Rituximab study in norway. An application to The Research Council of Norway

[DanME]

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 guess no. There are several antibodies used in treating autoimmune diseases. Retuximab is one of them and it targets B-Cells. Other target different cytokines like TNF-alpha and IL-2, slowing down the immune system and interupting inflamation. I guess the problem would be, that all the B-Cells would constantly produce more antibodies. It wouldn't help much. But if they identify an antibody, we would have a proper test and propably a good understanding of the underlying pathology of ME.

 

[Seven7]

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.

Do not start both at same time. Florinef did not give me any side effects, maybe raised my BP (I had it low) so you can monitor. DO NOT start at the dose prescribed start slow and increase slow, I see so many people not to do well because they went full force, I started half a pill for 3 days, then one pill.

Propranolol : Some people do well on beta blockers but it causes fatigue so keep a close eye.

With these you will have an increase energy intermediately, try not to give in so you can set aside what is side effects Vs crash symptoms, Your crashes symptoms will change and will have new patterns. Go slow and low. Good luck.

 

[daisybell]

I have just been reading about ANCA on the internet, having been looking at information about the endothelium, and have come across the notion of ANCA-reactive B cells. If the endothelium is dysfunctional in ME, then perhaps these B cells might be the culprit?

@Jonathan Edwards would you be happy to comment?

 

[Forbin]

I will begin on propranolol tomorrow. Either 40mg x3 or 80mg x3.

For myself, I would make a note of my resting pulse prior to taking propranolol so as to be able to more accurately judge any difference after treatment begins.

I took propranol very briefly many years ago but had to stop because it dropped my heart rate into the low 40's - and sometimes lower. When I came off of propranolol, my heart rate rose into the low 50's, which was the first time I can remember noticing that my resting rate (without propranolol) was that low.

 

[deleder2k]

My resting rate when I wake up in the morning is in the lower 60's. I have tried 20mg propranolol several times, and been using it regular for a week now to get ready for 40mg x3. It definitely helps with orthostatic intolerance. But i need something to fix my legs. Pain and cramps destroys my sleep. Feels like the blood can't pass the blood vessels.
I got some Cialis, maybe I should try them for a week. They should increase NO.

 

[Sushi]

My resting rate when I wake up in the morning is in the lower 60's. I have tried 20mg propranolol several times, and been using it regular for a week now to get ready for 40mg x3. It definitely helps with orthostatic intolerance. But i need something to fix my legs. Pain and cramps destroys my sleep. Feels like the blood can't pass the blood vessels.
I got some Cialis, maybe I should try them for a week. They should increase NO.

Compression knee socks can help with leg discomfort during the day. You can't wear them at night but getting the blood "pushed back up" during the day, might help with the pain at night. They make all styles and levels of compression. The good ones are very comfortable and look just like ordinary socks. I have some that are mostly cotton.

Sushi

 

[Sasha]

@Sushi, what make are your socks?

 

[deleder2k]

I have compression knee socks, but I am not sure if they help or not. I was operated a few months ago and was forced after the operation to stay in bed for 5 days without moving. They supplied me with compression tights that I had to wear for 5 consecutive days without taking them off. They were tight as hell. It was given to prevent thrombosis. Maybe I should try that instead.

 

[Sushi]

@Sushi, what make are your socks?

I get this one.

Sushi

 

[Jonathan Edwards]

I have come across the notion of ANCA-reactive B cells. If the endothelium is dysfunctional in ME, then perhaps these B cells might be the culprit?

@Jonathan Edwards would you be happy to comment?

I have just seen this thread and see there are a number of interesting suggestions maybe worth commenting on.

ANCA are the autoantibodies found in vasculitis. It is likely, although unproven, that by binding to antigens on neutrophils (ANCA= anti-neutrophil cytoplasmic antigen) they activate the cells and cause binding to and damage to endothelium. I don't think these are going to be relevant to ME, where there is no structural change in blood vessels. I think that Oystein Fluge's idea about antibodies targeting endothelium is very interesting but it would be in a more subtle way.

As with 'inflammation' I would make the point that 'endothelial dysfunction' can mean any of a hundred things. Don't start joining up ideas just on the basis of 'endothelial dysfunction' even if that's what people are doing in articles. Fluge is interested in a very specific and subtle form of dysfunction (which just means not working quite right) associated with nitric oxide signalling.

