NEO-EOD

N

Barts-MS rose-tinted-odometer: ★ (milk chocolate; bitter-sweet and addictive)

I often refer to MS as being a pink-ribbon disease as close to 70% of pwMS are women. 

The rising sex ratio from approximately 1:1 at the turn of the last century to almost 3:1 in most high MS incidence countries and to close to 5:1 in some areas of the world where the MS epidemic is still raging, justifies the pink-ribbon label. Explaining the rising female-to-male sex ratio really challenges those of us who think about MS and causation theory. If EBV is the cause of MS how does the EBV hypothesis explain the changing sex ratio? If you have any explanations or theories to explain the changing MS sex ratio I would be very very keen to hear them. 

AHSCT or autologous haematopoietic stem cell transplantation has been getting quite a lot of air time recently. It is because it is such an effective treatment with the majority of people treated becoming NEDA, i.e. having no evident MS disease activity, and having the rate of their brain volume loss ‘normalised’ to be within the range of what you expect as a result of normal ageing. I am beginning to refer to this as NEO-EOD (no evident ongoing end-organ damage). 

The problem with AHSCT is its safety profile and its associated adverse events (AEs). Despite the enthusiasm for AHSCT treatment from its very vocal supporters, the associated serious AEs are not trivial. The one AE that is the most troubling and often results in female patients saying no to a referral for AHSCT is the infertility risk. The chemotherapy used to mobilise haematopoietic stem cells and to ablate the immune system is toxic to the gonads. Men can easily bank sperm, but for women, the procedure of egg harvesting and egg banking is not trivial and it is expensive. In addition, many healthcare providers don’t cover the costs of banking; even in the UK, the latter is an NHS post-code lottery with some CCGs paying where others don’t. 

Therefore, some pwMS simply take their chances with fertility. I am aware that the London haematologist that sees most of our patients quotes a figure of 40-45% for the rate of premature ovarian failure post-AHSCT. I think this figure is based on all non-cancer patients and is not necessarily specific to pwMS.  Therefore it is reassuring to see the study from Italy below showing the rate to 30%, i.e. 70% of women with MS who are treated with AHSCT recover their menses. I suspect this is only half the story because the women who start to menstruate again may still be at risk of POF (premature ovarian failure) because the chemotherapy will have reduced their ovarian reserve, by culling a proportion of the ovaries oocytes or eggs. So this figure of 30% will increase with time and may end up being 45% or higher.

So it is not just about expanding access to AHSCT that is the issue but managing the AEs such as infertility that complicate the wide adoption of AHSCT for the treatment of MS. This is why I find patients tend to choose alemtuzumab over AHSCT when all of the pros and cons are presented side-by-side. So when you frame MS treatments with AHSCT as being the most effective treatment on the right people often move to the left and choose a treatment that may be less effective, but safer and unlikely to affect their fertility.   

Please note I say alemtuzumab may be less effective, but I could easily say as effective, as AHSCT. Until we compare these treatments head-2-head we won’t know which is more effective. What I can say is that alemtuzumab and AHSCT are the most effective DMTs at rendering pwMS NEO-EOD.

Massarotti et al. Menstrual cycle resumption and female fertility after autologous hematopoietic stem cell transplantation for multiple sclerosis. Mult Scler. 2021 Mar 12;13524585211000616.

Data on fertility after autologous hematopoietic stem cell transplantation (aHSCT) in women with multiple sclerosis (MS) are inconclusive. This study aims to report on post-aHSCT menstrual resumption in a multi-center MS-women cohort. Out of 43 women, 30 (70%) recovered menses after a mean time of 6.8 months. Older age (odds ratio (OR) = 0.5, p < 0.0001) and previous pulsed cyclophosphamide (OR = 0.44, p = 0.005) were independently associated with a reduced menstrual recovery probability. Conditioning regimens’ intensity resulted not associated with post-procedure amenorrhea. Our results highlight younger age as significantly associated with menses recovery; proper fertility counseling for MS women candidates to aHSCT both prior- and post-transplantation is therefore warranted.

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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.

