calcium overload and the resulting vicious cycle.
 
mariovitali said:
I see no actions for going back to the basics and investigating whether key metabolic perturbations exist in patients.
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As far as I can see researchers are still looking at metabolism and if anything more than ever with metabolomic and proteomic studies. The reality is that they are finding nothing that would account for symptoms. People tend not to emphasise negative findings when publishing but to me the negative data on metabolism is now pretty comprehensive.

In addition, the more I listen to people with ME/CFS the more I find it very difficult to explain symptoms on the basis of metabolic shifts. The timing of PEM and the longer term fluctuations seem much more consistent with signalling evens in nervous or immune systems. Some of us said that in our 'Biological Challenge' paper in 2016. (Fatigue 4(2):63-69. doi: 10.1080/21641846.2016.1160598. ) The DecodeME results look to me very much as we might have expected, although we would never have predicted the individual genes.
 
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