I'll write an answer to that in the upcoming weeks. I believe that I can give you very good arguments on all of the questions you raise that do make HHV-6b reactivation hypothesis the most plausible of all the ideas on causative mechanism that were brought forward.
Trial Report Plasma cell targeting with the anti-CD38 antibody daratumumab in ME/CFS -a clinical pilot study, 2025, Fluge et al
My lab gives very different NK count ranges for females and males. The ones in the study dont strikeme as particularly low, maybe they reported the compound range in the study?
Females: 77-321
Males: 67-516
Bisset LR, Lung TL, Kaelin M, Ludwig E, Dubs RW. Reference values for peripheral blood lymphocyte phenotypes applicable to the healthy adult population in Switzerland. Eur J Haematol 2004; 72: 203-12.
Females: 77-321
Males: 67-516
Bisset LR, Lung TL, Kaelin M, Ludwig E, Dubs RW. Reference values for peripheral blood lymphocyte phenotypes applicable to the healthy adult population in Switzerland. Eur J Haematol 2004; 72: 203-12.
I've been trying to make sense of some of the facts stated here.
- There is not a lot of difference in IgG levels between responders and non-responders.
- All the killing happens fast (JE)
- Yet a single dose is not enough
- and non-responders show no improvement at all.
So maybe all the important killing happens later and it's about having a steady stream of NK supply so whenever a B-cell expresses CD-38 there is something there to kill it. That would also imply CD-38 is a good target for picking the culprits.
Just my thoughts, not sure if it makes sense medically.
- There is not a lot of difference in IgG levels between responders and non-responders.
- All the killing happens fast (JE)
- Yet a single dose is not enough
- and non-responders show no improvement at all.
So maybe all the important killing happens later and it's about having a steady stream of NK supply so whenever a B-cell expresses CD-38 there is something there to kill it. That would also imply CD-38 is a good target for picking the culprits.
Just my thoughts, not sure if it makes sense medically.
Not really.
Well working with very small sample sizes here.
For non-responders:
Patients 3 and 9 weren’t able to reduce IGG much—8.2 and 7.7 at 5 months. Patient 4 was able to reduce IGG to 3.7 at 5 months but started at the lowest level—6.8. By month nine patient 6 was above 7 and the partial responder, patient 5, was back to 7.6.
Because I love cherries, if we exclude patient 4 and count the partial responder as a non responder, then by month 9, mean of responders is 4.6 and non-responders is 7.3–a 60% difference.
So with the exception of patient 4, if you can’t reduce and maintain low IGG you are less likely to respond.
Did this really quickly—please let me know if I made an error.
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Thank you. I have been fooled by the small sample size and Figure 6H. Still I find the ratio between IgG drops and response magnitude odd.
Rick Sanchez
Senior Member (Voting Rights)
I was just looking at some of the first rituximab studies, and comparing them to the Daratumumab trial like some members were doing on the first pages here. They do have a point. The resemblance between the self reported results are eerie!! Sadly, no step counts were measured in the P1 and Ptwo as far as I can see. So the only thing we can go by is the difference in the P3 rituximab and Dara P1. Where the difference in my opinion is huge.
In my twenty five years of MECFS I have only had one brief remission, and just as I was starting to get worse during said remission I bought a Fitbit to track my daily steps.
January represents my current daily steps.
June is when I bought the Fitbit
You can see the point where my ´´remission`` really starts going downhill in the middle of June.
If the P1 trial results can be replicated then in my opinion it doesn`t just have massive biological implications for MECFS, but also has the implication that step count is an important outcome measure that should be used from now on to predict if the patients are actually genuinely improving. It isn`t perfect. But if the results can be replicated in the placebo trial then the step counts seem a better indicator of improvement? Depending on the sort of patients you include of course (For the majority of my time as mild I could easily do and probably did 10k steps a day, thus if I were included when I was mild in a study daily steps would be useless).
Thanks to Murph who has the comparison between the different rituximab trials and Daratumumab on the first page, if anyone is interested.
In my twenty five years of MECFS I have only had one brief remission, and just as I was starting to get worse during said remission I bought a Fitbit to track my daily steps.
January represents my current daily steps.
June is when I bought the Fitbit
You can see the point where my ´´remission`` really starts going downhill in the middle of June.
If the P1 trial results can be replicated then in my opinion it doesn`t just have massive biological implications for MECFS, but also has the implication that step count is an important outcome measure that should be used from now on to predict if the patients are actually genuinely improving. It isn`t perfect. But if the results can be replicated in the placebo trial then the step counts seem a better indicator of improvement? Depending on the sort of patients you include of course (For the majority of my time as mild I could easily do and probably did 10k steps a day, thus if I were included when I was mild in a study daily steps would be useless).
Thanks to Murph who has the comparison between the different rituximab trials and Daratumumab on the first page, if anyone is interested.
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ryanc97
Senior Member (Voting Rights)
I mean yes, it’s about bloody time scientists realized surveys are not reliable and observed outcomes are much better than surveys.
Of course on bedbound people this may not be accurate, but it should still reflect, e.g from bedbound to housebound.
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Rick Sanchez
Senior Member (Voting Rights)
Yes. It is the relativity that is important.
