Two, four, six, eight, who do you appreciate?

T

Barts-MS rose-tinted-odometer: ★

This week I was asked by two patients independently of each other who had delayed access to treatment if this could explain why they now have secondary progressive MS. In parallel, I had a meeting with a friend yesterday, who was the primary driver of the 21-year interferon-beta follow-up survival study (see below), who said that to him this was the most convincing data to support the early treatment paradigm in MS. 

In summary, trial subjects in the pivotal original interferon-beta-1b study who had delayed access to interferon-beta-1b because they were randomised to receive placebo were 50% less likely to be alive at 21 years compared to study subjects with early access to treatment. Was this due to the impact of interferon-beta on MS or some other confounding factor? In the 69 pwMS for whom information on the relationship of death to MS was available 78% were judged to have died from MS-related complications. This tells us that IFN-beta increases your life expectancy by reducing MS-related complications that can cause death in the future. The latter include swallowing problems that are associated with aspiration pneumonia, urinary dysfunction that lead to urinary tract infections and septicaemia, immobility and pressure sores, falls and fractures, to name the most common causes of premature death in pwMS. 

You need to remember that this was a placebo-controlled study and the subjects on placebo were switched to active treatment after 3 years, with some subjects having to wait up to 5 years (trial recruitment was from June 1988 to May 1990; with placebo-treated subjects given free commercial supply as of October 1993). What this study shows is that delaying access to treatment by just 3-5 years has a major impact on long-term outcomes. 

Please note that apart from suicide most pwMS get to EDSS 10 or death as a result of MS by passing through EDSS stages 2, 4, 6 (stick), 8 (wheelchair/bed). So my answer to these patients was yes your delayed access to DMTs in the early 2000s is almost certainly the reason why you now have secondary progressive MS and are disabled. 

Please note this there is now overwhelming evidence from other controlled trials and real-life data to support the interferon-beta 21-year mortality data. In fact, the debate about early treatment and MS outcomes is so widely accepted that it has now has shifted from early access to DMTs to early access to highly effective DMTs, i.e. flipping the pyramid. It is clear that pwMS who are treated with more effective DMTs first-line do so much better than those who are asked to wait (watchful waiting) or are escalated gradually up the DMT ladder (slow escalation). This is why, despite us designing the early treat-2-target NEDA trial, our centre couldn’t participate in the trial comparing maintenance-escalation vs. flipping the pyramid. We simply don’t have equipoise; in other words, we don’t think it is ethical to randomise patients to a treatment arm that is less effective and hence will result in poorer long-term outcomes and probably poorer long-term survival. This is why it is our current clinical practice to offer pwMS who have active disease and are eligible under the NHSE algorithm for treatment access to highly effective treatment first-line. 

We are so convinced about the early treatment that we are doing the ATTACK-MS trial, which will explore if access to the highly effective treatment natalizumab, 2 months earlier than what happens in routine practice, improves outcomes. Yes, we will be randomising patients before they have finished the MS diagnostic pathway to treatment vs. delayed access, i.e. only 2 months later when they have a definitive diagnosis of MS. We anticipate that the ATTACK-MS study will activate the MS community to treat the MS brain as we treat the brain in stroke. Forget about years, every day, week or month for the untreated MS brain is like every second, minute or hour in the non-perfused brain of a person having a stroke.

Yes, in MS time really is brain and by delaying access to DMTs and potentially highly effective DMTs is unacceptable in the modern era of treating MS. The data below not only supports the maxim “Time is Brain” but “Time is Life“, why would anyone wait to treat someone with active MS knowing this?

Figure from Neurology 2012;78(17):1315-22.

Goodin et al. Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNβ-1b trial. Neurology. 2012 Apr 24;78(17):1315-22.

Objective: To examine the effects of interferon beta (IFNβ)-1b on all-cause mortality over 21 years in the cohort of 372 patients who participated in the pivotal randomized clinical trial (RCT), retaining (in the analysis) the original randomized treatment-assignments.

Methods: For this randomized long-term cohort study, the primary outcome, defined before data collection, was the comparison of all-cause mortality between the IFNβ-1b 250 μg and placebo groups from the time of randomization through the entire 21-year follow-up interval (intention-to-treat, log-rank test for Kaplan-Meier survival curves). All other survival outcomes were secondary.

