Smouldering multiple sclerosis: the ‘real MS’

Abstract

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.

Roles of Fatty Acids in Microglial Polarization: Evidence from In Vitro and In Vivo Studies on Neurodegenerative Diseases

“…Shadow plaques are formed by partially remyelinated plaques formed by oligodendrocytes. Others are smoldering plaques that expand to the peripheral region but are inactive at the center [123,124]. MS is a typical example of inflammatory demyelination.…”

Clinical trials in multiple sclerosis: past, present, and future

“…Much like the leap that took place when MRI replaced CT scans, advanced imaging techniques may shine a light on new measures of disease activity and provide further therapeutic targets for future trials. Of note is the volumetric analysis of the choroid plexus; this immunologically-sensitive organ closely tracks the biological events pertinent to CSF and exhibits volume alterations relative to both MS disease activity and type of DMT [36,37], and the identification and longitudinal assessment of chronic active MS lesions, also termed 'smouldering lesions' with paramagnetic rims [38][39][40][41].…”

MSProDiscuss™ Clinical Decision Support Tool for Identifying Multiple Sclerosis Progression

“…Multiple sclerosis (MS) is a chronic, potentially debilitating autoimmune-mediated neurological disorder of the central nervous system (CNS) and the most common acquired degenerative disease of the CNS in young adults [ 1 , 2 ]. MS pathology combines inflammation, demyelination, and axonal degeneration and results in a diverse range of functional and clinical manifestations, including physical disability, cognitive impairment, visual and sensory loss, bladder, bowel and sexual dysfunction, fatigue, and mood disorders [ 3 , 4 , 5 ]. The disease course of MS is highly variable and can be unpredictable, and individual patients may experience completely different symptoms [ 1 , 2 ].…”

“…In up to 50% of cases, the disease gradually evolves, transitioning to SPMS over the course of 15–20 years [ 1 , 8 , 9 ]. A consensus is growing that MS exists on a continuum, with an overlap between relapsing and progressive phenotypes [ 5 , 10 ]. Although it is widely recognized that relapses lead to disability (relapse-associated worsening), mounting evidence demonstrates progression independent of relapse activity [ 11 , 12 , 13 ].…”

“…Although it is widely recognized that relapses lead to disability (relapse-associated worsening), mounting evidence demonstrates progression independent of relapse activity [ 11 , 12 , 13 ]. Progressive neuroaxonal loss is responsible for the accumulation of disability and occurs from the outset; the pathology is thought to be driven by a primary ‘smoldering’ process, accompanied by concurrent inflammatory activity reflective of the patient’s immune response to various putative causative mechanisms, including axonal and synaptic loss; demyelination; macrophage/microglial activation; oxidative injury; age-related iron accumulation; mitochondrial damage; and infection [ 5 ]. Irrespective of disease duration, the clinical presentation of MS is characterized by decreasing inflammatory activity with age (i.e., fewer relapses and new lesions on magnetic resonance imaging [MRI]); counterintuitively, the risk of developing progressive disease increases with age, implicating silent progression that does not manifest as focal lesions or relapse events [ 5 , 14 , 15 ].…”