January Q&A 2019

J
The New Year has arrived and Now has the Q&A post use it to ask those questions that are unrelated to the posts.

I have not put a snowy picture because in my Garden the buds are popping and the new leaves are arriving, I fear to be eaten by the next “Beast from the East”, so for the insomniacs or early risers, we have a lunar eclipse.

About the author

MouseDoctor

62 comments

  • Could you please update me as to what the uptake of the third alemtuzumab has been and is the general consensus that if you have had breakthrough on two is it better to have a third alemtuzumab or move on to something else?

  • The data is out there (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595278/), I dont have the phase III in my head but remember the Cambridge data and the third alemtuzumab drove many more people into NEDA.

    But one needs to check your lymphocyte count to ensure that you are depleting, if you are not then the drug is not working (this will occur in very few people).

    Maybe ProfG will comment

    • Cumulative NEDA rates drop with time so by the time you are at 6-7 years out about 35-40% of 1st-line are NEDA and in switch patients this is in the order of 25-30%. This is however the trial patients and it is my impression that the retreatment rates are lower in real-life. The latter is not surprising as we are probably treating a less active patient population in real life.

  • Thanks for that hopefully someone will reply. I know something like 55% of people need and respond well to a third round but I just wondered what the general uptake has been by hospitals especially as there are New Kids on the Block

    • Too soon to tell. We have only recently been given permission to use a 3rd course and have done so in a small number of patients. Prior to the green-lighting of the 3rd course by NHS England we had to switch some of our active patients to other DMTs.

    • Which other dmts did you offer those patients before the third course of alemtuzumab was approved especially as alemtuzumab was supposedly strongest available before the third course was available and assuming those people had already tried natalizumab?

  • If one has not had any new enhancing lesions on MRI's for 5 years does that mean they do not have "active MS "? Do you take a DMT to prevent the possibility of a future relapse?
    Also, I know in the USA Ocrevus is approved for PPMS, but if MS is one disease shouldnt it work for SPMS too?
    Thanks for your dedication!

    • The detection of enhancing lesions is hit and miss. As lesions only enhance for ~3-4 weeks you only really looking at the last few weeks of activity with Gad. More importantly is whether or not you have new T2 lesions; this is the integrator of disease activity and more sensitive to change.

      Yes, ocrelizumab works in SPMS as well. It has an impact on disease progression independent of relapses (PIRA) to the same degree as it has an impact in PPMS. This is why it is licensed for relapsing forms of MS, which is a catch all term for RRMS and R-SPMS.

  • The black swan is 🙂

    Alive and Kicking

    Association of Rituximab Treatment With Disability Progression Among Patients With Secondary Progressive Multiple Sclerosis

    Key Points

    Question Does disability progression among patients with secondary progressive multiple sclerosis treated with the monoclonal anti-CD20 antibody rituximab differ from that among such patients never treated with rituximab?

    Findings In this cohort study of 88 propensity score–matched patients, those treated with rituximab had a significantly lower Expanded Disability Status Scale score for up to 10 years of follow-up and significantly delayed confirmed progression compared with matched controls. No associations between confirmed progression and individual patient baseline characteristics were identified.

    Meaning Therapeutic options for patients with secondary progressive multiple sclerosis are limited; however, these findings suggest that B-cell–depleting therapy may be beneficial

    –What you gonna do when things go wrong?
    What you gonna do when it all cracks up?….

    …..

    Rituxan of course

    https://jamanetwork.com/journals/jamaneurology/fullarticle/2719699?guestAccessKey=17fb9684-d054-4bd4-a067-c9e3bb1b9462&utm_source=silverchair&utm_medium=email&utm_campaign=article_alert-jamaneurology&utm_content=olf&utm_term=010719

    🙂

    Obrigado bom ano

  • Are those with arthritic hips more likely to develop osteonecrosis following steroid treatment for relapse, if so would hip replacement be encouraged in a pwms with advanced arthritis to avert problems in treating later relapses?

    • Rheumatoid arthritis, but not osteoarthritis is a risk factor per se for avascular necrosis. Steroids are an independent risk factor for the development of avascular necrosis, but the use of future steroids should not be the recommendation for hip replacements. Early mobilization is key after joint surgery as is physiotherapy.

