Monday, 20 November 2017

Rumble in the Jungle Part II

The "Rumble in le Jungle" at ECTRIMS2017 turned into a "Bumble in the Immunological jungle" as the Heavyweight clash turned into a love-fest. 

UPDATE: Slides added


Both contestants had taken too many "peace-pills" rather than defend their corner, both threw in the towel to conclude that T and B cells were both (equally important) central to the problem of MS.

After a promising start, Prof.Hauser slipped on the canvas never recovered and started to verbally-punch himself with counter arguments such that Prof Hafler didn't have to bother defending himself or attacking the alternative view. Just as well, as he forgot his boxing gloves and came with the Immunological Karma Sutra of T and B cell interaction. 

With the thought of "Fake News" in both of the American contestants minds, could they defend any extreme position?


Perhaps there was fear of losing?

So much fun was had, that ProfG has gone for Round Two, and this time has persuaded ProfB (Lightweight) to take the challenge to Heinz Weindl (Heavy Weight). Today 



But to make it easier for Prof Weindl to accept the challenge, the loop-hole has been closed so that the T and B cells can be the problem as you have to explain how ocrelizumab works, which was the majority view expressed at ECTRIMS, when given the Choice.


The motion is
"To B or not-T-B that is the question"; the key pathogenic cell in MS is a B-cell and is independent of antigen presentation to T-cells"

Sounds like ProfB is in for a verbal kicking from the opponent and probably the audience. 

However, when the vote went live to twitter sphere after people had watched the videos and could not say both


Rather than a Boxing Match, maybe we should think of if it as a trial with the MS problem in the dock, 



There has been a game of Whodunnit called Cludedo



We have a victim the Ms. Oligodendrocyte has been murd**ed (killed). (If I use the word m******d, it triggers google to make this an adult site).

Where did the event take place?


We found the Body in the "Brain Room", but is that where the crime was plotted?

What was the killing weapon? 




Importantly Who is the killer and guilty, (Princess) B or Mr T? Are there any accomplices?




You will hear two theories/cases and the audience can be the Jury to "Acquit One" and "Find the other Guilty" as charged




Can we expect to see the "Chubbacca defence(deliberately confuse the jury rather than to factually refute the case of the other side) from the Weindl Team



The punishment will be the Death Penalty for the Guilty Party unless there can be rehabilitation.



The debate isn't being filmed, but we will rehearse the arguments from both side after the debate.

*****************************************************

Here are the slides (The Jokes have been removed)


As you can see the task given to ProfB was to argue that B cells can cause MS and this was not mediated by T cells and the activity due to B cells was not antigen presentation. 

This view was against what most people thought (about 60%). 

(a) The Key Idea presented was that the important subsets would come from looking at the response to therapy.

(b) It was argued by the audience that animal studies show that B cells present antigens to T cells in animals.

It was said because MOG T cell receptor transgenic (developed optic neuritis but not EAE) x MOG B cell receptor (immunoglobulin) transgenic mice (do not get EAE) get EAE means that B cells present antibody to T cells. 

This is not necessarily right as MOG T cell receptor transgenic mice, which get optic neuritis in both eyes, get sub-clinical spinal cord EAE. Add anti-MOG antibody and you get augmentation of disease and this can make mice develop clinical EAE, so no B cell presentation occurring.

Although B cells may well present antigens and there is evidence to support, this based on my extreme stance is irrelevant as animal models lack validity, because the CD20 depleting antibodies have a modest/marginal effect compared to that seen in humans.  We know animal models are T cell mediated. The aim here was not to discuss any of the animal work. MS is a human disease let's have a human based explanation

(c) Importantly the case was made that T cell depletion had a marginal effect. Now I could argue why the T cell depletion trials had not worked but I was attacking this view,

Again there was uproar by the T cell immunologists when it was suggested by that their much loved Th17 cells didn't do much in MS. 

This was contentious as expected. The audience and Prof W argued that IL-17A blockage didn't fail...ProfB's response was he didn't say it failed, he said it was no better than beta interferon, which is hardly a view that interleukin 17 was something magic. 

