Wednesday, 19 April 2017

#ResearchSpeak: survival in people with MS is improving

Good news people with MS are living longer and catching-up with their peers. #ResearchSpeak #MSBlog

We have posted several times in the past on MS and mortality. 

The latest data to published from Norway, with 60 years of follow-up, confirms what we already know that MS reduces life expectancy. Importantly the so called standardised mortality ratio (SMR) of pwMS is higher than the general population and puts MS high-up the SMR league tables. In short MS is a bad disease, but has it changed its spots?

The SMR, is a quantity, expressed as a ratio quantifying the increase, or decrease, in mortality of a study cohort with respect to the general population. The SMR is simply the ratio of observed deaths in the study group to expected deaths in the general population. Hence a SMR of 2.7 amongst MSers means that 2.7 people died to every one person in the general population. A SMR of 2.7 is high. Of interest the SMR is higher for women with MS (2.9) than men with MS (2.5); this is because in the general population men are more likely to die young than women, hence a larger number of male deaths is the denominator. Life expectancy for pwRRMS was longer (77.8 years) than for pwPPMS (71.4 years). 

Mortality decreased over the course of the study, as pwMS with onset from 1997 to 2012 showed lower rates than those who fell sick from 1953 to 1974. In comparison, pwMS younger than 20 years of age at disease onset or diagnosis showed greater mortality than those above 60 years.
Interestingly, despite the high SMR the life expectancy of someone with MS is only shown to be ~7 years lower than the general population; this is a lower figure than previous studies. What this means is that pwMS in Norway tend to live a relatively long life. With an average age of MS onset of 30 years it means that the average MS must expect to live the majority of their lives with disabilities. 

As usual this is not necessarily a pleasant narrative, or is it? Overall survival from MS disease onset was more than twice as long as reported in the first study from 1969. The increase in survival over time is almost certainly the result of better MS treatments, improved diagnosis, socioeconomic factors, better treatment of co-morbidities and other lifestyle changes. 

Do you think this is a good news story?

Bøe Lunde et al. Survival and cause of death in multiple sclerosis: a 60-year longitudinal population study. JNNP April 2017.

Objective: Survival and causes of death (COD) in multiple sclerosis (MS) provide ultimate endpoints. We aimed to investigate survival and COD in a 60-year population-based MS cohort compared with the general population.

Methods: All patients with incident multiple sclerosis (MS) (N=1388) with onset during 1953–2012 in Hordaland County, Western Norway, were included. Data were obtained from patient records at Haukeland University Hospital and linked to the Norwegian COD registry. Survival adjusted for sex, age and disease course were estimated by Kaplan-Meier analyses from birth and from disease onset. Mortality and COD in MS relative to the general population were examined by standardised mortality ratio (SMR).

Results: Of 1388 patients, 291 had deceased, mainly of MS (56.4%). Median life expectancy was 74.7 years for MS and 81.8 years for the general population (p<0.001); 77.2 years for women with MS and 72.2 years for men with MS (p<0.001). Life expectancy for patients with relapsing remitting MS (RRMS) was 77.8 years and 71.4 years for primary progressive MS (PPMS) (p<0.001). Overall SMR was 2.7 (p>0.0001); 2.9 in women and 2.5 in men (p=0.0009). SMR was 2.4 in RRMS and 3.9 in PPMS (p<0.0001). SMR from disease onset during 1953–1974 was 3.1; 2.6 during 1975–1996 and 0.7 during 1997–2012 (p<0.0083). No difference in cause-specific deaths were found (p=0.0871).

Conclusion: We found a 7-year shorter life expectancy and almost threefold higher mortality in MS compared with the general population. A rise in survival in MS was observed during the entire observation period.


  1. 1) "With an average age of MS onset of 30 years it means that the average MS must expect to live the majority of their lives with disabilities."

    2) "Do you think this is a good news story?"

    The obvious answer is a yes if and only if QoL above stays an age-adjusted acceptable threshold.

    We have all learned that life is not about quantity but quality....

    Tony F

    1. couldn't agree more. But I can't forget a prominent neurologist taking me to task about my 'rebranding MS a preventable dementia' campaign. He said that a lot of his patients with late stage MS-dementia were happily ensconced in nursing homes with a very good quality of life and that if he had treated them all aggressively and early as I was suggesting then some of his patients would not be alive to live out their lives in this way. In other words he was saying treating MS with DMTs that have potential life threatening complications is wrong. In addition, he was adamant that we didn't have the long-term data at the time (~2013) to show that early-effective treatment made a difference in the long-term to MS outcomes.

