Sunday, 14 July 2013

Predicting progression at baseline

Progression & brain atrophy begets progression. #MSBlog #MSResearch

Epub: Lavorgna et al. Clinical and magnetic resonance imaging predictors of disease progression in multiple sclerosis: a nine-year follow-up study. Mult Scler. 2013 Jul.

OBJECTIVE: The objective of this paper is to identify clinical or magnetic resonance imaging (MRI) predictors of long-term clinical progression in a large cohort of MSers.

METHODS: A total of 241 relapsing-remitting (RR) MSers were included in a nine-year follow-up (FU) study. The reference MRIs were acquired at baseline (BL) as part of a multicenter, cross-sectional, clinical-MRI study. Volumetric MRI metrics were measured by a fully automated, operator-independent, multi-parametric segmentation method. Clinical progression was evaluated as defined by: conversion from RR to secondary progressive (SP) disease course; progression of Expanded Disability Status Scale (EDSS); achievement and time to reach EDSS 4.

RESULTS: The researchers concluded that conversion from RR to SP (OR 0.79; CI 0.7-0.9), progression of EDSS (OR 0.85; CI 0.77-0.93), achievement of EDSS 4 (OR 0.8; CI 0.7-0.9), and time to reach EDSS 4 (HR 0.88; CI 0.82-0.94) were all predicted by BL gray matter (GM) volume and, except for progression of EDSS, by BL EDSS (respectively: (OR 2.88; CI 1.9-4.36), (OR 2.7; CI 1.7-4.2), (HR 3.86; CI 1.94-7.70)).

CONCLUSIONS: BL GM volume and EDSS are the best long-term predictors of disease progression in RRMSers with a relatively long and mild disease.

"This study illustrates several points I have been trying to highlight on this blog. That despite feeling well and being fully functional MS may be shredding your brain. If you have evidence of this early on in the course of your disease, as measured by brain atrophy on MRI, in particular gray matter atrophy, you need to be more active with your treatment."

"Another observation is that if you are doing badly and have disability already you are more likely to progress further in the near future. In other words progression begets progression. This can be explained in terms of reduced brain reserve; if you are already disabled this indicates that you probably have already exhausted your reserve capacity in a particular neurological system, in other words you have a reduced capacity to compensate if any further inflammatory shredding occurs in that system."

"The problem we have is that very few neurologists are actually using brain atrophy to assess MSers at baseline. At the Royal London Hospital we are about to start doing this formally in our clinic. We will also be hosting a meeting on this issue later this year to see what needs to be done to get other neurologists to start incorporating brain atrophy measurements into routine MS clinical practice. It is clear from the survey results below that MSers want this issue taken seriously."

23 comments:

  1. Ah, another gloriously positively productive day in the world of Prof Giovannoni, with untold stories of shredding brains and complete lack of therapies to halt already progressive forms of MS.

    The scientists running this blog will have great secondary careers creating horror films because you certainly know how to scare your audience. It's heartening to know that my PPMS will inevitably begat more PPMS. That's JUST MARVELLOUS.

    Oh, well.

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    1. This post is not about PPMS; it is about RRMS.

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    2. No news is good news. If you don't want to hear news don't read this blog. Put your head in the sand, that is what my neurologist would want. An uninformed person with MS who doesn't ask questions. I wonder what he will say when I ask him if I have evidence of brain atrophy on my MRI?

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    3. He'll say yes and tell you there's nothing he /she can do for you. But at least you're informed!

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    4. Re -- Anon 1:07pm

      Prof G said: "Another observation is that if you are doing badly and have disability already you are more likely to progress further in the near future. In other words progression begets progression. This can be explained in terms of reduced brain reserve; if you are already disabled this indicates that you probably have already exhausted your reserve capacity in a particular neurological system, in other words you have a reduced capacity to compensate if any further inflammatory shredding occurs in that system."

      Therefore this post does concern PPMS. Read carefully before responding.

      Delete
  2. It's a fine balance - wanting to be kept informed so that you can ask your neuro the right questions.... but also needing to keep the right mental attitude. This is DIFFICULT when we know that we're not going to be offered more aqgressive therapy any time soon. Sometimes the utter hopelessness of it all just hits you, which is why I don't always read this blog. But alongside this I admire the truthfulness of Prof G's team. And I don't waste my time on reading other stuff.

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    1. I agree this blog does what it says on the tin: "interpreting good, bad and other research news".

      There is no point in trying to ignore that we have a bad disease and the best way to treat it is early and aggressively. Would you rather be fobbed off as having benign disease or told the truth about your future and what can and can't be done to prevent it.

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  3. I have sympathy with anon above. Surely we need to move on from the observation stuff, to actually identifying ways of addressing the destruction. When I was diagnosed 8 years ago I was hopefully that I'd see a time when the doctors could shut my disease down and provide something to promote some repair. I've lost all hope of this. The picture you paint is of a rampant disease destroying all nits wake AND THERE'S NOTHING that can be done about it. Piece of advice - don't get a disease where you need the help of a neurologist.

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    1. Brain atrophy what can be done about it? Possibly a lot. Natalizumab (year 2), fingolimod (year 1 & 2), alemtuzumab (year 2) and BG-12 (one trial only) all have an impact on brain atrophy. What you need is early access to more effective treatments or to move from first-line treatment to more effective treatments as soon as you know you are not a responder.

      We need a more proactive approach to treating MS. No more passive let's wait and see what happens. Active monitoring and more proactive approach to getting MSers who need them onto the most effective DMTs ASAP.

