Friday, 30 September 2011

Trends in MS disability progression at a population level

Epub ahead of printShirani et al. Temporal trends of disability progression in multiple sclerosis: findings from British Columbia, Canada (1975-2009). Mult Scler. 2011 Sep 27.

Background: Recent natural history studies suggest that MS is a more slowly progressing disease than previously thought. These observations are from studies separated by time, geography and methodological approach.

Objectives: The researchers investigated whether MS disease progression has changed over time in British Columbia, Canada. 

Methods: The British Columbia MS database was queried for relapsing-onset MS patients with symptom onset from 1975 to <1995, first assessed within 15 years from onset and with at least two Expanded Disability Status Scale (EDSS) scores. Latest follow-up was to 2009. Patients were grouped by 5-year onset intervals (1975 to <1980, 1980 to <1985, 1985 to <1990, 1990 to <1995). Outcome was defined as time to reach sustained and confirmed EDSS 6 within 15 years of disease duration. 

Results: A total of 2236 relapsing-onset MS patients (73.4% female; mean age at onset: 32.3 ± 8.8 years) were included. No significant trend was found in the proportion of patients reaching EDSS 6 (needing a walking stick) within 15 years from onset (28.5%, 26.4%, 27.7%, 22.3% for intervals 1975 to <1980, 1980 to <1985, 1985 to <1990, 1990 to <1995, respectively; p = 0.09). 

Conclusions: Rates of disease progression remained relatively stable over two decades of MS onset in British Columbia, Canada. Our results suggest that differences in disease progression findings between natural history studies may be related to factors other than time period.

"This is disappointing as we would hope the introduction of DMTs would have an impact on the rate of disease progression."

"We must not forget that the first-line therapies are not that effective and that too few subjects may have been followed in this cohort too see the impact of DMTs on disease progression rates; i.e. this study was under powered."

"We will need to wait to see the impact of the next generation of treatments on disease progression. If there is no effect we have got the facts or current dogma about MS wrong."

29 comments:

  1. I thought the DMTs (interferon etc) didn't start being use until the mid 1990s. I find it annoying that when the DMTs were introduced the neuros thought thye were great and now, 15-20 years later they are consider "not that effective". I would be more annoyed it is was the case that the neuro research community had "got the facts or current dogma about MS wrong". Given the time and investment over the last 50 years this would be a disgrace of epic proportions.

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  2. Agree with above comment - to go back to square one after all the efforts made to date would be unthinkable. Not sure what the current dogma is - MS is an auto-immune disease? I take some comfort from the Bone Marrow Transplantation trial in Canada - that progression can be dramatically slowed down with very aggressive treatment + Alemtuzumab appears to have a real impact on the disease (not sure if any of those treated in the RRMS stage have gone on to SPMS). Hopefully next motnhs ECTRIMS / ACTRIMS conference will provide some positive news i.e. that current research is heading in the right direction.

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  3. It's foolish to think you can control MS with drugs. Those with MS should accept their fate and make the best of things rather than chasing after snake-oil cures.

    DMTs are a total waste of time. Progression is progression. No medicine can stop progression.

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  4. I don't think anyone has claimed DMTs stop progression - they just say that IN SOME CASES they can SLOW progression, which is a different thing. It's all about whether an individual wants to give it a try seeing as there is no cure.

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  5. Ditto the above comment from Anonymous(4). I actually take DMTs but am under no illusion that in doing so I can "cure" the disease. If there is a chance that it could slow it down though, even if it's just a slim chance, I'd rather take it than do nothing!

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  6. My consultant told me he thinks all DMT are a waste of time. He says physio wil be a better option.

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  7. In the US 'an estimated 43% of people with RRMS are not on any form of DMD therapy'

    (from http://activemsers.blogspot.com/2011/08/going-ms-drug-free-flawed-arguments.html)

    Re 'My consultant told me he thinks all DMT are a waste of time' - change your consultant

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  8. Re: "I thought the DMTs (interferon etc) didn't start being use until the mid 1990s."

    That is correct; interferon-beta became available in N. America in 1993 and Europe in 1995. The point I was making that we should have started to see an impact of these treatments on disability progression at a MS population level. If they had a big impact on disease progression we should start seeing an increase in the time it takes to reach a disability milestone, in this case needing a walking stick.

    The first generation DMTs (interferon beta and glatiramer acetate) were never thought to be that effective; they only reduced the attack rate by 30% on average. Less that 20% of MS'ers on these treatments are relapse-free at 4 years. The next generation of DMTs are offering a step change in effectiveness.

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  9. Re: "got the facts or current dogma about MS wrong".

