Escalation from Low Efficacy RIP?


About Time!

Paradigm shifts: Early initiation of high-efficacy disease-modifying treatment in multiple sclerosis.
Hartung HP, Meuth SG, Thompson AJ.Mult Scler. 2021;27(10):1473-1476. doi: 10.1177/13524585211033190.PMID: 34472985 No abstract available.

Clinical development of disease-modifying drugs for the treatment of multiple sclerosis (MS) has been exceedingly successful over the past three decades. This in part reflects advances in our knowledge of the pathogenetic underpinnings of the disease and improvement in trial design permitting more rapid translation. The available arsenal contains up to 18 drugs depending on countries location and income that differ in efficacy, route and timing of administration, side effects, risks and tolerability. Starting with the injectable interferons and glatiramer acetate, the introduction of the first monoclonal antibody curtailing lymphocyte invasion of the central nervous system (CNS), the first long-awaited oral agents and the high-efficacy lymphocyte-depleting monoclonal antibodies, many patients with the relapsing forms of MS and fewer with progressive disease clearly receive therapeutic benefit from these disease-modifying agents.

Real world evidence, which defines treatment effectiveness and implementation in an environment beyond the strict confines of randomized drug trials, is collected from large data sets, health insurance databases, comprehensive national registries and international databases.

The importance of early treatment initiation was the clear message from the Swedish STOP-MS project which adopted this approach. They compared patients who started DMTs after 3 years of disease onset with those who embarked on DMTs within 1 year of disease onset. Later, DMT commencement carried a hazard ratio of 2.64. For each year of treatment delay, the risk to reach the Expanded Disability Status Scale (EDSS) 4 increased by 7.4%. These results were recently confirmed independently on a much larger patient cohort in the first report emanating from the Big Multiple Sclerosis Data (BMSD) network 

Drawing on data from 11,871 patients, the authors determined four outcomes: 3- and 12-month confirmed disability worsening and assignment of irreversible EDSS 4 and EDSS 6. Delayed first treatment was associated with an elevated risk to develop 3- or 12-month confirmed disability worsening (18% and 31%, respectively) and increased the risk of reaching EDSS 4 and EDSS 6 by 40% and 53%, respectively.

In aggregate, studies clearly underscore the greater benefits people with MS receive when DMTs are commenced early after disease onset. Given the ever broadening armamentarium to treat MS and the appearance over time of more effective DMTs, two fundamental management approaches have been developed and differentially adopted by neurologists but accumulating evidence may well shift the balance.

The escalation approach, long in favour, advocates use of a moderately or medium effective DMT initially and switching or escalating to other more efficacious and potentially higher risk agents should disease activity be insufficiently controlled. This philosophy is clearly dominated by safety concerns and the assumption that in many instances the disease may not run a severe course.

Early high-efficacy or early intensive therapy is based on the idea that one should capitalize on a window of opportunity open for drugs to unfold their maximal anti-inflammatory actions when they are most likely to be most beneficial. Patients deemed to have a poorer prognosis with clinical and radiological evidence of high disease activity would receive high-efficacy or intensive therapy. Natalizumab, alemtuzumab, rituximab, ocrelizumab, ofatumumab, cladribine or mitoxantrone are considered to belong to his group. Most experts would include the sphingosine-1-phosphate receptor modulators in this category.

Exploration of the relative merits of either strategy is best done using the gold standard of a randomized controlled trial. In fact, two such studies are currently underway: the Traditional versus Early Aggressive Therapy for MS (TREAT-MS) trial (NCT03500328) recruiting 900 participants is a pragmatic randomized single-masked controlled study. The Determining the Effectiveness of earLY Intensive versus Escalation approaches for the treatment of Relapsing-remitting MS (DELIVER-MS) trial (NCT03535298) enrolling 800 patients is open label. Neither trial will read out before 2024/2026……….

While it is now undisputable that early initiation of DMT generates greater benefit to patients both in the short- and long-term, deliberations are still ongoing as to whether the escalation approach commencing with medium-efficacy DMTs should be superseded by the high-efficacy/early intensive management approach. Given the large body of convergent evidence that has been accumulated recently through careful interrogation of large databases, there may now be sufficient evidence for the community to consider a new treatment paradigm now rather than waiting until the conclusion of the two ongoing controlled trials.

Iaffaldano, P, Lucisano, G, Butzkueven, H, et al. Early treatment delays long-term disability accrual in RRMS: Results from the BMSD network. Mult Scler 2021; 27(10): 1543–1555.


