Will the real MS say hello?

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The difference between religion, a belief system, and science, an experimental system, is that you can falsify the latter, but not the former. So when KoL (key opinion leaders) say they believe something they don’t really mean it literally. What they are really stating is a hypothesis that needs to be interrogated. 

So when I say that relapses and focal MRI activity are not MS, but are occurring in response to the cause of MS I am stating a hypothesis that needs to be falsified. Underpinning science are philosophical constructs on which to test hypotheses. One such construct, or system, is the Prentice criteria for defining a so-called surrogate endpoint in clinical medicine. 

According to the Prentice criteria for a surrogate endpoint to be considered as a substitute for the disease (or is the disease), it requires that (1) the baseline measurement of the endpoint is predictive of outcome, (2) changes in the measurement of the endpoint over time is predictive of outcome and (3) changes in the measurement of endpoint in response to a therapy is also predictive of outcome (Prentice, 1989). I would add a fourth criterion that (4) the measurement of the endpoint should predict outcome independent of treatment, i.e. it should behave in the same way whether a subject is on placebo or active treatment. 

When you apply these four criteria to relapses and/or focal MRI activity (new and/or enlarging T2 lesions or Gd-enhancing lesions) they don’t predict disability outcomes. This is why I state that the real MS is smouldering MS and the focal inflammatory activity is the immune system’s response to what is causing the disease. Suppressing the immune system’s response to the cause of MS may modify the course of MS, but it does not stop MS from smouldering away. 

The analogy I use is one put forward way back in 1994 to Ed Thompson my supervisor when I was a PhD student. I subsequently felt confident enough to present it at a European Charcot Foundation meeting in Lausanne under the title of ‘The yin and yang of inflammation in multiple sclerosis’. I subsequently published the hypothesis as a book chapter in 2004 (see below). 

It is interesting that my ideas, or hypotheses, about MS from 25 years ago haven’t changed very much. This is called cerebral stagnation. Maybe it is time to move on? 

The primary neurodegenerative hypothesis (1994): Although multiple sclerosis is a clinically heterogeneous disease it can be viewed as an inflammatory neurodegenerative disease with the clinical spectrum or phenotype determined by the presence or absence of focal inflammation, similar to that which occurs in infectious diseases, e.g. leprosy. The underlying neurodegenerative component of the disease may or may not be ongoing but it is modified by superimposed focal inflammatory events. The focal inflammation may be an appropriate host response directed at an unidentified aetiological agent or an inappropriate autoimmune response. These focal inflammatory events are responsible for clinical attacks and MRI disease activity. Although damaging in themselves the focal inflammation provides the biological substrate in the form of trophic and growth factors which promote repair and clinical recovery. Inhibiting the focal inflammatory events, e.g. with generalised immunosuppression, would reduce the relapse rate and MRI activity and remove the important trophic and growth factor support provided by the inflammatory infiltrates, but it may not affect the underlying primary neurodegenerative processes. This strategy would simply convert relapsing-remitting disease into non-relapsing progressive disease. There is evidence from infectious diseases that this phenotypic variability is linked to genetic susceptibility. 

Why use leprosy as an analogy? Leprosy is an infectious disease caused by a bacterium with a well-defined set of antigens that can be used to interrogate the adaptive immune systems responses to antigens. Depending on the immune response you get a different clinical picture. If you a brisk inflammatory response you get tuberculoid leprosy and it presents with very inflamed lesions. On the other side of the spectrum, you get lepromatous leprosy that is more of a smouldering disease with low-grade inflammation. Between these two extremes, you get a grey zone that is referred to as borderline subtypes. Interestingly people can convert from having lepromatous to tuberculoid leprosy if the shift their immune response to a so-called type 1 immune response that is driven by a cytokine called interferon-gamma.  

Primary progressive MS is lepromatous MS and relapsing-remitting MS is tuberculoid MS and the SPMS sits in the middle. Interestingly, gamma interferon may have the same effect in MS as it does in leprosy. We know that an early trial of gamma-interferon had to be aborted as it triggered relapses. I hypothesise that if you treat PPMS with gamma-interferon you would convert it to RRMS. Unfortunately, this is an experiment that is unlikely to occur but happens naturally when you get a viral infection. Interestingly, infections are a common trigger of relapses. These clinical observations are congruent with the ‘Leprosy Hypothesis of MS‘.

Do these observations support the ‘Field Hypothesis’ and the ‘Viral Hypothesis’ of MS?

Panitch et al. Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology. 1987 Jul;37(7):1097-102.

