Thursday, 1 February 2018

Does your age predict how well you respond to DMTs?

Did you know that if you have MS and are older than 53 years of age you are unlikely to respond to DMTs?




Statistical Speak: A regression analysis, described in the meta-analysis below, predicts zero efficacy of DMTs beyond approximately age 53 years. 

Plain English: Age is an important confounder when it comes to disability progression. Based on published data pwMS who are older than 53 years of age don't respond to DMTs when it comes to slowing down worsening disability. Are you surprised? 

Did you know that age is the most powerful predictor of developing 'progressive MS'? We need to tackle ageing and its impact on worsening MS. The evidence that early, or premature, ageing from the reduced brain, and cognitive, reserve drives worsening of MS in older pwMS. We urgently need methods to dissect-out premature ageing from MS-specific disease mechanisms. The other issue with ageing is the emergence of comorbidities as a driver of worsening MS; in particular, smoking, hypertension, hypercholesterolaemia, metabolic syndrome, diabetes and a sedentary lifestyle. The latter is the proverbial 'elephant in the room'. 

The meta-analysis also differentiates the high-efficacy DMTs from the low-efficacy DMTs. Surprise, surprise the high-efficacy drugs outperform low-efficacy drugs in slowing down MS disability worsening, but this was only noted for pwMS who were younger than 40.5 years.

Do you think regulators and payers should take age into account when licensing and paying for access to DMTs? 

P.S. This meta-analysis only tells half the story and does not take into account new insights, in particular, therapeutic lag. What the analysis is looking at is short-term observations across 2-3 years of phase 3 trials. With more advanced MS (and age) brain and spinal cord reserve are reduced and it, therefore, takes longer to see a treatment effect. So older people may see an effect, it will just take longer for it to manifest. I have plenty of examples (anecdotes in MedicSpeak) of more mature or older pwMS responding to DMTs. This analysis, however, does support the treat early and effectively philosophy; protecting Brain is easier when you have reserve and age on your side. 

Weideman et al. Meta-analysis of the Age-Dependent Efficacy of Multiple Sclerosis Treatments. Front Neurol. 2017 Nov 10;8:577. doi: 10.3389/fneur.2017.00577

OBJECTIVE: To perform a meta-analysis of randomized, blinded, multiple sclerosis (MS) clinical trials, to test the hypothesis that efficacy of immunomodulatory disease-modifying therapies (DMTs) on MS disability progression is strongly dependent on age.

METHODS: We performed a literature search with pre-defined criteria and extracted relevant features from 38 clinical trials that assessed efficacy of DMTs on disability progression. We fit a linear regression, weighted for trial sample size, and duration, to examine the hypothesis that age has a defining effect on the therapeutic efficacy of immunomodulatory DMTs.

RESULTS: More than 28,000 MS subjects participating in trials of 13 categories of immunomodulatory drugs are included in the meta-analysis. The efficacy of immunomodulatory DMTs on MS disability strongly decreased with advancing age (R2 = 0.6757, p = 6.39e-09). Inclusion of baseline EDSS did not significantly improve the model. The regression predicts zero efficacy beyond approximately age 53 years. The comparative efficacy rank derived from the regression residuals differentiates high- and low-efficacy drugs. High-efficacy drugs outperform low-efficacy drugs in inhibiting MS disability only for patients younger than 40.5 years.

CONCLUSION: 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.

ProfG    

64 comments:

  1. Prof G, I believe you will hit the magic 54 in April. If you were diagnosed wth RRMS in May, what drug would you opt for? Do you have many patients post 53 years old who are on Tysabri or other highly effective drugs? Are you seeing any patterns in such patients e.g. moving to the SPMS stage?

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  2. So what will happen to someone in their mid-30s who are good responders to Tysabri (i.e. no replaces). Will the party stop when they turn 40.5 ?

    Does that mean that I should shift to a low efficacy drug at 40.5 (what's the point of the higher risk?) and quit DMTs altogether when I am 53?

