Saturday, 1 December 2018

Unrelated Comments & Questions - December 2018

Sometimes you want to say something unrelated to the thread or ask a clinical question or some other MS-related question that has not been answered in past. This is the place for you.


28 comments:

  1. Is it true that alemtuzumab doesnt change the rate of converssion to secondary progessive? Recently i read some papers that say that

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  2. Which papers are you talking about the one i ready Tuohy et al 2015 suggested that the conversion rate was low. if you start late then the risks are higher. we should not be wasting your brain with the CRABs

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    1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077906/

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    2. This paper is about the CRAB drugs interferon and copoxone and provides yet more evidence why it is impperitive to get MS under control asap

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  3. Thank you for all your great work and for helping PwMS and their families understand the condition. I follow your blog daily, it has been an incredibly useful resource.
    I had a question about the extension of the Care-MS I trials (the ones where alemtuzumab was administred to recently diagnosed patients). Reading about the long-term, 8-year studies, the data on disability is impressive, with most people not worsening their disability or even improving. But what about those whose EDSS *did* worsen? Any data showing by how much their EDSS status changed after the 8 years? Thanks!

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    Replies
    1. Negative data from Genzyme...Not going to happen. This is a reason why all data should be made public.

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  4. Your comments on recent FDA warning for alemtuzumab and a severe adverse reaction much appreciated:

    https://www.medscape.com/viewarticle/905768

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  5. Thanks. Yes the FDA has issued a warning a on a risk of stroke. Seeing as ProfG hs gone AWOL, I don know if he will comment.

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  6. Is the risk for PML higher in an individual who was on Tysabri for three years, discontinued for two, and now thinking about starting Tecfidera ? Is it a cumulative issue?

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  7. I've read a few things recently that say that people of black ethnicity have a different disease course in terms of disability and progression. This is all data from the US and France. Does the same relate to minorities in the UK?
    I have a very vague recollection of this being mentioned very briefly in a blog post by Prof G once.

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    Replies
    1. Older people black people and males tend to be more likely to get progressive MS

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  8. From ProfGs twitter

    Bridging the gap between vaccination with Bacille Calmette-Guérin (BCG) and immunological tolerance: the cases of type 1 diabetes and multiple sclerosis.

    BCG appeared to delay the disease progression in early MS; the effects were long-lasting (years after vaccination) in both diseases. The recently demonstrated capacity of BCG to boost glycolysis may explain both the improvement of metabolic indexes in T1D, and the more efficient generation of inducible regulatory T cells, which counteract the autoimmune attack and foster repair mechanisms.

    https://www.ncbi.nlm.nih.gov/pubmed/30447407?dopt=Abstract

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  9. Long-Lived Plasma Cells are not a single subpoulation

    They can live up to 3,014 and 542 years

    Long-Lived Plasma Cells Are Contained within the CD19(-)CD38(hi)CD138(+) Subset in Human Bone Marrow

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4680845/

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    1. or about 24hours in culture. It is all about have other cells to keep them going

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    2. ;)

      Nice

      Just finnish reading this one that answer that question

      Factors of the bone marrow microniche that support human plasma cell survival and immunoglobulin secretion



      Its not only cells

      ;)

      Human antibody-secreting cells (ASC) in peripheral blood are found after vaccination or infection but rapidly apoptose unless they migrate to the bone marrow (BM). Yet, elements of the BM microenvironment required to sustain long-lived plasma cells (LLPC) remain elusive. Here, we identify BM factors that maintain human ASC > 50 days in vitro. The critical components of the cell-free in vitro BM mimic consist of products from primary BM mesenchymal stromal cells (MSC), a proliferation-inducing ligand (APRIL), and hypoxic conditions. Comparative analysis of protein-protein interactions between BM-MSC proteomics with differential RNA transcriptomics of blood ASC and BM LLPC identify two major survival factors, fibronectin and YWHAZ. The MSC secretome proteins and hypoxic conditions play a role in LLPC survival utilizing mechanisms that downregulate mTORC1 signaling and upregulate hypoxia signatures. In summary, we identify elements of the BM survival niche critical for maturation of blood ASC to BM LLPC.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135805/


      Our study also provides strong evidence for a survival benefit induced by hypoxic conditions that recapitulate the distinct BM microenvironment. Hypoxia in media alone afforded no survival advantage. However, hypoxia enhanced ASC survival above and beyond the benefit imparted by the addition of APRIL to the MSC secretome when added together. In contrast to other conditions tested, the effects of hypoxia were noted after 7 days in culture, a time frame that suggests the engagement of adaptation programs critical for maturation mechanisms

      Obrigado

      Por comemtar

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  10. New T cell discover

    https://medicalxpress.com/news/2018-12-newly-cells-role-cancer-diseases.html

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    Replies
    1. Interesting, I have MS, high antiphospholipid antibodies and negative oligoclonal bands :P

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  11. More memory b cell biology


    The establishment of resident memory B cells in the lung requires local antigen encounter

    https://www.nature.com/articles/s41590-018-0260-6

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  12. 1. Have you seen patients who have had Cladribine -IV or oral- for more than 6-7 years and didn't need further treatment?

