Framing

F

Barts-MS rose-tinted-odometer: zero-★’s – still seeing red

When the EMA doubted its wisdom and ran scared on alemtuzumab, after an Article 20 review of its benefits and risks, I was inundated with emails and queries.

“Gavin, didn’t you see this coming? Surely, alemtuzumab should never have been licensed as a 1st-line treatment for active MS? Clearly, the FDA got this right and the EMA made a mistake?”

What we are all forgetting in this debate is how bad MS can be as a disease and most of the early damage occurs occultly before people with the disease and their close ones realise the extent of the damage. What is lost in MS is lost forever. We have no magic treatment that can repair the damage and turn back the clock, which is why the Article 20 alemtuzumab review was so critical for the field. By the regulator’s taking away the ability of pwMS to assess and weigh up their own risks, and choose alemtuzumab first-line, has turned back the clock. In the UK alemtuzumab can only be used as a first-line agent in patients with rapidly evolving severe (RES) MS (two disabling attacks in a 12 month period), which is now a very small group of patients.

Early effective treatment in MS is about prevention; preventing the accrual of irreversible damage and giving pwMS the opportunity to age relatively normally. Now that alemtuzumab has become a 2nd- or 3rd-line option for pwMS many are seeking alternative treatment strategies and it has increased health tourism abroad for AHSCT. Is this what the EMA wanted?

As AHSCT is a procedure and not a drug, it doesn’t require EMA or MHRA approval. Therefore, we should be actively pushing for AHSCT to become a 1st-line treatment option. If I had MS, why would I want to watch and wait whilst I failed one or two DMTs before getting to the very high efficacy IRTs (immune reconstitution therapies) that have the biggest impact on preventing end-organ damage, reversing disability, inducing long-term remission and possibly offering a cure? Interestingly, both of these treatment options are considered to be the most cost-effective DMTs available.

When asked which DMT would I choose if I had MS, I have started saying AHSCT. When I admitted this a few years ago one of my patients, who I have been looking after for over a decade, sent me an email stating how upset she was that I had never offered her AHSCT. I clearly need to explain my position so as not to upset anyone else.

AHSCT is not on offer as a routine NHS therapy. At the moment AHSCT is only considered a 3rd-line treatment in the most active patients. Another problem is that it is not on offer across the country. There are only a handful of MS centres that are prepared to refer their patients for AHSCT. This means that access to AHSCT is not equitable and explains why an increasing number of patients travel abroad, at great personal cost, to receive this therapy.

The block in access to AHSCT seems to be at the level of the neurologist/MSologist. NHS England guidelines for bone marrow transplant (BMT) units allow them discretionary use of up to 15% of their AHSCT procedures to treat autoimmune conditions, which includes multiple sclerosis. As BMT units exist across the country access to these units would simply require a referral from a neurologist to the unit to request AHSCT as a treatment for MS. The latter, however, is unlikely to happen unless the local MSologist champions AHSCT as a procedure and gets their local haematology unit on board. It always takes a local champion to make things happen.

Another factor that has changed in the last 10 years is the strength of the evidence demonstrating how effective AHSCT really is as a treatment for MS. The MIST trial, the first large randomised controlled trial, and several meta-analyses of AHSCT confirm that AHSCT is a very effective therapy. At the same time, the risks associated with AHSCT have improved and the mortality in most BMT units is now below 1% for MS. This has now tipped the scales in favour of AHSCT becoming a mainstream treatment for MS.

There is however resistance from the MS community about AHSCT being offered as first-line therapy. Why? I suspect because the risk: benefit profile of AHSCT has yet to be compared in a head-2-head study against our most effective licensed treatment, alemtuzumab. This is why we are starting a head-2-head study, the STAR-MS trial, of alemtuzumab or ocrelizumab vs. AHSCT in the hope of generating evidence. With the EMA making alemtuzumab 2nd/3rd-line this trial will almost certainly recruit too few patients on alemtuzumab for a direct comparison of alemtuzumab vs. AHSCT. I predict the majority of patients in the comparator arm will be on ocrelizumab. This would not be asking the same question as ocrelizumab is used as maintenance therapy and may in fact do very well against AHSCT; the trial is using clinical NEDA (no relapses or disease progression) as the primary clinical outcome. Ocrelizumab is pretty good in the short term at achieving clinical NEDA. For me, end-organ damage or brain volume loss in years 2 and 3, after rebaselining at 12 months, would be a much more informative outcome. Do you agree?

