Slowing conversion to SPMS, why we need Neurological Chicxulub for MS


Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis.

Brown JWL, Coles A, Horakova D, Havrdova E, Izquierdo G, Prat A, Girard M, Duquette P, Trojano M, Lugaresi A, Bergamaschi R, Grammond P, Alroughani R, Hupperts R, McCombe P, Van Pesch V, Sola P, Ferraro D, Grand’Maison F, Terzi M, Lechner-Scott J, Flechter S, Slee M, Shaygannejad V, Pucci E, Granella F, Jokubaitis V, Willis M, Rice C, Scolding N, Wilkins A, Pearson OR, Ziemssen T, Hutchinson M, Harding K, Jones J, McGuigan C, Butzkueven H, Kalincik T, Robertson N; MSBase Study Group.

JAMA. 2019 Jan 15;321(2):175-187. doi: 10.1001/jama.2018.20588.


Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition.


To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition.


Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years’ follow-up.


The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017).


Conversion to objectively defined secondary progressive MS.


Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1).


Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies’ risks, may help inform decisions about DMT selection.

Hi Peeps I’m almost back on the blog but still have no idea how to use the new system so bare with the MDs. Whilst we where posting on HSCT, this paper slipped through. However, having sat through some talks by Neuros supporting the “do nothing and waiting and see”. I was thinking I am rather happy that I work with some Neurological Mammals and that they took a real interest in teaching the next generation of neuros and nurses that Time is Brain and not to be squandered by inactivity.

So my hope for the Treatment of MS this year would be to see introduction of the Neurological Chicxulub. Chicxuclub is not a new drug…although it sounds like it, but reading the above if may be be the tonic that many of you need. Chicxulub is the site that many believe is the site in Mexico where a giant comet/asteroid struck the Earth and created the climate change that killed off the Dinosaurs.

This study shows that all MS agents appeared to have a measurable, favorable effect on disease progression. Moreover, the group of therapies that was most effective at decreasing relapse rates also had the greatest benefit on disease progression. Furthermore, earlier initiation of these therapies uniformly appeared to have a more significant effect on disease course. The message is clear “Time is Brain”.

This study demonstrates that if you are prescribed one of the CRAB drugs you are more likely to develop SPMS than if you select a treatment with even modest efficacy. OK some people may respond well but the fact is many will not. They simply serve to eat up your neurological reserve. what you lose by being on such agents, you lose.

It is a dinosaur view to do nothing. For them we need preverbial asteroid to come along.

Now some say what about this Natalizumab does not stop atrophy

Gray matter atrophy in multiple sclerosis despite clinical and lesion stability during natalizumab treatment
A key observation of this study was that there was a progressive decline in brain volume despite treatment with natalizumab. This decline was seen in gray matter but not white matter structures. But it was not controlled and so how do you know how much atrophy would occur if no drug had been used. The people in the study had had MS for 9 years, which is hardly early treatment and therefore some of the damage may have been preprogrammed before natalizumab treatment that stopped new Tand T2 lesions. However we know that people with SPMS treated with natalizumab continue to progress.

COI. Multiple.. but not considered to be relevant

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  • Well, when I found out I had MS, had first symtoms, it turned out progressive from the “start”, i.e. PPMS. So I think we’d need another selective extinction event to get rid of all those effectively causing neuroprotctive development to sit on the back burner. All those pushing research into viral involvement, causes of MS and genuine cures into the back of the store cupboard. I fear pharma would be obliterated.

  • According to various posts on this blog MS is one disease and SPMS is not really any different to the relapsing phase. Do you still agree with this?

  • I’m sorry but this is a nonsense. All studies seem to overlook a key issue, which is that diagnosis often occurs late in disease course. By the time it is recognised and labelled there really is no time to waste. The most effective treatments need to be available and offered immediately on diagnosis. Messing around with an escalation treatment protocol is a nonsense that plays with people’s lives, like offering paracetamol to treat cancer. We know too that DMDs don’t have long term trial results. Dr Ebers, formerly of the JR in Oxford that DMDs states that a DMDs have very little impact on eventual timing of conversion to SPMS.

    Of course avoiding SPMS is needed, it doesn’t need a study to state the obvious. All that is required is for first line treatment to be the most highly effective available. The risk / benefit argument is moot in my view. MS is a nasty, aggressive condition that requires the best available treatment. The first two tiers of DMDs need consigning to history immediately along with the words moderately effective. Highly effective should be the only treatment offered and work on HSCT needs to be focussed and expedited to allow it to become a first line option soon.

    I wouldn’t wish the symptoms, disability, loss of dignity and downright misery of MS on my worst enemy. I told my neuro I wanted to hit it hard and fast immediately, when my edss was 1. His complacency and unwillingness to recommend the treatment I asked for means that I am condemned to live the rest of my life unable to be the person I was.

    His arrogance doesn’t stop him from working, seeing his family, seeing friends. He hasn’t lost everything he has spent his life striving to achieve. His failure to listen to me and take on board my views on treatment for myself, has effectively helped to condemn me to a life sentence of frustration and lost potential.

    Sadly I know that my story is one in many tens of thousands, that my opinions won’t change the approach of the establishment. I just have to hope that by expressing myself, someone who can make a difference will pick up the baton and run with it.

      • Not sure which post this is in reply to… what exactly is it that you have been trying to do for the last decade?

        • I believe DR G is replying to PHoenix2507’s final comment where PHOENIX2507 refers to the “approach of the establishment” being resistant to change.
          DR G is simply saying, I believe, that he has been trying to do his part in changing the ” approach of the establishment” through BartsMS Blog.

    • Wow. Thank you for this powerful post. By coincidence I read it this afternoon on the way to an appointment with my neurologist, in which I received my MS diagnosis. It certainly influenced my reply when he asked me about my initial thoughts on treatment. So thank you.

      • Sarah, I’m really sorry you have joined a club that nobody wants to be a member of. My key advice to you is to be your own best advocate and research as much as you can.

        There are thousands of “experts by experience” who are happy to share on all kinds of forums and social media. You will find differing and contradictory views amongst both people with MS and the medical profession, so in the end you have to make an informed decision for yourself.

        The MS Trust has a lot of good information when you are first researching. They have a good “decision maker” tool for disease modifying drugs. You should also research HSCT (try starting with

        Make sure that you are referred to your local MS Nurse too.

        My best advice is do not under any circumstances be convinced to wait and see ! MS is always mild until one day you wake up and its not. That day is when you know you waited too long. A phrase you will hear a lot is Time is Brain.

        Best wishes Sarah, I expect we will cross paths on social media soon.

        • Thank you Phoenix! Good advice. I have been lurking on several groups, seems there are some great resources and networks out there. I’ve only actively commented on this blog so far – it is excellent (and thank you to ProfG and all involved) – and I’m trying to get my head around a bit of the science! All the best, Sarah

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