Activity of secukinumab, an anti-IL-17A antibody, on brain lesions in RRMS: results from a randomized, proof-of-concept study.Havrdová E, Belova A, Goloborodko A, Tisserant A, Wright A, Wallstroem E, Garren H, Maguire RP, Johns DR. J Neurol. 2016;263:1287-95.
The objective of this study was to assess the effect of secukinumab, a monoclonal antibody that inhibits interleukin (IL)-17A, on number of new active brain magnetic resonance imaging (MRI) lesions in subjects with relapsing-remitting multiple sclerosis (MS). Subjects (N = 73) were randomized 1:1 to secukinumab 10 mg/kg or placebo by intravenous infusion at weeks 0, 2, 4, 8, 12, 16, and 20. MRI scans were obtained within 30 days prior to randomization, on a monthly basis during the treatment period, and at study completion. The primary endpoint was the cumulative number of combined unique active lesions (CUAL) observed on brain MRI scans from week 4 to week 24. Compared with placebo, secukinumab non-significantly (MEANS THE TRIAL FAILED as the primary endpoint was not met) reduced the number of CUAL observed on 4-weekly MRI from week 4 to 24 (primary endpoint) by 49 % (95 % CI -10 to 77 %; P = 0.087) and significantly reduced the number of cumulative new gadolinium-enhancing T1 lesions by 67 % (31-84 %, P = 0.003). CUAL reductions were progressively greater from week 4 (1 %) to week 16 (49 %) and persisted until end-study (50 %). There were no serious adverse events; the adverse event rate was comparable to placebo (53 versus 49 %), although mild-to-moderate infection was somewhat more frequent (37 versus 23 %). This proof-of-concept study provides the first evidence that blocking IL-17A with an antibody may reduce MRI lesion activity in MS. Further studies are needed to confirm this finding and determine the magnitude of effect. 

The primary endpoint did not reach significance and so the study failed....That's how we do trials.

What does Beta interferon do?
Ann Neurol. 1994;36 Suppl:S113-4. This trial was monitored by both clinical and magnetic resonance imaging (MRI) methods. Clinical effect was a 30% reduction in relapse rate in the group treated with a high dose. The MRI activity rate was reduced by a median of 70% in both treatment groups.

De Stefano N, Curtin F, Stubinski B, Blevins G, Drulovic J, Issard D, Shotekov P, Gasperini C; IMPROVE Study Investigators.
Rapid benefits of a new formulation of subcutaneous interferon beta-1a in relapsing-remitting multiple sclerosis. Mult Scler. 2010; 16(7):888-92.

This study evaluated the efficacy of a new formulation of subcutaneous (sc) interferon (IFN)-β1a in relapsing—remitting multiple sclerosis (RRMS). Patients (n = 180) were randomized (2 : 1) to IFN-β1a or placebo for 16 weeks; all patients then received IFN-β1a for 24 weeks. Monthly brain MRI was performed. At week 16, the mean number of combined unique active (CUA) lesions was lower with IFN-β1a than with placebo (p < 0.001; 69% fewer lesions). The mean cumulative number of CUA lesions was already lower with IFN-β1a by week 4 (post hoc analysis; p = 0.015). The new formulation of sc IFN-β1a has rapid beneficial effects on MRI outcomes in RRMS

So anti-IL17 is hardly in the league of something like natalizumab.  

Were the T cell immunologists deluding themselves?

However, is it the inhibition of interleukin 17 actually due to Th17 effects? IL-17 is involved in B cell development and can enhance B cell proliferation and germinal center formation. Therefore it could effect memory B cell formation. I guess we will have to wait to see if this is found in psoriasis where the blocking antibody is being used. 

(d) The argument was made that Tcellers stop people understanding of how MS works because they view MS as a single cell type. This was clearly evident in the argument of ProfW

(d) An argument was that memory B cells and EBV was interlinked
The question was asked if you have antigen specific B cells, there must be antigen specific T cells. What are they doing? 

If the question was turned around and you ask a T celler, what are the antigen specific B cells doing? The answer may be who cares about B cells.

However, if EBV is driving the memory B cell activity, 
Does there need to be a T cell help as the virus can make naive  B cells proliferate and differentiate into memory B cells and this could be without T cells

There are testable hypothesis that come for these studies, 

I suspect the T cellers will continue with their T cell stuff as usual. This is fine meaning we can do it.

However, there was enough open-minded  people in the audience to see sense and they are the people who may be treating you.

26 comments:

  1. Oh what hijinks and larks. So much fun. I almost forgot that nearly all DMDs are a wasted time and that you're paying lip service to treating pwMS and just playing in your sandbox world of pharma funded low efficacy drugs.

    Still ha, what fun with your funny light-hearted post.

    ReplyDelete
    Replies
    1. No its about education.
      You can present information in an entertaining way and it helps people remember.

      Delete
    2. Will you watch the miracle cure and come back with the same type of comment....I suspect not

      Delete
  2. Thank you for this entertaining read - it made me laugh out loud. Injecting a bit of fun into a serious topic makes it easier for civilian MSers like me to get the gist of topics that I might not otherwise quite get around to reading about, however good my intentions.