    2. I remember attending a presentation by a Canadian MS analyst (using Canadian data) 3 or 4 years ago at Barts, hosted by yourselves. She gave an evening session on MS epidemiology followed by drinks.

      I remember very clearly that her study showed a life expectancy shortfall of 7.4 ys as well. The question was whether the interferon-era data was still relevant today.

      Not much has changed or am I missing something?


    3. ProfG
      Can you change the mind of promient Neurologists?

      Do you think the debate at MS frontiers is futile.

      This house believes that, for MS, early treatment requires aggressive treatment Opening for: Dr Belinda Weller (University of Edinburgh)
      Opening against: Dr Wallace Brownlee (University College London)

    4. This is a James Lind Alliance Question that not sure has been answered by the MS Society (yet),

      HSCT trial not yet done. But perhaps this is something that pharam can answer. In MS CARE-I examined people getting interferon beta or alemtuzumab people were treated within 2 years or diagnosis (Is this early enough). I guess in Sweden people are getting rituximab rather than interferon/copaxone. What happenned in the ORACLE follow-up ,if rebaselined to 3 months, I'll explain this in thge future)

      So the fact that this debate is occurring is in my mind abit sad, and shows a lack of ambition and information. That someonone is be happy to debate against the motion says something. How much will support will they get. Maybe time to spot the laggard:-)

      In the UK one could prescribe alemtuzumab from onset, but for others they are second line unless MS is very active, but is this being done?
      If people were put on the MS register they would know the course of events in people where this had been done and could compare other treatments. Maybe Genzyme have such a register but they wont have the other data.

      The 7-10 year data of the Cambridge experience of Lemtrada (Tuohy et al.) has been publised. The 6 year extension data of the MS CARE studies have been published in abstract form, there has been ample time for this to surface by now. Is this pharma dumping data again?
      HSCT data is published. We know what aggressive therapy does.

      The MS CARE extension studies indicates that about 50% followed up of people did not third treatment (so yes failers must have been lost as there were 60% failers in the trials), fewer needed forth course and I think less than ten people had a fifth course (so active disease 5 years on).

    5. As I have said this weekend, neurologists are never wrong, based on their worldview they can justify anything. At the present the majority of MSologists favour the more conservative approach of start later (not early), start slowly and only escalate and take risks if you have to. The early-effective approach of treat-2-target of NEDA with zero tolerance is practised by very few MSologsists and Centres. MSologists, like most people, want to belong and not be outliers. So no I don't think I can change the minds of my colleagues, but I do think pwMS and their families and friends can. Activated patients are much more powerful than me. The question is how to activate patients?

    6. Surely this blog and all your educational activities are making a difference?

    7. Re: "Surely this blog and all your educational activities are making a difference?"

      Not sure we are. The blog is essentially a soapbox and those who read it are like-minded. We don't have a very wide reach. We have also been getting complaints that our posts are too technical and that most pwMS don't understand the jargon. We are going to have a refresher course in 'junking the jargon' to try and make the posts more easy to understand for pwMS. We are also going to move the #NeuroSpeak posts to another platform; this blog was never meant for neurologists.

    8. I guess not if the MS Soc are having this as a debate at their science meetng the message has fallen on deaf ears.

    9. Please don't water it down! There are 100+ MS layman blogs out there...

      We keep coming back to this one since it levels the field, gives us access to facts and figures, and pushes us to learn more.

      This blogs will loose its edge if it targets the mass market (i.e. lowest common denominator).

      Now how about my question regarding the Canadian study?


    10. Prof G, is there the Brain health: Time Matter in MS in a nutshell?
      I know there is the Executive summary but I was thinking a one page document of 5 or 6 bullet points that are one sentence long. It could be in the style of a formal poster, something eye catching. That takes about one minute to read.

      I would happily give a copy of the nutshell to all doctors and HCP's I see.

    11. 'We have also been getting complaints that our posts are too technical and that most pwMS don't understand the jargon.'

      Yes they can be tricky, but although it takes up more of your time, the summarising comments that are placed at the end of the technical bits are very helpful.

      Although some of the posts will be beyond what some can manage it would be a shame to lose the more challenging content for those that can get their head round it.

      You provide useful, tell it how it is, information and comments that are hard to find elsewhere.

