Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME (2018) Scheibenbogen et al

[hixxy]

Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME

Carmen Scheibenbogen , Madlen Loebel, Helma Freitag, Anne Krueger, Sandra Bauer, Michaela Antelmann, Wolfram Doehner, Nadja Scherbakov, Harald Heidecke, Petra Reinke, Hans-Dieter Volk, Patricia Grabowski

Published: March 15, 2018

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.

https://doi.org/10.1371/journal.pone.0193672

 

[Trish]

Tiny pilot study on a treatment that looks like it works for a subgroup of patients. Looks interesting, but clearly more work is needed.

 

[Joh]

It's the team at the Charité in Berlin. I believe it's the first time they call it CFS/ME instead of CFS. Progress.

According to their own research the named autoantibodies are only present in a subgroup of 30% (and only these patients are chosen for their studies, I think another tiny study was recently done with IVIG).

 

[Andy]

A Q&A with one of that team is still in the pipeline.

Thought this was interesting

This trial was supported with a grant by Fresenius Medical Care.

https://en.wikipedia.org/wiki/Fresenius_Medical_Care

Fresenius Medical Care is a German company specializing in the production of medical supplies, primarily to facilitate or aid renal dialysis.

 

[adreno]

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

May be mostly a temporary effect. Autoantibodies likely return over time.

 

[Londinium]

This might be a touch off-topic, but one thing that struck me personally is that patients are described as having 'chronic severe infection-triggered CFS/ME'. Looking at Figure 6, patients pre-treatment averaged ~5,000 steps per day. I consider myself to be mild/moderately afflicted, but I manage only around 2,500 per day - I can do 5,000 steps in a day but will have pretty bad PEM the following day and the last time I exceeded 6,000 steps for two days in a row I ended up off work for four weeks and was effectively housebound for three months. Does that mean (a) I'm more severely afflicted than I'd previously thought or (b) that the people treated here are in the mild to moderate range?

Off-topic step questions aside, it's an interesting study but as already noted above it's very small and desperately requires replication in a larger group. Also the movement data may indicate a placebo effect in action. Hopefully this small study will support a wider grant application.

 

[Andy]

Does that mean (a) I'm more severely afflicted than I'd previously thought or (b) that the people treated here are in the mild to moderate range?

A bit of both would be my suspicion. I don't think that many researchers, even ME ones, get how severe severe actually is, and because we do tend to have a better idea of what severe is like, we might have a tendency to discount how severe we are, if we aren't as bad as the image we have of severe. Not trying to depress you, but think of it this way, you are only able to reliably do 1/4 of the average number of steps that an average person in average health should be taking per day.

 

[Londinium]

A bit of both would be my suspicion. I don't think that many researchers, even ME ones, get how severe severe actually is, and because we do tend to have a better idea of what severe is like, we might have a tendency to discount how severe we are, if we aren't as bad as the image we have of severe. Not trying to depress you, but think of it this way, you are only able to reliably do 1/4 of the average number of steps that an average person in average health should be taking per day.

Thanks. I still tend to think of myself as mild because I'm (with adaptions) still in full-time work and I'm sure I read somewhere that 75% of PwME aren't. Indeed, I've always thought that the fact I'm down about 65% in terms of step count (I averaged 8,000 before I got ill) yet would still be classed as 'mild' shows what a horrendous illness this is. I do wonder if it's simply selection bias: when I've had very bad crashes there's no way I could have got myself to a hospital regularly to take part in a trial; bed-->bathroom-->sofa was enough.

 

[Sasha]

What do you think of this, @Jonathan Edwards, @Simon M?

 

[adambeyoncelowe]

It's interesting. Haven't other studies suggesting auto-antibodies against serotonin too? Antibodies against adrenergic and acetylcholine receptors could suggest one possible reason for cortisol dysfunction and muscle weakness, respectively.

Again, I'm reminded of Younger's suggestion that he's found three main sub-groups: viral, autoimmune/inflammatory and metabolic. Especially because the aforementioned 30% figure fits nicely (Younger said the sub-groups split nicely into thirds).

Again, though, it needs better follow-up. It's certainly interesting, though.

 

[Jonathan Edwards]

What do you think of this, @Jonathan Edwards, @Simon M?

Removing IgG until the level goes down to 0.7gm/L or in some cases less seems to me very risky. The rationale of rituximab is that it selectively reduces autoantibody, without reducing total antibody much. This treatment takes away protection against all infections.

There is no particular reason to relate this study to adrenergic receptor antibodies. If there is an effect nobody knows which antibodies might be involved - they are all removed. Moreover, the adrenergic receptor antibodies are not that much commoner in ME than normal so it is pretty unlikely that they play a causal role.

I think we probably need it to sink in that the evidence for autoantibodies being relevant in ME came largely from the phase 2 Norway study which was not replicated at phase 3 and only gave a suggestion of an effect anyway. We know that autoantibodies cause a range of diseases like luis and RA but nobody is using IgG absorption in those diseases simply because it is too risky. I would not want to pursue it in ME.

 

[Andy]

Thanks. I still tend to think of myself as mild because I'm (with adaptions) still in full-time work and I'm sure I read somewhere that 75% of PwME aren't. Indeed, I've always thought that the fact I'm down about 65% in terms of step count (I averaged 8,000 before I got ill) yet would still be classed as 'mild' shows what a horrendous illness this is. I do wonder if it's simply selection bias: when I've had very bad crashes there's no way I could have got myself to a hospital regularly to take part in a trial; bed-->bathroom-->sofa was enough.

