Interesting article on age and DMDs

[Jules A]

Excellent points everyone!

Badaimata, I much appreciate your input and definitely believe the quality of a study is crucial and agree I can't imagine how anyone could sort the kitty from the litter when it comes to the combo of MS + aging so I will keep that in mind as I read this article. My initial thought was due to it being a meta analysis of 38 clinical trials that although some of the studies might be lacking it is unlikely all of them are flawed although as you point out data can be presented in a skewed manner.

I'm slammed the next few days but hope to read it on Friday. I was waiting to access it at work but it is in fact available on line without a subscription.

https://www.frontiersin.org/articles...017.00577/full

Frontiers in Neurology is reported to be a peer reviewed journal.
https://www.frontiersin.org/journals/neurology

The other easily addressed concern includes the author's conflicts of interest and a lead author actually has an interest patents of a MS medication which is a significant litmus test, imo. The funding appears to be above board also:

"Conflict of Interest Statement
BB declares the following COI: she is co-inventor on several patents related to daclizumab therapy for MS and, as such, has received patent royalty payments from the NIH. The remaining authors have no competing interests to declare.

Funding
This study was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH)."

[MyGirlsMom]

Yes, Dr Vollmer at Univ of CO mentioned this to me years ago. In fact, Dr Corboy is leading this study. Last year or so I called to see if I could join (I am now 57 yrs old) but the only way to join was to be on a DMT and I was moving off Copaxone due to injection site issues. Thus, yes...I wonder if it is worth the risk of “other” complications getting back on a DMT. This decision part of MS is so hard to know what is best or right to do.

Check out the link: https://clinicaltrials.gov/ct2/show/NCT03073603

Does anyone know someone in this trial? Or heard any updates so far from their doctors on this? Curious as this is all I have heard....

[Mable]

Does anyone know someone in this trial? Or heard any updates so far from their doctors on this? Curious as this is all I have heard....

Yes. I’ve heard from a very good source that 1. Initially, it’s looking like non-medicated subjects are doing well. 2. My recent MRI activity would have made me a failed data point on the study. (If I hadn’t taken myself off Copaxone, I would have qualified for it)

Seriously, wait for the study results before acting on these hypotheses, no matter how air tight they sound right now!

[Bobby72]

Jules ~

I never thought about the age factor as much as the inflammatory stage vs neurodegenerative (progressive) stage.

The belief has been that the DMT's are effective against inflammation, but not so much for neurodegeneration.

I suppose inflammation decreases with age?

Take Care

Omg hmm u know Are so right. The last couple of years I've been in a steady decline. I hate that these flair ups keep hitting me like know tomorrow. Don't get me wrong I have some good days but it seems that I have more bad day than good lately. I'm hoping that it's just the weather that is making things worse.

[KoKo]

It seems perhaps the ability to keep up the inflammatory cascade wears down as we age? Which would make sense simply based on the old predictions of how many of us starting with RRMS end up SPMS.

Jules, this seems to be the case.

"DMT’s benefits appear to diminish as inflammation naturally wanes. In the normal, healthy population, the immune system starts becoming less functional around age 60. Observation of MS patients indicates that relapses also tend to diminish after that age, and that subsequent disease progression may not be immune-mediated, as it tends not to be associated with MRI-detectable inflammatory activity.

While this current study suggests that therapy directed at the immune system may no longer benefit older patients, prior studies involving patients of all ages indicate that outcomes of DMT discontinuation based on disease stability alone tend to be less successful."

https://consultqd.clevelandclinic.or...-appears-safe/

Take Care

[GardeningMSer]

re Interesting article on DMDs and Age

I hope other aging MSers don't stop DMDs because of this article. I believe the researchers did their work well, but as anyone who has been following research in other areas (healthy diets comes to mind) one quickly learns that a single article has a 99% chance of being superseded within 18 months.

As an MS sufferer since I turned 50 having been on DMDs for 20 years I am extremely reluctant to stop Ocrevus which I've been on for almost two full years. I'd been on Tysabri for the previous 8 years and my observant wife is 100% certain that Ocrevus works better for me.

I am a 70 year old male, left leg is weak because of MS. I use forearm canes for short distances, a scooter for longer trips.

Thank to Temagami for this link. I haven't gotten to the original article yet but this synopsis was interesting and seems to indicate the results from a meta analysis downplayed the efficacy of medications, even the newer meds, in older people with MS, on average.

My MS specialist actually said something about considering no meds at my last appointment due to being "stable" for so long and I thought he lost his mind, especially for the next 8 or so years while I'd like to continue working if I'm able.

Have you heard this before? Any insights/opinions?

"Specifically, the model predicted that on average DMTs cease to be effective beyond the age of approximately 53 years. When the low- and high-efficacy DMTs were modelled separately, the high-efficacy drugs were more effective than low-efficacy drugs only when used in people of 40.5 years or younger; after this point there was no benefit in the average person with MS using high-efficacy drugs. The authors highlighted that the continuous loss of efficacy with age reported in this study supports the notion that “progressive MS is simply a later stage of the MS disease process”."