    2.How do you interpet the difference in the success rates between the aggresive pwMS and the non aggressive in Cladribine trials? Does it have to do with B cells inflammation, which is responsible for only a specific part of the disease expressions?

    3. Can you comment on the drug's mediocre effect on brain atrophy rates (taken that it penetrates brain when Lemtrada does not)?

    Thank you.

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  13. We have some people from CLARITY our subcutaneous programme only started in 2014 and it is not controlled so you will not get the answer.

    What do you mean aggressive
    ..those that got HSCT. The rate on relapse rate was a good as any otHer DMT.
    DIAGNOSIS TO TRIAL START ALEMTUZUMAB 2 YEARS
    DIAGNOSIS TO TRIAL START CLADRIBINE 9 YEARS.

    We should do head to head studies.

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    1. Aggressive as highly active. Don't know were HSCT came from.
      I am talking about this:
      https://www.merckgroup.com/en/news/greater-treatment-effect-02-05-2018.html

      From your answer I understand that we know too little yet for long lasting results and we must not talk about brain atrophy because its kind of a deal breaker for solo-B cell theory. Is that so?

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    2. No talk away, it is up to the likes of Merck and Roche to do earlier studies to show better effects on atrophy, maybe you need t cells for potent inhibition of brain atrophy know

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  14. I am very interested in research regarding the antioxidant fisetin, which seems to be giving tantalising results regarding microglia. Anyway, grapes and apples seem to be a good dietary source, and I love grapes and apples. :)

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527824/

    https://www.ncbi.nlm.nih.gov/pubmed/24972270

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689181/

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  15. HSCT Australia

    https://msra.org.au/news/australian-ahsct-trial/?fbclid=IwAR1vSwdPlAUNn3N9cKz3GSX6mhFi2Lz4q8smWGvr52QVUqtFWI6TRPZtVFY

    https://jnnp.bmj.com/content/early/2018/12/11/jnnp-2018-319446

    Prospective phase II clinical trial of autologous haematopoietic stem cell transplant for treatment refractory multiple sclerosis

    Results Thirty-five patients (20 RRMS, 15 SPMS)
    completed AHSCT, with a median follow-up of 36 months
    (range 12–66). The median Expanded Disability Status
    Scores (EDSS) was 6 (2–7) and patients had failed a
    median of 4 (2–7) disease modifying therapies. 66% failed
    treatment with natalizumab. EFS at 3 years was 60%,
    (70% RRMS). Sustained improvement in EDSS was seen
    in 15 (44%) of patients. There was no treatment-related
    mortality. A sustained rise in CD39+ T regulatory cells,
    immunosuppressive CD56hi natural killer cells and ablation
    of proinflammatory mucosal-associated invariant T cells
    was seen for 12 months following AHSCT in patients
    with MS. These changes did not occur in patients with
    lymphoma receiving the same chemotherapy for AHSCT

    Eighty-three per cent of patients remained free of new/
    enlarging T2 lesions and 96% free of gadolinium enhancing
    lesions on last follow-up MRI, as determined by central neuroradiological
    review. While Atkins et al reported complete ablation
    of gadolinium enhancement and a single patient with new
    lesions post-AHSCT, this occurred with a high intensity regimen
    including busulfan and graft manipulation.11 Patients in the
    HALT-MS trial28 had an 86.3% MRI activity-free survival at 5
    years, suggesting intermediate intensity conditioning is able to
    achieve substantial improvements in radiological measures of
    disease activity. Consistent with other studies,12 28 mean annualised
    T2LV in our cohort decreased by −2.8% between the
    post-AHSCT baseline and last follow-up MRI scans. Annualised
    brain atrophy between rebaseline and last follow-up images,
    as measured by NeuroSTREAM LVV enlargement, fell within
    the healthy control range in the majority of patients. Atkins
    et al have demonstrated that centralisation of MRI review has
    provided reassuring data on the lack of progression of cerebral
    atrophy highlighting the importance of this analysis.11 In our
    study, atrophy was assessed as an exploratory outcome with
    Neurostream, a novel measure of LVV that is applicable to clinically
    acquired 2D or 3D FLAIR images and withstands inherent
    ‘real-world’ variability in brain imaging.
    Our overall survival of 100% confirms recent findings from
    the European Society for Blood and Marrow Transplant
    (EBMT) that a site’s transplant experience is likely to be a
    significant predictor of patient outcomes.31 Of interest, natalizumab
    was previously administered in 66% of our patients.
    Seventy-nine per cent of our patients had positive JC virus
    serology and yet there were no documented cases of PML at
    a median follow-up of 3 years. This analysis provides some
    reassurance to patients and their physicians that AHSCT can
    potentially be offered safely after natalizumab treatment.

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  16. Do lesions always show on an mri? Even in consecutive follow ups, are there any cases where the individual is eventually diagnosed with ms after having many mris in the past with no lesions? Have you ever known this to happen?

    Many thanks

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