Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
  1. Home
  2. Books
  3. Multiple Sclerosis Therapeutics
  • Cited by 10
Publisher:
Cambridge University Press
Online publication date:
December 2011
Print publication year:
2011
Online ISBN:
9781139023986
DOI:
https://doi.org/10.1017/CBO9781139023986
Subjects:
Neurology and Clinical Neuroscience, Medicine
Information

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.

Refine List

Actions for selected content:

Select all | Deselect all
  • View selected items
  • Export citations
  • Download PDF (zip)
  • Save to Kindle
  • Save to Dropbox
  • Save to Google Drive

Save Search

You can save your searches here and later view and run them again in "My saved searches".

Please provide a title, maximum of 40 characters.
Cancel
×

Contents

Page 3 of 3

Contents
  • 50 - The role of chronic cerebrospinal venous insufficiency in multiple sclerosis
    pp 574-582
  • View abstract

    Summary

    T-cells play a central role in the pathogenesis of multiple sclerosis (MS). Altered peptide ligands (APLs) have most commonly been used as T-cell receptor (TCR) ligands, to alter T-cell responses to presumed immunogenic or target antigens. The treatment therapies targeting T-cells non-specifically are: lymphocytapheresis, total lymphoid irradiation, anti-CD4 antibody, anti-CD3 antibody, anti-CD154 antibody, CTLA4Ig, interleukin-12, tumor necrosis factor alpha, interferon gamma and transforming growth factor beta. Although the T-cell is not the primary target of several drugs that are currently approved or are under investigation for the treatment of MS, many of these therapies have secondary effects on T-cell measures. The T-cell is an important target in MS therapeutics. The success of several drugs that specifically target the T-cell and T-cell responses reinforces this point. Further success of T-cell directed therapies depends on the appropriate targeting of phases of T-cell activation and function and the accurate identification of antigens.
  • 51 - Disease-modifying therapy for multiple sclerosis in clinical practice
    pp 583-603
  • View abstract

    Summary

    This chapter provides an overview of treatments targeting B-cells and humoral responses in multiple sclerosis (MS). Intravenous Ig (IVIg) and plasma exchange (PLEX) action provide successful treatment of active MS relapses or prevention of relapses. Rituximab has been evaluated for its potential to treat autoimmune states in which B-cells and autoantibodies have been thought to contribute to disease pathophysiology. Ocrelizumab is a humanized anti-CD20 monoclonal antibody (IgG1) that recognizes an epitope that overlaps with that recognized by rituximab. Ofatumumab targets an epitope different from rituximab and most other anti-CD20 antibodies. The initial pursuit of clinical trials with rituximab in MS was based on the consideration that such an approach would serve to decrease precursors to plasma cells, thereby reducing synthesis of potentially pathogenic central nervous system (CNS)-directed antibodies. The success of B-cell depletion in MS has opened the door to a therapeutic strategy.
  • 52 - Treatment for patients with primary progressive multiple sclerosis
    pp 604-613
  • View abstract

    Summary

    Since mechanisms of action of the approved therapies for multiple sclerosis (MS) involve anti-inflammatory effects, and since these treatments result primarily in a reduction in relapse rates, it is logical to hypothesize that mechanisms of action of the protective effect of pregnancy on MS relapses involve anti-inflammatory effects. Two estrogens (estradiol and estriol) and progesterone each increase progressively during pregnancy. Levels of estrogens that are in oral contraceptives or hormone replacement therapy may not be high enough to be protective in MS. Numerous factors other than sex hormones have been identified in sera during pregnancy and have been shown to be immunosuppressive either in cultures of immune cells in vitro or in experimental autoimmune encephalomyelitis (EAE) models. The combined anti-inflammatory and neuroprotective state of pregnancy, perhaps aimed at protecting the fetus, may be precisely what is needed to protect the central nervous system (CNS) of a mother with MS.
  • 53 - Diagnosis, pathogenesis, and treatment of neuromyelitis optica (NMO) spectrum disorders
    pp 614-631
  • View abstract

