Antibodies to ß adrenergic and muscarinic cholinergic receptors in patients with CFS

[Misfit Toy]

To stop autoimmune problems with drugs like this you need very high immune suppressing doses. Which is very damaging over time. How many know that drugs like this were the first line of treatment in some parts of the world in the late 70s? My aunt got something that I would call CFS after contracting Ross River virus (we lived on the banks of that river!). She was on high dose cortisol until they had to stop treatment due to side effects. These treatments suppress the problem, but do not eliminate the problem.

PS Low dose use of these kinds of drugs have hormone replacement effect, not immune suppression. Its a different use of the drug.

I'm on low dose prednisone and my Sjogrens pain is way less. My fatigue is not...but pain is better.

Also, Ritux doesn't stop the problem either. It only stops it as long as you are on it. It's not a cure.

 

[beaker]

I'm on low dose prednisone and my Sjogrens pain is way less. My fatigue is not...but pain is better.

Also, Ritux doesn't stop the problem either. It only stops it as long as you are on it. It's not a cure.

Actually, ritux can last long after you are off of it. It can put you in remission. Sometimes very long term. How it was explained to me ( and my memory sucks, so this is completely simplified )

That B cells have memory. It is the memory of the B cells that get triggered to remember that something needs to be attacked-- the anti bodies and in this case presumably auto antibodies. . If you can wipe out the B cells w/ the memory or enough of them, they won't attack anymore. The new ones being grown in the marrow will hopefully not get this memory, because no one will be around to give it to them.

 

[anciendaze]

Could someone who has kept up with Lipkin's work tell me if any of these autoantibodies would have been exclusionary conditions for the cohort he considers the "gold standard" for ME/CFS? I seem to recall that thyroid problems and elevated TPO would have been one of these. In that case it would be quite difficult to use that cohort to replicate this kind of finding. Some specialists in this disease report up to 85% of patients with thyroid abnormalities. If any other autoantibodies were used as exclusionary conditions, the result would be a cohort in which it was hard to detect anything remotely similar to this.

If my suspicions are correct, this is what comes of trying to avoid criticism from people who have totally failed to advance this research for the last 30 years. The researchers who published this new work have essentially abandoned diagnostic criteria promulgated by the U.S. and U.K. governments, except for the Fukuda definition, which could mean anything. Fortunately, they have not waited to see if SEID will mean anything when a useable clinical definition becomes available.

 

[adreno]

There are both activating and inhibiting autoantibodies, do we know anything more about the ones found in the paper?

 

[Jenny TipsforME]

This seems like actual progress! A couple of initial thoughts (without access to the full paper):

29% is a similar amount to the subgroup Julia Newton found with ME and POTS. I'm confused about the 8 people they had POTS data on. Was it only half (4) who had POTS or 4 who responded? Given the relationship with autonomic function and these autoantibodies it would seem really useful to get the autonomic data for more /all participants. Does anyone know if this is a planned follow up study?

Also in the meantime, until rituximab is available outside of a study, are there any other practical things we can try/avoid that may help? I'm just starting to try inosine for example, would that bear any relation to these findings?

When I go for my follow up POTS appointment if I mention this study will the cardiologist look at me weirdly, or will he go "ah yes if that's the possible cause such and such would be better than bisoprolol"? There are different causes of POTS. Does anyone know if there are other treatments specific to autoantibody triggers? Eg would you be looking more at the adrenergic side rather than blood volume?

 

[Forbin]

It would be interesting to know if these markers of autoimmunity are present at the onset of ME, or even before. Many people report developing ME virtually over night, sometimes within an hour. It seems like there is often some kind of dramatic tipping point in the evolution of ME.

Finding out just what is "tipping" would probably require some kind of surveillance, like the Dubbo study in Australia, only with blood being stored for the future analysis of those who come down with ME.

 

[BurnA]

Can someone explain what this means specifically in relation to POTS. ?

My interpretation of this is that of 8 patients they had data on, 4 had POTS, 4 didn't and they only found elevated autoantibodies in 2 of the 8 and these 2 didn't have POTS.

So i think it is saying they have not found a link to the symptom of POTS ?