  • Thank you for all the interesting material published and discussed on the blog!

    Question:
    Does retinal thinning after severe cases of optic neuritis ever stop – is it a chronic process? Damage of optic tract axons leads to death of retinal ganglion cells, and subsequently also to loss of other neurons in the retina I suppose. Is this comparable to brain atrophy? May a chronic inflammation develop in the retin – some kind of retinitis? I am not diagnosed with SPMS, but my eyesight is gradually fading – rather irritating.

    Grateful for any comments.

    • The loss of RNFL in particular is an acute on chronic process. Measurements of this layer has been linked to brain atrophy scores, though viewpoints are mixed on whether it correlates with the development of SPMS.

  • Retinal thinning occurs after optic neuritis, it is also reported even in people who have not reported optic neuritis.

    I suspect that it is due to damage somewhere in the visual pathway and effects in visual centres in brain may contribute to this.

    Although unrelated I suspect that changes in the visual pathway may relate to activity elsewhere in the brain as we have seen many, many correlation studies in the literature.

    Remember SPMS is just a label, the process of damage occurs before MS is diagnosed. If there is a lesion the up and downstream connectionsmay be affected for some time (years) afterwards.

    You can get inflammation of the retina. Whilst uveitis is uncommon in pwMS with multiple sclerosis (MS), the link between the two entities is established, you can look in the eye to see this. It is important to check that is is not due to inflammation of the retina as this has its own treatments

  • And the party goes

    On and on and on……

    "In 2016, companies paid physicians and teaching hospitals
    $978.96 million for nonresearch activities (Table 4), including
    $381.13 million to serve as faculty or speakers presenting companydeveloped
    materials during lunch or dinner talks. Other payments
    were for consulting ($210.05), food and beverages ($164.21 million),
    travel and lodging ($96.9 million), and honoraria (14.64 million)."

    "Key opinion leaders feature prominently in professional marketing
    as consultants and speakers across a drug’s lifecycle, developing
    commercialization strategies and serving as product champions.85
    These opinion leaders exert influence through research publications,
    presentations, media presence, and contributions to editorial
    boards, guideline committees, and professional societies.86 Payments
    to key opinion leaders, a function of reputation and specialty,
    reportedly account for approximately one-third ofcompanymarketing
    budgets.87

    https://jamanetwork.com/journals/jama/fullarticle/2720029

  • Novel imaging method developed to detect chronic active lesions in progressive forms of MS

    A new method using magnetic resonance imaging (MRI) from 1,889 participants from three separate multiple sclerosis (MS) phase III clinical trials were used to detect slowly expanding lesions as a marker for chronic active lesions. Chronic active lesions are more prominent in progressive MS than in relapsing forms of the disease and may have the potential to inform clinical prognosis of progressive MS patients.

    https://mssociety.ca/research-news/article/novel-imaging-method-developed-to-detect-chronic-active-lesions-in-progressive-forms-of-ms?force_lang=en_CA

  • IMPORTANT

    Can Viruses in the Genome Cause Disease? Jan 1, 2019

    "The patient had not only immune deficiency resulting from HIV infection, but amyotrophic lateral sclerosis (ALS) as well, and the neurodegenerative disease was causing his condition to deteriorate rapidly. For several months, the patient had noticed his hands and feet becoming increasingly sore and weak, making tasks such as eating with utensils or opening a window all but impossible. When Nath saw him, the 29-year-old had difficulty climbing stairs and couldn’t get up from a seated position on the floor without assistance.

    The patient was initially reluctant to take a combination of antiretroviral drugs to treat his HIV due to his rapidly progressing ALS symptoms, Nath recalls. “He said he would likely die from ALS before he died from HIV infection, so why take the [antiretrovirals]?” But the doctor had read some clinical reports about other HIV-ALS patients’ ALS symptoms improving after a course of antiretrovirals, and Nath suggested he take them. The patient agreed and, like the other patients Nath had read about previously, rapidly began to feel better. When Nath saw him a year later, the patient no longer complained of weakness or muscle twitching, and his gait was normal. “This patient’s symptoms [had] totally reverted,” Nath tells The Scientist. “It’s one thing seeing it in the literature, but another thing to witness it yourself.”

