Monday, 24 September 2012

Do relapses count?

This figures shows a clear difference in relation to the prognosis based on early relapses. MSers with zero or 1 attack in the first 2 years needed a walking stick on average 14 years later (year 20) compared to MSers with 5 or more relapses in the same period (year 6). 


"The question that has been posed by some of you is whether or not this can be altered by the use of DMTs. The data is now very clear that suppressing relapses in early MS delays disease progression. In addition,  MSers with highly-active disease going onto one of the more active DMTs may actually see an improvement in their disability." 

"Suppressing relapses in early RRMS is an important treatment aim; anybody arguing the contrary needs to reassess the data or challenge their dogma!"

"This delay in disability progression on DMTs has also translated into an improved survival rate."

"With this and other emerging data it would be a brave person with active MS to turn down the option of going onto a licensed DMT. It will also be a brave neurologist to advise against suppressing relapses."

29 May 2011; 
MS and survival - long-term betaferon treatment improves survival. I had to give a talk yesterday, at the European Neurological Society (ENS) Meeting in Lisbon, on how to handle the complexity that the emergence of new ...

CoI: Multiple

23 comments:

  1. Does a CIS count in the above?

    Is the tally including CIS (all relapses) or 0-1 relapses + a CIS?

    big difference.

    Thanks

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  2. ah!!!!
    just noticed that this study with published 23 years ago.

    I can't see how one can extrapolate these results on DMTs.

    Totally different premise and motion, but an easy study to do as no clinical work needed, just data collection...

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  3. Fresher (July 2010):
    "The natural history of multiple sclerosis, a geographically based study 10: relapses and long-term disability"
    http://brain.oxfordjournals.org/content/133/7/1914.long

    I believe by "needed a walking stick" you mean DSS 6. Yes, early relapse number matters, though not as much as 14 years:

    "1 relapse group = 22.7 mean years,
    2 relapses group = 18.7 mean years,
    ≥3 relapses group = 15.1 mean years."

    But, relapse number AFTER 2 years make no difference in RRMS:
    "In contrast, neither total number of relapsing–remitting phase attacks nor of relapses experienced during the relapsing–remitting phase after the second year up to onset of progression showed a deleterious effect on times from disease onset, from progression onset and from Disability Status Scale 3 to these hard endpoints."

    One more thing: There is no proof yet that MS with pharmaceutical relapse suppression equals MS with naturally fewer relapses. It is possible that one can still follow the progression prospect of his untreated condition.

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  4. what is your email address Vasilis?

    would love to take this discussion further, off-record.

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  5. When MS is very active it justifies a DMT for relapse suppression alone, even if there's a chance it won't improve long-term progression

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  6. http://multiple-sclerosis-research.blogspot.com/2012/01/what-is-your-story.html

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  7. Re "what is your email address Vasilis?"

    Feel free to click on the name.

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  8. Re: "Is the tally including CIS (all relapses) or 0-1 relapses + a CIS?"

    The number attacks refers to the number from onset; therefore the 1st attack or CIS event is not counted. This is why you can zero attacks in the first 2 years after CIS.

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  9. Re: ""1 relapse group = 22.7 mean years,
    2 relapses group = 18.7 mean years,
    ≥3 relapses group = 15.1 mean years."

    The 1989 paper refers to a different classification system (i.e. 0-1, 2-4 and >=5), a different population (Middlesex County, London Ontario) and a pre-DMT era.

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  10. Re: "But, relapse number AFTER 2 years make no difference in RRMS."

    Are you sure about this? Science requires repetition.

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  11. Re: "just noticed that this study with published 23 years ago."

    In the pre-DMT era; all data since then is contaminated by a change in diagnostic criteria, ascertainment bias and DMTs. MS has become more benign as a result of all of these factors. These are some of the reasons why the prognosis for MS is better today than it was back in the 1980s. I presented this data to make the point that if I had MS I would rather not have relapses, particularly early on. The other side of the coin is that relapses can be occasionally devastating; i.e. on spinal cord attack can leave you paralysed and wheelchair-bound. I have a handful of patients who have had relatively early disease in this situation.

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  12. alright Mr. G,

    now I totally understand what you mean.

    but a question comes to mind: how would that apply to someone who had no relapses but a significant increase in T2 lesions and black holes?

