Progressive multiple sclerosis is a misnomer

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Barts-MS rose-tinted-odometer: ★

In my opinion, the term ‘progressive multiple sclerosis’ is a misnomer. In general, progression means improvement, which is one of the reasons I prefer the term ‘late-stage MS’, which not only differentiates the terminologies but captures the associated disability that comes with this phase of the disease.

It is important to stress that the pathologies that drive neuroaxonal loss, or neurodegeneration (the pathological substrate that underlies ‘late-stage MS’) are there from the earliest stages of MS; even when people have asymptomatic MS. This means the neurodegenerative phase of MS is present prior to pwMS becoming physically disabled.

MS is 1-disease and not 2-3-or-4-diseases. As I have said before the false division of MS into several diseases is not backed up by science, nor by philosophical arguments. This false division of MS into many diseases has become counter-productive to the field of MS. The division of MS into relapsing and progressive forms was Pharma-led to get MS defined as an orphan disease, which allowed interferon-beta-1b to get a license based on the results of one pivotal phase 3 study.

One could argue that this has been good for MS in that it has attracted a lot of Pharma investment and has supercharged drug development in MS. However, MS as three or four disease entities is now slowing down drug development and making it very expensive. We need more affordable DMTs for late-stage MS; disability affects the cost-effectiveness models for reimbursement hence DMTs for late-stage MS need to be priced lower than those licensed for earlier or relapsing forms of MS.

Following on the point above the division between SPMS and PPMS is false. There is no pathological, genetic, imaging or other data that suggests these are different entities. We therefore should be doing trials in both late-stage MS populations simultaneously.

Slay the dogma that more late-stage MS has reduced inflammation or is non-inflammatory. There are clinical, imaging and pathological data that shows inflammation plays a big part in driving late-stage MS. Therefore not to target more late-stage MS with an anti-inflammatory is folly.

Accept that reserve capacity in particular systems plays an important part in how MS worsens. Neuronal systems with reserve, i.e. surviving and functioning axons, are more likely to be able to recover function and hence show a treatment effect compared to neuronal systems in which reserve capacity is exhausted. In the latter systems, it will simply take longer to show a treatment effect; we refer to this as therapeutic-lag. These observations are explained by the length-dependent axonopathy hypothesis. This means that we will need to focus more on arm-and-hand function as a primary outcome in pwMS who have lost too much function in their lower limbs (EDSS>=6.0).

Challenge the dogma that once someone has lost lower limb function and is a wheelchair user that the disease is not modifiable. We have good data that DMTs can slow the worsening of upper limb function despite subjects being wheelchair-bound. We feel very strongly about this point and are very keen that future trials in late-stage MS include wheelchair users. Why should we write-off people with MS who have lost leg function? What keeps pwMS independent and functioning in society is arm and hand function. We as a community have to think about that very carefully. We have rehearsed these arguments many times as part of our #ThinkHand campaign.

Accept that we will need to use combination therapies to make a real difference to more late-stage MS. I am not necessarily talking about two anti-inflammatories, but an anti-inflammatory targeting adaptive immune responses in combination with a neuroprotective therapy. I agree there is a good argument for combining an anti-inflammatory that targets innate immune mechanisms, which targets hot microglia – with a classic anti-inflammatory against targeting adaptive immune mechanisms.

We need to ditch the EDSS. The whole community knows that the EDSS is not fit for purpose in more late-stage MS. We need to get the regulators to accept this. We also need to use outcome measures that capture the whole impact of MS on someone with MS. We are getting there with the new rendition of the MS functional composite. But in my opinion, this is not enough. We need more PROMS in the battery, in particular, ones that capture hand-and-arm function, cognition and quality of life. 

We need to think creatively about our trial design. I am not an expert here, but some in the community are pushing for adaptive trials, i.e. a multi-arm phase 2 trial with a seamless design allowing it to be converted into a phase 3 study. Pharma doesn’t necessarily like adaptive designs nor do the regulators. I do think we do need two phases to trials in more late-stage MS, i.e. the standard head-to-head phase with a robust primary outcome, say a multi-outcome composite, followed by an open-label extension where the study subjects remain blinded to their original treatment allocation. This will allow us to capture therapeutic lag. If we had done this we would have had licensed treatments for more late-stage MS decades ago. The logic behind this trial design is explained in detail in our length-dependent axonopathy paper (see below).

Acceptance of more sensitive biomarkers to get proof-of-concept trials done more quickly. I know I am biased, but I really think neurofilament level monitoring in the CSF and blood will provide us with this tool. This means we will be able to do phase 2 studies a lot quicker and more cheaply than we have done them in the past. 

