Guest post: Primary Progressive MS Research: Treatment Outcomes

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This is a repost from MStranslate, with kind permission from Brett Drummond.


PPMS is characterised by a steady worsening of disease or accumulation of disability from onset without any lengthy periods of stability or ‘remission’. Some people with primary progressive MS may also experience acute attacks of active disease, commonly referred to as relapses, during which symptoms are exacerbated or new symptoms develop.


Up until the clinical trial results for ocrelizumab (Ocrevus), none of the current MS therapies appeared to have any benefits for pwPPMS. However, a recently published study in JAMA Neurology has provided some stunning new insights that may change this theory. The research was conducted using the large international multiple sclerosis clinical database, known as MSBase, and performed by researchers in the Clinical Outcomes Research (CORe) Unit associated with the Melbourne Brain Centre at the Royal Melbourne Hospital and The University of Melbourne.


In the featured video above, Associate Professor Tomas Kalincik (Research Leader, Clinical Outcomes Research Unit) describes the results of the published study. In a very logical and easy to understand way, Tomas walks us through how the study was performed and clearly illustrates the findings. Importantly, Tomas also discusses the potential outcomes of this work. In particular, he mentions how this research may provide evidence that can be used to initiate conversations with regulators in order to change the way some people with primary progressive MS access multiple sclerosis treatments. 


It is also worth noting that we are one of the first people to get access to be able to provide coverage of this research – this is due to Tomas’ desire and excitement to share the findings of the CORe team with the MStranslate community. 


Tomas approached us and offered his time and expertise to explain these findings and we are extremely appreciative of that. I think it is really important that we not only highlight when researchers do amazing work, but also when they make it a priority to ensure that their results are made accessible to the MS community.  Thank you Tomas and the CORe team!

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Rebecca Aldam

20 comments

  • Firstly, let me add my thanks to Tomas and the CORe team too.

    Very interesting results.

    And nice to see the blog getting back to scientific research – it is supposed to be a resarch blog after all…

    • Thanks for your comment JoH. Whilst I'm posting this reply as MStranslate, it has been written in consultation with Tomas.

      On behalf of Tomas and the CORe team, thank you for the kind words about our research. We are glad that you found them interesting. We hope to be able to share more of our outcomes with you in the future, as we continue to try and answer more questions and improve our understanding of multiple sclerosis – Brett Drummond (Researcher, Science Communicator and Co-Founder of MStranslate)

  • I hate to pour cold water on this but, truthfully, what is it telling us that is new in any way? I thought the Barts line is that MS is one, not three diseases. When this researcher divides his Primary Progressive MS patients into those with and without relapses, he is dividing them into those with and without ongoing inflammatory activity. Surprise, surprise, he finds that the drugs that suppress inflammatory activity help the patients with ongoing inflammatory activity and do nothing for those without it.
    The only thing this tells us is that the Australian doctors should be more careful who they label as having PPMS. Most doctors here wouldn't say people with relapses had PPMS and on the British MS Society website it says, for people with PPMS, "symptoms gradually get worse over time, rather than appearing as sudden attacks (relapses)."
    Better still, the Australians and the doctors here could get rid of the RR, PP and SP labels and just try and work out whether people (still) have inflammatory activity before they give them the hard hitter drugs.

    • So true. Goes to show that Team G et al are headless chickens scrambling about without consistency. No wonder they're fleeing to Twitter where debate is limited to soundbites.

      This blog is a decade old now and MS care in the UK remains terrible. What has this blog done?

    • I don't agree with the anonymous person(s) who agreed with me, at all. This is a duff bit of research but the vast majority of stuff on this website is interesting, informative and hard to find elsewhere. I have a suggestion for people who don't find this website helpful – maybe you could stop checking it? There are lots of other websites on the internet to go to.

    • "blog is a decade old now and MS care in the UK remains terrible. What has this blog done?"

      It really dropped the EBV ball. T cell therapy
      for EBV cancers have existed since 1995 so why not try it in MS.
      "Rooney and her team rescued the T cells removed from the donor marrow and separated out the ones that could specifically attack EBV. They then grew these ‘EBV killer T cells’ in the lab until they had sufficient numbers to inject into the children following their transplant."
      https://www.ncbi.nlm.nih.gov/pubmed/7799740

      Why no mention of this u.k. trial..?
      "Our researchers in Birmingham are leading a clinical trial to find out whether a vaccine designed to boost the anti-EBV immune response of patients with nasopharyngeal cancer is an effective treatment.
      "The vaccine acts as a sharp reminder to the immune cells that the cancer cells infected with EBV are dangerous and should be destroyed."

      https://scienceblog.cancerresearchuk.org/2014/04/09/epstein-barr-virus-and-the-immune-system-are-cures-in-sight/

    • "There are lots of other websites on the internet to go to."

