Immunoadsorption to remove ß2 adrenergic receptor antibodies in CFS/ME.

[Murph]

PLoS One. 2018 Mar 15;13(3):e0193672. doi: 10.1371/journal.pone.0193672. eCollection 2018.
Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME.
Scheibenbogen C1,2, Loebel M1, Freitag H1, Krueger A3, Bauer S1, Antelmann M1, Doehner W4, Scherbakov N4, Heidecke H5, Reinke P2,3, Volk HD1,2, Grabowski P1.
Author information
Abstract
INTRODUCTION:
Infection-triggered disease onset, chronic immune activation and autonomic dysregulation in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) point to an autoimmune disease directed against neurotransmitter receptors. We had observed elevated autoantibodies against ß2 adrenergic receptors, and muscarinic 3 and 4 acetylcholine receptors in a subset of patients. Immunoadsorption (IA) was shown to be effective in removing autoantibodies and improve outcome in various autoimmune diseases.

METHODS:
10 patients with post-infectious CFS/ME and elevated ß2 autoantibodies were treated with IA with an IgG-binding column for 5 days. We assessed severity of symptoms as outcome parameter by disease specific scores. Antibodies were determined by ELISA and B cell phenotype by flow cytometry.

RESULTS:
IgG levels dropped to median 0.73 g/l (normal 7-16 g/l) after the 4th cycle of IA, while IgA and IgM levels remained unchanged. Similarly, elevated ß2 IgG antibodies rapidly decreased during IA in 9 of 10 patients. Also 6 months later ß2 autoantibodies were significantly lower compared to pretreatment. Frequency of memory B cells significantly decreased and frequency of plasma cells increased after the 4th IA cycle. A rapid improvement of symptoms was reported by 7 patients during the IA. 3 of these patients had long lasting moderate to marked improvement for 6-12+ months, 2 patients had short improvement only and 2 patients improved for several months following initial worsening.

CONCLUSIONS:
IA can remove autoantibodies against ß2 adrenergic receptor and lead to clinical improvement. B cell phenotyping provides evidence for an effect of IA on memory B cell development. Data from our pilot trial warrants further studies in CFS/ME.

PMID:
29543914
DOI:
10.1371/journal.pone.0193672

 

[Murph]

Here are the results in graphical format for nine patients.

STEPS:

The next chart shows something called a FACT score, which is a measure of fatigue based on a 13 item questionnaire. Up is good, down is bad.

This last graph is a bit hard to read but up from 3 is good and down into the grey is bad. (3 unchanged, 4 slight, 5 marked improvement, 6 complete disappearance, 2 slight increase, 1 marked increase).)

In both cases (during treatment and follow-up) the horizontal axis is a time scale although I am a bit mystified by precisely what the axis is showing for the 'during treatment' graphs.

These graphs all come from the publication, which is available in full here.

This is a proof of concept study only, which means the sample size is deliberately kept small. I'm pretty hopeful about the idea of an autoimmune etiology and a role for antibodies. All that said, I have to be honest the pattern of patient improvement is not especially clear, especially in the last chart. Some patients got better for some of the time.

Perhaps the most hopeful thing is this narrative description of what happened:

Patient 8 had the most remarkable course. While she could hardly walk due to severe muscle fatigue before IA, she could walk several hundred meters at the last day of IA. After transient worsening of symptoms she then completely recovered for 7 weeks. Patient 6 had improvement of fatigue and cognitive symptoms for 6 weeks and went back to work, but then relapsed with severe post-exertional malaise and disease worsening for 6 months.

Two patients had short improvement of symptoms during IA with complete disappearance of immune symptoms (pat. 1) and almost complete resolution of all symptoms (pat. 2). After IA both patients deteriorated following a respiratory tract infection and patient 2 had a fluctuating course thereafter.

 

[Gingergrrl]

I'm pretty hopeful about the idea of an autoimmune etiology and a role for antibodies.

@Murph I agree that there is a sub-group, or misdiagnosed group, which is the group that I belong to, in which these kinds of treatments can be very effective. I never had plasmapheresis (or immunoadsorption) and it is very rare to obtain in the US and much more common in Europe and Asia from my research.

But I achieved significant improvements from high dose IVIG and Rituximab (but this takes a much longer period of ongoing treatment). PP or IA has the potential to see immediate results, but often they dissipate quickly as well. I don't know how to read the graphs but this topic is of great interest for me and I am bookmarking this thread for later. Thanks for posting it.

 

[junkcrap50]

I've never heard of Immunoabsorption. Very interesting stuff.

I wonder if this technology would be helpful for Ron Davis and his search for the agent in the blood causing CFS. Could they take all the antibodies collected in the immunoabsorption and then do a deep analysis on all antibodies? Perhaps something in particular might float to the top of the data.

 

[EtherSpin]

Very promising though some of the results look subtle and I wonder about variabilities in the patients , I'm probably burnt by cynicism about the PACE trial but I'd like to know how much jollying along there was of participants for their step count because as we all know , it's possible to feign considerably more function by eliminating our own leisure time, self care , spending money on prepared meals, dropping any small chore we might take pride in doing in our home etc.