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.


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.


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.


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.


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.

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.

About the author



  • “evidence of high disease activity would receive high-efficacy or intensive therapy. Natalizumab, alemtuzumab, rituximab, ocrelizumab, ofatumumab,”

    How can these be described as intensive therapy if none of them get the ms brain down to normal
    yearly brain loss..? And of course none of them stop the evolution of secondary progressive ms…they
    can only delay it.

    Sorry not good enough…just more false DMT hope Neuros love to put out to make it appear progress has/is being made.

    • OK, yes, we’d all love faster progress but I have a clear memory of what MS meant to my parents’ (wartime) generation. I heard stories of various friends of theirs who had someone with MS in the family. It was a death sentence, a living death, spoken about with dread and in hushed tones. Those stories haunted me when I got my own dx and so I was desperately glad to be offered a DMT plus clear advice on how to manage the condition. I wish stronger drugs had been around in 2003 but I refuse to be anything other than grateful for the progress that has been made.

      • “Maybe they do if treated early, and the BVL/progression is resulted from previous damages.”

        No…this is always the failed logic of failed science..
        ‘It would have worked if only we would have used it earlier”
        “The therapy would have worked but we designed the trial wrong”
        You can only fool others/yourself for a short time…before reality sets in.

    • I have seen data from Sweden where the brain atrophy rate is 0.18 which is normal aging range.The only place that can answer your question properly is Sweden as they are treating early from diagnosis , until we get rid of the CRAB drugs as a first line option then the next generation wont be helped either

  • I remember a article buy Prof G when nice refused to recommend all the crab meds stating it reduced patient choice. The sad fact is 50% of patients do very well on crab drugs depending on their genetics. Famous western music singer Clay walker has been relapse free for 20 years. Just taking crab drugs. But we all know. Only real effective treatments are HSCT and ale.tuzumab. And before you say it, MS is not B mediated disease so get over it and let the research move on!

    • “Famous western music singer Clay walker has been relapse free for 20 years.”

      Doesn’t matter “relapses aren’t the disease”..someone has no relapses…but they still
      are undergoing ms brain damage and turn into progressive ms. Most likely
      he’d be relapse free totally untreated as the natural nistory shows relapses fade
      away slowly over the first 10 years of ms. Again relapses aren’t the disease…relapses
      fade away but ms does not.

      Plenty of people have been rrms for 20+ years edss 0-2…but they turn progressive and
      within the 1 year are edss 6.5…Some one posted here that he was rr for 50 years untreated
      before he turned progressive…and then it was a night and day difference.

      No symptoms and progression for 50 years..and then nothing but symptoms/progression. You don’t hear about this from the drug co. or ms societies though…doesn’t fit the narrative they sell DMT.

      So this could be Clay Walkers 20 year relapse free brain…or anyone w/ms
      Hopefully if you have hsct this isn’t happening to your brain…but we know plenty
      of people fail …or respond initially but wind up progressing at the 5-10 years post hsct.

      “Time-lapse MRI movies reveal bright spots, representing multiple sclerosis brain lesions, that form and then grow, shrink, or disappear over 12 months in a man with RRMS—who experienced no flare-ups of symptoms in that period.”

      • Relapse is the real MS. When first the immune attacks the nylon the body repairs itself. As the repair cells are clustered around the attack site. The immune learns and infers the repair cells as enemy and attacks them. So progressive MS is just relapse MS with no repair. That’s why progressive MS 9s diagnosed much later in life. This probably the only degenerative disease that has cured and sitting in vault in some pharma head office.

        • “Relapse is the real MS. When first the immune attacks the nylon the body repairs itself. ”

          No…sorry this is terribly wrong on many levels.

          First you have confused myelin with nylon fabric.

          Second it’s now thought that there is more switching
          from damaged to undamaged brain than actual repair
          in ms relapses…So in progressive ms there is less reserve
          of undamaged brain to switch over to,

          “That’s why progressive MS 9s diagnosed much later in life.”

          No…people can be diagnosed progressive in the first 3 years
          of ms.

          This is what happened in the first hsct trials in
          1999-2003. People were diagnosed spms and edss 6.5 and
          they recovered to edss 2-3….and that’s where they remain
          20 some years later. Meanwhile all the people who were low edss back in 2000 are now spms because they were not given
          hsct but useless DMT’s.

