Team G review for Progressive MS points the way to success for progressive MS

Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Giovannoni G, Cutter G, Pia-Sormani M, Belachew S, Hyde R, Koendgen H, Knappertz V, Tomic D, Leppert D, Herndon R, Wheeler-Kingshott CA, Ciccarelli O, Selwood D, di Cantogno EV, Ben-Amor AF, Matthews P, Carassiti D, Baker D, Schmierer K. Mult Scler Relat Disord. 2017 Feb;12:70-78. doi: 10.1016/j.msard.2017.01.007. Review.

Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and a S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms. However, anti-inflammatory therapies may modify these damaged pathways, but with a therapeutic lag that may take years to manifest. Based on these observations we propose that clinically apparent neurodegenerative components of progressive MS may occur in a length-dependent manner and asynchronously. If this hypothesis is confirmed it may have major implications for the future design of progressive MS trials.

ProfG was recently at his debating Society and lost.

But in fact it is you who have lost, because the argument that ProfG was making, was falling on deaf-ears.

He said we should not simply see MS, as a two stage disease, one stage relapsing disease and the second stage progressive disease, but as a continuum.

However, the two stage disease has been winning the vote meaning people are buying-in to doing nothing, once frank progression starts.

You lose because their is no ambition to make a Treatment for all.

This was the tennet for ProfGs Ig Nobel prize and a few papers contribute to this view.

However, it should not be all doom and gloom because the data is there.

It is clear that one stage does not suddenly materialize. The inflammation starts from the get-go and persists in some guise and likewise the neurodegenerative component occurs from the word-go and persists in progressive MS.

So everyone can gain some benefit from curbing inflammation, with would be even better if we stopped inflammation and saved nerves and promoted repair.

If you have been reading the blog, the content of this paper should come as no surprise.

This is because the take-home message is that we should be aiming to preserve what we can preserve and aim to give “Treatment for All”. 

If your legs have gone, let’s aim to save your arms, and if your arms go let’s save the head.  We have focused too long on the legs and this has meant no treatments for people with progressive MS and no treatments for people in wheel chairs..

Had we focused on the arms, some form of treatment could have been available years ago.

However, this paper has taken 2 years to surface, as it was submitted in March 2015.  So there is some resistance within the community to maintain the blinkered view. 

The other cause of tardiness may have been down to profG:-(

Blinkers mean slow progress.


  • The longer the nerve pathway. 
  • The more likely is that it will be affected by MS lesions. 
  • Therefore disability will become more noticeable in these pathways. 

The longest nerve pathways are to the toes and so it is surprising that loss of movement is one of the major systems affected. 

So studies focus of mobility and the EDSS.  This paper suggests that there may be a hierarchy of the speed in which systems are affected.

This leads to the Asynchronous Progressive Disease model.

Each nerve pathway has some reserve capacity to compensate for damage, but this reserve gets exhausted at different rates, so system breakdown starting with the bladder and lower legs on the whole become affect first….there are always exceptions to the rule.

Let’s imaging that the nerves are like sparklers and once lit they will burn until they finish, and once started they are hard, but not impossible to put out. Once you have sparklers they are going to be lit one by one until the packet is finished

However, it is easy to stop the next sparkler being lit. This is what current DMT do, and whilst their use may be too late to stop progression in something that is already programmed to be damaged,  it may not be too later to stop the next nerve pathway accumulating so much damage it becomes a sparkler.

This can be achieved with some current MS drugs, but it we focus on our legs it may be too later to stop the progression. So trials fails and you have no treatment. However


Then you may be able to save lost function. Ocrelizumab saved leg function but saved even more of hand function. Focus on hands as a outcome and you would already have a treatment available.

But this has proved difficult to show and this is because it takes time for the benefit to show itself. If the trials are too short, they may be too short to see a benefit, because it is masked by the worsening due to the sparklers burning.

This is the therapeutic Lag
How do you disprove this, one of the best ways, is to do a well planned trial

Maybe the authors have the power to do this.

