What’s in a name?

W

The Barts-MS team are in the final stages of preparing a UK MS Society grant application to tackle the ‘real MS’ that lives inside you. Our focus is on studying or defining what is smouldering MS. This is a massive unmet need and refers to what we currently call inactive SPMS and PPMS. This is likely to affect a lot of you; at present, you remain in the so-called untreated MS camp. Ocrelizumab and siponimod are only licensed or reimbursed for patients with active PPMS and active SPMS, respectively. We are hoping our grant will be able to identify and/or repurpose drugs to modify this stage of MS or using current terminology inactive worsening SP/PP MS. 

Our campaigns of treat-early-and-effectively, treat-2-target, zero-tolerance, NEDA (no evident disease activity) have exposed the real MS, i.e. smouldering disease. Many pwMS who are NEDA on DMTS and ‘doing well’ are not necessarily doing well. When we interrogate these sorts of patients they almost all have subtle symptoms and signs of disease worsening; worsening fatigue, cognitive slowing, reduced walking distance, dropped feet on exertion, nocturia, sexual dysfunction, numbness and clumsiness of the hand, subtle unsteadiness of gait, poor balance in the dark and when tired, increased leg spasms at night, reduced auditory discrimination, problems with night vision, etc. Do you recognise yourself? 

The new norm is smouldering MS or more likely the realisation that the ‘real MS’ is smouldering MS. Our anti-inflammatory DMTs are doing what we say they should do, i.e. they are stopping focal inflammatory lesions and relapses, but are they getting to the core of the disease? I suspect not, or at least not in the majority of pwMS.

We have argued several times before on this blog that focal inflammation is not MS and that the real disease is what is driving the immune system to produce the focal inflammatory events. I suspect that effective DMTs are simply converting relapsing-forms of MS into what we used to call primary progressive MS, by exposing smouldering MS. The one hypothesis that is being explored at present is that if you treat MS early and effectively you may prevent the damage, innate immune activation and B-cell follicle formation that is thought to drive smouldering MS.

If you have MS this post will be very depressing, but as soon as the MS community faces up to the above the better. We could then start directing our limited resources to tackle smouldering MS.  This is the purpose of our grant application.

We are proposing to do deep phenotyping and biomarker studies and try and discover new treatments directed at CNS B-cells and plasma cells, microglia inhibitors or activators (both need to be tested), drugs that target astrocyte and oligodendrocyte biology, antiviral trials and in the future drugs targeting ageing mechanisms. 

I would like to thank you all for helping out with our grant naming survey. It is clear that from a scientific perspective PIRA (progression independent of relapses) only just won out. However, as PIRA only refers to relapse-onset MS we prefer the name smouldering MS. We will keep you posted on how things turn out. We are interested to know what the reviewers will say about the terminology and the concept of smouldering MS?

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.

43 comments

  • Prof G,

    Can I expect an apology from the MS research community / MSologists for (1) only uncovering the real MS some 60 years after research began in earnest and (2) encouraging me to take an induction therapy some 12 years ago on the basis that it would put my MS in to long term remission?

    “We are proposing to do deep phenotyping and biomarker studies and try and discover new treatments directed at CNS B-cells and plasma cells, microglia inhibitors or activators (both need to be tested), drugs that target astrocyte and oligodendrocyte biology, antiviral trials and drugs targeting ageing mechanisms.” This looks like a wish list drawn up by the MS research community to keep the MS research industry going until at least 2050. The U.K. MS Society won’t have the money to fund studies which will discover new treatments. Isn’t it time to do this on a global scale – get all the MS Societies to fund an international team to deliver on these studies?

    As we approach 2020, I don’t feel depressed, just extremely pissed off with the decades wasted on research papers, conferences, initiatives, anti-relapse drug trials etc., to be told in 2019 “sorry folks we got it wrong – duh”.

    • Anon 5.21
      You were born too early. Ironically, you can now argue your case for being active SPMS…. siponimod?
      Whatever the real MS is you are living proof that breakthrough inflammation continues throughout the disease course. See all the numerous posts on treatment pyramid on this blog.

      Possibly all of us reading this today were born too early. My hope lies with the youngsters, our children and grandchildren yet to be born.

  • Great post and good luck!