We know already that AHSCT will be more cost-effective than alemtuzumab and ocrelizumab, but will it be more effective and most importantly will it be safer? I suspect it may not be as safe in the short-term, but what about over a 10-20 year horizon? The one long-term AHSCT risk that worries everyone is the delayed secondary malignancy risk; cyclophosphamide that is used in both the stem cell mobilisation and ablation phases of AHSCT is a DNA alkylating agent and hence a mutagen. This is why long term follow-up data from the European Bone Marrow Transplant Registry will be so important to provide this information. The other downside of AHSCT is ovarian toxicity and infertility, which in my experience are the most common reasons for my patients saying no.

Please remember that most of the proponents of AHSCT as a treatment for MS recognise that the major benefits from treatment will only be derived if AHSCT is used early in the course of the disease. This explains why most BMT units don’t offer AHSCT to pwMS with more advanced, or progressive, MS. However, this has not stopped private, fee-for-service, units offering AHSCT to all-comers. If you have the money and are willing to travel abroad you will be able to find a BMT unit that will treat you. I think this is wrong and will not happen in the NHS if and when AHSCT becomes widely available. We have to be honest with our patients about the risks and the benefits of AHSCT and why we will limit AHSCT to those who will benefit the most. In fact, there is evidence that more advanced patients may actually be made worse by AHSCT; the chemotherapy used to ablate the immune system is neurotoxic and may speed up neuronal loss. In addition, serious life-threatening infections are more common when you have AHSCT, particularly in patients with more advanced MS, and infections are well known to worsen MS disability in more advanced disease.

Please be aware that AHSCT is not for the faint-hearted. It is a risky therapy with serious adverse events and quite a high mortality. Even a mortality rate of 0.3–0.5% is high when compared to licensed DMTs. Should this stop us from offering AHSCT first-line? I think not. If we have been prepared to offer alemtuzumab, with its risk profile as a first-line treatment, why not AHSCT? Most pwMS would agree that the decision regarding what is an acceptable risk to take should be taken by the patient and their families, and not the neurologist or other HCP. There is data showing that neurologists are much more risk-averse than pwMS. Neurologists need to acknowledge this bias, which is likely to be an unconscious bias, and let their patients make the decision.

What I am really trying to do by stating that if I had MS I would choose AHSCT as my treatment is to reframe the DMT debate, particularly in relation to access to highly effective DMTs. By focusing on AHSCT as a first-line treatment it should at least make you consider what your treatment objectives are in MS.

Framing is another cognitive bias that was identified by Daniel Kahneman, the Nobel laureate, and his partner Amos Tversky. By moving the frame upwards, or to the right, i.e to include AHSCT as a 1st-line therapy, it makes it more likely for pwMS and their neurologists to choose more effective, but arguably safer, treatments 1st-line.

We now know that people who start on a low to moderate efficacy DMT do worse on average than those who start on a high or very high efficacy therapies do better. Despite this, the majority of pwMS are not told this and are started on a low efficacy or platform DMTs without ever being given the option of a high efficacy DMT. Why? It is not due to lack of access to treatments as we now have several NICE and NHS England approved high efficacy DMTs available as first-line treatments.

So yes, if I had active MS I would want to have the full spectrum of high-efficacy DMTs available to choose from including AHSCT. I would want to know about their relative efficacy and what the aim of the treatments are. I would certainly want to have a discussion about the possibility of a potential cure.

By reframing the spectrum of efficacy by including AHSCT within the frame we may nudge pwMS and their neurologists to move up the treatment ladder and choose a high efficacy DMT sooner when they have more brain to protect.

Unfortunately, AHSCT as a first-line option is not going to happen any time soon, unless the MS community starts debating the issue in earnest. I am not alone, or out on a limb with my position;  I have a short, but growing list, of MSologists who have told me that if they had MS they would want AHSCT first-line. If your MSologist would like his/her MS treated with AHSCT, why wouldn’t you? 

PS: this blog post is adapted from a Medium post ‘Framing the DMT debate’ published on the 15th April 2019.

Conflicts of Interest

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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.

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.

61 comments

  • Paternalistic medicine at its finest…

    This needs a cultural shift in prescribing practices amongst neurologists. The words “watch and wait” send shivers down my spine……

  • Another corker of a post…..Thank you for explaining your position. As a follow up question…..knowing that you or your fellow forward thinking nuerologists could not access HSCT first line and may have to wait 5 years or longer (maybe never) to do so, would you pursue treatment abroad? it is a brave and bold move for patients at EDSS 0, 1, 2 when the treatment may be most effective and one that family members struggle to understand. I can see why……it sounds very dodgy to be shipping off to mexico or russia for such a serious procedure when to the outside world, not a great deal seems wrong with you

    • I personally think alemtuzumab is as effective as the non-myeloablative AHSCT protocols. The real point I am making is that pwMS living in the UK should have access to alemtuzumab 1st-line. No, I don’t think you should go abroad for AHSCT; we should be managing your MS in the UK.