    This remains a worry and has been discussed and debated before on this blog. The current dogma states that inflammation is the main driver of MS pathology. If we suppress all inflammation early on in the disease we will prevent damage the later accumulation of damage from the slow dying off of damaged axons.

    The alternative theory is that MS is a neurodegenerative disease and the inflammation is in response to what causes the disease. In this model suppressing inflammation does not alter the long-term prognosis of the disease. In this model immunosuppression reduces or prevents relapses, but the underlying neurodegenerative process continues and will eventually result in MS'ers presenting with progressive disease later on.

    Which is correct? We need to wait and see what happens to MS'ers rendered relapse and MRI disease-activity free with the newer more potent therapies. if they go 20 years without developing progressive MS scenario 1 above is correct. If on the other hand they come back with secondary progressive MS without evidence of inflammatory disease activity (relapses or MRI) then scenario 2 is correct.

    What do I think? We have to go with scenario one and treat MS aggressively early on. If we don't we will be doing MS'ers a disservice. We can't wait 20 years to get an answer before we change the way we treat MS.

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  10. Re: "It's foolish to think you can control MS with drugs. Those with MS should accept their fate and make the best of things rather than chasing after snake-oil cures."

    I disagree. MS is a biological disease, i.e. there is compelling evidence that the immune system is perturbed. This means that there are biological processes that underlie this perturbation; immune cells are alive and depend on complex programmes to function, therefore we can target these with drugs. So I believe that we can treat MS, however we need to target our treatments.

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  11. Re: "Those with MS should accept their fate and make the best of things rather than chasing after snake-oil cures."

    This attitude is very defeatist; if we had that attitude we would close up shop now and stop investigating the disease.

    I agree about chasing snake-oil cures; MS'ers should be very disciplined and sceptical about new treatments. There needs to be a compelling case for trying a new therapy and if there is no evidence for its effectiveness it should only be administered in the setting of a clinical trial. The problem is that out there, there are Charlatans who are prepared to peddle snake oil.

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  12. Re: "I don't think anyone has claimed DMTs stop progression - they just say that IN SOME CASES they can SLOW progression, which is a different thing. It's all about whether an individual wants to give it a try seeing as there is no cure."

    Wise advice!

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  13. Re: "My consultant told me he thinks all DMT are a waste of time."

    This is not the time for therapeutic nihilism. You should ask your consultant to justify his/her position; I bet they can't.

    I agree with the recommendation that you should get a new consultant or better still you should educate your consultant. I suspect you are not the only MS'er under their care.

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  14. Re: "In the US 'an estimated 43% of people with RRMS are not on any form of DMD therapy'"

    In the UK this figure will be closer to 75%. The problem in the US is that a some of MS'ers in the US will not be on treatment because of lack of insurance or money. In the UK it is due to strict guidelines on the use of DMTs and is some instances therapeutic nihilism (some neurologists don't believe MS DMTs are effective).

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  15. The issue of the two theories (inflammatory first or neurodegeneration first) and needing 20 years to wait the results of the more potent drugs looks like poor science. What about modelling? What about the tissue bank? What about the post-mortem studies? In 2011 you'd think that this fundamental questions could be answered. Is there really no way to answer the question in a shorter timeframe?

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  16. The comment above is so right and on the money.

    All this conjecture regarding the 'let's wait and see' theory is holding MS research back.

    There is strong evidence suggesting that MS is neurodegenerative from the moment it rear its ugly head. There's a consultant in America who says the RRMS ought to be changed to just RMS.

    I mentioned this blog to my neuro a few weeks ago and told him it was run by Prof G and his team of experts, and that it was a very educational tool for us lay MS'ers.

    My neuro shok his head and gave a tight smile, saying 'Prof G's views on aggressively treating MS is hard for him to agree with. My neuro felt that Prof G is too hardcore in his understanding of MS and that there is not enough evidence to support his claims.

    Truth be told, there's so many lazy neuros out there it's crazy. They're not even all that interested in new research and seem annoyed when you tell them about things you'd expect them to be interested in like new ways to curb progression, etc.

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  17. Re: "The issue of the two theories (inflammatory first or neurodegeneration first) and needing 20 years to wait ...."

    The experiment is already running; we need to see what happens to the MS'ers treated with Alemtuzumab in the phase 2 study. They are 7+ years into the 20 year follow-up. What worries me about Alemtuzumab and other aggressive therapies tried so far is that they don't get rid of the oligoclonal immunoglobulin bands in the spinal fluid. There is evidence that these bands, or at least the cells that make them, are driving disease progression. If this is the case Alemtuzumab treated MS'ers are still at risk of developing progressive MS later on. I hope I am wrong.