    12. Gawd! I so agree with Anon - please don't water down this site! So what if I don't understand all of the science, but the conclusions and very often the comments in response assist in getting a handle on,or the gist of, what's being shared.
      Am well grumpy that you're preaching to the small number of converted with T2T NEDA. Also well annoyed at the patronising neurologist talking about PwMS happy in dementia care homes. The whole reason dementia is gaining such attention is that everyone is now more scared of it than cancer! Bet that particular individual, their family and friends don't equate QoL with dementia!!

    13. Hi Fi
      It's the fact that dementia has risen in profile with the politicians, with more funding being allocated that is behind Prof G's strategy ie if we can come up with a neuroprotective strategy for dementia it should work for MS too. It'll take a lot of public money to bring this to fruition though as pharma doesn't seem very enthusiastic.

    14. I totally understand that any such strategy maybe along way off MD, but having the right attitude at the outset would be a start! Hence my anger towards the position adopted by the individual quoted by ProfG. Then add in all the other potential benefits of treating early and hard and... yeah! I just don't get it.
      What I've learned is that people are positive in response to ProfG's strategy. When I first mention it they recoil in horror at the idea of MS being identified as a form of dementia. Until that is, I explain the rationale behind it and then they're comfortable with it, as they'd like to see PwMS receiving their fair share of available resources, and when I explain more fully they appreciate that cognitive functioning is so very relevant in MS.
      Hats off to the Barts Team for keeping up the good fight, especially when you have to engage with certain colleagues. Please keep it up, because it's appreciated immensely!

    15. Believe me Fi, if the individual quoted had said that to me, I doubt I would be able to control myself.
      Regarding Prof G's strategy I'm reminded of Malcolm X's quote "By any means necessary". You keep banging your head against a brick wall and eventually a brick comes loose, hopefully before chronic traumatic encephalopathy sets in!

    16. Brain Health Guide in a nutshell for pwMS:

    17. I live in a tiny country Portugal ,i am being treat in a tiny hospital ,this hospital as +- 600 ms patients .
      My neuro doc says that out of those 600 pwms only 2 need Alemtuzumab (he thinks)
      Me? i am going with the fire department ....Hsct

  2. "With an average age of MS onset of 30 years it means that the average MS must expect to live the majority of their lives with disabilities."

    Why? Far fewer pwRRMS are converting to SPMS at the rate they were pre effective DMTs. One would expect this will become even more apparent once the highly efficacious DMTs like Alemtuzumab play out.

    Are you assuming that every relapse results in permanent disability that presents clinically? I think 'majority of their lives' is a bit of a stretch.

  3. Re: "Far fewer pwRRMS are converting to SPMS at the rate they were pre effective DMTs."

    Where are your stats for this?

    1. I would also like to see the stats. Are there any research papers?

    2. ECTRIMS 2016 - 214 - Effect of disease modifying therapies on long-term multiple sclerosis disability and mortality
      I. Poliakov, L.M. Metz Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada
      Aim: Determine the association between disease modifying therapy (DMT) and mortality, as well as long term disability, as measured by the expanded disability status scale (EDSS), in relapsing-remitting multiple sclerosis (MS).
      Background: While the beneficial effect of DMT on MS relapse rates and magnetic resonance imaging (MRI) lesion load is well established, the effect on long term disease progression and disability is less clear. Given the slow rate at which disability accumulates, prolonged gold standard randomized clinical trials for late stage changes are burdensome, and often unfeasible. Hence, observational studies have been used to determine whether DMT influences long term disability. Controversy still exists, as results are mixed - although most studies have shown some benefit.
      Methods: Analysis of EDSS and DMT data in the Calgary MS database, from consenting Calgary MS clinic patients. Patients were included if they were initially seen after January 1, 1996; had at least 5 years follow up; initially diagnosed with relapsing-remitting MS; and had an initial EDSS < 7. A comparison of final EDSS scores, disability outcomes and mortality was done between patients with at least 5 year cumulative DMT exposure and those with less than 5 years exposure (many of whom had no exposure). These groups were labeled DMT and non-DMT, respectively.
      Results: 1543 patients were included for analysis; 954 in the DMT group and 589 in the non-DMT group. Mean follow up was 12.03 years (range: 5.03 to 19.72). Initial EDSS scores were not statistically different between the DMT and non-DMT groups (2.21 vs. 2.28). Average cumulative time on therapy was much higher in the DMT group, compared to the non-DMT group (11.18 years vs. 1.17 years). Patients in the DMT group had lower final EDSS scores (3.17 vs. 3.62), lower EDSS change per year (0.073 vs. 0.116), and a lower percentage of patients with EDSS >= 3 (odds ratio (95% CI): 0.77 (0.62-0.94)), EDSS >= 6 (odds ratio (95% CI): 0.65 (0.52-0.83)), or deceased (odds ratio (95% CI): 0.55 (0.33-0.91)). Results were all statistically significant in univariate and multivariate analyses.
      Conclusion: This study suggests that prolonged use of DMT in the treatment of MS is correlated with decreased disability and decreased mortality, after more than a decade of follow up.
      Disclosure: This study did not require additional funding.
      Ilia Poliakov: Received advisory board honoraria from EMD Serono.
      Luanne M Metz: Nothing to disclose.