We treated 18 clinically definite relapsing-remitting MS patients with recombinant gamma interferon in a pilot study designed to evaluate toxicity and dosage. Patients received low (1 microgram), intermediate (30 micrograms), or high (1,000 micrograms) doses of interferon by intravenous infusion twice a week for 4 weeks. Serum levels of gamma interferon were proportional to dose and no interferon was detected in CSF. Seven of the 18 patients had exacerbations during treatment, a significant increase compared with the prestudy exacerbation rate (p less than 0.01). Exacerbations occurred in all three dosage groups and were not precipitated by fever or other dose-dependent side effects. There were significant increases in circulating monocytes bearing class II (HLA-DR) surface antigen, in the proliferative responses of peripheral blood leukocytes, and in natural killer cell activity. These results show that systemic administration of gamma interferon has pronounced effects on cellular immunity in MS and on disease activity within the CNS, suggesting that the attacks induced during treatment were immunologically mediated. Gamma interferon is unsuitable for use as a therapeutic agent in MS. Agents that specifically inhibit gamma interferon production or counteract its effects on immune cells should be investigated as candidates for experimental therapy.

CoI: multiple

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.

30 comments

  • Prof G,

    Do we not have data showing the outcomes of patients (RRMS) who never received a DMT and those who did? I thought there was some data showing that those who received interferon, on average, lived longer than those who did not received a DMT?

    You used to get excited about the Alemtuzumab data showing disability improvement for some and a normalising of brain volume loss for most recipients. How would this fit with the idea of the real MS being smouldering MS not relapses / focal inflammation i.e. treating the latter should not have much impact on smouldering MS?

    Is it possible to see smouldering MS on MRI or other imaging methods?

    How far away (or close are we) to treating smouldering MS? Is Prof Pender’s approach to treating EBV in MS patients possibly addressing smouldering MS?

    Sorry for all the questions, but your latest hypothesis has rattled me.

    Merry Christmas

    • Re: “I thought there was some data showing that those who received interferon, on average, lived longer than those who did not receive a DMT?”

      Yes, that is correct. But it doesn’t falsify the hypothesis. Superimposed inflammation may speed up worsening MS, but removing the inflammation does not necessarily stop the worsening.

      • If people treated with a DMT live longer than those with no treatment, is that from onset of MS or diagnosis? I’m interested because it would be useful to know how long I have left. New Years resolution and all that.

    • Re: “Is it possible to see smouldering MS on MRI or other imaging methods?”

      Yes, progressive brain volume loss and an increase in the slowly expanding lesion load.

    • Re: “You used to get excited about the Alemtuzumab data showing disability improvement for some and a normalising of brain volume loss for most recipients. ”

      Yes, but alemtuzumab trials were all done very early when the CNS has a very low smouldering disease burden. Not sure if we can extrapolate these early results to more advanced MS. The results of using alemtuzumab and for that matter, HSCT in more advanced MS is not very good, i.e. it doesn’t stop smouldering MS.

      • Will you kindly clarify what you mean by ‘early’ and ‘advanced’
        Do any or all of the following inform whether a persons ms is caught early or is too advanced?
        If referencing duration of having ms, what about the fact most of us have it for around 15 years prior to the first relapse.
        Or is the number and severity of relapses pertinent?
        Is it the length of time from the first relapse to treatment starting?
        Equally the use of escalation therapy v induction?
        Add in a person’s chronical age and presence of comorbidities?

        Do you think every PwMS will retain smouldering ms despite treatment or that some treated early enough with likes of Alem and HSCT will potentially be free of it? Am also someone who recalls your posing the question of whether in fact Alem can be considered a possible cure for RRMS. I’ve not adopted that view of it, accepting my ms may kick off again and being 56 (on Saturday) that I’m likely to/ will deteriorate due to the perfect storm of age and damage accued. It will however be helpful to understand smouldering ms in the wider context of the above.
        Thanks.

        • Early within 5 years of symptoms and with very little disability, i.e. lot of reserve or ability to recover function. MSers with longer duration of MS are older with less reserve and more likely to have a greater CNS disease burden or the substrate that drives smouldering MS.

          • is Alem still on hold in uk?
            Getting HSCT seems to be as likely as finding a hen’s tooth.
            So if someone with MS diagnosed a year ago, disability of 1, late 40’s would you say it’s about time it was hit hard with something potent?
            What’s “best” after Alem in Uk then?