Results: After a median of 21.1 years from RCT enrollment, 98.4%(366 of 372) of patients were identified, and, of these, 81 deaths were recorded (22.1% [81 of 366]). Patients originally randomly assigned to IFNβ-1b 250 μg showed a significant reduction in all-cause mortality over the 21-year period compared with placebo (p = 0.0173), with a hazard ratio of 0.532 (95% confidence interval 0.314-0.902). The hazard rate of death at long-term follow-up by Kaplan-Meier estimates was reduced by 46.8% among IFNβ-1b 250 μg-treated patients (46.0% among IFNβ-1b 50 μg-treated patients) compared with placebo. Baseline variables did not influence the observed treatment effect.

Conclusions: There was a significant survival advantage in this cohort of patients receiving early IFNβ-1b treatment at either dose compared with placebo. Near-complete ascertainment, together with confirmatory findings from both active treatment groups, strengthens the evidence for an IFNβ-1b benefit on all-cause mortality.

Classification of evidence: This study provides Class III evidence that early treatment with IFNβ-1b is associated with prolonged survival in initially treatment-naive patients with relapsing-remitting multiple sclerosis.

Goodin et al. Cause of death in MS: long-term follow-up of a randomised cohort, 21 years after the start of the pivotal IFNβ-1b study. BMJ Open. 2012 Nov 30;2(6).

Objectives: Compared with controls, multiple sclerosis (MS) patients die, on average, 7–14 years prematurely. Previously, we reported that, 21 years after their participation in the pivotal randomised, controlled trial (RCT) of interferon β-1b, mortality was reduced by 46–47% in the two groups who received active therapy during the RCT. To determine whether the excessive deaths observed in placebo-treated patients was due to MS-related causes, we analysed the causes-of-death (CODs) in these three, randomised, patient cohorts.

Design: Long-term follow-up (LTF) of the pivotal RCT of interferon β-1b.

Setting: Eleven North American MS-centres participated.

Participants: In the original RCT, 372 patients participated, of whom 366 (98.4%) were identified after a median of 21.1 years from RCT enrolment.

Interventions: Using multiple information sources, we attempted to establish COD and its relationship to MS in deceased patients.

Primary outcome: An independent adjudication committee, masked to treatment assignment and using prespecified criteria, determined the likely CODs and their MS relationships.

Results: Among the 366 MS patients included in this LTF study, 81 deaths were recorded. Mean age-at-death was 51.7 (±8.7) years. COD, MS relationship, or both were determined for 88% of deaths (71/81). Patients were assigned to one of nine COD categories: cardiovascular disease/stroke; cancer; pulmonary infections; sepsis; accidents; suicide; death due to MS; other known CODs; and unknown COD. Of the 69 patients for whom information on the relationship of death to MS was available, 78.3% (54/69) were adjudicated to be MS related. Patients randomised to receive placebo during the RCT (compared with patients receiving active treatment) experienced an excessive number of MS-related deaths.

Conclusions: In this long-term, randomised, cohort study, MS patients receiving placebo during the RCT experienced greater all-cause mortality compared to those on active treatment. The excessive mortality in the original placebo group was largely from MS-related causes, especially, MS-related pulmonary infections.

If you are interested you can watch my presentation from last year’s ACTRIMS-ECTRIMS meeting during which I make the case for flipping the pyramid. Please note the ATTACK-MS study paradigm takes this concept of time is brain even further. Do you agree with this approach?

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

36 comments

  • As always great to have your reminders on what we need to be fighting for and why. It is a battle let me tell you. You’re feeling unwell as it is and on top of that you’ve to fight for yourself.
    I always have the memory too of being a child in the 80s and seeing my aunts neighbour in her early 20s with MS in a wheelchair. She had a modified car and we would watch her as kids with fascination manoeuvring in and out of that car. Maybe it was ten years later that she had passed away from her MS.
    Yes times have changed with dmt’s and the wonderful invention of the mri but it’s always there at the back of my mind. The question am I doing enough to avoid a similar scenario in future. She was such a lovely, happy person through all her struggles.
    Thanks for never giving up on the MS community and educating us. The regular reminders are crucial.
    It’s hard dealing with a “dinosaur”, takes a lot of energy and causes quite a bit of stress.

