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.
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
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!
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?
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.
From ProfGs twitterBridging 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
Long-Lived Plasma Cells are not a single subpoulation They can live up to 3,014 and 542 yearsLong-Lived Plasma Cells Are Contained within the CD19(-)CD38(hi)CD138(+) Subset in Human Bone Marrowhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4680845/
😉 Nice Just finnish reading this one that answer that questionFactors of the bone marrow microniche that support human plasma cell survival and immunoglobulin secretionIts 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 mechanismsObrigadoPor comemtar
More memory b cell biologyThe establishment of resident memory B cells in the lung requires local antigen encounterhttps://www.nature.com/articles/s41590-018-0260-6
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.
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.
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.htmlFrom 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?
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
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/24972270https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689181/
HSCT Australiahttps://msra.org.au/news/australian-ahsct-trial/?fbclid=IwAR1vSwdPlAUNn3N9cKz3GSX6mhFi2Lz4q8smWGvr52QVUqtFWI6TRPZtVFYhttps://jnnp.bmj.com/content/early/2018/12/11/jnnp-2018-319446Prospective phase II clinical trial of autologous haematopoietic stem cell transplant for treatment refractory multiple sclerosisResults Thirty-five patients (20 RRMS, 15 SPMS)completed AHSCT, with a median follow-up of 36 months(range 12–66). The median Expanded Disability StatusScores (EDSS) was 6 (2–7) and patients had failed amedian of 4 (2–7) disease modifying therapies. 66% failedtreatment with natalizumab. EFS at 3 years was 60%,(70% RRMS). Sustained improvement in EDSS was seenin 15 (44%) of patients. There was no treatment-relatedmortality. A sustained rise in CD39+ T regulatory cells,immunosuppressive CD56hi natural killer cells and ablationof proinflammatory mucosal-associated invariant T cellswas seen for 12 months following AHSCT in patientswith MS. These changes did not occur in patients withlymphoma receiving the same chemotherapy for AHSCTEighty-three per cent of patients remained free of new/enlarging T2 lesions and 96% free of gadolinium enhancinglesions on last follow-up MRI, as determined by central neuroradiologicalreview. While Atkins et al reported complete ablationof gadolinium enhancement and a single patient with newlesions post-AHSCT, this occurred with a high intensity regimenincluding busulfan and graft manipulation.11 Patients in theHALT-MS trial28 had an 86.3% MRI activity-free survival at 5years, suggesting intermediate intensity conditioning is able toachieve substantial improvements in radiological measures ofdisease activity. Consistent with other studies,12 28 mean annualisedT2LV in our cohort decreased by −2.8% between thepost-AHSCT baseline and last follow-up MRI scans. Annualisedbrain atrophy between rebaseline and last follow-up images,as measured by NeuroSTREAM LVV enlargement, fell withinthe healthy control range in the majority of patients. Atkinset al have demonstrated that centralisation of MRI review hasprovided reassuring data on the lack of progression of cerebralatrophy highlighting the importance of this analysis.11 In ourstudy, atrophy was assessed as an exploratory outcome withNeurostream, a novel measure of LVV that is applicable to clinicallyacquired 2D or 3D FLAIR images and withstands inherent‘real-world’ variability in brain imaging.Our overall survival of 100% confirms recent findings fromthe European Society for Blood and Marrow Transplant(EBMT) that a site’s transplant experience is likely to be asignificant predictor of patient outcomes.31 Of interest, natalizumabwas previously administered in 66% of our patients.Seventy-nine per cent of our patients had positive JC virusserology and yet there were no documented cases of PML ata median follow-up of 3 years. This analysis provides somereassurance to patients and their physicians that AHSCT canpotentially be offered safely after natalizumab treatment.
According to this study, 6 out of the 15 SPMS patients had disease progression. So, next time you try to prevent an SPMS patients from HSCT maybe think twice.
