Am I cured?

A

Barts-MS rose-tinted-odometer: ★★★★★ (seeing purple; a Sunday morning purple)

Could you imagine if we made the treatment target in MS a cure? This is a very contentious issue; however, based on the current dogma that MS is an autoimmune disease driven by rogue autoreactive cells we should have the ability to either purge these cells from the body or imprison them via tolerance mechanisms indefinitely. Do you agree? 

After being taken to task on using the C-word (see blog post 19-May-21) I am relieved that you readers condone the use of the word. This means we can now hopefully refine the definition of an MS cure, look to see if any pwMS treated with immune reconstitution therapies (IRTs) fulfil the definition of an MS cure. Please be aware that an MS cure doesn’t mean the restoration of lost neurological function; you can be cured of further autoimmune attacks on the nervous system, but the damage that is already done won’t necessarily be repaired as part of the cure. This is why we need to at least offer IRTs as early as possible in the course of the disease, which is why we need to have the option of using IRTs first-line. I hope this makes sense.

Forms response chart. Question title: Do you think it is appropriate to use the word CURE in the context of treating multiple sclerosis?. Number of responses: 170 responses.

Forms response chart. Question title: Do you think discussing an MS CURE is raising false hopes?. Number of responses: 170 responses.

Forms response chart. Question title: Do you think the term LONG-TERM REMISSION is a better term than CURE to describe the concept of MS going away and never coming back?. Number of responses: 170 responses.

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

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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.

38 comments

  • My comment is not directly related to the post, although I would like to ask what is the reason why a clinical trial with Ocrelizumab + TAF is being conducted, and not a clinical trial with Alemtuzumab + TAF?

    Ocrelizumab at the dose given in the study will not work like the IRT ( the hypothesis is that Ocrelizumab+TAF may work as an IRT when administered together?). I think that to validate the hypothesis of B cell depletion and rebuild in a neutral environment, these people will need to be discontinued from Ocrelizumab. Was there no consent to conduct the trial with Alemtuzumab, or are there any other medical reasons for this?

    TAF = Tenofovir alafenamide

  • “based on the current dogma that MS is an autoimmune disease driven by rogue autoreactive cells we should have the ability to either purge these cells from the body or imprison them via tolerance mechanisms indefinitely.”

    I thought you didn’t support this view (autoimmune) of MS. You’ve repeatedly made the case that the immune system is responding to the real MS – smouldering MS (possibility caused by EBV). Surely a cure can only be claimed when the virus / smouldering MS is tackled effectively.

    Any updates on where the ever illusive add on therapies are? I don’t think we’ll see a true cure until we have a handful of therapies which tackle the various elements of MS. IRTs are only likely to provide a potential cure for some MSers who are treated very early after diagnosis. Please remember that those further along the MS spectrum also want to see a cure (defined as halting of further deterioration).

    • Sid, the EBV theory of MS causation is not incompatible with autoimmunity. One way EBV may cause MS is by lowering the threshold for autoimmunity and driving autoreactive B-cells. Kill the EBV and you kill the autoreactive B-cells.

      • Hello ProfG, I came across another hypothesis that MS can be caused by HHV-6A. Similarly to EBV the infection can be silent and no antiviral exist. What do you think about this? Could be that the immune system attacks HHV-6A under the drive of EBV infection?

      • Yes..but hsct and Alemtuz…do not really kill/remove EBV from patients.

        You have to look at the biology to determine a cure…and alter it
        to have a definite cure. Many on FB hsct groups thought they were in a cure/remission only to see it lapse at year 4/5 mark..just as in the trial below.
        Some days there are multiple people posting “symptoms returning at 4 year
        mark” …But even people hsct treated in Sweden within 2 years of diagnosis don’t respond and are told..”30% fail treatment and we don’t know why” So cure talk is too early.

        Absolute numbers of memory CD4 and CD8 T cells in peripheral blood prior to HDIT/HSCT and 5‐year clinical outcome

        “Of the 23 participants who received HSCT, 16 maintained event‐free survival to year 5 and seven did not. None of the immune cell reconstitution or expression patterns at any time‐point post-HSCT analysed….correlated with the 5‐year clinical outcome. However, prior to /HSCT treatment, the group of 16 patients who remained healthy throughout the 5‐year study had significantly higher numbers of central memory…and effector memory…CD4 and CD8 T cells in peripheral blood than the seven participants who experienced an MS‐related event..”

        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543487/

        • Re: “Yes..but hsct and Alemtuz…do not really kill/remove EBV from patients.”

          A few people treated with AHSCT and alemtuzumab do become EBV negative, but it may be a quantitative phenomenon. Reduce vial loads, or kill a mutant clone, and that may be sufficient to put MS into remisssion.

    • IRTs are alemtuzumab, cladribine, mitoxantrone and HSCT or AHSCT; they are given as a pulse or pulses to deplete your immune system and then allow it to reconstitute (recover). Some argue that we could also use anti_CD20 therapies as IRTs, i.e. after several courses, we stop treatment and allow the immune system to recover and hopefully MS remains in remission.

      • I find the anti CD20 angle dubious. Reading OPERA and the 5 year follow up, I am unconvinced people do go into remission even while on ocrelizumab, so it seems unlikely they would stay there after discontinuation. I think Swedish rituximab data also does not really point to remission. Slower degradation (I really dislike the word progression) compared to IFN, yes. Long term stability (which would seem to be the absolute lowest bound for a cure), not so much.

        Now possibly DODO ocrelizumab might do the job, but current dosing schedule I rather doubt.

      • “Some argue that we could also use anti_CD20 therapies as IRTs,..”

        Seems like you are the only one arguing that.

