Thursday, 4 January 2018

2017: Reflections on another year in multiple sclerosis

Depending on how you see the world, i.e. through rose-tinted glasses, you may reflect on 2017 as being a landmark year for the field of MS.

Prof G's rose-tinted view of the world!

The following are 10 of my highlights, and a few lowlights, from 2017.

10 MS highlights from 2017 in descending order:

#10 - Length-dependent axonopathy hypothesis: The gradual acceptance of the length-dependent axonopathy hypothesis as a theoretical construct to view and treat MS. At the European Charcot Foundation (ECF) meeting in Baveno in November several senior, and well respected, MSologists mentioned the length-dependent axonopathy hypothesis during their presentations and stated it as fact. This is an indication that the concept is finally being accepted, which is critical for our #ThinkHand campaign. We have a lot planned in 2018 to celebrate and promote hand function in MS. DrK is in the final stages of preparing a grant application to test off-label cladribine in people with advanced MS (wheelchair users). The aim of the study is to assess whether, or not, subcutaneous cladribine can protect upper limb and hand function in advanced MS (Chariot MS Study). We are also lobbying Pharma to do similar trials.  2018 will be a success if we can get a DMT trial off the ground in wheelchair users.

Giovannoni et al. Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Mult Scler Relat Disord. 2017 Feb;12:70-78.

Dubuisson, et al. Disease modification in advanced MS: Focus on upper limb function. Mult Scler. 2017 Dec;23(14):1956-1957.

#9 - #BrainHealth: We now have over 45 international endorsements of the Brain Health Time Matters in MS policy document. The fact that so many international organisations are endorsing the principles in our policy statement means that we are finally getting somewhere about what the aims of MS treatment are in the modern era. I sincerely hope our follow-on activities, including the development of a Brain Health quality improvement tool and patient checklist, also get such a positive response.

Giovannoni et al. Brain health: time matters in multiple sclerosis. Mult Scler Relat Disord. 2016 Sep;9 Suppl 1:S5-S48.

#8 - Autologous haematopoietic stem cell transplantation (AHSCT): Submission of a grant to the NHIR (NHS equivalent of the NIH) to compare AHSCT to alemtuzumab in highly active MS. In addition to the grant submission more observational data emerged on the effectiveness of AHSCT in MS. We have had many debates on the Blog about the value of AHSCT as a treatment for MS. The fact that AHSCT is emerging as an accepted treatment option for MS in the UK is clearly an advance. What we need to find out is how effective is AHSCT compared to our other licensed very high efficacy DMTs and its relative safety profile.

Muraro et al. Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. JAMA Neurol. 2017 Apr 1;74(4):459-469.

#7 - RIS: The observation that a proportion of people with radiologically isolated syndromes (asymptomatic MS) present later with primary progressive MS. This tells you that MS is one disease and that if we can diagnose and treat MS in the asymptomatic phase we may be able to delay the onset of PPMS.

Kantarci et al. Primary Progressive Multiple Sclerosis Evolving From Radiologically Isolated Syndrome. Ann Neurol. 2016 Feb;79(2):288-94.

#6 - Plasma Neurofilament levels: A whole body of data emerged in 2017 of the potential utility of peripheral blood neurofilament levels as a biomarker of neuroaxonal damage MS. If this data holds up and can be confirmed it may replace CSF neurofilament analysis. This means phase 2 neuroprotective clinical trials could be done using peripheral blood neurofilament levels. Please watch this space. This is an example of technological innovation changing a field. Politicians should take note; they need to invest and reward innovation. This is not always that obvious in the NHS.

Novakova et al.  Monitoring disease activity in multiple sclerosis using serum neurofilament light protein. Neurology. 2017 Nov 28;89(22):2230-2237.

#5 - Remyelination: When the second phase 2 study of opicinumab (anti-lingo-1), a remyelination therapy, was reported as being negative my heart sank. Could this be the end of neuro-restorative therapies in MS? However, when Biogen reanalysed the data they discovered a clear signal that a subgroup of study subjects responded to opicinumab. The responder subgroup is identifiable using MRI biomarkers and disease duration. Based on this Biogen have launched a further phase 2b study to look at opicinumab as an add-on therapy in MS. Many other companies would have canned this programme, but not Biogen. This may explain why Biogen has recently been rated as the world’s most innovative pharma company.