    HERV proteins in neurodegenerative disease

    The discovery of viral proteins in the eroded brains of MS and ALS patients has prompted researchers to investigate the role of HERVs in these diseases. Although this research is becoming more widespread, the mechanisms are still unclear and remain hypothetical.

    Multiple sclerosis

    The HERV-W envelope protein binds toll-like receptor 4 on microglia, triggering the cells to secrete proinflammatory cytokines (1). At the same time, the protein also inhibits these cells from scavenging myelin debris (2), a mechanism important for rebuilding myelin sheaths that are damaged in MS, and prevents oligodendrocyte precursor cells (OPCs)—which normally help remyelinate damaged axons—from maturing (3). Combined, these two pathways create an inflammatory environment that contributes to the development of lesions in the brain, while also impairing the ability of local cells to repair the damage. Researchers haven’t yet discovered what triggers the production of HERV-W in the first place.

    https://www.the-scientist.com/features/can-viruses-in-the-genome-cause-disease–65212?fbclid=IwAR3Q9gDLwEWHDrIAFssGiEfuCSJkNcPqmqgKNyD6go9XBcqYTxlSI82mvQs

    • Pretty good article above..it explains some stuff..

      "Julian Gold,virologist at Queen Mary University of London, is interested in using antiretrovirals to treat MS, but a 2014 pilot study of 20 MS patients proved disappointing: the antiretroviral drug raltegravir didn’t help reduce the number of new lesions"

      "Gold thinks this is because he used a single drug, and not a combination therapy that is typically effective in HIV."

      "..another reason for Gold’s disappointing MS trial—the use of an antiretroviral drug to target what Glanzman thinks is an inactive virus. If the HERVs that have been linked to these diseases are incapable of replicating, “trying to approach them with an antiviral treatment is not going to be effective,” says Glanzman."

    • HERVs are implicated in cancers too, like melanomas. There is enough knowledge and experience there to earn from, I don't know why they tried to invent the wheel with Raltegravir at this infamous study.

    • "I don't know why they tried to invent the wheel with Raltegravir at this infamous study."

      Believe the company behind Raltegravir funded it. So it was
      en economic decision.

      Hey..Someone just gave us money..let's go fund a party..err.study.

    • "Further analyses
      indicated increased levels of reactivity to EBV-viral capsid
      antibody (VCA) but not to EBV nuclear antigen-1 (EBNA-
      1) or to other human herpesviruses"

      Most Ms EBV studies focus on EBNA-1 this find no EBNA-1 antibody

      response… why?

      This study

      The antibody response to Epstein–Barr virions is altered in multiple sclerosis

      Journal of Neuroimmunology 254 (2013) 146–153

      Says that

      "But the broad range of EBV antigens has not been studied, and it is not
      clear that EBNA-1 is the most relevant EBV antigen for MS"

      No consensus

      🙁

      In terms of other environmental factors, it is of note
      that we found an association between levels of antibodies
      to EBV virion proteins and cigarette smoking in individuals
      with schizophrenia. An interaction between EBV
      exposure and cigarette smoking has also been noted in
      other EBV-associated disorders such as multiple sclerosis,
      possibly based on the many immunomodulatory effects
      of cigarette smoking.39

      Schizophrenia is Associated With an Aberrant Immune Response to
      Epstein–Barr Virus

    • "..AdE1-LMPpoly increases survival in patients with
      metastatic nasopharyngeal carcinoma, where the EBV-
      infected carcinoma cells express EBNA1, LMP1 and
      LMP2A."

      "Because EBV-infected B cells in the brain in MS
      express the same three EBV proteins,adoptive immuno-
      therapy with AdE1-LMPpoly might be an effective way to
      increase the number of CD8T cells available to eliminate
      EBV-infected B cells from the CNS."

      "Here we report the use
      of adoptive immunotherapy with AdE1-LMPpoly to treat a
      patient with secondary progressive MS, for which currently
      there is no effective treatment."

      Some kind of progress..