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
I have heard that a patient had a few clear MRI's, but the MRI scanner wasn't the most powerful. Patient not diagnosed with MS at this stage. It was suggested to them to get a MRI scan done on a much more powerful scanner. The patient organised this themselves, privately. MS lesions were visible on the scan by the more powerful MRI scanner. Prof G, have you come across this before? thanks.
Like Prince uses to say " Nothing but party yo"The recent investigation of a prominent cancer researcher for failure to disclose substantial financial and administrative relationships with drug and health care companies in leading medical journals and his subsequent resignation as chief medical officer of a leading cancer center has once again placed the issue of COI center stage.27 Although failure to disclose COIs is not limited to the field of oncology, a recent study found that 32% of 344 oncologist authors did not fully disclose payments from the sponsors of clinical trials of oncology drugs published in major medical journals.28https://jamanetwork.com/journals/jama/fullarticle/2712191?guestAccessKey=5269eeb3-2870-46ee-8c0c-c65e10a0ff59&utm_source=silverchair&utm_medium=email&utm_campaign=article_alert-jama&utm_content=etoc&utm_term=121118😁
I agree that they should be disclosed but go to a neuro talk and their disclosures are flashed up in a nano-second which is too small to see and very often the important COI is buried in the middle of a long list of company names. I always put the ones I think to be important first and dismiss the other others
Safety and Efficacy of Rituximab in Multiple Sclerosis: A Retrospective Observational Study.Results:A total of 89 rituximab-treated patients were included: 59 relapsing-remitting MS (RRMS) and 30 progressive MS (PMS). Patients were treated with 1000 or 2000 mg rituximab IV every 6-12 months for a mean duration of 22.2 ± 24.8 months. The subjects were 65.2% females with a mean age of 40.5 ± 12.3 years and a mean disease duration of 7.9 ± 6.2 years. During treatment, the ARR decreased from 1.07 at baseline to 0.11 in RRMS (p < 0.0001) and from 0.25 to 0.16 in PMS patients (p = 0.593). The mean Expanded Disability Status Scale (EDSS) remained unchanged in both RRMS and PMS patients. Between baseline and the last follow-up, the percent of patients free from any new MRI lesions increased from 18.6% to 92.6% in the RRMS group and from 43.3% to 82% in the PMS group. No evidence of disease activity (NEDA) was achieved in 74% of patients at 1 year of treatment. A total of 64 adverse events (AEs) (71.9%) were recorded with the most common being infusion-related reactions in 25.8% of patients, all mild in nature. Two of our rituximab-treated patients experienced serious AEs requiring surgical interventions: pyoderma gangrenosum vaginalis with perianal abscess and fistula and an increase in the size of a meningioma. No case of progressive multifocal leukoencephalopathy (PML) was detected.Conclusion:In our real-world cohort, rituximab was well-tolerated and effective in reducing relapse rate and disability progression in relapsing-remitting and progressive MS patients.https://www.ncbi.nlm.nih.gov/pubmed/30539030
Dont get enough vitamin D?Blame it on Magnesium"Magnesium deficiency shuts down the vitamin D synthesis and metabolism pathway," Dai said."Study shows magnesium optimizes vitamin D statushttps://medicalxpress.com/news/2018-12-magnesium-optimizes-vitamin-d-status.htmlObrigado
For those that say that biosimilares are different of the original3750 Single Centre UK Comparison of Biosimilar Rituximab (Truxima) with the Originator (MabThera) in Patients with Immune Mediated Thrombotic Thrombocytopenic Purpura DISCUSSIONRituximab is now off patent in Europe, and the EMA approval of Biosimilars offers an opportunity for significant cost savings as demonstrated here. Rituximab has been well established in iTTP, and rituximab biosimilars have demonstrated equivalence to the originator in rheumatoid arthritis and follicular lymphoma. Here we report the first published series of the rituximab biosimilar Truxima in iTTP, and demonstrate equivalence in terms of ADAMTS13 recovery, CD19 depletion, and platelet count at 28days and 3 months post administration, in addition to showing comparable infusion and infective complications
Hematologists on Alemtuzumab AE"Interestingly, Alemtuzumab has also been successfully used as a 2nd line agent to treat AIHA especially associated with B-CLL and other immune phenomenon (GVHD, aplastic anemia, conditioning regimen for transplantations) immediate and sustained lymphopenia effect. The proposed mechanism for this “paradoxical” AE related to Alemtuzumab is the reduced diversity and increased regeneration of “self-reactive” T cells during delayed time frame of the “recovery period” of lymphocytes. The reported post marketing incidence of AIHA for Alemtuzumab in RRMS is around 0.13%. Alemtuzumab associated AIHA when used for B-CLL has also been rarely reported."