  • Given the nature of relapse and remitting, in countries when the patients are required to pay a large portion of their treatments, it is very hard to convince the patient until it is late. Neuros started warning all possible damages of MS, patients think is this guy over treating me? Add on top of this it is not always straightforward for the diagnosis to be made in the first place. I wish you success in making new treatment standards/making noises by flipping the pyramid. Hopefully one day the effect will reach my country.

  • And something else you might be able to help with: can you give any rationale behind the approach of a conservative ms neurologist. Is it the way they are trained early in their career or is it personal to them? It feels like politics & being affiliated to a particular party/approach when this makes little sense to ms patients and their future. For me your words and rationale make so much sense so I don’t get why they don’t to the more conservative-approach ms neuros?

    • The MS Academy for Young Neurologists will probably miss ProfGs insight..perhaps one of the saddest consequences of his accident 🙁

      • The new generation of younger MS educators are perfectly capable of getting across the message that ‘time is brain’ 😉

        • No…you could not be further from the truth…

          Seen where Dr.Freedman and Dr. Burt..say not everyone needs hsct..”If they are on therapy and doing well…that’s where they should be”…”Not everyone needs the Elephant Gun..DMT therapy is more appropriate for them”….even these guys don’t get that big name brand DMT’s still allow too much brain atrophy compared to hsct.

  • Prof G,

    I’m the biggest supporter of flipping the pyramid. However, we seem to be getting some mixed messages of late.

    1. I saw a recent paper by yourself and Prof S arguing that MS was progressive from the start and that relapses were just super imposed. Yet here you refer to Secondary Progressive MS as in the old days ie after a time with RRMS a patient converts to SPMS. If relapses are super imposed why would anti-relapse drugs make any real difference?

    2. Are drugs such as interferons (or indeed the high efficacy anti-relapse drugs) tackling smouldering MS which you have argued is the real MS?

    3. While the anti B cell drugs seem to be tackling relapses, I’ve seen some researchers casting doubt on whether they have much impact on reducing long term disability accumulation. If so, is flipping the pyramid really about getting on Lemtrada or HSCT (not easy on the NHS)? What happened to your notion of a 15 year experiment with Lemtrada ie after 15 years it should be possible to assess whether MS is an auto-immune disease or a primarily neuro-degenerative disease (if patients on Lemtrada become disabled in the long term the latter is the case)?

    Thanks

    • Re: “Are drugs such as interferons (or indeed the high efficacy anti-relapse drugs) tackling smouldering MS which you have argued is the real MS?”

      Yes, they must be because they have a modest impact on end-organ damage and long-term outcomes. What relapses and MRI activity on DMTs tell you is that the treatment is not impacting on the ’cause of MS’ and the immune system is still reacting to the cause. However, the corollary doesn’t hold, i.e. if there is no activity (relapses of MRI activity) that the disease is necessarily under control. The former is what I call tuberculoid MS (active MS with focal inflammation) and the latter lepromatous MS (active MS with no focal inflammation).

      • Thanks for your response.

        “What relapses and MRI activity on DMTs tell you is that the treatment is not impacting on the ’cause of MS’ and the immune system is still reacting to the cause.” I had a light bulb moment and this makes sense. I hadn’t really grasped this before.

        Then you spoil it with this “ However, the corollary doesn’t hold, i.e. if there is no activity (relapses of MRI activity) that the disease is necessarily under control.” I assume this is where the ever elusive add on treatments come in? Why does MS have to be so f’ing complicated! When I was diagnosed the neuro told me that I was lucky to get RRMS and that there would soon be treatments to stop all relapses / the disease (Tysabri was on the horizon). His bow tie and plush leather chair will forever haunt me.

      • Prof. G, if you personally had RRMS today m, acknowledging time is brain and trials take time to report; beyond exercise/vit. D how would you seek to address the ‘smouldering’ component of the disease you describe? Acknowledging the paucity of data, both safety and activity would you consider supplementing with ALA for example the pre-clinical and clinical data (although small numbers) is compelling and as you know it is available OTC.