    Do you have any idea of the main groups working on this to keep an eye on other than yourselves as this is clearly the answer to end all forms of MS?

    Thanks for all you do and keeping MS patients in the loop. I still think you should monetize this website through advertising for all the time and effort your group spends sharing your thoughts.

    PS. Why doesn’t MD2 ever post his/her thoughts on inhibiting destructive innate immune changes of the CNS?

    • I will nudge him, but he has recently penned a peer-reviewed article on the subject.

      Gareth Pryce, David Baker. Oligoclonal Bands in Multiple Sclerosis; Functional Significance and Therapeutic Implications. Does the Specificity Matter? Mult Scler Relat Disord, 25, 131-137 Oct 2018. PMID: 30071507 DOI: 10.1016/j.msard.2018.07.030

      Since their discovery, the existence of secreted oligoclonal immunoglobulin in the central nervous system in people with multiple sclerosis has been the subject of scientific investigation and debate over several decades. Although autoantibodies can be detected in some individuals, probably secondary to release of neo-antigens after damage, evidence for a major, primary involvement of damaging antibodies is still relatively lacking. However, it is possible to construct a working hypothesis that establishes the interaction of plasma cells, which are the source of oligoclonal bands, microglia and astrocytes to create a self-perpetuating activated phenotype. This may generate an environment conducive to long-term plasma cell survival and the initiation and perpetuation of neurotoxicity that may contribute to disease worsening in multiple sclerosis. Therapeutic strategies to re-establish a homeostatic environment conducive to repair/recovery are indicated to control progressive multiple sclerosis.

  • Hi
    So if you have no evidence of activity
    on either an MRI or in spinal fluid are you saying that no dmts are worth taking as
    they only work on the inflammatory part of the disease and if there was any inflammation the signs would be in either of these two tests?

    At one time I thought Medics believed that there was inflammation which did respond to treatment but did not show up on the conventional tests.

    So even if there is an underlying cause which has not yet been discovered or treated do we now have to believe what the MRI and spinal fluid tell us?

    ie you no longer have have an aggravated immune system which can be dampened somewhat but instead simply an increasingly damaged immune system?

  • Wow, “I suspect that effective DMTs are simply converting relapsing-forms of MS into what we used to call primary progressive MS.”

    I thought I was luckier getting RRMS rather than PPMS. Looks like I was wrong. Can I sue my neuro?

    Will neuros still be prescribing DMTs given that they aren’t tackling the real MS just the immune response?

    Sad day. I’ve been following the blog since 2009 and was hopeful of real progress being made. Feels like a kick in the stomach to now be told we are decades away from addressing the real MS. At least you guys got your pay cheques, pensions and a nice retirement. The wonderful world of electric wheelchairs is all I have to look forward to!

      • Instead of wasting time checking ip addresses of posters, why not focus your efforts on researching the real MS? Did you imagine when you stated research 30 years ago, that in 2019 MS researchers would be saying that they’ve got it wrong and relapses / mri activity are not the real MS. If you were an MS sufferer you might feel let down.

        • That’s science for you, simultaneously the most satisfying career and also the most frustrating.
          “New scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die” – Max Planck.
          “There are three stages of scientific discovery: first people deny it is true; then they deny it is important; finally they credit the wrong person.” Alexander von Humboldt
          “The human mind treats a new idea the same way the body treats a strange protein; it rejects it.” Peter Medawar

    • I completely understand your frustration but the Bart’s team are not responsible for the current state of MS research. After following this blog for a while now, the following is fairly evident:

      1. Nobody really fully understands the aetiology of MS. Until this is fully understood, there will never be a cure.

      2. The endpoints used in MS studies are not measuring the true efficacy of MS treatments. Valid biomarkers are also lacking.

      3. Funding for MS research is difficult to obtain with many fighting for money from the same pot. Much is being wasted on studies that will lead nowhere or on studies where the researchers clearly haven’t completed a thorough literature review.

      4. As a consequence of point 3, and because the costs associated with drug development are significant, we are relying on big pharma to develop new treatments. This is resulting in second generation, repackaged drugs being the primary focus (the reason for this focus is obvious and revenue driven).

      Given the above it seems to me that the Bart’s team are actually trying to counter the current dogma in MS research. They have also been fantastic advocates for patient welfare (e.g. refusing to participate in placebo controlled studies).