This is a really interesting point use alemtuzumab in MS and you get )AIHA) Autoimmune hemolytic anemia and other autoimmmunities with high frequency (50% within 5 years) and use in cancer and this is very low. What is the difference and could this be used to reduce the autoimmune risk.(a) Is it the dosing schedule?(b) Is it the genetic of MS that makes you liable to other autoimmunities(C) Does this problem occur in other autoimunities where lemtrada/CAMPATH is used.For chronic lymphocytic leukaemia (CLL)Each single use ampoule of Campath contains 30 mg Alemtuzumab. This is nearly three times the MS does of (12mg). Campath 30 mg intravenously three times per week for 4 to 12 weeks Compared to 5 days foe lemtrada in MS.So 90mg a week for 12 weeks = 1080mg verses 60mg. This is knocking lymphocytes down differently, is probably going to ensure that CD19+ Immature B cells are really targeted. As they come out of the bone marrow they will be killed over and over again. Maybe allowing B cells to repopulate when there regulatory T cells. This could probably instantly reduce the autoimmune side effects. The level is depletion is going to be more significant as are the side effects.If doing for HSCT the dose is a short course in a 2 year trial the frequency of autoimmunity is 16% verses anti thymoctye globulin (2%) So it is not simply genetics, it has to be an issue with the antibody.Maybe ProfC knows more on the issue of dosing and secondardy autoimmunity however the idea of diversity and self-reactive T cells is unproven. The CAMTHY trial failed and the treatment to avoid this diversity didnt increase diversity it decreased it, so why didnt it make MS worse, is the idea all wrong.The profs at Cambridge will have insight on the issues of dosing and secondary autoimmunity but is it too late to turn back the clock and investigate
Well, if MS societies want to invest money somewhere, they should really consider this research… I don't see anyone else being interested (hope you do :/ )
QuestionIs it possible to go on other drugs after mavenclad? It hasn't worked for me unfortunately (doesn't mean it won't for others though!) and the neuro has said he doesn't know if it's possible to switch to other drugs once you've had it.
Who are they fooling if they think an NF kappa B variant that affects astrocytes is not affecting other cells in other ways in otjer tissues. There is nothing done to disprove the hypothesis. Tell me that this variant is not important to APC in lymph nodesNFKB is a master.regulator of cytokine responses..Come on have a think. The implication isthat we.should think of cells inside CNS are important.. It seems there is no knowledge of awareness outside Natureland.
I know you cannot give personal advice but do you neurologists have a guide as to which drugs to choose for your patients because it does seem all a bit hit and missFor example a patient who has had both courses of alemtuzumab but may still be progressing if you rule out therapeutic lag do or should a neurologist push for a third alemtuzumab or move on to another medication like ocrelizumab or cladribine?You encourage patient participation in the choice of drugs but as far as I can see it is getting even more confusing
The MS trust has a website.You have to ask the question if there is evidence of disease activity relapse or MRI lesions and neurofilaments ProfG says it may take 3 years for the therapeutic lagto play out.
