Inactive MS; does it exist?

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I had an interesting discussion with some like-minded colleagues recently about active and inactive MS. We seemed to agree on what active MS is, be it in the relapsing or progressive phases of MS. However, we couldn’t really agree on what inactive MS is. Take this following case scenario; many said he was inactive, but others felt he had active MS and should have his treatment switched. Would you agree?

When you look at post-mortem studies of people dying with endstage MS they all have active inflammation within their brains. Active inflammation refers to both adaptive (memory responses) and innate (hard-wired) immune responses. MSers at death still have T-cells, B-cells and plasma cells in their brains in addition to astrocyte and microglial activation. 

If we extrapolate these pathological findings to life then all MSers have active MS. What is the solution in terms of forming a common nomenclature? Surely MS is a biological disease rather than a clinical disease? If this is the case we need to come up with a biological classification system to describe active and inactive MS.  

On reflection, I think we need to get rid of the terms active and inactive and describe what we mean pathologically using metrics. For example, 

  1. This patient has evidence of ongoing focal inflammation (relapses, new and/or enlarging T2 lesions and/or Gd-enhancing lesions and/or raised CSF NFL levels) in the last 12 or 24 months. 
  2. This patient has no evidence of ongoing focal inflammation in the last 24 months but has worsening disability (physical and/or cognitive) and evidence of smouldering MS with increased brain/spinal cord atrophy and/or an increasing T1 black volume. 
  3. This patient has no evidence of ongoing focal inflammation in the last 24 months, is stable clinically (physical and cognitive) and has no evidence of smouldering MS, i.e. no increased brain/spinal cord atrophy and a stable T1 black volume. 

I suspect that we will have very few MSers in category 3, simply because with an MS-centric view of the world we are forgetting that MSers are human and will age and will get comorbidities. Therefore, how do we include ageing and comorbidities, which affect these biomarkers, into this classification system? In addition, none of our metrics is black-and-white so there is scope for miss-classification. What is clear that if you take this approach then MS is one, and not two or three, diseases. A person with PPMS with new lesions will be treated in the same way as someone in the relapsing-remitting phase of the disease. Do you have a problem with this?

Thoughts, please?  

CoI: multiple

About the author

Gavin

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

43 comments

  • How is this issue dealt with in other diseases eg cancer? One often hears of a patient who is in remission, I’m not sure how an oncologist reaches such a classification (I’m guessing based on scans and/or blood tests).

    What about the patients in the Canadian BMT trial (Dr Freeman). How are they classified?

    • Although many of the Canadian BMTers are NEDA two, I have been told a lot are progressing with worsening disability. These MSers will be in the same boat as this patient. Is it smouldering MS or premature ageing?

  • Another interesting case study….

    How was BVL reliably measured and monitored? Was there a protocol in place since 2016 or as the loss unanimously acute and visible to the naked eye?

    • And furthermore, assuming patient is SPMS – it seems to me that he has only 1 choice really or am I wrong?

      FDA label update to OCREVUS, now approved for CIS & SPMS W/ activity as well as RMS & PPMS!

    • objective vs subjective respectively.

      Diagnosticians can defer on methods and observations.
      Analysts (labs, radiologists, LP, etc…) give a straight forward figure.

  • One disease but very heterogeneous fenotypes?

    You forget something you dont like to talk about

    Benign Multiple Sclerosis – Recogniti
    on as a Defined Clinical Subtype
    Sophia Yang
    1
    , Madison Clague
    1
    , Saud Sadiq
    1
    1
    Tisch Multiple Sclerosis Research Center of New York
    Objective:
    Our objective is to determine if there is a subset of patients with multiple sclerosis who have a
    favorable long term clinically benign disease course.
    Background:
    It is believed that untreated or minimally treated MS is inevitably associated with long-term
    disability. However, most aggressive therapies are associated with potentially serious adverse effects and may
    not be necessary in all patients. In this study, we followed clinically definite MS patients for at least 15 years
    following initial diagnosis to define the entity of benign MS (BMS).
    Design/Methods:
    In this IRB approved study, we examined data from 1,520 consecutiive patients seen at the
    Tisch MSRCNY by a single neurologist. We selected patients as having benign disease if the following criteria
    were met: disease duration of at least 15 years or more during which neither clinical relapses or change in EDSS
    occurred and MRI findings remained stable. In addition, all patients were either untreated or treated with a single
    therapeutic agent. Furthermore, cognition evaluation was either formally or informally tested in all patients.
    Patients who had accumulated an EDSS of greater than 2.5 were excluded from the study.
    Results:
    Of the total number of patients, 265 met the criteria for BMS (17.4%). Of these BMS patients, 211 were
    female (79.6%) and 54 were male (20.4%). Approximately 62.6% were treated with a single disease-modifying
    medication and while 37.4% were untreated. The average age at disease onset was 33.7, and the average
    duration of disease was 22.6 years. Moreover, 25.3% (67 of 265) of BMS patients had been followed for more
    than 25 years post diagnosis. None of the BMS patients had significant cognitive impairment, cerebellar
    dysfunction or spasticity.