      What we need is a more researchers willing to explore different theories and treatment options. To do this, the MS community should be questioning every donated / public dollar spent on research that is not new, innovative, or adds value to the current knowledge base. Off label use of drugs should also be assessed by more physicians.

  • “Do you recognize yourself?”

    Unfortunately almost word for word…. This post basically confirms my suspicion that current DMT’s obliterating immune systems are not the fix for progression many people think (or hope) they are. I’m 39 and am moderately confident that there won’t be a medical therapy brought to market in the remaining time I am still ambulatory. It is quite obviously discouraging for PWMS as well as the few people like Prof G who actually give a damn that there isn’t enough money or money to work on fixing the real issue. Thank you for all you do Prof G. If there were more of you those of us with the disease would have a better chance in this world. Now to work on getting my B cells back and enjoy my last good remaining days.

    • Not sure; current DMTs do work based on disability outcomes and when used very early may prevent many of the disease processes that drive smouldering MS setting-up shop.

  • Smoldering MS = stigma. Awful name. Please poll in a representative sample of people with MS for views – not just an online support and advocacy group that does not have broad generalization (ie your previous MSers published research).

    Please carefully rethink before you broadly use this label.

    With respect
    Lisa

    • Have you heard of Marmite? You either love it or hate it. When you name something you want it to be Marmite; black and sticky. Sticky in the sense that it is adopted and sticks as a term. I think smouldering MS is a Marmite term and does the job for me; but then I love Marmite and loathe Bovril and Vegemite.

      • Vegemite is blacker than marmite. Once you go Vegemite you never go back. Bovril is just plain wrong. You have to be 80 and losing your sense of taste to go near the stuff. I imagine brown shoe polish tastes the same.

        • I have always *loved* Marmite. And nowadays there is even a delicious reduced salt version. I tried Vegemite, it is disgusting. Like putrified seaweed residue. Bovril is something entirely different, as far as I know, it is meant to be a (disgusting) beefy beverage, not a spread. 🙂

    • The haematologists have been using the adjective smouldering to describe a type of myeloma (malignant plasma cells) for decades. I am sure of people with smouldering myeloma are being stigmatized by have this descriptor added to the front of their disease.

      • What am I to call my smouldering MS, my PPMS, my slow/stable PPMS? MS par exellence? The real McCoy MS? “Stigma” doesn’t mean much to me – it is obvious to everyone that I struggle to walk. At least I don’t just look drunk any more. Maybe I cared about stigma then. Now I just want to call a spade a spade and see some real, genuine progress in treating this wretched disease. Call it by any name going.

  • Anon 5.21
    You were born too early. Ironically, you can now argue your case for being active SPMS…. siponimod?
    Whatever the real MS is you are living proof that breakthrough inflammation continues throughout the disease course. See all the numerous posts on treatment pyramid on this blog.

    Possibly all of us reading this today were born too early. My hope lies with the youngsters, our children and grandchildren yet to be born.

    • I’m not sure what you mean by breakthrough inflammation. I’m unlikely to be given any treatment that interferes with my immune system. I’m probably too old anyway.

  • As a woman who was diagnosed with MS 15 years ago who has had an “atypical” disease course and the benefit of many years of Tysabri therapy due to living in the U.S., I have been following this topic with great interest. Last week, I was informed that although my lesion load is very low, my grey matter volume is at the 6th percentile, nearly two standard deviations below the mean, while my whole brain volume is at the 18th percentile. I am in my early-40s and suffer from so-called “silent” symptoms that have been incredibly debilitating, including all of the symptoms you’ve listed sans the physical problems. Could the grey matter atrophy account all along for the vast majority of my symptoms? And although the Tysabri most certainly has prevented the formation of white matter lesions, did it jump-start the grey matter atrophy? Is there another DMT I should be using to prevent continued grey matter atrophy? Or can I just take a break at this point from DMTs altogether. Thank you for your continued research & service.

    • Philippa,
      My atrophy numbers are worse than yours, despite being NEDA on treatment. And as an aside, my EDSS is 0, so most neurologists didn’t worry about what was happening in my brain anyway. That said, looking at old MRIs, I can see most of my accelerated atrophy took place well before diagnosis. Treatment seems to have normalized it. I wouldn’t recommend going off treatment. I did that a couple years ago and earned myself a new brainstem lesion.

