Saturday, 31 December 2016

#HappyNewYear: a better understanding of progressive MS

MS is #1-disease-not-2-or-3-diseases - #HappyNewYear

One of your wishes for 2017 is 'a better understanding of progressive MS. I would love an explanation of why MS morphs from RR to SP'.

I have tried many times to explain this in plain English. The following is an updated version of a previous post that I wrote more than a year ago in response to a statement by Steve Hauser that a proportion of his patients with relapsing MS who had been treated with rituximab have gone onto become secondary progressive; why?

People with MS and those of us who treat the disease want a cure. However, we may have a cure in hand and yet we don't reverse or prevent progressive disease. How can this be? I have tried to capture all the issues in this infographic; it is a work in progress so if you don't understand it please let me know and I will adapt it.


Focal inflammation damages nerves in two ways. It can shred and destroy nerve fibres as part of the initial inflammatory stage (acute neurodegeneration) or it can damage nerves and leave them functioning, but the resulting damage primes them to die off in the future; so called delayed neurodegeneration. The mechanisms that result in delayed neurodegeneration of nerves are many and include innate immunity (hot microglia), energy deficits (mitochondrial dysfunction), excitotoxicity (calcium overload), free radicals (oxygen and nitrogen radicals), premature ageing, intrathecal plasma cell production of pathogenic autoantibodies, etc. Clearly anti-inflammatory drugs that prevent new lesions formation, such as natalizumab, alemtuzumab and ocrelizumab, will not be able to prevent the delayed neurodegeneration from previous inflammatory lesions. What has happened in the past has happened; i.e. the water under the bridge analogy. So if you have relapsing MS and have had a lot of inflammatory activity in the past that has damaged many nerve fibres, even if you go onto a highly effective DMT that renders you NEDA, it is not going to prevent the ongoing loss of nerve fibres that are primed to die off from previous inflammation in the future. This is why we are doing the PROXIMUS trial; an add-on neuroprotective drug to try and modify the delayed die-off of neurons and axons.

What protects you from entering the clinically-apparent secondary progressive phase of the disease is reserve capacity, i.e. the surviving healthy nerve fibres in nerve pathways keep you functioning normally. I therefore suspect that those patients of Steve Hauser, who have been treated with rituximab and have now become secondary progressive, had a low reserve capacity and a large number of damage nerve fibres that had been primed to die off in the future. In other words they were treated with rituximab too late to prevent SPMS.

Please note that Steve Hauser's observations, and the above theoretical explanation, are not new and have been noted with with other high efficacy DMTs, i.e. mitoxantrone, HSCT, natalizumab and alemtuzumab. There are two conclusions to be drawn from the above observations and theory; (1) it is best to have your MS treated effectively early in the disease course to maximise your reserve capacity, or (2) we need additional add-on neuroprotective therapies to target the delayed neurodegenerative processes referred to above. The latter includes avoiding or reversing factors that prematurely age the nervous system. The ageing hypothesis of progressive MS is one factor that underpins the component of the Brain Health campaign, which targets non-specific factors that have been associated with more rapid progression in MS (smoking, co-morbidities, lack of exercise, infections, etc.). If you have any New Year's resolutions please think about your general 'Brain Health'.


So unless you get treated with ocrelizumab, or another high efficacy DMT, early in the course of your disease it may not prevent you entering the progressive phase of the disease, i.e. it will not be the panacea you want. In addition, anti-CD20 therapies and almost all of the other licensed DMTs don't kill long-live plasma cells that continue to make intrathecal (within the CNS) antibodies that my drive progressive MS. The exception may be natalizumab there are several reports of pwMS on natalizumab losing their OCBs (oligoclonal bands or antibody bands). It now emerges that plasma cells live in a 'niche' or home and that to keep them in the niche they use the VCAM-1-VLA-4 adhesion molecule interaction. Natalizumab disrupts this interaction and hence it is plausible that natalizumab may reduce the life expectancy of intrathecal (inside the CNS) plasma cells. If this proves to be the case natalizumab may still have the edge on the other DMTs in this regard. However, the data on natalizumab and OCBs needs more work, a large German consortium of investigators' have not confirmed the earlier reports of the disappearing OCBs. To target the plasma cell, that are long-lived, we will need add-on therapies. The latter is something that is high on our list of priorities for 2017 and we have just been awarded a grant to test a myeloma (malignant plasma cells) drug in MS.