From:
https://www.msbrainhealth.org/treatm...-linked-to-age

[Myoak]

I hope other aging MSers don't stop DMDs because of this article. I believe the researchers did their work well, but as anyone who has been following research in other areas (healthy diets comes to mind) one quickly learns that a single article has a 99% chance of being superseded within 18 months.

As an MS sufferer since I turned 50 having been on DMDs for 20 years I am extremely reluctant to stop Ocrevus which I've been on for almost two full years. I'd been on Tysabri for the previous 8 years and my observant wife is 100% certain that Ocrevus works better for me.

I am a 70 year old male, left leg is weak because of MS. I use forearm canes for short distances, a scooter for longer trips.

Thank you! Your post is worth repeating!

[MisterMan]

I have a family friend who was diagnosed with RRMS in his late 60’s based on vision issues. If he was not on a DMD, I would think he would progress much faster.

So I’m not sure a specific age can be defined.

I would want to see multiple studies before I would make any decision on this.

[MSLazarus]

Good points.... I agree

Jules,
I've seen this article before and I believe it has a number of serious shortcomings.

First off, I didn't see anywhere in the study where they accounted for increasing disability due strictly to ageing and it seems to be a huge stretch to blame all of the increase of disability on efficacy of the DMT alone. Secondly, if you read the entire study, they admit to having made an awful lot of assumptions many of which are questionable. Thirdly, the linear regression model they use does not seem to fit their data very well. And fourthly, to say that "on average DMT's cease to be effective beyond the age of 53 years" is a grossly misleading generalization.

While the efficacy of a given DMT may well vary with age, the effectiveness of certain drugs still stands out on the scattergram. Ocrelizumab, Rituximab, Siponimab, and Glatiramer Acetate are all above the mean linear regression line at advancing age.

I, personally, am well into SP, I use Rituxan and plan to stay on it as the effect on the onset of my secondary progression was quite noticeable. Currently, I try to base effectiveness more on brain volume than other measurements.

I hope you will respond after you have read the study itself, I value your opinion.

Bottom line, I wouldn't give up based on this particular study.

I am 71 and also on rituximab. What I can say is that as the time for my next rituximab infusion gets close, I experience a resurgence of symptoms. After the infusion things quiet down.

I am a farmer and so my movements are varied and I manage to adapt to the MS disabilities that are active on any given day. I am strong and active mentally and physically as there are constant pulls on a farmer to keep all the parts moving. I have not been without some treatment since betaseron first came on the market.

Since 1993:
Betaseron, avonex, copaxone, Novantrone, 140g of IVIg each month, rituximab....
And that list is missing the 4 years of monthly steroid infusions and something else I cannot remember at the moment. Add in the daily baclofen, oxybutinin, ampyra etc. the goal of it all is to keep my farm active and it has all worked. Thank heavens my neurologist did not mention my age but talked about my work as we pursued treatments. I have been SPMS for many years.

[KoKo]

I am 71 and also on rituximab. What I can say is that as the time for my next rituximab infusion gets close, I experience a resurgence of symptoms. After the infusion things quiet down.

I am a farmer and so my movements are varied and I manage to adapt to the MS disabilities that are active on any given day. I am strong and active mentally and physically as there are constant pulls on a farmer to keep all the parts moving. I have not been without some treatment since betaseron first came on the market.

Since 1993:
Betaseron, avonex, copaxone, Novantrone, 140g of IVIg each month, rituximab....
And that list is missing the 4 years of monthly steroid infusions and something else I cannot remember at the moment. Add in the daily baclofen, oxybutinin, ampyra etc. the goal of it all is to keep my farm active and it has all worked. Thank heavens my neurologist did not mention my age but talked about my work as we pursued treatments. I have been SPMS for many years.

Your story is wonderful, MSLazarus!

Thank you for sharing it with us.

Take Care

[Myoak]

... Add in the daily baclofen, oxybutinin, ampyra etc. the goal of it all is to keep my farm active and it has all worked. Thank heavens my neurologist did not mention my age but talked about my work as we pursued treatments. I have been SPMS for many years.

Congratulations on the success of your treatment regimen over the years! Way to go!

May I offer one observation? Even though you obviously have success with oxybutynin you may want to consider an alternative like Vesicare if your insurance covers it. In the Medications and Treatments forum under the sub-forum New Treatments, Trials, and Research there is a thread titled, "Ditropan Reduces IQ by 7 Points?" that you may want to check out. Overtime, there may be a better option than oxybutynin even though you have enjoyed great success thus far.

Best wishes for great health! Thank you for adding your voice!

[MSLazarus]

Oxybutinin and brain drain

Congratulations on the success of your treatment regimen over the years! Way to go!

May I offer one observation? Even though you obviously have success with oxybutynin you may want to consider an alternative like Vesicare if your insurance covers it. In the Medications and Treatments forum under the sub-forum New Treatments, Trials, and Research there is a thread titled, "Ditropan Reduces IQ by 7 Points?" that you may want to check out. Overtime, there may be a better option than oxybutynin even though you have enjoyed great success thus far.

