Prevention vs. cure

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I was at a mid-summer party last night when someone suggested that I should not waste my time trying to answer peripheral or trivial questions in relation to MS and focus on the really big questions. 

This got me thinking about which are the biggest MS questions in MS that I can try to tackle and answer. Apart from (1) MS prevention, i.e. does preventing primary EBV infection with a sterilizing EBV vaccine prevent MS, the next major question must relate to (2) curing MS

The BIG-C issue is one I have been exploring on this blog for several years but is hampered by defining what an MS cure looks like and then looking for it. The problem with the latter is the issue of smouldering MS, which clouds the definition of a cure. Even if you cure someone from the biological drivers of MS, if they have relatively advanced MS they may still get worse from downstream smouldering processes that become independent of the initial MS attack(s). So the only solution is to test the hypothesis of an MS cure is very early in the disease, i.e. at the RIS (radiologically-isolated syndrome) or CIS (clinically-isolated syndrome) stage. 

To cure MS what treatment strategy do you need to use?  I have made the point that we can only cure MS with an IRT (immune reconstitution therapy) and at present we only have three IRTs that are used routinely in MS., i.e. cladribine, alemtuzumab and AHSCT. It is clear that cladribine is the safest IRT and has the added advantage as being the most CNS penetrant, which I think is important. Cladribine levels in the spinal fluid of treated patients are high enough to have an effect on CNS resident T and B-cells. Cladribine is also the safest and easiest IRT to use and therefore the most likely to get widely adopted. I am convinced  that a proportion of pwMS treated early, within 12 to 24 months of MS diagnosis, with either alemtuzumab and AHSCT are cured. Despite the stunning results of this treatment approach the adoption of both alemtuzumab and AHSCT as a mainstream treatment for MS has been abysmal. I suspect cladribine as an early effective treatment would have a greater chance of being adopted. My conclusion then is that the IRT has to be cladribine and it has to be done evry early at the CIS or RIS stage. 

But this experiment has already been done. The ORACLE study below was of oral cladribine in CIS. So what has happened to these patients? We don’t know, which is why Merck is doing the CLASSIC MS study to try and find out what has happened to these patients with CIS. Wouldn’t it be brilliant if a significant proportion of the cladribine exposed patients have not developed MS compared to those in the placebo group? Would this be sufficient to convince the wider MS community that very early cladribine treatment cures a proportion of people with CIS, i.e. prevents them from developing MS?  I suspect not. This is why a new global RIS-CIS study will need to be done. 

Please note some people would argue that stopping people with CIS from getting MS is MS prevention, whereas others would argue, including me, that CIS is already MS and hence preventing CIS from becoming MS is an MS cure. This is not just semantics but challenges disease definitions and is an important philosophical debate. This is why I want to study medical philosophy to tackle some of these issues.


Kaplan–Meier estimates of time to conversion to CDMS and McDonald MS in the intention-to-treat population during the double-blind period. Cumulative percentage probability of conversion to (A) CDMS according to the Poser criteria and (B) MS according to the 2005 McDonald criteria. CDMS=clinically definite multiple sclerosis. MS=multiple sclerosis. Figure from Lancet Neurol 2014.

Leist  et al. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol. 2014 Mar;13(3):257-67.

Background: Patients who develop relapsing-remitting multiple sclerosis (MS) present with a first clinical demyelinating event. In this double-blind, multicentre, randomised, phase 3 study we investigated the effect of oral cladribine on conversion to clinically definite MS in patients with a first clinical demyelinating event, when given at the same doses shown to be effective in relapsing-remitting MS.

Methods: Between Oct 21, 2008, and Oct 11, 2010, we recruited patients aged 18-55 years, inclusive, from 160 hospitals, private clinics, or treatment centres in 34 countries. Eligible patients had a first clinical demyelinating event within 75 days before screening, at least two clinically silent lesions of at least 3 mm on a T2-weighted brain MRI scan, and an Expanded Disability Status Scale score of 5.0 or lower. Patients with a first clinical demyelinating event ≤75 days before screening were randomly assigned (1:1:1) to receive cladribine tablets at cumulative doses of 5.25 mg/kg or 3.5 mg/kg or placebo. Randomisation was done with a central web-based randomisation system and was stratified by geographic region. Masking was maintained using a two-physician model. The primary endpoint of this 96-week study was time to conversion to clinically definite MS according to the Poser criteria. This study is registered with ClinicalTrials.gov, number NCT00725985.

