Sunday, 4 March 2018

Ask Barts-MS - March 2018

Want to ask a question or make a point unrelated to the threads?


This is the place for you

65 comments:

  1. Has there been a policy shift of offering alemtuzumab to patients? My care provider has linked my 2nd dose to my response on MRI at 6 month interval after 1st dose. Is Alemtuzumab on the way out in favour of caldribine?

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    1. Not that I have heard of...but the appeareance of ocrelizumab and cladribine will one imagines bite into the alemtuzumab cherry.

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    2. Ocrel. and Cladribine need to show what they can do for SPMS first. Then we talk.

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    3. Re: "policy shift of offering alemtuzumab to patient.."

      Not that I am aware of. We are still waiting for permission from NHS England for the 3rd course.

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    4. Thanks Prof G, MD. I rather have alemtuzumab. I was almost feeling normal in my first 6 months and walked 5 km in 1 hr 15 mins. Although on some days feeling wobbly.

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    5. Alemtuzumab has the best brain atrophy data. So if you are data freak then alemtuzumab is the most effective licensed DMTs out there at the moment. The latter is based on brain atrophy data or end-organ damage.

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    6. Apparently at actrims the third dose of lemtrada was discussed and declared definitely effective which prof g mentioned a long time ago here is the link. Will this help convince Nice?

      http://www.ms-uk.org/study-shows-third-course-lemtrada-improves-ms-patient’s-relapse-rate-and-disability

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  2. Is spinal osteoarthritis an issue for LP's?

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    1. Re: "Is spinal osteoarthritis an issue for LP's?"

      Yes, if the posterior longitudinal ligament is calcified it can be hard to insert a needle. In this situation is better to get the LP done under x-ray guidance.

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  3. Could you please comment on the Daclizumab “melt down” and try to answer the comments raised after Friday’s post as much as possible?

    The handling of this matter along with the (lacking) communication raise serious issues of trust in Pharma’s concern for patient safety.

    Thank you!

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    1. We can't make comments for Pharma, but for me (as a none clinician), my concern is where you place daclizumab in the MS ladder of therapy on a risk:benefit analysis.

      However there is also the issue of royalities. For daclizumab the profit would be shared between Biogen and Abbvie but based on efficacy it would eat into the Dimethyl fumarate market, where Biogen get 100% of the royalty.

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    2. After the cluster of encephalitides (German and Spain) were reported from patients treated with daclizumab the EMA triggered a second Article 20 procedure to re-evaluate the benefit:risk of daclizumab as a treatment for MS. Biogen and Abbvie decided that based on this new data that it would difficult to justify using daclizumab in the current DMT environment; i.e. there is not really an unmet need that justifies the risk of daclizumab. That is when Biogen and Abbvie decided to withdraw daclizumab from the market.

      Please note it is not that uncommon for a drug to be withdrawn from the market when a safety signal emerges after a drug has been launched. This tells us that the EMAs pharmacovigilance systems are working. Please note encephalitis post-daclizumab was not seen in the clinical development programme.

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  4. If inflammation is a key part of MS as we keep hearing in the blog, why aren't PwMS automatically stuck on Non-Steroidal Anti-Inflammatory Drugs (NSAID's) such as Naproxen, Diclofenac etc. to counter this? Maybe I'm missing something obvious here?

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    1. Inflammation means a lot of different things to different people and the inflammatory mechanisms targeted by MS-DMT are different from the inflammatory aspects targeted by NSAIDS.

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  5. Response from MS-Base re: meta-analysis of the phase 3 trials, when you have it, please ProfG.

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  6. Any ideas why there seems to be such a delay with the NICE/NHS decision about Ocrelizumab for relapsing patients whereas Cladribine appeared to be approved so quickly, or so it seemed that way?

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    1. The NICE STA is in process. If you recall it was only given a license by the EMA earlier this year. Nothing really can be done until this occurs. Cladribine was given its license in June last year; 6-months earlier than ocrelizumab.

      Please note that NICE is currently only looking at the relapsing indication. The PPMS indication will happen later.The question is how much later?

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    2. NICE's open/public meeting for the ocrelizumab STA (single technology appraisal) is happening tomorrow.

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  7. I dont think there has been a delay yet. It generally takes a year for a compound to go through the NICE process from ema approval. Cladribine was atypical because it wasn't NICEd in the sme way, as it was considered to be cost effective so it got the green light about a month after EMA approval.

    Maybe a deal was done on price. We planned to do a head to head trial with alemtuzumab and not treating 600 people would have saved the NHS £32,000,000 (It wasnt funded.

    ProfG probably could tell you ther ins and outs of this but he is probably under a secrecy agreement.