Political changes are needed to incentivise the repurposing of off-patent drugs. We have discussed this on this blog endlessly and we even wrote a paper on the so called ‘Big Pharma Alternative’ to explain our thoughts on this.

Regulatory changes are also required. We need to get the FDA and EMA to accept wheelchair users in trials, newer outcome measures and combination therapy approach. 

More detailed cost-effective models that focus on loss of upper-limb function and bulbar function (swallowing and speech) are needed. It is clear from the health economic data that the costs associated with managing MS increase as disability advances. 

We also need to tackle ageing and its impact on worsening MS. I think the evidence that early, or premature, ageing as a result of reduced brain and cognitive reserve underpins worsening MS in older pwMS, is beyond doubt. What we need is some way of dissecting-out premature ageing from MS-specific mechanisms. Another issue with ageing is the emergence of comorbidities as a driver of worsening MS, in particular smoking, hypertension, hypercholesterolaemia, metabolic syndrome, diabetes and a sedentary lifestyle. I sit on many trial steering committees and we deal with this problem by simply putting an age cap on the trial population. This is the main reason why trials in late-stage MS usually have a ceiling of say 55, or 60, years of age. This is ageist and we must develop better tools for dealing with this issue.  

We need to manage expectations. PwMS are expecting an effective treatment to restore function or return them to normal. The latter is not going to happen. The best we can expect is to slow down the rate of worsening disability, or flat-line their disability, with anti-inflammatory and neuroprotective strategies. I say this knowing that in pathways with reserve capacity there is a possibility of improvement in function, but not enough improvement for us to falsely raise their hopes. To get substantial and meaningful improvements in disability we need new treatment strategies, possibly remyelination therapies that work, but we will almost certainly need treatments that promote axonal sprouting, synaptogenesis and plasticity mechanisms to restore function.

As you can see we are passionate about tackling more late-stage MS. We have thrown-out many babies (DMTs) with the bathwater. Why? We haven’t thought deeply enough about some of the issues highlighted in the points above. We need a serious debate about these issues and get on with the job of protecting cognition, arm, hand and bulbar function in people with more late-stage MS. The good news is that we now have licensed therapies for both primary and secondary progressive disease that can act as the platform on which to build our pyramid and to tackle MS holistically to improve longterm outcomes. 

Giovannoni et al. Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Mult Scler Relat Disord. 2017 Feb;12:70-78.

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.

CoI: multiple
Twitter: @gavinGiovannoni              Medium: @gavin_24211

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

13 comments

  • Prof G,
    I find ‘advanced MS’ to be a misnomer. Synonyms for advanced include ‘leading’, ‘excellent’. I wouldn’t use these terms to describe an MS wheelchair bound patient with severe cognitive issues! I was proud to pass my Advanced Driving test, but wouldn’t be proud of the label Advanced MS! Late stage is a better descriptor – gives a better sense that a patient has lost a lot and their time is coming to an end.

    “Challenge the dogma that once someone has lost lower limb function and is a wheelchair user that the disease is not modifiable.” I can stress strongly enough how, for some of us, losing the ability to walk is a fate worse than death. When I get to that stage I won’t be hanging around for long. As a runner, could you comprehend a life slumped in a wheelchair? In my mind, there’s a big difference between living and existing.

    You have rehearsed the various points above many times and stayed the dogma of the past 50-60 years. So we start all over again with a clean slate.

    “It is important to stress that the pathologies that drive neuroaxonal loss, or neurodegeneration (the pathological substrate that underlies ‘advanced MS’) are there from the earliest stages of MS; even when people have asymptomatic MS.” Can anyone from Barts tell me what are the “pathologies that drive neuroaxonal loss” in simple terms. Surely these pathologies are the ones new drugs should be treating?

  • As a wheelchair user with severe upper body mobility issues I sincerely hope that the obsession with edss is not replaced with an obsession with hand and arm function because I have issues with neither bulbar function nor cognition so still consider myself lucky with a lot still left to preserve

    • Quite. One wonders why it has become so complicated. I have experience in other fields of academia where a group can be seen trying to hive of what they claim is a unique subset of something. Mostly so they can plant a flag and claim the subset as something different and worthy of an entire new set of definitions, research, journals, conferences etc. All of a sudden the protagonists become very large fish in a very small pond.

      Taking just a single step away from the obsessive shaving efforts and it is clearly one thing.

  • “Late stage” makes no sense to me as I experienced slow, subtle progression from young age, early 20s. I can’t really warm fully to your theories.

  • Thanks for this explicative post. I have a couple of questions after reading.
    About the therapeutic lag you posted:
    ….I have proposed that in progressive MS there is a lag between the onset of action of anti-inflammatory medication and its impact on the biology that underpins progression. The impact of anti-inflammatory medications in progressive MS will take several years to play out in the system that is already in the clinically progressive phase. In other words progression over the next 2 years is primed by focal inflammatory events that have occurred in the past. Therefore, suppressing inflammation today in progressive MS will have not have an impact over the next 2-years as the damage that has primed progression over the next 2 years has already occurred.