          • Oakley Dockley. Nylon stupid word predictor in android. Mind you if the nerve covering were made of nylon…..

  • CASE STUDY- My cousin (female) and I (male), both (mid 60’s) have MS, myself since 1988, she since about 1995. I, interferon 1995 on, she, steroids only. We are both about the same age, ambulatory with limitations (no running; be careful where you walk, use a cane when stability is threatened), and other stuff- fatigue, bladder issues, but overall not too bad. We are surprisingly about the same today.

    But I can say, I was really falling apart before starting my DMT. I was no longer remitting 100% and I had several (it seemed) areas of deterioration. So at the same time as starting Betaseron (Interferon Beta1-b), strong steroids were given to me for the 1st time and inflammation was explained to me with the directive to immediately treat any (even slight) hint of relapse with strong steroids. (Doctor was treating inflammation and saw that as the culprit.) Treating immediately meant within 2 or 3 days. (I improved slowly over time- markedly, but no quick recovery.) By 2000 I remained “NEDA”, and seems, about that way now, as well. I regained most of what I lost and remained stable. My cousin was also treated (exclusively) with steroids during hospital stays. She did the intravenous steroids a half dozen times and was also on a milder daily dose for a long time. I did 3 intravenous treatments and 4 or 5 strong oral treatments (early on, only.)

    Knowing then, what I know now, would I have preferred a high efficacy DMT? Not if it were a B cell depleting therapy. The pandemic, I believe, has changed the entire equation. In addition to MS, does one really want an additional new burden of being worried about all that, including behavior changes ad infinitum?

    So in summary, cousin- steroids only, myself- interferon + steroids. 25+ years later, about the same outcomes. We each believe our individual courses of treatment are responsible for our outcomes and we made the right choices, as you would expect, given our (relatively) positive outcomes. Keep in mind the pandemic may make preferences now, harder to arrive at.

    • “My cousin (female) and I (male), both (mid 60’s) have MS, myself since 1988, she since about 1995.”

      Pender says ms progression is controlled by cd8+ t cell levels which are inherited.
      So it makes sense that both you have had the same progression.
      Steroids however are simply a band aid to speed up ms recovery from relapses…
      they don’t affect the disease process…which is what caused the inflammation in the first place.

      You guys haven’t worsened because you haven’t turned sp. I know it seems like you’ve
      had ms forever and you feel the worst of it is far behind you….unfortunately it’s not…this disease is for life…and people on this blog find themselves sp and suddenly worsening
      after 40 or 50 years of easy manageable disease. I would suggest hsct for both of you…but
      sense you are very risk adverse..but don’t think you realize the risk you run of undertreated ms.

      “It also occurs in healthy blood relatives of patients with autoimmune diseases, suggesting it is genetically determined. Here it is proposed that this CD8+ T-cell deficiency underlies the development of chronic autoimmune diseases by impairing CD8+ T-cell control of Epstein-Barr virus (EBV) infection”

  • Like Prof G has said before, there are many patients that remain well with no obvious disease activity, no relapses, no new MRI lesions on first line treatment. i am sure we agree that they should not take any stronger treatment now . so i guess it worked well for them and is still working well. i assume for many it was the right decision to follow the escalation approach and they dont have to worry about COVID vaccination antibodies. So now we can monitor the disease with MRI and can escalate quickly ( as opposed to the old times) , i am still uncertain of what is the best initial treatment approach. I can see the better short term results with the monoclonals but i dont know about the long term. I really dont know the answer . That is the reason i still think we need randomised trials rather than look what happened many years back when we didnt have MRI and we were not escalating fast enough . call me traditional , but many times we have been fooled by observational data. CONFLICT OF interest : i am one of the investigators of the DELIVER MS study

    • “Like Prof G has said before, there are many patients that remain well with no obvious disease activity, no relapses, no new MRI lesions on first line treatment.”

      First line treatment is the same as no treatment.

      Writer Joan Didion was diagnosed in 1972…20 years before first dmt.
      In Dec. she’ll be 88 no progression…no disability and no DMT ever.

      If fist line treatment worked they would work on more people…first line
      drugs only work on people who need no treatment at all.

    • “Like Prof G has said before, there are many patients that remain well with no obvious disease activity, no relapses, no new MRI lesions on first line treatment.”

      Other thing is people can do well for 20..30..40..and yes even…50 years and suddenly find
      their rrms is spms and in 1-3 years they now use wheelchair. It is what it is.

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