Wednesday, 13 September 2017

#ResearchSpeak: slaying the PPMS dogma

How can we change the way the world thinks about PPMS? #ResearchSpeak #1-disease-not-2-or-3-diseases

Summary: This post makes the case for MS being one disease and that PPMS is no different to other types of MS.

This is a repeat post, but it needs saying over and over again. A lot of people simply accept that (1) PPMS in non-inflammatory, (2) that pwPPMS don't have relapses and (3) PPMS is a different disease to relapse-onset MS.


Dogma 1: PPMS in non-inflammatory - WRONG!



A pathology study done at the Institute of Neurology (Queen Square) when I was doing my PhD clearly showed, beyond doubt, that PPMS is inflammatory, albeit at a slightly lower level than SPMS. The dogma has crept in because we tend to view MS through the spectacles of an MRI; pwPPMS have fewer focal lesions on MRI. This, however, does not mean that there is no inflammation; focal inflammation is simply occurring at a level below the detection level of the MRI. What an MRI sees in relation to focal lesions is simply the tip of the iceberg. The PPMS iceberg simply looks different with less above the surface. In addition, pwMS have oligoclonal IgG in their CSF. If they were no inflammatory you would expect these OCBs to be absent or disappear. 

Revesz et al. A comparison of the pathology of primary and secondary progressive multiple sclerosis. Brain. 1994 Aug;117 ( Pt 4):759-65.

Background: The dynamics of primary progressive multiple sclerosis differ from those of the more common secondary progressive form. The observation by MRI that the frequency of enhancement with gadolinium-DTPA, a marker for blood-brain barrier dysfunction, is significantly less in the primary progressive form, has led to the hypothesis that inflammation is less intense in this group.

Aims: To test this, we have studied postmortem material from 9 cases judged from a retrospective analysis of case notes to show clear clinical evidence of either primary progressive or secondary progressive disease.

Methods: 578 lesions were analysed.

Results: There was significantly more inflammation in secondary progressive multiple sclerosis (as judged by the frequency of perivascular cuffing and cellularity of the parenchyma) than in primary progressive disease.

Conclusions: These observations have implications for therapeutic strategies in progressive multiple sclerosis.

Dogma 2: pwPPMS don't have relapses - WRONG!

In almost all PPMS trials done to date a proportion, albeit a small proportion, of pwPPMS go onto have relapses. For example in the Rituximab trial in PPMS (Olympus Trial), 11 out of 439 (2.5%) of study subjects had a relapse during the 96 weeks of the trial. In the Ocrelizumab (ORATORIO) study protocol-defined relapses were reported for 11% of subjects in the placebo group and 5% subjects in the ocrelizumab group.


Similarly, about 5% of study subjects in the glatiramer acetate PPMS, or PROMISE, trial had relapses. Unfortunately, the exact number of relapses is not reported in the main manuscript. What is reported is MRI activity; 14% of 938 study subjects had Gd-enhancing lesions on MRI during the study. The latter is the MRI equivalent of relapses. 


Based on this data can we say that PPMS is non-relapsing?

Dogma 3: PPMS is a different disease to SPMS - WRONG!

Did you know that it not uncommon in siblings pairs with MS for one to have relapse-onset disease and the other to have PPMS? The figure from the UK sibling study is in fact 23% (please see article and table below). This indicates to me that relapse onset and PPMS are the same disease.


Chataway et al. Multiple sclerosis in sibling pairs: an analysis of 250 families. J Neurol Neurosurg Psychiatry. 2001 Dec;71(6):757-61.



(33.7+27) / (84+68.3+33.7+39.3+27+9.7) x 100 = 23%


Other arguments in favour of PPMS and SPMS being the same disease relates to genetic and natural history studies. People with PPMS and relapse-onset MSers have the same genetic background. Once people with relapse-onset MS enter the so-called clinical phase of SPMS they progress at exactly the same rate as pwPPMS. 

Kremenchutzky et al. The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease. Brain. 2006 Mar;129(Pt 3):584-94.