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    2. But why are you telling us this? We can't prescribe. All I want is the best / most effective treatment available. Your role, as with oncologists, is to give us the option of such treatments. We can do anything about the hurdles that currently prevent this. A few good men (woman) neurologists could start putting the patients first and find ways round the mechanisms put in place to stop this from happening.

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    3. You may be interested to hear that I have spent the better part of 3 weeks helping lobbying NSH England to try and changing their DMT prescribing policy. The aim is to try and get MSers in England access to highly effective DMTs in a timely manner and to allow us to prescribe them more safely. The issue with NICE and the NHS is that any policy has to be evidence-based and cost-effective. These are high hurdles to jump and will take time.

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  4. Prof G,

    If you want a good return from the consultancy fees you get from pharma, invest in companies who make electric wheelchairs, hoists and stair lifts. The current research underway is not likely to impact on demand for such products over the next 30 years.

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    Replies
    1. Not sure if this is sound advice. I suspect as soon as treat-2-target of NEDA (no evidence of disease activity) becomes the norm most MSers will not need a wheelchair. This has happened in developed countries with artificial joints in RAers (people with rheumatoid arthritis); as soon as rheumatologists adopted a zero tolerance strategy with regard to inflammation in joints joint replacements have become a rare event in RAers.

      We need to fight for access to highly effective DMTs so we can duplicate the RA success story.

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  5. Hope spring eternal - but not in the Blizzard Institute! Jekyll and Hyde stuff from Prof G. I prefer DR Hyde ie nice Prof G. I remember when he blog gave me hope and kept me up tp date with e latest breakthroughs and trial results. A defeatism seems to have taken over. The dreadfulness of this disease is highlighted again and again. I'm off to get some Vit D in the garden and try to keep up my positive attitude (despite the fact that my brain is being shredded).

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    1. I am very positive and upbeat. What we need to fight is therapeutic nihilism and the concept that MS is a benign disease. I can't tell you how well MSers are doing under my care who have had early access to highly effective therapies. This is what I am fighting for. Next time your neurologist tells you have benign MS challenge him/her with the facts. Ask if you can have an MRI to see if you have evidence of brain atrophy and gray matter atrophy. Ask to see how many lesions you have on your MRI and how many are active or enhancing post gadolinium. Ask for a neuropsychological testing to see if you have any hidden cognitive impairments. Ask for lumbar puncture to see if your spinal neurofilament levels are raised. Ask whether or not you can have a repeat MRI in 6-12 months time to see if you have progressive brain atrophy. Be active.

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    2. The newer highly effective DMTs are not as safe as the existing 1st-line treatments. They have a different risk:benefit ratio. To assess this risk:benefit ratio you need to know what the risks of MS are. When it comes to telling you what the risks of MS are don't pull my punches. Why should I? You need to know that MS is a bad disease and we have highly effective treatments that if used early can flat-line your disease progression. Is this being pessimistic? I can't tell how up I have been since the CHMP (EMA) has recommended that alemtuzumab be given a 1st-line license for MSers with active disease. It is the best news the field of MS has had in decades. I am also very proud to have played a small part in the development of Alemtuzumab for MS. Alemtuzumab is not a perfect drug, it has too many risks. We now need to focus on de-risking the drug. Can we predict who will get the autoimmune complications from alemtuzumab treatment and can we prevent them from occurring?

      Stop being a Killjoy there are lots of successes to celebrate and more to come. If you have progressive MS there are 4 trials running at present and more to start. It is only a matter of time before have an impact on progressive MS. I agree there are problems with trial design and getting drugs to market, but that is what gets me up in the morning and why I spend most of waking day doing.

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    3. Re " It is only a matter of time before have an impact on progressive MS"

      That's the problem, Prof G. I don't have the luxury of time being on my side.

      Goddamn, it was a hot day today.

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  6. I didn't invent the term shredding it comes from the script of the West Wing:

    Abbey Bartlet: We had a deal!

    President Josiah "Jed" Bartlet: Yes, we had a deal.

    Abbey Bartlet: Yes, Jed. Look at me! Do you get that you have M.S.?

    President Josiah "Jed" Bartlet: Abbey...

    Abbey Bartlet: Do you get that your own immune system is shredding your brain? And I can't tell you why. Do you have any idea how good a doctor I am and that I can't tell you why?

    President Josiah "Jed" Bartlet: I've had one episode in two years.

    Abbey Bartlet: Yes, but relapsing-remitting M.S. can turn into secondary-progressive M.S. oftentimes ten years after the initial diagnosis which is exactly where we'll be in two years! Do you know what that's going to look like if it happens?

    Abbey Bartlet: Memory lapses, loss of cognitive function, failure to reason, failure to think clearly. And I can't tell you if it's going to happen. I don't know if it's going to get better, I don't know if it's going to get worse. But we had a deal. And that deal is how you justified keeping it a secret from the world. It's how you justified it to God... It's how you justified it to me.

    http://www.imdb.com/title/tt0745713/quotes

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  7. Prof G,

    Many thanks for responding to a number of different posts. I believe you and us (the patients) share the same frustrations. Our assessment of success is very personal ie what effective treatments is there for me now. Yours is at the broader level. You also hae knowledge about ongoing trials that we don't know about.

    Have no doubt that we are all very grateful for your efforts and your dedication to patients. Progress can never come quick enough, but it is moving forward.

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  8. In full agreement with the above poster. Thanks for responding.

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  9. Yes, thanks. We need to know what neurologists are reading and thinking. The situation now for RRMS/PRMS is so much better than 15 years ago.
    There were a lot of angry MSers who were denied any disease modifying treatments because 'it wasn't cost effective'.
    In my case, it damn well was!

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