52 comments

  • In the event BTK inhibitors are effective in progressive ms, where do you see the next big breakthrough after that ?

      • It appears that to provide an MSer with the best chance of a near normal life there needs to be a combo of:
        HSCT or Alemtuzumab;
        Neuro-protective drug (?drugs to be tested in the Octopus trial);
        Anti-viral drug;
        Anti-plasma drug (I assume the drug being tested in the Sizomus trial).

        This seems to chime with a piece by Professor Coles in 2019: “I hope in 10 years’ time, a person will be given a handful of treatments to tackle all the different elements of MS, and they will be offered hope that their life will be minimally affected by the condition.”

        How would this work in practice? If an anti-viral showed it was effective in reducing disease activity, could a neuro then offer it to their patient who has had Alemtuzumab? Or would there need to be a trial combining Alemtuzumab and the anti-viral compared to Alemtuzumab and a placebo drug? It’s frustrating that MS is still a single therapy disease given that drugs are needed to tackle the array of underlying processes ie it’s way more that relapses / focal inflammation.

        • RE ” How would this work in practice? If an anti-viral showed it was effective in reducing disease activity, could a neuro then offer it to their patient who has had Alemtuzumab?”

          Would such antiretroviral therapy work for someone who received alemtuzumab 5 years ago? After depletion, B lymphocytes have already rebuilt in the environment with the EBV virus, and are probably re-infected.

          If the theory with EBV proves to be true, the question of whether antiviral drug administration a few years after HSCT / Alemtuzumab will still be effective or will require “another” reconstitution of the immune system?

        • I am surprised that one talk about a handful treatments ( drugs with side effect) and think people can live uneffected by ms.
          Drugs,drugs,drugs. Where is the cure? Why do we not see more research why ms and hos to stop ms?

          What do the doctors usually say? 1 drug ok, 2 drugs you start to not be sure what an how Things work 3 drugs it is chaos.
          When old people enter the nurseries They are on several drugs and the doctors take away most of them.
          Another thing is that our body tries to eliminate drugs by balancing them so They usually become ledd effective after some time.

    • The problem with short term comparison of HSCT/Alemtuzumab is that aHSCT is way more harsh and strong, it is much more effective in short-term follow-up, however what happens after 7-10 years post aHSCT is not that well known yet – at least for a large cohort.

      We know how Alemtuzumab works after 9-12 years however long-term data on aHSCT is not yet that clear, or not yet published. I myself know multiple people who failed aHSCT (relaspe/new lesions/cdw) after 5-7 years post procedure, therefore it seems that the success ratio still goes down in time even after 6+ years. (Some people relapsed after 10-11 years post aHSCT, that must mean something in terms of MS pathology).

      • “Some people relapsed after 10-11 years post aHSCT, that must mean something in terms of MS pathology).”

        Yes…clearly hsct does not get rid off EBV.

        You have took at biology to see who is cured and who is just remission.
        This is how they analyze in Sweden…”the disappearance of oligoclonal bands (antibody synthesis) in the cerebrospinal fluid (CSF) is a good indicator of this. They have also included into this definition stabilization of CSF neurofilament levels into this (i.e. no further ongoing neuronal injury).”………..

        Out of 10 at 5 years…only 3 cured…”Two out of the ten went onto have a clinical relapse, and were started on Copaxone” 5 in remission. So you can assume remission can end at any time but they all lasted 5 years in the study.

        https://multiple-sclerosis-research.org/2019/07/hsct-is-it-remission-or-is-it-a-cure-for-ms/

        • HSCT generally comes with a course of anti virals as protection during immune reconstitution. That might infact protect from EBV reinfection for a while.

          I do wonder if bundling alemtuzumab with antivirals would close a lot of the supposed gap in efficacy.

          • I failed aHSCT after 5.5 years (new lesion), I am leaning towards trying Lemtrada + tenofowir alafenamide.

            I am wondering about 2 things,
            – Should I go with alemtuzumab + TAF,
            – Should I just go with TAF as I had aHSCT 5 .5 years ago, and “possibly” my smouldering MS is somehow halted and brain atrophy is slowed and I should focus only on EBV depletion.