It is for the reasons above that there is a strong argument for doing trials on combined populations of progressive MS. In other words, we should combine PPMS and SPMS populations into one study. I am aware that this is a controversial topic, particularly in the eyes of the regulators, but it needs serious and prolonged debate. If we don't do this then treatments will continue to be licensed for one subtype of progressive MS, and not the other clinical subtype, until additional trials are done. This is not in the interests of pwMS. Additional trials cost money and time. Time is not a something people with progressive MS have on their side. 5-years in the life of someone with progressive MS may be the difference between using a walking-stick and becoming bed-bound.

CoI: multiple

26 comments:

  1. It is more important that you convince your colleagues that PPMS, SPMS and RRMS are one disease. Neurologists need to be in agreement on this.

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    1. Re: "Neurologists need to be in agreement on this."

      I think they are the new Lublin classification hints at getting rid of the PPMS and SPMS label and prefers to refer to the group as progressive MS with or without activity and with or without worsening.

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  2. But how to persuade pharma to do the trials?

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    1. Not pharma, they want to do the trials, but the regulators. At present the regulators are insisting on doing both SPMS and PPMS trials.

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  3. This is an interesting post. I have a few comments on it.

    The first is an issue of consistency on this blog. In the past you have wondered aloud on a few matters. Is, you have asked, Oligoclonal band negative MS different from Oligoclonal band (OCB) positive MS. You have also posted articles that show that in people with PPMS there are different proteins and filaments found in their CSF. This is not a criticism - more a comment about the challenges of this disease across the board: it offers similarities and then it offers differences. It is, in this sense, a bipolar disease: predictable only for its unpredictability in the end.

    The second point I’d like to make is about the issue of OCBs. Yes, people with PPMS have positive OCBs. There are also people with PPMS with negative OCBs. The argument that there is an inflammatory response going on here, I venture, would be sorted if you looked at clinical trials of PPMS’ers and showed that, on application of certain B-cell immunosuppressants, their OCB status shifted from positive to negative. This was seen in some with RRMS. If you could change the OCB status of someone with PPMS then the argument that it is not a different disease is strengthened.

    The third point is about twins: I do not know a great deal about twins, but I think I understand a little about luck and chance. So my question is framed around this: it is relatively rare to be a twin. It is relatively rare to have MS. To be one part of a twin with MS might be very rare. To both have MS might be incredibly rare. So incredibly rare that it might just be chance. If you look hard enough for something you will find it. If I wanted to find what % of twins there were where one had MS and the other had RA, I wonder what that figure would be. Or one with MS and the other with a high IQ. You get the point. You always stress on this blog the need for a larger cohort of patients in clinical trials when the cohort is small. I’d say the same applies to twins (no offence to any twin reading this).

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  4. The fourth point I’d like to raise is the issue of cause and effect. The thing that has struck me when reading about MS is that so many people have different tales to tell about how their MS kicked in. Some were involved in car crashes, some had viral infections etc. I would love it if this blog did a poll and asked your readers what they thought ‘triggered’ their MS. I think you’d be surprised at the differences. In short, then, perhaps the issue isn’t about x causes MS and y is the response. Perhaps it is just that our bodies have failed us in one way or another, and that failure has remarkably similar consequences. Perhaps the causes of PPMS in some is the same as the cause of RRMS in some (say a virus), and the cause of PPMS in others is the cause of RRMS in others (say trauma). What I think is needed is a global analysis of the CSF of PPMS and for that to be the focus - for if we can find similarities that exists in just PPMS and not in RRMS then your argument might shift. I do not say fail: I think that the effects of PPMS and the effects of RRMS are very similar. I am just wondering if in your ever-search for a singularity of cause then you will always be frustrated.

    My final point is this: as DMTs show more and more their capacity to reduce the inflammatory response in MS, then I worry that big Pharma will increasingly shift away from developing new drugs for this disease. The profit margins after R&D costs are frustrated will ebb away. I venture we are in the golden age of trials and that that golden age will end and those left not responding to these new drugs will be the unlucky few. However, all is not lost. Where the big money seems to be is in the prevention of neurological-degeneration. Alzheimers, Parkinson’s, ALS and a host of other diseases are all frustrating neurologists the world over because, like PPMS, they involve a slow death of axons and neurons that cannot be prevented. The person who manages to stop neuro-degeneration might just be the person who, like gazing upon the face of God, manages to stop death. Will this happen? Perhaps not. Perhaps we can never end the slow and steady descent and decay of our mitochondria and of our nerve cells. Perhaps those who have PPMS are just the unlucky few who are forced to die a little faster than the rest of us, but not fast enough to make it a good death.

