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

[Joolz]

They're certainly looking in the right place and its a sizeable sample which is good.

The total number of patients is high, but it's only 25 patients from the Rtx trial. From an open trial, that is.

This does not identify responders and nonresponders. What it does is show that patients with particular autoantibodies may respond. The fact that nonresponders did not show an antibody decline might however mean they are justified in repeated treatment until they do respond.

Yes, you're right about repeated treatment, at least from my layman's perspective However, treatment of those with low antibodies is just as justified as it is for those with high antibodies - from the figure, around 50% of Rtx responders didn't have elevated β2 antibodies in the first place!

However, if it proves possible to select cases for rituximab based on data like this then that makes a huge difference to getting a therapeutic programme of the ground. One of the most important brakes on the programme is the worry that treatments like rituximab would have to be used hit and miss in a condition that is hard to pin down diagnostically and that may include people for whom this is the wrong approach. Take away that worry and treating ME by B cell targeting begins to look much more similar to lots of other diseases.

We don't really get any information about for whom Rtx might work out of this paper, do we? We get a hint on what Rtx might be doing for those who do have elevated antibodies, but we don't get any information on who might respond to Rtx based on the specific antibodies they tested?

I'm not saying this piece of research isn't encouraging! I'm just thinking that some people might get discouraged when they read mature or less-mature conclusions about strong or not-so-strong correlations. Having read this thread before the paper, I caught myself thinking, damn, my IgG subclasses are quite low (IgG1 and IgG3), so probably I won't have elevated antiautobodies to β2 etc., which means I won't respond to Rtx - that's of course no valid conclusion, so there's hope Maybe I didn't read all the comments properly, but aren't we all a bit egoistic while we're on the hunt for a therapy that cures our very individual CFS? (apart from @Jonathan Edwards, who wants to help all of us at once ;-) )

 

[Freddy]

.... Having read this thread before the paper, I caught myself thinking, damn, my IgG subclasses are quite low (IgG1 and IgG3), so probably I won't have elevated antiautobodies to β2 etc., which means I won't respond to Rtx - that's of course no valid conclusion, so there's hope Maybe I didn't read all the comments properly, but aren't we all a bit egoistic while we're on the hunt for a therapy that cures our very individual CFS? (apart from @Jonathan Edwards, who wants to help all of us at once ;-) )

Hi @Joolz ,

I'm happen to be a patient in their statistics. As a layman I would have thought in a similar way. But: In 2014 I had very low IgG3, and in summer 2015 it was still low, but within normal range. At the same time I had strongly elevated autoantibodies to β2, if I understood the doctors correctly, I'm fighting to win the highscore. Our immunsystem is extremly complex not easy to understand and surprises always possible... @Jonathan Edwards may correct me...

 

[Joolz]

Interesting @Freddy. It's a weird feeling when your lab values are beyond what doctors have seen in their patients before. You're feeling kind of special while you're realizing that something is in fact very, very wrong with your body (in case you didn't notice that before, lol). You're not included in the plasmapheresis trial are you?

Since you're a patient of Prof Scheibenbogen: Does she have any clue why the patients she treated with Rtx (10?) didn't respond? I guess she didn't keep blood samples of those prior to and after Rtx treatment - otherwise they'd be included in the study?

 

[Freddy]

Hi @Joolz,
it's premature to conclude from lab values to the chance to respond to rtx, as far as I understood. You are very well informed. I'm actually part of the plasmapheresis trial, in late february.

Where do you know from, that the german patients did not respond to rtx? More than rumors?

 

[Joolz]

I'm actually part of the plasmapheresis trial, in late february.

Wow, that's so exciting! I'm keeping my fingers crossed. I hope you'll write about the trial here, unless you're not allowed to. How many participants are there? Is it a one-time treatment? Is the protocol available online?

Where do you know from, that the german patients did not respond to rtx? More than rumors?

Rumors, more or less. And I know the Bodden story that is untypical in many ways, but still, poor guy. Do you know more about the other nine? Did none of the patients have the slightest response? Were they all diagnosed according to the Canadian criteria?

Sorry for the OT.

 

[Freddy]

Wow, that's so exciting! I'm keeping my fingers crossed. I hope you'll write about the trial here, unless you're not allowed to. How many participants are there? Is it a one-time treatment? Is the protocol available online?

I even hesitated to mention the trial at all, the Charite people are overrun by patients. In Berlin I will ask what I'm "allowed" to mention publicly. It is of course just a trial. They will try to learn more about pathogenesis.In case I improve, this would be a true secundary illness gain, in a totally different sense than psychiatrist would reason.