    Conclusions:
    BMS is an entity that should be considered as an entity when treatments with potentially serious
    adverse events are initiated

    http://indexsmart.mirasmart.com/AAN2019/PDFfiles/AAN2019-000544.pdf

    Aan 2019

    Background and aims

    Multiple sclerosis (MS) typically begins in young adulthood and has a variable prognosis. Up to 85% of patients with multiple sclerosis stop working within 15 years of the onset of disease. However, there is a cohort of patients with a benign course of MS. The aim of the study was to define predictive factors of benign disease course.
    Methods

    This is a prospective, observational study conducted from January 2012 to January 2013. Patients from regional registry with BMS according to three criteria (Expanded Disability Status Scale ≤4 , disease duration ≥10 years, totally or partially employed) were observed for the period of 5 years. Single way ANOVA and discriminant analyses were performed to explore prognostic factors associated with BMS.
    Results

    80 patients (12,59% of all MS patients from regional registry) with benign MS were enrolled in 2012-2013. 74 (92,5%) patients competed the study. The mean age of study sample was 46,45±8,36 years, with 26 male and 48 female. Most of patients presented with monosymptomatic 44 (59,5%) onset. The estimated frequency of BMS after 5 years follow-up was 45,95%. Positive prognostic factors for BMS included age of patient, age of disease onset, monosymptomatic onset, lower step of EDSS after 10 years of disease. The created predictive model inclusive type of onset and age at the fist symptom in BMS patients with a 5-years follow-up was successful in 68% cases.
    Conclusion

    We concluded that age at onset of the disease and type of onset are the strongest predictors in patients with BMS.

    EAN 2019

    What about this patients how would YOU manage them?

    Do nothing ?
    Refer to hsct?
    Switch to natalizumab?
    .
    .
    .
    Can we say that their ms is inactive?…Why?

    Why not treat them?

    Are their post mortem brain tissue equal to those all other ms´ers?

    Obrigado

    • We don’t know what benign MS looks like at post-mortem except to say that ~25% of people with MS in their brains are not diagnosed in life. I suspect the majority of these have benign MS.

      Most benign MSers are now on treatment; i.e. the therapeutic aim is to convert as many MSers as possible into having benign MS.

  • In my eyes this is a case where in only six years EDSS 4 to 6 shows how ineffective fingolimod has been . MS active or not that doesn’t make much difference because this patient will be totally disabled at the end of the run the same happened to me five years on Fingolimod from the very beginning absolutely disabled after that period of time . Sorry but I don’t buy on the message of treat early you will be better off because even when you treat early you go into S… so unfortunately you should be focusing on finding a cause of ms and treat it accordingly otherwise it’s a total waste of time , my opinion .

  • The three categories make sense to me, particularly if we enter an era when treatments suitable for those with smouldering MS but no focal inflammation become available.

  • Forget MRI the human being Escalated from EDSS of 4 to 6 in just two years that’s not tolerable. how is there anything else being considered other than escalation? To me to stay on current DMD would be criminal – the question is not WHETHER to change the question is what to use (hsct, lemtrada, ocrevus…) so Dr G and mouse doctor – what do you give this patient?

  • “many said he was inactive, but others felt he had active MS and should have his treatment switched. Would you agree?”

    This is a loaded question. I agree he should be treated but he has a different type of “active” MS which current immunotherapies for treatment of adaptive response (ie. aimed at B and T-cells) are NEVER going to work.

    The FDA wisely pointed this out with the selective-bias trials of Ocrevus, Mavenclad and Mayzent for progressive MS which had no effect above placebo if the bias was removed and even if the trial was somehow “mysteriously” underpowered.