However ProfG’s view 
in hindsight
“This paper is Treacle to Read”

Maybe DrK or ProfG can explain betterer

So what is the significance of all this

Well have a look at the Poster from the up and Coming 
AAN Meeting in Boston in April 2017
(Abstracts are online Now…What’s interesting to You)

I’m surprised that ProfG isn’t on this one 
because he has been banging on about it for enough time 
i.e. Think-hand and focus on hand function.
Do trials for Longer than 2 years.

Do this and you have a drug (Natalizumab) that impacts 
on progressive disease!

Maybe no poster publication but he can feel snug 
with the “I told you So”

ASCEND Phase 3 Trial Open-Label Extension Study Results: Natalizumab May Delay Disability Progression in Secondary Progressive Multiple Sclerosis (SPMS) Hans-Peter Hartung , Douglas Arnold, Mark Freedman , Eva Havrdova , Douglas Jeffery, Raju Kapoor , Aaron Miller , Finn Sellebjerg , Haihong Li, Nisha Lucas, Diego Cadavid, Nolan Campbell, Pei-Ran Ho, Deborah Steiner10 

Objective: To investigate long-term (>2 years) effects of natalizumab treatment in the ASCEND open-label extension. Background: During ASCEND’s 2-year randomized treatment period, natalizumab did not delay disability progression in SPMS patients with advanced disease (so the TRIAL FAILED) assessed by the primary composite endpoint (Expanded Disability Status Scale [EDSS], Timed 25-Foot Walk [T25FW], and 9-Hole Peg Test [9HPT]), but did slow progression on the 9HPT (upper-limb) component. (If Hand Function was main outcome the trial would have been positive

Design/Methods: Patients who completed the 2-year, randomized, placebo-controlled treatment phase and entered the extension phase received open-label natalizumab (The trial was extended for more than 2 years to 3 years). Original treatment assignments remained blinded to investigators and patients throughout the extension. Disability progression was assessed for up to 3 years using the primary composite endpoint. 

Results: Of 888 randomized, dosed ASCEND patients, 566 (63.7%) participated in the open-label extension (switched-from-placebo: n=274, median follow-up=156.9 weeks; natalizumab-continuers: n=292, median followup=160.4 weeks). Baseline characteristics and disease history were similar between groups and consistent with the overall ASCEND population. Fewer natalizumab-continuers than switched-from-placebo patients were composite endpoint progressors (52% vs 61%; adjusted odds ratio [OR]: 0.67; 95% confidence interval [CI]: 0.47- 0.94; P=0.02). Natalizumab reduced 9HPT progression (19% natalizumab-continuers vs 28% switched-from placebo; adjusted OR: 0.59; 95% CI: 0.39-0.88; P=0.01). (Benefit was still seen when hand function was analysed) T25FW and EDSS progression comparisons favored natalizumab (T25FW, adjusted OR: 0.80; 95% CI: 0.57-1.12; P=0.20; EDSS, adjusted OR: 0.73; 95% CI: 0.48- 1.10; P=0.13). Not quite a positive for saving leg function but indications start to appear maybe trails need to be 4 years long 

Conclusions: The ASCEND open-label extension showed clinically meaningful benefits of natalizumab on disability progression in advanced SPMS patients. Consistent with 2‑year results, the largest treatment benefit was seen on preserving upper-limb function (9HPT), but preservation of ambulatory function (T25FW and EDSS) was also observed, leading to overall benefit on the primary composite endpoint. (When all issues are compared benefit is seen that may have lead to success) These results suggest that, while some benefits are evident after natalizumab initiation, full benefits on disability progression, particularly lower-limb function, in advanced SPMS patients may not be evident until after longer treatment duration.(Study Supported by: Biogen)

This suggests progressive MS trials need to be longer than 2 years or we have to swap primary endpoint outcomes. These are consistent with the ideas from the paper above.

This is retrospective analysis.

Why don’t we do some perspective analysis and test out whether we can control loss of hand function in people with advanced MS? 

We should aim for treatment for all across the whole EDSS spectrum.