We have also made the argument that we should not be using the term progressive MS. The term is wrong. Progressive means progress, an improvement, however, in the context of MS it implies worsening. We prefer the term worsening MS. Instead of progressive MS we prefer the term advanced MS; which implies worsening disability. There is really very little scientific reason to split MS up into different sub-types, i.e. relapsing, vs. secondary and primary progressive disease. MS is one disease. As I have recently discovered defining MS two or three diseases was a ploy by Pharma to get MS recognised as an orphan disease, which allowed them to get interferon-beta licensed on the data from one trial and to charge a higher, than expected, price for the drug. MS is 1-disease-not-2-or-3-diseases.

Finally, those of you interested in animal models will find the study below of interest. This model has been developed by the Mouse Doctors over two decades models both the the early and late effects of inflammation in driving neurodegeneration. In other words there is animal data to support the delayed neurodegeneration theory presented above; our theory on what drives progressive MS is not a thumb suck.

Hampton et al. Neurodegeneration progresses despite complete elimination of clinical relapses in a mouse model of multiple sclerosis. Acta Neuropathol Commun. 2013 Dec 23;1:84. doi: 10.1186/2051-5960-1-84.

BACKGOUND: Multiple Sclerosis has two clinical phases reflecting distinct but inter-related pathological processes: focal inflammation drives the relapse-remitting stage and neurodegeneration represents the principal substrate of secondary progression. In contrast to the increasing number of effective anti-inflammatory disease modifying treatments for relapse-remitting disease, the absence of therapies for progressive disease represents a major unmet clinical need. This raises the unanswered question of whether elimination of clinical relapses will prevent subsequent progression and if so how early in the disease course should treatment be initiated. Experimental autoimmune encephalomyelitis in the Biozzi ABH mouse recapitulates the clinical and pathological features of multiple sclerosis including relapse-remitting episodes with inflammatory mediated demyelination and progressive disability with neurodegeneration.

OBJECTIVES: To address the relationship between inflammation and neurodegeneration we used an auto-immune tolerance strategy to eliminate clinical relapses in EAE in a manner analogous to the clinical effect of disease modifying treatments.

RESULTS: By arresting clinical relapses in EAE at two distinct stages, early and late disease, we demonstrate that halting immune driven demyelination even after the first major clinical event is insufficient to prevent long-term neurodegeneration and associated gliosis. Nonetheless, early intervention is partially neuroprotective, whereas later interventions are not. Furthermore early tolerisation is also associated with increased remyelination.

CONCLUSIONS: These findings are consistent with both a partial uncoupling of inflammation and neurodegeneration and that the regenerative response of remyelination is negatively correlated with inflammation. These findings strongly support the need for early combinatorial treatment of immunomodulatory therapies and neuroprotective treatments to prevent long-term neurodegeneration in multiple sclerosis.

CoI: multiple

18 comments:

  1. Can you explain how primary progressive MS fits in. Especially those without any enhancing lesion.

    In your account, the inflammatory phase was "hidden" or just very short-lived?

    Why?



    (I have an identical twin who went RRMS-->SPMS over 10 years. I was diagnosed 6 years after her and eventually it's thought to be PPMS, but very stable.)

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    1. In the beasties the secondary progression can be after one attack in other strains, sexes, ages it takes more attacks

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  2. Is this the only theory?

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  3. If it's ever proved that NTZ can eliminate OCBs or/and can significantly reduce NFL, would you consider it as the most effective DMT for RRMS? Would it be the most effective drug to delay SPMS? Would you review its use to JCV+ patients accepting a higher risk of PML if it can be so effective towards MS? Do you think that ocrelizumab may have similar capabilities?

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  4. I agree about the term progressive which I see as a positive term. I also feel the same about the term 'advanced' which I see as a positive term e.g. intellectually he was very advanced for his years. I prefer terms like early stage, mid stage and end stage in relation to MS. End stage would capture EDSS 8 onwards. It also reflects the amount of damage done. I for one don't plan to be around for the end stage of the disease - it's clear from your post that we are along way to understanding the mechanisms causing the damage and treatments to repair damage are still in the world of science fiction. At diagnosis, my partner said "at least it's not cancer". Given the strides made in cancer (for many types of cancer) I would gladly have swapped MS for a common cancer with a chance of a reprieve. Neurology is a bucket where they plonk all the vile diseases with no chance of getting your old life back.

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  5. 'EARLY' - a word that is beginning to haunt me, and seems to be referenced casually, with what I'm rightly or otherwise, reading as: a presumption of early diagnosis. I was diagnosed November '15, a month before my 52 birthday, and was told by the neurologist that I have almost certainly had RR for years. Prior to my diagnosis I was seen as fit and well. One clinician saying to me 'as healthy a woman as you' just 7 months before my diagnosis. I was pleased to receive Alemtuzumab in November this year and to tick all the Look After Your Heart boxes. But I'm increasingly finding it difficult to marry up the two conflicting positions of: have treatment and look after yourself will be of benefit versus the unless you get it caught early you're on a road to nowhere! Do we live wth some degree of hope, being proactive, or is it essential to get to grips with - MS equates with appalling outcomes, despite the availability of DMTs ?!?!??