    3. ECTRIMS 2016

      Abstract: P1217

      Type: Poster

      Abstract Category: Therapy - disease modifying - Long-term treatment monitoring

      Background: The concepts of No Evidence of Disease Activity (NEDA) are being increasingly considered to assess disease evolution. After 6-10 years, approximately 25-40% of patients with relapsing-remitting multiple sclerosis (RRMS) convert to secondary progressive multiple sclerosis (SPMS).

      Objective: To investigate proportion of patients with RRMS converting to SPMS over 8 years and the predictive value of NEDA status and baseline parameters of patients converting to SPMS.

      Methods: Post-hoc analysis of pooled FREEDOMS and FREEDOMS II studies (both 2 year placebo-controlled) and their extensions in a total of N=2355 RRMS patients. Kaplan-Meier estimates of time to conversion to SPMS are presented at month (M) 96, hazard ratios (HR) and p-values are from a Cox proportional hazard model. Onset of SPMS was defined by a progressive increase in Expanded Disability Status Scale (EDSS) of at least 6 months duration in the absence or independent of relapses, from an initial EDSS ≥3.0 (increase in EDSS by ≥1 from an initial EDSS of 3-5 or by ≥0.5 points for EDSS ≥5.5, respectively). NEDA-3 is defined as: no MRI lesion activity, no relapses, and no confirmed progression of disability. NEDA-4 also includes annual brain volume loss < 0.4%.

      Results: By M 96, the cumulative conversion probability to SPMS was 7.5% for patients who were continuously treated with FTY 0.5mg and 10% for patients who were initially treated with placebo and switched to FTY 0.5mg. Patients who did not convert to SPMS tended to be younger (38.5 vs 40.6yrs), with shorter disease duration (9.2 vs 11.0yrs), lower EDSS (2.3 vs 3.9), lower T2 burden of disease (5.7 vs 9.9 cc) and higher brain volume (1521 vs 1473 cc) at baseline. Differences were also seen for Paced Auditory Serial Addition Test (48.2 vs 43.0), 9-Hole Peg Test (22.1 vs 27.5) and Timed 25-Foot Walk Test (5.8 vs 8.2), while no difference was found for pre-study relapses and T1 Gadolinium-enhancing lesion activity. Comparing FTY-treated patients who did not achieve NEDA-3 in year 1 with those who did, the HR for time to SPMS was 1.59 (p=0.0568) while for NEDA-4 it was 2.01 (p=0.0225).

      Conclusions: Less than 10% of patients on continuous FTY treatment converted to SPMS over 8 years. Disease severity at baseline and NEDA-4 status at one year were significantly predictive of time to conversion to SPMS. These findings support long-term benefit of FTY and the use of NEDA-4 as a comprehensive and balanced measure for predicting future disease evolution.

    4. J Neurol Neurosurg Psychiatry. 2015 Feb;86(2):208-15. doi: 10.1136/jnnp-2014-307721. Epub 2014 May 21.

      Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy.