If I understand them correctly, the trial is expensive, and possibly not suitable for normal treatment...

I also know the Bodden case, truely sad. I will try to ask them concerning their rtx experience end of february, but they are understandably hesitant to release info.

 

[jimmy86]

Just fyi, I did some labs tests for POTS recently and I got my lab to test for M3 autoantibodies (they do not do adrenergic beta 2 or M4 autoantibodies).

My test result was 3,7, while the relevant range was >10.

 

[Gingergrrl]

So, if you have the typical autonomic symptoms along with antibodies to either N-type calcium channel, P/Q-type calcium channel or Potassium voltage-gated channel VGKC but no antibodies to a3-nAChR, you can still be diagnosed as seronegative (to a3-nAChr) AAG.

@kangaSue Can you explain this in more detail (and I apologize I was not able to read the whole thread in case I missed it.) I have many autonomic symptoms confirmed by testing, and I also have the antibody for the N-type calcium channel (but none of the other antibodies.)

I am just learning that this can imply seronegative AAG vs. everything I am finding on Google which links it to paraneoplastic syndromes or small cell lung cancer.

Do you also have the N-type calcium channel antibody and if so, how did you treat it? If this is not relevant to anyone else, am happy to discuss via PM. Thank you in advance for any info.

 

[kangaSue]

@kangaSue Can you explain this in more detail (and I apologize I was not able to read the whole thread in case I missed it.) I have many autonomic symptoms confirmed by testing, and I also have the antibody for the N-type calcium channel (but none of the other antibodies.)

I am just learning that this can imply seronegative AAG vs. everything I am finding on Google which links it to paraneoplastic syndromes or small cell lung cancer.

Do you also have the N-type calcium channel antibody and if so, how did you treat it? If this is not relevant to anyone else, am happy to discuss via PM. Thank you in advance for any info.

@Gingergrrl, I'm hard pressed to find accurate information myself, none of my doctors have any experience with this and aren't giving much guidance so I'm not sure what the full definition is for seronegative AAG but I believe it to be having at least one of the cation channel antibodies along with other autonomic dysfunction symptoms so I gather you should qualify as seronegative if you haven't tested positive to gAChR Ab.

This is not necessarily linked with a paraneoplastic syndrome and can be restricted to just chronic g.i. dysfunction alone without other autonomic involvement. I know of a couple of others with this in Australia where cancer is not a factor.

I have N-type calcium channel antibodies but only in the normal range.The gAChR Ab test isn't done here in Australia so I've just had some bloods sent to Mayo for testing.

Treatment options are pyridostigmine (Mestinon) and or prednisone, IVIG, plasmapherisis and rituximab

 

[Gingergrrl]

@Gingergrrl, I'm hard pressed to find accurate information myself, none of my doctors have any experience with this and aren't giving much guidance so I'm not sure what the full definition is for seronegative AAG but I believe it to be having at least one of the cation channel antibodies along with other autonomic dysfunction symptoms so I gather you should qualify as seronegative if you haven't tested positive to gAChR Ab.

I agree it is quite difficult to find a lot of info on this stuff or to sort out what is accurate. I will be doing a phone consult next week with the PA who works for the doc who ordered these tests for me and hope to learn more then. I really do not know if I would be considered sero-negative AAG or if I just have a totally separate issue.

I am positive for anti GAD65 antibodies (and really do not know yet at all what this means) and also for the n-type calcium channel antibodies as I mentioned. I do have other autonomic issues (POTS, dyspnea, abnormal sweat to feet/autonomic neuropathy of long-branch nerves to feet?), hypotension, etc.

I did the "PAVAL" panel through Mayo and am negative on everything else including, "AChR Ganglionic Neuronal Ab" and "CRMP-5 IgG" etc. Are these the antibodies that you were referring to?

This is not necessarily linked with a paraneoplastic syndrome and can be restricted to just chronic g.i. dysfunction alone without other autonomic involvement. I know of a couple of others with this in Australia where cancer is not a factor.

The weird thing is that I do not have GI dysfunction as a main symptom- not even remotely. My main symptom is greatly reduced lung capacity and lung/breathing weakness especially when I am orthostatic/standing. My lung cat scan back in Oct was completely clear and no cancer/neoplasm but I've had an abnormal V/Q scan, high PA pressure on an Echo, and failed four PFT tests showing greatly restricted pulmonary functioning (but no interstitial lung disease or fibrosis on cat scan.)

I have N-type calcium channel antibodies but only in the normal range.The gAChR Ab test isn't done here in Australia so I've just had some bloods sent to Mayo for testing.