What do you think?
Can we do a DMT trial for People in wheelchairs? 
(Somewhere in the World?)


p.s. I know Hannah does not have MS, but let’s use the paralympic spirit and say
                                                                     “Yes I(we) can” (click)                                                Let’s go for it

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  • Dear David, I am surprised you say that they don't believe Gavin. What you say here is simply a fact-not even an alternative one;)

    I got even teached about this long time ago during residency (longer tracts, such as spinal, being more vulnerable because of lenght).
    And regarding trials, we knew this ever since the famous methotrexate trial in PP MS, that showed preservation of hand function only (this is where the 9-hole peg test was used first; Goodkin trial) and no effect on EDSS.
    So no Nobel price I am afraid-but very happy you guys emphasise the importance of hand function!
    Rogier Hintzen, neurologist Rotterdam, The Netherlands

    • Hi Thanks for this

      I'm not sure of the referees gripes on this one but thanks were were aware of the methotrxate data and glad they teach anatomy properly in the Netherlands.

      However, whilst it may be common knowledge or even common sense, it is has to be said therefore that we have not learned from it. As such many, many years later we are stil wasting drugs and peoples time and hopes with failed trials.

      I am not expecting a Nobel Prize but would like a study to come out of this.

      Best wishes

    • So the problem appears to be assimilating the information

      As MD2 said whats the difference between a neuro and a computer?
      You only have to punch the information into a computer once:-)

  • Does that mean that very tall people are statistically worse off as far as legs are concerned than short people? ( if you take men and women then that is probably true, women are statistically shorter than men and probably prgress more slowly than men on average. Unfortunately also different in other ways :-), but gender would be an easy thing to adjust for.

  • Thanks for posting. It would be great if ProfG – and others – would persevere with this line of thought (and persuasion) so that people with progressive MS have some chance of slowing the deterioration that is happening to their bodies, despite best efforts at eg exercise and clean living!Thanks for efforts so far Bouncy

  • "Ocrelizumab saved leg function but saved even more of hand function. Focus on hands as a outcome and you would already have a treatment available."

    How can you save hands if people go from EDSS 3-7 while on Rituximab?
    Hope and optimism is one thing the clinical treatment history
    speaks for itself..after many years there is lesion
    formation on thoraccic spine despite being on therapy. So how
    can you save hands or legs if new lesions form ?

    Just don't know everything I read just shows progression.
    Even being a "VIP" patient and getting Rituximab way back in
    2003 when the average "Joe" patient just got betaseron doesn't matter..there is still progression.

    "Dr. Hauser related the story of a "leading citizen of California" with long-standing RRMS who had experienced ongoing inflammatory activity despite adherence to many disease-modifying therapies. He was treated with rituximab off label since 2003. To date, he has demonstrated an excellent response to rituximab in terms of inflammatory activity. Still, his disease continues to progress clinically. Over the past 10 years, he has gone from an EDSS score of 3 to requiring bilateral crutches. MRI tractography has revealed ongoing atrophy of the motor cortex. Dr. Hauser commented, "I think that the best question here is, are there B cells in lymphoid follicles that are contributing to percolating of disease activity?"This anecdote highlights our incomplete understanding of ms

    • Yes, so this is the other end of the cable… the cortex where the signal starts and the relays in the spinal cord through which it passes.
      The person with cortical atrophy and lesions in the brain probably does not produce a good enough signal to start with.
      I am with the people who think that inflammation primes the system and then something else (degenerative in nature) drives it forward. The two processes go side-by-side until the system cannot compensate and fails to deliver. Addressing inflammation will never be enough.
      MD, do you hear me? 😉 Hint hint hint.

    • Quite correct, addressing just inflammation will never be sufficient which is why for the last decade and more we've been working and publishing on potential neuroprotective therapies for MS from cannabis to a range of other agents, which laid the groundwork for Prof G's phenytoin trial and the ongoing Proximus study. Take up by pharma has sadly been glacially slow as they are focussed on inflammation only in the main.

    • Adam.
      No treatment including HSCT at the extreme end is 100% effective and there are elements of progression that simply do not respond to current immune therapy including HSCT, so rituximab is not going to do much better. In the case report they started rituximab treatment many years (about 15) after onset. This is the problem.

      We can show this easily in the animals, start early good result, start too late and you have progression

      Next I am not yet convinced that it is the B cell follicles. but it is the easy cop-out. However, we should do the experiment. But do it properly. We should be depleting plasma cells getting rid of oligoclonal bands and not messing about with anti-CD20 like people have been. We we know CD20 does not deplete plasma cells. Depleting the peripheral immune component does not get rid of OCB.