    This is the worst study I have seen in a while - proper depressing.

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    1. here we go:

      "The results of ASCEND trial (Table ​(Table1;1; Figure ​Figure3),3), in which more SPMS patients treated with natalizumab achieved sustained disability progression in comparison with placebo (although the difference did not reach statistical significance), should not be ignored. Rather, in view of this meta-analysis, it should serve as a reminder that aggressive immunomodulatory DMTs may be harmful in older MS patients, irrespective of cumulative side-effects"

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    2. Im also in my late 30's and been on tysabri for 3 years. I begain to wonder how things will be in 10 more years

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  3. "Inclusion of baseline EDSS did not significantly improve the model. "

    Oh god! What's the point of fighting it.

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    1. Never give up hope. Haven't Barts seen promising results from using Cladribine off-label on a compassionate basis for patients with advanced MS??

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  4. I had my first infusion of Alemtuzumab 10 years ago and the second 9 years ago. I've just turned 50. My MRIs show no disease activity and my EDSS is 2.5 (completely stable since first infusion). I've had no relapses (large number before first infusion). I feel very healthy / fit. Are you saying that in the next 3-4 years it's all going to go tits up e.g. hello SPMS, hello worsening disability? If my disease reactivated will DMTs offer no help? My neuro (top MS researcher) said I'd be offered another round of Alemtuzumab. PS please post some happy research as it's all been a bit depressing recently.

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  5. As I did not have any definite symptoms, other than fatigue, until I was 58 I couldn't have been diagnosed any earlier. As I have PPMS I had already assumed my age will rule me out for potential treatment. What about all the people I know with RRMS who are in their 40's and 50's who are currently on DMTs? This is definitely depressing news for them.

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  6. So not really a wise move to start Alemtuzumab (with all its potentially serious side effects) in your late forties/early fifties? Especially after waiting several years before getting the actual diagnosis of MS?

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    1. If you're considering it please don't rule it out without lots of thought and looking at all aspects of treatment with Alemtuzumab.

      I had my first round in November 2016 since which my walking has improved and whilst most are still there, some symptoms have eased or even disappeared.

      I had a the second round of infusions 11 weeks ago and the improvement in my energy levels since is really quite marked! I was 54 in December.

      It is true that the MRI on my actual birthday in December :) shows two new lesions, but there's a 50/50 on Alemtuzumab working anyhow + there's the argument it's not worth scanning until 6 months post the complete induction + as MD said: those two lesions may possibly have been four or ten without treatment.

      Please make the decision that feels appropriate and logical for you!

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    2. Agreed this study analysis seems like hubris to me anyway

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  7. The study would perhaps be trying to show that if you have diagnosed MS still young it's best to try to do what possible to contain the disease at this stage because after the accumulation of lesions so far the lever of degeneration, neuronal death will already be at full steam, and you still have no way to pull the lever back?

    That is, we also urgently need neuroprotectors.

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  8. I would like to see much more detail about the study - number, age profile, treatment duration, responder status, year of diagnosis etc of patients taking each of the 13 drugs as it feels like huge conclusions are being drawn from this literature-based research that could influence prescribing funding and decisions.

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    1. Click on the link, it's open access and free to view.

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  9. This is terrible news. I fit that bill. Age 52.5. On Tysabri for 13 years and stable. Why would I come off the drug to "see". My Neuro always told me hit hard and maintain all of the reserves you can.

    Please Prof G we need your words of wisdom.

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    1. Please see Prof G's comment below, he has doubts as to the veracity of the study.

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  10. To give everyone some good news: Craig Milverton (aged 50), the talented jazz pianist, has indicated recently in the media (Channel 5 news report found on You tube) that he's seen real benefits after being treated with Ocrelizumab through the drug trial and I believe he was diagnosed with PPMS and started the drug in 2012 which was 2 years following his diagnosis.

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  11. What's with the elephant in the room? Shouldn't it be a gorilla?

