Jonathan Edwards
Senior Member (Voting Rights)
There aren't that many of us anywhere, but there were several in the US long before me. (I had no private income. I just made use of some of my government salary.) And there are enough of us to constitute a fairly major proportion of innovation in chronic disease treatment. The drug companies just come in to do the second generation stuff.
I suspect much of the problem is simply that medicine has been taken over by greed like everything else in the last forty years. And no intelligent youngster goes in to medicine if they can make it rich in finance.
And what sort of doctor is that? Too busy handing out stuff they don't know if it even works.
I actually have seen it, and it turned out exactly like you said – not very rigorous. Dr. Luke Liu in Anchorage did a trial on stellate ganglion blocks for ME/LC/something like that, and he didn’t blind it. When I was there, we argued a lot about it – he said it was impossible to do, I said it was difficult but not impossible and gave him some ideas for how to do it. Ultimately he decided not to blind it. I don’t know what his clinic’s finances are like so I don’t want to cast aspersions. I do know he gave away a ton of free treatment and that probably consumed significant resources and made it difficult to carry the trial out as I suggested. Essentially I suggested two things – 1) add a third arm with a pill-based treatment so that everybody would get some pill to take and the ones receiving the sham SGB could at least wonder whether they got the treatment pill (LDN, one of those OTC blood thinners that were popular for a time among patients who thought they had microclots, whatever), and 2) isolate the patients after the SGB in a room for a few hours without a mirror or a phone so they couldn’t look at themselves and see whether they had the Horner’s reaction. Both would have required a lot more resources.
Trials have gotten really expensive to run with all of the reporting requirements.
PEM isn't simply "more intense fatigue after more intense exertion".
The exhaustion is out of all proportion to the effort. It's often delayed, involves multiple symptoms like the sickness/flu-like feeling, muscle or other pain, fatigue and worsening of other symptoms and lasts for a long time.
Like I mentioned before, autoimmune diseases among other symptoms also present in ME like fatigue, can have post exertional symptom exerbation, which as a difference to PEM isn't delayed, mostly not that long lasting and has a lesser amount of different symptoms.
I didn't want to attack you or to invalidate your experience, what I wanted to ask is if you can be sure that you didn't experienced those symptoms due to the autoimmune neuropathy BEFORE your symptoms of orthostatic intolerance occurred.
But that's not my point, my point is you can't claim that IVIG helped your ME if you have autoantibodies indicating autoimmune neuropathy, an illness where there is (low-grade) evidence that IVIG may help.
And I'd argue that at least in your case with positive autoantibodies against TS-HDS in the blood, you can't make the argument that it's maybe the same as ME, I am pretty sure we would know by now if this was something that is really common in pwME. Afaik it isn't exactly a routine test, but after all Flugge/Mella and especially Scheibenbogen have searched for all sorts of autoantibodies in the blood of their ME patients for years and I sincerely hope and believe they would have noticed this.
Like I said my biggest takeaway from your story is the importance of looking for possibly treatable comorbidities and I am really glad you had the opportunity to find one and treat it.
Yes that would have been smart and you were definitely right in your arguing with him. Also he could at least have a waiting group or a 'usual care' control, because many people recover in their first year of Long Covid.
Among small case studies of 2-3 people the only bigger study he has published to date on Long Covid is this retrospective one with 33 participants:
https://www.sciencedirect.com/science/article/pii/S1566070224000493
And my problem would be less with the study itself, it's understandable if he has no money there, but with what he makes of it.
Of 33 persons 10 were deemed as long term responder (1 month). He excluded persons with pre-existing ME, POTS as well as fibromyalgia. He did no personal follow-up except for the questionnaires at 1 months.
The problem is despite these in my humble opinion, sobering results, he went on the public Stanford symposium for ME and declared it a promising treatment. One thing is the mediocre result in Long Covid patients, another thing is the presentation of this treatment at an ME conference when having absolutely no data about it in this illness.
