Saturday, 30 December 2017

End of Year Revision

As the year draws to a close, it has been a productive year for papers and ideas. 

I predict that during 2018, we will get even more clarity on the story.

But do you believe the academic minnow or the whale?

As we have said many times before, people do not all agree on the driving force of MS.

Most people are still in the T cell camp or midway into the T cell camp. Even those in the B cell camp are not convinced and so do not provide any clarity into what is going on. 

Is it Chewbacca Science, like the chewbacca defence...you throw a load of facts in the air and it simply confuses every one, so every one agrees with you but non-one knows what's really going on. 

You are never wrong because you suggest every possibility. Everyone is happy.


However, it allows you to lack focus and so waste time by not doing the important things.


 Chewbacca Science-Lovely and Cuddly


Greenfield AL, Hauser SL.B Cell Therapy for Multiple Sclerosis: Entering an Era. Ann Neurol. 2017. doi: 10.1002/ana.25119.

Monoclonal antibodies that target CD20 expressing B cells represent an important new treatment option for patients with multiple sclerosis (MS). B cell depleting therapy is highly effective against relapsing forms of the disease and is also the first treatment approach proven to protect against disability worsening in primary progressive MS. Moreover, evolving clinical experience with B cell therapy, combined with a more sophisticated understanding of humoral immunity in preclinical models and in patients with MS, have led to major progress in deciphering the immune pathogenesis of MS. Here, we review the nuanced roles of B cells in MS autoimmunity, the clinical data supporting the use of ocrelizumab and other anti-CD20 therapies in the treatment of MS, as well as safety and practical considerations for prescribing. Lastly, we summarize remaining unanswered questions regarding the proper role of anti-CD20 therapy in MS, its limitations, and the future landscape of B cell-based approaches to treatment. 

In my opinion, this paper seems to be little more than an advert for ocrelizumab, particularly as it states the manufactures provide "writing assistance for CD20-related presentations"

Anyway, it says:

"Although most disease-modifying therapies for MS have traditionally been conceptualized as functioning via T cell-based mechanisms, a growing body of data indicates that all have demonstrable effects on B cells as well".

"Common themes include 
  • Promoting naive rather than memory or plasmablast (alemtuzumab); 
  • Shifting B cell cytokines towards an anti-inflammatory tone (beta interferon, glatiramer acetate, fingolimod);
  • Increasing B-regs (beta interferon, glateriamer acetate, fingolimod and dimethyl fumarate); 
  • Decreasing class II MHC and constimulatory molecules on B cells required for antigen presentation (beta interferon and dimethyl fumarate); 
  • Sequestering B cells in lymphoid organs (fingolimod); 
  • Blocking VLA-4 mediated B cell trafficking to the CNS (natalizumab); or
  • Direct cytolysis of B cells (alemtuzumab, teriflunomide, mitoxantrone)" 
As for ocrelizumab
  • Potentially pathogenic memory B cells remain at reduced levels
  • Fewer GM-CSF producing B cells and higher levels of IL-10
  • Fewer pro-inflammatory Th1 & Th17 cells
  • Large number of CD25+FOXP3 regulatory T cells
So as the year draws to a close, 

I ask you to remember what you have learnt this year and ask you to consider this ....


Do you want to believe the Jumble of Conflicting and Inconsistent Ideas? as all the above are possible. It means the MS treatment landscape is difficult to comprehend and navigate or


Is it simpler that MS treatments all physically or functionally deplete memory B cells (maybe to stop them becoming plasmablasts) to prevent them entering the CNS.


This gives a unifying idea on aetiology, pathology and response to treatment?


It makes treatment choices easier.

Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K. Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine. 2017;16:41-50.

Which fits the MS reality?

Let's put it to the test and see what happens in 2018.


I predict that more people will fall off the fence



Or maybe I'll eat humble pie.

