Monday, 5 February 2018

How important is age in the development of progressive MS?

More about ageing and MS; this time about the development of progressive MS. 




The main message below is that most pwMS who are destined to develop progressive MS do so before age 75 and the onset of this phase of the disease is more dependent on age than the duration of MS.

Does this mean you are all destined to develop progressive MS? No in this study only 38% people with RRMS went onto develop progressive MS by age 75. Why some RRMSers don't develop progressive MS is probably due to biological factors and DMTs.

So the message in this post is mixed, i.e. the onset of the progressive phase of MS is age-dependent and not all pwRRMS become progressive.

This is no consolation for PPMSers. However, with the licensing of ocrelizumab for treating early-active PPMS we now have a DMT that can modify the course of PPMS, despite the treatment response to ocrelizumab being age-related. As with RRMS is better to treat PPMS as soon as possible after the onset of the disease; there is no point in waiting to lose reserve and neurological function and the advantage of youth before starting ocrelizumab.

The important question from a biological perspective is how is age modifying the course of MS and is there anything we can do to slow down or stop the ravages of ageing? I would start with a Brain Healthy Lifestyle. However, ageing is a biological programme and I have little doubt that scientists will crack the code and identify pathways that are modifiable. One hurdle still exists, however, society still considers ageing a normal phenomenon. Until we redefine ageing as a disease and healthcare payers agree to pay for anti-ageing treatments the incentive for Pharma to invest in ageing research won't materialise anytime soon.

We have had this debate before on the blog. Do you agree that ageing is a disease? 


I would be interested in your thoughts on the issues above. 

Tutuncu, et al. Onset of Progressive Phase is an Age Dependent Clinical Milestone in Multiple Sclerosis. Mult Scler. 2013 Feb; 19(2): 188–198.

Background: It is unclear if all patients with RRMS ultimately develop progressive MS. Onset of progressive disease course seems to be age- rather than disease duration dependent. Some forms of progressive MS (e.g. PPMS) are uncommon in population-based studies. Ascertainment of patients with PPMS from clinic-based populations can facilitate a powerful comparison of age-of-progression-onset between SPMS and PPMS but may introduce unclear biases.

Objective: To confirm that onset of progressive disease course is more relevant to patient's age than the presence or duration of a pre-progression relapsing disease course in MS.

Methods: We studied a population-based MS cohort (n=210, relapsing-remitting MS n=109, progressive MS n=101) and a clinic-based progressive MS cohort (n=754). Progressive course was classified as primary- (PPMS; n=322), single attack- (SAPMS; n=112) and secondary-progressive (SPMS; n=421). We studied demographics (chi2 or t-test), age-of-progression-onset (t-test) and time-to-EDSS6 (Kaplan-Meier analyses).

Results: Sex-ratio (p=0.58), age-of-progression-onset (p=0.37) and time-to-EDSS6 (p=0.16) did not differ between the cohorts. Progression had developed before age 75 in 99% of patients with known progressive disease course; 38% with RRMS did not develop progression by age 75. Age-of-progression-onset did not differ between SPMS (44.9±9.6), SAPMS (45.5±9.6) and PPMS (45.7±10.8). In either cohort, only 2% of patients had reached EDSS 6 before the onset of progression.

ConclusionsPatients with RRMS do not inevitably develop progressive disease course. Onset of progression is more dependent on age than the presence or duration of a pre-progression symptomatic disease course. Moderate disability is sustained predominantly after the onset of a progressive disease course in MS.

ProfG    

18 comments:

  1. Prof G, aren't all these averages a waste of time? A 78 year old woman next door to my mother-in-law has RRMS (c35 years). Every couple of years she has an attack and needs to use a walking stick. She is given steroids and recovers after a few weeks. I also know of a 23 year old woman who got very aggressive RRMS at Uni and has been a fulltime wheelchair user since she was 21. She is now classified as SPMS and her parents are her carers. I am 55 (female) who had Alemtuzumab infusions 13 and 14 years ago. I'm still classified as RRMS (no relapses since first infusion and totally stable / NEDA). Experiences with this disease are so varied ad trying to set out average experiences / journeys seems futile.

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    1. Re: "Prof G, aren't all these averages a waste of time?"

      Yes and no. As academics and clinician we need averages to guide us. But at an individual level exceptions are very common. This is why we need better predictive algorithms to identify people who need more aggressive treatment and those who don't.

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  2. Re "only 38% people with RRMS went onto develop progressive MS by age 75":
    Isn't MS progressive right from the start? I thought this blog has been saying that there isn't really any distinction between Progressive and Relapsing MS

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    1. Re: "Isn't MS progressive right from the start?"

      Yes and no. There will always be some people who will turn out to have benign MS. Then there will be those become benign because of a DMT. There will be those who will have already acquired a lot of damage prior to manifesting with MS (CIS or PPMS) and will be progressive from the start. And finally there will be those don't respond to DMTs and will acquire damage as a result of poor disease control and become progressive.

