OK Neurologists, this is not about COVID but Read and Take Note..Yep Time Really is Brain and it’s not yours that you maybe wasting. Make sure you diagnose correctly and treat early

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I was once at an MS meeting and a collaegue from a country who are known for being blunt was speaking to someone who had been using an injectable and was having injection site reactions. MD2 and I were shocked when we heard “It is rubbish, throw it in the bin”. ProfG has been crusading for the Time is Brain movement, arguing that you should be diagnosed as quick as possible, and treated effectively as quick as possible….yet there are still many neurologists who are happy to do nothing and follow Watchful waiting approach. However even if you on a so called highly effective treatment and it takes 4-6 years to start effective drug you have lost out from not getting early action. ProfK has proposed the Brain Attack Trial where you are put on natalizumab on first consultation to bide some time whilst the diagnostic work-up occurs.

Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study. He A, Merkel B, Brown JWL, Zhovits Ryerson L, Kister I, Malpas CB, Sharmin S, Horakova D, Kubala Havrdova E, Spelman T, Izquierdo G, Eichau S, Trojano M, Lugaresi A, Hupperts R, Sola P, Ferraro D, Lycke J, Grand’Maison F, Prat A, Girard M, Duquette P, Larochelle C, Svenningsson A, Petersen T, Grammond P, Granella F, Van Pesch V, Bergamaschi R, McGuigan C, Coles A, Hillert J, Piehl F, Butzkueven H, Kalincik T; MSBase study group.Lancet Neurol. 2020 Apr;19(4):307-316. doi: 10.1016/S1474-4422(20)30067-3

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 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.

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.

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MouseDoctor

9 comments

  • This is the only thing that worries me about covid. Us patients being able to continue on our high efficiency DMTS like Ocrevus. I’m sure a lot of us would be pissed if we get downgraded to a less effective DMT… and God forbid a 30% effective decades old drug!! Personally I know i’d rather take my chances on catching the Covid than the MS.
    I really hope we can make our own decisions, though understandably it will be harder to give us infusions if the NHS is really stretched and the nurses are redeployed?! Not a good time for anyone or anything.
    Thanks again for all the work you guys do keeping us updated. At least it’s sunny today.

    • I have been indoors alll day too bust, although I have put WIFI into the garden using the electricity supply.

    • “Us patients being able to continue on our high efficiency DMTS like Ocrevus. I’m sure a lot of us would be pissed if we get downgraded to a less effective DMT… and God forbid a 30% effective decades old drug!! ”

      You do realize that Ritux/Ocrevus is actually a 23 year old drug.

      “Rituximab was developed by researcher Nabil Hanna and coworkers at IDEC Pharmaceuticals under the name IDEC-C2B8. The U.S. patent for the drug was issued in 1998 and expired in 2015.”

      https://en.wikipedia.org/wiki/Rituximab

  • Thankfully my neurologist already subscribes to this and put my on ocrelizumab ASAP (not before the diagnosis was confirmed with CSF and booster vaccination was done though).

    Now going one step further, should we use HSCT much earlier, too?

    • Probably not at the moment…but I believe the UK study is now ready to go….but has been put on hold due to COVID

  • “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”

    Problem 1: Many, if not most, patients are not diagnosed within 2 years.

    Problem 2: Why do immunosuppressants, which dampen a downstream effect of the real MS, work less effectively after two years? Shouldn’t an effective therapy work at all times in disease process? This is like putting out the campfire flames but leaving the cinders in the fire roaring..

    Problem 3: What is the use of this study when > 80% of people transition, even on highly effective immunosuppressants, to SPMS stage at 15-20 years. This study is not long enough and efficacious DMDs may slightly “flatten the curve” so that a RRMS may have a less bumpy ride but to the same miserable endpoint of progressive MS. Where is there any proof current in this paper that DMDs stop RRMS transitioning to SPMS as this is when most of the mobility problems become most prevalent?

    • Problem 3: What is the use of this study when > 80% of people transition, even on highly effective immunosuppressants, to SPMS stage at 15-20 years

      You can’t say that, as the really effective DMTs have not been used for that length of time and this study indicates that even after 6 years, a highly effective DMT significantly flattens the rate of deterioration. Not sure the dog in the manger attitude is warranted.

    • Problem 1: We need to train peole to refer to neurologist and diagnose quicker.
      Problem 2: Should a drug work at the same rate at all time…it suggests no. This is probably because you functional reserve in most intact but with more and more insult this gets eroded and then there is no more reserve to save.
      Problem 3: This certainily was not the case in the alemtuzumab study.

    • Age is an important factor affecting clinical outcomes in MS. The age of 35 seems to be critical with regard to the compensation of CNS damage caused by MS. Patients with disease onset later 40 years have a higher risk for disability progression independent of other disease characteristics. This should be considered when designing clinical trials or choosing DMT

      Age at disease onset and clinical outcomes in patients with multiple sclerosis on immunomodulatory treatment

      https://www.professionalabstracts.com/ectrims2019/iplanner/#/presentation/198

      Defining the risk factors for the conversion to secondary progressive multiple sclerosis: a retrospective cohort study of the Italian MS register

      Both the multivariate models showed that an age at onset >40 years, a multifocal onset, a higher baseline EDSS score and a higher number of relapses during the RR phase were all significant risk factors for the conversion to SP. Female sex, a longer duration of the RR phase and a longer exposure to disease modifying therapies (DMTs) were all protective factors against the transition to the SP. Only for the neurologist’ definition a shorter time from disease onset to the first DMT start was associated to a reduced risk of conversion to SP.

      https://www.professionalabstracts.com/ectrims2019/iplanner/#/presentation/205

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