Early treatment is important to limit accumulation of disability

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Iaffaldano P, Lucisano G, Butzkueven H, Hillert J, Hyde R, Koch-Henriksen N, Magyari M, Pellegrini F, Spelman T, Sørensen PS, Vukusic S, Trojano M. Early treatment delays long-term disability accrual in RRMS: Results from the BMSD network. Mult Scler. 2021 Apr 26:13524585211010128. doi: 10.1177/13524585211010128.

Background: The optimal timing of treatment starts for achieving the best control on the long-term disability accumulation in multiple sclerosis (MS) is still to be defined.

Objective: The aim of this study was to estimate the optimal time to start disease-modifying therapies (DMTs) to prevent the long-term disability accumulation in MS, using a pooled dataset from the Big Multiple Sclerosis Data (BMSD) network.

Methods: Multivariable Cox regression models adjusted for the time to first treatment start from disease onset (in quintiles) were used. To mitigate the impact of potential biases, a set of pairwise propensity score (PS)-matched analyses were performed. The first quintile, including patients treated within 1.2 years from onset, was used as reference.

Quintiles (Q) of time from disease onset to the first DMT start, years, median, (min–max). Q1 0.6 (0.0–1.2), Q2 1.8 (1.3–2.7), Q3 3.8 (2.8–5.3), Q4 7.3 (5.4–10.1), Q5 14.6 (10.2–41.0)

Results: A cohort of 11,871 patients (median follow-up after treatment start: 13.2 years) was analyzed. A 3- and 12-month confirmed disability worsening event and irreversible Expanded Disability Status Scale (EDSS) 4.0 and 6.0 scores were reached by 7062 (59.5%), 4138 (34.9%), 3209 (31.1%), and 1909 (16.5%) patients, respectively. The risk of reaching all the disability outcomes was significantly lower (p < 0.0004) for the first quintile patients’ group.

Conclusion: Real-world data from the BMSD demonstrate that DMTs should be commenced within 1.2 years from the disease onset to reduce the risk of disability accumulation over the long term.

This study suggests that early treatment (The first DMT was a first-line agent (n = 10,925 interferon beta (IFN beta) or glatiramer acetate (GA); n = 814 azathioprine) in 98.9% of patients, whereas it was a second-line agent (natalizumab, fingolimod or mitoxantrone) in 1.1% of patients) is important to limit the potential for the accumulation of disability in the future. This view is supported by other studies. You have asked how quickly should ideally treatment be started and this real world data suggests ASAP as it is clear that there can be disability progression even if treatment is started early on. Whilst I appreciate that many readers of the blog will not have had this experience, it is important that we do better now than we did in the past. The http://www.msbrainhealth.org has set standards to aspire too, it would be good to see who are achieving these. The only way to know this is to monitor this and I know that our Health Care Team are doing this

Hobart J, Bowen A, Pepper G, Crofts H, Eberhard L, Berger T, Boyko A, Boz C, Butzkueven H, Celius EG, Drulovic J, Flores J, Horáková D, Lebrun-Frénay C, Marrie RA, Overell J, Piehl F, Rasmussen PV, Sá MJ, Sîrbu CA, Skromne E, Torkildsen Ø, van Pesch V, Vollmer T, Zakaria M, Ziemssen T, Giovannoni G. International consensus on quality standards for brain health-focused care in multiple sclerosis. Mult Scler. 2019;25(13):1809-1818.

The next question what is the time window and how to optimise benefit, I have seen data that sugggests based on different treatments there is a window larger than that recorded above. However, it is logical that when ever effective treatment is started, there will be benefit. Next up does it matter about the treatment and its percieved level of efficacy. I also believe there is data on that too, but you know I’m a broken record on that one.

ProfK is about to start a study of natalizumab use at presentation in a study called ATTACK MS. At the moment I believe this study will be done at three centres in the London area. The idea is to get people onto high-efficacy therapy ASAP to stop further attacks occuring in untreated MS, whilst the person/neuro decides how best to move forward.

COI Multiple

Disclaimer: Please note that the opinions expressed here are those of the author and do not reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust or Queen Mary Univeristy of London.

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16 comments

  • Posts like this always take me back to the same question…..If a diagnosis cannot be made until a second episode then how can the practice of treating as early as possible (within 1.2 years of disease onset) be effectively implemented. Prof G said recently that 80% of CIS ends up being MS. For many, the second episode may take years to take place but they have been carrying the disease all of that time, missing the opportunity to be treated early and effectively. Yes, cladribine has CIS on its label. However, nobody actually gets offered this due to the NICE criteria. The logic is totally flawed in my view

    • Macdonald 2017 with MRI can pick up the lesions in time and space from one scan and one time point.

      Next point even if it were decided that the problem was not MS, you can stop natalizumab treatment it washes out and nothing happens, so you have had a futile antibody treatment but you have not had the second disease episode that could occur if you did nothing. That is why it is going to be key to explain this and if you are being offered this it will be alot to take in.

