Efficacy of daratumumab in refractory primary Sjögren disease Nocturne 2023

https://rmdopen.bmj.com/content/9/3/e003464


Here, we report the first two cases of patients with severe complications of SjD, refractory to RTX and successfully treated with daratumumab.

 

An interesting report.
Sjogren's is a difficult condition to interpret but it may be a good target for an anti-plasma cell agent because it is associated with hypergammaglobulinaemia.
It will be interesting to see how far this approach can be extended to other autoimmune diseases. If it works in Ro and Sm positive lupus there would be quite a good case for trying it in a small group of ME cases (maybe with positive ANA initially).

 

You mean to only trial it in MECFS patients with a positive ANA test?

 

I don’t know how common it is in pwME, but I’ve had multiple positive 1:160 or 1:320 ANA tests with homogeneous pattern

 

Ooh, my always-positive-speckled-ANA just perked up. Might this be one for Fluge and Mella?

 

Yea seems like a good idea ---maybe try post on Twitter/X and tag them/someone in that group.

I've flagged Jonathan's post above to someone I know who is in contact with Carmen Scheibenbogen (Charite - Berlin). They may also have some contact with the Bergen(?) group - Fluge and Mella.

 

In the first instance yes.
When we tried rituximab in RA we limited it to people with a positive antibody test, since we were targeting antibodies. We later confirmed that people with 'RA' who did not have autoantibodies generally showed no response.

I think it is much more likely that a small proportion of PWME have an autoantibody-related illness than that all do. ANA is relevant because we know some ANAs do not respond to rituximab. I am much less convinced that anti-adrenergic receptor antibodies mean much.

 

If hypergammaglobulinemia is a biomarker(?) then I wonder if e.g. Nath measured this? Even if no-one has, presumably it would be fairly easy to do this e.g. using samples in one of the biobanks?
Same for anti-nuclear antibodies (ANA) --- although I do wonder how accurate some autoantibody tests are.

From Google search -
"Hypergammaglobulinemia (polyclonal gammopathy) refers to the overproduction of more than one class of immunoglobulins by plasma cells. It is most commonly associated with liver disease, acute or chronic inflammation, autoimmune disorders, and some malignancies."

 

Same here, except I've had even higher titres (1:640) during serious relapses. I don't understand why no one is pursuing this angle.

 

My "understanding" is that Fluge & Mella are doing a small study in ME - 6 participants?

 

One case study from their May 2023 presentation.

 

Thanks—can you provide the direct link to this presentation?

 

Quick search, but Can t find the YouTube link.

From this conference.
https://mecfs-research.org/mecfs-conference2023/


B and Plasma Cell Targeting in ME/CFS
Øystein Fluge

 

the norwegian team arent using ANA so i dont feel thats relevant. we know it didnt work for everyone, we know its safer than ritux, I can only hope we get a better phase 3 as rituxs phase 2 were so good then, well we all know what happened.

 

I don't quite follow that.

By Norwegian team I presume you mean Fluge and Mella. What are they not using ANA for? As far as I know we do not have a better marker.

What is it that did not work for eveyone? Daratumumab? We haven't had a formal trial so I am not sure what we can know yet, unless there are already some people who have not improved?

Do we know it is safer than rite? You would need to treat thousands of people to know that I think.

What do all know happened? As far as I am concerned the phase 3 ritual trial was an excellent study that showed no effect. The phase 2 blinded study did not meet its endpoint either. The decision to go to phase 3 was I believe in part related to the fact that I had pointed out to Oystein Fluge that their original efficacy time point was probably not the right one based on our RA experience.

 

Please note typo above— might confuse folks.

 

What i mean is in their trial they are not using ANA to diagnose ME/CFS and treat patients in this trial, because its not commonly associated with post viral disease, its not seen in long covid either but massive b cell activity is...... I dont think they are using the celltrend AABs but operating on the idea that its some sort of autoimmune, or intense immune issue, and are using a few markers can act as a stand-in, they published a paper recently (i cant find but will try and do so later) about blood flow, POTS etc that is being used as a bio marker.

So my question is why start with ANA markers when they have not done so? that would be changing the entire approach of the study.......

In terms of safety Dara has been used in thousands for MM and just in general, aside from first infusion side effects that are usually transiet, safer than the heavy ritux so thats better for people on the trial as well hopefully.

 

The reason for picking people with ANA is that going back over the last twenty years of B cell/plasma cell depletion for autoimmune disease (I did the first formal proof of concept trial in RA in 2001 and the first trial in lupus a bit later) it has become clear that although ANAs directed against protein antigens are likely pathogenic they do not go down much with anti-CD20 and clinical benefit is uncertain. A significant minority of people have such ANA - including healthy people - and I think if ME is autoantibody driven at all it is likely to involve such antibodies in at least a few cases. The story is very complicated.

I am not particularly suggesting that Oystein Fluge changes his current study. But I think if one is going to select cases at all something like ANA is about the only marker of B cell involvement likely to be useful. The same probably applies to Long Covid. I am not impressed by the various reports of other autoantibodies in Long Covidor even any evidence that it involves B cell activation.

Most side effects from rituximab are transient. The only major issue I am aware of, apart from infection, which will occur with any of these agents if Ig levels go down, is sterile pneumonitis with ritux. We identified that very early but the drug company was slow to document it. It may be that sever side effects are less with daratumumab but do we actually know that? I am not sure what you mean by 'heavy' ritux? If daratumumab is going to be better it will have to be 'heavier' in terms of Ig reduction I think.

 

Maybe they are checking ANA but im guessing they didnt present it as data as its not meaningful, i dont see why you are fixated on just ANA? Regardless we wont know until study is published. Come to think of it I believe they did this study after than awful chemo drug, saying it showed moderate efficacy but they dont want to have to give patients awful chemo if they can avoid 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 because there are so many high quality studies its bursting out my ears, in terms of celltrend aabs i dont think its enough either - and the german team have just said their immune apheresis which remove IgG and filters had a moderate effect that DIDNT correlate with suspected aab (beta 2 iirc), so they are ammending hypothesis.

There are a few nerologists out there who are praising Dara for its autoimmune effiacacy and safety because of its target sites, CD38. You are the sepcialist i dont know why this might be safer than ritux but I accept this isnt a proved thing yet and still early trials.

I used the UK medical adverse effects site to check Ritux VS dara, and whilst i know patient population is different and homogenous, its clearly mildly safer. I accept only continued studies would should this, I more meant in reference to the side effects and hospitalisation.

 

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.