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  12. Hope I'm not inadvertently sending this twice!
    This is a hard hitting post for someone who had her second round of Alemtuzumab in November '17 just a month before my 54th birthday.

    Very importantly the significance in respect to Bart's push to treat to preserve hand function and to include people in wheelchairs in trials.

    How significant is it Prof G - does this research have sufficient weight to influence the future of DMT development and the prescribing of existing DMTs by neurologists???

    In reply to your specific question: surely it will be far too draconian to use age as the overriding determinant of receiving or refusal of a DMT. As with so many other conditions the decision should be based on the person sitting in front of the clinician, and their individual suitability for any treatment

    This research has been thrown out like a huge bomb with the potential to be devastating for PwMS, who already live with a poor roll of the dice!

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  13. The elephant (sedentary lifestyle) is the one that I, at age 67, diagnosed 22 years ago and EDSS 8.5, struggle with most avidly.

    My, up coming Guest Post here, will tell some war-with-the-elephant stories.

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  14. This meta-analysis is wrong; it does not take into account therapeutic lag. What it is looking at is short-term observations across 2-3 years of phase 3 trials. With more advanced MS (and age) reserve is reduced and it takes longer to see a treatment effect. So older people will see an affect it just takes longer for it to manifest.

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    1. Wouldnt you still expect the effect to be different based on the effectiveness of the DMT? Also didnt they account for different EDSS scores at the older ages? Would that be a proxy to how much reserve was available?

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    2. I think the effect ageing is not only about EDSS and anatomical reserve. Ageing or senescence is a biological process and involves genetic programmes. Once the latter are activated things like recovery of function become less likely. We seem to forget that a lot of treatment effects are driven about recovery of function.

      We know from advanced MS trials, e.g. ocrelizumab in PPMS and siponimod in SPMS, that age is a major confounder. In reality people over the age of 50 in these trials responded poorly to the DMTs in the time-frame of the trial.

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    3. Not necessarily. I imagine that the lag would only be manifest on the upper end of the data tape (i.e. older patients) and should be captured by the 95% confidence level of the Gaussian distribution.

      It would be a statistical error not to report it if it was significant.

      Guys this is the most important paper you have posted here for a while. Posting it (originally) as an open question to regulators is besides the point. Rebutting it on a weak argument is even more pathetic. I would take a twitter holiday if I were you until you formulate a proper opinion. This one matters.

      Open questions: The lead author does not have a COI with regards to Ocrel (she developed Dacalizumab). So why is Ocrel better than the rest in their figures?

      2) The Canadian population-wide MS study on SPMS conversion age and longevity was posted on this blog 4 or 5 years ago. The 14 year conversion time to SPMS still resonates in my head. If the median confirmed MS diagnosis is at 29 years - thos figures tie up beautifully: 29+14=53. But the Canadian study was pre high efficacy DMTs. So this ties up with the authors conclusions that high efficacy is not slowing disease progression.

      3) Why is our favourite black beast missing from this very important debate? If all DMTs are useless on the medium term, how would HSCT fair up using the same methodology.

      Many (many, many) more questions to come - but let's start with those for now.

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    4. Sorry yes - was typing the above at 3 in the morning

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  15. I'd be careful putting too much weight on this in terms of individual management. We know that ageing is a fatal condition; few of us will be around past 120, the physiological lifetime.

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    1. I'd be careful about dissing the findings of this study before reading your point-by-point rebuttal first.

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    2. "I'd be careful putting too much weight on this in terms of individual management"

      I can't see where is equates to "dissing the findings".

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  16. Thanks Prof G for the addition of the PS, that made for a much better nights sleep, following the heartfelt discussion with my husband after he got in from work.

    The whole thing reinforces I believe, that it's time for those posts, you've previously mentioned, on diet and exercise.

    Lets hope this research doesn't cause collateral damage, especially with those who haven't accepted or who don't have knowledge of therapeutic lag

    I look forward to your guest post David and when you can confirm your study is fully underway Dr S.

