Efficacy of daratumumab in refractory primary Sjögren disease Nocturne 2023

[Jonathan Edwards]

i dont see why you are fixated on just ANA?

I am not fixated but gave the specific reason for picking it.

I mean if you are contesting the now numerous data points showing increased b cell activity in long covid I really dont know what to say

Like what? All I have seen looks like dross so far. I have been reading papers on autoantibodies for forty years. Most of them are dross. Can you cite a 'high quality study'?

There are a few nerologists out there who are praising Dara for its autoimmune effiacacy and safety because of its target sites, CD38.

That sounds like neurological-wishful thinking to me. I am not aware of hard data and by and large neurologists do not understand autoimmunity very well.

its clearly mildly safer.

Currently available data are unlikely to be reliable since ritux has been going since 1996 and the serious problems took time to emerge. Daratuzumab has had nothing like the range of usage yet.

 

[siobhanfirestone]

Could you please post some of these studies that find some vast B-cell differences in LC patients? I have been following the research very intently and I'm pretty sure that almost every study on LC has been posted on this forum and to me the B cell data often looks quite noisy, or at least it is certainly not clear data or consistent, see for instance https://www.nature.com/articles/s41590-021-01113-x and https://www.biorxiv.org/content/10.1101/2021.05.26.442666v3 (and that includes studies such as this one by Iwasaki). If anything I would say the CD8 T-cell data is the more convincing, but I wouldn't claim it to be very convincing just yet either.

You just linked the Iwasaki study that literally says: A number of significant changes in circulating leukocytes, including increases in non-classical monocytes, activated B cells, double-negative B cells, exhausted T cells, and IL-4/IL-6 secreting CD4 T cells, and decreases in conventional DC1 and central memory CD4 T cells were identified?
You read things like this, and note that immunotherpaies are the only stuff in the literature that isnt poor quality that is helping people, and you totally dismiss b cells?
Im not saying we have the complete theory, im saying its strong enough to pursue and is being pursued by quite a few teams
https://www.medrxiv.org/content/10.1101/2022.08.09.22278592v1

 

[siobhanfirestone]

I am not fixated but gave the specific reason for picking it.



Like what? All I have seen looks like dross so far. I have been reading papers on autoantibodies for forty years. Most of them are dross. Can you cite a 'high quality study'?



That sounds like neurological-wishful thinking to me. I am not aware of hard data and by and large neurologists do not understand autoimmunity very well.



Currently available data are unlikely to be reliable since ritux has been going since 1996 and the serious problems took time to emerge. Daratuzumab has had nothing like the range of usage yet.

I will go tell my neurologist who is running a trial for stem cells in MS that he is wrong then haha

 

[EndME]

You just linked the Iwasaki study that literally says: A number of significant changes in circulating leukocytes, including increases in non-classical monocytes, activated B cells, double-negative B cells, exhausted T cells, and IL-4/IL-6 secreting CD4 T cells, and decreases in conventional DC1 and central memory CD4 T cells were identified?
You read things like this, and note that immunotherpaies are the only stuff in the literature that isnt poor quality that is helping people, and you totally dismiss b cells?
Im not saying we have the complete theory, im saying its strong enough to pursue and is being pursued by quite a few teams
https://www.medrxiv.org/content/10.1101/2022.08.09.22278592v1

I don't dismiss the Iwasaki study or B cells at all, that's why I posted it. However, “numerous data points showing increased b cell activity” and “there are so many high quality studies its bursting out my ears” is very different to me than having less than a handful of extremely noisy studies, with several studies not finding this difference or even somewhat contradicting these results. Replication and building on Iwasaki's results is certainly desperately needed, but for now the only thing I'm certain of is that modulating CD20 B cells is insufficient.

 

[Jonathan Edwards]

Im not saying we have the complete theory, im saying its strong enough to pursue and is being pursued by quite a few teams

Actually I would dismiss the Iwasaki study as telling us nothing reliable. The data quoted looked entirely like noise to me. Real immunology isn't picking out odd populations a bit more than others like this. There were hundreds of papers of this sort on RA and SLE and none of them told us anything useful.

Real immunology sticks out not so much as like a sore thumb as like a sore giraffe's neck when you hit on it. All I see at present is wishful thinking.

 

[siobhanfirestone]

I don't dismiss the Iwasaki study or B cells at all, that's why I posted it. However, “numerous data points showing increased b cell activity” and “there are so many high quality studies its bursting out my ears” is very different to me than having less than a handful of extremely noisy studies, with several studies not finding this difference or even somewhat contradicting these results. Replication and building on Iwasaki's results is certainly desperately needed, but for now the only thing I'm certain of is that modulating CD20 B cells is insufficient.

im out at the moment, will find my list when i get home in a few days - plz nudge if i forget

 

[siobhanfirestone]

I don't dismiss the Iwasaki study or B cells at all, that's why I posted it. However, “numerous data points showing increased b cell activity” and “there are so many high quality studies its bursting out my ears” is very different to me than having less than a handful of extremely noisy studies, with several studies not finding this difference or even somewhat contradicting these results. Replication and building on Iwasaki's results is certainly desperately needed, but for now the only thing I'm certain of is that modulating CD20 B cells is insufficient.

Before i start i should say i do find t cell findings very interesting as well, if targeted therapies come out for that i would be intrigued to see effect

(reduced list for brevity) Ok to keep it simple the b cell stuff and aab stuff i have found to be good/high quality is both theory and practise in terms of:

theory:
As previously mentioned Klein, J. et al. Distinguishing features of Long COVID identified through immune profiling. Preprint at medRxiv
patients with pain https://openres.ersjournals.com/content/9/suppl_10/205.abstract
general, albeit patchy, aab theory - https://www.frontiersin.org/articles/10.3389/fimmu.2022.981532/full


practise:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9932260/ (i accept IVIG is a lil tricky but the working hypothesis is b cell orientated)
https://www.medrxiv.org/content/10.1101/2023.08.31.23294813v1

the immunopheresis study, we know a few people on it. they did very well and then relapse quickly, its clearly not enough, i can see why carmen is mixing it with some b cell therapies as well.

There is more out there but im travelling atm, best wishes

 

[siobhanfirestone]

I don't dismiss the Iwasaki study or B cells at all, that's why I posted it. However, “numerous data points showing increased b cell activity” and “there are so many high quality studies its bursting out my ears” is very different to me than having less than a handful of extremely noisy studies, with several studies not finding this difference or even somewhat contradicting these results. Replication and building on Iwasaki's results is certainly desperately needed, but for now the only thing I'm certain of is that modulating CD20 B cells is insufficient.

also yes to the CD20 b cell, fluge is on to something hopefully and i hope we get a blinded placebo phase 2 with his dara because i really dont want to have to do full chemo