Source IdeaPharma

#4 - B cells: The publication of the observation that all effective DMTs seem to have an impact on the peripheral memory B cells. I am aware that this hypothesis is controversial, but at least it is starting a discussion on the central role B cells play in driving MS disease activity. The real question is how does the B-cell hypothesis fit in with other well-established observations about MS; for example the strong HLA association. The latter suggests T-cells must also be involved, but how?

Baker et al. Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine. 2017 Feb;16:41-50.

Baker et al. Both cladribine and alemtuzumab may affect MS via B-cell depletion. Neurol Neuroimmunol Neuroinflamm. 2017 Jun 5;4(4):e360.

#3 - Paediatric MS: The reporting of the fingolimod in paediatric MS trial (Paradigms Study). This is the first positive-controlled trial of a DMT in the paediatric space. In summary, fingolimod reduced the annualised relapse rate in children with MS by 82% compared to intramuscular interferon-beta (Avonex). The relapse rate on fingolimod was 0.12 per annum vs. 0.68 on interferon-beta. The relative effectiveness of fingolimod surpassed my expectations and at least gives children with MS and their parents some confidence about the effectiveness of fingolimod (and it is an oral agent). With all the other DMTs we have to extrapolate from adult data, but not with fingolimod. Could this be the end of injectables for paediatric MS? Let's hope the EMA give fingolimod a 1st-line license for treating MS.

#2 - Oral Cladribine: The final licensing of oral cladribine (Mavenclad) as a treatment for relapsing MS. I have been intimately involved with the development of oral cladribine as a treatment of MS since 2002. Oral cladribine is the first selective immune reconstitution therapy (SIRT) and offers many advantages over other IRTs such as alemtuzumab and AHSCT. I think oral cladribine is going to really disrupt the MS space. Hopefully, a licensed formulation of cladribine will have a ‘halo effect’ and give neurologists working in resource-poor environments the confidence to prescribe off-label cladribine to their patients.

Alvarez-Gonzalez et al. Cladribine to treat disease exacerbation after fingolimod discontinuation in progressive multiple sclerosis. Ann Clin Transl Neurol. 2017 May 17;4(7):506-511.

#1 - PPMS: Licensing of ocrelizumab as the first DMT for people with PPMS. I can’t stress how important this is to people with PPMS and the wider field of MS. The fact that PPMS is now modifiable changes the whole MS space and slays several dogmas that have crept into our psyche. I remain concerned, however, that NICE won’t greenlight the use of ocrelizumab in PPMS in the NHS.

Montalban et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):209-220.

The following are some of my low-lights for 2017:

#4 - #MS-is-1-not-2-or-3-diseases: The failure of Barts-MS to get across the science of MS is being one disease and modifiable at all stages of the disease. At several key meetings in 2017 KoLs (key opinion leaders) were still talking about MS being several diseases. They are still classifying PPMS and SPMS as two different diseases. Then there is the concept that RRMS and SPMS are also different diseases. Help! How can we slay this dogma?

#3 - Diagnostic criteria for MS: I am very disappointed that the McDonald Diagnostic Criteria Committee did not include asymptomatic MS as part of the definition of MS. This means we cannot diagnose presymptomatic MS and hence we can’t treat it. This was an opportunity missed and we will have to now wait another 5-6 years before the next review of the diagnostic criteria occurs. In that time we may have the first positive clinical trials of DMTs in asymptomatic MS and we won’t be able to offer people with RIS (radiologically isolated syndromes) treatment for their MS. In general, Healthcare payers only cover the costs of treatment for a real disease, i.e. as defined by the experts.

Thompson et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2017 Dec 21. pii: S1474-4422(17)30470-2.

#2 - Brain atrophy: In the late-breaking session at ECTRIMS we saw that high-dose biotin had the opposite effect on brain atrophy to what we expected; study subjects treated with biotin had significantly more brain atrophy than study subjects on placebo. The investigators reported this as being a valid treatment effect and that shrinkage of the brain was due to normalisation of pathological enlarged brain volume. If this is the case it means brain atrophy cannot be used as an outcome measure in phase 2 neuroprotective clinical trials. More focus on the grey matter may be a solution.

Carassiti, et al. Neuronal loss, demyelination and volume change in the multiple sclerosis neocortex. Neuropathol Appl Neurobiol. 2017 Apr 18. doi: 10.1111/nan.12405. 