        • Most people stay in remission for some time when you stop an anti-CD20. Do a few remain in long-term remission (>10 or 15 years)? Surely we should attempt to find out. This is why we want to run the ADIOS trial.

          • Can you outline what you mean by remission in this context?

            As outlined, I am not buying this based on Opera. The progession graphs seem to increase more or less linearly over time, albeit less steeply than for the controls (open to the possibility that I am misreading that chart).

    • Alemtuzumab – various serious side effects (though it was proven that it can be partially derisked)
      aHSCT – various serious side effects
      Cladribine – I think it’s on the way on being used more commonly, at least in my country it is offered pretty widely as of what I heard, either orally as Mavenclad, or IV.
      Mitoxantrone – I think it was already removed from DMT list for MS, as I recall it had very serious side effects.

  • Is cladrabine far off being considered a first line treatment for MS?

    May it be a middle ground between to meet to have highly effective treatments early. Or will the guidelines never bend?

  • Is the majority who is currently on ocrevus likely to convert to SPMS? Is there a point of no return that a NEDA patient may pass without even realizing? Who do you know when you’ve been cured?

    • Swedish data on Rituximab shows that anti-CD20 therapy is not very efficacious at preventing pwMS from “converting to SPMS”. It is however the most efficacious drug in terms of stopping Relapses/new T2/T1 lesions if I am correct.

      Prof G also had mentioned it in his “smouldering MS” videos on his YouTube channel.



      Part from 10:00 up to 15:00 is where you will get an answer to your question about the actual part of disability that is due to inflammation and the part which is accumulating in absence of relapse activity. In the Ocrevus studies it was around 88% of disability that happened in absence of relapses (PIRA) – according to the analysis of Prof G.

        • “I always assumed that ocrevus counters spms because it is approved for ppms.”

          Just because it got approved doesn’t mean it works well.

          • Anti-CD20 therapies simply slows down worsening disability in PPMS and SPMS; it does not stop it.

      • I wonder if it is possible to run analysis on how much PIRA is dependent on previous damage/attacks.

        • When you suppress relapse with an anti-CD20 for example close to 90% of worsening is due to PIRA or smouldering pathology. Not good news for those of you expecting more.

          • Thanks Prof G for the reply – if I interpreted correctly, PIRA is mostly dependent on smouldering pathology (continues to progress), little is dependent on degradation from previous damage (which will stop at a point)?

          • Prof G,

            “close to 90% of worsening is due to PIRA or smouldering pathology.”

            Your comment summarises everything which is wrong with MS research (across the world). There was / is an obsession with addressing relapses (and generating big money for pharma). The limited efforts to address PIRA / smouldering pathology has condemned tens of thousands of MSers to worsening disability. The Verve’s song The Drugs Don’t Work pretty much sums it up for the injectables, pills and anti CD 20 infusions. But no one seems to be listening! You can’t be the only MSologist who sees that anti-relapse drugs aren’t tackling the real MS. It’s similar to the Alzheimer’s research story – an obsession with amyloid plaques. Trial after trial goes after the same target without success. No one seems to want to learn from past mistakes and try a different approach.

  • How close are we to getting an approved potent antiretroviral agent in ms ( how many years ) ?

    • I believe that all it takes is 1-2 clinical trials that will show how effective the antiretroviral therapies can be when used with other drugs that are currently on the market. One clinical trial will end in 2014/2015, if it shows a great success – hopefuly a large part of the drug companies will jump right into it…

      It has been mentioned numerous times here, it’s the Ocrevus + tenofovir alafenamide vs Ocrebus.

  • This question will expose my ignorance but I want to understand. If a person with MS is “cured” but has ready suffered atrophy and cortical damage, will a so called “cure” prevent further axonal loss and neuronal destruction? Or has the unraveling process already begun?

    • A cure such as using antiretrovirals against ebv to cure ms will allow to have the normal rate of brain volume loss everyone has. So yes even though their is damage from the past lesions or atrophy with a cure that damage will stop and your brain will age at the normal healthy rate from that point on therefore no excessive neuronal dammage should occur.

      • Please note that EBV and HERVs remain a hypothesis. We have no idea whether or targeting these agents will make a difference.

    • “MS is “cured” but has ready suffered atrophy and cortical damage, will a so called “cure” prevent further axonal loss and neuronal destruction? Or has the unraveling process already begun?”

      Cured from ms brain loss..but not brain loss from ageing.

      Someone can move good at 90 but then at 95 they are not so stable and need a cane.
      Will this happen to the cured who have ms brain atrophy earlier…..at 60..70..80…? Who knows.?

      • Re: ” … the unravelling process already begun…”

        Yes, the unravelling processes may have already begun. Some of it is the pathology associated with smouldering MS. Don’t forget ageing is an unravelling process, which we can’t escape.

        • Thank you for the replies. I wish it were different but The only escape truly available is not the type of cure I want or seek anyway. 😉

    • Good question
      If the losses continue , then it’s not a cure
      Maybe the treatment came too late for that person

  • Hi Prof G, ‘Am I Cured’ is a sentence all pwMS would want to say/ask! It is without a doubt giving huge hope and I don’t think there’s nothing wrong with that. The various hypotheses and excellent comments raised with such a post, helps tremendously getting folk talking and sharing information. I’m keen on the post that included the elixir of life! To stop ageing would be the ‘cure’ for pwMS, as I’m convinced, the older you seem to get with the disease, the blimming worse you feel! Partly, because with ageing, especially if you have other issues, has a habit of reminding you your body in degenerating as we speak! I hope you and your team are able to move forward with different trials and to mix up and use different therapies. The smouldering part is the inflammation which needs to be targeted and soothed. Less or no inflammation, no pain, general symptoms and less damage to the spinal cord and brain. Finding a drug that targets the inflammation – I would sign up for the trial today!

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