Multiple sclerosis: emerging epidemiological trends and redefining the clinical course

Abstract

Multiple sclerosis is a chronic, inflammatory, and neurodegenerative disease of the central nervous system and a major cause of neurological disability in young adults. Its prevalence and incidence are increasing, and it has been estimated at over 2.8 million cases worldwide, in addition to recent trends towards a shift in MS prevalence to older ages, with peak prevalence estimates in the sixth decade of life. Although historically the relapsing and progressive phases of the disease have been considered separate clinical entities, recent evidence of progression independent of relapse activity (PIRA) has led to a reconsideration of multiple sclerosis as a continuum, in which relapsing and progressive features variably coexist from the earliest stages of the disease, challenging the traditional view of the disease course. In this Series article, we provide an overview of how the traditional description of the clinical course of MS and epidemiological trends in Europe have evolved. For this purpose, we focus on the concept of PIRA, discussing its potential as the main mechanism by which patients acquire disability, how its definition varies between studies, and ongoing research in this field. We emphasise the importance of incorporating the assessment of hidden clinical manifestations into patient management to help uncover and quantify the PIRA phenomenon and the possible implications for future changes in the clinical classification of the disease. At the same time, we provide insights into overcoming the challenges of identifying and defining PIRA and adopting a new understanding of the clinical course of MS.

Keywords: Clinical classification; Epidemiology; Multiple sclerosis; Progression idependent of relapse activity.

Fig. 1

Percentage of RAW and PIRA events over the follow-up period and early PIRA (within the first 5 years of follow-up) in relapsing MS patients. RAW: Relapse Associated Worsening; PIRA: Progression Independent of Relapse Activity; MS: Multiple Sclerosis.

Fig. 2

Widening the focus on hidden symptoms of MS. PIRA may frequently remain undetected due to the low granularity of clinical measures. Widening the focus on clinical features beyond motor disability alone (as measured by the EDSS) could improve the definition and identification of PIRA, as it occurred when assessments of walking ability (using the T25FWT) and manual dexterity (using the 9HPT) were included (see text for details). MS: Multiple Sclerosis; EDSS: Expanded Disability Status Scale; 9HPT: 9-Hole Peg Test; T25FWT: Timed 25-foot Walk Test; PIRA: Progression Independent of Relapse Activity.

Fig. 3

MS phenoptype may depend on clinical/paraclinical detection threshold. Recent evidence points to an unified view of multiple sclerosis (MS), in which “inflammatory” manifestations (blue line), including clinical relapses and focal magnetic resonance imaging (MRI) activity (new/enlarging T2 lesions, gadolinium-enhancing lesions), mainly driven by adaptive immunity, coexist since the earliest phases of the disease with “neurodegenerative” features (grey line) including disability progression, atrophy, slowly expanding lesions/paramagnetic rim lesions at MRI, mainly driven by innate “smoldering” inflammation. In this scenario, the manifest clinical course of the disease may depend on the type and granularity of the observations. For instance, in assessments relying on less refined clinical measures, such as the Expanded Disability Status Scale, classical primary progressive or relapsing-remitting with later conversion to secondary progression could emerge. However, in the same patient, increasing the granularity of the clinical/paraclinical detection threshold, including advanced MRI measures, composite clincal scales capturing hidden symptoms beyond typical manifestations, patient-reported outcomes, fluid biomarkers (such as neurofilament light chain or glial fibrillary acid protein), could unveil earlier disease acitivty, with inflammatory and neurodegenerative mechanisms largely overlapping since onset. Improving assessments clearly lead to the anticipation of MS diagnosis, pushing back in time the boundary separating the presymptomatic phase from clinically manifest MS, providing the opportunity for early therapeutic interventions. Likewise, the onset of the progressive phase could be identified eralier, becoming coexistent with the initial inflammatory manifestations of the disease.