Journal Club: Early vs. Late or Low vs. High efficacy


You are welcome to watch our online journal club discussing the following paper.

Anna He et al. Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study. Lancet Neurol 2020 Apr;19(4):307-316.

Background: High-efficacy therapies in multiple sclerosis are traditionally used after unsuccessful treatment with first-line disease modifying therapies. We hypothesised that early commencement of high-efficacy therapy would be associated with reduced long-term disability. We therefore aimed to compare long-term disability outcomes between patients who started high-efficacy therapies within 2 years of disease onset with those who started 4-6 years after disease onset.

Methods: In this retrospective international observational study, we obtained data from the MSBase registry and the Swedish MS registry, which prospectively collect patient data that are specific to multiple sclerosis as part of routine clinical care. We identified adult patients (aged ≥18 years) with relapsing-remitting multiple sclerosis, with at least 6 years of follow-up since disease onset, and who started the high-efficacy therapy (rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab) either 0-2 years (early) or 4-6 years (late) after clinical disease onset. We matched patients in the early and late groups using propensity scores calculated on the basis of their baseline clinical and demographic data. The primary outcome was disability, measured with the Expanded Disability Status Score (EDSS; an ordinal scale of 0-10, with higher scores indicating increased disability), at 6-10 years after disease onset, assessed with a linear mixed-effects model.

Findings: We identified 6149 patients in the MSBase registry who had been given high-efficacy therapy, with data collected between Jan 1, 1975, and April 13, 2017, and 2626 patients in the Swedish MS Registry, with data collected between Dec 10, 1997, and Sept 16, 2019. Of whom, 308 in the MSBase registry and 236 in the Swedish MS registry were eligible for inclusion. 277 (51%) of 544 patients commenced therapy early and 267 (49%) commenced therapy late. For the primary analysis, we matched 213 patients in the early treatment group with 253 in the late treatment group. At baseline, the mean EDSS score was 2·2 (SD 1·2) in the early group and 2·1 (SD 1·2) in the late group. Median follow-up time for matched patients was 7·8 years (IQR 6·7-8·9). In the sixth year after disease onset, the mean EDSS score was 2·2 (SD 1·6) in the early group compared with 2·9 (SD 1·8) in the late group (p<0·0001). This difference persisted throughout each year of follow-up until the tenth year after disease onset (mean EDSS score 2·3 [SD 1·8] vs 3·5 [SD 2·1]; p<0·0001), with a difference between groups of -0·98 (95% CI -1·51 to -0·45; p<0·0001, adjusted for proportion of time on any disease-modifying therapy) across the 6-10 year follow-up period.

Interpretation: High-efficacy therapy commenced within 2 years of disease onset is associated with less disability after 6-10 years than when commenced later in the disease course. This finding can inform decisions regarding optimal sequence and timing of multiple sclerosis therapy.

Funding: National Health and Medical Research Council Australia and MS Society UK.

Do you think we still have clinical equipoise when ….

  1. We randomise some with MS to a low efficacy therapy compared to a new potentially high efficacy DMT?


2. We randomise to someone with active MS to a low-efficacy maintenance-escalation treatment strategy compared to flipping the pyramid with high-efficacy therapy?

CoI: multiple

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  • As a non-medic (mother of a 23 yr old, on Gilenya for last 3 years, after diagnosis at 19) I find these articles and videos of your discussion so illuminating, thought provoking and confidence building. Thank you for sharing them so widely.
    My question relates to Gilenya (Fingolimod). I notice it wasn’t on the list of high efficacy treatments in this study, and it often is shown ‘on the cusp’ of that line. For the purposes of this study, for example, where would you be more inclined to place it . . . ie high efficacy, or not? I’m wondering whether I should be taking some comfort that my daughter would fit in the early treatment with high efficacy group – or should I be concerned that we may have missed an opportunity. I asked her consultant here in Edinburgh last year about whether we should be considering a higher efficacy treatment (prevention being better than cure – with some risk assessment obviously) and was met with ‘that’s not how we do it on the MS’. I hadn’t realised the conundrum of Fingolimod being effective (no new lesions – but some definite ‘events’ wrt walking and hands at times) and therefore no clinical rationale for going up a level (escalation model!) in terms of treatment. As a mother this is hard to accept IF Fingolimod isn’t considered high efficacy.
    I would very much welcome any thoughts on this as we are meeting him for the annual appt in 12 days time (promise not to quote you 😉 ).
    Thanks – and keep doing what you are doing guys . . . we all appreciate it so much.

