TY - JOUR

T1 - Smouldering multiple sclerosis

T2 - the "real MS"

AU - Giovannoni, Gavin

AU - Popescu, Veronica

AU - Wuerfel, Jens

AU - Hellwig, Kerstin

AU - Iacobeus, Ellen

AU - Jensen, Michael B.

AU - García-Domínguez, José Manuel

AU - Sousa, Livia

AU - De Rossi, Nicola

AU - Hupperts, Raymond

AU - Fenu, Giuseppe

AU - Bodini, Benedetta

AU - Kuusisto, Hanna Maija

AU - Stankoff, Bruno

AU - Lycke, Jan

AU - Airas, Laura

AU - Granziera, Cristina

AU - Scalfari, Antonio

N1 - Publisher Copyright: © The Author(s), 2022.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - multiple sclerosis

KW - progression independent of relapse activity

KW - progressive multiple sclerosis

KW - smouldering multiple sclerosis

U2 - 10.1177/17562864211066751

DO - 10.1177/17562864211066751

M3 - Review

C2 - 35096143

AN - SCOPUS:85123704451

VL - 15

JO - Therapeutic Advances in Neurological Disorders

JF - Therapeutic Advances in Neurological Disorders

SN - 1756-2856

ER -