      Tuohy O1, Costelloe L2, Hill-Cawthorne G3, Bjornson I1, Harding K4, Robertson N4, May K1, Button T1, Azzopardi L1, Kousin-Ezewu O1, Fahey MT5, Jones J1, Compston DA1, Coles A1.
      Author information
      Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
      Department of Neurology, Beaumont Hospital, Dublin, Ireland.
      Sydney Institute of Emerging Infectious Diseases and Biosecurity, University of Sydney, Sydney, Australia.
      Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, Cardiff, Wales, UK.
      Biostatistics Unit, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia.
      Alemtuzumab is a newly licensed treatment of active relapsing-remitting multiple sclerosis (RRMS) in Europe, which in phase II and III studies demonstrated superior efficacy over β-interferon in reducing disability progression over 2-3 years. In this observational cohort study, we sought to describe our longer-term experience of the efficacy and safety of alemtuzumab in active RRMS.
      Clinical and laboratory data including serial Expanded Disability Status Scale (EDSS) assessments, from all 87 patients treated with alemtuzumab on investigator-led studies in Cambridge, UK, from 1999 to 2012, were collected. The occurrence of adverse events including secondary autoimmunity, malignancy and death, and pregnancy outcomes was recorded. Baseline variables including age, disease duration and relapse rate were compared in univariate and logistic regression analyses between groups with different disability outcomes.
      Over a median 7-year follow-up (range 33-144 months), most patients (52%) required just two cycles of alemtuzumab. In the remaining patients, relapses triggered re-treatment to a total of three cycles (36%), four cycles (8%) or five cycles (1%). Using a 6-month sustained accumulation of disability definition, 59/87 (67.8%) of patients had an improved or unchanged disability compared with baseline. By an area under the curve analysis, 52/87 (59.8%) patients had an overall improvement or stabilisation of disability. Higher baseline relapse rate was associated with worse long-term disability outcomes, with trends for longer disease duration and older age at first treatment. Secondary autoimmunity was the most frequent adverse event occurring in 41/86 (47.7%) patients, most commonly involving the thyroid gland.
      Alemtuzumab is associated with disease stabilisation in the majority of patients with highly active RRMS over an average seven-year follow-up. No new safety concerns arose over this extended follow-up.

    5. Jane A:

      Anon has posted several publications below.

  4. When I read the Norwegian study this week I was horrified. I've read many times about the 7 year life expectancy that's less than those without MS. This study was small but horrifying.

    My question: I was diagnosed in 1986 before approved medications were available. The first medication I could withstand was Copaxone in 1996, which I've been on ever since. For 10 years I went without medications. Does this mean about my life expectancy is much shorter? Any thoughts would be greatly appreciated, Dr. G.

    1. Cathy,
      Everyone's MS is different, it depends where your lesions are and how quickly you progress, some do, some don't, some are much slower than others. Everyone is different, so don't be too despondent.

  5. Please do not "water down" the medical jargon. It is really not that tough for the layperson to understand. It is refreshing to read a blog that uses appropriate medical terminology and discussion. As prior responders pointed out, there are hundreds of "easy to understand" MS blogs out there. This blog however is unique. We need it! Please keep it as it is, and let the naysayers reach out to the "easier" blogs! Thank you very much!

    1. By the way. Do people realise I put links to wiki in my posts for most of the science stuff

    2. of course. Keep doing it, please

    3. Prof G,

      Why have you said that the average pwMS "must expect to live the MAJORITY of their lives with disabilities"?

  6. "must expect to live the MAJORITY of their lives with disabilities?"

    My disabilities are not visible. I have bladder and sometimes bowel issues. Also pain and fatigue but several people have said to me I don't look like I have MS.

    Bladder issues are a common problem in the general population thought to affect millions of people. Pain is also a common problem, such as back pain.

  7. I get the same reaction Anon. Even when I went into hospital for a tooth extraction last year, one of the doctors exclaimed 'YOU have MS!?!' The reality is though that we all have 'disabilities' in the broadest sense of the word e.g. MS fatigue. Plus for RRMS the weird 'here today gone tomorrow' disabilities as with walking with a stick to not needing it, in my case. Stupidly I felt 'disabled' when they took my driving license to replace it with the 3 yearly one.
    I think Stephanie Buxhoevenden has it right in her TEDTALK where she says that at 25 she realised she'd have more years living with the disease than all the years she'd lived without it. My diagnosis came so much later in life, but I get the concept of living the majority of life with disabilities because I think that's the reality for most young people with the diagnosis. Not necessarily obvious physical disabilities but as Stephanie brilliantly highlights in her talk: all the unseen ones. Then there's the social ones of partnerships and having children and pursuing careers etc. I hope that acknowledgement of the wide range of 'disabilities' both from PwMS and the wider world, might go somewhat towards assisting those of us living with it and MS not just being seen as : you can end up in a wheelchair.
    Btw Stephanie is a PwMS who is also an MS nurse and her talk is really quite good.

  8. Please don't water down the medical jargon - this is a fantastic resource, and I want to learn more, so I can keep up with research - I for one intend to "brain up" - and it's good for your brain health to learn something new and difficult, is it not?


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