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  6. I don't agree with the thinking on the term "progressive" here at all. I think progressive is a much more sensible term to use than "advanced MS", particularly when we still know so little about the pathology of progressive MS with certainty. Advanced MS doesn't imply worsening disability any more than progressive MS does to me. Besides, the implication of advanced MS is that there is some end stage that everyone with MS reaches, which - even without drug intervention - is not known to be the case, everyone's disease is different in its course and severity throughout life. People with no obvious permanent impairment through life may in fact haved some clinically silent progression. We simply don't know for sure - that is my understanding.

    I find this issue a bit silly and pointless, to be honest. It depends on your understanding / feeling for the Engish language. Looking at the Oxford dictionary definition, progressive is the most appropriate term: https://en.oxforddictionaries.com/definition/progressive

    I won't ever refer to my PPMS as "advanced". Even if my medical team start doing it; I do hope they will not. I don't wish to be polemic, but to be honest, the promotion of this new term sounds like a way of twisting terminology to put people like me with PPMS into a box labelled "too far gone (to bother caring about)".

    Happy New Year when it comes.

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    1. I might add that I don't regard my slow PPMS of many years as being the "worst" kind of MS there is. I have heard from others that aggressive relapsing MS can be very rapidly disabling. Bits of me are a bit kaput, right enough, but an awful lot of me (still) isn't. Another reason that the term "advanced MS" doesn't sit well with me. Anyway, less time reading about MS is part of my brain/emotional health regime in 2017, so I will let you do as you please with the wording! All the best.

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  7. 2016 doesn't seem such a great year MS wise. I started the year as RRMS but ended it RRMS + SPMS + PPMS (according to Prof G it's the same disease). My private neuro (£300 an hour ten years ago) told me I was lucky because I was RRMS and didn't have the dreaded PPMS) - am I entitled to a refund? Progressive as a term to describe neuro-degenerative disease is no longer to be used. All this sounds like moving the deckchairs on the Titanic. Ocrelizumab wasn't as impressive as I had hope - doesn't stop the progressive disease for all, but slightly slows it for a small proportion. I was gutted that Charcot 1 trial was negative. If Team G was a pupil, the 2016 school report would be 'C', failed to match expected performance. There would be a reference to Mouse Doctor's improved behaviour - less prone to excessive reactions to posts. Prof G as Head Boy has performed effectively, but can be too emotional and his work / messages can be a tad repetitive. In 2017, Team G needs to push on with exiting projects and deliver some breakthrough research or trial results.

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    1. yep on the case in my bestest behaviour:-)

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    2. Messages repetitive...but still some don't listen

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    3. P.S. What is the expected performance?

      Importantly who would you give an "A" to and why?

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  8. A Happy 2017 to all Team Barts!!!
    To everyone who accompanies and visits the Blog too!
    Health, peace, love, prosperity, knowledge, wisdom and many congratulations!!!!


    MS is really bad, but I really would like to understand this plague. Why do people with the so-called Primary Progressive and Recurrent MS deteriorate in the loss of function faster? Why are there EMRR manifestations that will not enter advanced MS at any time, even though the axonal/medullary lesion damage eventually programmed future neuron/ nerve death?
    There are so many "why"s, I hope 2017 can bring the precise answer to at least some of these questions, which is a vigorous year and elucidations for Science, especially in the field of EM...

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  9. SPMS then is like a post-polio syndrome. with the same treatment of mainly PT and exercise and progress inch by inch rather than mile by mile.

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  10. Here is one (possibly the only one?) of the patients that Stephen Hauser was referring to, who transitioned to SPMS on rituximab.: http://onlinelibrary.wiley.com/doi/10.1002/acn3.377/full

    At rituximab administration onset, the patient was 53 years old, had previously had 12 relapses, and was EDSS 3.5-4.

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    1. Thanks, I'll let ProfG comment on this, as Prof Hauser spoke to ProfG on this very subject and it may not be the only one...but if you are having numerous attacks it is a poor prognostic feature for transitioning into SPMSS

      But its aying lets do an trewatment from onset trial with orcelizimab, This person had seven relapses whilst on beta interferon, it was pre -2006 and not much alternative but would you accept this now.

      It is clear that disease is still active, despite rituxima, as seen by the accummulation of spinal cord lesions, wonder if there were neutralising antibodies?

      The person had seven relapses whilst on aveonex and they was

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