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      Risks and risk management in modern multiple sclerosis immunotherapeutic treatment

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          Abstract

          In recent years, there has been a paradigm shift in the treatment of multiple sclerosis (MS) owing to the approval of a number of new drugs with very distinct mechanisms of action. All approved disease-modifying drugs primarily work directly on the immune system. However, the identification of an ‘optimal choice’ for individual patients with regard to treatment efficacy, treatment adherence and side-effect profile has become increasingly complex including conceptual as well as practical considerations. Similarly, there are peculiarities and specific requirements with regard to treatment monitoring, especially in relation to immunosuppression, the development of secondary immune-related complications, as well as the existence of drug-specific on- and off-target effects. Both classical immunosuppression and selective immune interventions generate a spectrum of potential therapy-related complications. This article provides a comprehensive overview of available immunotherapeutics for MS and their risks, detailing individual mechanisms of action and side-effect profiles. Furthermore, practical recommendations for patients treated with modern MS immunotherapeutics are provided.

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          Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial.

          Teriflunomide is an oral disease-modifying therapy approved for treatment of relapsing or relapsing-remitting multiple sclerosis. We aimed to provide further evidence for the safety and efficacy of teriflunomide in patients with relapsing multiple sclerosis.
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            Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies

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              Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2

              Dimethyl fumarate (DMF) (BG-12, Tecfidera) is a fumaric acid ester (FAE) that was advanced as a multiple sclerosis (MS) therapy largely for potential neuroprotection as it was recognized that FAEs are capable of activating the antioxidative transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. However, DMF treatment in randomized controlled MS trials was associated with marked reductions in relapse rate and development of active brain MRI lesions, measures considered to reflect CNS inflammation. Here, we investigated the antiinflammatory contribution of Nrf2 in DMF treatment of the MS model, experimental autoimmune encephalomyelitis (EAE). C57BL/6 wild-type (WT) and Nrf2-deficient (Nrf2(-/-)) mice were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 (p35-55) for EAE induction and treated with oral DMF or vehicle daily. DMF protected WT and Nrf2(-/-) mice equally well from development of clinical and histologic EAE. The beneficial effect of DMF treatment in Nrf2(-/-) and WT mice was accompanied by reduced frequencies of IFN-γ and IL-17-producing CD4(+) cells and induction of antiinflammatory M2 (type II) monocytes. DMF also modulated B-cell MHC II expression and reduced the incidence of clinical disease in a B-cell-dependent model of spontaneous CNS autoimmunity. Our observations that oral DMF treatment promoted immune modulation and provided equal clinical benefit in acute EAE in Nrf2(-/-) and WT mice, suggest that the antiinflammatory activity of DMF in treatment of MS patients may occur through alternative pathways, independent of Nrf2.
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                Author and article information

                Contributors
                Journal
                Ther Adv Neurol Disord
                Ther Adv Neurol Disord
                TAN
                sptan
                Therapeutic Advances in Neurological Disorders
                SAGE Publications (Sage UK: London, England )
                1756-2856
                1756-2864
                01 April 2019
                2019
                : 12
                : 1756286419836571
                Affiliations
                [1-1756286419836571]Department of Neurology with Institute of Translational Neurology, University of Münster, Building A1, Albert Schweitzer Campus 1, 48149 Münster, Germany
                [2-1756286419836571]Institute of Clinical Neuroimmunology, University Hospital; Data Integration for Future Medicine consortium (DIFUTURE), Ludwig-Maximilians University, Munich, Germany
                [3-1756286419836571]Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany
                [4-1756286419836571]Institute of Clinical Neuroimmunology, University Hospital, Ludwig-Maximilians University, Munich, Germany Munich Cluster for Systems Neurology, Ludwig-Maximilians University, Munich, Germany
                [5-1756286419836571]Brain and Mind Centre, University of Sydney, NSW, Australia
                [6-1756286419836571]Brain and Mind Centre, University of Sydney, NSW, Australia
                [7-1756286419836571]Department of Neurology with Institute of Translational Neurology, University of Münster, Building A1, Albert Schweitzer Campus 1, 48149 Münster, Germany
                Author notes
                Author information
                https://orcid.org/0000-0003-4310-3432
                Article
                10.1177_1756286419836571
                10.1177/1756286419836571
                6444778
                30967901
                04efc583-5a64-4be1-822e-8279b3523548
                © The Author(s), 2019

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 30 July 2018
                : 14 February 2019
                Categories
                Review
                Custom metadata
                January-December 2019

                multiple sclerosis,treatment,risk management
                multiple sclerosis, treatment, risk management

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