    To try to slow his “active” MS will require a drug, like ibudilast or alpha lipoid acid, that works on his innate immunity like hot microglia, A1 astrocytes, neuronal death or oligodendrocyte function. Again, however, this will likely just slow his eventual decline and is still years away from a reality.

    The answer for actually improving the QOL in this patient, along with every late RRMS, SPMS and PPMS patient, lies not in current recycled immunotherapies treating a downstream reaction of B or T-cells but in treating the actual underlying cause of MS with neuroprotective, remyelination and/or neurorestoration therapies.

    Researchers current fascination with Pharma driven non-innovative recycled immunotherapies for disgusting profits has done very little to provide a meaningful treatment that actually helps cure or improve a patient’s QOL, which is all that matters and has been virtually neglected.

    • We shouldn’t forget that MS has done well from the Pharma innovation cycle. The prognosis of MS has been transformed by DMTs. What we now need is the investment to make sure the next round of innovation takes outcomes to the next level; i.e. neuroprotection, remyelination, neurorestoration, safer HSCT, better symptomatic treatments, MS prevention, etc.

        • 1. “The prognosis of MS has been transformed by DMTs”

          This statement does not apply to a single progressive phase patient. They will have missed the small window of opportunity for treatment as a RRMS patient for this outcome to happen by either taking an ineffective DMD, having a delayed diagnosis or being a PPMS patient. Improved QOL should be the goal, not just delaying the inevitable.

          2. It is not only Pharma’s fault. Pharma will always abide by rules that are laid out by approving/governing bodies like FDA, EMA etc.

          These rules are guided by top neurologists/researchers in MS. Unless it is a breakthrough drug, these rules need to be progressive and only allow comparison of a new drug to the most efficacious drugs for it to be approved.

          Any comparison to anything else is not furthering treatment of MS and does not have the patient’s best interest at heart.

        • Not only sad, but tragic. The pharmaceutical companies are publicly traded for-profit entities, and as such have a fiduciary responsibility to their shareholders to increase shareholder value, which can often run in conflict with producing the best drugs possible. This model puts drug company corporate officers in breach of the law if they pursue cures for diseases that earn significant profits for their companies. Thus, the constant flow of “me too” drugs and the lack of revolutionary treatments.

          Case in point, Gilead Pharmaceuticals, who came up with a cure for hepatitis C. Their reward for this tremendous breakthrough? Their stock price has been hammered, and shareholders have been punished. Company management has been much maligned. The wonders of the marriage between capitalism and medicine…

          • So, clear focus and direction using a model with high throughout. That sounds easy enough with the right management. The money thing is a problem. Anyone know any billionaires who want to eradicate MS?

          • Sure – there are trillions in the capital markets funding pharma and biotech innovations.
            You will need to assemble a first class team and put together a convincing pitch. Money will flow afterwards.

            What do you have?

          • ‘What do you have’ – Nothing other than a belief that MS research needs a more focused approach using a model with high throughput that ensures the end product is priced in a manner so it is accessible to all. I have worked with MMV historically and I’m a true believer in their model. Not only because it is equitable but because it delivers results.

            Given such a model isn’t designed to deliver eye watering profits, I suspect the trillions you speak of just ain’t there.

          • Tony F – You seem very knowledgeable. How do get such a model / organisation funded without relying heavily on philanthropy?

  • Interesting that elevated neurofilament levels would be considered “active”. Wouldn’t all patients experiencing ongoing progression of disability have elevated neurofilament levels, due to ongoing destruction of nerve tissues?

    In this scenario all patients except those showing no signs of progression, relapses, or MRI activity would be considered “active”. Yet we see that such patients very often have little or no response to the current crop of DMTs.

    I would include Ocrevus in this disappointing treatment group, as a 25% decrease in progression is simply too little to be considered truly “effective”, IMO. Yes, something is better than nothing, but considering a 25% progression decrease somehow successful defines success way below the kind of result most progressive patients are desperately seeking. I certainly hope clinicians, researchers, and treatment developers aren’t satisfied with this level of “success”, profits and pharmaceutical company largesse be damned…

    • Re neurofilament levels; all the latest data suggest raised levels simply indicate active MS and correlate very closely to relapses and new lesions on MRI.

      Smouldering MS is associated with normal or even low NFL levels. As you lose axons the bulk levels actually drop.

      NFL is not going to be the neurodegenerative maker we hoped.