    ReplyDelete
    Replies
    1. It does the exact opposite actually. It obfuscates exactness and precise arguements. It also blurs important nuances such as the reader being mislead or incorrect use od data.

      Aside from that it's not 'fun'. Car chases, fairground rides and alien landings are exciting and fun. Not some obsured boxing match parallel.

      Delete
    2. The debates are debates....they are what they. It blurs important nuances...not necessairily

      Delete
    3. My reaction: exactly the same as Chris and Alison: I laughed out loud and was grateful to MD for presenting info in a lay person accessible way and with a degree of humour, that for myself, was not inappropriate. The life of MS, in all its manifestations, can be overwhelming dire and/or miserable, including sometimes, the scientific aspects, so a light hearted touch being used sometimes, is welcome to some of us.

      Delete
  3. Honest, work ,great post (allthough i disagree in some parts)

    Keep up

    Obrigado

    ReplyDelete
    Replies
    1. it is a debate and you have to take extreme views some you agree on some you don't but it is up to the other side to argue against these views and this did not happen

      which parts do you disagree on because if it is wrong we should modify and move forward

      Delete
  4. B cell depletion appears to decreasead relapses but not progression

    Abstract
    Objective: To compare treatment effectiveness and persistence in relapsing-remitting multiple sclerosis
    patients who initiated rituximab versus glatiramer acetate (GA) or interferon-beta (IFN-β).
    Methods: A total of 461 patients from the Swedish MS registry in the rituximab arm were propensity
    score matched on a 1:2 basis with 922 patients from the IFN-β/GA comparator, between April 2005 and
    November 2015. Annualised relapse rate (ARR) was compared using the Poisson method. A marginal
    Cox model was used to analyse time to first relapse, 3-month confirmed disability progression and treatment
    discontinuation in the matched sample. A signed-rank test was used to compare Expanded Disability
    Status Scale (EDSS) change from baseline.
    Results: Rituximab was associated with a reduction in ARR (0.003; 95% confidence interval (CI) = 0.001,
    0.009) relative to IFN-β/GA (0.026; 95% CI = 0.020, 0.033) (p < 0.001). Rituximab was associated with
    an 87% reduction in the relapse rate (hazard ratio (HR) = 0.13; 95% CI = 0.04, 0.41) and an 85% reduction
    in the discontinuation rate (HR = 0.15; 95% CI = 0.11, 0.20) relative to IFN-β/GA. EDSS regression from
    baseline was greater in the rituximab group at 12 and 24 months.
    Conclusion: Rituximab appears to be superior to first-generation disease-modifying treatments (DMTs)
    with respect to relapse control and tolerability, whereas superiority on disability outcomes is less clear.

    DOI: 10.1177/
    1352458517713668

    Also this paper shows that Cd4+ t cell are important in b cell

    maturation. Maybe thats why you dont get much ms in hiv infected

    populations (cd4+ disease)

    Idiopathic CD4 T lymphocytopenia is associated with increases
    in immature/transitional B cells and serum levels of IL-7

    Idiopathic CD4 T lymphocytopenia (ICL)
    is a rare heterogeneous disorder defined
    by CD4 T-cell counts below 300 cells/ L
    in the absence of human immunodeficiency
    virus (HIV) infection or other known
    immune deficiency disorders. Here, we
    report the expansion of immature/
    transitional B cells in patients with ICL,
    which is associated with elevated serum
    levels of IL-7. Both the percentage of
    immature/transitional B cells and levels
    of IL-7 were inversely correlated with levels
    of CD4 T-cell counts and directly
    correlated to each other. Further analyses
    of B cells indicated that, in contrast to the
    activating effects of HIV disease on mature
    B cells, the expansion of immature/
    transitional B cells in patients with ICL
    occurred at the expense of memory
    B cells. These findings extend previous
    reports on primary immunodeficiencies
    as well as HIV disease by suggesting that
    CD4 T-cell lymphopenia has an impact
    on human B-cell development either directly
    or indirectly via the associated elevation
    of IL-7 levels.

    (Blood. 2007;109:
    2086-2088)


    Last if your Ebv hyphotesis is correct teriflumonide should be the

    most potent drug around and not(Alemtuzumab,cladribine,rituximab,hsct
    )

    Thanks Md

    Obrigado

    ReplyDelete
    Replies
    1. Not sure why teriflunomide would be most active, it is an anti-proliferative drug. In memory B EBV is quiescent, I would predict its depletion effect on memory B would not be that startling based on efficacy, If it is the hypothesis begins to fall apart.