Am I the only one who is surprised they only have data on 8 patients ? You would think they at least would know all the patients in the Norwegian trial if they had POTS or not ?

Would be nice to know if there were more or less responders amongst the 4 who had POTS or the 4 who didn't, even if the numbers are small.

 

[alex3619]

There are both activating and inhibiting autoantibodies, do we know anything more about the ones found in the paper?

I don't think so, but I have a suspicion that we might be talking about activating muscarinic receptors. Just a hunch, my brain is not working too well right now. I might also be wrong. We need to look more closely at what symptoms are caused, and whether we have more or less of those, receptor type by receptor type.

 

[alex3619]

It would be interesting to know if these markers of autoimmunity are present at the onset of ME, or even before. Many people report developing ME virtually over night, sometimes within an hour. It seems like there is often some kind of dramatic tipping point in the evolution of ME.

Finding out just what is "tipping" would probably require some kind of surveillance, like the Dubbo study in Australia, only with blood being stored for the future analysis of those who come down with ME.

My best guess, and its only a guess, is that the answer is yes. We have the B cells producing the autoantibodies, just in low numbers. Some illness comes along and puts a huge oomph on B cell replication. Something goes wrong and B cells that should not be multiplying get caught up in the chaos.

This of course presumes that these autoantibody findings are important, and its still too early to be sure.

 

[deleder2k]

I'm on low dose prednisone and my Sjogrens pain is way less. My fatigue is not...but pain is better.

Also, Ritux doesn't stop the problem either. It only stops it as long as you are on it. It's not a cure.

That we don't know yet. Several patients are in remissions after 5 years without Rituximab. It looks like some of them are cured.

Edit: quoted the wrong post. Fixed it now.

 

[anciendaze]

Incidentally, the idea that the Norwegian researchers happened on a lucky fluke when they noticed patients recovering from both leukemia/lymphoma and CFS after treatment with rituximab is misleading. This has happened in the U.S. at about the frequency you would expect given the incidence of these diseases. There has been no follow up here.

 

[Scarecrow]

Incidentally, the idea that the Norwegian researchers happened on a lucky fluke when they noticed patients recovering from both leukemia/lymphoma and CFS after treatment with rituximab is misleading. This has happened in the U.S. at about the frequency you would expect given the incidence of these diseases. There has been no follow up here.

Yes, it was the patients that noticed it as I'm sure they have done all over the world. But it was the Norwegian doctors who took them seriously.

 

[msf]

Do we know if any diseases can be cured with Ritux? I know cancers can be put into remission, but how about RA and autoimmune diseases?

 

[MsJustice]

Drawing your attention to the original Ramsay definition of ME; the first ME diagnostic criteria. Under Autonomic System, one of the objective, measurable signs (not just a symptom, like most of the CFS diagnostic criteria), is orthostatic tachycardia. Also, circulatory symptoms. Ramsay was right. Still the best criteria, in my opinion. The others are in danger of drifting away from the original entity and this as well as having a sign, which can be tested for, also defines muscle fatigue, more than generalised fatigue. Just sayin'!

http://www.cfids-me.org/ramsay86.html

 

[leokitten]

The most interesting remarks I found in this paper are these:

Similar to our findings, in most other diseases autoantibodies are found in only a subset of patients with a wide overlap of levels in patients and controls.

This, of course, does not exclude other autoantibodies (not investigated in the present study) with functional activity in CFS.

There is evidence that a subset of patients experienced major distressing life events before CFS onset and that CFS is frequently triggered by an infection. Thus it is tempting to speculate that chronic adrenergic stimulation may lead to conformational changes of receptors resulting in more immunogenic epitopes and that infection-triggered immune activation induces the autoantibody response.

The main reservation I had at first about this study is that yet again they only find a possible biomarker in a subset of less than 50% of patients. But the authors show us that even in clearly defined autoimmune diseases we only find autoantibodies in a subset and levels do overlap controls.

This study is also beginning to shed light as to why non-responders aren't responding, that it likely isn't because they have a completely different pathophysiology (e.g. chronic infection) but that rituximab treatment did not effectively reduce autoantibody levels.