#1 - Laquinimod: The failure of laquinimod to slow down disease progression in RRMS (Concerto Trial) and the failure of laquinimod show an effect on brain atrophy in PPMS (Arpeggio Trial). Laquinimod promised to be the first neuroprotective drug to be licensed in MS but failed to live up to its promise. Let’s hope other neuroprotective drugs emerge as potential add-on therapies for MS. Possibly ibudilast? However, unless ibudilast demonstrates a clinical signal, or a signal on peripheral blood neurofilament levels, over and above its effect on brain atrophy I will remain doubtful of its utility as a neuroprotective therapy in MS.

ProfG     <!-- Add font awesome icons


  1. "Submission of a grant to the NHIR (NHS equivalent of the NIH) to compare AHSCT to alemtuzumab in highly active MS"

    "We await the completion of phase III clinical trials. The MIST trial, currently
    recruiting, is comparing current best DMT to low intensity I/AHSCT for RRMS
    ( identifier: NCT00273364) and a European trial is currently being
    designed to compare current best DMT to intermediate intensity I/AHSCT 20. A phase III
    trial should also be considered to investigate the efficacy of I/AHSCT in the treatment of
    SPMS patients with active inflammatory disease, for whom no therapy is currently

    Progress and prospects for the use and
    the understanding of the mode of action
    of autologous hematopoietic stem cell
    transplantation in the treatment of multiple
    Fredrika Collins, Majid Kazmi & Paolo A Muraro

  2. Nice Summary Dr Gavin. If current ms progress was amount of money raised for charity and the target amount was the cure. How far down the road are we until a cure? Obviously it's personal opinion and no one would hold barts to it. Or is that completely impossible question to answer even if we are just taking a educated guess?

    1. We may have already found a cure, but have yet to confirm it:

    2. Is acedemia then suggesting that absence of radiologically observable neuroimmunological activity for a certain period of time automatically infers that the underlying pathological processes in PwMS has fully stopped?

      If that's the case, wouldn't they be concerned of being ridiculed for oversimplifying a sickness for which the actual pathogenesis has not been understood to date?

      What would their explaination be to patients who experience desease rebound after any "NEDA" was proclaimed? "Sorry, you were just kinda healed..."?

  3. "The latter suggests T-cells must also be involved, but how? "

    In MS patients, CD8+
    T cells outnumber CD4+
    T cells in active lesions and
    closely interact with oligodendrocytes and demyelinating
    axons [12, 19, 41]. CD8+
    T cells infiltrates in active white
    matter lesions (WML) are oligoclonal and persist in CSF
    and peripheral blood [5, 48, 55]. Human cMSAg-specific
    T cells lyse human leukocyte antigen (HLA) class
    I-matched oligodendrocytes in vitro [26, 35, 57]. The
    cytotoxic effector mechanisms involve both the Fas/FasL
    and perforin/granzyme B (grB) pathways [11, 40, 50, 57].

    Phenotypic and functional characterization of T cells in white
    matter lesions of multiple sclerosis patients

    DOI 10.1007/s00401-017-1744-4


    1. CD8 = anti-viral, virus from B cells? , which virus uses HLA DR to infect B cells?

    2. "which virus uses HLA DR to infect B cells?"

  4. I think 2017 was another big year for vitamin D, no?

    1. Re: "I think 2017 was another big year for vitamin D, no?"

      Not really nothing has changed re vD. We have not class 1 evidence to supports its use as a preventive strategy and no class 1 evidence to support its use as a DMT.

    2. Vitamin d will have a significant effect only when the mother's of those who are susceptible to MS have enough vitamin d for all their lives and so do their offspring. This will only happen when they correct the RDA and it is added to food. We would then all end up with a similar risk as those in Northern Australia.

  5. "What we need to find out is how effective is AHSCT compared to our other licensed very high efficacy DMTs"

    HSCT is not a DMT! Get over it.

    1. It absolutely is a DMT..Get over it yourself:-)

    2. "HSCT is not a DMT! Get over it."

      HSCT is not a cure! Get over it.

    3. I never said it was. So that's unfair to level that criticism at me.

      Here's you, on the other hand said it was 'another DMD'.

      It's not. It's a procedure, involving more than one drug and more than one step. So it's not a DMD.

    4. A DMT is defined as a treatment, or treatment strategy, that alters the natural history of MS. Using this standard definition HSCT is a DMT.

      I am not sure why we are even debating this. If it is not a DMT what is it then?