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  8. How is the launch of Mavenclad going where it is approved? Is it popular? Why isn't it a 1st line treatment?

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    1. Re: "Why isn't it a 1st line treatment?"

      Because the EMA recommended we apply for a restricted license to treat highly-active MS. It can be used 1st-line in patients with highly-active disease.

      As for the launch you would need to contact Merck and ask them. We are not privy to commercial information.

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  9. Is it true that any left over symptoms after a 12 months from a relapse, you’re likely stuck with those symptoms indefinitely?
    Is there anything that can assist recovery? Exercise, diet? Etc etc?

    I’m looking to reading the series from Prof G regarding diet. I know you’re currently doing a lot of reading on the subject, alongside your day job.

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    1. Sometimes, when cortisone doesn't help, plasma apheresis does. The location of the lesions can indicate the effectiveness of the treatment http://multiple-sclerosis-research.blogspot.com/2018/03/personalising-plex-individualised.html

      Of course the sooner done the better.
      Physiotherapy can help too.
      (Not a doctor)

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  10. A friend of mine has just been diagnosed with Guillain-Barré syndrome.

    I was surprised to learn that he suffered from the same symptoms as mine (RRMS) but in a fast forward way...and that he may recover in full.

    Now I understand, that GBS is believed to be triggered by a viral infection - are there any overlaps here with the Charcot Project?

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    1. Re: "GBS is believed to be triggered by a viral infection - are there any overlaps here with the Charcot Project?"

      No not really. GBS and MS are different. We know in a proportion of cases of GBS and infection triggers and autoantibody immune response against gangliosides in the peripheral nerve myelin that leads to the symptoms. Although the symptoms are similar the disease is very different to MS.

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  11. Looking at the data about ocrevus and breast cancer it seems like there is a possible increase risk of 1 percent that occurs after 1.5 years on the med. Do you recommended that patients switch out to another med after 1.5 years? Unlike Tysabri where we at least had JC virus titers to look at least,this data is difficult to contend with.

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    1. The breast cancer risk on ocrellizumab is still undefined. The confidence intervals in terms of risk still cross 1, i.e. we are not yet sure if there is a risk or not. What we would recommend is that women on ocrelizumab are enrolled in a standard breast cancer screening when appropriate.

      Women are meant to self-examine their breasts once a month; this should be taught and encouraged. There is a lot of online content regarding this; the following are some examples:

      https://www.youtube.com/watch?v=UnJbwx9ncvY

      https://www.youtube.com/watch?v=s8dUPuejoRE

      https://www.youtube.com/watch?v=L7xjiqGwhW4

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  12. Hi, can you give any recommendation on which mri I should choose for diagnosis of MS? I have tingling in my legs and feet but so far no diagnosis. Head mri was negative so I go for spine next.

    Head mri was at a a GE signa pioneer 3t, but that is very far away from my home. Any good alternatives with great resolution and preferably short run time (also happen to have tinnitus)?

    Any comment on which sequences I should ask for?

    Any help is greatly appreciated!

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    1. I already had one 2 years ago. Mildly elevated protein but no OCB or other markers.

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  13. How about some MS science around here for a change?

    Immune modulatory effects of statins

    The immunomodulatory effects of statins in different disease models have meanwhile been supported by robust data from multiple independent groups. The potency of statins with respect to immunosuppression is lower than that of many of the established immunosuppressive drugs, which may be an advantage when immune-modulation rather than strong immunosuppression is required. Also, based on their mode of action, which is mainly via inhibition of protein geranylgeranylation and protein farnesylation, a combination strategy with inhibitors of different pathways may result in a synergism. In agreement with this, early studies on such combination therapies have been completed, combining statins with cytokine receptor inhibitors such as tocilizumab against IL-6R or JAK inhibitors. Interesting novel aspects are the increased Production of Ang-1 under certain statins, which thereby impact endothelial function, and the direct effects on T cells via calcium ion influx and IL-2 production. Overall, statins hold promise for combination therapies as they reduce cholesterol levels induced by certain immunosuppressive drugs and modulate the immune response.

    http://onlinelibrary.wiley.com/doi/10.1111/imm.12902/full?utm_content=buffer4c6de&utm_medium=social&utm_source=facebook.com&utm_campaign=buffer

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    1. Way ahead of you, we were publishing on this subject, well before the blog was a twinkle in Prof G's eye ;-) Our co-author John Greenwood is behind the statin trials in MS.
      https://www.ncbi.nlm.nih.gov/pubmed/11937568
      https://www.ncbi.nlm.nih.gov/pubmed/12626426
      https://www.ncbi.nlm.nih.gov/pubmed/15699169

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  14. I had an MRI taken six months ago. As a result of that scan, I'm now in the process of changing treatment to Cladribine. Should I be having another MRI before commencing the new DMT?