    In conclusion: I agree with you that those with PPMS should not be prevented from joining trials, but the entire neurological community has become obsessed with changes on MRIs. I would venture that for there to be a shift in thinking about PPMS and trial inclusion, you need to show that lumbar punctures - as horrible as they are for us patients - is the way forward. Light neuro-filament level analysis, however, hasn’t proven itself absolutely. Perhaps tau proteins might. Perhaps NFH. Perhaps a host of other as yet unknown elements in our swirling spinal fluids might. So, yes, invest in a bigger, better T7 MRI and get to work on PPMS with that. And then start making LPs a necessity in all trials. Let’s be honest: in an age of effective DMTs the people who will be included in trials are the most desperate: the inclusion of LPs in that trial might not be a deterrent if it stops their slow and terrible decline.

    I hope that this over-long message isn’t too hard to read, both emotionally and literarily.

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    1. Good post. I agree the CSF analysis is under-utilized in MS trials probably due to the cost and inconvenience for both patients and staff.

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  5. Doesn't one attack grey cells and the other white cells. That's why ppms is always progressive. As you take out the building blocks of the neural network. Maybe same mechanism. But the target surely justifies a different classification?

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  6. Another interesting aspect of the relationship between RRMS and PPMS is that RR is markedly more inflammatory (Pathology and MRI data) than PP. If inflammatory products and processes are the primary drivers of progression, we might well expect RR to be more 'progressive' and more serious in its clinical profile than PPMS. This is not the case. This raises the question, if not primarily inflammation, then what other factor is operating in 'progressive' damage? It seems fairly likely from the histological data that progression is related to axonal degeneration, if so we are looking for a primary insult (?cause) that primarily causes degeneration.
    It is therefore of importance to note that the earliest lesions described to date are characterised by a marked (and unexpected) lack of T cells and at this stage an intact Blood-Brain Barrier. Inflammation is not yet established. However the resident microglia have been activated by 'something', the oligos are undergoing apoptosis and the axons locally are degenerating. (Gay et al Brain 1997;120:1461, Barnett and Prineas Ann Neurol2004;55:458, and Gay 2006 Clin Neurol Neurosurg ;108:324.
    Gay et al have observed a candidate axonal and oligodendroclial insult at the scene of the crime (Gay Mult Scler Rel Dis 2013;2;213. in these primary lesions. It might be worth following this up?

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    1. Re: "If inflammatory products and processes are the primary drivers of progression, we might well expect RR to be more 'progressive' and more serious in its clinical profile than PPMS."

      In natural history studies once RRMS becomes SPMS they progress at the same rate. My interpretation of this is that RRMS and PPMS are the same disease and the only difference is that PPMSers have missed out on the early relapsing phase.

      MRI studies show that RRMSers and PPMSers losing brain volume at the same rate. No difference.

      The fortunate thing for RRMSers is that by having attacks allows you to get daignosed earlier and treated earlier.

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  7. I saw a presentation from a researcher in Australia, that his theory was that PPMS is the opposite process to RRMS, as in PPMS the attack starts from the axons to myelin rather than the opposite. Because of that it is not early detectable and thus preventable. At the end of the day SPMS and PPMS have destroyed axons.
    This theory would be just another theory if they hadn't created a very promising injectable treatment that worked on the axons that made a mouse totally paralysed walking again. A mouse is a mouse and EAE is not MS but it was really something... It will take many years to see if this can work on human or not of course.

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  8. There is no doubt at all that these are the same disease, the epidemiology data of which there are copious volumes, alone, strongly indicates one distinct disease. Nevertheless, as you point out there are differences is trajectory which demand explanation. The answer lies ......well I will quote the late Colin Adams.
    'It hardly needs to be said that the detailed Pathology of the initial stages of lesion development......must hold the key to the pathogenesis of the disease'. I give you a second quote pertinent on the current obsession with the 'significance' of the plethora of DMT 'experiments'
    'Pathology is the indispensable compass with which experimental and epidemiological research must be steered and without which that research will be wasteful and meaningless' (Colin Adams, quoting Charles Lumsden)

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    1. Not too many posts on lesion pathology on this blog, however. To the contrary, too much fuss on trials counting UBOs on MRI.