      • Benny, thank you for your response. I, too, discontinued medication for a couple of years and developed 2 new lesions, so I am back on the Tysabri. But because I feel better physically when I am not taking a DMT, I was just curious how much do the white matter lesions really matter when they are so minimal in number? And, as questioned by Anom below, is the Tysabri actually driving the disease to become more progressive? Should I reassess my treatment plan?

  • ” I suspect that effective DMTs are simply converting relapsing-forms of MS into what we used to call primary progressive MS.”

    can someone confirm that I am interpreting this right? the recommendation for me to take an “effective” DMT, in my case Tysabri, is actually driving the disease to become progressive?

    So, how does this translate to those already on treatment? should we be reassessed.

    i think you are truly brilliant Prof G, as someone else pointed out, you obviously genuinely care and give a shit!

    I would just appreciate that some more time is put into what this all means in laymen terms…when i was first diagnosed, i watched some of your talks online and followed this blog ever since.

    I was convinced that taking a dmt was the best thing to be doing, but it does feel kind of unclear now.

    perhaps this is the whole point you are making… things were misunderstood and time to restartt? blackswan moment?

  • Hallelujah! Wishing you all the success for speedy results. Like many, I’ll be waiting and worsening!

  • “However, as PIRA only refers to relapse-onset MS we prefer the name smouldering MS.”

    Speaking as someone with ~20 years of slow/stable PPMS, I agree with this.

    I am happy to read about efforts to tackle the true core of MS.

  • So What is the point of the the two trials Oratario and Chariot if as prof g said the dmts are only useful at the start of the disease for inflammation?

    • It is never too late to modify the course of MS; even in wheelchair users we may be able to prevent further damage and slow down the worsening of disability.

      • But that suggests you are able to address smouldering MS – the cause of MS progression. If you have drugs which can do this, why do you need to undertake studies into all the elements listed in your post?

        Also, what about the results of Professor Freeman’s BMT where most patients have been stable for many years. Was the treatment protocol having an impact on smouldering MS?

      • But only if there is an inflammatory component based on this entry of yours?

        You say that dmts only work on inflammation and without inflammation you have the so-called smouldering MS which is not helped by any DMT

        So how do you reliably confirm inflammation?

        If MRI scans and spinal fluid checks are reliable for checking for inflammation then you should only be given dmts if either of these are positive and do indeed prove inflammation is present. Any trial of the current dmts on any level of MS should therefore based on your argument only be given to candidates with proven inflammation
        Or
        If neither the MRI nor the spinal fluid prove inflammation which is what I thought your argument was for trials like Chariot maybe hidden inflammation is in fact the smouldering MS so what should be argued for is that dmts are effective on inflammation which may be present even if not visible

        The question is then how to prove invisible inflammation to avoid treating people who will not respond perhaps by seeing someone’s reaction to steroids?

        I really hope you respond to this

  • Very nice post professor G. I had to read it twice to understand really what you meant . Specially the sentence : “I suspect that effective DMTs are simply converting relapsing-forms of MS into what we used to call primary progressive MS.“ it sounds very dramatic from a normal person reading this. Please correct me if I am wrong , did you mean MS has 2 components , progressive form which is always there , and the relapse component . Medication stops the relapse component , it does nothing to the progressive component . By saying dmts convert ms to progressive form it sounds really scary , It is like negative to have DMTs. DMT stop relapses but we will be progressing anyway regardless .

    • Interesting “Seb” and certainly anything that can inhibit microglial activation is in my opinion a good thing. My caveat is that this is an antibody so, given we have a blood/brain barrier to keep things like antibodies from gaining access to the CNS, how much of it gets in to the brain to have an effect? A dirty little secret so many pharma companies try to ignore. Of course it may be that in some pwMS the barrier is leakier so the blood/brain barrier might not be as much of an issue, though never addressed by the clinicians or the companies involved.

    • One wonders on closer inspection what is the point in doing such a trial for one year.

      Sounds more and more like a dud.

By Prof G

Translate

Categories

Recent Posts

Recent Comments

Archives