            Unfortunately I can’t find any answer, I have read hundreds of clinical trials, articles, most of the EBV/HIV/MS cases. I am still not sure if the another reconstitution + TAF is needed, or the TAF could do the work by itself if the EBV hypothesis is correct.

            I am simply a little bit scared of Alemtuzumab’s side effects.

          • I am much the same wrt to alemtuzumab, good data on its side effects is hard to come by – so much so that HSCT seems like a bad few months (especially myeloablative) but more predictable medium term.

            So far my neuro did not seem in favor about moving away from ocrelizumab but I feel like I am gradually declining so something needs to happen.

      • Where do you get the data that Alemtuzumab works for 10-12 years and how does it work? I mean stopping attacks do not correlate with edss increase.
        The research I have read (among some research, i read one from MS centres in England, not run by drugcompanies, where they followed people up to 6 years at that time) – where they documented that edss gets better in the start but after 4-5 years it is back to baseline and gets worse, and 34% had to take alemtuzumab year 3 and 8% had to take alemtuzumab year 4)
        Is it OK that 50% of those trying Lemtrada gets another autoimmune disease? and have greater cancer risk?
        In Sweden they started in 2004 with HSCT i think, and Ida the first one was paralysed, got better, have no signs of previous disease. Now 17 years after. I know a few that HSCT didn not work, some of them took HSCT again, and then it worked so far.
        And what about SPSM/PPMS? HSCT works for some of them as well.

        A lot of people goes from Norway to Russia, gets the HSCT and get back and gets a new life. Stops the disease. Goes back to work etc.

        Why should Alemtuzumab or Mavenclad work better than HSCT? HSCT is to try to rebuilt your immune system. I know some says alemtuzumab and mavenclad and rituximab – all of them tries to rebuilt the immunesystem.

    • “This doesn’t count? It’s observational, but HSCT seems to be vastly more effective there.”

      Yes..observe how much more effective…”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%)..”

  • It will be interesting when smell detection of MS is available. At what stage of the MS disease can the dog smell it from? Does this reveal anything about the ratio of men and women with MS? As in may be there are a number men with dormant / inactive MS that have not been diagnosed.
    And more women are diagnosed than men due to their various hormone levels, which somehow contributes to higher relapse activity than in men.

    I find future thinking about MS, including detection fascinating.

    • Prof G, is there a research team or group that is working on future thinking of MS? I know there is Preventing MS groups.

      The future thinking group could cover new and earlier ways of MS diagnosis, etc. I would love to be part of it!

      • “I know there is Preventing MS groups.”

        Yes..a very cruel trick. If you have the ms genetics..you will get ms.
        Trying to do diet…exercise…not smoking….is all just going to be a
        drop in the bucket…unfortunately it really seems genetics is destiny.

  • I am starting to develop 2 theories about why so many women diagnosed with MS.
    First is lack of vitamin D over prolonged period of time. At a “newly diagnosed info day” a group of 3 women from Saltash, Cornwall said they’d all worked in same back office of a Bank for 35 years where no windows and no natural sunlight. An Occupational Therapy lecturer at same time referred to an article documenting a group of women in an area of Iran or Iraq, all of whom had been encouraged to stay indoors rearing their own and others’ children for decades, all diagnosed with MS. I have never managed to track down this article sadly.
    My second proposed theory is that WwMS (Women with MS) have a high incidence of child abuse/neglect in their background. As this is such a sensitive area, I have naturally not asked all the WwMS I encounter. Also are females disproportionately affected by child abuse?

    • I also wonder whether the widespread adoption of hormonal birth control could be contributing in any way.

    • “all worked in same back office of a Bank for 35 years where no windows and no natural sunlight.”

      Problem is more men work in dark offices/garages/warehouses probably than women. Also
      some people are in sun all day and still get ms.

    • What about womens(or mens) that works at night?

      Example: security personel, bartendes ,bargages staff, etc?

  • Prof G you are getting your nouns and pronouns wrong. You should not be referring to menstruaters as necessarily being women and young women as necessarily being menstruaters. They are very different things.