      We are planning to do this, but is the treatment the right one?.

      Maybe shark antibodies against CD138 would do it?


      Not sure what you are getting at. Spell it out
      My position at the moment is that is inflamation that drives both the relapsing element and the neurodegenerative element. Therefore, you may be wrong that addressing inflammation will never be enough.

      However the inflammation that drives the relapsing element is different from the inflammation that drives the degenerative element.
      The solutions to stopping each type of inflammation is different.

      This is where the problem arises as people do not see the degenerative process as inflammation.

      We have clearly demonstrated this in the animals

      I think the evidence is there in humans, but a monotherapy to target one element of the inflammation without targeting the other element is always going to be suboptimum. That is main point. We can now do something about the former.

      Even once compensation in one system is lost, there may be evidence in another systems of the two processes occuring. This can be found post-mortem.

      I like MD2 idea that the OCB may be non-specifcally activating the microglia, which drive progression. Maybe we should see if we can get progression in B cell deficient mice.

    • The problem is that in mice you are pulling the strings and know when you started the process.
      In humans, not so. The process has probably been going on for something like 9-10 years on average when the patient presents to the healthcare professionals and is lucky enough to be diagnosed without any further delays. Epidemiological studies tell us that it takes about 10 years of exposure to … something(we don't quite know what, could be many things infectious, environmental, smoking, lifestyle or diet related) for a genetically susceptible individual to develop MS after moving to a country with high MS risk. And when we are starting treatment early, we are already late… if you know what I mean.

      And is degeneration an inflammatory process… yes it could be. (The rheumatologist in me says: can you just zap it with some corticosteroids? So can you? would mice get better if we did treat them at that stage?)

    • CD20cell
      Depends what you mean by inflammation ie overt lesions or grumbling low-level driven by activated microglia. We can shut down any further inflammatory attacks at any stage of the disease by re-inducing antigen-specific tolerance (we have a number of publications on this). However, shutting down relapses particularly in the later stages in our mice does not stop secondary progression, which continues to develop at a slow rate, indicating we need neuroprotection too.

    • I totally agree with you ,MD2, that we need neuroprotection,and probably from day 0 (the day of clinical diagnosis, which is probably something like 10 years from the day things started rolling down the slope.)
      And although I know mice is what we have to test our ideas on… I am not sure the model reflects the clinical truth ( bacuase what is the antigen we could induce tolerance to in MS? Or RA? or any other autoimmune disease? so the model is OK for some things, but not OK for others.)
      And how does one control for natureal aging in an experiment like yours, mice don't live that long( yeah, how long do mice live? 🙂 when they die from the so called natural causes?

    • Our model isn't perfect but it does have many of the features of MS ie relapsing/remitting course then secondary progression due to neurodegeneration and the pathology is similar. The disease course is of course accelerated compared to pwMS but again mice live fast and die young (2 year life-span more or less). Yes we know what the antigen is in the mice, which is a huge benefit, we don't in pwMS, which makes re-induction of tolerance problematic and probably impossible, we've been looking long enough.
      The longest we've run an experiment is 8 months or so, quite an undertaking with daily monitoring (including weekends.

    • I think that might be doubtful, though it does get into the brain and if it managed to get rid of plasma cells that secrete oligoclonal bands, which may activate microglia, then maybe but that's a lot of maybes.
      Personally, a simple approach might be aspirin, a well described downregulator of activated microglia.
      sadly, there's no money to be made out of aspirin so a trial is as likely as me headlining at the O2.

    • Thumbs up to aspirin, MD2! There surely must be a way of funding a study for something cheap and cheerful with a potential effect to many – NIH?

    • There is some evidence on clad reducing OCB but it is not going to touch microglia directly I think.

      Cladribine doesnt work in mice (in contrast to a couple of papers that are obviously crap…because mouse lymphocytes arent depleted by cladribine it is an issue with the enzymes that make cladribine work.

      We found out the hard way many many years ago when we first tested clofarabine-an oral cladribine variant interestingly sat on I think a Genzyme shelf rotting (so no one takes on alemtuzumb with it). We got ProfG to get us some cladribine and we confirmed that it does not work in mice. Must publish this some day. I guess that day could be if we can get humanized mice going.