      • Thanks Prof….should be, yes. Unfortunately, this is not the case and therefore me and other patients alike are left to pursue the most effective treatment for our most horrible disease outside the limitations of the NHS. Perhaps I am influenced by reading this blog on a daily basis but the other advantage of the IRTs in my mind is the potential ‘calmness’ it brings that patients have done all that they could, that they have ‘fought hard’ that they might even be ‘cured’ even if ultimately they aren’t, that they can back to their normalish life with a degree of confidence that MS isnt lurking so closely. Dom touches on it in his later comments. The constant need to act, chase, pursue treatment is tiring and stressful. Neither are good for MS and can bring of symptoms, which is turn leads to more stress. Its a vicious circle. Avoiding all of this is a secondary benefit of the IRTs in my mind

        • Re: “Perhaps I am influenced by reading this blog on a daily basis…”

          I suspect so. Only a few thousand people read the blog each day, when we are trying to change the behaviour of 10s of thousands of people. It is a hard and slow slog.

      • “I personally think alemtuzumab is as effective as the non-myeloablative AHSCT protocols..”

        I used to think..same..but go to the Alemtuz/Lemtrada FB sites and read how many people failed/bad experiences with it…then there’s the study results…it’s not close…

        “Compared with Lemtrada, AHSCT was also associated with a significantly lower annualized relapse rate (0.04 vs. 0.1 in the Lemtrada group), and a significantly greater proportion of patients free from MRI events (93% vs. 55%), relapses (93% vs. 70%), or confirmed disability progression (97% vs. 82%).

        In addition, significantly more patients given AHSCT had reduced disease (57% vs. 45%), while a significantly lower proportion showed disease worsening (1% vs. 12%), compared with those on Lemtrada.”

        https://multiplesclerosisnewstoday.com/news-posts/2020/11/10/stem-cell-transplant-more-effective-than-lemtrada-rrms-neda-study/

    • “a serious procedure when to the outside world, not a great deal seems wrong with you”

      No..you don’t get it…you do this before disability…to prevent…there’s no guarantee it will fix disability once you have it.

  • “What we are all forgetting in this debate is how bad MS can be as a disease”.

    I don’t think this is ever really explained to a newly diagnosed patient. The neuro who diagnosed me made some flippant comment that “I’ve got patients that are walking unaided 15 years after diagnosis”. At the time, 15 years seemed far far away. Plus I was told I was “lucky” that it was RRMS.

    The MS Societies’ websites say bland things like “MS only reduces life expectancy by an average of 7-10 years”. What isn’t mentioned is the likely suffering that occurs the previous 10-15 years (bed ridden, care home). My aunt died of MS in her late 40s. One of my neuros produced a paper 12 years ago reporting that the average life expectancy after diagnosis was 30 years – not great if you are diagnosed in your 20s.

    My GP is always happy to see me (once a year) as I’ve done well on Alemtuzumab / my personal regime, but she’s mentioned two women patients with MS who are in their mid 30s and in a care home. Truly horrendous.

    I don’t think the MS Societies’ websites help with the obsession of photos of happy people in wheelchairs with two thumbs up and claiming they have a very fulfilling life. Each to their own, but I’ve always lived by the philosophy of ‘kid who you like in this life, but don’t kid yourself’. At the wheelchair stage, many MSers will have lost their jobs and have had to move in to single storey accommodation etc.

    What we need is some robust figures setting out (in a table):

    – the average age of death (by gender) of someone diagnosed with MS;
    – the average age (by gender) when an MSer needs a cane, wheelchair;
    – the percentage of MSers (by gender) who are still in employment 10, 15, 20 years after diagnosis.

    I know some of these numbers are around, but to take an informed treatment decision a patient needs to know what can happen / is likely to happen. A friend’s daughter 25 was diagnosed c.5 years after me. I suggested Alemtuzumab, but she was swayed (as you would be) by her neuro and started on an injectable. She also took a view that as she was young / sporty she was likely to have Benign MS. She is now 37, using two canes and back home with her mother.

    My post isn’t intended to be scaremongering, but we need to combat the view held by many that real damage doesn’t kick in until a conversion to SPMS some 20+ years after diagnosis. I recently heard a well known US neuro state that she doesn’t use the term Relapsing / Remitting as the damage is always accruing ie there is no time when the disease is silent / no damage is accruing.

    Informed decisions about treatment options, Risk / Benefit, need to be based on robust data / real life cases, rather than bland statements that “most MSers do well”.

      • Prof G,

        I didn’t want to burden you with more work.

        I just think a newly diagnosed patient needs a clear steer of what’s likely (from MS) in the future. The data banded around on MS Societies websites doesn’t seem to fit with real life experiences. Perhaps there are MSers in their 70s (diagnosed in their 30s) playing golf unaided, but I just don’t see it.

