Journal Article

Smouldering multiple sclerosis: the ‘real MS’

Popescu, Veronica, De Rossi, Nicola, Airas, Laura, Jensen, Michael B., Sousa, Livia, Wuerfel, Jens, Stankoff, Bruno, Fenu, Giuseppe, Bodini, Benedetta, García-Domínguez, José Manuel, Giovannoni, Gavin, Iacobaeus, Ellen, Kuusisto, Hanna-Maija, Hupperts, Raymond, Lycke, Jan, Granziera, Cristina, Hellwig, Kerstin, Scalfari, Antonio

2022

Overview

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). We provide a range of evidence to argue that the ‘real MS’ is in fact driven primarily by a smouldering pathological disease process. 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. In addition, the progressive accumulation of disability in MS can occur independently of relapse activity from early in the disease course. This scenario is underpinned by a more diffuse smouldering pathological process that may affect the entire CNS. 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. 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. 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.

• Publisher: SAGE Publications,SAGE PUBLICATIONS, INC,SAGE Publishing
• Subject: alemtuzumab / Alzheimer disease / amyotrophic lateral sclerosis / antioxidant / ascorbic acid / biological marker / brain atrophy / brain damage / brain size / Bruton tyrosine kinase / carrier protein / CD68 antigen / cellular immunity / Central nervous system / clinical outcome / Clinical trials / Cognition / deferoxamine / degenerative disease / demyelination / diffusion tensor imaging / disease activity / disease course / disease duration / disease exacerbation / edema / Epstein Barr virus / Expanded Disability Status Scale / Fc receptor / gliosis / glutathione / hematopoietic stem cell transplantation / homeostasis / human / Human endogenous retrovirus / imaging / immunoglobulin enhancer binding protein / inflammation / Inflammatory diseases / innate immunity / iron / iron chelation / Life Sciences / Magnetic resonance imaging / memory B lymphocyte / microglia / Multiple sclerosis / myelooptic neuropathy / natalizumab / nerve degeneration / Neuroimaging / Neurons and Cognition / neuroprotection / Neurosciences / Neurovetenskaper / nitric oxide synthase / nuclear magnetic resonance imaging / ocrelizumab / optic neuritis / oxidative stress / Patients / phenotype / positron emission tomography / progression independent of relapse activity / progressive multiple sclerosis / protein p22 / reactive oxygen metabolite / relapse / Review / rheumatoid arthritis / rituximab / scoring system / smouldering multiple sclerosis / Spinal cord / T1 weighted imaging / thioctic acid / tissue injury / upregulation / white matter