    • CD20 cell.
      Although we do know the antigens, the way we did this is that we dont need to know them. We gave the animals a mixture of antigens, they select what is interesting to them we dont need to know. However we are never going to be able to use human brain mush to do it (in case we are transfering virus) and since BSE animal brain is likely to be a no no. We believe the target is in the oligodendrocytes so we have been using dead myelinating oligodendrocytes to induce tolerance. Unfortunaetly the tolerancce induced just wastn't in our opinion good enough, compared to the brain mush, so we have put this on hold. Whilst we have a rethink. MAybe we could try a mixture of antigens but then you have to pick your favourite ones. The other problem was we could not get a source of CD4 antibody to do the depletion in humans and when we tried CD52 it was not good, but at least it made us figure out how alemtuzumab may work and how it causes autoimmunity…Shame Genzyme didn't buy the idea.

    • MD2 : This was an eye-opener :-). Working with lab animals is a lot of work. I guess mice don't tell you where it hurts or what is not working as it should, so all you are left with is your observations of how they are doing. Daily. Blyme. Plus all the other stuff like feeding, cleaning, injecting drugs etc. That is quite an investment of time and effort!

    • MD : this sounds rather macabre, actually (as if you were trying to induce kuru model in mice. I know it works and I know it is the best we have, but still). But then when you think of kuru – could MS be some form of a prion disease???

  • Yes, thanks for all your efforts so far team at Barts MS. As Bouncy says it is horrible seeing our bodies failing despite our very best efforts. Yes, we are losing out.
    At 46 I feel too young to be written off 🙁
    Re CD20 question above – on the bright side I'm really short 😉

    • Judy, the difference between a short woman and a tall man could be half a meter of extra "cable" (sorry: nerve) for a signal from the head to reach the foot, so … less wire to go wrong for you :-).
      But then again there is

    • Hahaha! You're right on both counts there CD20 I reckon even after 11 years of MS I can multi task better than my husband 😉 😀

  • The continuum makes so much more sense. I like the draining lake model of MS that was posted on this blog a while back. I think some lay person's version​ of this should be given to patients early on to help them understand that feeling well doesn't equate with being well. It was in no way clear to me that progression happens from the start. I might have made different choices if i had understood the disease better.

    • Neither to me… but then I did not get that diagnosis yesterday, so maybe how we look at things changed as well in the course of the years! Progress.(not progression 🙂

  • I'm not sure about this length dependent theory at all. I've had PPMS for more than one and a half decades and, although I have to pause often, every few metres, when walking, I can still wiggle my toes well and my feet "work" well. I put this down to having walked barefoot a lot as a child – probably I have more nervous system networking / neurological reserve dedicated to the function of my feet as a result of that. I think it is more likely that walking is one of the first things to suffer as it is relatively not a very neurologically complex activity. Hands, on the other hand, must perform much more complex actions in response to touch, visual and audiory information. So there is a much greater capacity for compensation, much more complex "wiring". That doesn't fly in the face of the idea we should save what's left of the nervous system. But I was of the impression that current DMDs don't work well for people like me with PPMS – for any part of my body, however well-wired. That the side-effects would probably outweigh the benefit. Maybe I am wrong. Who can tell me for sure? No one probably.

    • This is a good suggestion, reserve capacity is part of the equation.
      Likewise there are people with MS with short pathways and these are severely affected e.g people who go blind from first attack. What ever we say there will always be exceptions.

      It is true they dont work well, but it is not true that they dont work at all. There are about 15% of PPMS who are having gadolinium lesions, this part of PPMS will definately respond to treatment.

      I bet alemtuzumab would work on that, but proper tests in progressive MS were never done, likewise ocrelizumab will work and I suspect cladribine will work to. Fingolimod will also work, but if we believe the mechanism of acction you may create a time bomb, there have been a number of recent reports indicating that disease activity can return bigtime after fingolimod. Is this the race horse effect where you dont kill the bad horses you keep them in check under "starters orders" all lined up waiting to race to the brain once fingolimod is stopped.

      I believe we have a number of people would have been treated with off-label cladribine
      and indeed have a paper submitted describing a case report.

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