Thursday, 17 August 2017

Are MS drugs a waste of time......for progressive MS

Lorscheider J, Jokubaitis VG, Spelman T, Izquierdo G, Lugaresi A, Havrdova E, Horakova D, Trojano M, Duquette P, Girard M, Prat A, Grand'Maison F, Grammond P, Pucci E, Boz C, Sola P, Ferraro D, Spitaleri D, Lechner-Scott J, Terzi M, Van Pesch V, Iuliano G, Bergamaschi R, Ramo-Tello C, Granella F, Oreja-Guevara C, Butzkueven H, Kalincik T; MSBase Study Group. Anti-inflammatory disease-modifying treatment and short-term disability progression in SPMS. Neurology. 2017 Aug 9. pii: 10.1212/WNL.0000000000004330. doi: 10.1212/WNL.0000000000004330. [Epub ahead of print]

OBJECTIVE: To investigate the effect of disease-modifying treatment on short-term disability outcomes in secondary progressive multiple sclerosis (SPMS).
METHODS: Using MSBase, an international cohort study, we previously validated a highly accurate definition of SPMS. Here, we identified patients in MSBase who were either untreated or treated with a disease-modifying drug when meeting this definition. Propensity score matching was used to select subpopulations with comparable baseline characteristics. Disability outcomes were compared in paired, pairwise-censored analyses adjusted for treatment persistence, visit density, and relapse rates.
RESULTS: Of the 2,381 included patients, 1,378 patients were matchable (treated n = 689, untreated n = 689). Median pairwise-censored follow-up was 2.1 years (quartiles 1.2-3.8 years). No difference in the risk of 6-month sustained disability progression was observed between the groups (hazard ratio [HR] 0.9, 95% confidence interval [CI] 0.7-1.1, p = 0.27). We also did not find differences in any of the secondary endpoints: risk of reaching Expanded Disability Status Scale (EDSS) score ≥7 (HR 0.6, 95% CI 0.4-1.1, p = 0.10), sustained disability reduction (HR 1.0, 95% CI 0.8-1.3, p = 0.79), or change in disability burden (area under the EDSS-time curve, β = -0.05, p = 0.09). Secondary and sensitivity analyses confirmed the results.
CONCLUSIONS: Our pooled analysis of the currently available disease-modifying agents used after conversion to SPMS suggests that, on average, these therapies have no substantial effect on relapse-unrelated disability outcomes measured by the EDSS up to 4 years.

I'm back....(What! you didn't notice that I've not been around and that there were slow responses).

I been in the Third World.....................of internet access, with zero email and essentially no access to the web...with even the paid-for "high speed" (yeah right) net.


Where?..........yep you got it........in the USA. 

In a number of National Parks the internet access has been woeful

Who would have thought that a gas (petrol) station in the middle of nowhere, would turn out to be a cyber oasis compared to the dearth for International Travellers.


However, I saw an amazing example of "thinkhand" and why giving access to people in wheelchairs access to treatment to save upper limb function is something we really must do. 


If you look at the picture above you can see on the right of the top of the waterfall there is a platform, which is full of people watching the waterfall. This waterfall is 308 feet (94 metres), where the top is some 600 feet down the canyon.  


I was passed on the way up the canyon, by a hand-driven wheelchair, OK with some help from their partner and encouragement by the kids. They were at the top looking down by the time I got there. Why shouldn't we stop deterioration of loss of hand function.


Anyway more news from the MSBase people and they haven't done a post on this one but it is something the Pharmaceutical nihilists will be shouting out loud about why it is OK to do nothing. This study suggests that use of DMT does not influence the course of secondary progressive MS if used after onset.


ProfG will be sitting on a beach somewhere in the USA pondering what this means for his therapeutic lag idea, but more importantly what it could mean if hand function was the main outcome. 


The take home message of this story is more reason not to use DMT in SPMS. Which is not what we have been saying.

There were about 25% in the untreated ground that had MRI lesions and about 20% in the treated group (so not effectively treated)

However, you can see the (median) follow up was for only two years although it was longer for many people, and when the ASCEND trial of natalizumab looked  and there was no change in EDSS over two years. However if the trial was followed for 3 years then they was an influence. So the follow up in this study may not have been long-enough for the therapeutic lag effect to show itself, (if it existed, which it didn't when it was looked for).

Likewise, I really would like to see if you look at the effect of only highly-effective DMT/HSCT use and subsequent course of MS. Yes, I know that use of CRAB drugs is the real life situation, but the picture is going to be muddied if you include use of CRAB drugs. 

We know progression will often occur because this has already been seen with alemtuzumab and HSCT, but will the rate of decline change? 