Study reveals PRRX1 gene expression results in cell cycle arrest and quiescence of oligodendrocyte progenitors, blocking myelin production.Source: University at Buffalo.New research on remyelination, the spontaneous regeneration of the brain’s fatty insulator that keeps neurons communicating, could lead to a novel approach to developing treatments for multiple sclerosis (MS) and other inflammatory diseases.https://neurosciencenews.com/remyelination-prevention-10376/?fbclid=IwAR3BPnecUmXwYdnNU5TU4Dy1S3w7X23lZ4NcfijdsSwCLtg2AarrSk-qJFs
Lets.see.how they get on its an open.label trial. But just another route to the same active compound. Being a cynic getting ready for.end of patent life
I don't think you have the facts right about Biogen and MS. The have rather a deep pipeline in the MS space and have just poached back one of their ex-staff to run their early MS development pipeline. Biogen is an MS company and they are not giving up on it. You also need to remember they take a big slice of the ocrelizumab sales; the IP came to Biogen via Idec.
A potential biomarker for MSResearchers at Purdue University and the Indiana University School of Medicine found that acrolein, a molecule previously suspected as a metabolic waste product that accumulates in people with certain neurological disorders such as multiple sclerosis and Parkinson's disease, could possibly be used to help diagnose MS."We are in the process of trying to correlate acrolein levels with MS disease activity, which potentially would help us monitor disease activity with a blood test," he says. "If this is validated, it would help us decide how aggressive to be with immunotherapy, or whether a therapy is working or there is a need to switch to a different therapy.""There are drugs already on the market that are known to be acrolein scavengers, and it is possible that one of these drugs could be repurposed as a possible therapy for MS," Shi says. "But these drugs also have strong effects on other targets, so more study would need to be done to see if they have a therapeutic effect to eliminate acrolein at a safe level."The two drugs in this category are hydralazine, used to treat high blood pressure and heart failure, and phenelzine, which is used to treat major depression.
International Consensus on Timely Care for Multiple Sclerosishttps://www.ajmc.com/newsroom/international-consensus-on-timely-care-for-multiple-sclerosis
Expanding the Potential Therapeutic Options for Remote Ischemic Preconditioning: Use in Multiple Sclerosishttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018107/
Is it true that alemtuzumab doesnt change the rate of converssion to secondary progessive? Recently i read some papers that say that
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
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077906/
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
Thanks
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!
Negative data from Genzyme…Not going to happen. This is a reason why all data should be made public.
Your comments on recent FDA warning for alemtuzumab and a severe adverse reaction much appreciated:https://www.medscape.com/viewarticle/905768
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.
hes posted
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?
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.
Older people black people and males tend to be more likely to get progressive MS
From ProfGs twitterBridging 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
Long-Lived Plasma Cells are not a single subpoulation They can live up to 3,014 and 542 yearsLong-Lived Plasma Cells Are Contained within the CD19(-)CD38(hi)CD138(+) Subset in Human Bone Marrowhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4680845/
or about 24hours in culture. It is all about have other cells to keep them going
😉 Nice Just finnish reading this one that answer that questionFactors of the bone marrow microniche that support human plasma cell survival and immunoglobulin secretionIts 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 mechanismsObrigadoPor comemtar
New T cell discoverhttps://medicalxpress.com/news/2018-12-newly-cells-role-cancer-diseases.html
Interesting, I have MS, high antiphospholipid antibodies and negative oligoclonal bands 😛
More memory b cell biologyThe establishment of resident memory B cells in the lung requires local antigen encounterhttps://www.nature.com/articles/s41590-018-0260-6
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.
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.
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.htmlFrom 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?