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  18. Re: "My neuro shook his head and gave a tight smile, saying 'Prof G's views on aggressively treating MS is hard for him to agree with. My neuro felt that Prof G is too hardcore in his understanding of MS and that there is not enough evidence to support his claims."

    Can I disagree? If we don't treat aggressively early on we will never find out. I am grateful to my rheumatology and renal colleagues who have shown beyond doubt, with their diseases, that early aggressive treatment protects joints and kidneys. I am sure the same hold true for the brain. Please tell your neurologist that unlike joints and kidneys, the brain cannot be replaced or transplanted.

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  19. I hadn't heard about the issue of the bands with Alemtuzumab. But I take my hat off to Prof Compston and co. They moved away from the endless EAE research and tried a real treatment on real people. Those I know who have received it have been relapse free and stable 5-6 years after their last infusion. Even if it all goes wrong (SPMS) later on, the 5-6 years has been priceless.

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  20. Prof,

    Say suppressing inflammation with aggressive treatments such as Alemtuzumab do not prevent patients becoming SPMS. This would suggest theory 2 is right - neuro-degenerative from the start. Who is working on this issue ie drugs to stop neuro-degeneration? Surely if there were two theories, the research world should have split 50/50 so that solutions could be developed for both.

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  21. Re: "Say suppressing inflammation with aggressive treatments such as Alemtuzumab do not prevent patients becoming SPMS. This would suggest theory 2 is right - neuro-degenerative from the start. Who is working on this issue ie drugs to stop neuro-degeneration? Surely if there were two theories, the research world should have split 50/50 so that solutions could be developed for both."

    I agree. What you are talking about is combination therapy. I would not do a clinical trial of neuroprotection without addressing the inflammatory component of MS as well. What is the point of trying to protect nerves from dying without suppressing the process that we believe damages them in the first place. In my opinion the most well designed neuroprotection trial is the Riluzole in early MS study; it is being added to interferon-beta.

    More on this later!

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  22. Re: "I hadn't heard about the issue of the bands with Alemtuzumab. But I take my hat off to Prof Compston and co."

    Me too! Prof. Compston treated the first MS'er with Alemtuzumab in 1991; it has been a long and winding road with many obstacles and detours. A gold medal for perseverance; let's hope the community is ready for it. I am certainly ready; I can't wait to start using it in general practice.

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  23. Prof G,

    As ever, many thanks for you response.

    Enjoy a day off tomorrow - top up your Vit D.

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  24. Concept of immmune depletion with monoclonal antibodies to modify the immune response was firmly established in prior animal studies....but i'm sounding like the dad off My big fat Greek wedding... but proof is in the pudding..so its hats off for the persistence to the two A's from Cambridge

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  25. Re: "Concept of immmune depletion with monoclonal antibodies to modify the immune response was firmly established in prior animal studies..."

    We also have to remember that alemtuzumab was not developed as an immune modulator or suppressive drug; its initial indication was to target cancer (lymphoma and T cell leukaemia). In addition, its target CD52 is not present in mice. A transgenic mouse model has subsequently been created to study autoimmune mechanisms post-alemtuzumab; reverse translation.

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  26. I know everyone's different and you can't draw conclusions from a single persons' experience but I consider myself fortunate to have only had 2 'proper' relapses (one of which was optic neuritis and trigeminal neuralgia) and a few very minor instances of numbness on my feet. But am now (30 years later) SPMS, giving support to the 'neurodegenerative from the start, argument'. What I'm trying to say is that I didn't have many relapses, yet have still fallen prey to the progressive form of MS :-(
    Maybe if DMDs had been around I would've had even fewer exacerbations, who knows? Keep up the good work, Team G, it is much appreciated. I feel there is m ore a sense of urgency surrounding this work somehow.

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  27. Could you say more about this idea that the cells that make o-bands are driving disease progression? Or point to somewhere with more info? Thanks!

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  28. I realise this is an old post but can someone point me to the data re: Alemtuzumab and O-bands and also O-bands and progression? I'm about to start Alemtuzumab and this would potentially make me reconsider... Do we follow O-band reduction for any other DMTs eg BG12?

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  29. If you search blog for oligoclonal bands you will get alot of things

    Not sure about OCB and Alemtuzumab and BG12 has been published

    Not sure OCB links to progression
    http://www.ncbi.nlm.nih.gov/pubmed/22961214

    There was a post on Nataluzumab and oligoclonal bands

    http://www.ncbi.nlm.nih.gov/pubmed/22041091

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