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Lecture by dr Hanne Thürmer - RituxME and current development

deleder2k

Senior Member
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1,129
Lecture by dr Hanne Thürmer, Notodden Hospital

From a lecture given at the local department of the Norwegian ME-association in Notodden, avd Telemark, Norway, February 8th 2016.
Lecturer: Hanne Thürmer, dr. med at Notodden Hospital.

Dr Hanne Thürmer is a senior consultant in the field of internal medicine and cardiovascular diseases, and has been involved in ME since 2009. She is also a member of the Norwegian ME-association’s Board of Medicine.
Here are our notes from the lecture.


It is available here: https://fryvil.com/2016/04/13/lecture-by-hanne-thurmer-notodden-rituxme-and-current-development/

Some interesting points:

The RituxME study takes place at 5 centers in Norway, and at Notodden we have patients from Risør to Drammen. A total of 152 patients in Norway are included in the study.
The drug has been used for 20 years, but we must find out whether it is safe for this patient group. It destroys the immune system.

Query: «Are there serious side effects?»
– MabThera (which is the same as Rituximab) has been used for many years. It’s about the same mortality rate as paracetamol. Cyclophosphamide is stronger, but it does not give as many side effects and can be given to the most severely affected. (It is being researched in another study at Haukeland, not in Notodden.)

Query: «How will the approval procedure be if Rituximab proves to be effective?»
– It’s depends a bit on how clear the effect is. If there still are 70 % who improve, the approval may go quickly. This is easier than if it [the drug] were something completely new.

Query: «What about Rituximab for children?»
– Children will have to wait longer, it’s safer for adults. We do not know enough to give clear answers. But we are generally more careful with children because of growth and vulnerability.

Nitroglycerin can be of help, we are testing this in the study of the endothelial function on a blood vessel in the patient’s arm. It helps some patients while it gives other patients a headache. This is something that can be tested, and it is not expensive! It is a spray under the patient’s tongue. In some patients the effect lasts for 3 days! Usually, the effect passes within a few minutes, but the body of ME-patients do not react normally. It is not dangerous to try out nitroglycerin.
 

TiredSam

The wise nematode hibernates
Messages
2,677
Location
Germany
Good lecture. So is she saying there's no harm in getting a nitroglycerin spray and testing it to see if it helps?

Probably should remember not to smoke at the same time

upload_2016-4-13_16-6-13.jpeg
 

Marco

Grrrrrrr!
Messages
2,386
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Near Cognac, France
Interesting that they're finding both ritux and nitroglycerin helpful. It almost sounds like a kind of antiphospholipid syndrome (including apparent links with lymphoma).

Co-incidentally in the last few days I've noticed for the first time that I have a touch of mottling of the skin (although thankfully it wasn't a sign of 'impending death' as Google first suggested ) which looks awfully like livedo reticularus .
 

ryan31337

Senior Member
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664
Location
South East, England
Nitroglycerin can be of help, we are testing this in the study of the endothelial function on a blood vessel in the patient’s arm. It helps some patients while it gives other patients a headache. This is something that can be tested, and it is not expensive! It is a spray under the patient’s tongue. In some patients the effect lasts for 3 days! Usually, the effect passes within a few minutes, but the body of ME-patients do not react normally. It is not dangerous to try out nitroglycerin.

Funny - I had a tilt test today and was reading up beforehand on Nitrogylcerin as it is often used to provoke a response mid-test by enhancing vessel dilation. I saw that it was a potent NO booster and also came in patch form and thought surely someone should try that... :thumbsup:
 

Sasha

Fine, thank you
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17,863
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UK
Funny - I had a tilt test today and was reading up beforehand on Nitrogylcerin as it is often used to provoke a response mid-test by enhancing vessel dilation. I saw that it was a potent NO booster and also came in patch form and thought surely someone should try that... :thumbsup:

I was wondering if that was the same stuff! I was still OK after about 20 minutes on my TTT so they gave me a squirt of something and I started to faint (but they put me horizontal before I did).

So that's weird... some of us it's helping and some it's hurting?