      "Panel E demonstrates three periventricular gadolinium-enhancing lesions (arrows) 5 weeks before the commencement of therapy whereas Panel F shows no enhancing lesions 9 weeks after the completion of therapy."
      https://journals.sagepub.com/doi/pdf/10.1177/1352458514521888

    • Its all SH1… I guess it works for some things,,,,but is one of many trials in all sorts of disease. This one aims to look at meaningless cytokines as an endpoint, surely they need to look at an imaging endpoint but n-40 , it will be too snall

  • Dont get rid of those t cells 🙂

    They help opcs

    Activated T cells induce proliferation of oligodendrocyte
    progenitor cells via release of vascular endothelial cell growth
    factor-A

    DOI: 10.1002/glia.23501

  • Fever alters immune cells so they can better reach infections

    Our findings show that this mechanism not only applies to lymphocytes but also to innate immune cells like monocytes,” says Chen. “It is a general mechanism that can apply to lots of different immune cells expressing α4 integrins.”

    The researchers also believe other stresses, not just fever, can induce Hsp90 expression. “That’s why we think that in different situations, such as autoimmune disease and cancer, this Hsp90-α4 integrin pathway may be involved,” says Chen. In autoimmune disease, aberrant trafficking of immune cells to different organs or tissues may lead to disease. “But if you block this pathway, you can maybe inhibit the trafficking of the immune cells during chronic inflammation or in autoimmune diseases,” he says.

    https://medicalxpress.com/news/2019-01-fever-immune-cells-infections.html

  • Party ,Party….

    Study reveals financial interests of patient organizations assessing NHS treatments

    More than two thirds of patient organisations involved in assessing treatments for NHS use received funding from the maker(s) or a competitor of that treatment, yet decision makers were aware of less than a quarter of these interests, finds a review in The BMJ today.

    https://medicalxpress.com/news/2019-01-reveals-financial-patient-nhs-treatments.html

  • If one has to discontinue Tecfedera because of lymphopenia, how long does it normally take for cell counts to recover? What DMT do you use while waiting for things to normalize?
    Thanks!!

  • Nice

    Researchers have developed a new way to image the brain with unprecedented resolution and speed. Using this approach, they can locate individual neurons, trace connections between them, and visualize organelles inside neurons, over large volumes of brain tissue.

    The researchers also studied patterns of axon myelination in different neurons. Myelin is a fatty substance that insulates axons and whose disruption is a hallmark of multiple sclerosis. The researchers were able to compute the thickness of the myelin coating in different segments of axons, and they measured the gaps between stretches of myelin, which are important because they help conduct electrical signals. Previously, this kind of myelin tracing would have required months to years for human annotators to perform.

    The system could also have applications beyond neuroscience, Boyden says. His lab is planning to work with other researchers to study how HIV evades the immune system, and the technology could also be adapted to study how cancer cells interact with surrounding cells, including immune cells.

    https://neurosciencenews.com/high-resolution-brain-mapping-10570/?fbclid=IwAR2EODbxh1gO5WFv3TCDNYM8LOvdxbG38CETLP9ERlBmyVdCzv-azgliXoo

  • Mention is often made of hopes for restorative therapies in the future. But how realistic is this, when damaged axons are covered in scar tissue? Or so I thought?

    • The strategy for me is to prevent things getting to that point, which I think is increasingly feasible. We just need a proven neuroprotectant to go with the effective DMTs.

  • Some more oligodendrocytes

    “We have found that the Chi3l3 protein plays a central role in the body’s capacity to produce new myelin-forming oligodendrocytes,” says the study’s first author, Dr. Sarah-Christin Staroßom of Charité’s Institute for Medical Immunology. “The Chi3l3 protein initiates the differentiation of neural stem cells into myelin repair cells, which restore the electrical insulation around damaged nerve cells.”

    Using a mouse model, the research team were able to show that a reduction in Chi3l3 levels in the brain significantly impairs the body’s capacity for oligodendrocyte production, while a Chi3l3 infusion leads to an increase in the production of myelin repair cells. The same reaction was observed during an in vitro experiment using human cells.

    https://medicalxpress.com/news/2019-01-multiple-sclerosis-cells.html?fbclid=IwAR0cfUpbYoBqRMsyuVNkER137wh6lx1rvVhyMnSVfR8G7qUFWGb7oKsYgGk

  • Dysbiosis and the “hygiene hypothesis” (not a crazy fan)

    The mice treated with P. histicola showed “significantly decreased incidence and severity of arthritis, as compared to controls.” The researchers tried a similar experiment with mice engineered to develop MS. In the study, which was published in 2017 in Cell Reports, P. histicola showed a similar ability to dampen the body’s immune response and lessen the symptoms and progression of MS.