15 comments:

  1. Coming up with an agreed understanding of what's drving MS won't happen in 2018. It's the equivalent of Turkeys voting for Christmas. MSologists (researchers and clinicians) have feasted on this disease for 50 years. Teams have carved out areas of interest (genes,viruses,sex, progressive MS, childhood MS etc. etc.) for decades. Why would they kill the goose which lays the golden egg (research grants, overseas conferences, consultancy fees)? I can't imagine the mouse doctors getting real jobs and what about all those future PhD students who will no longer churn out worthless research papers based on the rubbish which is EAE. Mouse Doctor 1 is Mr EAE, Mr T Cell. I find it a bit rich that you are now so evangelical about B Cells. In 2018, i'd like to see a successful outcome to MD1's spasticity trial. He can then retire in comfort and there will be a boost for the UK's real ale business, an upsurge in heavy metal CD sales and a big dividend from my shares in Greggs the Bakers. Happy New Year Team G.

    ReplyDelete
    Replies
    1. All change in 2018, except... trust that MD will keep banging the drum about B cells. It helps that he's fundamentally much less interested in the animal disease EAE than the human disease MS.

      On the matter of nutrition & exercise, BartsMS are due to resume their own individual Brain Health programmes, which includes reducing much of the above except - hopefully for MD - a moderate and if so highly deserved windfall for developing from scratch an entirely new drug to treat spasticity (and perhaps more).

      Happy New Year to you too!

      Delete
  2. Happy New Year!!! Thanks for all you do to benefit us with MS, and I’m eagerly awaiting the anti spasticity drug.

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  3. I am due to start treatment with Cladribine in January so feeling hopeful. Thankyou for the time you all dedicate to research at Barts to help people with this horrible disease and I wish you all a very peaceful 2018.

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  4. A word of encouragement, a kindly word, a cheery smile (thank you Dr Schmierer); all help to make this world a better place, especially when you're having to deal with a chronic illness like MS, whether as a patient, carer or health professional.

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  5. Until Roche releases brain atrophy results for ocrelizumab that shows equivalent efficacy as alemtuzumab. The jury is still out and rightly so. You can't say the disease is b cell driven Until brain atrophy is not reduced by equivalent amount to non b cell therapy. Patient selection does not explain the difference. For the following reasons.
    Not all patients are diagnosed same time
    Not all patient progress same rate.
    Not all patient go into remission same length of time.
    One should fight all forms zealot like belief until we have ALL the data that proves your zealot like belief is justified. Happy New year.

    ReplyDelete
    Replies
    1. surely it needs to be head to head or an identical trial

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    2. Thanks MD. Yes indeed. But if I was a betting man I'll put my money on b cells. But this not enough to persuade equally qualified t cell enthusiasts.

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  6. Maybe we are hesitant because the only thing that has been proved till now -in other autoimmunes too, is that memory B-cells are playing a major role in autoimmune inflammation (even if all existing MS drugs do exactly that). Maybe, because noone has proposed a curative therapy based on memory B-cells. Maybe, because we know that it works too at the low-hanging fruits and it doesn't prevent progressive MS, not because it works on the periphery (Lemtrada does too). Maybe because the T-cell mafia, that spreads to most of the immune diseases, has better ideas to move forward and not only deplete.
    But we know much less for B cells than for Ts, so the possibilities are open!
    Happy New Year to Barts team!

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    Replies
    1. I thik progressive MS is another issue but that maybe 2018 crusade

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  7. Thank you for all you do!! I read your blog religiously. As I progress each day loosing a little bit of myself it is difficult to know there are so many not willing to put time and money into repairing and restoring us to our former selves. For the record I am worth it!

    ReplyDelete
    Replies
    1. There is loads going into repairing and restoring some of it is not yet ready for prime time

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  8. Just the one interesting question for me: what is Ibudilast doing for MS and how?

    ReplyDelete
    Replies
    1. We heard the ECTRIMS report we need to see the full data and an digest it.

      Delete
  9. This seems interesting - https://medicalxpress.com/news/2017-12-potential-path-multiple-sclerosis-damaged-nerves.html

    ReplyDelete

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