Another thought I've had on this topic. It can depend on what drains your energy. Anecdotally, there would seem to be people who have a higher tolerance to either physical activity compared to mental activity, and obviously vice versa. I would rate my physical tolerance levels as higher than my mental tolerance levels, so it might be physically I'd be able to tolerate a part-time job but mentally I couldn't be "switched on" enough for the time I was working. I guess it shows how difficult it is to come up with a severity scale for us.

 

[Lisa108]

Removing IgG until the level goes down to 0.7gm/L or in some cases less seems to me very risky

This treatment takes away protection against all infections.

"After the 5th IA cycle all patients received 25 g IgG i.v. (Octagam, Octapharma)."
"(...)levels of total IgG and the specific IgG against tetanus and pneumococcal polysaccharide after 3 and 6 months remained unchanged."

But also: "After IA both patients deteriorated following a respiratory tract infection and patient 2 had a fluctuating course thereafter." [italics mine]

 

[Jonathan Edwards]

"After the 5th IA cycle all patients received 25 g IgG i.v. (Octagam, Octapharma)."
"(...)levels of total IgG and the specific IgG against tetanus and pneumococcal polysaccharide after 3 and 6 months remained unchanged."

But also: "After IA both patients deteriorated following a respiratory tract infection and patient 2 had a fluctuating course thereafter." [italics mine]

So it seems that IgG was replaced, but only after going seriously low. One would expect natural IgG to recover about a month after depletion, but then that would include all the autoantibodies, as well as a return of tetanus and pneumococcal. There is also the problem that people become sensitive to IVIg and replacement is not always straightforward.

 

[Inara]

Looking at Figure 6, patients pre-treatment averaged ~5,000 steps per day. I consider myself to be mild/moderately afflicted, but I manage only around 2,500 per day

The thing is the actometers which are used measure any movement that's strong enough to trigger a count, i.e. brushing the hair can be around 100 steps, showering even more and so on. The actometers are carried the entire day and night, not only for walking. Considering all that I'd say 5000 steps aren't so much. It definitely doesn't mean "5000 steps".

May be mostly a temporary effect.

My information was that at follow-up (a year later? don't nail me) most participants still felt better. It sounded like improvement was significant.

Since there is no funding in Germany, researchers need funding from abroad or collaborations with companies.

I hope we will learn more in the Q&A-session.

 

[Inara]

So it seems that IgG was replaced, but only after going seriously low. One would expect natural IgG to recover about a month after depletion,

Yes, it was replaced. I don't know the specifics though. To me, as a person who had low Igg3, I wouldn't want Igg that low. Even with "only" low Igg3 I had one infection after the other.

My take-away was: If you have auto-immune issues, immunoadsorption might be a good try. But it is EXPENSIVE.

 

[adambeyoncelowe]

Looks like this is their previous study on similar receptors/auto-antibodies: https://www.sciencedirect.com/science/article/pii/S0889159115300209?via=ihub

 

[Milo]

The thing is the actometers which are used measure any movement that's strong enough to trigger a count, i.e. brushing the hair can be around 100 steps, showering even more and so on. The actometers are carried the entire day and night, not only for walking. Considering all that I'd say 5000 steps aren't so much. It definitely doesn't mean "5000 steps".

Correct. The actometer counted steps while i was on my mobility scooter, from the bumps on the sidewalks.

 

[Mattie]

Merged thread

They used a blood purification technique called immunoadsorption to eliminate the B2 antibodies from people with ME/CFS who’d had a post-infectious onset and high B2 antibody levels. Immunoadsorption (IA) was given five times over seven days to completely wash out the antibodies. Over the next six months the participants’ symptoms, muscle strength, endothelial functioning and immune factors were watched

Significant improvement eventually followed by a relapse was the order of the day. One patient who could barely walk prior to the treatment was able to walk several hundred yards at the end of the IA process. She completely recovered for seven weeks and then relapsed. Another patient improved enough to go back to work but then relapsed. Five patients who improved started to relapse by the end of the six months. Three patients – a good third of the study – felt significant improvements in fatigue lasting at least 12 months.

Scheibenbogen’s first ME/CFS publication In 2014 found ME/CFS patients mounting a feeble response to Epstein-Barr virus (EBV) . The reduced response to EBV reactivation could help explain the ups and downs seen, particularly during stressful situations.

In 2016, figuring that when Rituximab worked in ME/CFS it probably did so by whacking antibody producing B-cells, her group examined antibodies against a variety of receptors that affect blood flow, the autonomic nervous system, etc. They found that about 30% of ME/CFS patients in a large study (n=293) had increased levels of antibodies to adrenergic (B2) and/or muscarinic M3/M4 acetylcholine receptors (M3/M4).

That suggested that the immune systems of a significant subset of ME/CFS patients might be attacking the receptors on cells which regulate blood flow, lung functioning, muscle contractions and attention. Furthermore, the finding (a “remarkable” one they said) that the antibody levels of two receptors correlated with a host of immune factors (immunoglobulin levels, T cell activation, elevated ANA, TPO antibodies) suggested that this subset of ME/CFS patients are suffering from an autoimmune disease. Scheibenbogen has suggested that the kind of ME/CFS you have may be dependent on the kind of autoantibodies present in your system

Full article:
http://simmaronresearch.com/2018/04/hope-mecfs-autoimmune-subset-german-researcher-steps-forward/

 

[Keela Too]

Well this rings true to the flu type feelings I get. A good line of research to follow up methinks. Now where’s the substantial funding required?