The idea that there might be an easier way to get at an endothelial problem than rituximab, even if the problem is due to antibodies, is certainly something Dr Fluge has mentioned he is interested in. I think he would be happy for me to say that both of us agree that rituximab may be more important as a way to work out where to look for simple effective treatment rather than the ultimate answer to how to treat a subset of ME. It would also make sense to try to get rid of just the antibodies affecting endothelium (if they are) but this is a problem we are faced with all autoimmune diseases that respond to rituximab - we do not know how to get rid of specific types of antibody - all we can do is shut down new production of all antibody-producing cells.

Some of the other queries we have discussed on the thread with my name in it. The reason why it takes a long time for autoimmune diseases to improve after rituximab is that the antibodies are not actually produced in bulk by B cells but by daughter plasma cells that are not directly killed by the rituximab. You have to wait not only for antibody level to fall by their half life (maybe a month) but also for the plasma cells to drop out according to an even longer half life, which looks to be about 3 months for autoimmune plasma cells. One lucky factor is that plasma cells making useful antibodies tend to have half lives of years - we don't know why there is a difference.

I will look back through to see if there are more points to reply to.

 

[Jonathan Edwards]

Another point is the use of plasmapheresis. This removes all antibodies and so is even less specific than rituximab turns out to be but it does have the advantage of working within days. It has been tried in patients with CFS/ME but only very few and the results are not interpretable as far as I can see. Plasmapheresis is not without problems and on its own will produce effects that will last for not more than a month or so, so I don't think it is a practical solution even if it might provide more scientific evidence.

A good question someone asked was whether we might be able to find antibodies to endothelium stuck on the endothelium. Unfortunately, this is unlikely. In some disease antibodies form complexes with their antigens that build up huge latticeworks or precipitates in the basement membrane of blood vessels. This is called immune complex deposition and the complexes can be found in the tissues using stains that bind to the antibody. This is how we came to understand the nephritis of lupus. However, if a handful of antibody molecules bind to antigens on a cell surface and cause it to malfunction there is no way you can see these antibody molecules amongst the millions that are in the plasma next to the cell surface anyway. Put it this way, if you look in a tin of paint you cannot tell if the paint is 'sticking' to the inside of the tin or not - there's just lots of paint. On the other hand if it's an old tin of paint and some has congealed into big lumps on the underside of the lid, you can. So in RA, for instance, we think tiny complexes of antibody are causing inflammation but you cannot see them amongst all the other antibody around, but in lupus the big deposits show up.

 

[daisybell]

Many thanks for your comments @Jonathan Edwards
I appreciate so much your interest and willingness to answer our questions.

 

[IreneF]

I have just seen this thread and see there are a number of interesting suggestions maybe worth commenting on.

ANCA are the autoantibodies found in vasculitis. It is likely, although unproven, that by binding to antigens on neutrophils (ANCA= anti-neutrophil cytoplasmic antigen) they activate the cells and cause binding to and damage to endothelium. I don't think these are going to be relevant to ME, where there is no structural change in blood vessels. I think that Oystein Fluge's idea about antibodies targeting endothelium is very interesting but it would be in a more subtle way.

As with 'inflammation' I would make the point that 'endothelial dysfunction' can mean any of a hundred things. Don't start joining up ideas just on the basis of 'endothelial dysfunction' even if that's what people are doing in articles. Fluge is interested in a very specific and subtle form of dysfunction (which just means not working quite right) associated with nitric oxide signalling.

The idea that there might be an easier way to get at an endothelial problem than rituximab, even if the problem is due to antibodies, is certainly something Dr Fluge has mentioned he is interested in. I think he would be happy for me to say that both of us agree that rituximab may be more important as a way to work out where to look for simple effective treatment rather than the ultimate answer to how to treat a subset of ME. It would also make sense to try to get rid of just the antibodies affecting endothelium (if they are) but this is a problem we are faced with all autoimmune diseases that respond to rituximab - we do not know how to get rid of specific types of antibody - all we can do is shut down new production of all antibody-producing cells.

Some of the other queries we have discussed on the thread with my name in it. The reason why it takes a long time for autoimmune diseases to improve after rituximab is that the antibodies are not actually produced in bulk by B cells but by daughter plasma cells that are not directly killed by the rituximab. You have to wait not only for antibody level to fall by their half life (maybe a month) but also for the plasma cells to drop out according to an even longer half life, which looks to be about 3 months for autoimmune plasma cells. One lucky factor is that plasma cells making useful antibodies tend to have half lives of years - we don't know why there is a difference.

I will look back through to see if there are more points to reply to.

How much variation is there in the B cell and antibody production life cycle? Can a person be a fast antibody producer? I'm asking because I went through the rituximab treatment and had a remission of only 4-6 weeks after about six months. I felt like I might have done better if the infusions were closer together.