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  15. While examining human brain tissues, researchers from the University of Alberta and McGill University unexpectedly found that the tissues from people who had MS contained an extremely high level of a protein named calnexin, compared with those who hadn't had MS.

    "It turns out that calnexin is somehow involved in controlling the function of the blood-brain barrier," said Marek Michalak, a distinguished professor of biochemistry at the U of A. "This structure usually acts like a wall and restricts the passage of cells and substances from the blood into the brain. When there is too much calnexin, this wall gives angry T cells access to the brain, where they destroy myelin."

    https://insight.jci.org/articles/view/98410

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  16. Merck KGaA’s evobrutinib led to significant reductions in relapsing multiple sclerosis patients’ brain and spinal cord lesions, compared with a placebo, a Phase 2b clinical trial showed.

    Evobrutinib, also known as M2951, is an oral inhibitor of a protein called Bruton’s Tyrosine Kinase (BTK), which is vital for the development and functioning of several immune cells. These include antibody-producing B-cells and macrophages.

    https://www.prnewswire.com/news-releases/merck-kgaa-darmstadt-germany-announces-positive-phase-iib-results-for-evobrutinib-in-relapsing-multiple-sclerosis-676117323.html

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  17. I'd like to find a scientific reason for the fact that Malarone makes me feel better. I have PPMS and EBV, but no malaria or parasites. Four years ago EBV was off the charts, above 40 times the minimum, nowadays only 10 times the min. Acyclovir and a couple of months of Malarone each year have made me feel better, but if I look at this objectively, I don't know why. Both EBV and malaria bind to CD35, does this have anything to do with it?

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  18. Have u seen this?
    Yale - Science - gut E.Gallinarum leaks cause auto immunity

    https://www.genengnews.com/gen-news-highlights/leaky-gut-lets-bacteria-slip-away-and-stir-up-autoimmunity/81255571

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  19. I know Alemtuzumab can sometimes lead to a secondary autoimmune condition such as Graves' disease.
    I wondered could other DMT's lead to Graves' disease such as DMF/Tecfidera? thanks

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  20. I have a feeling you're already aware of this recent case report: https://www.sciencedirect.com/science/article/pii/S2211034818300828

    EBV and HAART #2 case report. To be featured any time soon?

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    1. Funny I was just searching on the same, profG had posted this on his twitter few days ago. It is very very interesting indeed, post if possible :)

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    2. Failure to further investigate nucleoside analogs and MS is bordering on medical negligence. There have been other reported cases of anti-retrovirals and MS in the past. Another question is how this medical student was able to start treatment with combivir without a dr. authorization? Do other patients suffering with MS have such an option?

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  21. Could this be why OCBs exist in MS??

    “Our study suggests otherwise, though, as we found that a certain type of B cell is quite abundant in the ventricles, meninges, and choroid plexus in the brains of young mice,” explained lead author Shogo Tanabe. “Even more surprising, these cells appear to stimulate axon myelination in the surrounding neurons."

    T cell research links this immune cell to learning and memory function in the meninges, but this is the first study to place B cells in the brain, aiding in myelin production during early development.

    "Our findings provide direct evidence that B cells reside in the mouse neonatal brain and promote both oligodendrocyte proliferation and neuron myelination,” explained lead investigator Toshihide Yamashita. “This suggests to us that B cell dysfunction in early development may contribute to later mental disorders, a possibility that we believe deserves further exploration in future studies."

    "It turns out that so-called natural antibodies secreted by B-1a cells induce oligodendrocyte precursors to proliferate,” Tanabe explained. “These antibodies are typically involved in immune surveillance, but in this case they promote the myelination of axons."

    https://www.nature.com/articles/s41593-018-0106-4

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  22. A social matter

    A young Stephen Hawking would never have made it in today’s age of austerity

    The late physicist was a genius and a visionary but it is hard to imagine those qualities thriving with cuts to disability support and the NHS under attack
    https://www.theguardian.com/commentisfree/2018/mar/14/a-young-stephen-hawking-would-never-survive-in-todays-age-of-austerity?CMP=fb_gu


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  23. BBC news website page today:
    Stem cell transplant 'game changer' for MS patients
    Doctors say a stem cell transplant could be a "game changer" for many patients with multiple sclerosis.

    Results from an international trial show that it was able to stop the disease and improve symptoms. Just over 100 patients took part in the trial, in hospitals in Chicago, Sheffield, Stockholm and Sao Paolo.
    Here we go again...
    http://www.bbc.co.uk/news/health-43435868

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    1. Yep, I think the abstract was published a few weeks ago

      Last week we reported on a paper by the lead author that socia media should not be trusted and yet the author is happy to use social media

      "The data is stunningly in favour of transplant against the best available drugs - the neurological community has been sceptical about this treatment, but these results will change that."