        The other approach in terms of steering a patient to a treatment which will maximise their future health / abilities, is for a patient to set out what they hope for in the future. Mine were / are:
        – to walk my daughter down the aisle unaided;
        – to take the grand children (none as yet) to EuroDisney and fully participate;
        – to cycle (on a normal cycle) from London to Lyon (to see a friend) when I’m 60.

        My conversation with the neuro (at the diagnosis point), would be to say, these are my hopes / dreams for the future, what treatment would give me the very best chance of achieving them. An informed neuro (based on trial data and experience of the patients they cover) should be steering me to Alemtuzumab or HSCT (and pointing out the risks).

        • That is so well said…

          I think it happens to every pwMS upon diagnosis. I was also told that I am lucky to have RRMS not PPMS, and that I will be having relapses but I will not end up in a wheelchair for the nesxt 15 years for sure and that I should be happy about it. The problem is that most of the poeple are diagnosed in their 20’s or 30’s, therefore if it takes “as long as” 20 years to be needing to use a wheelchar, these people will still be in their 40’s or 50’s, not to mention other disabilities that are not connected to mobility/legs…

          I am pushing hard for alemtuzumab right now, was just told an hour ago by neurologist that I should reconsider going for Alemtuzumab as I am still young and this drug is quite harsh, I guess that she forgot that MS is even more harsh.

          About the possible MS outcomes, there are numerous charts on that, however they are mostly based on pwMS who did not have an access to a high-efficacy DMTs.

          https://www.researchgate.net/figure/Patient-derived-Multiple-Sclerosis-Severity-Score-Table_fig2_235682883

          https://www.researchgate.net/figure/fig1_235682883

          Cheers! 🙂

        • I started on beta Interferon almost immediately after diagnosis. My MS was fairly benign. It has been 21 years since diagnosis and I am now receiving natalizumab. I have not escaped without problems. I have urinary incontinence and have lost the ability to ride a bike. I think that dementia is beginning to affect me too. I still would not go to Mexico for hsct. It is too dangerous. I take fampyra which works very well but without it I’d be in a wheelchair. I also have sativex. I can not live with the pain from spasticity. Am I doing well? The answer is yes, if compared to total disability.

          • Normski, I agree with you. A worldview at 30 with an EDSS of 1.0 is very different from a worldview at 50+ with an EDSS at 7.0. I think pwMS adapt. Just the same way I am adapting to getting older and less mobile etc. You resent expectations. But even from this perspective, this is not a reason not to offer pwMS high-efficacy DMT and IRTs early in their disease course.

    • Would be interested in these stats too
      Agree with you that you don’t really get told how bad it can be. Though not sure how mentally useful that is when you’re just diagnosed, maybe it isn’t helpful. My GP made a comment something along the lines of “you can still brush your hair” and I remember feeling shocked that it was even a possibility that it might be bad enough that I couldn’t brush my hair. She also said she had another patient who was bed bound. I think mentally it’s probably for the best to be around other MS patients who are at a similar stage to you. With an awareness of what can happen… to scare you enough to take the risks of the stronger treatments…. but not scare you enough that you don’t live your life with overwhelming anxiety.
      Now a few years into diagnosis I would take the risks with Alemtuzumab, not sure I would have at first. But I would not be ready to take the risk of HCST

      • “…not sure I would have at first. But I would not be ready to take the risk of HCST”

        You Do you know the hsct risks or has Prof G scared you with cancer talk..?

        • No Prof G has never scared me from anything. I didn’t know cancer was a risk. However, cancer is a risk in life anyway..
          The infertility risk and the (albeit) small chance of death is enough for me. Never mind the whole procedure is pretty full on… not a walk in the park is it? Something that needs a recovery, the privilege of being in a financial position to take the hit of being potentially out of work for a period of time, or a job that is ok with it. The mental health to deal with it. Not everyone wants to uproot their world. I know MS long term can be worse long for those 3 things and maybe it’s delaying the inevitable unless you’re one of the lucky ones, but my circumstances are that I wouldn’t be comfortable with that risk for the benefit at this stage of my life/ms journey. Maybe if things change my mind would change.

      • Hi Hannah, rather shocked by your GP’s careless remarks and hoping you can find an alternative GP in your area who has far more compassion and empathy. Take care.

        • Thank you Anon. She is a great GP to be fair and i really like her, but sometimes has a way with words i guess. lol!

  • “What we are all forgetting in this debate is how bad MS can be as a disease and most of the early damage occurs occultly before people with the disease and their close ones realise the extent of the damage. What is lost in MS is lost forever. We have no magic treatment that can repair the damage and turn back the clock”

    One of the great frustrations with MS is trying to communicate just how godawful it can feel. There seems to be a general level of dismissiveness of the physical sensations, the mental sensations, and the screaming frustration at having the best treatments seemingly withheld until a certain level of irreversible decay has taken place.