Findings: Of 903 participants assessed for eligibility, 616 patients received cladribine 5.25 mg/kg (n=204), cladribine 3.5 mg/kg (n=206), or placebo (n=206). At trial termination on Oct 25, 2011, cladribine was associated with a risk reduction versus placebo for time to conversion to clinically definite MS (hazard ratio [HR] for 5.25 mg/kg=0.38, 95% CI 0.25-0.58, p<0.0001; HR for 3.5 mg/kg=0.33, 0.21-0.51, p<0.0001). Adverse events were reported in 165 (81%) patients in the cladribine 5.25 mg/kg group, 168 (82%) patients in the cladribine 3.5 mg/kg group, and 162 (79%) patients in the placebo group. We noted no increase in risk of adverse events with active treatment versus placebo apart from lymphopenia, which was a severe event in 10 (5%) patients in the 5.25 mg/kg group and four (2%) patients in the 3.5 mg/kg group.

Interpretation: Both doses of cladribine significantly delayed MS diagnosis compared with placebo. The safety profile of cladribine was similar to that noted in a trial in patients with relapsing-remitting MS. Further research could clarify the potential effects of oral cladribine treatment in the early stages of MS.

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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 and are not meant to be interpreted as personal clinical advice. 

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.

45 comments

  • “Please note some people would argue that stopping people with CIS from getting MS is MS prevention, whereas others would argue, including me, that CIS is already MS and hence preventing CIS from becoming MS is an MS cure. This is not just semantics but challenges disease definitions and is an important philosophical debate. This is why I want to study medical philosophy to tackle some of these issues.”

    Is there a risk that you are overthinking these issues? Preventing, curing, halting the processes which destroy CNS tissue is not a philosophical debate. An MSer just diagnosed with RRMS will want a cure ie IRT to stop further attacks / stop the establishment of smouldering MS, an MSer with children will want something for their children (?ebv vaccine) to prevent them ever getting MS, an MSer with Progressive MS will want something to stop smouldering MS which drive progressive disability. It’s not rocket science!

    Aren’t there any lessons from Polio – a virus which gets into the CNS, causes disability, but is now preventable? What about HIV – a disease which is now controllable, with better treatments on the horizon?

    You say that cladribine is more CNS penetrant – but has it stopped / delayed RRMS patients moving to SPMS? I assume it does something as it’s being trialled for those in wheelchairs to “halt” further deterioration (arm function).

    Are there any anti-viral trials in MS that are due to report soon? I’m assuming if ebv activity is arrested it would possibly be a preventative therapy and perhaps address smouldering MS?

    If I’d met you at the party I’d have asked why we are still in the navel gazing / philosophising stage and not doing real stuff. Time is brain we are told, but the barriers to testing the various hypotheses are the real reason so many MSers are getting more disabled. Addressing smouldering MS would be a game changer, but it’s always jam tomorrow!

  • “If you cure someone from the biological drivers of MS, if they have relatively advanced MS they may still get worse from downstream smouldering processes that become independent of the initial MS attack(s).”

    Back in the day when they were trying to get interferon authorised as an orphan drug they had to redefine what MS was to ensure that the permissible group was small enough. Thus we have RRMS, PPMS, SPMS. Prior to that we had MS.

    Hopefully this work on Cladribine shows that these subdivisions are incorrect.

    Instead we have early-stage MS without smouldering and later-stage MS with smouldering. And therefore we need treatments for smouldering once the MS drivers have been removed. Those MS drivers would be B cell processes etc or removing EBV from the equation. And the later-stage MS smouldering might be driven by memory outside the B cell system – memory T cells (if they exist) and other parts of the immune system that keep smouldering…

    It’s all moving in the right direction though.