      These are an on going trial and one hopes that reports such as these do not cause prolems for the validity trial as they surely re-inforce placebo effects. Postive efficacy has been continually reported.

      In the report it states "The transplant costs around £30,000, about the same as the annual price of some MS drugs".

      "Doctors stress it is not suitable for all MS patients and the process can be gruelling, involving chemotherapy and a few weeks in isolation in hospital".

      Dr Susan Kohlhaas, director of research at the MS Society, said the stem cell transplant HSCT "will soon be recognised as an established treatment in England - and when that happens our priority will be making sure those who could benefit can actually get it".

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    2. I think you should report on this. Its flooding the news.

      Delete
  24. You're probably being inundated with this but here goes: In light of the 'game changer' news about HSCT announced on BBC1 this evening, do you think HSCT will now be available on the NHS and if so, what time scales are we looking at?

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    1. If you are willing to be randomised to HSCT...I wonder why you would be be happy with and opt for a CRAB treatment?

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    2. I wouldn't I'd opt for HSCT all the way if it were available to me. I'm currently stable on fingolimod but I'm 56 and aware that time could be running out on me before I drift into SPMS and wouldn't have the option to take HSCT

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    3. In London we have reported on the criteria we use for NHS-access to HSCT.

      Delete
  25. Thanks Mouse, I'll look into it further.

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  26. Using electrochemical stimulation and robot assisted rehabilitation techniques, researchers restore walking ability in a paraplegic rat. The study reports reorganization of neural branching in the reticular formation leads to new connections and is key to motor skill recovery.

    EPFL scientists have observed for the first time that the brain reroutes task-specific motor commands through alternative pathways originating in the brainstem and projecting to the spinal cord. The therapy triggers the growth of new connections from the motor cortex into the brainstem and from the brainstem into the spinal cord, thus reconnecting the brain with the spinal cord below the injury.

    https://www.nature.com/articles/s41593-018-0093-5

    http://neurosciencenews.com/paraplegic-rat-walks-8664/

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  27. I notice you published a research paper from April 2016 on Gender Identity Disorders - see link: http://multiple-sclerosis-research.blogspot.com/search?q=gender+identity. This research concludes an increased MS risk both inherently and secondary to treatment in undergoing male to female conversion. However, neither the MS Society nor the MS Trust have a single member of staff with information on the subject. To the best of my knowledge, Gender Identity Clinics are currently unaware of any risk. When will this research be recognised and alternatives be provided to those at risk? And.....how will those who in the meantime have most definitely been affected
    be treated?

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  28. I notice with interest that your website includes research on gender identity disorders and multiple sclerosis risk by Julia Pakpoor in April 2016 - http://multiple-sclerosis-research.blogspot.com/search?q=gender+identity. When I contacted the MS Trust and the MS Society recently they were unaware of any research and were unable to put me in touch with anyone for advice on GID's & MS. Will you be taking this research on board? If so, when will that happen? NHS Gender Identity Clinics also appear unaware of the risks so those people who present to them for male-to-female conversion are at far greater risk. What are their alternatives?

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  29. What do think about this and how it relates to MS?

    Data show big rise in deaths of people with neurological disorders

    BMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k1278 (Published 19 March 2018)
    Cite this as: BMJ 2018;360:k1278

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  30. How similar are biosimilars?
    I see rituximab biosimilars are emerging.
    But how is this technically possible? I read elsewhere that you have to have exactly the same cell line to produce exact antibody, so if Roche owns the line what is the reason to give it to competitors.

    In other words, are those drugs identical or just another anti-CD20 mee-toos?
    This from Sandoz: https://www.novartis.com/news/media-releases/sandoz-biosimilar-rituximab-regulatory-submission-accepted-european-medicines

    Biocad (page in Russian) https://biocad.ru/product/autoimmune_acellbija/
    They all say it’s rituximab.

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    Replies
    1. Some MS patients have started Truxima to save from Rituxan costs

      Delete
  31. Macrophages stimulated to produce potent anti-inflammatory molecule

    Using human cells and mice models, the team have uncovered a new metabolic process that switches off inflammation.

    The macrophage takes the nutrient glucose, whose day job it is to provide energy, and surprisingly turns it into itaconate. This then blocks production of inflammatory factors, and also protects mice from the lethal inflammation that can occur during infection."

    https://www.news-medical.net/news/20180329/Macrophages-stimulated-to-produce-potent-anti-inflammatory-molecule-in-new-study.aspx

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  32. How common is autoimmune hepatitis among pwms?

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