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  17. Surely, Cladribine which penetrates into the brain & actually destroys immune cells rather than just imprisoning them in the lymph tissue/ periphery is likely to be better for progressive & older patients.

    I wouldn't have thought the likes of Tysabri & Fingolimod would have much success. No point confining a few of the boys to barracks (the periphery) if most of the army have already started a cascade of havoc in the brain/spine.

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  18. The irony is that Gavin's article is quoted in the meta-analysis.

    Can someone take a minute to explain the results in Figure 2 and Figure 4?

    Why does Ocrelizumab seem to outperform Alemtuzumab and Natalizumab?

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  19. Can we see similar results to other autoimmunes at the same age? Is there any interference of the immune system (and even relation to EBV) too?

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  20. I'm 30 a good respondent to Tysabri and young, but after reading that post I felt that my future is doomed and that there is a time bomb ticking for me.

    Since other readers have expressed similar feelings, could you do another post explaining this paper? Does it mean that all the young pwMS will stop responding to high-efficacy drugs when they get 40 and then will stop responding to all DMTs once they turn 53 (or so)? Don't newer drugs have an effect that will delay (or even completely prevent) that? What about the 'potential cure' theory you talk about? Are nerves going to degenerate in our mid-50's no matter what our previous medical history has been?

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    1. "Does it mean that all the young pwMS will stop responding to high-efficacy drugs when they get 40 and then will stop responding to all DMTs once they turn 53 (or so)"

      That's what that paper, with a solid methodology, free of COI and a lead writer with strong street credentials says.

      I am very much in your position and have not slept for a minute last night. I felt the urge to read George Jelinek this morning (a "clown" I quickly dismissed when I jumped on the Tysabri band wagon many years ago)

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    2. No, it doesn't mean you stop responding, it says the later you leave taking a high efficacy DMT, the less of an effect you will get as you will already on average have accumulated some deficit. If you have been taking a DMT for a number of years before you hit 5o, they won't suddenly stop working when you reach a certain age. It's saying treatment should be the sooner the better.
      From the paper (free to view);


      "Delaying any DMT, even for a few years, leads to a decrease in cumulative efficacy that cannot be easily regained by opting for more aggressive treatments at a later ageThis meta-analysis does not suggest that all patients older than 53 should remain untreated. The model is based on mean outcomes within trial cohorts. Behind every mean lies a distribution (e.g., Gaussian), and where on that distribution a specific patient falls cannot be determined from group data as it likely depends on patient-specific genetic and environmental factors. Indeed, if a patient older than 53 has MS relapses and abundant contrast-enhancing lesions on CNS imaging, s/he is likely to receive higher than average benefit from immunomodulatory DMT."

      So, though the take home message looks worrying the reality (as ever) is rather more nuanced.

      Hope this helps ;-)

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    3. I must add the following positive spin.

      MD2's post just above is utter rubbish - straight to the bin

      BUT

      what a high efficacy DMT is buying you is time - what time buys you is exposure to the pharma development pipeline.
      In other words, you have to hope that something better will be developed, test, approved and licensed over the next 23 years (assuming you are 30).

      That's why you should stay on the high efficacy stuff. Time is on the side of the younger good-responding patience.

      Best of luck everyone.

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    4. And as the Dude so rightly said, "That's like, just your opinion, man" (as is mine);-)

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    5. Does The Dude have MS?

      The above is unfortunately not correct and needs a slight correction - you don't have 23 years, just 13.5 years (30 to 40.5)

      I have much less

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    6. The Dude also said," Given the paucity of long-term follow-up data in this cohort treated with the new generation of effective DMTs, it is possible that a definitive judgement may be premature at this time".

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    7. "Given the paucity...."

      Where is this from? I repeat myself yet again: are we reading the same article?

      All of your comments are off the chart.

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  21. And it says: "Inclusion of baseline EDSS did not significantly improve the model. "

    So no one cares if you are EDSS 0.5 or EDSS 5 when you turn 53 - you will still convert to SPMS.