  • Thanks a lot for the video. Very useful. Is it possible to get the slides ? 🙂

    No doubt there is no equipoise anymore. But it was already the case before this paper I think.

    By the way, that’s thanks to THIS blog that realised I needed to flip the pyramid to preserve my health (no one told me that in my medical team because my MS was supposedly mild and not highly actice). Thanks to YOUR work I began highly efficacy DMT (ocr) very early before any visible progression and I hope I will be able to keep this way with EDSS 0.

    Now what I really want as a pwMS are clinical trials (with drugs and lifestyle modifications) for addon therapy for my anti CD20 DMT.

    Thanks again

  • Can I ask a question about disease onset. Using the McDonald criteria (space and time) it is difficult to receive a diagnosis until a second event has occured. So if a CIS case converts to MS in say 5 years, you may be treated within 6 months of the diagnosis but this is still 5.5 years after the onset of disease, is it not? So whereas a large gap after the initial episode is considered a positive prognostic factor, this is countered by not receiving or bring eligible for treatment during the initial, critical period. Is this not a major flaw of the diagnostic process?

      • Thanks Luis. I get that but my point was that the criteria on which to receive a diagnosis and therefore treatment, requires ‘time’. For some, this may only be a few months. For others, it could be years. So is the McDonald criteria not out dated given the current mantra of hitting disease hard and early?

  • The discussion towards the end of this video, around the ethics of clinical trials, makes me proud to be a reader and supporter of this blog. It really reflects the character and compassion of the individuals on the BartsMS team that contribute to this blog. I actually participated in one of the trials you were discussing. Thankfully I was randomized into the high efficacy group, as I would not have participated if it ended up the other way. However, I ultimately removed myself anyways after needing to stop Ocrevus and then getting the overwhelming feeling my doctors clinical recommendations for my next DMT choice were bias towards “the integrity of the trial”. One of my doctors looked like he wanted to punch me when I suggested your IRT and iTeri studies. He had the balls to tell me “stop Googling”.

  • Finally got around to watch this – well done! Definitely interested to see more of it.

    Suggestion: Could you also provide 1080p video to make busy slides easier to read on the video (was not a big issue here but definitely have come across the issue in other webcasts)…

  • I was on Rebif for 16 years and in 2016, I had a really bad relapse that affected my short term memory and concentration and I became incontinent and had to wear thick pads as my bladder voided itself after just 3. minutes of walking. Then I met my new neuro and she gave me a referral to the wonderful urologist, who after some very intimate tests, put me on to betmiga. This was a bit of a miracle. The latest lesion was still active but natalizumab helped. I am still receiving infusions. She told me to be patient and that I may even experience improvements.
    4 years later, I am JC negative and whilst I still have to take betmigam my bladder function has improved to the point where I dont need incontinence pads. I am aware of my bladder and now know when to empty it. I never have to get up in the night. This is a HUGE improvement. I rarely have minor accidents.
    The combination of natalizumab and betmiga and good luck has changed my life. I will wear a pad if I have to go for a walk , but quite often I can forget my bladder problems and just walk!
    Things can get better, even for late starters -17 years after diagnosis.

  • Thanks. Great discussions. I agree with comments regarding comparison in subgroups (Natalizumab, Mitoxantrone and Rituxinab). Anyway, there is another support in favour for being vigilant of disease activity and treatment escalation.

  • Started ocrelizumab 1 year post diagnosis. Feel fortunate I have a ms doc in the US who is a believer think it’s borderline criminal we still use escalation therapy to treat knowing once damage is done it is forever.

    Imagine if we took the same approach with cancer?

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