  • I see rather HAART with an anti CD20 therapy as a possible cure than cladribine… What do you say about the study that compares clad to natalizumab and aubagio and concludes that it has the same efficacity as aubagio? I have my doubts about mavenclad although its mechanism seems to be close to lemtrada and aHSCT. And in this moment I would rather do AHSCT in Russia( the dosis seems to be the same as in Europe without rATG) than take mavenclad.

    • Look at the data. Exclude the first few months prior to the onset of action of cladribine and the curve is flat. How long does it stay flat for?

      We simply don’t have this kind of data for anti-CD20 therapy followed by HAART. In addition, anti-CD20 therapy, particularly low-dose anti-CD20 therapy doesn’t get into the CNS.

  • The whole CIS diagnosis is something I really struggle with and is perhaps influenced by my own experience. A patient is diagnosed with CIS. 5 years later, a second event leads to a diagnosis of MS. This patient has always had MS. The ‘gap’ to a second event is a good prognostic factor but at the same time their MS has been left untreated for 5 years. So treatment arrives shortly after the letter pops through the door saying you have MS, theoretically within the 12-24 month window. However, this is still 5 years on from disease onset. This is a major flaw in the treat early and effectively approach in my eyes or am I missing something?

    • You’re missing nothing.

      According to ProfG, “CIS is already MS” – so hit it with as big a hammer as possible, as soon as possible, because time is brain. Anything else is navel gazing, prevaricating and leading to inevitable and permanent brain volume loss and function loss. CIS should be treated as “MS in all but name”. What’s to lose? OK – some people MAY be unnecessarily medicated. But how many more will be pre-emptively and effectively medicated and consequently never be affected “that much” by MS?

      I had 3 years between my “clinically isolated” incident and my next episode but this was back in the bad old days of “watch and wait” (in my case augmented by my GP’s refusal to refer me to a neurologist – but I had a very “special” GP…).

      But – yes – this is a major flaw if MSologists aren’t prepared to treat CIS as “it’s MS in all but name”.

    • I feel the same way about the treat early approach. Sounds great in theory, but probably doesn’t work out so well in the real world.

      Considering that nearly 20% of those diagnosed with MS don’t actually have MS, I’m not sure how the treat early trope works when true early diagnosis seems so elusive. Later diagnosis apparently has a significant problem, super early diagnosis seems like it would be even more fraught with the danger of misdiagnosis.

      And forget CIS for a moment, there are those of us – and I’d argue it’s a pretty large group – who didn’t even have a CIS to point to. Our MS started a lot earlier than our official diagnosis too, but the symptoms, like this or that odd paresthesia, or random exhaustion for no apparent reason, were relatively mild and ignored by us if possible. If we couldn’t ignore them, they could be and were attributed to something else, or simply treated as an isolated symptom, without anyone interested in the big picture. So from where I’m sitting, no, you’re not missing something, that “treat early” stuff is a needle that rarely gets threaded. I don’t necessarily blame docs for this delay, but it certainly does point to a glaring need for better diagnosis of MS at all stages.

      In my case I was diagnosed past 50, so there was another whammy to my ability to derive the most benefit from “effective” treatments (had any of them even been offered, which they were not). Peering through my personal crystal ball tells me that I probably started the process around 2002-3, which was about 5 years after what I’m pretty sure was a significant reactivation of the EBV I contracted in ’93. So according to me, I was minimum 12 years into MS before my official diagnosis, and I went straight to “early cane”. Clearly, I missed anything remotely resembling “early”. I suspect my experience is not all that uncommon.

  • If alem only gets into the CNS in low doses….when does the treatment window for this particular treatment close? Does the risk / reward balance tip after 2/3 years and 3/4 relapses?

  • Sorry to sound jaded. This is a pointless article. Name me one trial reaching phase 2 in the last 20 years aiming to cure MS regardless of its status? Is it because we are clueless about curing MS? But have well informed science in treating to a tune of 1 billion pounds , cost it takes to bring a drug from pre clinical trials to authorization. Really? There will never be cure for Ms or any other condition until government forces Pharma by legislation to spend 50% of revenue on trials leading to cures. I am so confident in my view will bet you £50,000 we will have no cure for MS in the next 10 years!! Or for that matter any other condition!