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
Re: "Have you seen patients who have had Cladribine -IV or oral- for more than 6-7 years and didn't need further treatment?"Yes
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/24972270https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689181/
HSCT Australiahttps://msra.org.au/news/australian-ahsct-trial/?fbclid=IwAR1vSwdPlAUNn3N9cKz3GSX6mhFi2Lz4q8smWGvr52QVUqtFWI6TRPZtVFYhttps://jnnp.bmj.com/content/early/2018/12/11/jnnp-2018-319446Prospective phase II clinical trial of autologous haematopoietic stem cell transplant for treatment refractory multiple sclerosisResults Thirty-five patients (20 RRMS, 15 SPMS)completed AHSCT, with a median follow-up of 36 months(range 12–66). The median Expanded Disability StatusScores (EDSS) was 6 (2–7) and patients had failed amedian of 4 (2–7) disease modifying therapies. 66% failedtreatment with natalizumab. EFS at 3 years was 60%,(70% RRMS). Sustained improvement in EDSS was seenin 15 (44%) of patients. There was no treatment-relatedmortality. A sustained rise in CD39+ T regulatory cells,immunosuppressive CD56hi natural killer cells and ablationof proinflammatory mucosal-associated invariant T cellswas seen for 12 months following AHSCT in patientswith MS. These changes did not occur in patients withlymphoma receiving the same chemotherapy for AHSCTEighty-three per cent of patients remained free of new/enlarging T2 lesions and 96% free of gadolinium enhancinglesions on last follow-up MRI, as determined by central neuroradiologicalreview. While Atkins et al reported complete ablationof gadolinium enhancement and a single patient with newlesions post-AHSCT, this occurred with a high intensity regimenincluding busulfan and graft manipulation.11 Patients in theHALT-MS trial28 had an 86.3% MRI activity-free survival at 5years, suggesting intermediate intensity conditioning is able toachieve substantial improvements in radiological measures ofdisease activity. Consistent with other studies,12 28 mean annualisedT2LV in our cohort decreased by −2.8% between thepost-AHSCT baseline and last follow-up MRI scans. Annualisedbrain atrophy between rebaseline and last follow-up images,as measured by NeuroSTREAM LVV enlargement, fell withinthe healthy control range in the majority of patients. Atkinset al have demonstrated that centralisation of MRI review hasprovided reassuring data on the lack of progression of cerebralatrophy highlighting the importance of this analysis.11 In ourstudy, atrophy was assessed as an exploratory outcome withNeurostream, a novel measure of LVV that is applicable to clinicallyacquired 2D or 3D FLAIR images and withstands inherent‘real-world’ variability in brain imaging.Our overall survival of 100% confirms recent findings fromthe European Society for Blood and Marrow Transplant(EBMT) that a site’s transplant experience is likely to be asignificant predictor of patient outcomes.31 Of interest, natalizumabwas previously administered in 66% of our patients.Seventy-nine per cent of our patients had positive JC virusserology and yet there were no documented cases of PML ata median follow-up of 3 years. This analysis provides somereassurance to patients and their physicians that AHSCT canpotentially be offered safely after natalizumab treatment.
According to this study, 6 out of the 15 SPMS patients had disease progression. So, next time you try to prevent an SPMS patients from HSCT maybe think twice.
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
No. They have to be bih enough to be seem
Thanks MD appreciate the response. Have you come across people who have had multiple clear mris only to have another one years later and lesions show?
Which is why most MSologists do annual MRIs.
I have heard that a patient had a few clear MRI's, but the MRI scanner wasn't the most powerful. Patient not diagnosed with MS at this stage. It was suggested to them to get a MRI scan done on a much more powerful scanner. The patient organised this themselves, privately. MS lesions were visible on the scan by the more powerful MRI scanner. Prof G, have you come across this before? thanks.