    I had a conversation with a fellow MSer recently where we fantasised about interrupting their neuro, out of the blue, in the midst of their day. We’d blur one eye, send endless spiders crawling up one leg, start a repetitive electrical sound in one ear that came and went without warning, deprive them of sleep for several days, weaken a limb, induce numbness in a few random parts of the body, end their career etc. You get the idea. There was no malice in this. Just a desire to try and help them understand a bit of what it can be like.

    When they (understandably) freaked out we’d then tell them m to buck up because it’ll pass. When? No idea. A repeat? No idea. Drugs? Treatments? Sure. But let’s not be too hasty. These are costly things with a litany of scary side effects so best not to rush into anything. Have you met our lovely MS Nurses? They’ll see you through the decline. I believe they are running a self-catheterisation class next week.

    It feels like being trapped in a Kafkaesque nightmare. How can a highly educated – allegedly compassionate – doctor be doing anything other than trying to help the patient make MS as small a part of their lives as possible?

    Because I have MS, the matrix through which I apply judgements over risk has lurched far from that of many doctors. I loathe it when they want to overlay their conservative treatment approach onto my deteriorating brain and body and then try to shield themselves from taking a tough and possibly risky decision by quoting guidelines and the occasional horror story they dredged up and reserve for these instances of the uppity patient to justify their unwillingness to treat my MS as aggressively as possible?

    I’ll get off my soapbox now.

    • Thank you for this post. I have actually role played with my husband what I want to say to my Neurologist before my appointment and then in the moment, I cave. Afterwards I am so disappointed with myself for my intimidation in front of her. Yes, she has a remarkable education – but she should be my partner in my care, my guide on the side. I have more expertise than I hope she ever has living with MS. As my MS has progressed the level of my aversiveness to risk has also changed, but this is never part of our discussions. In some ways I put some of the blame on myself. How can I hold her accountable if I am not expressing bluntly how I feel? Also how does one possibly reach this level of true communication in a 15 minute appointment structured around addressing individual symptoms and their management and not a review of me as a whole person – more than the sum of my symptoms. It sometimes feels a very lonely habilitation road.

  • I believe you’re seeing patients of different ages and stages of Multiple Sclerosis. My MS Diagnosis came at least 12 years before being diagnosed. 1995-2007. At 63 now, I am content on daily Glatopa and yearly Neurologist visit. Nowadays, people with symptoms are being diagnosed faster. HSCT isn’t a walk in the park so being younger helps.

  • When asked, my neurologist completely agreed with me that alumtuzumab or ahsct would be the best treatment for my specific situation. He also informed me that due to bmt guidlines the best he could do for now is tysabri and i would need to fail this first before trying something else. He is a huge proponent of irt’s but is governed by silly guidlines set by nice and the nhs. There is something seriously wrong when the pwms , the neurologist and neurology profesors are writing posts stating they would choose it as a therapy if diagnosed with the disease but the decision and risk management is taken out of their hands by guidlines set by a comittee or board that dont look at each specific case. No mattef how much me and other people struck with this rubish disease debate it or how much we push for it we are met with walls of rules and refferals that end up stopping us get the most effective treatment. In no other disease would this happen.

  • I absolutely think that people should be able to choose alemtuzumab or HSCT up-front. But at the same time, I declined starting alemtuzumab at diagnosis because of the shock. I was just not ready to face an up-front thyroid risk, and the idea of doing an induction therapy seemed appalling to my mind that was already having an existential crisis having just received an MS-diagnosis.
    However, now – three years later – i regret the decision, even though I started Rituximab and am NEDA since diagnosis. This is primarily because of long-term infection risks, covid-19 and the fact that I know I’ll be working as a from august. If the vaccine proves only mildly effective in rituximab-patients, and children and youth are not vaccinated – this will certainly be a concern for me, and has made me consider switching to cladribine (alemtuzumab is no longer an option for me in Norway). Bummer.

  • As I’ve mentioned on the Blog previously I used the word ‘perverse’ when the neuro told me about the escalation model approach. He looked so shocked when I stated that it seemed perverse to me to ‘save’ the more effective treatments until you were more disabled.

    I find it so distressing that this is the conservative approach here in the uk, with no reference in early consultations, from the point of diagnosis, to anything other than the fact that most don’t end up in a wheelchair and definitely no mention at all about the fact that MS damages your brain as well as your body!

    Neurology 2018:
    ‘The study concluded that the incidence of late-onset multiple sclerosis more than doubled among the female population’

    I was one of those diagnosed over the age of 50. Luckily I found the Blog and learned about Alem. Fortunately I eventually saw a neuro at one of the London centres who was happy to let me have it. With respect to ‘framing’ I feel she did not see it as a waste of time due to my age.