      • Re: “…pointless post”

        The point of this post is to try and get the wider MS community to use cladribine earlier preferably in the CIS stage. At the moment it tends to be used much later and in most countries not first line.

        If you had CIS what treatment would you want?

        • I would ask my Neuro’s opinion, based on my disease burden/activity and age. If I understood correctly, Cladribine potentially would cause end-organ damage from toxicity. Medium-term efficacy seems related to B-cell suppression, long-term efficacy disappointing and would I now for sure the time needed to follow up with another DMT? After the second event? That doesn’t make sense. I can’t bet on the odds of 10%~20% of “long-term remission”, which Ocrelizumab may have the capability to achieve the same thing if not better – and my prefered choice.

          I can see the potential benefit of CNS penetration of Clad, but I would like to see head to head comparison to CD20 treatments in medium to long term. And I still wouldn’t choose Cladribine unless my neuro would agree to follow up with CD20/BTKi.

    • Re: “Is it because we are clueless about curing MS? ”

      No, because when we try it is too late. Once the nervous system is damaged some of the processes that drive further damage (smouldering MS) are self-perpetuating. In other words, even if you stop new MS lesions and MS pathology from forming the damaged CNS is destined to continue to be shredded.

      This is why AHSCT when used early works and when used too late is much less effective. The story is repeated for alemtuzumab and cladribine. It is all about early treatment to prevent this from happening.

      • Prof G,

        “Once the nervous system is damaged some of the processes that drive further damage (smouldering MS) are self-perpetuating. In other words, even if you stop new MS lesions and MS pathology from forming the damaged CNS is destined to continue to be shredded.”

        Few readers of this blog would disagree that the best option is treating very very early (CIS) with a highly effective anti-inflammatory therapy. You are preaching to the converted. Unfortunately many readers have missed this opportunity (probably weren’t offered it) and many will have smouldering MS. Your summary above provides no hope for those of us in that position ie shredding will continue. This leaves us with little hope (hence some of the frustrated posts). Is any MS team working on this issue ie to stop the processes which drive further damage? We’ve pretty much cracked the issue of addressing the external immune system involvement (relapses / focal inflammation). Surely MS teams should now be focused on stopping the dreaded shredding.

        • Until we can get pharma interested in neuroprotectants in MS we are greatly hampered as the trial costs are onerous. There are many, many promising candidates, as this group and others have shown but unfortunately a couple of decades back pharma got its find gers badly burned lokking for neuroprotectants for stroke. They identified many but in the real world situation, they couldn’t be administered quickly enough to be effective. The good news is that there are not the same time constraints in MS as there are in stroke and many of the compounds have already been through safety assessment etc and are lying on pharma shelves just waiting to be repurposed.

        • I agree with this comment.

          And I personally, although I have had ‘PPMS’ for over 2 decades, am still able to do my own pedicures very satisfactorily.

          As much as I respect the writers of this blog, I am generally finding it a very depressing, uninspiring read these days and am moving towards stopping visiting altogether.

          • Sadly, we’ve run out of gilt for the lily, delivery is unavailable due to Brexit.

        • Re: “Your summary above provides no hope for those of us in that position ie shredding will continue.”

          This is why we pushing for add-on trials and the holistic management of MS. This is the thread of my argument in my ‘Ask Not‘ post from last week.

      • They are self perpetuating mostly in late SPMS, in RR stage it’s all still reversible. What about the case report with the HIV infected man who’s still in remission after 12 years?

          • If we don’t hit at the cause of MS(if it can be done), yes, with the current DMTs the shredding will indeed continue. I hope that for HAART that’s the case.

