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Multiple Sclerosis Therapeutics
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  • Cited by 6
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    This (lowercase (translateProductType product.productType)) has been cited by the following publications. This list is generated based on data provided by CrossRef.

    Mütze, Tobias Glimm, Ekkehard Schmidli, Heinz and Friede, Tim 2018. Group sequential designs for negative binomial outcomes. Statistical Methods in Medical Research, p. 096228021877311.


    Asendorf, Thomas Henderson, Robin Schmidli, Heinz and Friede, Tim 2017. Modelling and sample size reestimation for longitudinal count data with incomplete follow up. Statistical Methods in Medical Research, p. 096228021771566.


    Correale, Jorge Gaitán, María I. Ysrraelit, María C. and Fiol, Marcela P. 2016. Progressive multiple sclerosis: from pathogenic mechanisms to treatment. Brain, p. aww258.


    Hang, Yaming Hu, Xiao Zhang, Jie Liu, Shifang Deykin, Aaron and Nestorov, Ivan 2016. Analysis of peginterferon β-1a exposure and Gd-enhanced lesion or T2 lesion response in relapsing-remitting multiple sclerosis patients. Journal of Pharmacokinetics and Pharmacodynamics, Vol. 43, Issue. 4, p. 371.


    Correale, Jorge and Farez, Mauricio F. 2015. The Role of Astrocytes in Multiple Sclerosis Progression. Frontiers in Neurology, Vol. 6,


    Correale, Jorge Ysrraelit, María C. and Fiol, Marcela P. 2012. Benign Multiple Sclerosis: Does it exist?. Current Neurology and Neuroscience Reports, Vol. 12, Issue. 5, p. 601.


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    Multiple Sclerosis Therapeutics
    • Online ISBN: 9781139023986
    • Book DOI: https://doi.org/10.1017/CBO9781139023986
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Book description

This book comprehensively reviews the current state of clinical trial methods in multiple sclerosis treatment, providing investigators, sponsors and specialists with current knowledge of outcome measures and study designs for disease and symptom management. The status of the rapidly evolving field of disease-modifying drugs is presented, with emphasis on the most promising therapies currently being tested. Experts discuss disease and symptom management for MS subtypes, including neuromyelitis optica and pediatric MS. In addition, key scientific advances in MS pathology, genetics, immunology and epidemiology are presented. The fourth edition has been extensively revised, featuring more than 50% new material. All chapters have been substantially updated to provide current information on rapidly evolving topics and this volume contains 15 new chapters, reflecting the growth of the field in recent years. This book is an essential reference for practitioners caring for MS patients, investigators planning or conducting clinical trials, and clinical trial sponsors.