    No, I’ve not seen the improvements that someone twenty odd years my junior might (hope they all do!) but 3.5 years since completing my second round, I’ve NEDA, am showing no signs of deterioration and most importantly the report on my MRI in 2020 stated that I had BVL greater than expected for my age, but no further BVL from the 2019 scan.

    All those young PwMS who are swayed and reassured by the neuros who tell them they’ll be fine sticking to injecting or swallowing a pill should be given, if not scary details, then at least the knowledge that their brain is under attack too, and this may give them a different slant on the risks/benefits scale.

    ProfG you’ve been banging this drum for a number of years and the charities continue to give the person in wheelchair with thumbs up image of MS (as Sid so accurately puts it) However, I’m at a loss as to how we can change this! I can only see meaningful chance of reserving the pyramid happening when neurologists band together in a large international group taking a clearly defined and loudly voiced stance on things.

    • Re: “ProfG you’ve been banging this drum for a number of years and the charities continue to give the person in a wheelchair with a thumbs-up image of MS (as Sid so accurately puts it)..”

      I have invited someone from the MS Society to do a guest post on the issues raised around my posts on the refuseniks and robotniks; let’s hope they accept.

  • Your other blog post last week about post traumatic stress etc in MS

    Mentioning to people reading this blog with active or newly diagnosed MS that they need alemtuzumab or aHSCT to really treat there MS, may have a negative effect on people.

    Preaching to people who can’t get access to these treatments or healthcare professionals who can’t make a difference is pretty pointless and highly likely makes people reading it feel worse regardless of how true it maybe

    We get the point, they are highly effective and your right.

    So what’s being done to change the treatment culture around MS? For the benefit to people with MS?

    Is there anyone reading or writing these blog posts that can make a difference to the way MS is treated?

    • I guess it might have some impact on the neurologists, if “dozens” of people confront them about Lemtrada/HSCT or any other high-efficiacy drugs instead of leaning towards beataferons etc. I guess some of them might start noticing that pwMS are aware of the best DMTs and they might take it into cinsideration.

      I just had a phone call with Sanofi Genzyme medical consultant and it turned out that she knows the “TheMS Blog” and recognizes Prof G pretty well, even though we come from completely different country. The word is spreading in my opinion, it will take lots of time, that’s for sure.

      • Re: …pwMS are aware of the best DMTs…”

        Many pwMS who are recently diagnosed don’t have the knowledge, which takes time to acquire. Therefore they are dependent on their neurologist and other HCPs to make the best decisions for them. This is why we need education, education, education, …..

    • Re; “Is there anyone reading or writing these blog posts that can make a difference to the way MS is treated?”

      Yes and no. I am not sure how many HCPs read this blog, but clearly not enough. Yes, I was on a large number of committees/initiatives to try and shape policy and affect change, but I have recently resigned from almost all of them to focus on MS Prevention and EBV causation theory. I am not a politician and have very little influence when it comes to change.

      • Wishing you the best for your chosen path to tackle MS.

        If you and others of your stature cannot change treatment policy’s, then what chance do patients have in influencing decisions on the use of high efficacy treatments.

        Hopefully a high efficacy non immunosuppressive treatment will come along in the near future.

  • Thank you for this. I cannot get HSCT in the us and have been frustrated about that since day one. I would if I could. Patients should absolutely be able to do it first line. Why are neuros so afraid of death? Who is to say that death isn’t preferable to watching your brain shrink and watch your life and cognitive functioning get smaller and smaller? It’s an insidious disease and we are still terrible at predicting prognosis and therefore why does the community insist on watch and wait? In oncology it would be malpractice. I for one appreciate people like yourself who don’t polish turds. More options are better. As you said this is not a good disease. Hit it early hit it hard.

    • Re: “Hit it early hit it hard”; I have been saying this since natalizumab emerged. I even did due diligence on AHSCT in 1999 when working at the Royal Free. I was advised against setting up a BMT programme in MS; I was told it was too risky. Possibly, another Prof G mistake. I should have trusted my instincts.

      • Was this the full myelo HSCT study on secondary progressive ms performed at Erasmus Rotterdam? 30 to 40% of those patients actually remained stable after treatment. Unfortunately the TRM was too high because for the conditioning regiment with harsh chemotherapy (busultan etc) and total body irradiation (TBI). Not so strange since it were high EDSS progressive ms patients. Early treatment is key to prevention and also to actually being able to ensure such a strong treatment. Still given the fact that HSCT can work in higher EDSS progressive ms patients, is it still ethical to not offer those patients IRT as well? Should it not be up to the specific patient themselves to decide on the basis of their own risk benefit evaluation to try an IRT? Even though the odds are not in their favour. At least they would have had the option to try in their own country and not spend their savings or more travelling abroad to non JACIE certified Centers.

