Papers during the week



Here are some papers you may or may not find interesting
Whilst NICE no longer supports the use of CRAB drugs, this study does say that on first signs of MS, these agents work although it takes a few months to see this. So we wait to see what are the consequences of early intervention with a high activity agent. Problem is NICE has tied the hands of the neuro on this one. Maybe time to re-appraise after all “Time is Brain.”
BACKGROUND:In the PRISMS study, interferon beta-1a subcutaneously (IFN β-1a SC) reduced clinical and radiological disease burden at 2 years in patients with relapsing-remitting multiple sclerosis. The study aimed to characterize efficacy of IFN β-1a SC 44 μg and 22 μg three times weekly (tiw) at Year 1.
METHODS: Exploratory endpoints included annualized relapse rate (ARR), 3-month confirmed disability progression (1-point Expanded Disability Status Scale increase if baseline was < 6.0 [0.5-point if baseline was ≥6.0]), active T2 lesions, and no evidence of disease activity (NEDA; defined as no relapses [subanalyzed by relapse severity], 3-month confirmed progression, or active T2 lesions). Effect of IFN β-1a SC in prespecified patient subgroups was also assessed.
RESULTS:Patients were randomized to IFN β-1a 22 μg (n = 189), 44 μg (n = 184), or placebo (n = 187). At 1 year, IFN β-1a SC tiw reduced ARR (p < 0.001), risk of disability progression (p ≤ 0.029), and mean number of active T2 lesions per patients per scan (p < 0.001) versus placebo. Clinical and radiological benefits were seen as early as Month 2 and 3. Outcomes in subgroups were consistent with those in the overall population. More patients treated with IFN β-1a SC tiw achieved NEDA status, versus placebo, regardless of relapse severity (p ≤ 0.006).
Gil-Varea E, Urcelay E, Vilariño-Güell C, Costa C, Midaglia L, Matesanz F, Rodríguez-Antigüedad A, Oksenberg J, Espino-Paisan L, Dessa Sadovnick A, Saiz A, Villar LM, García-Merino JA, Ramió-Torrentà L, Triviño JC, Quintana E, Robles R, Sánchez-López A, Arroyo R, Alvarez-Cermeño JC, Vidal-Jordana A, Malhotra S, Fissolo N, Montalban X, Comabella M.
J Neuroinflammation. 2018 Sep 14;15(1):265. doi: 10.1186/s12974-018-1307-1.


It remains unclear whether disease course in multiple sclerosis (MS) is influenced by genetic polymorphisms. (Give up now if you do not know that genetic polymorphisms influence disease course, of course they do it is called variation) Here, we aimed to identify genetic variants associated with benign and aggressive disease courses in MS patients.


MS patients were classified into benign and aggressive phenotypes according to clinical criteria. We performed exome (bits of DNA shed in DNA balls in blood) sequencing in a discovery cohort, which included 20 MS patients, 10 with benign and 10 with aggressive disease course, and genotyping in 2 independent validation cohorts. The first validation cohort encompassed 194 MS patients, 107 with benign and 87 with aggressive phenotypes. The second validation cohort comprised 257 patients, of whom 224 patients had benign phenotypes and 33 aggressive disease courses. Brain immunohistochemistries were performed using disease course associated genes antibodies.


By means of single-nucleotide polymorphism (SNP) detection and comparison of allele frequencies between patients with benign and aggressive phenotypes, a total of 16 SNPs were selected for validation from the exome sequencing data in the discovery cohort. Meta-analysis of genotyping results in two validation cohorts revealed two polymorphisms, rs28469012 and rs10894768, significantly associated with disease course. SNP rs28469012 is located in CPXM2 (carboxypeptidase X, M14 family, member 2) and was associated with aggressive disease course (uncorrected p value < 0.05). SNP rs10894768, which is positioned in IGSF9B (immunoglobulin superfamily member 9B) was associated with benign phenotype (uncorrected p value < 0.05). In addition, a trend (stop-a trend means nothing) for association with benign phenotype was observed for a third SNP, rs10423927, in NLRP9 (NLR family pyrin domain containing 9). Brain immunohistochemistries in chronic active lesions from MS patients revealed expression of IGSF9B in astrocytes (Brainseq2 says it is immature astrocytes) and macrophages/microglial cells, and expression of CPXM2 (BioGPS says it is expressed in the vascularture rather than macrophages, ) and NLRP9 restricted to brain macrophages/microglia.


Genetic variants located in CPXM2,and IGSF9B have the potential to modulate disease course in MS patients and may be used as disease activity biomarkers to identify patients with divergent disease courses. Altogether, the reported results from this study support the influence of genetic factors in MS disease course and may help to better understand the complex molecular mechanisms underlying disease pathogenesis. 

