Observational Study of Repeat Immunoadsorption in Post-COVID ME/CFS Patients with Elevated Beta-2-Adrenergic Receptor Autoantibodies,2023, Stein et al

Scheibenbogen et al

Abstract
There is increasing evidence for an autoimmune aetiology in post-infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). SARS-CoV-2 has now become the main trigger for ME/CFS. We have already conducted two small proof-of-concept studies of IgG depletion by immunoadsorption (IA) in post-infectious ME/CFS, which showed efficacy in most patients. This observational study aims to evaluate the efficacy of IA in patients with post-COVID-19 ME/CFS. The primary objective is to assess the improvement in functional ability. Due to the urgency of finding therapies for post-Covid-Syndrome (PCS), we report here the interim results of the first ten patients with seven responders defined by an increase of between 10 and 35 points in the Short-Form 36 Physical Function (SF36-PF) at week four after IA. The results of this observational study will provide the basis for patient selection for a randomised controlled trial (RTC) including sham apheresis and for a RTC combining IA with B-cell depletion therapy.

https://www.medrxiv.org/content/10.1101/2023.08.31.23294813v1

 

For the immunologists on this forum: Can anybody explain a more precise hypothesis why exactly Obinutuzumab is what Scheibenbogen is planning to accompany her Immunadsorption study with?

From what I've understood Obinutuzumab is something like "the new Rituximab", with possibly some advantages, however it isn't clear to me why it should be prioritised above some of the others (I guess Ocrelizumab, Ofatumumab, Ublituximab) if the only aim is to somehow deplete memory B-cells in the hope that that changes the production of GPCR-AABs. It makes sense to not trial Rituximab again, because who wants to study something that has already failed, but similarly one could then argue against any type of CD-20 antibody or am I missing something? I suppose one could also try to adress long lived plasma cells, so try to do what Rituximab doesn't, but she seems to believe in some amplifying feedback loop between GPCR-AABs and B-cells with CD-20, whilst at the same time this amplification isn't seen in the measurements of GPCR-AAB levels.

I'm sure similar discussions would have been had when the Rituximab trials were discussed and I suppose it would be very relevant to try to learn from any possible shortcoming of those trials.

Interestingly in this new study she writes "There was no correlation between AAB levels and efficacy, and patients with symptom improvement at week four showed similar recurrence of AAB levels. Thus, mechanisms other than mere AAB depletion most likely account for improvement in a subset of patients. Among these is the apoptosis of AAB-producing B cells. B cell phenotyping in our previous study provided first evidence for an effect of IA on memory B cells [10]. GPCR AABs belong to a network of natural AABs that communicate with receptors regulating physiological processes in healthy individuals.". For me that sounds somewhat like hinting at the fact that GPRC-AABs might just be some background factor part of a network of natural AABs and that the AAB that might be causing ME/CFS hasn't been discovered yet, so we might as well go down the B-cell route again to see if we can find a signal.

 

I am afraid not. Even I have lost touch with developments in the CD20 monoclonals (or CD19, CD21). Venkat Reddy in our department has worked a lot on the higher efficacy of some of the newer ones and obinutuzumab is a popular choice. However, my general thought would be that we have little evidence that it matters much in terms of proof of concept. Rituximab works very well where anything works. Others may do a tad better but I am not even sure we have good evidence for comparisons.

In simple terms, what I have seen of levels of these receptor antibodies is that the differences between controls and cases are so marginal as to provide fairly strong evidence that they are irrelevant.

B cell depletion is not a trivial thing to do. With rituximab there were a few deaths. I doubt the other antibodies are much different. The motivation for using in RA was based on barn door evidence of masses of antibodies not found in normal people.

 

Thank you for the response.

A bit dissapointing that Hand grip strength, which played a bigger role in her new study as prognostic marker https://www.s4me.info/threads/long-...-observational-cohort-2023.35012/#post-491497, or other objective markers don’t seem to be mentioned in the preliminary trial data. They are all part of the trial protocol https://classic.clinicaltrials.gov/ct2/show/NCT05629988, so hopefully they can still be made available before the full study with 20 participants is completed.

 

Now published:
https://www.mdpi.com/2077-0383/12/19/6428