Want a full or half dose?….Does it matter? Stop eating too much.

W

Yesterday, we had the online challenge from ProfG about whether MD is only interested in targeting relapse and not the real MS. I was asking about the interval between dosing with ocrelizumab and questioning how much more information we need to know that simply dosing at 6 months was more than is needed for many people. This is based on the idea that cells within the memory B cell pool are important. ProfG countered this by making the argument, (which he would as an Investigator of the double dose study), that we are actually underdosing and that by double-dosing we may be able to affect progression, the so called real MS. This was based on the suggestion that smaller (lighter) people progress less than the bigger people who don’t deplete their B cells as well.

However, before you are thinking he has started a Civil War, I have no issues with extending the the interval or doubling the dose. If you double the dose you may well get more into the brain to target progressive MS. However, it means that the antibody will be circulating for at least another month because the half life is about a month (it takes a month for half of the drug o break-down) . So you probaly could extend the interval of dosing between the dose even more. Maybe enough time for a treatment-free pregnancy, no relapses and less progression.

However, one of the readers made a comment and so the paper published below is very pertinent to the argument. So is it the dose? or is it the issue that the recipients were just fat?….So the double dose is not what will be the key but being overweight is the issue. , as being obese contributes to progression, so being smaller you will not progress. If the obesity is the issue than double-dosing may not affect this. So profG, more issues to think about. Is waist size the difference?

In the phase III studies having a BMI over 25 was associated with progression. Another question In the cladribine CLARITY trial a near double dose was used, did it make a difference in progression? or is it not relevant as cladribine gets in the brain? Are there other ways to target smouldering MS? Big questions….. but in terms of the question above, the double dose-study is being done and you will hopefully get an answer. I hope the double dose reduces progression.

Bodyweight Measures and Lifestyle Habits in Individuals with Multiple Sclerosis and Moderate to Severe Disability.Livne-Margolin M, Tokatly Latzer I, Pinhas-Hamiel O, Harari G, Achiron A.J Clin Med. 2021 May 12;10(10):2083. 

Multiple sclerosis (MS) is a chronic disease marked by progressive disability and decreased mobility over time. We studied whether individuals with MS of higher disability levels will be more overweight/obese as a result of their immobility and/or recurrent steroid treatments. In a prospective study, 130 individuals with MS and significant disability were classified according to the Expanded Disability Status Scale (EDSS) score as belonging to four groups: EDSS 3.0-4.0 (n = 31, 24%), EDSS 4.5-5.5 (n = 24, 18%), EDSS = 6.0 (n = 44, 34%) and EDSS ≥ 6.5 (n = 31, 24%). Medical history, body mass index (BMI), waist circumference and the level of engagement in physical activity were obtained. The mean ± standard error age was 55.8 ± 0.5 years, disease duration 18.2 ± 1.0 years and EDSS score 5.5 ± 0.1. Disease duration, the number of steroid courses per disease duration, weight, BMI and physical activity did not differ according to the four disability groups. The mean waist circumference increased significantly with increased severity of EDSS, p = 0.03. Increased disability in individuals with MS was not correlated with disease duration, lifestyle habits or overweight/obesity. However, increased disability was associated with central obesity.

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

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13 comments

  • The ocrelizumab-dose effect on disability progression was linked to peripheral B-cell depletion and not weight. There is no way Roche would be spending $300+M on their high-dose studies if it was due to obesity. The trial statistician working on this study is super-sharp and really knows what he is doing. I suggest you look at the embedded slide show for details and the science that underpins the study design.

    The real question is it better peripheral B-cell depletion or better CNS B-cell depletion that is driving the greater impact on smouldering MS? Based on some unconventional MRI data I suspect it is the latter.

    P.S. BMI does play a role as well, which is what the #BackTo21 challenge is all about

    • Is the ocrelizumab-dose effect on disability progression linked to peripheral B-cell depletion or the weight of the patient?

      As Harry Hill would say “There’s only one way to find out: FIGHT!” It’s David “Big Daddy” Baker v Gavin “Italian Stallion” Giovannoni.

      You sound like a couple of schoolboys fighting over who gets to sit next to the teacher on the school trip to the zoo! Please shake hands and make up. A group hug is needed.

      Your little spat reminds me of the best story of 2018 (not a great day for the medical profession):

      https://www.thesun.co.uk/news/7141947/surgeon-punched-colleague-spain-holiday-row-laura-kuenssberg-smile/

    • Forgive the segue, but related to weight loss; laziness on my part, but have you identified an optimal intermittent fasting regimen for yourself – I am keen to incorporate.

    • It seems that there are no data on B cell depletion, it says drug exposure and shows that higher concentration of ocrelizumab in the blood is connected to less disability. However if ocrelizumab goes in to the brain killing b cells, it should be ”consumed”, so the concentration should be lower with less disability or?

  • If you have MS the question you really should be asking is would you rather be NEIAD (no evident inflammatory disease activity) or NEIAD-AND-NEOEOD (no evident ongoing end-organ damage) and how is the best way to achieve these targets? This question is what MS and its future treatment are all about!

    • I think the real question is how to get to NEOEOD (and some would ask at what price, personally HSCT and alemtuzumab would be acceptable risks if that was the path…)

      • “personally HSCT and alemtuzumab would be acceptable risks if that was the path…”

        hsct has the best chance…all the cure talk here is too much…seems like
        only 30% get cured.

        Out of 10 treated here in Sweden…only 3 were cured…2 still had active ms..
        and 5 were in remission.

        “Sustained complete remission was defined as ‘no evidence of disease activity-4’, sustained for a period of at least 5 years without any ongoing disease-modifying treatment.
        Furthermore, MS was considered as ‘resolved’ if intrathecal IgG production and cerebrospinal fluid neurofilament light levels were normalized as well.”

        https://multiple-sclerosis-research.org/2019/07/hsct-is-it-remission-or-is-it-a-cure-for-ms/

        comment from that page:
        “My post HSCT hematologist Dr. who knows EVERYTHING about everything dealing with HSCT says that they have been saying for years that HSCT should be a frontline treatment because their perspective coming from cancer treatment is hit it with the biggest drug you have and kill the disease. Neurologist’s perspective is do the lease impactful thing possible to avoid doing any harm.”

  • Very rare opportunities to hear more from Immunologists 🙂 Thank you MD & MD2 making more noises. Although bit more on Prof G’s side on this one as data looks too good (Prof G’s slides) if BMI is the only contributing factor.

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