I do not see pwms but am sure this happens to some
Like Prince uses to say " Nothing but party yo"The recent investigation of a prominent cancer researcher for failure to disclose substantial financial and administrative relationships with drug and health care companies in leading medical journals and his subsequent resignation as chief medical officer of a leading cancer center has once again placed the issue of COI center stage.27 Although failure to disclose COIs is not limited to the field of oncology, a recent study found that 32% of 344 oncologist authors did not fully disclose payments from the sponsors of clinical trials of oncology drugs published in major medical journals.28https://jamanetwork.com/journals/jama/fullarticle/2712191?guestAccessKey=5269eeb3-2870-46ee-8c0c-c65e10a0ff59&utm_source=silverchair&utm_medium=email&utm_campaign=article_alert-jama&utm_content=etoc&utm_term=121118😁
I agree that they should be disclosed but go to a neuro talk and their disclosures are flashed up in a nano-second which is too small to see and very often the important COI is buried in the middle of a long list of company names. I always put the ones I think to be important first and dismiss the other others
Thanks Thats why i value your work
Safety and Efficacy of Rituximab in Multiple Sclerosis: A Retrospective Observational Study.Results:A total of 89 rituximab-treated patients were included: 59 relapsing-remitting MS (RRMS) and 30 progressive MS (PMS). Patients were treated with 1000 or 2000 mg rituximab IV every 6-12 months for a mean duration of 22.2 ± 24.8 months. The subjects were 65.2% females with a mean age of 40.5 ± 12.3 years and a mean disease duration of 7.9 ± 6.2 years. During treatment, the ARR decreased from 1.07 at baseline to 0.11 in RRMS (p < 0.0001) and from 0.25 to 0.16 in PMS patients (p = 0.593). The mean Expanded Disability Status Scale (EDSS) remained unchanged in both RRMS and PMS patients. Between baseline and the last follow-up, the percent of patients free from any new MRI lesions increased from 18.6% to 92.6% in the RRMS group and from 43.3% to 82% in the PMS group. No evidence of disease activity (NEDA) was achieved in 74% of patients at 1 year of treatment. A total of 64 adverse events (AEs) (71.9%) were recorded with the most common being infusion-related reactions in 25.8% of patients, all mild in nature. Two of our rituximab-treated patients experienced serious AEs requiring surgical interventions: pyoderma gangrenosum vaginalis with perianal abscess and fistula and an increase in the size of a meningioma. No case of progressive multifocal leukoencephalopathy (PML) was detected.Conclusion:In our real-world cohort, rituximab was well-tolerated and effective in reducing relapse rate and disability progression in relapsing-remitting and progressive MS patients.https://www.ncbi.nlm.nih.gov/pubmed/30539030
Sorry but Post on this and I'll get a kicking for not talking about my own work:-(.
Dont get enough vitamin D?Blame it on Magnesium"Magnesium deficiency shuts down the vitamin D synthesis and metabolism pathway," Dai said."Study shows magnesium optimizes vitamin D statushttps://medicalxpress.com/news/2018-12-magnesium-optimizes-vitamin-d-status.htmlObrigado
For those that say that biosimilares are different of the original3750 Single Centre UK Comparison of Biosimilar Rituximab (Truxima) with the Originator (MabThera) in Patients with Immune Mediated Thrombotic Thrombocytopenic Purpura DISCUSSIONRituximab is now off patent in Europe, and the EMA approval of Biosimilars offers an opportunity for significant cost savings as demonstrated here. Rituximab has been well established in iTTP, and rituximab biosimilars have demonstrated equivalence to the originator in rheumatoid arthritis and follicular lymphoma. Here we report the first published series of the rituximab biosimilar Truxima in iTTP, and demonstrate equivalence in terms of ADAMTS13 recovery, CD19 depletion, and platelet count at 28days and 3 months post administration, in addition to showing comparable infusion and infective complications
Canada Hsct4624 Complications and Toxicities Associated with Autologous Stem Cell Transplantation for Severe Autoimmune Diseases: Single Center Experience https://ash.confex.com/ash/2018/webprogram/Paper119797.html
Alemtuzumab AE2331 Severe Coombs Positive Autoimmune Hemolytic Anemia after Alemtuzumab Infusion for Relapsing Remitting Multiple Sclerosis. What Can We Learn?https://ash.confex.com/ash/2018/webprogram/Paper112724.html
Hematologists on Alemtuzumab AE"Interestingly, Alemtuzumab has also been successfully used as a 2nd line agent to treat AIHA especially associated with B-CLL and other immune phenomenon (GVHD, aplastic anemia, conditioning regimen for transplantations) immediate and sustained lymphopenia effect. The proposed mechanism for this “paradoxical” AE related to Alemtuzumab is the reduced diversity and increased regeneration of “self-reactive” T cells during delayed time frame of the “recovery period” of lymphocytes. The reported post marketing incidence of AIHA for Alemtuzumab in RRMS is around 0.13%. Alemtuzumab associated AIHA when used for B-CLL has also been rarely reported."