      Unfortunately there are not.
      If I can get treatment in a trial and stop my MS..I will
      start my own webpage/forum to inform others next year.

    • Thanks for your comments Cordelia. Although I am posting this response as MStranslate, it was written in consultation with Tomas…

      Certainly, the discussion around the importance of the relapsing-remitting, secondary-progressive and primary-progressive classifications is an important one and one that needs to, and is, being had around the world. However, in the current situation, these ‘labels’ do exist and are strictly adhered to by regulators. The reality of the situation is that many people with progressive MS forms don’t have easy access to immunotherapies because of the regulations currently in place. We hope that the outcomes of this study might be able to provide enough evidence to help make a change in this area – move away from the strict labels towards the model of MS that is a mix of progressive and relapsing components. In a setting where no one with PPMS is allowed to access immunotherapy, we are proposing that people with relapses should have access to therapy as long as there is evidence of episodic inflammation. MSBase is a global collaboration in 33 countries, including UK, and the labels that we are trying to 'soften' are currently being used by clinicians and regulators in all these jurisdictions.
      We are currently performing other studies that aim to answer the last part of your comment. Just like you, we think it is critically important that we begin to shift to a much more personalised model of treating people with multiple sclerosis. To do this, we need to improve our understanding of exactly what is the right treatment for the right person at the right time. To this end, we need to learn to identify markers of good response to the available therapies in individuals with MS, like we did in the present study. We are working hard on this and many other multiple sclerosis studies at the moment and we hope to be able to bring those findings to you in the future – Brett Drummond (Researcher, Science Communicator and Co-Founder of MStranslate)

    • But why are people who are having relapses being labelled as having Primary Progressive MS in Australia? I looked up the definition of PPMS on the MS Australia website. It is as follows: "Primary progressive (PPMS) – a progressive course from onset. Symptoms generally do not remit. 15% of people with MS are diagnosed with PPMS, although the diagnosis usually needs to be made after the fact, when the person has been living for a period of time with progressive disability but not acute attacks."
      Prof Tomas starts by stating that they are studying how people who have relapses on top of their PPMS do on disease modifying drugs, in comparison to those who do not have relapses. But by the two definitions I have given, people who are having relapses should not be labelled as having PPMS (and should eligible for disease modifying treatment).
      This is a very basic problem with this research, not a definitional problem.

    • "But why are people who are having relapses being labelled as having Primary Progressive MS in Australia?"

      Hmm..good point..uhmm..No Clue..?

      "Primary progressive multiple sclerosis (MS) differs from the more common form of MS which has an initial relapsing-remitting course in a number of ways, including pathological features, clinical course, differential diagnosis and response to treatment. The lesions in primary progressive MS tend to be more diffuse, less inflammatory and less likely to remyelinate than those occurring in relapsing-remitting MS and secondary progressive MS; there are also fewer focal lesions in the brain in primary progressive MS."

      "Recent evidence suggests that antibodies to central nervous system (CNS) antigens have an important role in disease progression. Such antibodies could cause demyelination, inhibit remyelination and cause axonal destruction. Ongoing immune attack by autoantibody and lack of CNS repair could be responsible for the gradually increasing disability in primary progressive MS."

      https://www.ncbi.nlm.nih.gov/pubmed/15337125

    • Hi Cordelia – passing on another reply from Tomas regarding your previous comment…

      Dear Cordelia,

      I appreciate that the diagnostic definitions may be confusing, in that they have changed four years ago. Our study compares two closely associated phenotypes, which were previously called PPMS and PRMS (i.e. PPMS with relapses). Because the neurological community recognises that the distinction between the two is really fine, Lublin et al. have redefined the classification of progressive MS forms. For both primary and secondary progressive MS, two subtypes are now recognised – active (i.e. with relapses in addition to the progressive course) and not active (i.e. progressive course without relapses). This classification is now being used globally, not only in Australia but also in UK, EU and US. The article by Lublin et al. is freely accessible from Neurology at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117366/ . Please have a look at Figure 2, which nicely illustrates the concept and the differences between the 1996 and 2013 classifications.