      However, the EBV effect would have occurred before you have MS. Based on US service data this would be 2 or more years before MS surfaces


      In my argument I was not allowed to discuss how T cells could influence B cell development, but there clearly are T cells that help B cell development. This why I did not say they were inoccent they must be facilitators.

      it is interesting you pick up IL-7 and as you know IL-7 receptor is an MS suceptibility gene. It was seen as a T cell protein but as you suggest IL-7 can affect B cell function. IL-7R is on pre B cells. I think immature cells entering the blood is a space filling response.

      I would have to read the paper as it suggests that as immature cells go up memory B cells decrease. If they are working on percentages if one goes up another comes down or if one goes down another goes up. we need absolute number.

      "rituximab stops relapses not progression". I will read paper but would need to see data of rituximab from diagnosis

      Delete
    2. How B cells influence progression is another talk

      Delete
    3. Dear Luis
      The disease duration for rituximab was median (IQR) 10.6 (7.4-15.0)
      verses 5.7 (2.0-11.1) so say DMT does not stop progression I want to see rituximab and interferon treatment data within 1 year

      Delete
    4. Well spoted Md did nt see that coming

      This one as 33months followup and disability improvement

      Background:
      Rituximab is a monoclonal antibody directed at CD20 positive B-lymphocytes and a
      potential therapeutic option in the treatment of multiple sclerosis. The safety of recurrent dosing is
      not established.
      Objectives:
      The objective of this work was to report the experience of long-term rituximab adminis-
      tration in a comprehensive multiple sclerosis care clinic.
      Methods:
      This was a single-center retrospective observational analysis of patients receiving rituximab
      for the treatment of multiple sclerosis from 2004 to 2015. Different dosing regimens were reviewed to
      determine whether frequency or dose may affect safety. CD19 and CD20 counts were collected to
      evaluate B-cell suppression during therapy. Relapses, magnetic resonance imaging activity and ritux-
      imab-related adverse events were collected by chart review and prospective database entry.
      Results:
      Of 107 patients included, the average duration of treatment was 33.2 months. Seventy-seven
      patients received recurrent rituximab dosing after initiation. CD19/20 reconstitution occurred in
      approximately 20% of patients at 6 months, regardless of dosing strategy. Despite CD19/20 counts of 0,
      three patients had relapses or magnetic resonance imaging activity. Mostly mild side effects in relation
      to therapy were seen, with the exception of three patients requiring hospitalization for urinary tract
      infections.
      Conclusions:
      In our clinic population, rituximab was well tolerated and safe with recurrent
      administration.

      DOI: 10.1177/
      2055217316672100

      This Systematic Review confirms the swedish study
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699597/
      1
      Is rituximab effective in reducing the time to confirmed disease progression (CDP)?

      Only one of the studies used CDP as an outcome. Rituximab appeared to reduce progression by a marginal amount although the difference did not achieve statistical significance except in pre-planned analysis comparing young patients (under age 51 years) to older patients, and in those comparing patients with baseline Gad-enhancing lesions compared to those without baseline Gad-enhancing lesions. Another study explored disease progression comparing EDSS at the end of the study with baseline EDSS. Most patients (21/30) remained stable.

      So mix results on progression taking rituxan

      Obrigado

      Luis

      Delete
    5. again response to therapy tells us that inhibiting peripheral B cell response is not enough for progression

      Delete
  5. I love this post. Thanks I needed the science with Mr Tee. Play that again in your pharma sandbox. I support you and I’m no gullible MSer.

    ReplyDelete
  6. How do you account for the apparently superior efficacy of alemtuzumab in terms of normalizing brain atrophy and improvements in disability over the b-cell depleting agents? Does alemtuzumab do a better job of depleting B cells? If not, then doesn't this suggest that T cells are implicated in the disease process in significant ways?

    ReplyDelete
    Replies
    1. We need a head to head, the people in the alemtuzumab trials were on drug very quickly and so have more repair potential.

      Does it do a better job at depleting B cells...I doubt it...I bet they are similar.

      I am sure T cells play a role in MS, but is it in a way EAE suggests...I currently doubt it...Tomorrow could be different.

      Delete
    2. Alemtuzumab doesn't penetrate the brain either, so this is not a reason if RTX isn't as effective...

      Delete
    3. Has rituximab been used to start treatment early...maybe in sweden they could look to see if there are any difference in atrophy data comapring early verses late treatment. However brain atrophy as an outcome is flawed.

      Delete

    4. "However brain atrophy as an outcome is flawed."

      How so..?

      Delete
    5. Brain volume is a composite it can shrink due to an anti-inflammatory effect

      Delete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.