Invisible MS aging: Grey pride movement kick-off!


There are currently several ongoing clinical trials that examine whether disease-modifying treatments (DMTs) can be stopped in pwMS with stable disease or above 50 years old. They will evaluate whether clinical relapses and new MRI lesions are more frequent upon discontinuation vs. continuing therapy. Ironically, they coincide with the registration of siponimod as a DMT in secondary progressive pwMS. In the siponimod trial, the median age of pwMS was 49 years old with an upper age limit of 60. Admittedly, there were rather limited disability gains in the siponimod trials as confirmed disability progression was seen in on average 26% versus 32% of treated versus untreated individuals, respectively. Of note, the numbers are in sheer contrast with the MRI outcomes: 18% between-group differences in brain volume loss and 86% reduction in enhancing lesions. Although different study populations, siponimod’s efficacy in progressive MS is not that different from fingolimod in relapsing MS: 25.3% confirmed disability progression vs. 29% in treated vs. untreated individuals, respectively.

However, when moving from the trial bubble to the real MS world many clinicians are not convinced by the siponimod data, and are hesitating to initiate siponimod in secondary progressive MS. This attitude is driven by the fact that MS becomes progressively more invisible at older age: 

  • Older pwMS are less likely to have MS relapses. The relapse rate decreases by 17% every 5 years between years 5 to 30 after onset. 
  • PwMS over 50 years old are half as likely to have enhancing actively inflamed lesions compared to their peers of less than 30 years old. If new MRI lesions on interval scans do not enhance at older age, there is always this looming thought: Could this new lesion be of vascular origin? This means the lesions are not caused by demyelination but the consequence of clogged blood vessels. 
  • The rating scale for MS-related disability, EDSS, becomes less sensitive with time/advanced disability. The scale rates disability from 0 – no disability to 10 – death. In a large study of 2054 individuals with MS, it took 11.7 year to move between EDSS step 6 and 6.5. In clinics, this corresponds to the difference of being able to walk more or less than 50 m with a walking stick. Illustratively, the difference between a score of 2.5 and 2 is ‘only’ 4.9 year. 
  • The consequences of reduced cognition are less likely to be attributed to MS at older age, and their impact on professional performance and potentially accelerating retirement age are unknown. 
  • Although there is no direct evidence that immunosuppressive drugs at older age are more likely to be associated with malignancies than when initiated at younger age, the association of certain DMTs with malignancies subjectively becomes more of an issue when growing older. 

Overall, the impact of MS on the ageing brain and on performance around retirement age is difficult to quantify, and this is irrespective of disease duration. On the contrary, inflammatory activity is still present in a significant proportion of pwMS at older age, and it’s undeniably damaging precious brain tissue. Hence, clinicians have doubts about the risks versus benefits of treating and suppressing MS lesions with DMTs in older pwMS. Part of the solution is gathering large ‘natural history’ datasets on the evolution of the disease in older pwMS. This will allow us to understand better how MS impacts on life after 50 and whether we are targeting this with a DMT. Moreover, I wonder whether it would be advantageous to group older pwMS in separate clinics dedicated to give them a more personalised advice on risks versus benefits of starting or stopping treatment.

To all pwMS (over 50 years old): Any ideas on how we could measure the impact of the disease on your life? 

Twitter: @SmetsIde

Disclaimer: Please note that the opinions expressed here are those of dr. Ide Smets and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

 Curr Opin Neurol 2021 Aug 1;34(4):598-603. doi: 10.1097/WCO.0000000000000960.

Stopping disease-modifying therapy in relapsing and progressive multiple sclerosis

Hans-Peter Hartung 1 2 3, Sven G Meuth 1, Deborah M Miller 4, Giancarlo Comi 5Affiliations expand

  • PMID: 33990101
  • DOI: 10.1097/WCO.0000000000000960


Purpose of review: To assess the reasons for considering discontinuation of disease-modifying therapies (DMTs)in patients with multiple sclerosis (MS). Relevant aspects of the natural history, pathology, and immunology are analyzed.