This is a really interesting point use alemtuzumab in MS and you get )AIHA) Autoimmune hemolytic anemia and other autoimmmunities with high frequency (50% within 5 years) and use in cancer and this is very low. What is the difference and could this be used to reduce the autoimmune risk.(a) Is it the dosing schedule?(b) Is it the genetic of MS that makes you liable to other autoimmunities(C) Does this problem occur in other autoimunities where lemtrada/CAMPATH is used.For chronic lymphocytic leukaemia (CLL)Each single use ampoule of Campath contains 30 mg Alemtuzumab. This is nearly three times the MS does of (12mg). Campath 30 mg intravenously three times per week for 4 to 12 weeks Compared to 5 days foe lemtrada in MS.So 90mg a week for 12 weeks = 1080mg verses 60mg. This is knocking lymphocytes down differently, is probably going to ensure that CD19+ Immature B cells are really targeted. As they come out of the bone marrow they will be killed over and over again. Maybe allowing B cells to repopulate when there regulatory T cells. This could probably instantly reduce the autoimmune side effects. The level is depletion is going to be more significant as are the side effects.If doing for HSCT the dose is a short course in a 2 year trial the frequency of autoimmunity is 16% verses anti thymoctye globulin (2%) So it is not simply genetics, it has to be an issue with the antibody.Maybe ProfC knows more on the issue of dosing and secondardy autoimmunity however the idea of diversity and self-reactive T cells is unproven. The CAMTHY trial failed and the treatment to avoid this diversity didnt increase diversity it decreased it, so why didnt it make MS worse, is the idea all wrong.The profs at Cambridge will have insight on the issues of dosing and secondary autoimmunity but is it too late to turn back the clock and investigate
Well, if MS societies want to invest money somewhere, they should really consider this research… I don't see anyone else being interested (hope you do :/ )
I spoke to Genzyme this week and will see if they come back.The ms socs probably have their sights elsewhere.
(Probably asked before)Do we know when serum NFl levels test will be available for pwMS internationally?
Get them sent to London
QuestionIs it possible to go on other drugs after mavenclad? It hasn't worked for me unfortunately (doesn't mean it won't for others though!) and the neuro has said he doesn't know if it's possible to switch to other drugs once you've had it.
The case for inside-out outside in diseasehttps://m.medicalxpress.com/news/2018-12-gene-variant-brain-complicit-ms.htmlBrain ms cell a not so 'normal'
Who are they fooling if they think an NF kappa B variant that affects astrocytes is not affecting other cells in other ways in otjer tissues. There is nothing done to disprove the hypothesis. Tell me that this variant is not important to APC in lymph nodesNFKB is a master.regulator of cytokine responses..Come on have a think. The implication isthat we.should think of cells inside CNS are important.. It seems there is no knowledge of awareness outside Natureland.
I know you cannot give personal advice but do you neurologists have a guide as to which drugs to choose for your patients because it does seem all a bit hit and missFor example a patient who has had both courses of alemtuzumab but may still be progressing if you rule out therapeutic lag do or should a neurologist push for a third alemtuzumab or move on to another medication like ocrelizumab or cladribine?You encourage patient participation in the choice of drugs but as far as I can see it is getting even more confusing
The MS trust has a website.You have to ask the question if there is evidence of disease activity relapse or MRI lesions and neurofilaments ProfG says it may take 3 years for the therapeutic lagto play out.
https://m.medicalxpress.com/news/2018-12-gene-variant-brain-complicit-ms.html Remylination issues
Thanks ill do a post.