      The cladribine label is daft, I suspect the company were told to request a lael for highly active MS to get their licence, it should have been simply active MS. Malcolm QALY (not spelt correctly on purpose) from the NHS England has said a case would have to be made to get it first line. Who has the time to do this

      • Thanks MD and good that the criteria has progressed but still means 80% of ms patients presenting with cis will go untreated until episode no. 2. Attack ms is a start but a long time and a lot of brain before this is the norm

  • With a resolutely low (self assessed ) EDSS of 1.0 and symptoms going back >30 years, I suppose I’m ineligible for DMDs, but I’m perennially concerned about brain volume. Loss is cited as faster in pwMS and I’d like to hang on to as much of my brain as I can. What do I do about it? It seems to be a postcode issue as I’ve only ever been offered anything when living overseas

    • I agree there is a post code lottery, (I have seen data) however how do you find out about this. Is there site giving details of prescription/disbaility. However, I need to add 30 years ago there was nothing to offer, otherwise I may end up in triple secret probabtion:-).

      What could I do, I guess this is where a surrogate tests like neurofilament in a blood spot may be useful. If significnt change is occuring you would pick it up. My be you are just worrying and it is great you are EDSS 1 30 years on

  • Does the ‘optimal timing’ have any relevance to the number lesions it only to the physical manifestations of disability accrued? I.e someone could have many lesions but be fully mobile low Ed’s vs few lesions but significant disability… probably a silly question but I ask as someone diagnosed later with much damage on mri not too much in reality

    • I am similar to someone else in the comments. I was diagnosed at 46 after having optic neuritis. My MRI came back with a moderate amount of lesions on the brain and lots on the spine. Looking back I have had strange things happening to me since I was 25, but never a big deal. Besides some bladder issues that I control with a pill, which I had previously assumed were from having kids, I feel fine. I jog 3-4 miles every day and hold a senior position at a large company in technology. The thing is, I am scared. It has been two years since I was diagnosed and I spend hours everyday researching. I would have done HSCT or Lemtrada if offered to feel like I had a cure. I took out gluten, soy and dairy from my diet. Is there any hope anyone can give me? I feel like it was caught too late and I am waiting until I need a wheelchair.

  • The result section of this abstract seems incomprehensible.

    “Quintiles (Q) of time from disease onset to the first DMT start, years, median, (min–max). Q1 0.6 (0.0–1.2), Q2 1.8 (1.3–2.7), Q3 3.8 (2.8–5.3), Q4 7.3 (5.4–10.1), Q5 14.6 (10.2–41.0)

    Results: A cohort of 11,871 patients (median follow-up after treatment start: 13.2 years) was analyzed. A 3- and 12-month confirmed disability worsening event and irreversible Expanded Disability Status Scale (EDSS) 4.0 and 6.0 scores were reached by 7062 (59.5%), 4138 (34.9%), 3209 (31.1%), and 1909 (16.5%) patients, respectively.”

    So I think I know what they are trying to say. That the earlier you get on a good treatment the lower your EDSS score will be at a future date compared to others who start treatment later.

    But the Quintiles (5 groups) start with people who are treated the earliest and then go to those who are treated the latest.

    The results are 4 groups and start with worse percentage outcome and get smaller. Then it uses the word respectively where there is unclear context.

    Perhaps this is the four groups 3 mo disability worsening, 12 mo disability worsening, EDSS=4.0, EDSS=6.0?
    The summary mixes the word AND in the description of the analysis in a confusing way.

    But then this result does not reflect the premise that getting treatment earlier has impact as it has nothing reported due to the quintiles ?

    Maybe there is something in the actual paper, but I don’t have access. A badly written summary usually means the details are a mess as well.

    But maybe I just am moody because MS is hurting us all.

    • They compare to the earliest quintile i.e 20% of the group 5 quiniles = 100%
      Early you get on treatment the better

  • I am similar to someone else in the comments. I was diagnosed at 46 after having optic neuritis. My MRI came back with a moderate amount of lesions on the brain and lots on the spine. Looking back I have had strange things happening to me since I was 25, but never a big deal. Besides some bladder issues that I control with a pill, which I assumed were from having kids, I feel fine. I jog 3-4 miles every day and hold a senior position at a large company in technology. The thing is, I am scared. It has been two years since I was diagnosed and I spend hours everyday researching. I would have done HSCT or Lemtrada if offered to feel like I had a cure. I took out gluten, soy and dairy from my diet. Is there any hope anyone can give me? I feel like it was caught too late and I am waiting until I need a wheelchair.

      • I agree with Luis, spinal lesions are not good. Hopefully you are at least on one of the high efficacy DMTs. It is better late than never. After a certain age, the list of available DMTs gets even smaller.

        • Thank you for replying. I am on Tysabri. I am completely mobile which is strange based on my MRI, but I am feeling pain in my neck and spine. Not really bad and feels better when I workout so I just go for a jog. This is really scary.

  • There were some treatments once I’d been diagnosed in 2004 but they were never discussed with me in England. I wouldn’t have known about brain volume loss if I hadn’t got hold of Brain Health: Time Matters at Torquay Information Day 2018. Maybe that’s the price you pay for keeping yourself informed. I’d rather know than not which is why I read this blog.

    • In 2004 the interferons betaferon/betaseron rebif, avonex, copaxone, nataliumab came and was withdrawn until 2006, then nothing until 2010 (fingolimod)

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