Recent findings: A number of retrospective observational studies in aggregate indicate that stopping DMTs may be attempted in older individuals with stable disease. Prognostic factors have been identified informing about the risk of recurrence of disease activity after DMT discontinuation.

Summary: Several clinical scenarios provide a rationale to stop DMTs in people with MS. Cumulative evidence has been gathered recently allowing us to more precisely weigh the risks against the benefits. This information aids in the decision process.

About the author

Ide Smets


  • Why is 50 the magic number? Surely there is a more objective way to measure an individual’s age.

    Cardiovascular capacity, cognitive ability, lung lung function etc rather that picking a fixed point in time after birth?

    COI: I am 52 and in reasonable shape and object to just being broad brushed into a category in such a crude way.

    • Hi Dominic,

      These are the trials that are currently ongoing:

      – Disease Modifying Therapies in Multiple Sclerosis ( NCT03073603, last update February 25, 2021).Inclusion criteria include age of 55 or above, relapsing-remitting MS (RRMS), SPMS or PPMS.
      – STOP-I-SEP trial (Disease Modifying Therapies Withdrawal in Inactive Secondary Progressive Multiple Sclerosis Patients Older Than 50 Years; identifier NCT03653273)
      – DOT-MS trial (Discontinuing Disease-modifying Therapies in Stable Relapsing-Onset Multiple Sclerosis; identifier NCT04260711) Inclusion criteria > 18 yo.

      As you see, in 2/3 of the trials age is an explicit inclusion criterium and for the third trial it’s going to be implicit, because stopping treatment will only be suggested to pwMS at older age in practice.

      I agree, there needs to be a much more intelligent way of selection people to stop treatment than mere age. U

  • It is difficult to compare MS and non-MS state of overall health as the years progress because there are too many variables. I was definitely an outlier at the point of dx aged 53. Nobody in my acquaintance had anything significant wrong with them so the fact that I was walking badly stood out a mile. Now I’m 71, still walking badly but less conspicuous, now that my contemporaries are lining up for new knees and hips. A few have become diabetic, there have been cancer scares and somebody exactly my age has atrial fibrillation. I am far from the only one attending hospital clinics. How my MS would have been impacted if I’d been in poorer shape earlier on is unanswerable and I think I’d have tried even harder to improve fitness if I’d known then how much MS outcomes are inseparable from overall health.

    • This is indeed the information we need: how do you compare to your peers at 71 years old, and do we make a difference there with tx. But you illustrate how difficult it will be to measure, because there are so many confounders by 70.

  • I am not over 50 and I think that to answer your question we should look at how our society is built today. 50 years old people work and have a social life. The same is for 60 years old people. They are also an invaluable resource for young couples with children. So, we have to conclude that these people should be considered young in terms of disease perception, consequently the disease should be considered as impacting their lives as if they were 20 years old and treated accordingly.
    To summarize, if there is no contraindication people should be treated to save brain irrespective of age. Then we can discuss about which treatment: first line? EID ocrelizumab? BTKis? Imods?
    Also, how do you decide when it is safe for a specific person to de-escalate or to stop? We lack markers. Basing this decision on natural history seems a bit frightening because natural history is built on large numbers and in case of a degenerative disease the situation is not like vaccines where to save many it can be acceptable that a small risk exists. In the degenerative disease case you can “save” all, so in my view we need to be able to do a personalized choice using what we have: only additional health conditions of the specific patient.

    • I absolutely agree that 50 is the new 20, and that mere age cut-offs are never a good guidewire.

      The discussion is indeed much more broad than stopping treatment at older age. It’s about rationalising treatment duration in every individual with MS. This is also about 30 year olds that are treated now indefinitely with ocrelizumab.

      • You got my case now! 😀 In absence of markers I would like to be treated until my IgGs reach a dangerous zone. At the moment IgM stabilized below the LLN and IgG are unchanged so still some time to go on with ocrelizumab but basically if IgG stay high I don’t see a reason to cut ocrelizumab: if they are high in the blood it is likely that they are still in CNS as well. On the contrary, I think that the decrease of peripheral IgG level could be an indirect marker of CSF IgG levels and after a marked decrease in blood I would feel a bit safer for MS so it would be ok to stop or deescalate. When this will happen I think we will be few years into the BTK era and we will know what happens with those DMTs. And we will be also in the post SIZOMUS time…

        • The problem is we don’t have good IgG cut-offs, and there is a poor correlation between exact levels and infection risk.