    JK Rowling was almost cancelled as a result of suggesting we call people who menstruate as women.

  • This may be a bit uncomfortable to ask but I was wondering who did you mean was acting like a Troll in the last few posts ?

    • This was in response to a comment by somebody in relation to AHSCT being a cure. The trolling refers to AHSCT zealots from a few years back. It is clear that AHSCT may work very well, but it may not work very well. It is not the be-all and end-all of MS treatment. There are other options. It is clear that AHSCT as practised today is simply too risky for mainstream adoption and as a result, its use will remain limited. I think we have a greater chance of getting alemtuzumab and cladribine adopted widely.

      • “It is not the be-all and end-all of MS treatment. There are other options. ”

        Problem is you posted yesterday someone who probably has uncontrolled brain atrophy on DMT….and rising She is out of options now…If she had
        children they will now 16 years later will need to be helping w/ her care.

        .”She was 42 years of age and had had MS for 16 years. After a relapse in 2016, she was switched from interferon-beta to fingolimod. Despite being NEDA-2 ( no relapses or focal MRI activity) since starting fingolimod her disability has worsened with her EDSS going from 4.5 (walking unaided for more than 300m) to 6.0 (needing a walking stick to walk 100m). Clearly, fingolimod is doing what it should do, i.e. keeping relapse and MRI activity at bay. “

      • But if they (the patient) can choose? In my country a lot of people wants the choise. decide if they take the chance. Why should they have to take drugs, cost more, and only slows down the diseas some. DR Burman from Sweden wrote his doctorate saying “is hsct a cure”. And he says it is a reluctant attitude among neurologists against hsct, and the have a “wait and see” attitude. as he says; Meanwhile, every wheelchair is a failure and every premature death is a tragedy.

        Let the patient choose if they want to try it? The risks are as far as I know/have read very small, and people dies from drugs as well.

        I mean to have read that you wrote something about the inflamations prosess- is not the only prosess, but you have the athrophy/degeneration prosess. The plasmacelles/oligoclonals, mikroglia and astrocytes.

        IF MS is only autoimmune, why do HSCT not stop it for all that tries the procedure? (MS does not fit the criterie of an autoimmune disease).

        “For a disease to be regarded as an autoimmune disease it needs to answer to Witebsky’s postulates (first formulated by Ernst Witebsky and colleagues in 1957 and modified in 1994):

        1. Direct evidence from transfer of disease-causing antibody or disease-causing T lymphocyte white blood cells
        2. Indirect evidence based on reproduction of the autoimmune disease in experimental animals
        3. Circumstantial evidence from clinical clues
        4. Genetic evidence suggesting “clustering” with other autoimmune diseases”

        Some Norwegian doctors (and others) wrote an article about inside out/outside in theories. Inside out because of autopsy of MS brain showed unexpected findings and myelin injuries from within working out. They wrote also about “is MS mitokontria mediated disease”. So is there different MS diseases? or sereval prosesses going on?

        And we do see drugs give 0 attacks but it do not stop disease progression in form of edss.

        The Clarity Study of mavenclad; Compare with placebo. (Very narrowed “homogenous” research group. )

        drugs/no drugs

        Yeraly relapsreate 0,14-0,15/0,33…….difference 55%
        Relapsfree part 80% /61%………difference 19%
        time to change of EDSS 13,6 months/10,8 months……diff. 2,8 months
        Patients with no edss change 86%/79%……..difference 17%

        And from Clarinet (Italy)- small number, but representative. Different type of MS, mainly RRMS.
        -57% relapsfree after 60 months (but they had changed drugs during the periode?).
        -Time to edss change- 63,7% after 5 yeas/60 months (quite well)

        And something I do not quite understand because they say in the study that 54 out of 80 patients changed to another drug than Mavenclad during observation periode. (did mavenclad fail?) that means 28,1 % did not change drugs during 60 months (5 years) and 71,9% did change drugs, which i find high. (median time was 32 months) So how can they give measures up to 5 years as if everybody is on Macenclad? OK they say it works for aprox 3 years after last pill.