      • WCK 25% progression decrease is in the legs (EDSS & T25FW) and over 3 years. It was double this in the arms (9HPT). With survival curves the differences get bigger with time; so 25% at 3 years maybe 50% at 6 years and 70% at 9 years.

        PPMSers on ocrelizumab stay walking almost 5 years longer than PPMSers on placebo and maintain their upper limb function almost 9 years longer. Try and tell someone that by being treated with ocrelizumab you will have 9 years extra of being independent (upper limb function) and they are unlikely to say no thank you.

        Also, innovation often happens in small incremental steps; ocrelizumab is the first step and who knows what will happen when we start testing combination therapies with ocrelizumab as the base?

        • I don’t want to say too much about my personal situation on a public forum, but I’ll say that I have had PMMS for 2 decades, I’m now in my early 40s and I wouldn’t want ocrelizumab personally. I don’t want the dubious cancer risk, reduced ability to fight infection etc., the incessant monitoring. But I’m not eligible for it anyway, given the presentation of my disease.

        • Thanks for this updated info. I must question, though, whether or not it is indicative of all progressive MS patients. The progressive ocrelizumab trials were frontloaded with suspected responders (those with enhancing lesions), so does this follow-up data include this same pool of patients? As has been well documented, the trial was underpowered to differentiate between subgroup results, and I’d be very interested to see whether or not the drug is as effective in those with active versus inactive disease.

          Regarding innovation, yes, it is often an evolutionary process. However, what we really need is revolution. The immunosuppressant/immunomodulating drugs do not directly address the root cause of MS, which of course remains unknown. A concerted effort to find that cause would move us towards a cure, which none of the current DMTs (except for, maybe, HSCT) represents. Hard to be overwhelmed by incremental progress when your life is going down the tubes…

          • I am sorry WK, but i have to respond here since I am a big fan of your blog and contribution to the MS community.

            The conspiratorial reasoning is simply not true, even if it makes sense to many.

            MS is a “multipolistic” market driven mostly by a handful of treatments that generate 80% of annualised revenue.
            The way to think about this setting is not micro (i.e. balance sheet driven) but macro (i.e. Game Theory). Allow me to explain further:

            1) Companies A, B and C benefit from status quo (call it maintenance therapy but not treatment), 2) A, B and C DO NOT TALK to each other on pricing strategy (price setting is a serious criminal offense) or development pipeline (industrial espionage is a criminal offense). 3) A, B and C are in perfect competition and have to balance their marketing budget (harvesting from existing remaining patent portfolio) vs R&D expenditure (increasing revenue weighted average patent life

            The setting above is the challenge facing a senior pharma exec. Now let’s say Company A stumbles on a cure (gut microbiome, viral or some other moonshot project). “A” has 2 options: (i) conspire with all their staff and researchers to hide all evidence of a cure (the “Kill JFK” conspiratorial approach) or (ii) release their drug for $1m (yes, those prices exist) and 10-15 year remaining patent life (2m MSers worldwide, do the math), effectively killing the market of companies B and C before this new patents expire.

            This, I am afraid, is what motivates executives in real life. The rest is for the birds really. The only pressure activists like you and me can put is on yearly expenditure on Marketing vs R&D. We would like to see much more on the latter.

            I hope this makes sense. The math of Game Theory can be challenging but the concept is easy to grasp if you are interest in some mental masturbation. Prisoner’s Dilemma is the way to start.

          • Perfect competition yeah right.

            Thanks for your insight. Pharma is regulated. However it does appear to behaves as a virtual cartel and the prices are kept high. Remember they all get slices of the pie. Biogen gets royalties on ocrelizumab a Roche product Cladribine is Merck and Teva so it is not A B and C. Until a small molecule arrives after its patent has expired there will not be competition to bring prices down. This has happened in the medical marijuana supply. A race to the bottom is not the way to go.

            Until that time pharma is interested in MS. They have not only given you treatments but MS nurses arguably a great DMT

          • Tony – I understand game theory, and appreciate your take on the topic. However, the environment in which real-world pharmaceutical companies operate is not a perfect market, but one in which intercompany collaboration and collusion is rife.

