Monday, 14 September 2015

NeuroSpeak: talk on new MS treatment targets

Keele CNS inflammation talk on MS treatment targets. #MSBlog #NeuroSpeak

"As promised the following are my slides from Saturday's talk. Apologies, I couldn't attend on Friday, but I had an extra clinic. As you can see many of slides are old and if I say so myself rather jaded. May be I need to refresh them."



CoI: multiple, Biogen sponsored the meeting 

32 comments:

  1. Induction therapy is potentially curative. Will we wait 15-20 years for know if it is actually curative?

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    1. It will take long-term follow-up to determine whether this is indeed the case but reducing/stopping overt diase activity has to be important on slowing/stopping potential progression. My guess is that induction therapy should be accompanied by neuroprotective therapy (to be determined).

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    2. Re: "Induction therapy is potentially curative. Will we wait 15-20 years for know if it is actually curative?"

      This will only apply to a proportion of subjects treated with induction therapies. We know this as a minority of patients treated with Alemtuzumab or HSCT have breakthrough disease and require retreatment.

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    3. Researchers have known for a long time that disease activity (in this case relapses) have no impact on long term disability:

      http://www.nejm.org/doi/full/10.1056/NEJM200011163432001

      There Is no reason to wait 15 years to come to a conclusion.

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    4. That paper is 15 years old, well before the current much more effective disease-modifying therapies.

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    5. "The absence of a relation between relapses and irreversible disability suggests that there is a dissociation at the biologic level between recurrent acute focal inflammation
      and progressive degeneration of the centralnervous system.

      This apparent paradox is consistent with the persistence of the progression of disabilityin patients with multiple sclerosis despite infection with the human immunodeficiency virus22 or despite suppression of the cerebral inflammation after treatment with a potent antileukocyte monoclonalantibody.23"

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    6. Researchers have known for a long time that disease activity (in this case relapses) have no impact on long term disability:

      Please read through the blog as there numerous posts that argue against this view

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  2. I attended the meeting and this talk provoked heated discussion amongst neurologists both during and after the meeting. I would say that we have not proven that disability progression is fully independent of relapses and that things have certainly changed in the last 15 years. Fifteen years ago we had no effective treatments for MS.

    Neurologists may well be stopping patients from getting effective treatments. We need to record our patient outcomes in the era of effective treatments for relapsing remitting MS. If we do not use highly effective treatments we may be consigning another generation of people with MS to early and long term disability. We may not manage to prevent secondary progression but we owe it to out patients to try. We should have clear and sensible discussions with patients about the risks and benefits of all the available drugs.

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    1. what does this say about us when we put our head in the sand and do nothing or very little. It should not need a brain surgeon to tell uz that diseazse activity is a bad thing and should not be tolerated but you have a marketing machine pulling the wool over peoples eyes.

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    2. It just makes logical sense, treat early and effectively means less damage and less impact in the future.

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  3. What's the case for arguing against induction treatments in preference to a less effective maintenance treatment? Risks? The risk of not treating effectively early seems far greater than any risk associated with induction treatments.

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    1. From the point of view of Team G, everyone should start on Lemtrada. The fact is that this treatment is appropriate for only a slight minority of MSers with highly active disease.

      Team G would like to scare you into thinking that if you are not on this you will become disabled.

      It is no coincidence that the placebo relapse rate in trials was above 1 in the pre-DMD era and in the post DMD era it is hard to find results that compare to this rate.

      The point is Induction therapies are appropriate for those with active disease but not so much for the bulk of MSers.

      But the Team G marketing machine will keep pushing the latest therapies to be approved while relegating the rest as less effective as time goes by. The skies the limit.

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    2. Re: "From the point of view of Team G, everyone should start on Lemtrada. "

      Incorrect; if you look at our T2T-NEDA there is quite a few decisions that MSers need to make. In fact the minority of our patients choose the induction-alemtuzumab route. Some simply find it too risky.

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    3. Yes, what I was saying that if it was up to Team G (and not the patient), everyone would be on Lemtrada. It seems you would not waste anytime determining if a person responds to a less effective drug.

      Since Lemtrada is a first line in the UK this would be what you recommend to all your patients, correct?

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    4. Incorrect, at any one time most people with early disease have inactive disease or if they have active disease don't fulfill the criteria for active disease as defined by the EMA license. The latter is based on the entry criteria of the clinical trials. In the UK we can only prescribe DMTs according NHS England guidelines; based on this may 10% (max) of people with early MS will be eligible for alemtuzumab. The reason why we are seeing a lot of early alemtuzumab activity is warehousing and referral of patients from other centres who are not up and running with their alemtuzumab service. Also most of our alemtuzumab-treated patients are switch patients and not 1st-liners.

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    5. many year ago there were no treatments and so the relapse rate was high, no with MS nurses and treatments people with hghly active disease with get treat and so don't need to enroll in trials and so the relapse rate of the placebo groups drops because we are looking at a different demographic

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    6. Anon 11:26; "this treatment is appropriate for only a slight proportion of MSers with highly active disease"

      This may be the case purely due to prescribing criteria. Not because it won't work for the majority. My disease is early & inactive currently, but chances are almost certain that it WILL become active at some point. Why wait for the inevitable when there's an induction therapy with a good chance of preventing disease progression? Not to mention putting a stop to sub-clinical progression & brain atrophy that is most likely occurring now.