    Do I get it right if I understand that in MS a patient has focal activity (mri) then gets worse/better until that neural pathway stabilizes that is all nerve fibers reach their fate of recovery or death.
    If so if we stop focal damage from occurring then once the damaged nerves are stabilized no further worsening should occur in other systems, right? Is this observed in the clinical practice?

    About neuroprotection, do you have an hypothesis on how lipoic acid helps?

  • I don’t understand the problem with “progressive” at all. First synonym offered by Cambridge of “progressively” is “increasingly”, with the example; “My eyesight has got progressively worse over the years.”
    https://dictionary.cambridge.org/de/worterbuch/englisch/progressively

    And their definition of “progressive” is “developing or happening gradually”. These are the examples given:

    – There’s been a progressively decline in the standard of living over the past few years.
    – a progressive disease

    https://dictionary.cambridge.org/de/worterbuch/englisch/progressive

  • Prof G, you’ve made all of the points in the above post many times before, and I agree with all of them. However, on each and every point you are fighting against an entrenched MS status quo, which will fight tooth and nail your efforts to upend it. Unfortunately, you may be taking on the role of Sisyphus.

    Simply put, there is just too much money being made by all of the MS powers that be (pharmaceutical companies MS Neurologists, MS clinics, etc.) to allow for the type of revolution you propose – and make no mistake, what you are outlining is revolutionary.

    Yes, we need to redefine many of the commonly accepted terms and vernacular associated with the identification and treatment modalities of and for multiple sclerosis. Yes, we need a complete rethink of strategies for attacking the disease and its dreadful effects on patients. Yes, we need to redirect the financial spigots from research into drugs that, at their core, are merely treating the symptoms of a much deeper problem (i.e., drugs targeting a supposedly aberrant immune response, whilst nothing is being directed at finding, much less treated, the underlying cause of that response).

    As you’ve talked about before on this blog, EBV is the most obvious choice for a laserlike focus on getting to the underlying roots of not only MS but also the entire family of autoimmune diseases. Likewise, let’s look at the relationship between EBV and Human Endogenous Retroviruses, which in my mind may be the holy Grail MS research has been searching for all these many decades. If EBV flips the “on switch” of Endogenous Retroviruses, thus prompting them to express proteins identifying a patient’s own cells as invaders, well, there’s your “autoimmunity” in a nutshell. The immune system isn’t acting in an aberrant way at all, it’s simply attacking cells that appear to be invaders. Unfortunately, the cells are the patient’s own.

    In the meantime, there are many out here, myself included, who are long past the point of desperation. Without a sudden reversal in fortune, I’m not planning on sticking around to see myself become a fertile brain entombed in a prison of useless flesh and bone. And that’s an outcome I am getting frighteningly close to.

    The primary and overarching goal of each and every MS researcher and clinician should be to put themselves out of a job. Enough with all of the academic arguments and ivory tower mumbo-jumbo. Those of us suffering from this scourge need action, not words. And we don’t have decades to watch largely useless animal studies prove themselves obscenely misguided.

    I for one would gladly volunteer to take the place of a test animal in any study with at least a 10% chance of putting the brakes on my disease, and which targets some candidate for the root cause of my illness, regardless the dangers. Might as well go out with a bang rather than a whimper, and on the wings of hope rather than despair.

    • No truer words have ever been spoken! No one understands MS until they have MS. The despair of people with MS is unlike anything I have ever seen. The fear of how this disease will ravage our bodies is unreal. I’m so sick of reading at the end of every clinical trial, “more research needs to be done in order to…….”. Blah blah blah…. HSCT has been in clinical trials for over 20 years and has been proven to be quite effective, but still hasn’t been shifted from clinical trial to clinical practice. I had HSCT in March. I pray that I have put MS into remission for good. Im hopeful that there will be something soon for remyelination. I too, believe that EBV has a direct link to MS. I also believe that it could be other viruses, in particular, the herpes virus. Herpes lies dormant in the nervous system as well. If you have a stressful situation, the herpes sores can appear. Very similar to stress and symptoms of MS. Anyway, someone needs to listen to MS patients. We have probably done more research on finding a cure than most of the “researchers” in a lab or clinic. We don’t have a voice when it comes to our own, very personal disease. The MS society should let us have a “write in” section of their publication where we can ask questions or express thoughts about MS. Maybe even ask a doctor who does research or can get answers to questions that we have.
      Anyway, I just pray that we have something soon. Stopping the progression first, but Remyelination is the holy grail. That is the key.

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