  • Prof G.,
    What you describe fits my MS saga. I had high dose cytoxan in 07′ or 08′. After 20+ years of MS, it stopped the attacks, but I was already progressive. My disability temporarily went from a score of 6 to a 3.5, and then I actually seemed to progress more quickly. Despite 2.5 years of intrathecal methotrexate and, more recently, Ocrevus, nothing has touched the rate of my progression. My brain has shown no change on MRI’s-still only minor atrophy my spine still looks like swiss lorraine cheese. But, yes, the attacks stopped. If I’d known then what I do now, I wouldn’t have subjected myself to that clinical trial-the sudden, chemical menopause wasn’t worth it.

    • Re: “chemical menopause wasn’t worth it.”

      This is the main reason why MSers say no to HSCT. They don’t like the idea of infertility.

  • “Suppressing the immune system’s response to the cause of MS may modify the course of MS, but it does not stop MS from smouldering away.”

    Yes..dmt has no effect on time to progressive ms.

    • Re: “Yes..dmt has no effect on time to progressive ms.”

      Not true DMTs do delay time to disability time points; they just don’t necessarily stop the progression, which still occurs but at a far slower rate. I am not saying you should be treated with DMTs, but we need add-on treatments to target the processes that drive smouldering MS.

      This is what we are planning to study with our MS Society Centre of Excellence grant we recently submitted.

      • “Not true DMTs do delay time to disability time points”

        Hmmm…this study says otherwise.

        Onset of secondary progressive multiple sclerosis is not influenced by current relapsing multiple sclerosis therapies
        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077906/

        “In conclusion, we consider it likely that long-term treatment with DMTs might reduce the number of patients who will develop SPMS. However, in patients who do convert to SPMS, time to conversion, age of transition and subsequent cumulative disability are not influenced by current therapies.”

          • In fairness, Anono is just quoting a study here. Hardly heresy. I think we should avoid Jeremy Kyle Show language such as labelling people “killjoys”.

            I was practically shouted down on here in the past for my failure to be convinced that current DMTs would benefit my PPMS. Or so I understood it at the time.

          • In fairness, our self-appointed world expert and HSCT proselytiser, anono is fond of dishing it out in a pretty disrespectful manner. No problem, we have the hides of non-exfoliated rhinoceroses but anono should expect a little gentle incoming, which is all “killjoy” is.

  • Maybe it s more complicated than that

    Molecular signatures of different lesions types in the white matter of SPMS

    “The target of natalizumab, VLA-4 was highly expressed in active lesions even in the SPMS phase”

    Discussion: Our data indicate that the impact of molecular pathways is substantially changing as different lesions develop. This was also reflected by the high number of unique DEGs that were more common than shared signatures. A special microglia subset characterized by CD26 may play a role in early lesion development, while astrocyte-derived TGFbeta-R2 and TGF-beta pathways may be drivers of repair in contrast to chronic tissue damage. The highly specific mechanistic signature of chronic active lesions indicates that as these lesions develop in SPMS, the molecular changes are substantially skewed: the unique mitochondrial/metabolic changes and specific downregulation of molecules involved in tissue repair may reflect a stage of exhaustion.

    Ectrims 2019

    http://www.professionalabstracts.com/ectrims2019/iplanner/#/presentation/227

  • Reading this today, about the Herpes HHV-6A and HHV-6B. ( https://www.medicalnewstoday.com/articles/327196.php#1 ) has got me wondering.
    Herpes seems to be dormant for years in some people and then erupts and produces spots/sores.
    Can’t people with MS go for years without anything happening too?
    Could the lesions on our brains be herpes spots/sores that appeat when the herpes is reactivated and cause so much trouble for our bodies because they are in the brain/spinal column which is essentially the boiler room of our bodies?

    Also I had no idea that EBV is part of the herpes family!
    I had stuff to paint on me when I had shingles at the age of 9 (looked like a Tipex bottle), any idea what that would have been?
    thanks

  • You are far from in a rut or in a state of cerebral stagnation, Dr. G. Your thoughts are brave, liberated and informed which is the absolute opposite of the current state of MS treatments and research. MS patients depend on your awakened state as we have no voice.

  • “I hypothesise that if you treat PPMS with gamma-interferon you would convert it to RRMS. Unfortunately, this is an experiment that is unlikely to occur but happens naturally when you get a viral infection. Interestingly, infections are a common trigger of relapses.”

    I have very slow PPMS, but live in fear of catching the common cold, respiratory viruses. I associate these with worsening, progression.

    When I asked the last neurologist I saw about this, she said there’s no evidence for viral infections causing progression. I did not believe her.

  • “It is interesting that my ideas, or hypotheses, about MS from 25 years ago haven’t changed very much. This is called cerebral stagnation. Maybe it is time to move on?”

    What do you mean by moving on?

    I really hope you follow these ideas.

By Prof G

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