  • I’m 60 next birthday. Dx aged 51 with only 2 lesions. I’ve had one more since then but been NEDA since starting Fingolimod 5 years ago. I would gladly give up fingolimod as I go into my 60s as I fear the effects of permanent immunosuppression more than ms at the moment. I’ve had shingles, numerous Actinic keratosis and now a reactivation of the HPV virus after my last smear test – don’t even get me started on the covid antibody response. I know it’s risky to stop Fingolimod but it’s something I plan to discuss at my next neuro appt.

    • Thanks for sharing, and I understand your position. This is why Barts-MS keeps emphasising the need to optimise vaccinations before starting with an immunosuppressive therapy. Especially with fingolimod, it’s worthwhile discussing with all starters and people who are currently treated to have the Shingrix vaccine against zoster. Admittedly, the vaccine has only been registered two years ago for this indication. The same is true for the HPV vaccine. Immune suppression indeed makes you more susceptible to HPV reactivation which can be potentially avoided by the vaccine – although no solid data to back this up.

    • I had exactly this discussion with the neuro after being on fingolimod for five years and coming up to my 70th birthday. I was especially worried about the vaccination situation, but also skin issues. I was offered a choice between staying on fingo, going back to copaxone or cladribine as an alternative. I chose cladribine and have just finished round one. Absolutely no regrets, just wish I could have had this years ago.

  • “To all pwMS (over 50 years old): Any ideas on how we could measure the impact of the disease on your life?”

    Hello Doctor- I assume you are including mainly social life rather than biology under a microscope. To measure the impact then, Open ended question just as you put it, evaluate responses and look for themes, perhaps reassess for sub-themes, assign numbers to the themes and sub-themes according to an objective criteria, perform quantitative analyses.

    This is right up my alley, so I’m thinking of anything to say that may be useful… First, it’s a very important topic that I am currently navigating. The data you lay out is hard to follow (for me). I’m not a rocket scientist any more but more of sophisticated lawn mower guy. I have to conclude that what you are saying, in part, is that there is not convincingly strong DMT evidence to continue DMTs forever, and perhaps, is there another way to evaluate if one should continue DMT. My current “navigation” on this issue includes 25 years on Betaseron (I’m now 64) followed by a one year stint on Ocrevus, after believing ankle/foot pain was newer MS (which apparently it wasn’t), combined with a pandemic where wisdom told me early on that immunosuppression might not be a great idea. I’m free of that concern now, and I feel relatively confident (MS vs. Covid and the risks each poses), which is important, I believe, “heading into the final stretch.”

    That brings up contributory point #1- I think there is a psycho-social element to the question; your answers are going to be influenced by one’s awareness of getting old and what that personally means. To many, 50 is still quite young and they are not prepared to reflect on being in “the final stretch”. I know, for instance, I am in the final stretch because 3 of my close acquaintances have already died and another has recovered from a stroke which puts him right up there with me, in terms of deficits. It was a wake-up for him in terms of “the final stretch” and he sees things in a whole new light, now that he knows he can’t get back and the past is gone. The meaning of MS, up to 10 years (let’s say) after diagnosis, is going to be much different than the meaning 30 years on. So maybe, a closely related topic is the differences in meanings and how that impacts personally, treatment goals and strategies?

    Contributory point #2 is that… I think by 50, for many of us who started around 30 (like me), the worst of it is over. Were you able to get your ducks in a row? The occupational and income stress part, closely related to the finding or keeping a partner part? If those are in line to your satisfaction (and others, too, I am sure), then MS deficits may not seem to matter as much and may not be reported as much, as such a big deal.

