Progressive MS is just inflammation

Steinman L, Zamvil SS. Beginning of the end of two-stage theory purporting that inflammation then degeneration explains pathogenesis of progressive multiple sclerosis. Curr Opin Neurol. 2016. [Epub ahead of print]

PURPOSE OF REVIEW:The review discusses future directions in research on multiple sclerosis and neuromyelitis optica, as long-held beliefs about these diseases are undermined with data from recent clinical trials.
RECENT FINDINGS: Results of clinical trials for registration (phase 3) were reported in the last year. Anti-inflammatory approaches, such as daclizumab high-yield process targeting IL-2 receptor, and ocrelizumab targeting CD20 B cells, confirmed a beneficial role of immune suppression in relapsing-remitting disease. And now for the first time achieving the primary end point in primary progressive multiple sclerosis was attained with ocrelizumab.
SUMMARY: The results in the past year challenge the long-held belief that relapsing-remitting disease is inflammatory, whereas progressive forms of the disease are ‘less inflammatory’ and more ‘degenerative.’

Well the tide is changing, some people have believed that all aspects of MS are a problem of autoimmunity…largely T cell autoimmunity. Then came along rituximab and ocrelizumab and MS, and slowly EAE becomes a B cell disease. If this is true surely the end of progressive MS is nigh. 

The hint of efficacy of ocrelizumab in PPMS now means that the idea that progressive MS harbours a neurodegenerative process is going to be dismissed according to this new view. 

Is this going to be the new world view.

Personally I would not be too hasty to do this as all you have to do is actually look in progressive MS and you can see that it indeed progressive MS is less inflammatory and there is nerve loss.
The trial with ocreluzimab was loaded with potential responders but it did not halt progresive MS so in my opinion not yet time to relax, we need to do better.

So one swallow does not a summer make unless you live in California I guess 🙂

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  • I think Dr Mark Freedman summed up Ocrelizumab very well in this video:

    I have so-called PPMS and I'm not sure I'd want to take this drug.

    "The hint of efficacy of ocrelizumab in PPMS now means that the idea that progressive MS harbours a neurodegenerative process is going to be dismissed according to this new view."

    I really, really hope not.

    • So we may have a battle the freedman view and the Stanford view. I suspect the eae ologists will lap up the Stanford view. How many ms ologists will depends on their blinkers

    • If you have PPMS and ocrelizumab gets licenced it will be the first option available. It will give some benefit I am sure but it think you will need more but it is the base on which other agents can be laid

    • "it is the base on which other agents can be laid"

      I'm not sure about how this could be – when it's not clear that everyone with "PPMS" responds to Ocrelizumab, when there are serious health / toxicity concerns, when it's not really known what the long term risks are, and it is not known how long someone could be / would have to be exposed to this drug. For me personally, at present, it is the basis of very little; it seems to only target one element of progression – which may occur only in a discrete time window – with a potentially very high cost to some individuals.

    • I suspect everyone with ms has inflammation that may respond and everyone with ms has inflammation that does not. It will be a spectrum of high responders and low responders progressive Ms will be in the low side.

  • What are the differences MD one sees in the brains of PPMSers as compared to RRMSers?

    To my simple mind it always looked as if the fires (inflammation in RRMS) just got out of hand and burned the house down (brain) so only ashes are left (progressive stage due to too much nerve loss).

    I would think in PPMS it looks the same just much quicker so that you've got much more ashes much sooner than RRMS.

    • Yes I think many of the same processes occur in RRMS the differences are the level of lesions.At the moment I currently prefer a two stage process entry of the immune system into the brain that drives relapses and a different type of inflammation that drives progression the former conditions the latter. This better fits the treatment data.

      Replacing the immune system with hsct is the ultimate immune treatment and the current data is the more progressive the higher chance of lack of success. If progression is caused by antibodies and plasma cells then we can do better than ocrelizumab. The tools to address this are there. We are on the case

    • I am glad too. What is your sense of the timeline for effective treatments for PPMS. It's more than 20 years, right?

    • If the laquinmod trial succeeds a lot less than that, if the ibudilast succeeds alot less than that. I am more upbeat

  • I even going to comment here on the blog about this study.
    What MS as a whole, and especially the progressive forms of MS, it is in need of a potent anti-inflammatory or immunosuppressive B-cell associated with something that fight against JCV (vaccine, antiviral, etc.) is a potent neuroprotective.
    Very important that the blog has been doing on neuroprotection.
    I saw my neuro redefining a man of 27 years old, a computer scientist, with MS Secondary Progressive (I personally think he has Relapsing Primary).
    He is in Fingolimod, brain atrophy diminished but rather the neurodegeneration continues.
    Of course he needs neuroprotective and/or something to fight against neurodegeneration.
    Since I started reading about MS always seen all forms of MS as one, what will differentiate one or the other is the degree of neurodegenerative commitment. What makes it faster progress than I? Then I ask the resident in neuro who answered me about what they were doing on neuroprotection. He told me that my doctor, head of the neurology sector would only take prescription possible Neuroprotective as Phenytoin, Oxcarbazepine, etc., when more studies corroborate the practice.
    That was the answer I received, sad but it's true.

    One of the many questions that must be answered. Also I think that science is getting closer to reaching the consensus that it is the inflammation that generates all the neurodegenerative process and not a random attack autoimmunity. Another favorable point Prof. G to investigate the real implication of EBV in MS and MDs to investigate the plasma cells in the disease. I know it's corny but I say that I am not a fan of this blog for nothing…

  • Re: "Also I think that science is getting closer to reaching the consensus that it is the inflammation that generates all the neurodegenerative process…" Then why have all the RRMS meds failed in clinical trials? Clearly they are not targeting the neurodegenerative pathway.

    • Precisely for this, because they act only by suppressing the immune system.
      There is nothing being done pair protect neurons/nerves of inflammation itself and the immune attack.
      Now no one discovers MS "preventive" way, because not even the Science has yet to do this.
      So when the disease is diagnosed throughout the event in inflammation-degeneration chain has already started.
      Once it the nerve/neuron has suffered the first damage is very difficult for a pure and simply immunosuppressive agent can do all the work yourself, even for those with RRMS because if not it is a chance to make the transition to SPMS is high. So then the need more urgent for combined treatments, which also aimed at neuroprotection, and who knows in the future partial or full compensation of the damage.

    • Whatever became of the study of periodic pulsed IVMP in conjunction with Rebif or Copaxone? I thought there was some clinical benefit and not so much a risk for osteoporosis.

  • Are there any other neurodegenerative diseases that have any immune system response to the degeneration? Does this response look anything like PPMS/SPMS? In other words is the inflammation in PPMS/SPMS simply a generic brain response to damage that will continue whilst the damage is there, in other words pretty much indefinitely?

    Thanks as always for the blog.

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