      In our research, we have proposed that the distinction between these phenotypes is rather fluid and that progression and episodic inflammation represent two continua that are, to a certain extent, independent. Why this is more than just an academic question? Because it influences the way we may treat progressive MS. If our research had shown that in progressive MS it did not matter if one did or did not have relapses and immunotherapy simply was not effective, then we would have had to admit that regulators were right and exposing people with progressive MS to immunotherapies did not improve their outcomes. However, we have generated evidence that helps us better identify those with progressive MS who will benefit from immunotherapy. As we know, every therapy has its side effects and it is therefore important that we offer it to people who are likely to benefit from it. The next (difficult) conversation to have is that with regulators – Tomas

    • Hi Adam – just passing on a reply from Tomas regarding your recent comment…

      "Progressive MS forms are associated more commonly with formation of folliculi of immune cells in the meninges and plaques in the cerebral cortex. The spectrum of lesions found in patients with PPMS is enriched for smouldering, inactive and shadow plaques. [Frischer et al., Ann Neurol 2015, 78:710, the paper is freely available from the Annals of Neurology at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4623970/%5D However, none of these pathological findings are pathognominic for primary progressive disease. Once again, this indicates that the amount of progression is a quantitative trait." – Tomas

    • Hi Tomas. I read the paper you recommended and I found the following quote
      "Thus, a patient with PPMS who has not progressed over the past year would be classified as PPMS–not progressing. A patient with SPMS who has gradually worsened and has gadolinium-enhancing lesions on MRI would be classified as SPMS–active and progressing."
      This seems to suggest that the patients you are classifying as having PPMS with relapses actually have SPMS–active and progressing. The most effective MS disease modifying drugs are advertised as reducing relapse rates and slowing progression. For example, Natalizumab reduces relapses by 68% and reduces progression by 42% (on average).
      It seems to me straightforward that people with MS who have relapses (who have what you call active MS) also have inflammation and are likely to benefit from DMDs. I don't understand why these people are labelled as having PPMS in Australia – I don't believe they are labelled like this in the UK.
      Your research seems to me to show that there is NO fluidity between the phenotypes. People with relapses and progression fit in the SPMS–active and progressing category and will benefit from DMDs. People who have progression but have no relapses (PPMS) will not benefit from DMDs and DMDs are not licensed for such people.

  • Can you tell us what the study was called? Your link only goes to the general JAMA website and if I search for multiple sclerosis, I cannot seem to find anything that would be similar to the study you mention. Thanks!

  • Previous "Anonymouses" from 3:22 and 5:23: unless somebody is forcing you to read this blog or you are feeling masochistic or you have nothing better to do, why do you even look at the blog if you think it is so terrible? Go out there and fight ms rather than senselessly annoying the many who appreciate this blog and who, to an extent, rely on its insights and research summaries for the management of their ms! To those people at least, and I am one of them, your trolling in this blog is respectless. Makes me think you're not actually interested in alleviating ms at all! Seriously!

  • First, to be blunt, I have to ask what planet the people who seem dead set on disparaging this blog are living on? Granted, the state of MS treatment leaves many patients frustrated and angry, but to take it out on the keepers of this blog seems extremely misguided. I've found these pages to be highly informative, thought-provoking, and invaluable to my own understanding of MS research and its implications. My advice to those who seem only capable of offering nonconstructive criticism: stop reading.

    In regards to this particular post, I must agree that there's really nothing new here. Genentech established back in 2008, with its first Rituxan PPMS trials, that there is a cohort within the greater PPMS population that has signs of active inflammation and respond to anti-inflammatory drugs. Isn't this why the ocrelizumab trials were frontloaded with just such patients?

    What's new here is the unbridled acknowledgment of this fact, I suppose. Seems that the drug industry folks would like to blur this distinction in order to peddle their wares to the whole PPMS population. The fact that the ocrelizumab trials were well designed for success and yet were still "underpowered" in regards to ferreting out just which subgroups did or did not benefit from the drug would be laughable if it wasn't such a blatant effort at medical research sleight-of-hand.

    So, yes, those people with PPMS who suffer relapses and/or have enhancing lesions can benefit from some of the immunosuppressant drugs. I've yet to see compelling evidence that the greater PPMS population – those without active inflammation – stand to benefit, at least enough to offset the potential risks associated with these treatments.

    That said, let's get to work on finding some real solutions for those with truly progressive disease, who are still left out to dry while watching themselves slowly wither on the vine.

  • Thank you for your support.

    We are trying to improve the Blog by creating a platform for other researchers and MSers to use; hence the increase in guest posts. We also don't want to overload you with poor quality posts; hence trying to stick to one post a day.

    We also need to free up time for our other activities. The blog is not our core activity. We need to find the right balance to make our blogging activities sustainable in the long term.

By Rebecca Aldam

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