            Do you honestly think that the rules and guidelines set forth by governing agencies are adhered to? Just take a look at it how these companies circumvent the ridiculously flimsy guidelines regarding their payments to the doctors who prescribe their drugs. Do a search on some of the prominent US MS neuro’s on the “Dollars for Docs” website and prepared to be gob smacked. Many of these doctors pull in tens if not hundreds of thousands of dollars a year in pharmaceutical monies completely unrelated to any legitimate research purposes. In any other industry such payments would be considered kickbacks and bribery, but somehow this pocket lining of doctors by Big Pharma is perfectly legal when camouflaged by the terms “honorarium” and “consulting”. It’s a farce.

            Moreover, the system is further rigged by the pharmaceutical companies extending their tentacles into the medical journals, to the extent that they can control much of what gets or does not get published. I am extremely well acquainted with a prominent MS researcher who runs an independently funded research lab, who has told me point blank that if he found the cure for MS he is certain he would not be able to get it published in any mainstream medical journal precisely because of this pharmaceutical company control. He says he would probably have to go underground via the Internet to get the word out. These are not the words of some fringe mad scientist, but a respected researcher at the forefront of new techniques and technology regarding the treatment of the disease.

            Do you think it is mere coincidence that all of the MS drugs are priced within a few thousand dollars of each other? This includes 25 year old drugs that are far less effective than the next generation drugs that came after them, drugs whose prices have increased 20X-30X in the decades since their introduction. What other industry do decades old products see such mind-boggling increases in price? The workings of a free market? Ludicrous.

            As far as R&D goes, the researchers involved naturally gravitate towards research that will get funded, and the research that gets funded is that which stands the most chance of generating huge profits for the pharmaceutical companies doing the funding. This is where fiduciary obligations come to play. A Pharma company exec would quite literally be breaking the law if he directed funding towards research that would be injurious his company’s status quo profit-making business model. Thus we get an overabundance of research into yet more ways to tinker with the workings of the human immune system, and very little into looking for the root cause of the disease. Difficult to get any true disruption under these circumstances. As has been noted by other commenters, very often the truly disruptive technologies developed by smaller companies get bought out by larger concerns, for better or worse. Maybe I’ve been wearing too many tinfoil hats, but my suspicion is that it’s usually for the worst.

            Academic researchers often refer to the “valley of death” between some of the promising basic research they do and getting that research funded, in order to bring it out of the lab and move it forward into wider trials. There once was a nonprofit called the Myelin Repair Foundation, run by a man with PPMS, that was devoted to bridging this yawning gap, but they unfortunately went belly up several years ago. While they were around, though, they very eloquently and effectively lobbied against much of what I have outlined above. A terrible loss when they went under…

      • Thanks for this info, very interesting. What to make of a patient with high NFL levels in their CSF who continues to progress despite having no new or active lesions? Very disappointing that NFL will not be the Neurodegenerative marker we hope for…

        • Mouse Doctor: The above was not addressing pricing but status quo vs innovation – pricing is a different conversation. If I was a pharma exec, I would price in the same way. WK is correct on this one that management has a fiduciary duty of profit maximisation towards their shareholders.

          One last point I did not touch on is the influence of the cost of funding on innovation. Large pharmas are diverse and well established. They can fund there-selves cheaply by issuing borrowing for <4%. Their objective is to generate a return on capital employed in excess of this.

          A small biotech like GeNeuro or Active Biotech Ab are in a different ball game. They raise very expensive capital (venture equity expecting 10x return) and are dependent on the binary outcome of their lead patent. Which is why their life-cycle is so short (hit or miss). Now I had a lenthy call with the CFO of Geneuro 3 weeks ago. He has funding to keep him afloat for another year,

          So disruptive innovation has to happen away from the large pharma since the capital (and culture) deployed in small entities is disruptive by design.

          Another tricky topic here,… I hope it all starts to make sense.

          • Thanks for your insight…I know about the consequence of a miss. I’m not.a shareholder anymore:-(

          • If they became to much disruptive guess what will happen?
            They will be bought

            By… Big pharma

            Happens time and again remember YouTube, whatapp, Instagram

            They where very disruptive and them…. Got ‘eaten’ by the big guys

  • Super cruel in my opinion. To be written off when we all know it’s all one bloody disease with ever cruel phases. I’m currently in Moscow getting myself sorted out out coz no-one else will….

    Sorry only I have the right to play god with my own life

  • Very interesting. I feel that be it relapsing remitting or progressive bottom line is the patient still has M.S either degree surely is irrelevant the disease is still living in them.

By Gavin

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