Ma D, Wang B, Zadwadzka M, Gonzalez G, Wu Z, Yu B, Rawlins EL, Franklin RJM, Zhao C. A sub-population of Foxj1 expressing, non-myelinating Schwann cells of the peripheral nervous system contribute to Schwann cell remyelination in the central nervous system. J Neurosci. 2018 Sep 18. pii: 0585-18.
New myelin sheaths can be restored to demyelinated axons in a spontaneous regenerative process called remyelination. In general, new myelin sheaths are made by oligodendrocytes newly generated from a widespread population of adult CNS progenitors called oligodendrocyte progenitor cells (OPCs). New myelin in CNS remyelination in both experimental models and clinical disease can also be generated by Schwann cells, the myelin forming cells of the peripheral nervous system. Fate mapping studies have shown that Schwann cells contributing to remyelination in the CNS are often derived from OPCs, and appear not to be derived from myelinating Schwann cells from the PNS. In this study we address whether CNS remyelinating Schwann cells can also be generated from PNS derived cells other than myelinating Schwann cells. Using a genetic fate mapping approach, we have found that a sub-population of non-myelinating Schwann cells identified by the expression of the transcription factor foxj1 also contribute to CNS Schwann cell remyelination, as well as to remyelination in the peripheral nervous system. We also find the ependymal cells lining the central canal of the spinal cord, which also express foxj1, do not generate cells that contribute to CNS remyelination. These findings therefore identify a previously unrecognised population of PNS glia that can participate in the regeneration of new myelin sheaths following CNS demyelination.SIGNIFICANCE STATEMENTRemyelination Failure in chronic demyelinating diseases such as multiple sclerosis drives the current quest for developing means by which remyelination in central nervous system can be enhanced therapeutically. Critical to this endeavour is the need to understand the mechanisms of remyelination including the nature and identity of the cells capable of generating new myelin sheath-forming cells. Here we report a previously unrecognised sub-population of non-myelinating Schwann cells in the peripheral nervous system, identified by the expression of the transcription factor foxj1, which can give rise to Schwann cells that are capable of remyelinating both PNS and CNS axons. These cells therefore represent a new cellular target for myelin regenerative strategies for the treatment of CNS disorders characterised by persistent demyelination.
Schwann cells (1 cell to one nerve) myelinate peripheral nerves, whereas oligodendrocytes myelinate nerves in the CNS (1 cell to many nerves). In MS and models of MS you can get invasion of swann cells to the CNS to cause myelination. In this study they report that these cells carry markers that distinguish them from being those that myelinate peripheral nerves

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  • Effect of interferon beta-1a subcutaneously three times weekly on clinical and radiological measures and no evidence of disease activity status in patients with relapsing-remitting multiple sclerosis at year 1

    This study and analyses were supported by EMD Serono, Inc., Rockland, MA, USA (a business of Merck KGaA, Darmstadt, Germany) and Pfizer Inc., New York, NY, USA. The sponsor planned the post hoc analyses reported here in cooperation with the authors. Analysis and interpretation was performed by the authors. The authors were involved in all stages of development and finalization of the manuscript and received editorial assistance from an independent medical-writing-services agency paid by EMD Serono, Inc., Rockland, MA, USA (a business of Merck KGaA, Darmstadt, Germany) and Pfizer Inc., New York, NY, USA.

    Competing interests

    A Traboulsee has acted as a consultant for Biogen, Genzyme, Roche, and Teva, and is Principal Investigator on clinical trials for Biogen, Chugai, Genzyme, and Roche.

    D Li is the Director of the UBC MS/MRI Research Group, which has been contracted to perform central analysis of MRI scans for therapeutic trials with Genzyme, Hoffmann-La Roche, Merck Serono, Nuron, Perspectives, and Sanofi-Aventis. He has acted as a consultant to Vertex Pharmaceuticals; has served on scientific advisory boards for Novartis, Nuron, and Roche; has served on a data and safety advisory board for Opexa; and has received research funding from the Canadian Institute of Health Research and Multiple Sclerosis Society of Canada



    • Any neurologist who is any good has worked with pharma. If they haven't there is an issue.

      The problem with conflict statements is that it does not state if they are felt to be relevant. People like ProfG for example often give a long list of conflicts and the real stuff gets buried in the middle of a sea of alphabetical names.

      However the information is there, the interferon study is about rebif (3 times a week), which is Merck serono, but there is competition fron other companies.

      scientitsts virtually never report conflicts, but filing patents are conflicts, which often go unmentioned. Sitting on grant panels is another one seldom mentioned. How many papers have your mates been referee/editor of. e.g. I recently saw on where the editor and author have co-written 50 papers. Is there not an editorial conflict there.

      On it goes

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