      • Another Prof G mistake? You are being unfair on yourself, as you have said on here before, ideas and opinions change over time as new information becomes available. You acted on the advice given back then.

        You could write a post about all the things you got right, your favourites and the ones you are most proud of, and all the good work yet to come. You don’t need to post it, but writing it may be good for you as your recovery continues and your career changes direction.

  • Please allow me to give you the definitive solution to the problem.

    All MS patients should be reclassified as Haematology/Oncology patients. If you want to get REALLY clever, then let’s rename MS as “Immune System Cancer”. Pass all the MS funding to the Haematologists and up their 15% of ISC patients (keep up folks, remember we’ve renamed MS) to at least 50%. Use the money saved on DMDs, to fund stand alone HSCT wards in all current bone marrow transplant experienced hospitals. Do not let the Neurologists feel sad that we have been reassigned; we prefer the better treatment that cancer patients receive and you chaps have more than enough work to do on Alzheimer’s, Parkinson’s, Tourette’s, ALS/MND, myasthenia gravis, strokes, tumours and epilepsy etc. etc.

    Just sit back and watch us finally be treated seriously, as soon as we are sick, with no requirement to get worse first. I have it on good authority that no oncologists make their cancer patients get worse first…

  • “There are only a handful of MS centres that are prepared to refer their patients for AHSCT.”

    Just to clarify – a GP referral to a neurologist practising HSCT for MS will suffice (in England). Many patients give up because they think that a ‘no’ from their neurologist is the end of the matter. It isn’t. Generally, a GP seems to be far more cooperative, sympathetic and supportive than a Neurologist.

    More education is needed for neurologists too – we get a steady stream of misinformation from neuros on an almost daily basis. If they don’t know what they’re talking about, it’s better that they hand over to someone who does.

    In just the last week we’ve heard of a neuro who advised a patient not to have HSCT in Russia because ‘it’s non Myelo – you’d be much better having Myelo in the U.K.’ (it’s non Myelo in the U.K. too), and a colleague of yours (who shall remain nameless but should know better) who is still advising patients that the mortality rate is 3%.

    At AIMS and in the U.K. HSCT forums we advise patients to seek a referral from their GP if their neurologist is unsympathetic.

    • Maybe HSCT in MS is another information vs. disinformation war. Who is on the wrong side? Or who is on the losing side?

      • If you were being cynical (and I am a fully paid up member of that cohort), the manufacturers of DMTs for MS would lose an extremely lucrative income stream if HSCT was routinely used as a first line therapy on diagnosis of MS.

  • I am certainly one of the lucky ones, I was diagnosed with MS in Aug 2018 and started alemtuzumab in Oct 2018, so first line therapy. I weighed up all the risks and wanted to take the most effective DMT available. I haven’t regretted my decision once. I have thyroid issues but I would rather deal with this known side effect than worry about the unknowns MS brings. Thank goodness I found a neurologist who allowed me to decide what treatment I wanted. My body, my decision.

  • On diagnosis, I was well aware of how bad MS can be. An ex work colleague husband having died from MS complications at a young age. My Aunt (via marriage rather than blood relative) also died from complications of MS and as a young child I can remember the family talking about her son having to lift her off the toilet. Yet, I get told by my relatives that I’m negative, worry too much, medication has moved on etc. When I question prognosis with HCP – yes I get given the lines that a few of you have already mentioned. I’m on the most effective drug offered to me, which I think is classed as moderate. I have a question for you however, if I may. I’ve read the ABN guidelines and I believe you were on the panel, not knowing how these things work, were you “out voted” – as you seem to disagree with the guidelines as they stand.

  • I would advise everyone to read the Joachim Burman’s dissertation “Curing Multiple Sclerosis: How to do it and how to prove it.” He is a Swedish neurologist working on HSCT in MS for more than 15 years at the Uppsala medical university. This was written in 2014! and unfortunately not much or actually too little has changed in the overall global consensus by the ms neurology establishment. Could be that some statements in his dissertation are currently outdated, but the overall vision and conclusions are still relevant and accurate.

    He puts it the way it is:

    “…Multiple sclerosis is a gruesome disease. On average it takes ten years of life. Even today, the most severely afflicted will die in their middle age. Not only will life be significantly shorter, the final years will be spent in agony. As a neurologist, I have seen too many wither away in the heart of life.

    I sincerely believe that MS can be cured, and that we have the means to do it. Every year, some one thousand Swedes are diagnosed with MS. Currently, less than 1 % of them will be treated with hematopoietic stem cell transplantation. Why are so few patients treated?…”

    • “Swedes are diagnosed with MS. Currently, less than 1 % of them will be treated with hematopoietic stem cell transplantation.”

      This was in 2014…so how many are treated today..?