I'll try to read over this a dozen more times

 

[M Paine]

I've never heard of Immunoabsorption. Very interesting stuff.

Neither. Interesting concept, presumably selectively neutralizing antibodies somehow? Does this also effect B and T cell receptors? Or just IG? Anyone know more?

 

[Gingergrrl]

Could they take all the antibodies collected in the immunoabsorption and then do a deep analysis on all antibodies?

My understanding (which might be totally wrong) was that PP or IA (immunoadsorption) removes auto-antibodies vs. (viral/pathogen) antibodies but now I am not sure if this is correct?

it's possible to feign considerably more function by eliminating our own leisure time, self care , spending money on prepared meals, dropping any small chore we might take pride in doing in our home etc.

This would not be the case for me, but I know it is for most people, and when I read sentences like this it is very helpful and reinforces that I have a different diagnosis. For me, the auto-antibodies cause both POTS/autonomic problems and muscle weakness and the severity of them were constant and were worsening prior to treatment. There was nothing I could do to feign them being better until they actually were better from treatment.

Interesting concept, presumably selectively neutralizing antibodies somehow? Does this also effect B and T cell receptors? Or just IG? Anyone know more?

I am the last person to answer this, but from my limited understanding, PP or IA removes the autoantibodies from the blood (which were originally created by B-cells). So it would be a very quick way to diagnose if someone has B-cell driven autoantibodies causing their symptoms but then the autoantibodies could very quickly come back.

Versus high dose IVIG knocks down autoantibodies through another mechanism (that no one truly understands) but takes much longer for symptom improvement and Rituximab wipes out the B-cells which stops new autoantibody production at the source (but is also slower than PP or IA). In an emergency situation (like Guillain-Barre) they often do PP to eliminate the autoantibodies very quickly from the blood, vs. other chronic conditions, they might use high dose IVIG or Rituximab (or other treatments?) hoping to re-set the immune system over the longer term. Please someone correct me if anything I have said here is wrong!

 

[Jesse2233]

Not surprised at all. This should be first line therapy. Low risk and highly effective

Great to see this paper finally published

 

[Gingergrrl]

This should be first line therapy. Low risk and highly effective

Do you mean PP or IA (or something else)? I tried every avenue I could think of in 2016 to try this treatment but every road was a dead end. My two main doctors were against it as were three Neuros that I saw. Both of my main doctors 100% supported me doing high dose IVIG and Rituximab but felt PP was too risky for me for many reasons. Even if I was willing to take the risk (which I was), I was not able to find a single doctor in the US who was willing to prescribe it.

Great to see this paper finally published

I agree.

 

[M Paine]

Can someone please clarify, by immunoadsorption, are we just talking about plasmapheresis? Or are we talking about a selective form of plasmapheresis?

 

[sb4]

I wonder if someone can help me understand this part of the study [ https://ars.els-cdn.com/content/image/1-s2.0-S0889159115300209-gr1.jpg ].

Are the units used here (Units/ml) the same units used in the cell trend antibodies test (also Units/ml) or is Units a variable unit you can use?

The reason I'm asking is, though I came back all negative for the antibodies tested (B1/2 M1/2/3/4/5) M3 and M4 where significantly higher than the rest. Most where around 10% of the positive values yet M3 and M4 where 47% and 53% respectively (just below the at risk).

Now if the units line up with that of the study I am well below most people but I can't shake the feeling that this is significant. M3 in particular correlates very well with my worst symptoms. Perhaps the ratio of antibodies is important, or perhaps some are more potent than others.

 

[Gingergrrl]

Can someone please clarify, by immunoadsorption, are we just talking about plasmapheresis? Or are we talking about a selective form of plasmapheresis?

My understanding (which could be totally wrong!) is that PP (often called PLEX) is what is done in the US and the entire plasma is filtered/removed and replaced with either blood transfusion or a substance such as albumin.

Versus IA is more common in Europe and Asia and the blood plasma is filtered to remove the autoantibodies but then put back into the body (vs. replaced).

Please someone correct me if I am wrong and I don't want to share incorrect info!

 

[junkcrap50]

My understanding (which could be totally wrong!) is that PP (often called PLEX) is what is done in the US and the entire plasma is filtered/removed and replaced with either blood transfusion or a substance such as albumin.

Versus IA is more common in Europe and Asia and the blood plasma is filtered to remove the autoantibodies but then put back into the body (vs. replaced).

Please someone correct me if I am wrong and I don't want to share incorrect info!

You're correct, based on my researching and looking up the difference.

 

[junkcrap50]

Some details from the study. They used the immunoadsorber Globaffin made by Fresenius Medical Care.

GLOBAFFIN is the first synthetic broadband immunoadsorber. It is completely free from products of animal origin. GLOBAFFIN adsorber uses synthetic peptide GAM ligands to bind specific groups of antibodies. Peptide GAM is covalently bound to an insoluble Sepharose carrier matrix. It has a strong binding affinity, especially to the constant (Fc) section of subclass 1, 2 and 4 IgG antibodies.