@Jonathan Edwards, is using nitroglycerin likely to be a test of who is likely to benefit from Rtx, if the people who do well on it have an autoimmune disease attacking the endothelium? Or have I jumped too many logical steps there?
 

deleder2k

Senior Member
Messages
1,129
@Sasha, it looks to me that almost everyone with ME suffer from endothelial dysfunction. Dr. Newton did a study on this: http://www.meresearch.org.uk/our-research/completed-studies/endo-function/

The experience from Haukeland regarding FMD looks to be the same. They conclude that we suffer from endothelial dysfunction. It looks like almost everyone of us has a lower FMD % rate than healthy controls. Since Rituximab doesn't work for all I don't know if one can use the test as biomarker for RTX.

But who knows. Could it be that those who have the lowest FMD in the group of ME patients are more likely to respond from RTX?

We need a cardiologist on this forum. This is a short list of drugs that increase vasodilation:

adenosine, alpha blockers, alcohol, amyl nitrite, histamine-inducers, nitric oxide inducers, l-arginine, THC (?!), theobromine, minoxidil, papaverine, estrogen and apigenin.

I have tried isosorbide mononitrate, glyceryl trinitrate (spray), l-arginine and l-citrulline and alcohol. Alcohol makes me feel almost healthy. My OI is gone when i drink a lot. Muscle spasms vanish. My brain fog and the extreme fatigue almost disappears. The only issue is that I need to drink a lot. After 6 beers ++ things start to happen.

None of the other vasodilators had any effect on me. Perhaps the dosage was too low.
 

Sasha

Fine, thank you
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17,863
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UK
I get migraines and I think vasodilators are supposed to be a migraine trigger. :(
 

deleder2k

Senior Member
Messages
1,129
@Sasha, they can be. I have headaches from time to time, but a single puff of nitrolingual didn't give me a headache. I could feel that something happened, but it didn't really hurt. For longer lasting nitrates like isosorbide mononitrate headache is a pretty common side effect. One start off by talking 30 mg and then titrate the dose. Taking ibuprofen could be helpful for a few days.

A few patients of Haukeland received up to 120 mg Imdur (isosorbide mononitrate) for a while. I think I recall that 4/6 responded favourably. I haven't heard much about it since their patent application was filed.
 

deleder2k

Senior Member
Messages
1,129
Found this:
Most side effects are direct consequences of the vasodilation and the following low blood pressure. They include headache ("nitrate headache") resulting from the widening of blood vessels in the brain, reflex tachycardia (fast heart rate), flush, dizziness, nausea and vomiting. These effects usually subside after a few days if the treatment is continued.[2]
 

Sasha

Fine, thank you
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17,863
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UK
@Sasha, they can be. I have headaches from time to time, but a single puff of nitrolingual didn't give me a headache. I could feel that something happened, but it didn't really hurt. For longer lasting nitrates like isosorbide mononitrate headache is a pretty common side effect. One start off by talking 30 mg and then titrate the dose. Taking ibuprofen could be helpful for a few days.

A few patients of Haukeland received up to 120 mg Imdur (isosorbide mononitrate) for a while. I think I recall that 4/6 responded favourably. I haven't heard much about it since their patent application was filed.

I wish I understood this stuff! It all seems so paradoxical. I'm seeing a cardio for my OI but I don't understand it all well enough to know what to suggest to him. If there's something that's safe, won't give me migraines and that I won't adapt to and be left worse off in the long run, I'd like to try it.

I'm really glad that you've found something that gives you a bit of help!
 

deleder2k

Senior Member
Messages
1,129
@Sasha, I don't understand it either. It is very complex stuff. Did you try to read this: http://www.meresearch.org.uk/our-research/completed-studies/endo-function/ ?


Do also read this:

Our substudy of endothelial function (Bergen Notodden) in 72 patients will use flow-mediated dilation to test large blood vessel endothelial functioning. We will also test microvascular endothelial function in Bergin using skin laser-doppler measurements.


Is a problem in the blood vessels triggering the sympathetic nervous system activation found in ME/CFS?

We believe that endothelial function is important in ME/CFS. Even though many symptoms can be ascribed to the central nervous system we are not convinced that ME/CFS is primarily a central nervous system disorder. We believe the sympathetic nervous activation seen in ME/CFS may be (partly) secondary to an underlying (peripheral) pathology.