I had those things! Muscle aches in parts of my body that I did not exercise. Headaches, sore throats, and brain fog that came on within a day or so delay after exercise. Sorry that I did not list exhaustively every symptom that I had in my original post. Fatigue was the most debilitating, so that's what I focused on. But I also had the more unique-to-ME things. It was already getting very long and I blocked out that part of my life because it was so painful. Another thing, to be honest, that I blocked out was the dynamics of these online patient communities, and the skepticism that mild people encounter that they were ever really sick. But yes, I had these symptoms.
I can't be sure, and neither can you or anybody else, because none of these diseases are well researched, diagnosed, or even diagnosable enough. Autonomic neuropathy is not even directly observable when a patient is alive, because you can't biopsy autonomic nerve fibers without killing somebody and dissecting them. You can only infer it indirectly through a skin punch biopsy, which analyzes sensory nerve fibers, which are related to autonomic nerve fibers in that they're peripheral but are a bit different as I understand. And by the way, my skin bunch biopsy came back borderline negative – the neurologist had to make the case that I had it due to my age (like, it was within the reference range, but she found some study suggesting that the reference range was overly conservative for somebody in their 30s). And I asked later if we should redo it and she basically said no, these tests aren't that reliable anyway, the only purpose was to get insurance approval and now that we have it, we don't want to risk doing it again and it being negative. Just to give you an idea of how unsettled the science around SFN is.
I wrote my post to try to avoid making strong causal assertions. If you reread it, you'll see that I state the sequence of events. It's impossible to not come up with causal theories about your own life, so yes, I think it was critical to the recovery, but nobody's story is ever going to be that convincing. There's just no way around the fact that you have to run a RCT and/or have a deep biological understanding that we don't have.
As for low-grade evidence that IVIg may help SFN – it's so low-grade that there's a consensus statement advising against it, in fact! Insurers and doctors have somehow been friendlier to prescribing IVIg to people with immune-mediated SFN, but I think you're taking that fact and making an unwarranted leap about the evidence base. I don't think the evidence that IVIg helps SFN is that much stronger (if at all stronger!) than the evidence that IVIg helps ME/CFS. I think the reason there's more friendliness among insurers and neurologists to prescribing IVIg is because there's a bit stronger of a basis for diagnosing SFN. But as far as I know, there's no RCT, just a bunch of case studies – which we actually also have for ME!
As for evidence of SFN undercutting an ME diagnosis – tons of ME-diagnosed patients have this! Same with ME-diagnosed patients and POTS diagnoses.
I actually took two autoantibody tests. The first time, with CellTrend, it was positive for TS-HDS and negative for FGFR3. The second time, with WUSTL, it was the opposite. Which is to say, these autoantibodies are fickle and not indicative of much other than that an insurer might approve IVIg for you. The neurologist I have dealt with have been pretty clear that none of this is well understood and all of this is a bit of a game with an insurer. So I disagree with your pretty categorical assumptions of what this all means – that I definitely have SFN, that other people with ME definitely don't, etc.
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Dude
Senior Member (Voting Rights)
During the filming of the documentary Perversely Dark, Kristine, who had been completely bedridden and living in total darkness for six years, entered a remission phase in 2013 after receiving immunoglobulin treatment. The film’s second protagonist, Björnar, also received immunoglobulins, but they did not help him.
Source: Instagram – video
Source: Instagram – video
Dude
Senior Member (Voting Rights)
It’s quite fascinating, especially because Jonathan mentions it quite often. I just read a little about the history of rheumatoid arthritis, and it made me think that there are actually some interesting parallels.
Could ME/CFS be similar to rheumatoid arthritis, where rituximab doesn’t always work because autoantibodies continue to be produced by long-lived plasma cells, and therefore targeting these plasma cells directly, for example with daratumumab, might work better?
Sorry if this question has already been asked many times. I just find RA really interesting at the moment.
All the anecdotal reports do make it seem to me that there might be a subgroup of patients who could respond to this kind of treatment. The big question is: how do we identify them?
Could ME/CFS be similar to rheumatoid arthritis, where rituximab doesn’t always work because autoantibodies continue to be produced by long-lived plasma cells, and therefore targeting these plasma cells directly, for example with daratumumab, might work better?