17 comments:

  1. Is this the waterfall at Yellowstone? I went there with my young son and a guide a few years after being diagnosed with PPMS. I wanted to go with him while I could, even though he was a little young. On the way to that waterfall platform, we saw a young man being carried by a small group from his wheelchair and then up the stairs to see the waterfall. He was carried the whole way. I cried when I saw that.

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  2. "Are MS drugs a waste of time"
    Thst´s a really good question for barts blog team

    Brave post by the way

    Luis

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    1. I should clarify this is for progressive MS

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    2. Lolllllllllllllllllll

      You correct it after
      Luis

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    3. Sure i correct things after they are posted. Have you seen my spellin..I have to read stuff again due to the dyslexia (I don't always spot the mistakes:-(

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    4. We've missed you MD. Welcome back to the online world :)

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  3. MouseDoctorThursday, August 17, 2017 8:05:00 am
    Sure i correct things after they are posted. Have you seen my spellin..I have to read stuff again due to the dyslexia (I don't always spot the mistakes:-( meaning that he is very THICK .

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    1. Anon at 2.51 you must be quite uneducated as well as very rude. Did you know that certain companies only employ dyslexics? Such as architects and marketing consultancies. This is because dyslexics think differently.

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  4. I really appreciate alternative perspectives on MS, exploration of theories. Who wants to live in a deluded world of half truths and lies.

    But I, as someone with PPMS of quite some years now (I started in my 20s, I'm now in my 40s) am very unsure of your assertions about current DMTs being useful in PPMS.

    Firstly, my inflammatory activity must be "low grade". The kind of distinct relapses some PwMS have are generally quite alien to me. I have not experienced optic neuritis, and my bothersome symptoms have slowly, slowly evolved over the years.

    Certainly, I might hope for a couple more years leeway if I was put on a potent DMT tomorrow, but the dampened fires that were lit long ago, perhaps when I was a teenager even, will carry on smouldering unabated. And I would have to deal with all the risks, side effects - and incessant monitoring - involved in being on an immunosuppressive DMT. All that on top of the burden I already bear in coping with this disease.

    Do not call me a treatment nihilist. I am not. I love life, look after my health in every way I can, and I dream of neuroprotectives - I feel that is the only kind of treatment which would make any sense for me.

    As much as I respect the work of your team, I find myself moving away from following this blog because I feel you generally only beat the drum for the same old immunosuppressives, when this - in my opinion - cannot be the answer for PPMS.

    Perhaps I am wrong. Perhaps I should be making a case to my medical team to put me on something. But I just feel I would be opening Pandora's box. Inheriting a box of unknowns - possibly including some very unpleasant - if not downright dangerous - things.

    I have been told many times "treatment is not indicated". But I can think for myself and I can see (and feel, know) why. I am grateful for not just being handed out a treatment which would very possibly, on balance, just cause more struggle and disappointment.

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    1. "You only beat the drum for the same immunosuppressives when this cannot be the answer for PPMS".... we can only beat a drum for what is available and at the moment that is what is available, but I do not think it is the solution for PPMS, but it may be part of the solution.

      Just to be clear, we have not been working on immunosuppressives as a research interest for over a decade. We are doing neuroprotective trials as I write.

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    2. Very very wise post
      You should post more often

      Thanks Luis

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    3. Neuroprotection and neurorestoration already exists, it's just not approved by the bureaucrats.

      HGH, testosterone, 7,8-dihydroxyflavone, alpha lipoic acid, biotin, etc on the chemical side of things. Direct intrathecal or intracranial injections of cultured neuronal stem cells on the neurorestoration side.

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  5. Welcome back MD. Now that the current DMD's have been shown to have little effect in progressive MS, researchers can get back to business and focus on A1 astrocytes, hot microglia, altered myelin formation, neuron mitochondrial dysfunction or neuron apoptosis or even EBV induced memory B-cells in follicles in the brain.

    Current DMD do not address any of the above problems, including ocrezulimab, and would expect them to fail miserably in progressive MS patients, except selection biased "inflamed" progressive MS patients. They may slightly delay the inevitable deterioration of a progressive MS patient, which is great, but will not improve their current clinical condition, including their EDSS. This is unacceptable.

    Hopefully, we can now focus on improving the reserve of progressive MS patients through remyelination, neuroprotection and neurorestoration. While relapses are very scary, it is progression that MS patients should fear the most.

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  6. MS is progressive from the beginning. The key is the brain reserve which reduces over time. Tysabri, OCR proved, and Siponimod also...
    Life is a neurodegenerative disease, after 35 yrs the brain stared to shrink, with MS this atrophy would be bigger. Highly effective meds have a robust impact of this atrophy! If U use one of these and your brain has reserve capacity it could regenerate itself, without this capacity your decline would be 'smaller'.

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