        In my opinion the developement of EDSS is the important thing.
        We see from the results- Mavenclad is stopping attacks very well, but disease goes on.

        Too much to read, too much on my mind.

  • “no evident ongoing end-organ damage”

    The most important questions still remain,

    -how long does this effect last after transplantation? Is it permanent?
    -If it is permanent, shouldn’t everybody get a aHSCT and then use anti-inflammatory maintenance therapy?
    -Do people with renewed disease activity (relapse, new lesions, progression of disability) still maintain the effect of slowed brain atrophy?
    -Should there be usage of any maintenance treatment after the transplant? (antiviral)?

    If the slowed brain atrophy effect doesn’t stay for “forever” or atleast for many many years – I would say that aHSCT is not the most effective DMT in terms of NEO-EOD, alemtuzumab has 9-12 year data on BVL and it’s quite promising, for aHSCT the data is stil not there.

      • “Similarly, should we start using maintenance therapy after alemtuzuma or cladribine?”

        Maintenance therapy…you mean the one that keeps ms in remission..?

        Sorry…don’t think one exists.

        • We don’t know that for sure. We only know that none of the treatments individually do so, in proper sequence things might turn out different.

      • The answer is yes, and the neurologists in my area already do it. It’s simply a no-brainer (hah).

          • Just another lower-efficacy DMT as a prophylactic against the MS coming back. Although my neurologist says he would never use an injectable, so it’s basically one of the available low-risk oral therapies chosen in conjunction with the patient. Once I am finished with my IRT course I intend to go with teriflunomide because of the anti-viral properties and the out-sized effect on brain atrophy.

    • “NEO-EOD, alemtuzumab has 9-12 year data on BVL”

      No doubt it would be in those who respond to therapy…
      Question is how many do not respond to therapy or
      who relapse. Is it 50/50 or much higher 70-90% respond
      to therapy….If you look on FB alemtuz boards…people who
      post are either cured….or progressed and very unhappy with it.

      • The thing is that there is no separate data for people “who responded to the therapy” and for people “who did not respond to the therapy” it is all cumulative. Assuming that after 12 years, around 34% people remained NEDA, that means that this BVL ratio is made of 2/3 people who “did not respond” and 1/3 of people who “did respond” so it still has to be pretty low BVL ratio even for the people who did not respond if the mean BVL is low. It is hard to say – and unfortunately we won’t know what are the BVL ratios for both of these groups.

      • How can you tell. People I know have 9 and 12 years between attacks, and in the time between very little feeling of MS. But the attacks are really damaging. So what is drug and what is the nature of MS?

    • If hsct fails in Norway they giev you rituximab. They say they see that the MS has calmed down even if changes comes after hsct.

  • “If EBV is the cause of MS how does the EBV hypothesis explain the changing sex ratio? If you have any explanations or theories to explain the changing MS sex ratio I would be very very keen to hear them. ”

    My feeling is that hormones must play a part in MS in some way. Women are spared relapses when pregnant and increasingly I read that there seem to be quite a few women who have had a late diagnosis which coincides with the menopause.

    Why the proportion of women being diagnosed is becoming greater, who knows, except maybe (feminist viewpoint here) that women are becoming more represented in the medical community now and are perhaps less willing to put up with things, including health issues, than in the past.

    • Re” My feeling is that hormones must play a part in MS in some way.”
      Yes, it seems so. For MTF transgender persons, the risk of MS may be increased. Also, some MTF transgender persons, that have an MS diagnosis have anecdotally said the HRT has helped eased some MS symptoms. (If I have understood correctly).

      • I don’t seem to read much about the possibilities of a link between female hormones and MS despite the link between pregnancy and reduced relapses and anecdotal evidence about the good effects of HRT. Maybe it is not of much interest to most researchers.