 

[Sasha]

IANCA are the autoantibodies found in vasculitis. It is likely, although unproven, that by binding to antigens on neutrophils (ANCA= anti-neutrophil cytoplasmic antigen) they activate the cells and cause binding to and damage to endothelium. I don't think these are going to be relevant to ME, where there is no structural change in blood vessels.

I thought there was some research funded by MERUK (possibly at Vance Spence's unit) showing that blood vessels in PWME are more rigid than normal (I hope someone who knows the literature better than me can provide a reference). Is that different from the sort of structural change that you're thinking of?

both of us agree that rituximab may be more important as a way to work out where to look for simple effective treatment rather than the ultimate answer to how to treat a subset of ME.

That's very interesting - and depending what sort of drugs might do that, perhaps it holds out hope for faster treatment than if we have to wait for Rituximab to jump through all the necessary hoops before it could be approved for treatment for ME (assuming that the "simple, effective treatment" already exists and is seen as less risky than Rituximab).

 

[Jonathan Edwards]

How much variation is there in the B cell and antibody production life cycle? Can a person be a fast antibody producer? I'm asking because I went through the rituximab treatment and had a remission of only 4-6 weeks after about six months. I felt like I might have done better if the infusions were closer together.

A good point. One of the problems with rituximab is that you have to understand why you are using it and exactly what you are trying to do in order to get a reliable result. Everything depends on how long the B cells are depleted for (between 5 and 8 months usually but sometimes 60 months), the rate of decline of autoantibody producing plasma cells (can take 3-9 months or again longer) and the point at which new autoantibody producing cells get going (from 6 to 80 months, always after b cells have come back but you never know when on the first cycle). Whereas using most drugs is like putting the bread in the toaster and pressing the handle, using rituximab is more like making an omelette or stir fry - you have to keep thinking all the time exactly how things are going and adjust accordingly. Otherwise you have raw bits in the middle or everything stuck to the pan.

Unfortunately virtually nobody using rituximab for autoimmune disease is aware of these things. Most clinics treat people on a standard schedule. If that is frequent then you will get a response but at the risk of giving too often - expensive, unnecessary and with a risk of losing useful antibodies. If the frequency is stretched out you will get short remissions and relapses that may last longer. It is a pity but the problem is that most doctors simply do not understand the immunology. (I would point out that the Norwegian team know exactly what they are doing and why.)

Which brings us to the point Sasha picked up on - that if rituximab is this complicated to use optimally then the sooner we can find something simpler the better. A drug that rebalances an error induced by an autoantibody (to say endothelium) directly could work within hours just by taking a pill. It would not produce long lasting remission, but that is probably only going to happen with a small proportion after rituximab anyway. So far it is a mystery exactly what sort of drug one would be looking for, and perhaps it is disappointing that none of the wide range of drugs acting on blood vessels (including viagra!) does the trick. But it is not so surprising. Cells are very complicated and there is no particular reason why the right sort of drug should have been invented by chance. On the other hand remember that viagra was developed in the hope that it would help heart disease!

 

[Simon]

The reason why it takes a long time for autoimmune diseases to improve after rituximab is that the antibodies are not actually produced in bulk by B cells but by daughter plasma cells that are not directly killed by the rituximab. You have to wait not only for antibody level to fall by their half life (maybe a month) but also for the plasma cells to drop out according to an even longer half life, which looks to be about 3 months for autoimmune plasma cells. One lucky factor is that plasma cells making useful antibodies tend to have half lives of years - we don't know why there is a difference.

Thanks, I hadn't seen that before - does it explain why rituximab can have its therapeutic effect while having only a relatively minor effect on protection from infection?

 

[deleder2k]

@Jonathan Edwards, thank you so much for contributing. Are we sure that Viagra/Cialis have no effect at all? They should increase NO, shouldn't they? Are there other drugs that could ease symptoms if we think for a second that Fluge's and Mella's hypothesis is correct?

We know that beta blockers eases symptoms on some. What about medicines that expand the blood vessels? ACE-inhibitors, Moxonidin?

 

[Jonathan Edwards]

Thanks, I hadn't seen that before - does it explain why rituximab can have its therapeutic effect while having only a relatively minor effect on protection from infection?

Yes, if autoimmune plasma cells and useful plasma cells had the same half life then rituximab would be not much use for those diseases where it has to be given repeatedly. For those diseases that can go into long term remission with rituximab (because the signals to generate a new lot of autoimmune cells seem to have been cleared out) it would still work very well.

 

[Jonathan Edwards]

@Jonathan Edwards, thank you so much for contributing. Are we sure that Viagra/Cialis have no effect at all? They should increase NO, shouldn't they? Are there other drugs that could ease symptoms if we think for a second that Fluge's and Mella's hypothesis is correct?