Maybe a bit off-topic, but apparently Scandinavia is one of the places with the highest step counts in the world (where I also happen to be from). The billion dollar question is if the improvement is down to placebo....
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ryanc97
Senior Member (Voting Rights)
To me, the question is not whether it is placebo. Clearly it works. For some. The question is why it works for responders, why it doesn't for non responders and also what does this reveal about the underlying mechanism of ME/CFS.
You don't triple your step count consistently for months due to placebo.
I would want to figure out the underlying mechanism, because if it works, technically, it cures ME/CFS.
V.R.T.
Senior Member (Voting Rights)
They do seem to have got a lot better. The other thing is a lot of people try something, say they're feeling much better and crash horribly a few months later. These responders stayed better for two years.*
*at least one has since partially relapsed and been retreated as per the last case study update, and they say they are retreating more so I assume more people have relapsed somewhat. The point is they stayed well for a long time.
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ryanc97
Senior Member (Voting Rights)
Well believe it or not nobody in ME/CFS trial history has bothered to do a pre recording of step counts and step counts.... insanity.
Rick Sanchez
Senior Member (Voting Rights)
I would really not say clearly when the study was N=10 and we have some patients that we know for certain had no response. I am saying this as someone who is irrationally optimistic on Daratumumab, I`ve even donated to the Placebo trial.
Placebo covers so much. They could very well just have gotten ´´unlucky`` with the patient selection in a N=10 trial. Especially given that a couple were completely unresponsive.
Jonathan Edwards
Senior Member (Voting Rights)
The trouble is that although your intuition may be right that a person with the disease that most members here probably have may well be unlikely to triple a step count for months, we cannot discount the possibility that some people with a diagnosis of ME/CFS have other diseases that may be critically different in this respect. You are assuming they all had the ME/CFS you are familiar with. I don't think you can know that.
I would like to believe Dara works but I have seen enough trial results to know that you cannot take these findings as proof of 'response'.
V.R.T.
Senior Member (Voting Rights)
Agree with what you're saying, but I think the fact it is Fluge and Mella who ran this trial as opposed to say, the US recover program makes it more likely that they carefully selected patients representative of most pwME as we are familiar with them.
Jonathan Edwards
Senior Member (Voting Rights)
One would hope so but who knows whether the criteria we use differentiate? Haemophilia turned out to be two almost identical diseases. ME/CFS is a bit different but not because it is easier to pin down!
ryanc97
Senior Member (Voting Rights)
I think the chance of it being another disease is impossibly small, because F/M chose the patients.
I think the chance of placebo is very low, because it’s not a survey, it is an observed outcome, and if it were placebo, step counts would not be sustained. The patients will crash and go back after a month of increased steps.
Another Possibility is that the data was faked or manipulated (eg inflating step counts or faking it) but given what I understand of F/M, this is unlikely. This is my worst fear.
So as I mentioned the main question is why it didn’t work in non responders, and if LLPC is the culprit
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ryanc97
Senior Member (Voting Rights)
On a side note, I am very curious on why the response was minimum two months.
If it were antibodies, surely the response would be linear in time?
One can argue for the long live of IGG and saturation of what it binds to, but assuming whatever they bind to is saturated, that does not account for different severity levels (ie more severe = more AABs)
If it were antibodies, surely the response would be linear in time?
One can argue for the long live of IGG and saturation of what it binds to, but assuming whatever they bind to is saturated, that does not account for different severity levels (ie more severe = more AABs)
Jonathan Edwards
Senior Member (Voting Rights)
I know Oystein and Olav well. I have sat talking with them for hours. They are very honest and humble folk and I think would agree that they cannot possibly know how many diseases their patients fall under. What I am sure of is that they would not fiddle data. But they cannot know if there are two illnesses that look the same, one of which is the one you are familiar with and one of which is not. It may have a lot in common but may fluctuate very differently.
Plently of trials have recorded pre trial step count and post trial step count, even if that data is often not commented on. I think Fluge and Mella have put in quite a bit of additional effort on trying to recognise step count trends including a longer pre recording phase, but even PACE had objective (null) data. Even CBS clinicans sometimes use actimeter data as part of their monitoring process.
The Rituximab trial included actometer data, including step count (pre trial for a week and then later at 17-21 months during follow-up), and I'm sure you will find people in the placebo group that had the same improvements as the people here in the Daratumab study (you will probably even find some individuals in the PACE study who had similar sustained improvements in step count in both arms despite the treatment having no efficacy). "Placebo" in this case includes "natural full recovery" and in a recent high profile study of ME/CFS patients that were probably selected at least as rigourously as here, that rate was not 0. This happens. I'm sure you can find hundreds of unblinded studies with objective outcome measures that looked drastic but where it turned out that things do not do anything. I don't see how one can draw any conclusions before the placebo-controlled study is completed.
I agree that it is hard to explain how exactly the recovery rate could be so large in this study if the drug were to have no efficacy but then again you have the possibility of all sorts of other biases contributing to the seen data. I’d be surprised if Fluge and Mella thought that this data looked categorically different from their Rituximab data, which turned out to have no efficacy.