This paper is a good first step towards biomarker discovery working on Fluge/Mella's theory and samples from their rituximab trials, bravo. I know I've said it a million times, but my opinion as a scientist is that we desperately need a lot more research in this area. I think the major American research groups need to take note that they are spending zero resources on studying the autoimmune pathophysiology of ME/CFS and this theory is not only the quickest and most promising path to effective treatment but also the quickest path to validation that this is a real disease. We patients need this.

The chronic infection theory, in my personal opinion, if it even pans out at all, will only be relevant for a small subset and one could argue that this subset isn't really even ME/CFS, it's an infection by a particular pathogen (e.g. Lyme, Chagas, etc). As we have seen in so many examples, post-Ebola, post-polio, post-sepsis, West Nile induced myasthenia gravis, likely many cases of post-Lyme, and more, that the infection isn't there anymore but it helped to trigger a disease that's now completely driven by the immune system. This is fundamentally different than having a chronic infection and therefore a different disease. Also, when one does pick up infections or has reactivations after their immune system goes into this autoimmune and dysfunctional state we need to make clear that while this does contribute to symptoms it most certainly isn't part of the core pathophysiology of the disease.

It's the immune system, stupid.

 

[anniekim]

We provide evidence that 29.5% of patients with CFS had elevated antibodies against one or more M acetylcholine and ß adrenergic receptors which are potential biomarkers for response to B-cell depleting therapy. Th

I apologise but this paper and discussion is way over my head but in very simple terms is this paper saying out of the 268 CFS patients whose blood was looked at only 29.5% showed elevated antibodies and of those not all responded to the x number of rituxamab infusions? So that would mean 70% of CFS patients this area of research is of no relevance? Nearly 30% is still significant of course but 70% is still a high number. Or perhaps it's the 70% could be still having auto immune problems but not in the area these researchers were looking at? Many thanks

Ah, I posted this before seeing Leokitten's post so perhaps the paper is saying it's too early to say if the 70% whom do not have elevated auto anti bodies are not a separate disease group. I think I will stop writing now. This is way all above my head

 

[leokitten]

For those in this thread who mentioned targeting of plasma cells, this has been discussed at length here on PR, e.g.:

http://forums.phoenixrising.me/inde...-lessons-from-b-cell-depleting-therapy.37229/

An anti-CD319 (e.g. Elotuzumab) or anti-CD269 (anti-BCMA) would have to be used in combination with an anti-CD20 to be effective at completely wiping out all autoantibodies and the feedback mechanism which continues the vicious cycle.

The major caution here is that we don't want to wipe out to much of the immune system and then have to battle opportunistic or other infections.

 

[leokitten]

M4 seems to be a bit ominous. Only found in the brain, seems to be involved in extrapyramidal motor control via dopamine.

This could also explain many of the motor symptoms of ME. Different from Parkinson's, symptoms like constant arm and leg tremors equally on both side of body, motor clumsiness and missing targets when moving, etc.

 

[Scarecrow]

Different from Parkinson's, symptoms like constant arm and leg tremors equally on both side of body, motor clumsiness and missing targets when moving, etc.

I tend to hit more targets than I intend to when moving and have the bruises to prove it.

 

[Kati]

I apologise but this paper and discussion is way over my head but in very simple terms is this paper saying out of the 268 CFS patients whose blood was looked at only 29.5% showed elevated antibodies and of those not all responded to the x number of rituxamab infusions? So that would mean 70% of CFS patients this area of research is of no relevance? Nearly 30% is still significant of course but 70% is still a high number. Or perhaps it's the 70% could be still having auto immune problems but not in the area these researchers were looking at? Many thanks

Ah, I posted this before seeing Leokitten's post so perhaps the paper is saying it's too early to say if the 70% whom do not have elevated auto anti bodies are not a separate disease group. I think I will stop writing now. This is way all above my head

This is where cohort definition is extremely important. Ideally, there needs to define their cohort and subsets (ie: viral onset, POTS or no POTS, early on in disease vs sick 10 years or more, etc. The larger the cohort, the larger subset numbers, the better . Post exertional relapse needs to be mandatory.