We know that beta blockers eases symptoms on some. What about medicines that expand the blood vessels? ACE-inhibitors, Moxonidin?

I am afraid this is not my field of expertise. Viagra is a phosphodiesterase-5 inhibitor. I am not sure if that has anything to do with NO. ACE inhibitors block the angiotensin system - again not sure if that has anything to do with NO. There are lots of different pathways to vasoconstriction/dilatation and symptoms may be due to changes in vessels of a particular calibre in a particular set of organs. Maybe someone else knows more about this?

 

[DanME]

I did a bit of reading into the topic of the vascular endothelium, NO and the mechanisms of Viagra (PDE5 Inhibitors).

Endothelium:

All blood vessels of the cardiovascular system are lined with one layer of endothelial cells (the lymphatic vessels as well). Interestingly the total weight of all endothelial cells is one kilogram and they cover 4.000 to 7.000 m2 (a bit smaller than a soccer field). Endothelial cells in arteries and veins appear more continuous and thicker than those in capillaries, which are fenestrated and thinner to allow for exchange of metabolites and gases. The Endothelium has a various of functions.
1) It acts as a barrier between the blood and the surrounding tissue, controlling the passage of materials and the transit of white blood cells into and out of the bloodstream.
2) It prevents blood clotting and acts as an non-thrombogenic surface.
3) It regulates constantly the vascular tone by releasing different vasoactive factors like NO, PGI2, EDHF (dilatation) and TXA2, ET-1 (constriction) and thus influences the blood pressure and the blood supply of tissues and organs.
4) Furthermore, it plays also a role in inflammatory processes and growth of new vessels.

Arteriols consist mainly of smooth muscle cells which are highly innervated by sympathetic nerves, allowing the arterioles to regulate blood flow to the tissue by dilating or constricting in response to sympathetic (de)activation. Another stimulus that can cause dilation of arterioles is shear stress (the dragging frictional force exerted on the vessel wall by laminar blood flow). Arteriols are also called resistent arteries.

The role of NO:

Nitric oxide (NO) acts as an endothelial-based vasodilator of the underlying smooth muscles inside the arteries. NO is synthezised by an enzyme called eNOS (out of L-Arginine), which has three isoforms. A neuronal one, nNOS (here NO acts as neuronal transmitter), a macrophage or inducible isoform iNOS, which is only expressed in cells that have been exposed to inflammatory mediators and the endothelial one eNOS. If activated eNOS converts L-Arginine to NO. Sheer stress (or increased blood flow) is able to activate eNOS in order to widen the vessel. Once released NO diffuses into the smooth muscle cells and binds to a specific receptor, which releases a second messenger called cGMP. cGMP reduces the calcium concentration inside the muscle cells and thus relaxes them (calcium is the main messenger of muscular contraction). The mechanisms described above are continuously active and produce NO to maintain a basal vasodilator tone. They are several substances which increase the realease of NO (bradykinin (BK), acetylcholine (ACh), adenosine tri-phosphate (ATP), adenosine di-phosphate (ADP), substance P and thrombin). And several other substances which decrease the releasing.

Viagra

Viagra is a selective inhibitor of the enzyme phosphodiesterase type 5 (PDE5), which disintigrates cGMP. After NO triggers the releasing of cGMP inside the smooth muscle layer, Viagra and other PDE5 inhibitors stop cGMP from degrading. The concentration rises and thus the vessels relaxe stronger and for a longer amount of time. So Viagra prolongs the effect of NO. It is not the trigger of vasodilation, but works as an amplifier. The following smooth muscle relaxation leads to vasodilation and increased inflow of blood into the spongy tissue of the penis, causing an erection. Without sexual stimulation, and therefore lack of activation of the NO/cGMP system, Viagra can not cause an erection.

PDE5 inhibitors are also used in pulmonary arterial hypertension. PDE5 is primarily distributed within the arterial walls of the lungs and the penis. The smooth muscle layers of all the other arteries and veins use PDE3 (another isoform), but also synthezise PDE5 to a smaller amount. Viagra induces only a mild vasodilation inside the peripheral vasculature. The side effects are usually connected to vasodilation (headaches, flushes and a small decrease in blood pressure). An absolute contraindication is the use of nitric oxoide donors like nitroglycerin in combination of Viagra, with the risk of circulatory shock.


Sources:


Use of Sildanafil (Viagra) in Patients with Cardiovascular Disease

http://circ.ahajournals.org/content/99/1/168.full


The Endothelium and Its Role in Regulating Vascular Tone

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3040999/

and Wikipedia