    • Re: “While the anti B cell drugs seem to be tackling relapses, I’ve seen some researchers casting doubt on whether they have much impact on reducing long term disability accumulation.”

      They do have an impact, but as great as what we see with alemtuzumab or HSCT. The latter statement is based on brain volume loss data and long-term progression data. We also know that despite being NEDA there is a clear dose-effect on ocrelizumab, i.e. patients who are small and getting more ocrelizumab/kg with greater peripheral and possibly central B-cell depletion do better in terms of disability progression. This is why we were pushing for the DoDo (double-dose) ocrelizumab study, which is now happening.

  • Interesting. Personally I don’t like to read this sort of stuff because it gets me frothing at the mouth in anger at the fact it took over a year for me to convince my GP to refer me to a neurologist, six weeks for the abnormal results of my (private!) MRI to come back, and then a year waiting for a lumbar puncture to confirm diagnosis on the NHS. I know that’s just the unfortunate way things happened and not really anyone’s fault, but it’s a hard pill to swallow. I remember reading (while despairing about all this) about similar relatively worse outcomes for the people who had the placebo first for two years in the ocrelizumab trials. Since that’s essentially the wait I had, I didn’t enjoy hearing that.

    Of course you don’t want to jump the gun and start treating people at a point where they might not even necessarily have MS, but I personally as a patient would much prefer to take that risk. Not even being facetious, I reckon if I’d been waiting any longer for treatment, I’d have ended up trying to buy Tecfidera on the dark web. 😐

  • When I lived in London and was a patient at a very well known central London neurology hospital I was actively discouraged from starting interferon. I was told that the treatment was not that effective and that it would not make much of difference to my outcome. In hindsight I should never have accepted the advice. That was in late 1999. I sincerely hope this hospital has changed its practice. I now live elsewhere, where the approach to treating MS is very different. However, saying that I am now in a wheelchair.

    • Sadly your story reflects the antagonism that British neurology had against interferon-beta and glatiramer acetate in the early days. This was driven by NICE saying that these treatments were not cost-effective, which the wider neurology community interpreted as being not effective. The damage that NICE, the ABN and many neurologists did in dismissing the effectiveness of interferon in the late 90s and early 2000s is coming back to haunt us in many ways. For example, the president of the ABN, who was not an MS expert, said the money the NHS was spending on interferon-beta and glatiramer acetate would be better spent on occupational therapists.

  • I am NEDP (Progression, a/c to the MRI of Oct 2020).
    EDSS 2.0 a/c to MA Register self assessment.
    But I re-read “Brain Health: Time Matters,” before lending it to a friend in case I have a long wait getting it back (she’s shielding). It concerns me me that I may have accelerated brain loss. MD’s blog on the retinal ganglion layer added another layer of concern, especially as I’m unable to exercise until May following two minor medical treatments. Should I be lobbying my neurologist for a DMT? I take on prescription medication and no over the counter meds currently.

    • If it was me, I’d be lobbying for that.
      Or referral to an MS specialist who is known to be aggressive against MS.
      Or both.
      In the meantime I’d also be looking at vitamin D3 supplementation (yes, I know, vitamins = quackery but there’s some evidence that 2000iu – 5000iu of D3 daily can help delay things – hopefully long enough to get on a proper DMT).

  • We are all convinced by the flipping the pyramid approach Prof. Where I struggle is with the diagnosis dilemma and the need for lesions in space and time. In my own case the gap from my first episode was 4.5 years. Even if I was treated the day of my second event, I would have lived 1600+ untreated days with MS. How can this be improved / avoided?

  • Do you think the time is life paradigm will apply to CIS patients? I had to wait 7 years for my second attack to be diagnosed as MS and then a further 14 months for my next attack before being able to start betaseron in 2004. I wonder how different life would be if I had been started on treatment back in 1996 when I had my first attack of optic neuritis.

    • Yes, CIS in most cases turns out to be MS. The Queen Square CIS study showed that 80% of people with CIS go on to develop MS and that the lesion load at baseline and acquired in the first 5-years of having CIS is very predictive of long-term outcome. So depending on how active CIS is and it can be very active in some patients at a subclinical level, i.e. on MRI, this will apply.