It is important to get an understanding of which symptoms that are caused by the primary pathology, and those which may be ascribed to secondary (compensatory) mechanisms. We are working to elucidate whether endothelial dysfunction, and subsequent inadequate fine-tuned autoregulation of blood flow to meet the demands of tissues, may be an important feature of ME/CFS.

A study from Dundee in 2011 showed endothelial dysfunction to be present in ME/CFS. Our pilot studies in a group of ME/CFS patients suggest it is as well.

In the substudy to RituxME, we ask if we can reproduce the endothelial dysfunction in a larger cohort of ME/CFS patients? Is there a relation between endothelial dysfunction and disease severity? Is there a relation between endothelial function and a later clinical response (in the rituximab group)? In patients that improve after B-cell depletion therapy (Rituximab) is there a relation between improvement in self-reported symptoms or in physical activity levels, and changes in endothelial function?

We have written a manuscript on our thoughts and hypotheses including the relation between immune response, endothelial function, and the possible effector system for symptom maintenance in ME/CFS. However, we still believe that we need more data to underpin out thoughts and have therefore not submitted the paper yet.

[Dysfunction of the endothelial cells lining the blood vessels in the circulatory system has been a subject of interest in ME/CFS since MERUK’s pioneering efforts in the early 2,000’s. These cells – present everywhere from largest arteries to the small capillaries – control how dilated or narrowed the blood vessels are, affect inflammation, control blood clotting and more. Each of these factors have been implicated in ME/CFS at one time or the other. In 2012 Newton et al. reported both small and large blood vessel dysfunction was present in ME/CFS.

The finding last year that autoantibodies to the adrenergic receptors found on endothelial cells are present in postural orthostatic tachycardia syndrome (POTS) suggested an autoimmune process was knocking out one group of POTS patients. Now Fluge/Mella appear to be proposing that a similar autoimmune process is messing up the blood vessels and producing the sympathetic nervous system activation in ME/CFS. If that’s so Rituximab’s efficacy could lie in its ability to restore proper blood flows (and presumably blood volume) to ME/CFS patients allowing them to exercise, think, digest, etc. as healthy people do. This is a hypothesis that is pregnant with possibilities.

Fibromyalgia patients should note that Rice has found evidence of small blood vessel dysfunction in the hands that may also be impeding normal blood flows throughout the body. – Cort. ]

- See more at: http://simmaronresearch.com/2015/01...e-rituximab-fluge-mella/#sthash.2qjWDhqM.dpuf

Source: http://simmaronresearch.com/2015/01/chronic-fatigue-syndrome-rituximab-fluge-mella/


The half-life of nitro spray is only 2-4 minutes, so I assume that if you get a headache it will vanish rather quickly.
 

Sasha

Fine, thank you
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17,863
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UK
Yup. Very interesting. The supplement contains something that turns into l-arginine which boosts NO if I am not mistaken. Have you seen this: http://forums.phoenixrising.me/inde...ith-or-without-b-cell-depletion-in-cfs.36592/

I probably can't answer you, but is there anything specific you don't understand?

I saw that thread but I don't understand any of it! o_O I just don't have the biomedical knowledge. A lot of people on the NO2 thread seem to be getting worse with that supplement. It all seems so random whether any of this NO-related interventions make us better or worse. I don't know what to suggest to my cardio (if anything).
 

Marco

Grrrrrrr!
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2,386
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Near Cognac, France
@Sasha
Alcohol makes me feel almost healthy. My OI is gone when i drink a lot. Muscle spasms vanish. My brain fog and the extreme fatigue almost disappears. The only issue is that I need to drink a lot. After 6 beers ++ things start to happen.

Same here deleder but a couple of glasses of wine is enough for me to banish the symptoms. Unfortunately alcohol is such a messy drug (as in it affects so many things) that it's difficult to attribute any benefit to any specific pathway.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
I was wondering if that was the same stuff! I was still OK after about 20 minutes on my TTT so they gave me a squirt of something and I started to faint (but they put me horizontal before I did).

So that's weird... some of us it's helping and some it's hurting?

@Jonathan Edwards, is using nitroglycerin likely to be a test of who is likely to benefit from Rtx, if the people who do well on it have an autoimmune disease attacking the endothelium? Or have I jumped too many logical steps there?

I think you should ask Dr Fluge. He is good at keeping up with jumping logic!