    The microbe damps down the body’s immune response — not only in the gut, but also throughout the body. It increases activity of regulatory T cells that modulate immune response and influence dendritic cells. These dendritic cells present antigens to the immune cells to start the immune response. P. histicola also countered leakiness of the gut and the blood-brain barrier, traits of patients with autoimmune diseases. It also seems to restore some normality and stability to the microbiome, reducing the chemical signals that trigger inflammation.
    But how exactly does a single organism accomplish all that? By regulating the cellular response directly? By producing byproducts that dampen the immune response? Or by regulating other microbes to bring the microbiome into the normal range? All of the above?

    https://discoverysedge.mayo.edu/2019/01/14/recruiting-microbes-to-fight-autoimmune-diseases/?cauid=100502&fbclid=IwAR3KY6HxAvSxIgdD5LtJCm6ip-ru-9EB7-47fboeHdBTxgHWpDUKa3PGAtY&geo=national&linkId=62678478&mc_id=us&placementsite=enterprise&utm_campaign=mayoclinic&utm_content=post&utm_medium=sm&utm_source=facebook

  • Demyelination precedes axonal loss in the transneuronal spread of human neurodegenerative disease

    This study demonstrated strong topographical spread of neurodegeneration along recognized neural projections and showed that myelin and glial pathology precedes axonal loss in the process, suggesting that the mechanism of trans-synaptic damage may be at least partially mediated by glial components at the cellular level. The findings may have broad biological and therapeutic implications for other neurodegenerative disorders.
    https://academic.oup.com/brain/advance-article-abstract/doi/10.1093/brain/awy338/5296574

  • An interesting trial

    Positive Safety Data Reported for High-dose MS Treatment Candidate Temelimab (known as GNbAC1)

    The development of temelimab is the result of a quarter century of research into human endogenous retroviruses, which are stretches of foreign, viral DNA inserted into the human genome. Some human endogenous retroviruses are known to be associated with auto-immune diseases. For example, one of these viruses, the MS-associated retrovirus (MSRV), encodes a protein (MSRV-envelope protein, or MSRV-Env) that is found in MS patients, particularly in active lesions.

    Temelimab, a monoclonal antibody, works by neutralizing the MSRV-Env protein associated with MS, and subsequently blocks inflammation.
    Also, the therapy was shown to restore myelin, which is the insulating sheath around nerve fibers that is compromised in MS patients.

    Now, in the Phase 1 trial, GeNeuro tested the safety of temelimab at a higher dose range. Four doses were tested: 36, 60, 85, and 110 mg/kg. The trial was a randomized, double-blind, placebo-controlled study with 24 healthy volunteers.
    “The results from this high-dose study support and expand the large amount of positive clinical data we already have regarding temelimab’s safety, tolerability and efficacy,” Jesús Martin-Garcia, chairman and CEO of GeNeuro, said in a press release.
    https://multiplesclerosisnewstoday.com/2019/01/25/positive-safety-data-high-dose-temelimab-ms-treatment-candidate/?utm_content=bufferb43fe&utm_medium=organic+social&utm_source=facebook.com&utm_campaign=buffer

  • The interesting part is that it addresses the gap between researchers and patients .

    The Australian National University study was funded by MS Research Australia and is based on a new approach in letting the usual research subjects also become researchers, Ms Fanning explained.

    It will combine the medical expertise of scientists with the real-life experience of people who live with MS, in the hope of finding better, more personalised treatment. It is also aimed at breaking down communication barriers between scientists and patients.

    People from around Australia would be given wearable devices, participate in at-home tests and take part in regular workshops with the research team.

    Ms Fanning said the need for personalised treatment was extremely important for a disease in which the pace of decline differs drastically between people — especially because it is not known why certain medications work for some people but not others.