    5. It's not. It's a procedure, involving more than one drug and more than one step. So it's not a DMD.

      Take cortiocosteroid, inject alem a few times, take anti-viral (more than one drug) repeat next year (more than one step) = DMD

      DrK asks should we called is a DMP? Sounds like a political party.

    6. Fact. Hsct is the most effective treatment for pwMS, to date. If barts and neurologists and researchers put the money, time and effort they did in dmd's, into a (to date) most effective treatment, then a lot of pain and heartache would be avoided.

      Flip the pyramid as you say. Treat early. First line treatment. Reduces risk and increases efficacy.

      Then there wouldn't even be the whole secondary ms arguement being less effective with hsct.

      It's hideous the stance you take.

    7. What is the point of researching HSCT in animals?....Our grant application on it was turned down..isn't that hideous?

      We work within the framework of the 3Rs. What would you do in animals that you can't do in humans?

      We have helped other people do the HSCT work they want to do....So get over it.

      You cannot have a monoculture of research and as we have said over and over again, you cannot do everything.

      If you can't put proper energy into doing what you do, then you should not do a half-assed job.

    8. I agree with those points.

      But the more less effective treatments are prioritised (in both research and administration) over more effective treatments, then that wrath you feel will always be a reflection of the pain pwMS feel.

      I wasn't trying to bate you. It was a practical and logical point. If researchers put the time, money and effort into furthering THE most effective MS treatment (hsct) to-date, think about where we'd be now.

      Treat early. Treat hard. And in a generation you can prevent MS from ever progressing beyond RRMS.

    9. The practical point is that research costs, except the fluffy stuff. To do a trial costs 1-4 million for an academic trial in USA it costs more, this is because you are not suing for salaries of doctors infrastructure,etc. A pharma trial costs ten-twenty times more because of the extra that they do and have to do to get a regulatory trial. That pharma fund alot of research dictates it is what they are interested in.

      The academic stuff competes with the rest of science from the same funding pot. So competing against cancer heart problems baby problems etc etc etc there are 14 licenced therapies but for many other conditions there are none.

      We tried to do a academic trial and it would have taken one fifth of the countries annual budget for research.

      So the reality will cause more wrath.

      The HSCT study profG referred to was applied for over two years ago. This is the reality of academic funding.

      As for animal work it has to be be paid for to buy a lab mouse can cost £100 + VAT then they have a daily charge for being looked after, they they have to be disposed of by proper contractors and this all costs and so you can only do what you can get funding for.

      If you lobby the MS societies to fund this type of work , this is what they will do, look at the millions wasted with CCSVI.

      But what questions are you going to ask?

    10. Your argument applies to DMD's, so why differentiate? HSCT is more cost effective, and more effective than DMDs.

      The reality is that people are opting for HSCT, the results too, are speaking for its efficacy.

      Attempting to go down the age old funding argument is quite a lame argument.

    11. "Attempting to go down the age old funding argument is quite a lame argument."

      A pretty ill informed comment.

    12. This comment has been removed by the author.

  6. Very good news about the pediatric fingolimod results. Any idea why it is so effective in children? The results are much better than the TRANSFORMS study.

  7. Biogen must love the free publicity!

    1. It's not always good....

      They are not always happy

  8. At the European Charcot Foundation (ECF) meeting in Baveno in November several senior, and well respected, MSologists mentioned the length-dependent axonopathy hypothesis during their presentations and stated it as fact.

    Really. But it is not yet "fact". For a long time, the Earth being flat was "fact". And some people still think it was created in 7 days.

    Fingolimod, Siponimod, upper limbs???

    1. Re: "Fingolimod, Siponimod, upper limbs???"

      The outliers; I hypothesise that the S1P1 modulators block remyelination and recovery mechanisms hence no length dependent observations (I have posted on this before). More to come on this later.

  9. Thank you for the overview prof. G.

    Local news (Flanders/Belgium) informs me of another trial concerning Remyelination,
    (not sure if it fits in your list), regards

    1. I saw this, apparently they haven't released any information on how they plan to re-myelinate cells so nobody has anything to comment on yet! It does make me happy to see that people are pursuing new avenues of treatment i.e. repair and neuroprotection rather than immune suppression!

  10. May I ask why you don't have much hope for Ibudilast? Do you think that there's no chance that a slowing of atrophy could be linked with a slowing of disability? Sorry I must comment on every single one of these posts but I'm trying my best to get my head around MS and reading the research helps me (though sometimes it has me rather disillusioned!)


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