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    7. One thing that Team G will never mention is that your immune system is vital for cancer surveillance. Removing large components of this system and expecting it to regenerate such as that of an infant will not happen because your thymus degrades as you age.

      So, you may feel better in the short term but if you sit down and think about if this therapy is a wise approach you may have second thoughts.

      So the question is what will deleting wide swaths of your immune system do to cancer rates down the road? My guess it can only be detremental.

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    8. We've voiced our concers on general immunosuppression and the possible risk of cancers etc on many occasions. At the monent, general immunosuppressants are the tools available. We need more specific therapies, an area we've been heavily involved in over many years.
      http://multiple-sclerosis-research.blogspot.com/2014/09/profiling-antigen-specific-therapy.html
      "Antigen-specific therapy is the only way to control autoimmunity, whilst limiting the effects on generalised immunosuppression,that can lead to infections, in some instances cancer. At present we are using a "hammer to crack a nut" and most immune modulating drugs take out large parts of the immune system and can result in things such as PML, which is sometimes a lethal infection caused by lack of immune monitoring of the brain by the immune system."

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    9. As we're talking about cancer. What I would like to know, is why my multiple undiagnosed cancers didn't metastasise, even though they were not thought to be cancer for a long time? Never been on any treatment for MS, so is my disease protecting me? Anyone can get cancer, with or without treatment, we all have a choice, doctors give us their opinion, but they don't make the final decision.

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  4. Perhaps a meta-analysis of cancer risk after alemtuzumab treatment may be useful - certainly this paper from a renal unit using alemtuzumab as induction therapy for renal transplants found no increased risk of cancer.

    http://www.ncbi.nlm.nih.gov/pubmed/23480032

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  5. Anon 11:08am; Theoretically your point has merit. But trials & long standing experience with Alemtuzumab as Campath show no increased incidence of secondary malignancy.

    So what you're saying is that as the thymus ages, it produces higher ratios of 'cancer-prone' cells?

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  6. Anon Wednesday, September 16, 2015 12:31:00 p.m.,

    Actually one theory is that the immune system is in balance at keeping cancers at bay because your immune system can regenerate when you are young. But as you age, new immune cells are not generated from the thymus and the immune system relies on memory cell (look up thymic involution).

    This is an explanation of why cancer become prevalent at older age. So, it seems that induction therapies like HSCT and Lemtrada do shuffle the composition of your immune system but this is not due to a new regeneration of immune cells.

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  7. Thanks. Prof G, could you please add your thoughts on the effect of intense immunosuppression caused by Lemtrada on cancer risk?

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    1. I think the induction therapies like Lemtrada and HSCT are indeed experiments. 15-20 years to see if it halts MS but also 30-40 years to see what effect it will have on cancer rates.

      Here is a good overview of how the immune system functions in terms of cancer surveillance:

      http://annonc.oxfordjournals.org/content/23/suppl_8/viii6.full

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    2. there is plenty of published literature on cancer post HSCT (and I'm going to guess on lemtrada, though i haven't looked into it). granted, the published literature is in the context of cancer patients, but some of it is transferrable to auto immune disease. just because these treatments are new to the ms world, doesn't they're actually new.

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  8. What conclusions were drawn from the group following your presentation Prof G? Did you meet any resistance / disagreement? I'm very interested to know what peoples views were re shared decision making and if it is felt the paternalistic approach still has a role.

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    1. Re: "What conclusions were drawn from the group following your presentation Prof G? "

      A lot of disagreement. The majority of MS Centres in the UK don't have the staff, time and resources to treat-2-target. Some neurologists don't think the evidence is strong enough to treat to target and want to wait the 15-20 years to see the data before they change their practice. The latter is why we need to test this concept in a clinical trial; we need to copy what the rheumatologists did in RA.

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  9. Re "Some neurologists don't think the evidence is strong enough to treat to target and want to wait the 15-20 years to see the data before they change their practice."

    As far as RRMS goes - some neurologists probably need a big kick up the backside then - it's not their 15-20 years of decline and increasing disability, lost earning capacity, wrecked lives, etc while they sit round to wait and see the data.. There has been much discussion on this blog about patients being involved in decision making about treatments, and while some people don't want to make their own decisions and just want to do what the "good" doctor tells them, there are plenty of others who want to be included in deciding what treatment is used.

    As far as progressive MS goes - we need to keep the pressure on to find treatments for progressive MS, but I'm sure the same "doubting Thomas" neurologists will also want to see 15-20 years of data for that also. Again - it's not their lives being stuffed up.

    Maybe a few of these neuros should do a bit of walking a mile in MS shoes, or get sent on a boot camp type of training course that will wake them up to what those of us with significant loss of function due to MS have to deal with every day (you know - give them some drugs that cause bladder and bowel problems, numb their legs up a bit, generate a few tremors and some spasticity and muscle spasms, cause a few unpredictable bouts of the dizzies, generate a bit of devastating fatigue and cog fog - I'm sure readers get the picture...........)

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    1. "As far as RRMS goes - some neurologists probably need a big kick up the backside then..."

      Form an orderly queue.

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