    Are we reading the same paper here?
    This paper is OBVIOUSLY saying:
    1) High Efficacy DMTs buy you risk and reward until the age of 40.5
    2) There is advantage of buying oh a high efficacy DMTs between the age of 40.5 and 53 - as you will be buying CRABS reward for a really high risk
    3) There is no point being on a DMT after the age of 53 - it does not matter how much brain reserve, functionality, etc... you have - you will still convert to SPMS
    3*) (three star that is). High efficacy DMTs may work against you after the age of 53, per the observations collected from the ASCEND trial + ocrel only test up until age 55.

    There is no nuance whatsoever - clear at the sun.

    It feels like Team G is in the first of the 5 stages of grief! you guys can do better - where is the proper analysis of this work?

    I shall keep ranting until you publish one.

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    1. I'll repost what Prof G wrote upthread.

      This meta-analysis is wrong; it does not take into account therapeutic lag. What it is looking at is short-term observations across 2-3 years of phase 3 trials. With more advanced MS (and age) reserve is reduced and it takes longer to see a treatment effect. So older people will see an affect it just takes longer for it to manifest.

      Prof G may care to do a more detailed analysis on this as this paper has obviously generated a fair amount of heat (though perhaps not light), irrespective of your ranting ;-)

      Delete
    2. That reply does not stand - You should know better that you can't bin the serious work of a first class team just by claiming its wrong. We need more.

      Delete
  22. ERRATA: 2) There is NO advantage of being oh a high efficacy DMTs between the age of 40.5 and 53 -

    I am dyslexic

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  23. Replies
    1. And I hope you get it MD2 !!

      Don't really want the debate left at this point on whether this research is fundamentally flawed or has nailed the truth of DMT age-related efficacy.

      There's been occasions previously where I've been left feeling ignorant and naive and/or in limbo-land and I don't want this to be one of those times.

      Please provide more on this as it does seem to me,as a PwMS of limited knowledge and comprehension of medical science, statistics, research analysis methods etc, as vitally important so as to be able to accurately plan for and manage our lives!

      Delete
  24. MD, not trying to be rude, but what does this say about any B-cell treatment in MS?

    B-cells are present when you are 40.5 yrs of age or 53 yrs of age in similar numbers to when we are in our twenties. If you have eliminated them with some potent B-cell therapy and the disease continues to worsen, what does this say about B-cell therapies? Does this make you believe that something other than B-cells are driving the disease to progress?

    I have no doubt that they reduce some neuroinflammation early on but obviously are not driving the worsening or progression of the disease as the patient ages. Shouldn't focus now be on neurodegeneration, remyelination and neurorestoration if this publication is true?

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  25. This is meta-analysis of phase 3 trials and does not include long-term follow-up. I have emailed the MS-Base team to get them to look into this question from their real-life data set. The MS-Base data will capture therapeutic lag.

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    1. I have had a response from MS-Base already. They are working on it, but this is a big data project and it will take them some time to complete.

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    2. The advantage of MS base is they have individual level data and look at trajectories of individual patients. They will almost certainly be able refute or confirm this meta-analysis.

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  26. You also need to realise that age is relative. Chronological age is a rough estimate for biological age. What we need is better markers for biological ageing. It seems that healthy ageing is linked to a young biological age. I have little doubt that the same hold for people with MS. The question is how do you keep yourself biologically young? It is all about brain health.

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  27. Thank you for reaching out to those with information that you think we might find useful. I think for many of your readers who are not involved in the science but are pwMS this article's post did not come with enough everyday explanation thus all of the back and forth.

    FYI the link to the article is only the abstract, conclusions and graphs. It is not free for the entire article.

    As a patient who is 52.5 years old I would like to know that the past 12 years on Tysabri have not been a waste.

    Debbie

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    1. This meta-analysis only looks at average group data and not data from individual study subjects. So hidden in the data will be people who do well and those who won't. The data is also driven by EDSS or lower limb function and as we have shown before the arms have more reserve and a greater response rate. So based on these new findings I think we need to take this data for what it is.