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Page 1 of 3


  • 7 - Assessment of neuropsychological function in multiple sclerosis
    pp 65-78
  • https://doi.org/10.1017/CBO9781139023986.010
  • View abstract
    Summary
    Relapsing remitting multiple sclerosis (RRMS) patients have periodic relapses occurring at variable rates, but generally less than one per year. The factor complicating MS clinical trials is disease heterogeneity, which is one of the hallmarks of MS. The annualized relapse rate or the number of relapses is the most common primary outcome measure for RRMS clinical trials. Relapses are subjective. As symptoms fluctuate, and are influenced by many factors- fever, high ambient temperature, anxiety, intercurrent illness, and sleep deprivation, among others - it is often not clear whether an individual MS patient has experienced a relapse or not. Also, the required duration beyond which symptoms must persist has not been standardized. There are no demonstrably effective therapies for primary neuroprotection, though it appears possible to slow the neurodegerative process in early-stage MS with immunomodulatory or immunosuppressive drugs. Presumably, this form of neuroprotection is secondary to the anti-inflammatory effect.
  • 9 - Measures of acute and chronic lesions visualized by conventional magnetic resonance imaging
    pp 91-111
  • https://doi.org/10.1017/CBO9781139023986.012
  • View abstract
    Summary
    In acute multiple sclerosis (MS) lesions, axonal pathology and the number of transected axons correlate with the number of immune cells and therefore with inflammatory activity. In addition to the commonly described white matter locations, demyelination also occurs in the gray matter of MS patients. The concept of MS as an inflammatory demyelinating and neurodegenerative disease provides a framework to help explain disease progression and development of permanent neurological disability in MS patients. Prevention of persistent neurological disability is the main goal when treating neurological diseases. In contrast to most neurodegenerative diseases, patients with MS can be identified early before the occurrence of extensive neurodegeneration by the presentation of symptoms mediated by inflammatory demyelination. Therefore, neuroprotective therapeutics may have a greater probability of clinical efficacy in MS patients since treatment can be initiated before extensive axonal loss. Regardless of the cause of MS, axons and neurons are important therapeutic targets.
  • 10 - Measures of magnetization transfer
    pp 112-127
  • https://doi.org/10.1017/CBO9781139023986.013
  • View abstract
    Summary
    This chapter focuses on how the immune system is thought to contribute to the multiple sclerosis (MS) process through the different disease phases, including initiation and propagation, and in different anatomical compartments. Several subsets of regulatory T-cells are capable of inhibiting activation of other T-cells, including suppression of autoimmune responses. Clinical trials of B-cell depletion with rituximab and more recently ocrelizumab have demonstrated substantial reductions in new brain lesions, and relapses in MS patients. The innate immune system rapidly senses foreign pathogen-associated structures without the need for adaptive antigen-specific recognition or memory responses. The presence of clonally expanded CD4 and CD8 T-cells persisting in the CNS, suggests that T-cells can be activated or re-activated within the central nervous system (CNS) compartment. Cellular immune responses and soluble factors can have protective and potentially growth permissive influences capable of limiting injury, as well as promoting survival and repair of neural elements.
  • 11 - Measurement of CNS atrophy
    pp 128-149
  • https://doi.org/10.1017/CBO9781139023986.014
  • View abstract
    Summary
    The human leukocyte antigen (HLA) gene cluster in chromosome 6p21.3 represents by far the strongest multiple sclerosis (MS) susceptibility locus genome-wide, explaining approximately 7%-10% of the total (genetic and non-genetic) variance. Two main biological issues contributed to thwart gene discovery efforts in MS. First, the effect attributable to each individual allelic variant is modest. Second, the true signals need to be isolated from the abundant genetic variation that characterizes the human population as a whole, leading to the inescapable conclusion that the discovery of genes influencing MS risk must rely primarily on very large patient datasets and well-matched controls. Concordance in families for some clinical metrics such as severity or age-of-onset suggests that genes modestly influence disease trajectory and course. High throughput methods of analysis have enabled the characterization of gene expression signatures characteristic of the disease and multiple efforts are underway to identify biomarkers of therapeutic response.
  • 12 - Axonal pathology in patients with multiple sclerosis
    pp 150-164
  • https://doi.org/10.1017/CBO9781139023986.015
  • View abstract
    Summary
    The Expanded Disability Status Scale (EDSS) represents the most widely accepted measure of disease progression in multiple sclerosis (MS), and is used in many natural history studies. This chapter discusses natural history of relapsing onset MS, primary progressive MS, changes in natural history and impact on clinical trial design, traditional prognostic factors, and other factors which may influence prognosis such as race, comorbid diseases, and health behaviors. Pharmacoepidemiological studies using real world data derived from clinical practice represent a cost-effective means of evaluating the long-term effectiveness of immunomodulatory drug treatments for MS. Along with evidence from the basic sciences, epidemiological studies can provide insights into potentially novel treatments, as well as the rationale and hypotheses for testing these treatments in clinical trials. For example, vitamin D and estrogen are being evaluated in clinical trials based partly on epidemiological observations. Heterogeneity remains the hallmark of MS.
  • 13 - Imaging of gray matter lesions in multiple sclerosis
    pp 165-174
  • https://doi.org/10.1017/CBO9781139023986.016
  • View abstract
    Summary
