DMF inhibiting B cells numbers

D

 

Times are a changing folks. 
Not a year ago the same type of phenotpying data was reported in the blood of people treated with DMF. 
The focus has now changed, guess where.
Høglund RA, Polak J, Vartdal F, Holmøy T, Lossius A.
Mult Scler Relat Disord. 2018 Sep 6;26:90-95. doi: 10.1016/j.msard.2018.08.032. [Epub ahead of print]
 


BACKGROUND:

B cells may contribute to the immunopathogenesis of multiple sclerosis (MS). Dimethyl fumarate (DMF) has recently been shown to reduce the frequency of memory B cells in blood, but it is not known whether the drug influences the cellular composition in the cerebrospinal fluid (CSF).


METHODS:

A cross-sectional study examining the cellular composition in blood and cerebrospinal fluid (CSF) from 10 patients treated with DMF and 18 patients receiving other disease modifying drugs or no treatment.


RESULTS:

Patients treated with DMF had reduced proportions of memory B cells in blood compared to other MS patients (p = 0.0007), and the reduction correlated with treatment duration (rs = -0.75, p = 0.021). In the CSF, the absolute number of mononuclear cells were significantly lower in DMF-treated patients compared to the other patients (p = 0.023), and there was a disproportionate decrease of plasmablasts (p = 0.031).


CONCLUSION:

The results of this exploratory study support a B-cell mediated mechanism of action for DMF in both blood and CSF.
A year ago the other authors did this and selected to focus on T cells, and CD8 T cells at that as the major cell type depleted by DMF. 


Memory B cells were a close second and didn’t get a look-in.


Fastforward  a year and we have more of a focus on memory B cells. They are dropped in the blood following treatment and supports the hypothesis we and others created. 


(OK I a guess it is ocrelizumab being licenced that is driving all this interest in B cells:-0)


This study looks in the CNS. In most countries, the CNS is out of bounds but the Scandinanvias are made of stern stuff and lumbar puncture studies are often done. 
This study from Norway looks at the influence of dimethyl fumarate and finds that there is a drop in plasmablasts. 


Memory B cells are generally the dominant subtype in the cerebrospoinal fluid and brain, but have the capacity to change into plasmablasts and plasma cells.This may reflect a maturation step due to seeing a target of interest but it may put us a step closer to thinking about progression of MS.


If we look at the data, In this study memory B cells are about 25-35% of cells in the blood but are about 75% of B cells in the spinal fluid. This wasn’t lower than other treatments and there was not a decrease in the intrathecal antibody. So maybe DMF is is not sufficiently active in the CNS.
We have recently propossed a B cell centric mechanism whereby B cells in the brain could easily become plasma blasts  and contribute to progressive MS. We would hope to see fewer cells in the brains of people treated with DMT and this study ticks that box.
Biogen did a fantastic immunophenotyping study in the blood with tecfidera ( I only saw this presented at ECTRIMS), 
it would be really good if Sanofi did one on teriflunomide so we can get the data there. I’ve seen a p 


One would predict it is varied to reflect the variable efficacy and not that great and maybe if used second line it might be less varied, if ProfG is right about relative efficacy second line.


If fact I can say it won’t be that great based on the data from arthritis with leflunomide which is broken down to teriflunomide once injected


Wijesinghe H et al. BMS musculoskeletal Disorders 2017:18:310.

It says no effect on whole T or B cell populations but a modest depletion of memory B cells compared to highly active agent like rituximab which has marked impact on B cells and memory B cells

This is a hypothesis with teriflunomide, I’ld like to test. On a mean basis memory B’s will go do in absolute terms but it won’t be great


Gandoglia I et al.Teriflunomide treatment reduces B cells in patients with MS. . 2017; 4(6): e403.


But not sure we have enough people taking the drug.

About the author

MouseDoctor

9 comments

  • Great to hear someone has reported on Memory B cells at last. In CSF too! Wonder how long depleted for? Maybe not long if you have to keep taking dmf to be effective 🙁
    P'raps we all need to be like the Scandinavians and monitor CSF B cell subsets rather than meaningless total lymphocyte counts from peripheral blood.

    • Judging by Biogens own (preliminary)PROCLAIM data, the max effect of DMF on memory B cells seems to occur only after several months of therapy. I have yet to see any immune reconstitution data, addressing how/when these effects are reversed.

  • You suggest that plasma cells play an important role in MS progression. But DMF doesn't have an impressive impact in MS progression (38%). Does this turn the theory?

    Also DMF, with such a modest impact on memory B cells -where with the anticd20 agents even a few hidden larking b*ches can cause a relapse- it would just be a lousy DMT, if it was working through this mechanism. But its not that lousy.
    DMF affects T cells too, but its not why its working.
    Is B-cells the new hype?

    I am more sold into this theory for DMF
    http://multiple-sclerosis-research.blogspot.com/2018/04/how-does-dimethyl-fumarate-work.html

    • I would like to highlight that the absolute count of CSF mononuclear cells actually was significantly lowered in DMF treated patients. If you extrapolate and consider this in light of stable relative numbers, the numbers of memory B cells were probably also reduced in absolute terms. The number of plasmblasts however, were reduced even more. Thus the memory B cell hypothesis still stands, in my opinion.

    • Thanks for this the absolute number is key to the understanding.

      I have just noticed a paper on teriflunomide and the percentage of memory B does not change, but the absolute number of B cells drops so there are less memory B.

      So they drop but not that much so it fits with the hierarchy of efficacy

    • MD You try to prove what you want to prove. Seems simplistic and contradictive to your own theories to me.

      PS R.A. we would like to see you more around!

    • MD you try to prove what you want..
      Nonense, you have been challenged to find the contradictiv the idea

By MouseDoctor

Translate

Categories

Recent Posts

Recent Comments

Archives