    • An English doctor married to a Norwegian wanted to figure out the reason and proseses behind arthritis (autoimmun) because her mortehr died from the disease. She observed some of the same, women pregnancies etc. better disease outcome during pregnancies etc. Her name is Anita Kåss. She wrote a book after having sold her research to a Japanese drug company for quite some hundred millions. She wanted to block important hormones in the brain. They gave the patient an GnRH- inhibitor to stop the production of sex hormones. They ahve seen that GnRH stimulating drugs increase rhe chance of getting an autoimmun disease. They saw that patienst given GnRH inhibitor had less cytocines to cause inflamation, especially TNF, the architekt behind arthrites,- which almost dissapared with the patients that had remision.
      they tried the GnRH inhibitor on bechtrews and ulcerøs cholitis, systemic scløeroses and lupus and some of the patients got better, really much better. 🙂

  • “Some people relapsed after 10-11 years post aHSCT, that must mean something in terms of MS pathology).”

    Yes…clearly hsct does not get rid off EBV.

    You have took at biology to see who is cured and who is just remission.
    This is how they analyze in Sweden…”the disappearance of oligoclonal bands (antibody synthesis) in the cerebrospinal fluid (CSF) is a good indicator of this. They have also included into this definition stabilization of CSF neurofilament levels into this (i.e. no further ongoing neuronal injury).”………..

    Out of 10 at 5 years…only 3 cured…”Two out of the ten went onto have a clinical relapse, and were started on Copaxone” 5 in remission. So you can assume remission can end at any time but they all lasted 5 years in the study.

    https://multiple-sclerosis-research.org/2019/07/hsct-is-it-remission-or-is-it-a-cure-for-ms/

  • I just thought of another issue, I would love to discuss it with someone.

    Prof Giovannoni stated numerous times that Alemtuzumab/HSCT may be a cure for some people – if used early enough. In my opinion this doesn’t go with the EBV hypothesis. If HSCT/Alemtuzumab doesn’t remove the EBV from pwMS, how can it be a cure? The EBV will come back at some point, the disease will become active again.

    I do not understand the “if used early enough” part. Does it make any difference for the EBV hypothesis whether pwMS is treated 5 years after diagnosis or 15 years after diagnosis? I am not talking about disability level, (which is obvious that the sooner the better) but strictly about the EBV part.

    Cheers

    • Something like the immune may keep developing in the wrong directions to the point part of damaging mechanisms do not involve cells treatable with Alemtuzumab, or memory cannot be wiped out by Alemtuzumab. So if get in early, these won’t happen – A layman’s guess.

  • There is no guarantee that the sex ratio at the turn of the last century indicated something all that revealing about MS then versus now, (whichever “last century” you’re talking about 19th or 20th, .. because a ratio of around 1:1 sounds kinda low for the ratio if you really meant 1999) or even indicated the actual ratio of the time. In fact, I think it’s pretty safe to say that it couldn’t have been the actual ratio at the time. so all the hand-wringing about the massive increase might be a bit premature.

    Fewer women than men had access to health care in the first half of the 20th, so there is one thing that could have contributed to the closer to 1:1 ratio of the time. People just didn’t think in terms of going to the doctor, that was something you did when you were very sick or near death, not when you had intermittent symptoms and not when you were not the primary breadwinner. The whole mindset in and out of medicine and in the culture was different.

    It’s also doubtful that a significant number of doctors of the time would have had the skill to make such a difficult diagnosis, which was even more difficult at the time. Of those who could accurately diagnose MS, how many of them saw what it was and refused to tell the patient (often a delikit (sic) female) what it really was because it was such a depressing diagnosis? Doctors STILL do that today, in fact.

    Now of course, we have the Holy MRI to guide us, and we are continually pushing the lower limit of what we are calling MS (or at least, trying to prescribe MS meds for). Plus we have the reported near-20% of those with MS who have been misdiagnosed and actually have something else, a 20% that has not been broken down by sex, so we don’t know which sex, is being misdiagnosed more often.

    So, has the number really increased so much in 100+ years so that we must go straight to pondering environmental/hormonal/viral/genetic causes and ignore other pretty obvious things like the changing sex ratio of who has had more or less access to health care in that time, diagnostic inflation, and flat-out misdiagnosis? It may have actually increased due to environmental/hormonal/viral/genetic causes, but not trying to tease out the other less sexy potential causes, seems short-sighted.

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