Best wishes for great health! Thank you for adding your voice!

I know about the concerns about oxybutinin. For some reason the vesicares, ditropans and other more expensive drugs ( I have tried about 6) do not work. I have very disabling bladder issues. I tried Botox a few months ago. For me, the injections were excruciating. Perhaps a Valium before would help but I wanted to avoid paternalistic insistence that I arrange for someone to drive me!

Anyway, I could arrange for out patient hospital injections. However, it only lasted 2 months for me. And I need to learn how to self cath. Also excruciating so I Amy not ever be able.
In the meantime, oxybutinin which I have been using for 23 years, is what I will use. I asked and discovered that I was only using 25% of the allowed daily dose! So, I increased the dose and am free once again. For the time being, I am done fooling around until oxy does not work at the increased dosage.

[Myoak]

In the meantime, oxybutinin which I have been using for 23 years, is what I will use. I asked and discovered that I was only using 25% of the allowed daily dose! So, I increased the dose and am free once again. For the time being, I am done fooling around until oxy does not work at the increased dosage.

Sounds like a good plan!

[Myoak]

Have you heard this before? Any insights/opinions?

"Specifically, the model predicted that on average DMTs cease to be effective beyond the age of approximately 53 years. When the low- and high-efficacy DMTs were modelled separately, the high-efficacy drugs were more effective than low-efficacy drugs only when used in people of 40.5 years or younger; after this point there was no benefit in the average person with MS using high-efficacy drugs. The authors highlighted that the continuous loss of efficacy with age reported in this study supports the notion that “progressive MS is simply a later stage of the MS disease process”."

From:
https://www.msbrainhealth.org/treatm...-linked-to-age

My thoughts….

Of all 38 trials in this meta-analysis only one had a mean age of 50+. So, its pretty difficult to know what effect any DMT will have or not have in older PwMS in the absence of any trial data on people beyond age 55.

Plus, think about this…

We know that relapse and remit is typical of RRMS, obviously. We know that younger people, or lower EDSS have more neurological reserve than older people, or higher EDSS. What if the patients are EDSS 2 at baseline, when a trial begins and EDSS 2.5 at the end two years later on one med? And, what if they were 3.0 at the beginning and 4.0 at the end of two years on another med? Which is the better DMT?

We might think the first drug was superior because the EDSS change was only .5 compared to 1.0 in the second trial. But not so fast! We know that younger people with lower EDSS have more reserve; they have more reserve ability to recover function and lower their EDSS score independent of a DMT.

The only way to achieve an accurate comparison is to have identical EDSS at the beginning, at baseline. Otherwise, comparison of effectiveness is not legitimate. Make sense? The point being that this meta-analysis has serious weaknesses which should be recognized and understood because a surface reading would be misleading. I believe the research authors made some attempt to mention it’s limitations w/o explaining them.

Also, look at the EDSS scale in MS… there is no assessment of upper limb function, even though upper limb function is absolutely critical to a person with impaired lower limbs. Yet, we have no charts (there are none in existence I am aware of) comparing the various DMTs on the performance of upper limb function. There is only one trial I can mention… Tysabri demonstrated preservation of upper limb function in a trial of progressive MS, however that trial was considered a failure because upper limb function was not one of the trial’s end points. Amazing, isn’t it? How very, very short-sighted!

The 38 trial meta-analysis does not include upper limb function not does it include bulbar function which is speech and swallowing. People need these functions preserved. These critically important values are never the typical end points of trials.

Normally, trial endpoints in MS include 3 values… relapses, new lesions seen on MRI, and changes in disability as measured by EDSS, which, as we have seen is a flawed scale because it concentrates almost totally on the ability to walk. Nothing in it about swallowing until EDSS 9.5 when it is far too late to preserve any function nor anything in the EDSS scale about hand and arm function.

The conclusion of the meta-analysis was that efficacy depended on age. But the problem with that conclusion is that the meta-analysis left out critically important measures of efficacy, notably, upper limb function, speech, and swallowing.

We need data on those functions and we rarely, if ever see it. When someone says that DMTs have no effect on disability progression after a certain age it is a very weakly supported position for two reasons.

Number one, show me trial data involving people over 55. There is not one that I have seen, ever!

Number two, show me data involving speech, swallowing, and upper limb function.

The meta-analysis scores a zero on those two critical points. There is no way a rational person could justify altering treatment decisions based on conclusions of a meta-analysis not incorporating the critical values mentioned here. JMHO.

[MisterMan]

When someone says that DMTs have no effect on disability progression after a certain age it is a very weakly supported position for two reasons.

Number one, show me trial data involving people over 55. There is not one that I have seen, ever!

Number two, show me data involving speech, swallowing, and upper limb function.

The meta-analysis scores a zero on those two critical points. There is no way a rational person could justify altering treatment decisions based on conclusions of a meta-analysis not incorporating the critical values mentioned here. JMHO.

Great analysis, myoak! Thank you.