Study reveals PRRX1 gene expression results in cell cycle arrest and quiescence of oligodendrocyte progenitors, blocking myelin production.Source: University at Buffalo.New research on remyelination, the spontaneous regeneration of the brain’s fatty insulator that keeps neurons communicating, could lead to a novel approach to developing treatments for multiple sclerosis (MS) and other inflammatory diseases.https://neurosciencenews.com/remyelination-prevention-10376/?fbclid=IwAR3BPnecUmXwYdnNU5TU4Dy1S3w7X23lZ4NcfijdsSwCLtg2AarrSk-qJFs
Big news for MS #NOTFDA Asked to Approve Diroximel Fumarate as Oral Treatment for Relapsing MS“The filing of diroximel fumarate by our partners at Alkermes demonstrates our enduring commitment to people living with MS,” said Biogen (who has almost abandon MS research).https://multiplesclerosisnewstoday.com/2018/12/18/alkermes-biogen-request-fda-approval-of-diroximel-fumarate-for-relapsing-ms/
Lets.see.how they get on its an open.label trial. But just another route to the same active compound. Being a cynic getting ready for.end of patent life
I don't think you have the facts right about Biogen and MS. The have rather a deep pipeline in the MS space and have just poached back one of their ex-staff to run their early MS development pipeline. Biogen is an MS company and they are not giving up on it. You also need to remember they take a big slice of the ocrelizumab sales; the IP came to Biogen via Idec.
A potential biomarker for MSResearchers at Purdue University and the Indiana University School of Medicine found that acrolein, a molecule previously suspected as a metabolic waste product that accumulates in people with certain neurological disorders such as multiple sclerosis and Parkinson's disease, could possibly be used to help diagnose MS."We are in the process of trying to correlate acrolein levels with MS disease activity, which potentially would help us monitor disease activity with a blood test," he says. "If this is validated, it would help us decide how aggressive to be with immunotherapy, or whether a therapy is working or there is a need to switch to a different therapy.""There are drugs already on the market that are known to be acrolein scavengers, and it is possible that one of these drugs could be repurposed as a possible therapy for MS," Shi says. "But these drugs also have strong effects on other targets, so more study would need to be done to see if they have a therapeutic effect to eliminate acrolein at a safe level."The two drugs in this category are hydralazine, used to treat high blood pressure and heart failure, and phenelzine, which is used to treat major depression.
VERY HAPPY CHRISTMAS TO ALL THE BLOG TEAM🎄Thanks for another year of excellent information and insights!Here's to a good 2019.
Feliz natal Bom ano novoPara todos no Barts blogBoas entradas ObrigadoLuis fernando varatojo
Women in MS Seek Greater Parity in FieldAn international group of female neurologists and neuroscientists specializing in MS has formed to advocate for greater representation of women at all levels of professional leadership, from clinical trials to editorial boards to academic departments.https://journals.lww.com/neurotodayonline/Fulltext/2018/12200/Women_in_MS_Seek_Greater_Parity_in_Field.7.aspx
International Consensus on Timely Care for Multiple Sclerosishttps://www.ajmc.com/newsroom/international-consensus-on-timely-care-for-multiple-sclerosis
Losing neurons is sometimes not all badhttps://medicalxpress.com/news/2018-12-neurons-bad.htmlPortuguese research:)Obrigado
Out of curiosity: is there record of an individual having MS and also tropical spastic paraparesis (caused by HTLV)?
Two brilliant BBC stars both struck with MS… How one award-winning correspondent gambled on life while the other lost so much dignity and independence she went to Dignitas https://www.dailymail.co.uk/news/article-6533923/amp/How-two-BBC-stars-took-different-paths-dealing-MS.html
Its Dr mouse time :)https://jamanetwork.com/journals/jamaneurology/article-abstract/2630677
Expanding the Potential Therapeutic Options for Remote Ischemic Preconditioning: Use in Multiple Sclerosishttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018107/
Getting rid of oligoclonal bands is obviously important (see profG's announcement of the new clinical trial you at Barts are planning to do http://multiple-sclerosis-research.blogspot.com/2018/12/will-2019-be-year-of-sequential.html?showComment=1546013637498). What is the status regarding that for all current DMTs? I know that Cladribine cleared OCBs in >50% cases in that Polish study, but what do you see in clinical practice? Any papers regarding that?