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  13. My experience was similar to the previous poster - no 'proper' relapse for almost 2 years after starting interferon but lots of MRI activity. Mild symptoms appeared sometimes and went away soon. There was no fatigue and no cognitive problems

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  14. Re: "How would that apply to someone who had no relapses but a significant increase in T2 lesions and black holes?"

    I view MRI activity without clinical symptoms or signs as being subclincal relapses. The lesions that come and go with out relapse also cause damage. Those that leave behind black holes more damage.

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  15. Re "The 1989 paper refers to a different classification system (i.e. 0-1, 2-4 and >=5), a different population (Middlesex County, London Ontario) and a pre-DMT era. "

    The 2010 paper followed patients from 1972 to 2000. Since DMTs were initiated in 1993 (the clinical studies some 4-5 years earlier), we conclude that the first 2 years with CDMS in all patients were BEFORE DMT era.
    Also, any purported influence of DMTs on disease progression would apply on ALL patients groups (with regard to their initial relapse numbers). Thus, the difference between them should be preserved.

    The difference in population is the most plausible explanation.

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  16. http://multiple-sclerosis-research.blogspot.com/2012/01/what-is-your-story.html

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  17. Re: "No 'proper' relapse for almost 2 years after starting interferon but lots of MRI activity."

    We have just submitted a meta-analysis of MRI activity as a marker of non-response to IFN-beta. It is clear that if you are IFN-beta and have MRI activity at 6 or 12 months (new lesions or Gd-enhancing lesions) your are non-responder, and much more likely to suffer relapses and disease progression. In my opinion this is an indication for switching treatment.

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  18. Re "No 'proper' relapse for almost 2 years after starting interferon but lots of MRI activity." / Non-responder:

    But on the surface IFN-beta had a magical effect for 2 years. Before starting IFN-beta (after first reported symptoms), there was no remission at all for some months. IV steroids would make symptoms go away, followed by oral steroids, and fresh symptoms would start when the oral steroids were tapered down.

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  19. Dr G:

    When patients are treated with drugs that effectively stop relapses (campath, hi-cy, bone marrow transpant) do they still have progression?

    Does stopping relapses almost completely in the early stages of the disease prevent the transition to spms?

    I remember reading (maybe on your blog) that there is some data on this question coming from the CARE-MS trials?

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  20. Re: "Does stopping relapses almost completely in the early stages of the disease prevent the transition to spms?"

    Unfortunately we don't know the answer. We need to wait 15-20 years after treatment to see if this is correct. Some of the early cases of active RRMS treated with Alemtuzumab/Campath-1h seem to go into long-term remission and avoid the onset of SPMS at an early stage when it would be expected from natural history studies. Only time will tell if it will prevent long-term SPMS. I sincerely hope so.

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  21. "This delay in disability progression on DMTs has also translated into an improved survival rate"

    The 21 year betaferon study looked at all cause mortality, not only MS related mortality, so your conclusion is unjustified.

    Moreover the 16 year betaferon follow-up study with the same patients as the 21 year study, didn't show ANY significant delay in disability progression. How can you say the opposite?

    http://multiple-sclerosis-research.blogspot.gr/2011/12/predicting-disability-in-ms-on-dmts.html

    I could also remind you the latest canadian study about the zero long term effect of INF-B. The efficacy of DMT's is at least questionable, to be polite. But you just ignore all these data. Why?

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  22. But you just ignore all these data. Why?

    I am not sure why you think this and can remind you :-) that this was commented on by Prof G.

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  23. http://multiple-sclerosis-research.blogspot.co.uk/2012/07/research-beta-interferon-and-progression.html

    Prof G says "The problem with the data from the Canadian study is that it is not controlled and hence their will a lot of bias that cannot be taken into account. For example, the untreated contemporary and historical cohorts had a longer disease duration for the same level of disability at baseline; this would imply that they had more benign disease. They would therefore expect to do better than a cohort with more active disease (shorter disease duration for same level of disability). The fact that they did as well as each other to EDSS 6.0 implies that IFNbeta must have been doing something".
    Furthermore Prof G says "The bottom line is IFNbeta is not a very effective treatment; this study confirms this. That doesn't mean we shouldn't use it as some MSers respond better than others and in the UK, at least, you have to fail first-line treatments to access the more effect second-line treatments. For this reason alone IFNbeta has many years left in its legs and hence the rush to develop long-acting preparations and cheaper biosimilars. My main worry with them is the legacy NABs to INFbeta will leave behind."

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