    This chapter deals with the measurement of impairment or disability for use in multiple sclerosis (MS) clinical trials from a medical model perspective, focusing on global clinical trial outcome measures. It addresses the methodological issues in measuring impairment and disability. The measures of neurological impairment and disability in MS can be grouped into four classes: biological assays, performance measures, rating scales and self-report measures. The Incapacity Status Scale and the multiple sclerosis (MS) Quality of Life Inventory are examples of such self-report measures, also called patient reported outcomes or PROs. Surrogate outcome measures have been studied in a variety of diseases and have been hoped for within the MS community. The development of the Multiple Sclerosis Functional Composite (MSFC) resulted from the analysis of a pooled data set of placebo control groups and natural history study databases.
  • 15 - Diffusion imaging in multiple sclerosis
    pp 186-197
  • https://doi.org/10.1017/CBO9781139023986.018
  • View abstract
    Summary
    As the prevalence and functional consequences of multiple sclerosis (MS)-related cognitive dysfunction became more widely recognized, several definitive trials of disease-modifying medications for relapsing remitting MS and progressive MS incorporated neuropsychological (NP) outcome measures. This chapter lists clinical trials designed to assess the efficacy of medications as symptomatic treatment for cognitive impairment. Several factors complicate the assessment of NP outcomes in MS trials, although none is insurmountable. With the recent development of functional magnetic resonance imaging (fMRI), it has been possible to image MS patients while they perform cognitive tests in the scanner. In general, these fMRI studies have demonstrated that, even when cognitive testing is comparable to healthy controls, MS patients exhibit a larger number of activated regions, an increase in MR signal change and spatial extent in regions also activated by controls, and a decrease in laterality indices.
  • 16 - The use of MRI in multiple sclerosis clinical trials
    pp 198-212
  • https://doi.org/10.1017/CBO9781139023986.019
  • View abstract
    Summary
    The Food and Drug Administration (FDA) has offered guidance on using health related quality of life (HRQoL) measures to support labeling claims, and the definition of HRQoL has become more systematized. HRQoL measures look at patients' reports of their perceived health in either very general or very particular terms. Utility assessment is an increasingly active area of research in multiple sclerosis (MS). HRQoL data are used for three general purposes: to classify or group patients by levels of disease severity, predict the health of subjects at a future point in time, and as outcome variables. MS-specific HRQoL measures have been included as endpoints in many clinical studies, including some randomized controlled clinical trials. Selection of the most appropriate disease-specific measures by investigators should be based on available validity and reliability data for those measures and the specific questions that the researcher hopes to answer.
  • 17 - Optical coherence tomography to monitor axonal and neuronal integrity in multiple sclerosis
    pp 213-224
  • https://doi.org/10.1017/CBO9781139023986.020
  • View abstract
    Summary
    There are four conventional magnetic resonance imaging (cMRI) components readily visible to the clinician considering the extent of multiple sclerosis (MS) pathology in individual patients that might be compared with the extent of MRI-defined pathology from group data derived from natural history or clinical trial cohorts. These include: the presence, number and quality of enhancements; the aggregate number and volume of lesions defined on T2-weighted images; the number and volume of T1-weighted hypointense lesions; and net tissue loss or atrophy. Since initially inactive subjects may not contribute much to measuring efficacy over time, many trials rely on a design including an enrichment strategy based on enhancement on one, or sometimes multiple screening MRI studies. Many consider enhancing activity to be an MRI equivalent of clinical relapse. Most studies show little or no correlation between enhancing lesions and composite disability measures at one point in time, or over a few years.
  • 19 - Selection, interpretation, and development of end-points for multiple sclerosis clinical trials
    pp 232-243
  • https://doi.org/10.1017/CBO9781139023986.022
  • View abstract
    Summary
    Image analysis software allows for quantitative estimation of widths, areas, and/or volumes of central nervous system (CNS) structures directly from digital images. Although atrophy is not pathologically specific, it primarily reflects irreversible tissue loss due to multiple sclerosis (MS), and therefore, it is a valuable marker of disease severity. Brain atrophy can be detected very early in the course of MS, and appears to progress almost from disease onset. Current evidence suggests that atrophy correlates better with neurologic measures of disability than do conventional lesion measurements. Atrophy is an attractive component of a magnetic resonance imaging (MRI)-based outcome assessment in MS clinical trials because it reflects diffuse pathologic processes that are not accounted for by lesion measurements, and yet it can still be measured from images acquired with conventional MRI pulse sequences. Gray matter atrophy may provide a feasible measure of the extent of cortical pathology.
  • 20 - The challenge of demonstrating long-term benefit of disease-modifying therapies in multiple sclerosis
    pp 244-252
  • https://doi.org/10.1017/CBO9781139023986.023
  • View abstract
    Summary
    The inflammatory response itself is probably partially responsible for some of the acute conduction block in multiple sclerosis (MS). Proton magnetic resonance spectroscopy (1H-MRS(I)) studies of neuroaxonal NA levels have emphasized that axonal disturbance in the brains of patients with MS can be substantial and widespread, encompassing both the lesional and normal appearing white matter and gray matter. The ability to observe axonal disturbance in vivo allows for correlations across time to be made between measures of axonal pathology and measures of clinical disability. The role of glutamate in mediating neuronal, axonal and oligodendrocyte damage in MS is a promising area of investigation enabled by 1H-MRS(I). 1HMRS(I) has an important role to play in the assessment of new treatments for MS that are directed towards either limiting the damage to the neuro-axonal central nervous system (CNS) or to enhancing its recovery after inflammatory damage.

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