    So I would imagine, that most of the measures to be used are already there, to draw conclusions from. But a false assumption is that a particular deficit to one person is going to mean the same to another, which it won’t. You don’t want to be measuring the variability of what it means to get old. How objective do you want your measure to be? Are you happy? Can you walk 100 meters in x time? Has this changed since you were 50 and does it make any difference to you now? Going further,…
    What were you looking for and did you find it? Did you have to change or modify your goals? How so? Do you think you are as satisfied now, with MS, as you would have been if you didn’t have MS? These can actually be tough questions, which with the right mind-set (interview atmosphere), the answers can be quite rough also.

    • Biological outcomes would obviously be preferable as – as you illustrate – all other outcomes are highly influenced by your mindset and views on ageing. The problem is we don’t have a good biomarker for how active your MS is at younger age either. Nonetheless, it would be interesting to have an MS-focused questionnaire available on the social impact of MS.

  • Is there some subtle underpinning prejudice going on here concerning the value in treating the Olds v Young Ones? Also are the studies, whatever the conclusions, potentially going to reinforce neuros hesitancy to provide DMTs?
    I’m totally convinced by the reversing the pyramid model of treatment, most particularly when I think about those in their 20s and 30s who have their whole lives ahead of them.
    I also completely endorse Fabio comments concerning the roles and contributions made by the over 50s. Added to which, as an ageing society, we need to invest as much as possible in the health and quality of life for the older generations. This is reinforced by the shocking statistic on today’s media about the projected shortage of care staff by 2030.
    I was diagnosed age 51 and treated with Alemtuzumab a month before my 52 birthday, when still treatment naive. (Still possible 6yrs ago)
    By this point I was riddled with brain and spinal lesions. Since which I’ve had NEDA and my EDSS remains 2.5.
    I would also echo Kay’s points: now 58, unlike lots of my known contemporaries I’ve no comorbidities and am a sound weight.
    My observations have sometimes been that the healthy subconsciously expect to remain healthy and are therefore not risk adverse, nor do they bother with thinking longer term. Those I know, like myself, with underlying health conditions are more likely to be doing IF, exercising, learning a foreign language etc because we comprehend the need to facilitate hanging on to what’s left to us for as long as possible.
    None of these factors are taken into account within such studies and I’m very nearly offended by them – not just for those of us over 50 but also for all those twenty-somethings who will be 50 one day!

    • Yes there are. One of the studies that feeds the discussion is the meta-analysis of Weideman et al. ‘Meta-analysis of the age-Dependent efficacy of Multiple sclerosis Treatments’ published in 2017 which groups data on DMT efficacy of 38 clinical trials:
      “Conclusions: The meta-analysis supports the notion that progressive MS is simply a later stage of the MS disease process and that age is an essential modifier of a drug efficacy. Higher efficacy treatments exert their benefit over lower efficacy treatments only during early stages of MS, and, after age 53, the model suggests that there is no predicted benefit to receiving immunomodulatory DMTs for the average MS patient.”

      The problem is as I outlined that this futility conclusion is all based on EDSS-associated outcomes.

  • I was diagnosed suddenly and dramatically aged just over 50. Was put onto a low efficacy treatment and continued to feel awful and get more lesions. Was then put on a high efficacy treatment, stabilised, felt miles better and generally got back to doing the things I used to … so really cannot agree that there is a case for not treating someone of any age with as strong a treatment as possible. As to taking them off treatment or not giving them a treatment … my MS was rapid evolving and making me very ill … why would I want to come off treatment? So I just don’t see the case for a cut-off point for treatment based on age, the number.

  • I’m very late to this post but as a pwMS aged 73, I think fewer research studies should have cut-off ages below 60. Like other respondents, I have lost several friends and now I see more and more contemporaries with morbidities and skeletal problems. We need much more data on how older people perform, both when taking meds and in day to day activities, so more not fewer research opportunities are needed that we can engage in.
    We need to bear in mind that while we, some of us, are bouncing around like spring chickens; well I am anyway, we are among the groups being triple vaccinated for a good reason. 50 may be the new 20, but our telomeres are shorter, our skin is thinner and we all have BVL.

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