      Despite this age and response or non-response is old news. We have known about this for decades. The problem is nobody knows how to dissect out MS-related problems for ageing. Maybe this paper will act as a catalysis to get the ageing community involved with MS.

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  28. Am I surprised? As surprised as any woman of 55 might be, when she has been on Tysabri for 7 years with (touch wood) no relapses and no sign of progression. So it sounds like tosh to me, quite honestly, but then I'm not an expert.

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  29. So that begs the next question. For 12 years the Neuro has been following my status by looking at my MRI. I would say I am NEDA at present. If aging has other signs specific for MS what are they and why are the Neuros not looking at those? While I realize we are in a new era for DMT and patient aging for pwMS for the first time I have started to worry about what my future looks like.

    I am left not even knowing what questions to ask. The post this morning talked about changing from one DMT to another. I do not even know how to insert myself into that scenario.

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  30. "There are now over a dozen disease modifying therapies (DMTs) approved for MS since 1993, and these have significant impacts on development of new relapses and MRI changes, but much less effect on slow progression. Almost all clinical trials identifying benefit of MS DMTs have had a maximum age of 55, and subgroup analyses by age of many different MS clinical trials reveal that response to presently available DMTs is greatest in younger patients, especially those under age 40."

    "The relative futility of presently available DMTs in aging MS patients, especially those with progressing symptoms, argues strongly for development of approaches that diminish neurodegeneration and enhance CNS recovery and/or regeneration."

    Disease modifying therapy in the aging multiple sclerosis patient

    https://onlinelibrary.ectrims-congress.eu/ectrims/2017/ACTRIMS-ECTRIMS2017/202618/john.corboy.disease.modifying.therapy.in.the.aging.multiple.sclerosis.patient.html?f=media=3

    Obrigado

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    1. Trials are loaded with young responders, maybe older responders need a different trial design, e.g like getting rid of the EDSS for hand function, biology surely cant stop. We know that your immune response worsens with age.

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    2. I agree with MD. This meta-analysis is really based on EDSS (walking). I am sure if we could do it using 9-HPT then the story would be very different.

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    3. Indeed, the authors themselves state that one of the limitations of their meta-analysis is that there is a lack of data for patients younger than 30 or older than 55 years due to the inclusion and exclusion criteria of clinical trials. If you read through the data sheet appended to the publication, you can see that there is only study in their data-set where the mean age of patients is above 50 (specifically 50.4). In order to fully assess the significance of their findings, it would be useful to know how many patients above 50 were included among the 28,000 patients included in the analysis as a whole. In addition, the older patients enrolled in many recent studies would be patients that were either treatment-naive or more likely, patients that had failed to stabilize their conditions on previous therapies. Isn't it likely therefore that older patients in these trials have more aggressive or less easily controllable forms of MS than what you might find in a real world population cohort? The bottom-line is that the only way to know for sure whether DMTs work in older MSers is to run a randomly controlled clinical trial that includes a large enough population of older MSers and uses EDSS as well as other outcome measures.

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  31. I've spend the weekend discussing the paper with a statistician from the CNRS in France. In short: the methodology is solid.

    The sample is questionable, as it has been in the comments above. But the laws of averages were properly respected.

    I suggest that Team G invites an experienced guest statistician to comment on meta-analysis studies of this magnitude as well. We may well find the leads and lags were captured by the regression as well.

    Furthermore, Prof George Jelinek wrote to me yesterday providing his thoughts on this paper (found here: https://overcomingms.org/disease-modifying-drugs-not-effective-average-person-ms-aged-53-major-study-findings/)
    I am not the biggest fan of his philosophy, but he is always worth listening to.

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  32. Where do we stand with this highly important post? Will there be a follow-up or shall we just bury it under the blog's mantra of "treat early and good luck to you2?

    ReplyDelete

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