  • Yes, a trial is needed to do this but it would be better that patients participating to clinical trials should be kept under track for life for this kind of diseases by regulations… at least to track a mean to contact them in case an update of the study is needed or if negative stuff pops out many years later to intervene. About cladribine first study my neuro when I was diagnosed told me that they have patients of the first cladribine study still disease free. The point is: do we know how to predict this kind of response? Not yet unfortunately. I have become more and more convinced that we need to work on all immune cells involved in MS: B T and plasma cells. Cladribine affects the latter only to a minor extent. Could this be dependent on the age of plasma cells? Would it be useful to compare cladribine resistance of plasma cells obtained from memory b cells maturation from blood donors (ie young) and plasma cells drawn from bone marrow (ie old)?

  • ”Even if you cure someone from the biological drivers of MS, if they have relatively advanced MS they may still get worse from downstream smouldering processes that become independent of the initial MS attack(s).”

    This got me thinking about what you really mean when you say ”smouldering MS”. Do you believe that people with a low baseline EDSS (let’s say <2) have a smaller chance of experiencing smouldering disease?

    And what are your current thoughts on early anti-cd20 therapies? Just postponing inevitable neurologic degeneration?

    • ”Even if you cure someone from the biological drivers of MS, if they have relatively advanced MS they may still get worse from downstream smouldering processes that become independent of the initial MS attack(s).”

      I thought Prof G had put the case forward for (a) MS being one disease and (b) smouldering MS was the real MS. With regard to (b) I thought Prof G was arguing that the external immune system (focal inflammation. / relapses) gets involved (in RRMS) once it picks up on the ongoing damage caused by smouldering MS in the CNS.

      I think there’s still quite a bit of work to do to identify which comes first. To some extent therapies which tackle smouldering MS should address both scenarios ie if smouldering MS kicks it off and the external immune system gets involved, or if smouldering MS is caused by the external immune system ie damage / inflammation is left behind and festers away causing ongoing damage within the CNS.

    • At the very least, by stopping new lesions and relapses anti-CD20 is significantly increasing quality of life for the 10-20 years before conversion to SPMS. That alone is worth a lot.

      • “by stopping new lesions and relapses anti-CD20 is significantly increasing quality of life for the 10-20 years before conversion to SPMS”

        Why not get hsct and maybe you remove any future progression and
        can live a full lifespan w/o disability…instead of only 10-20 years.

  • “Wouldn’t it be brilliant if a significant proportion of the cladribine exposed patients have not developed MS compared to those in the placebo group?”

    All you can ever say is that they haven’t YET developed MS

  • How are things going with professor Julian Gold to get the next charchot ( HAART ) project funded ? Maybe zidovudine ( cns penetrant and anti-ebv ) ?

    • HSCT has been stuck in the clinical trial phase for 20+ years now. This shit never ends. It almost feels like someone is trying to stop it from ever becoming widely adopted (and let’s be honest, MS specialists would basically be put out of business if everyone realized the power of HSCT and MS treatment was partially taken over by hematologists, plus there would be no more juicy infusion money for their clinics).

    • “Finally, a post about the positive benefits of Cladribine.”

      They been pushing it here alot…but the study results.. I just don’t know.

  • How do people know they have CIS? Strange symptoms which disappear can be anything and most people either ignore them because they are fairly fleeting and go away after a bit or go to the GP to be told they might have sprained something or slept the wrong way or be having migraines or whatever. Just don’t see how the average person having for example a numb leg for a day is going to end up at a neurologist, having an MRI and getting a diagnosis of CIS? Five, ten years later maybe they will have a major episode which leads to investigation and diagnosis but by that time they have full blown MS and hitting it early is no longer possible. Further, only certain neurologists will at that point it hard. A lot still want another episode before something highly effective. Just genuinely puzzled how MS can be treated early?

    • Good question.
      How I knew is because of a first degree relative with MS. So I was very aware of what MS symptoms can be

    • Re: “Big C blah blah blah”

      Let’s wait for the data of the long-term follow-up of the ORACLE subjects to emerge. It would really be blah, blah if a large number of cladribine treated CISers have not developed MS compared to placebo-treated CISers. It will then be hurrah, hurrah, hurrah that big-C is really a BIG-C 😉

  • I just uploaded a YouTube video in which we explain this blog post with the help of the topographical model of MS.

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