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    2. Playing devil's advocate there are many who don't accept the data that some of the more effective DMTs are delaying or preventing SPMS. There position is reasonable as the follow-up of the treated cohorts is too short.

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  3. Your figures contain a contradiction. The 38% of RRMSers - is this the number that are progressive by the age of 75 or the number who have not progressed?

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  4. I am so, totally, enthralled by this line of thinking. At EDSS 8.5 I am consigned by all the "powers that be" (neurologists, doctors, aged care management, wife, OT, physio) to the dust heap of history yet I started paid work in an Accessible Towns team yesterday and am, stronger and fitter than I was ten years ago.

    I pedal for an hour each day, visit the gym four days a week, and substitute other upper body and core exercise the other three.

    I am hot to trot (in the sense of launch on their way) several research projects that are relevant to this...

    I WILL NOT lie down and die and I understand my good fortune in being able to say so.

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  5. Let's look hhow robust this work is:

    Sample size: 754+210 = 964 | P-value of 0.37!

    Now let's compare it to that other now famous paper (Meta-analysis of the Age-Dependent Efficacy of Multiple Sclerosis Treatments):

    Sample size: c.28,000
    R2 = 0.6757, p = 6.39e-09

    Which one is more reliable?
    This paper is a mere distraction...

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  6. Ageing is NOT a disease but a normal biological process affecting every living thing and leading to death, the ultimate state for every living being, including humans. I don't know the answer to how we give a decent quality of life to old old people, or even middle-aged old people. But we are in a pretty bad situation now, where many people live for a long time when they themselves would prefer to be dead, because they are in bad health and have nothing to live for. The idea of viewing ageing as a (treatable) disease seems to take us further in that direction.
    I wish I knew the way we should go, because if I did I could tell the following people, all of whom are relatives of me or one of my friends (and only a subset of the old people I know of with big problems):
    - 98 year-old woman with dementia who can't remember that her husband died three weeks ago and refuses to move out of the house they shared
    - 82 year-old woman who had a big stroke on the 2nd Jan and now can't speak, walk, control her bladder or bowels
    - 86 year-old man (ex-universty prof) who developed dementia four years ago and is now unable to speak or walk and spends each day in a chair in his bedroom before being hoisted back into his bed each night
    - 90 year-old woman who broke her hip in August and opened a varicose vein last week, but is still walking around and is completely with it, but can't see the point in still being here.
    Hearing about these people makes me aware that we have a huge societal problem because modern medicine can keep people alive but can't keep them in a good state of health. I don't believe that viewing ageing as a disease is the answer - I think that is what has got us to the position we are in.

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    1. I do disagree. I speak from the frontline, so to speak, living in aged care and surrounded by people such as you describe.

      The "ageing is a disease" statement should not be heard as "live forever" - perhaps a less easily misunderstood version of this should be "premature ageing is a disease''

      There is undoubtedly a use by date, possibly telomer-related, to the human form but death, at that stage, would very likely not be sickness induced.

      All the people that you describe, and the vast majority of those here in Ellery House, are suffering from some disease that wise folk, such as Gavin, will find a cure for.

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    2. Wow "There is undoubtedly a use by date, possibly telomer-related, to the human form but death, at that stage, would very likely not be sickness induced."
      Death that was not sickness induced. I would love to know what that looks like. Everyone I have ever heard of who died did so because of sickness or injury. Is there another kind of death?
      Also, it is not reasonable to suggest that doctors will find a cure for every disease that afflicts humankind.

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    3. I think that Gavin posted such a description some time ago that brought tears to my eyes.

      I think it was 16/12/17 http://feedproxy.google.com/~r/blogspot/WvYVL/~3/cP8Nci0tdpo/dying-on-your-terms-is-it-possible.html

      As for "reasonable"? How much of the stuff being blithely discussed here would have seemed reasonable, or imaginable, ten years ago?

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    4. PS Gavin - what is your take on Mark's latest (mycobacteria) WK post?

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    5. "Mark's latest (mycobacteria) WK post?"

      100 year old drug BCG they try for FDA appproval..
      She says if you get TB then you don't get MS..???

      https://www.youtube.com/watch?v=BMmO2MWECv0
      Denise Faustman MD, PhD “The Value of Advanced BCG Drug Development in Human Autoimmunity; Mechanistic Biomarkers for Trial Design; Vaccine for Type 1 Diabetes”

      http://www.wheelchairkamikaze.com/2018/02/can-100-year-old-tb-vaccine-stop-ms.html#comment-form

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  7. This study suggests never to late to treat! MSers have a chanche without inflammation! Finally life is a neurodegenerative disease.
    http://n.neurology.org/content/88/16_Supplement/P5.356

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    1. As the old saying goes, Life is a sexually transmitted disease, with 100% mortality ;-)

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    2. "Finally life is a neurodegenerative disease."

      Think full saying was life is a terminal sexually transmitted neurodegenerative disease..can't remember if picked it
      up here from GG or a Marilyn Manson interview/song..hmmm.
      This is sure a fun place sometimes..ah..hilarious..good times.


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