      • Oh..yeah I’ve read it…seems like alot get treated early in Sweden…but they still
        have 30% relapse rate..and all they do is tell them this is what happens…and we’re not sure why..But if you look at this analysis of the 2010-2015 Halt ms myelo rr trial. It shows it’s not treatment failure but levels of cd4 and cd8 tcells prior to hsct that determined who stayed in remission.

        “While none of the treatment effects studied correlated with clinical outcome, patients who remained healthy throughout the 5‐year study had significantly higher absolute numbers of memory CD4 and CD8 T cells in the periphery prior to stem cell transplantation.”

        Basically if you have more tcells to control EBV infection you stay in remission..Also don’t understand why Sweden still does myelo hsct since
        it’s not more effective..it’s just more harsh and destroys more brain leading to a longer recovery. All the u.s. trials are myelo now since they are done by
        oncologists who don’t understand ms. More chemo is not the way to better results…you need to add an EBV therapy as hsct does not get rid of EBV.

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

  • HSCT is not a cure. It may stop MS but its the equivalent of sawing off your arm and cauterizing it instead of applying a tourniquet. I’m afraid normalizing stronger DMTs will mean that MS is “cured”.

    • No. I think you’re wrong. HSCT if done early enough, as with some cases with alemtuzumab, there is the very real possibility of a “cure”. Though the follow up to see if that is correct will obviously take decades.

      • That’s not what I meant, it might cure MS for large % but a bonesaw to the hip and secondary autoimmunity risk doesn’t hit the sweet spot.

        • You’re right but for now it’s all/best we’ve got. MS is having a small stroke every day..so after 10..20..30 years it adds up to disability…So yes you have to destroy(temporary) your immune system before it destroys your brain.
          Going forward there is therapy from cancer that destroys EBV by infusing you with donor t cells.
          But it’s not here now and hsct is..and some people can’t wait based on their disability/disease activity.

          “T-cell therapies have so far made the biggest impact in oncology, with the FDA approvals of two treatments for blood cancer, Novartis’ Kymriah and Gilead Sciences’ Yescarta. Both products are personalized in a complex process that involves removing T cells from patients and engineering them to be able to recognize and attack their cancers. The success of those treatments has inspired research aimed at applying the technology to other diseases—and simplifying it by developing off-the-shelf cells.”

          ““While the immunosuppressive approaches may help to address some of the molecular and cellular dysfunctions that give rise to MS symptoms, they might not directly target the underlying pathogenesis of the disease,” …EBV

          https://www.fiercebiotech.com/research/ectrims-atara-s-off-shelf-t-cells-for-ebv-driven-ms-show-promise-small-study

          https://www.healio.com/news/neurology/20200921/ata188-shows-promise-against-ms-in-early-phase-trial

  • Suprised that you have placed Cladribine in Tier 2, not tier 3? Would you advise someone to take Ocrelizumab rather than Cladribine at the moment, bearing in mind the blunted response to the COVID vaccines and increased infection risk with Ocrelizumab? Very hopeful comments from Clifford Reed
    May 7, 2021 at 10:19 am

    Professor G,
    I have close to 50 MS patients who have cognitive (presumed superficial and deep GM, cerebellar, etc. PIRA ( smoldering ) and LE and neurogenic bladder spinal cord PIRA ( smoldering ), despite being on many of the stronger, or weaker, MS DMT’s, who finished their 1st or 2nd round of oral Mavenclad here in the USA under my care. All 50, even within months after round 1, and especially months after round 2, have stabilized. About 10 of the 50 slightly improved, despite longstanding MS ( patient reported for cognition–not SDMT or Neurotrax, which I did not do, or have available ), and ( patient reported, and motor examination confirmed, for somewhat improved asymmetrical LE strength). Do you have generic injectable Cladribine at your disposal for these 2 patients? As you well know, better than anyone, Cladribine can find autoreactive B>T cells where they hide and penetrates all 3 compartments of the CNS. (Rejdak, with the elimination of the Oligoclonal bands, which I think is vital data for hemispheric cognition and cord motor/ bladder stabilization). Then you could follow later, if needed, with immunologically safe, broad antiviral, including Covid 19, CNS penetrant, with excellent brain atrophy reduction data ( end organ ), Teriflunomide. These are my ” 2 cents ” for what it is worth, since you asked.

    Clifford Reed MD–West Reading, Pennsylvania
    Reply

    • Re: “Suprised that you have placed Cladribine in Tier 2, not tier 3?”

      It has got to do with its BVL data, but it is not a closed book. The ORACLE CIS BVL data in early younger subjects is very good. However, Merck are not happy with how the data was analysed.

  • Serious question – are you seriously considering this?
    How will you go about it? For example, will you enroll for the Philosophy Master’s in your university
    How will you spend your time after that?

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