Progression in multiple sclerosis – a long-term problem

Abstract

Purpose of reviewDisability progression in multiple sclerosis (MS) is strongly linked to central nervous system (CNS)-specific pathological processes that occur throughout all disease stages, but that become clinically evident in later phases of the disease. We here discuss current views and concepts for targeting progressive MS.Recent findingsDetailed clinical assessment of MS patients has identified an even closer entanglement of relapse-remitting and progressive disease, leading to novel concepts such as ‘progression independent of relapse activity’. Evolving clinical concepts together with a focus on molecular (neurofilament light chain) and imaging (paramagnetic rim lesions) biomarkers might specifically identify patients at risk of developing progressive MS considerably earlier than before. A multitude of novel treatment approaches focus either on direct neuroaxonal protection or myelin regeneration or on beneficially modulating CNS-intrinsic or innate immune inflammation. Although some long-awaited trials have recently been unsuccessful, important lessons could still be drawn from novel trial designs providing frameworks for future clinical studies.SummaryTargeting progressive disease biology and repairing established damage is the current central challenge in the field of MS. Especially, the compartmentalized adaptive and innate CNS inflammation is an attractive target for novel approaches, probably as a combinatory approach together with neuroprotective or myelin regenerating strategies.

Harmonizing Definitions for Progression Independent of Relapse Activity in Multiple Sclerosis

“…We identified 48 eligible studies of 119 single records (eFigure in the Supplement). Characteristics and methodologies are given in the Table . Excluded articles and reason for ineligibility are provided in eTable 2 in the Supplement.…”

“…Patients with PIRA show increased brain, cortical, and spinal cord atrophy as well as an increased proportion of paramagnetic rim lesions . Additionally, leptomeningeal inflammation, failure of compensatory mechanisms, and focal spinal cord pathology have been discussed to be potentially linked to PIRA.…”

Exploring miRNAs’ Based Modeling Approach for Predicting PIRA in Multiple Sclerosis: A Comprehensive Analysis

“…Recent evidence has emphasized the effectiveness of high-efficacy-DMTs in reducing relapse rates, inflammation foci, and slowing down the relapse-associated accumulation of disability over time [ 10 ]. Current research indicates, however, that disability progression in MS patients is not solely linked to new focal inflammatory demyelinating lesions and clinical relapse [ 11 ]. Instead, it is increasingly recognized that progression independent of relapse activity (PIRA) [ 12 , 13 , 14 ] and the accumulation of disability in the absence of relapse-associated worsening (RAW) [ 12 ], as determined by the Expanded Disability Status Scale (EDSS), may occur from the disease onset [ 10 , 15 ].…”

Ferroptosis induces detrimental effects in chronic EAE and its implications for progressive MS

“…There are currently limited effective treatment options available for primary progressive MS (PPMS) and secondary progressive MS (SPMS) [ 1 – 3 ]. Anti-inflammatory treatments that are effective in relapsing–remitting MS (RRMS) are not effective in progressive MS, suggesting that inflammation may not be the key driver of progressive MS pathology [ 1 , 2 , 4 ]. There is evidence that oxidative stress that leads to neurodegeneration may be an important contributor to progressive MS [ 4 – 6 ].…”