    Summary

    Hematopoietic stem cell (HSC) can be either allogeneic (from another person) or autologous (from the recipient). Autologous hematopoietic stem cell transplantation (HSCT) was first suggested by Burt as a form of intense immunesuppressive therapy. HSCT was proposed as a treatment for multiple sclerosis (MS) based on favorable results in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The toxicity and efficacy of an autologous HSCT is entirely a consequence of the conditioning regimen. Initial HSCT protocols employed aggressive malignancy-specific myeloablative regimens in patients with progressive MS. Unlike autologous HSCT, the immune compartment arising from allogeneic stem cells have a different and presumably more disease-resistant genetic predisposition towards disease recurrence. Both autologous and allogeneic HSCT require a chemotherapy conditioning regimen to suppress or ablate the immune system. HSCT is the only therapy to consistently demonstrate improvement in neurological disability.
  • Chapter 54 - Management of pediatric multiple sclerosis
    pp 632-644
  • View abstract

    Summary

    The potent immunomodulatory properties of mesenchymal stem cells (MSCs) are particularly relevant for multiple sclerosis (MS). MSCs inhibit T-cell proliferation stimulated by polyclonal activators, cognate antigen and allogeneic mixed lymphocyte reaction. MSCs inhibit B-cell proliferation in culture via soluble factors, accompanied by inhibition of B-cell differentiation and production of IgM, IgG, and IgA. The property of MSCs relevant to MS is their potential ability to lessen damage and augment repair in numerous tissue injury models. In general, MSC transplantation in humans, including with allogeneic MSCs, has been very well tolerated. The several potential adverse events (AEs) that require close attention in planned trials are: infusion-related toxicity, infection, cancer, ectopic tissue formation, rejection, and autoimmunity. MSCs have potential immunomodulatory, tissue protective, and repair promoting properties. There is rapidly accumulating experience with both autologous and allogeneic MSC transplantation in a number of conditions.
  • 55 - Use of MRI in the clinical management of multiple sclerosis
    pp 645-653
  • View abstract

    Summary

    This chapter reviews the mechanisms for both inflammatory and non-inflammatory mediated neural degeneration in multiple sclerosis (MS) and discusses potential therapeutic targets for neuroprotection. The classical pathological description of the MS lesion has focused on the perivenular inflammatory infiltrate characterized predominantly by lymphocytes and monocytes. Progressive axonal loss occurs in the central nervous system (CNS) of patients with MS, and the extent of this axonal loss correlates with the degree of permanent neurological deficit. Careful consideration to the pathophysiology of MS is necessary to identify candidate drugs for therapeutic trials. Stem cells may serve to enhance the function of host tissues, to provide missing chemicals or enzymes or to halt a degenerative or neoplastic process. As the currently available immunomodulatory treatments for MS have only a modest impact on progressive axonal loss and disability, there exists a pressing need to develop strategies to prevent this axonal loss.
  • 56 - Multiple sclerosis-associated fatigue
    pp 654-665
  • View abstract

    Summary

    More closely analogous to the use of combination therapies in multiple sclerosis (MS) is the use of combination therapies in autoimmune diseases such as rheumatoid arthritis. In the case of MS, drugs could be directed at different therapeutic domains such as tissue destruction and tissue repair. Currently, natalizumab is approved only as a monotherapy. This is due to concern over combined toxicity because of the two cases of progressive multifocal leukoencephalopathy (PML) that occurred in patients enrolled in the combination arm of the SENTINEL trial. Perhaps the most frequently used combination therapy approach utilized in clinical practice for patients with relapsing-remitting MS and continued disease activity while on platform therapy is the ad hoc addition of periodic courses of corticosteroids, most often intravenous methylprednisolone. This chapter discusses cytotoxic therapies and combination trials with other immunomodulating agents such as daclizumab, terilunomide and statins.
  • 57 - Management of spasticity
    pp 666-675
  • View abstract

    Summary

    Dalfampridine is a lipid-soluble small molecule that more readily crosses the blood-rain barrier and, therefore, its effects on the central nervous system (CNS) have been the subject of greater focus. The initial Phase 2 study determined the safety of escalating doses of dalfampridine in subjects with multiple sclerosis (MS), to explore a number of outcome measures, and examine dose related efficacy. A battery of assessments was performed weekly, including the MS Functional Composite (MSFC), fatigue questionnaires, lower extremity manual muscle testing, and spasticity assessment using the Ashworth scale. The results supported the idea that quantitative functional outcome measures (such as walking speed derived from timed gait and lower extremity muscle testing) were sufficiently sensitive to demonstrate efficacy. Based on evaluation, the US food and drug administration (FDA) approved the extended release (ER) formulation of dalfampridine (daily oral dose of 10 mg BID) for use in MS to improve walking.
  • 58 - Management of bladder and sexual dysfunction in multiple sclerosis
    pp 676-695
  • View abstract