      It is a pity that the Prineas research on the 17-hour symptomatic lesion has been put aside as irrelevant to MS, just because it challenged dogma to the bone.

      http://onlinelibrary.wiley.com/doi/10.1002/ana.20351/full

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    2. You need to use the search function and go back to a post in 2011:

      https://multiple-sclerosis-research.blogspot.com/2011/06/article-of-interest-2-relapsing-and.html

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    3. Where is the progress in MS pathology since 2011? Any hard evidence that answers the questions raised?

      Should we count the posts on B-cells and drug trials to see what keeps researchers busy instead?

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    4. t is a pity that the Prineas research on the 17-hour symptomatic lesion

      Last time I heard pathologist talking about this case....they said it was not MS:-(

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    5. "absence of T lymphocytes in the immediate vicinity of apoptotic oligodendrocytes is especially significant, because such changes have not been reported in any form of the animal model, experimental allergic encephalomyelitis (EAE)."

      http://onlinelibrary.wiley.com/doi/10.1002/ana.20351/full

      What do they think it was..?

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    6. "Last time I heard pathologist talking about this case....they said it was not MS:-("

      So, in 2017 there are no data on the pathology of early MS lesions. Encouraging...

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  9. Aside from pathology, are the clinical profiles similar between the sub types? do SPMS and PPMS present in the same manner? In general, What are the presentations like between the sub types that you see in the clinic?

    I do believe when you say that all MS is progressive from the get go. It's just a matter of how much and how fast the neurological reserve is depleted.

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  10. "pwPPMS don't have relapses - WRONG!"

    "In almost all PPMS trials done to date a proportion, albeit a small proportion, of pwPPMS go onto have relapses "11 out of 439 (2.5%)(Olympus Trial) "

    "14% of 938 study subjects had Gd-enhancing lesions on MRI during the study. The latter is the MRI equivalent of relapses."

    Professor:Gavin Giovannoni

    Can i assume from your words that because
    2,5% and 11% of patients with ppms get relapses so ppms is a relapsing disease like rrms?

    If we flip the equation thats and we finds that 2.5% and 11% of RRms patients dont get relapses what should we do then? How do you

    classify? Non relapsing non ppms non spms?

    Obrigado

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  11. do neuros agree on what a relapse is yet? it took a lot of teeth grinding and pulling 2.5 yrs ago to get a coherent answer...

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    1. We I was diagnosed I read this funny definition. "A relapse can last from a day to a year and symptoms can vary from mild to strong", an interestingly uniformative and broad definiton.

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  12. The bad guy in a cut is the knife not the following inflammation. Likewise the immune system might not be in the wrong in MS. The cut may be due here to the oligodendrocyte apoptosis caused by a viral infection. This would make more sense from the viral point of view, A virus interests is to spread (go out from dying cells) not to make immune cells crazy just for fun. I remember writing that once in a previous comment...

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  13. Where can I find citations to support this kind of claim? Maybe I will just cite you and this post, but this seems more alarming that most of the natural history studies I've seen.

    "5-years in the life of someone with progressive MS may be the difference between using a walking-stick and becoming bed-bound."

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    1. "Where can I find citations to support this kind of claim?"

      Just look at posts on www.thisisms.com..some people here
      talk like ms is a managed condition like diabetes...

      "Wed Dec 14, 2016 10:51 am
      took 24 years but I'm finally bed bound. not bad no life left but I'm 51 so I guess i did alright :sad: Had ms for 24 years now.'

      Enough said.

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  14. "My interpretation of this is that RRMS and PPMS are the same disease and the only difference is that PPMSers have missed out on the early relapsing phase."

    IF thats true, it totally turns upside down the "benign" theory as PPMS seems the absolut "benign" version of MS. Also, shows how RRMS is still nothing but a missed opportunity.

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