Discussion in 'Rituximab: News and Research' started by deleder2k, Jul 5, 2014.
Sorry to repeat myself, but will the result be accurate from just one blood sample?
Back to the slides. The hypothesis is immensely interesting and I am surely excited. A severely disregulated blood flow by the vascular system would explain a lot of symptoms and findings. OI of course and why most of us feel relieved while lying down. Also the early reach of the anaerobic threshold. If the muscles don't get the necessary amount of blood and thus oxygen, they have to switch energy production to the anaerobic pathway. This builds up lactic acid as an end product. And leads to exercise intolerance and fatigue. The brain needs very small changes in its blood flow constantly to work in proper ways. An impairment could lead to headaches, concentration problems, ataxia etc. It would also cause problems in releasing the right amounts of hormones. Maybe the autonomous nervous system isn't affected directly, but indeed tries to regulate the blood flow with impaired vessels. Maybe the vessels need some month to repair themselves, to build new enzymes and receptors after Retuximab got rid of all the B Cells. This is all highly speculative, but I am intrigued. I ll definitely research further into the topic of endothelial dysfunction and vascular flexibility. This study by the University of Dundee supports the idea of highly inflexible vessels and endothelial dysfunction. I ll see what other studies I am able to find.
I think the Dundee study may be what got Fluge and Mella thinking about this...they did mention it...
Ok. Lets do some problem solving. If the problem lies in the endothelial function, is there anything worth trying to ease our symptoms?
The following study is about acute vascular endothelial inflammation, but it's a start.
Also cope with my apparently circular reasoning, niacin is used to lower cholesterol, statins are the lipids lowering drugs of choice and in recent years there has been anecdotal evidence that a statin at very high doses works as a DMT (disease modifying therapy) in certain cases of MS and finally ME as per CCC/ICC has quite some commonalities with MS and really lastly Rituximab has been used in small clinical trials for MS with great success.
If I remember correctly all of Fluge and Mella's patient in the phase II trial were selected/referred by neurologists. A fact that is IMHO very important.
I'm just throwing a lot to see if we can come up with something useful and translatable for PWME.
Does anyone know if there is further research happening in this area? That Dundee study was two years ago.... Are they following it up? It also seems to me that it is really important to look at impaired endothelial function as not just about cardiovascular risk.. I guess one of the problems is that researchers looking into this area will probably have a background in cardiology...
I thought this was pretty interesting:
I've wondered why the response to B-cell depletion took so long. If the B-cells were doing something, why the long delay after they were eliminated before improvement was seen? I sort of assumed that the B-cells must have been producing something that lingered after the cells were depleted, but this is the first time I can recall seeing that idea put forth by the researchers in print.
Elsewhere in the paper, they say that "Most change in fatigue are seen between month 6 and 10." They suspect that the B-cells are producing something (perhaps an antibody) with a half-life of 3-4 weeks. In 6 months, that would be a reduction of about 99% of the original amount of whatever it is - though part of the recovery time could be attributed to healing the damage that has already been done.
At any rate, it looks like one of their ideas is that the B-cell autoantibodies are either directly or indirectly affecting the endothelial cells. If so, it would seem that the antibodies would be the root cause as opposed to the endothelial cells, which makes me wonder if just treating the endothelial cells would help.
[Excuse me if I'm just re-stating the obvious here. ]
But this would mean that studying the endothelial cells should be a good place to start, wouldn't it? If the antibodies are indeed affecting our endothelial function, then we should be able to find them there....? Has this ever been done? Is it possible?
I would agree that the endothelium is not the cause, but what if it is the major affected area?? Looking for the process there would make sense to me.
I agree. It would definitely make sense to see if whatever is going on in the endothelial cells can be controlled, which might be a lot more practical than depleting the b-cells. I was just thinking in terms of eliminating the root cause rather than managing the disease.
I think maybe I didn't explain my thinking very clearly!
IMO whatever is going on for most of us does involve our B-cells. But so far the auto-antibody has eluded detection... I was just positing the thought that we might find that antibody in/on the endothelial cells.... I am not aware that anyone has looked for it there. Defining the antibody would be a major step forward if the theory holds true. Treatment might however still involve depleting B cells?
If B-cells attack certain structures in the body (endothelial or not), they would be the root cause of ME as in any autoimmune disease. Maybe the trigger would be a pathogen (like EBV or an enterovirus) or you have a genetic disposition or both (it is quite possible, that there are different types of ME).
The control and regulation of our blood flow is extremely complex, especially on the endothelial level and yet not fully understood. To study the endothelial cells would be possible, but only in a research environment at a university.
I guess, if this is indeed Flugge and Mellas hypothesis, they are going to do exactly that. Finding an epitiop (the structure, the antibodys attack) would be the key to understand the disease (and to find a valid test for it).
I wonder, if they consider trying plasmaphoresis to wash the antibodies out after the retuximab treatment (this works for example with Myasthenia gravis). Has anybody ever done this? Probably not, I guess.
I don't know if you could say that the endothelial hypothesis is in any way related to this, but it I thought it was interesting that a doctor who studied the 1975 outbreak in Sacramento, California called the disease Infectious Venulitis.
Are you sure, the slides are indeed for open discussion?
All the information translated by me is at your own risk. I am not qualified health personnel nor a certified translator. The slides are publicly available through The Research Council of Norway's website.
I just wanted to be sure they are publicly available. Do you know, if Fluge and Mella have already published the results of the second trial, where they treated the last 15 placebo controls with Retuximab?
I went quickly through your translation, and it looks correct. My head did not allow me to understand what I read earlier today, but as I read it now at 1:30am, I must say this is intriguing.
Sorry if this is a silly question, but if they manage to discover an antibody - do you guys think one could develop a medicine that can directly attack and eliminate the antibody and get a more or less immediate result?
I do, I am happy with my vassoconstrictor. I use midodrine + florinef and I am happy so far, still working full time and have a pretty normal live (with limitations and need to PACE).
In a randomized phase II study of rituximab two infusions two weeks apart versus placebo in 30 patients with chronic fatigue syndrome, we then completed an open-label phase II study 28 patients received rituximab induction and maintenance therapy, a total of 6 infusions over 15 months.21 patients (72%) had response to defined criteria, 18 patients (64%) had clinical significant improvement in most CFS symptoms.Duration of response within 36-month study period, the mean 108 weeks for 14 major responders and 68 weeks for 4 moderate responders, and 11 are still in response at 36 months follow-up.Side effects: two with allergic reactions, two with upper respiratory tract infections, uncomplicated two with late-onset neutropenia.
Tried to find out more about midrodrine, but it seems that its not available in Norway... :/
I will begin on propranolol tomorrow. Either 40mg x3 or 80mg x3. I am also considering florinef. I guess things that increase the blood flow and total volume are good according to Fluge's and Mella's hypothesis?
I am also considering trying Cialis every day for a month, as it should increase blood flow in persons with dysfunctional endothelial dysfunction.
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