    Summary

    Multiple sclerosis (MS) individuals who use complementary and alternative medicine (CAM) generally do so because they experience improvement in their quality of life, and in various MS symptoms such as fatigue, spasticity, or pain. The different CAM therapies used commonly by individuals with MS are: mind-body therapies, dietary changes and supplement use that include low fat diet, essential fatty acids and anti-oxidants, ginseng, acupuncture, low-dose naltrexone and cannabis. Despite the widespread use of CAM therapies among MS patients, most of these therapies have not been evaluated in well-designed, randomized, controlled clinical trials, the lack of which is the main reason why most neurologists do not incorporate CAM therapies into their management of MS patients. Clearly there are certain therapies, such as anti-oxidants and essential fatty acids, which have a scientific rationale for use in MS and are also supported by preclinical or pilot clinical data.
  • 59 - Depression in multiple sclerosis
    pp 696-706
  • View abstract

    Summary

    Zamboni hypothesized that venous stasis resulting from cerebrospinal venous insufficiency (CCSVI) leads to increased iron deposition in the brain parenchyma, and that this iron triggers multiple sclerosis (MS) inflammatory activity. A number of authors have challenged the CCSVI hypothesis on several grounds including the redundancy of the venous system. CCSVI has received considerable attention from the mainstream media and the lay public. This has led to increasing pressure on physicians by patients seeking venous imaging and endovascular angioplasty, commonly referred to as the liberation procedure. New therapeutic strategies aimed at reducing venous pressures and venous reflux could be developed and might be more effective than the immunomodulatory and immunosuppressive therapies currently being used. It is, therefore, imperative to confirm and further characterize the association of CCSVI and MS before proceeding with interventional studies and, more importantly, venous procedures in clinical practice.
  • 60 - Assessment and treatment of pain disorders in multiple sclerosis
    pp 707-713
  • View abstract

    Summary

    Disease modifying therapy (DMT) with one of the approved agents should be considered in all patients with active relapsing-remitting multiple sclerosis (RRMS) once the diagnosis of MS is confirmed and in selected patients with a clinically isolated demyelinating syndrome (CIS). Interferon beta modulates T-cell and B-cell function, decreases expression of matrix metalloproteinases reversing blood-brain barrier disruption, and alters expression of cytokines. A series of double-blind, placebo-controlled Phase 3 trials in RRMS supported the benefit of interferon in reducing relapses, disability progression, and MRI lesion activity and accrual. All of the available agents have been reported to reduce relapse rate, magnetic resonance imaging (MRI) lesion activity, and accumulation of disability in RRMS. Patients need to be seen on a regular basis after starting treatment to address potential side effects. This chapter discusses treatment of acute relapses, progressive multiple sclerosis and treatment in special populations including children.
  • 62 - Rehabilitation in multiple sclerosis
    pp 724-730
  • View abstract

    Summary

    The atypical characteristics of primary progressive multiple sclerosis (PPMS) have presented problems in the recruitment to and design of therapeutic trials. The problem areas in the implementation of therapeutic trials are: diagnostic criteria, sample size calculations, and choice of outcome measures. Although there is no definitively proven disease-modifying treatment available for PPMS, several randomized controlled trials have now been specifically designed for this group. The clinical trials in PPMS are based on glatiramer acetate and rituximab. The planned clinical trials in PPMS are based on fingolimod (FTY720) and cladribine. The smaller trials in PPMS are based on Interferon beta-1a, Interferon beta-1b, mitoxantrone and riluzole. A retrospective open-label study of intravenous cyclophosphamide and methylprednisolone in progressive MS included 128 patients with PPMS. PPMS may be the ideal model to investigate disease progression and neuronal protection, and is becoming an important focus for treatment trials in these areas.

Page 3 of 3

Metrics

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Book summary page views

Total views: 0 *
Loading metrics...

* Views captured on Cambridge Core between #date#. This data will be updated every 24 hours.

Usage data cannot currently be displayed.