Peptide GAM also binds with lower affinity to IgG subclass 3 as well as to IgM and IgA antibodies. The amount of IgG antibodies and immune complexes removed depends on the volume of plasma treated.1

Also it appears that the patients in the study also received IVIG therapy.

The IA was performed using Globaffin columns containing peptides specifically binding IgG (Fresenius). IA was conducted in 5 cycles on days 1–3 and 6–7 with 2 to 2.5-fold plasma volume filtered. After the 5th IA cycle all patients received 25 g IgG i.v. (Octagam, Octapharma). Immunoadsorptiion is licensed in Germany for the treatment of patients with autoantibodies.

 

[Gingergrrl]

@junkcrap50 So is "Globaffin" the substance that cleans/filters the autoantibodies from the blood but then the original blood is returned to the person's body? I just want to make sure that I really do understand what I am talking about!

Also, did the patients in the study only receive one single dose of 25 grams of IVIG (or did this happen multiple times)? From my experience and understanding, I am not sure how one single dose of IVIG would be effective, unless there is some synergistic effect from using IA and IVIG together that I am not understanding? Also, 25 grams is a low dose (for immune deficiency versus autoimmunity).

I believe this is the study that @Freddy participated in (because he posted about it on PR at the time) but I do not know if he is still reading or posting on the board now?

 

[Gingergrrl]

Are the units used here (Units/ml) the same units used in the cell trend antibodies test (also Units/ml) or is Units a variable unit you can use?

I don't know the answer but am curious, too (if anyone else knows).

The reason I'm asking is, though I came back all negative for the antibodies tested

I remember talking to you about this at that time, that you were negative on all nine of the Cell Trend tests but I was positive on 7 of the 9 (and I did the test twice to be certain and both times I was positive on 7/9).

Now if the units line up with that of the study I am well below most people but I can't shake the feeling that this is significant. M3 in particular correlates very well with my worst symptoms. Perhaps the ratio of antibodies is important, or perhaps some are more potent than others.

Can you explain more what you mean re: that you can't shake the feeling that this is significant? Also, how do you determine that "M3" is the autoantibody that correlates with your particular symptoms? Is there a list or description somewhere of which specific symptoms correlate with each autoantibody? (I sincerely apologize if you have told me this before and I did not retain it)! Science is not my background at all.

 

[junkcrap50]

So is "Globaffin" the substance that cleans/filters the autoantibodies from the blood but then the original blood is returned to the person's body? I just want to make sure that I really do understand what I am talking about!

Yes. You're correct. Here's a link that compares plasmapheresis vs immunosorption.

In PE, plasma separated with a plasma separator is discarded and replaced with the same volume of fresh frozen plasma (FFP) or albumin solution.

However, since this method discards everything including substances that are needed by the body, the following two methods have been developed to selectively remove only harmful substances, while leaving necessary substances in the blood.

In DFPP, plasma separated with a plasma separator passes through a plasma component separator which removes harmful substances while leaving valuable proteins such as albumin to be returned to the patient.

In PA, plasma separated with a plasma separator flows into a plasma adsorption column which selectively removes harmful substances.

Notice that the plasma in plasmapherisis is collected as waste. Whereas the plasma in immunoasorption is recirculated into the body.

 

[junkcrap50]

Also, did the patients in the study only receive one single dose of 25 grams of IVIG (or did this happen multiple times)? From my experience and understanding, I am not sure how one single dose of IVIG would be effective, unless there is some synergistic effect from using IA and IVIG together that I am not understanding? Also, 25 grams is a low dose (for immune deficiency versus autoimmunity).

I think, that they just received 1, single dose of IVIG. Though, I don't know why they chose to do that as it seems to complicate the study and not provide a clear-cut response from only immunoabsorption.

 

[Gingergrrl]

Notice that the plasma in plasmapherisis is collected as waste. Whereas the plasma in immunoasorption is recirculated into the body.

Thanks for posting that and the chart was very informative.

I think, that they just received 1, single dose of IVIG. Though, I don't know why they chose to do that as it seems to complicate the study and not provide a clear-cut response from only immunoabsorption.

I agree and the one dose of IVIG seems very odd to me and makes it a confounding variable (IMO) that would be hard to separate from the immunoadsorption. Do they explain this?

 

[imitate-past-reign]

I agree and the one dose of IVIG seems very odd to me and makes it a confounding variable (IMO) that would be hard to separate from the immunoadsorption. Do they explain this?

Plasmapheresis depletes IgG globally so they were replenishing it after the trial had been completed.

None of the patients completely recovered.

They could have used a non-elution comparator as a placebo or saline vehicle with crossover at six months.
The reason this was not done is because the authors have a monetary conflict of interest in the auto-antibody portion of their study.

The FACT-F fatigue scale has a +2 placebo effect if I recall (I have never seen that used before in CFS) and that would alter the effect size outside of significance. If someone can find the FACT-F study that included a... urological cancer?, double-blinded, from Europe. I do not particularly subscribe to the placebo effect, especially in severe patients, but if just one had a large one it alters the trial measurably here.