    She said it would benefit the research by involving people like herself, because often researchers had never even met someone with MS.
    “There are things we know about our condition that scans can’t show,” Ms Fanning said.

    https://www.abc.net.au/news/2019-01-23/multiple-sclerosis-study-turns-patients-into-researchers/10743960

  • Calcium Influx through Plasma-Membrane Nanoruptures Drives Axon Degeneration in a Model of Multiple Sclerosis

    Axon loss determines persistent disability in multiple sclerosis patients. Here, we use in vivo calcium imaging in a multiple sclerosis model to show that cytoplasmic calcium levels determine the choice between axon loss and survival. We rule out the endoplasmic reticulum, glutamate excitotoxicity, and the reversal of the sodium-calcium exchanger as sources of intra-axonal calcium accumulation and instead identify nanoscale ruptures of the axonal plasma membrane as the critical path of calcium entry.

    https://www.cell.com/neuron/fulltext/S0896-6273(18)31123-1

  • Oligodendrocytes and Their Precursors May Play a More Complex Role in Multiple Sclerosis Progression, Suggesting a Potential Therapeutic Target

    A subset of oligodendrocytes and their progenitor cells may have more in common with immune cells, suggests a study in a mouse model of multiple sclerosis. The oligodendrocytes may be important targets for modulation of autoimmunity and have a higher impact on the disease than previously thought, the study authors suggest.

    The discovery of an antigen-presenting phenotype in oligodendrocytes and OPCs came as a surprise to the study’s principal investigator, Gonçalo Castelo-Branco, PhD, associate professor and principal investigator at the Karolinska Institute in Stockholm. In previous work his group had shown that oligodendrocytes were a heterogeneous group of cells, divisible into multiple subclasses based on their patterns of gene expression. The main aim of the current study, published in the December 2018 issue of Nature Medicine, was to begin to understand the transcriptional states of OPCs in the experimental autoimmune encephalitis (EAE) mouse model of MS, using single-cell RNA sequencing, which provides a highly detailed snapshot of gene activity within a single cell.

    https://journals.lww.com/neurotodayonline/Fulltext/2019/01240/Oligodendrocytes_and_Their_Precursors_May_Play_a.6.aspx

  • Researchers have successfully created stem cell derived brain cells which can generate oligodendrocytes, neurons and astrocytes.

    Now, Stanford University School of Medicine investigators have proved that a system they developed a few years ago for culturing balls of stem-cell-derived human brain cells, which mimic aspects of real brain circuitry, can generate oligodendrocytes together with neurons and a third type of brain cell called astrocytes.

    Pasca’s group is looking at a number of genetic disorders affecting myelination that arise in fetal development or early childhood. But oligodendrocyte-containing brain spheroids could also prove useful in studying demyelination disorders, such as multiple sclerosis and cerebral palsy — and even some psychiatric conditions not usually thought of as myelin-associated.

    https://neurosciencenews.com/myelin-brain-cell-generation-10659/?fbclid=IwAR2qWT973dotwSB6M6pxLAguqkB-lYF0rR3RGRHVAPJDH1inWk5D_TxtdyQ

  • Cost-Effectiveness of Alemtuzumab in the Treatment of Relapsing Forms of Multiple Sclerosis in the United States.
    https://www.ncbi.nlm.nih.gov/pubmed/30711061

    Alemtuzumab’s dominance was primarily driven by savings in treatment costs because alemtuzumab has long-term duration of response and is initially administered as 2 annual courses, with 36.1% of patients requiring retreatment over 5 years, whereas comparators are used chronically. In model scenarios where alemtuzumab’s long-term duration of response was assumed not to hold and therapy had to be administered annually, probabilistic sensitivity analyses showed that alemtuzumab remained cost-effective versus ocrelizumab at a willingness-to-pay threshold of $100 000/QALY in 74% to 100% of model runs.

  • I didn’t see February Q & A.

    I thought this was an interesting layperson’s explanation of the relationship between activated microglia and neuropathic pain. http://relief.news/pain-101-how-the-immune-system-influences-chronic-pain/

    Because some of us — maybe mostly those with PPMS? — experience severe dysesthetic extremity pain that may be related to spinal lesions, I am interested in learning more about studies that examine these connections in the context of multiple sclerosis.

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