      From a theoretical perspective, this will apply to RIS (radiologically isolated syndromes) or asymptomatic MS as well. The problem we have at the moment is that RIS is not defined as a disease, i.e. it is not MS, therefore we can’t offer treatments. With CIS we can treat high-risk patients, i.e. those with high lesion loads.

      • Results: At 30 years, 27 participants remained classified as having had a clinically isolated syndrome, 34 converted to relapsing remitting MS, 26 to secondary progressive MS and 16 had died due to MS. The mean age at baseline was 31.7 years (SD 7.5) and the mean disease duration was 30.8 years (SD 0.9). Change in medullary and third ventricular width within the first 5 years, allowing for white matter lesion accrual and Expanded Disability Status Scale increases over the same period, predicted clinical outcome measures at 30 years. 1 mm of medullary atrophy within the first 5 years increased the risk for secondary progressive MS or MS related death by 30 years by 583% (OR 5.83, 95% CI 1.74 to 19.61, p

        So i spend all afternoon thinking about this study that Doc Mouse put up

        A week or 2 ago

        After 30 years 16 patients had died due to MS

        (12.1%) (these people (86%) had no drug taken in 30 period

        The study you mention there was 81 deaths

        37 in placebo (30,6%)

        22 in IFN-1b 250 micr g (18.0%)

        22 in IFN-1b 50 micr g (17.9%)

        Why there is such low mortality from people with cis after 30 years even compared with those in your study that have taken IFN-1b and after 21 years ?
        Thanks

    • If you are in the U.K. beta interferonwas the only game in town and NiCE didn’t allow it to be prescribed until somewhere around 2002-2004
      I was there and have remarkably similar timescales to those you describe. I remember lobbying Tony Blair when I have the opportunity to meet him and being fobbed off but it was eventually made available on a risk sharing agreement with the drug company.
      On Ocrevus now , but only on my second full dose so don’t know if it’s doing anything.

  • How infuriating it is to think about my relief and gratitude when I was told in 1999, by the private neurologist in a well regarded London hospital, after my MRI showed lesions, that it miiight be MS but, since there was nothing to be done, the best thing I could do is take up my civil service posting to South Africa and enjoy life in the sun. I just wanted any excuse to not think about the horrendous possibility of a future life as a pwMS. Further tests, a confirmed diagnosis and counseling was never offered. Instead I had a minor breakdown, shook myself out of despair and suicidal thoughts, and packed my bags for Pretoria.
    It wasn’t until 2004, FIVE bloody years after that first MRI, after I moved to NY, that I had a lumbar puncture to confirm the MS diagnosis and was immediately put on Interferon (till I rebelled when I realized my deterioration was accelerating nonetheless, and put myself on a plane for HSCT in Mexico in 2017).

  • We really do have to give thanks to those patients who participated in these trials. Trailblazers who paved the way for trialling more effective treatments for those of us with MS. I really do feel for those who received the placebos though. Must be hard for them to come to terms with knowing that the delay of treatment adversely affected their health outcomes.

    • “I really do feel for those who received the placebos though. Must be hard for them to come to terms with knowing that the delay of treatment adversely affected their health..”

      Even the ones who got the BetaSeron all wound up becoming spms…it’s an ineffective therapy..think it just cut relapses by 30% or something.

      • Yes , betaferon ‘only’ cut relapses by a third . But it was the only game in town and was hard fought for against the NICE ‘ value of life ‘ argument.
        When diagnosed in 1999 by a bow tied consultant “ a smart young lady like yourself will have worked out by now that you have Multiple Sclerosis “
        Well , no I hadn’t. And I was just told to go off and carry on with life but probably avoid hot weather. That was it , no drugs , no nurse , no anything , off you pop , carry on stiff upper lip.

        Betaferon came along in about 2003 , was fantastic even at 30% reduction. It was normal to have one or two relapses a year, no real treatment just steroids . No physio or any therapy of any sort.
        I’m glad I took it looking at the reports results, as the people who didn’t have had much worse deterioration outcomes . Thank God and neurologists for high efficacy drugs now !!

  • And yet so many people on the UK are still given no treatment for PPMS, not even the only one available. Oh yes money is far more important than these people going down the what is it 2, 4, 6, 8 and oh yes death.

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