Can you clarify this re: that you have the n-type calcium channel antibodies but they are in normal range? In my test, all of the other antibodies either said "Negative" or they said "0.00" meaning none were detected. But for the N-type calcium channel one, it had the cut off range at 0.03 and my number was 0.05. There was no range and it strictly said that the antibody was identified and it linked me to one article on paraneoplastic syndromes and cancer .

Treatment options are pyridostigmine (Mestinon) and or prednisone, IVIG, plasmapherisis and rituximab

Do you mean treatments for AAG or for the calcium channel AB? I had a horrible reaction to 1/8 of a Mestinon pill so this is not an option for me. I have never tried any of the other things you mentioned. The docs seem to recommend immunosuppressive therapy but I have yet to learn what this means specifically and will find out next week. I have another doc (who did not run this panel) but is very familiar with it and he thinks IVIG is the better choice. It's all very confusing.

Am glad you were able to send bloods to Mayo for testing. I have a friend in another country who wanted to do this but we were not sure how so hope to learn the details from you. I am in the US, so it was not as difficult (although the average doctor here would have no clue about these tests.)

ETA: Have you ever heard of someone presenting with lung weakness vs. GI issues in these kinds of syndromes?

 

[wastwater]

Does this have something in common with myasthenia gravis

 

[Gingergrrl]

Does this have something in common with myasthenia gravis

Am not sure if you were asking me but in my case, I am negative on the antibodies for myasthenia gravis, myesthenic syndrome and MuSK.

 

[kangaSue]

All my research efforts are based on having mostly chronic g.i. dysfunction so it skews my knowledge of AAG a bit but to quote from this paper http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2837591/ [Autoimmune autonomic ganglionopathy (AAG) is characterized by prominent and selective involvement of the peripheral autonomic nervous system due to an autoimmune process. Patients typically develop generalized autonomic failure including orthostatic hypotension, anhidrosis, and parasympathetic dysfunction. The onset can be acute, subacute, or gradual. Because 50% of cases don't have a finding of ganglionic AChR antibodies, this suggests that the clinical phenotype of AAG, persistent severe autonomic failure, unassociated with ganglionic AChR antibodies could have another underlying autoimmune etiology and may respond to immunotherapy.]

I don't quite know from that whether or not it's implied that one can assume having AAG without having the ganglionic AChR antibodies.

Just to throw something else out there, VGCC antibodies are found in Lambert-Eaton Myasthenic Syndrome, the symptoms of that are quite similar to ME/CFS.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360501

I did the "PAVAL" panel through Mayo and am negative on everything else including, "AChR Ganglionic Neuronal Ab" and "CRMP-5 IgG" etc. Are these the antibodies that you were referring to?

The AChR Ganglionoc Neuronal Ab is found in about 50% of seropositive cases of AAG.

Can you clarify this re: that you have the n-type calcium channel antibodies but they are in normal range?

Mine report says range was under 30, my level was 15 so that would be 0.015. They tested for Myasthenia Gravis too, normal range under 0.50, mine was 0.20.

Do you mean treatments for AAG or for the calcium channel AB?

If it's assumed seronegative AAG, I take it it's still the case to trial immunosuppresion for calcium channel antibody, though could just be steroids though. Mestinon stops the breakdown of acetylcholine so if you don't have ganglionic AChR antibodies I don't suppose it would be of benefit.

I haven't come across lung weakness as a symptom but in all honestly, I wasn't looking for that.

We have a free public hospital system in Australia. My bloods were drawn in the Pathology Dept and they handle all the arrangements to get it to Mayo so I can't advise on the procedure for sending blood overseas.

 

[Gingergrrl]

I don't quite know from that whether or not it's implied that one can assume having AAG without having the ganglionic AChR antibodies.

My guess is that I do not have AAG and I have an illness that correlates specifically with the n-type calcium channel antibodies but that is all I know for sure at this point.

Just to throw something else out there, VGCC antibodies are found in Lambert-Eaton Myasthenic Syndrome, the symptoms of that are quite similar to ME/CFS.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360501

I keep investigating this since LEMS and my antibody are so highly correlated but everything on LEMS talks about it starting with leg weakness and I do not have any leg weakness so I am confused.

The AChR Ganglionoc Neuronal Ab is found in about 50% of seropositive cases of AAG.

So AChR Ganlionic Neuronal Ab is the one associated with AAG? I just want to double confirm that I understand.

Mine report says range was under 30, my level was 15 so that would be 0.015.

My report said it's negative if under 0.03 and mine was 0.05 but it does not give a complete range so I am not sure how high it can actually go. I am not sure if 0.05 is considered low or super high?

