Protocol of the study if a relapse occurred, there was one neurologicalĪssessment outside of the schedule, at a point corresponding to the leftmost NeurologicalĪssessments were scheduled to occur every 12 weeks, according to the Relapses (at initial event and confirmation points). Remain free of relapses to fulfil the criterion of independence from Represent the intervals around the neurological assessments that had to Visit from which subsequent changes are measured over time. Trials, this is the time of randomisation to study treatment, but in theĬontext of the clinic, this would be the reference disability assessment Point for disability changes measured over time in the context of clinical Non-mutually exclusive drivers of confirmed disability accumulation (CDA) inīoth relapsing and progressive forms of MS. and is a schematic representation of RAW and PIRA, which are Relapse-Associated Worsening (RAW) and Composite Progression Independent of Multiple sclerosis progression independent of relapse activity progressive multiple sclerosis smouldering multiple sclerosis. This should also be complemented with a holistic approach to the management of other systemic disease processes that have been shown to worsen MS outcomes. We hypothesise that therapeutically targeting a state of 'no evident inflammatory disease activity' (NEIDA) cannot sufficiently prevent disability accumulation in MS, meaning that treatment should also focus on other brain and spinal cord pathological processes contributing to the slow loss of neurological function. Many putative pathological drivers of smouldering MS can be potentially modified by specific therapeutic strategies, an approach that may have major implications for the management of MS patients. This scenario is underpinned by a more diffuse smouldering pathological process that may affect the entire CNS. In addition, the progressive accumulation of disability in MS can occur independently of relapse activity from early in the disease course. In natural history studies and clinical trials, relapses and focal activity revealed by magnetic resonance imaging (MRI) in MS patients on placebo or on disease-modifying therapies (DMTs) were found to be poor predictors of long-term disease evolution and were dissociated from disability outcomes. We provide a range of evidence to argue that the 'real MS' is in fact driven primarily by a smouldering pathological disease process. Using a philosophical approach or deductive reasoning, we challenge the dominant clinico-radiological worldview that defines multiple sclerosis (MS) as a focal inflammatory disease of the central nervous system (CNS). 18 Centre for Neuroscience, Department of Medicine, Charing Cross Hospital, Imperial College London, London, UK.17 Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research and Biomedical Engineering, University Hospital Basel and University of Basel, Basel, Switzerland.16 University of Turku, Turku, Finland.15 Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.14 Paris Brain Institute, Sorbonne University, ICM, CNRS, Inserm, Paris, France APHP, Saint-Antoine Hospital, Paris, France.13 Department of Neurology, Tampere University Hospital, Tampere, Finland Department of Customer and Patient Safety, University of Eastern Finland, Kuopio, Finland.12 Paris Brain Institute, Sorbonne University, Paris, France Department of Neurology, APHP, Saint-Antoine Hospital, Paris, France.11 Department of Neurology, Brotzu Hospital, Cagliari, Italy.10 Zuyderland Medisch Centrum, Sittard-Geleen, The Netherlands Maastricht University Medical Center, Maastricht, The Netherlands.9 Spedali Civili of Brescia, Brescia, Italy.8 Centro Hospitalar e Universitário de Coimbra, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal.7 HGU Gregorio Marañón, Madrid, Spain HM Hospitales, Madrid, Spain.6 Department of Neurology, Nordsjællands Hospital, Hillerød, Denmark.5 Karolinska University Hospital, Stockholm, Sweden.4 Katholisches Klinikum Bochum, Klinikum der Ruhr-Universität, Bochum, Germany.3 MIAC AG, Department of Biomedical Engineering, University of Basel, Basel, Switzerland Charité - University Medicine Berlin, Berlin, Germany.2 Universitair MS Centrum, Hasselt, Belgium Noorderhart Hospital, Pelt, Belgium Hasselt University, Hasselt, Belgium.1 Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark St., Whitechapel, London E1 2AT, UK.
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