Sorry if this question has already been asked many times. I just find RA really interesting at the moment.
All the anecdotal reports do make it seem to me that there might be a subgroup of patients who could respond to this kind of treatment. The big question is: how do we identify them?
Jonathan Edwards
Senior Member (Voting Rights)
Actually, rituximab reduces autoantibodies pretty well in most cases of RA. The few that do not respond are mostly people with irreversible damage in my experience.
But yes, the analogy with diseases like RA is what got Fluge and Mella started and the question about long lived plasma cells is very relevant to lupus and scleroderma and has been the main motivation for the Norwegian programme for the last 10 years.
'Might' is doing the heavy lifting though. Remember that there were 'anecdotal reports' of people 'responding' to placebo in ritux phase 3.
Dude
Senior Member (Voting Rights)
Interesting topic either way.
Was it similar with RA, was rituximab tested before it was really known whether B cells were driving the disease, or was there already stronger evidence for the mechanism?
And regarding Mecfs, if daratumumab works in a subgroup of patients but not in others, how would that be evaluated in a clinical trial? At what point would a study be considered positive if only a subset of patients responds?
V.R.T.
Senior Member (Voting Rights)
The dara pilot was considered positive but only half of patients had a large sustained improvement. 4/10 had no improvement at all.
Dude
Senior Member (Voting Rights)
The new study is double-blind, right? I imagine that makes things more difficult if some of the participants are unlikely to respond to the treatment.
V.R.T.
Senior Member (Voting Rights)
Double blind, 44 patients get drug 22 placebo iirc
Dude
Senior Member (Voting Rights)
That helps me clarify my question. Let’s say, for example, that half of the 44 patients show a meaningful improvement. Would the study be considered positive because there appears to be a responder subgroup, or would it still be considered negative because a certain overall response rate is required?
V.R.T.
Senior Member (Voting Rights)
It's occurred to me that the drug group might be double the placebo group to counterbalance this issue?
Jonathan Edwards
Senior Member (Voting Rights)
Jo Cambridge and I worked out the RA was totally B cell dependent, contrary to all thinking at the time (our hypothesis article was rejected by the Lancet on the grounds that there was a perfectly good T cell theory (based on misreading of some of my earlier work by others)). We proposed using rituximab in a review article explaining why we thought it might produce benefit. We got things slightly wrong, but it didn't really matter. It took me two years to persuade the drug company to let me try it (I had to buy the drug though). It worked very nicely. We then tried lupus and it worked nicely. We did a big phase 3 trial to prove it for RA. From then on people used it for just about any autoimmune disease you can think of.
Utsikt
Senior Member (Voting Rights)
It would all depend on the control group. If there is no difference compared to the control group, none of them should be classified as responders.
The lower limit for what can be classified as a success would depend on the statistical power. If you have enough participants, a minuscule difference between them can produce a low enough p-value. You’d also need the difference to be large enough to pass the threshold of clinically meaningful.
It depends on the response rate in the drug group and in the placebo group (x people out of 44 vs y people out of 22, if as per the trial design 44 people get the drug and 22 get the placebo). You compare these two fractions (x/44 and y/22) calculating if they are statistically different from each other with 5% significant level test statistics (using a two proportion Z-test). So the answer to the question “how many people should respond to the drug in the drug group for the trial to be successful” depends on the placebo response rate (which is also an unknown factor).
So let’s assume 50% people respond to placebo (11out of those 22). If the AI has calculated that correctly, at least 34 people among those 44 who are given the real drug must feel the positive effect for the trial to be successful. In trials for autoimmune conditions though the placebo response rate is usually 20-40%. Don’t remember the response rate in the Rituximab study for ME/CFS, though.
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This is pure speculation, but could it possibly also be that pharmaceutical companies have started to set the threshold for ‘responders’ as low as possible in general?
Given a drug has an advantage over placebo, investors will surely be more excited the bigger the responder rate is.
Now, if you raise the number of people classified as responders through lowering the threshold both treatment responders and placebo responders will increase - the former would excite investors as this means more people to sell the drug to, whilst the latter would be of little interest to them as long as the drug is deemed effective.