If it's assumed seronegative AAG, I take it it's still the case to trial immunosuppresion for calcium channel antibody, though could just be steroids though. Mestinon stops the breakdown of acetylcholine so if you don't have ganglionic AChR antibodies I don't suppose it would be of benefit.

I got respiratory depression from 1/8 of a Mestinon and do not tolerate it at all. I think they will be recommending immunosuppressants but not sure how they can do this without ruling out cancer first.

I haven't come across lung weakness as a symptom but in all honestly, I wasn't looking for that.

No problem and I understand. My lungs are so weak now, it is hard to even inhale a normal breath or talk with a loud enough voice for people to hear me. I just wish I knew why.

We have a free public hospital system in Australia. My bloods were drawn in the Pathology Dept and they handle all the arrangements to get it to Mayo so I can't advise on the procedure for sending blood overseas.

I was just curious for a friend in Europe how this might be done but no worries on this.

 

[kangaSue]

@Gingergrrl, Just reading through the first pubmed paper again that I quoted above, under "Methods" it reads;
[In the absence of a confirmatory ganglionic antibody titer, patients with idiopathic pandysautonomia were required to have the following characteristics to be considered seronegative putative AAG: 1) orthostatic hypotension, defined as a systolic blood pressure reduction of ≥30 mm Hg or mean blood pressure reduction of ≥20 mm Hg occurring within 3 minutes of head-up tilt; 2) significant gastrointestinal symptoms with predominant upper gastrointestinal dysmotility; and 3) severe autonomic dysfunction on standardized autonomic testing]
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2837591/
This is suggesting that if you don't have chronic g.i. dysfunction as a symptom then it doesn't qualify as being AAG in the absence of gAChR antibodies.

Doing a quick read on Lambert-Eatons myasthenic syndrome, the P/Q calcium channel antibodies are the most prominent finding which you would have had tested already with the Mayo PAVAL panel.

 

[Gingergrrl]

@kangaSue I just sent you the PM that I planned to send yesterday, sorry for the delay!

I do have hypotension but I do not have GI symptoms or dysmotility. I do have POTS and other autonomic issues found on TTT and QSART but I do not have the gAChR antibodies. That is why I think I do not have AAG.

I am also negative on the P/Q channel antibodies from the Mayo PAVAL test (which are closest related to LEMS) and am only positive on the N-type (and on the anti GAD65 Ab- whatever those mean?)

Am trying to figure out if my dyspnea and lung weakness are directly from this antibody or another reason (with several other potential problems to be assessed next week.) It's a complete mystery still that I have not been able to solve.

 

[kangaSue]

@Gingergrrl, when you say you have no g.i dysfunction, does that extend to not having a problem with constipation?

 

[Gingergrrl]

@Gingergrrl, when you say you have no g.i dysfunction, does that extend to not having a problem with constipation?

@kangaSue In general I do not have any problems with constipation. There are occasions like when I first added daily fiber/oats to my diet that I had constipation but this resolved in about a week and did not return. With the mast cell disease, I am actually more prone toward diarrhea (sorry for TMI ) but even that is sporadic and not an ongoing problem.

ETA: This is not to say that I do not have problems with my gut/microbiome and am certain that I do, but they do not interfere with my life. What stops me from any real level of functioning are the breathing/lung problems and the MCAS.

 

[kangaSue]

@kangaSue In general I do not have any problems with constipation. There are occasions like when I first added daily fiber/oats to my diet that I had constipation but this resolved in about a week and did not return. With the mast cell disease, I am actually more prone toward diarrhea (sorry for TMI ) but even that is sporadic and not an ongoing problem.

ETA: This is not to say that I do not have problems with my gut/microbiome and am certain that I do, but they do not interfere with my life. What stops me from any real level of functioning are the breathing/lung problems and the MCAS.

It was just asomething to think about as either hypermotility (diarrhea) or hypomotility (constipation) can be accepted as the chronic g.i. dysfunction component for AAG.

Just found this paper finding AAG to occur with N-type Calcium Channel antibodies in the absence of g AChR Ab so I guess it's not entirely out of the question.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739271/

 

[Gingergrrl]

It was just asomething to think about as either hypermotility (diarrhea) or hypomotility (constipation) can be accepted as the chronic g.i. dysfunction component for AAG.

In general diarrhea is not an ongoing problem for me unless I eat something that I do not tolerate with my MCAS or if it is caused by a medication.

Just found this paper finding AAG to occur with N-type Calcium Channel antibodies in the absence of g AChR Ab so I guess it's not entirely out of the question.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739271/

I think I have seen this link but will look at it again to be certain. It seems like not a lot is known about these antibodies and there is a lot of guess-work.