Abstract
Despite therapeutic suppression of relapses, multiple sclerosis (MS) patients often experience subtle deterioration, which extends beyond the definition of “progression independent of relapsing activity.” We propose the concept of smouldering-associated-worsening (SAW), encompassing physical and cognitive symptoms, resulting from smouldering (smoldering) pathological processes, which remain unmet therapeutic targets. We provide a consensus-based framework of possible pathological substrates and manifestations of smouldering MS, and we discuss clinical, radiological, and serum/cerebrospinal fluid biomarkers for potentially monitoring SAW. Finally, we share considerations for optimizing disease surveillance and implications for clinical trials to promote the integration of smouldering MS into routine practice and future research efforts. ANN NEUROL 2024
Graphical Abstract
Introduction
Multiple sclerosis (MS) is considered a disease predominantly driven by focal inflammation and demyelination of the central nervous system (CNS) mediated by the adaptive immune system. The current classification system is based on separate clinical stages, including relapsing–remitting (RR), secondary progressive (SP), and primary progressive (PP) courses1 and places emphasis on the white matter (WM) focal inflammation, which represents the biological substrate for clinical relapses and new magnetic resonance imaging (MRI) lesions and has been the ubiquitous target of disease-modifying treatments (DMTs).
In a large proportion of people with MS (pwMS), we succeed at therapeutically inducing disease remission with no evidence of inflammatory disease activity (NEIDA). However, despite stable inflammatory parameters, pwMS often experience disability worsening, highlighting a dissociation between focal inflammatory mechanisms and those accounting for the accumulation of disability in a more indolent fashion, and arguing against the current phenotypic distinction of separate relapsing and progressive stages.
Recent studies demonstrated that, in addition to relapse-associated worsening (RAW), progression independent of relapse activity (PIRA) occurs from the early RR phase,2, 3 indicating that MS is underpinned by a biological continuum with different pathological mechanisms tightly intermingled since the earliest stages of the disease.4 However, subtle accumulation of symptoms and signs is often not captured by the definition of PIRA, which is predominantly based on clinical scales of motor performance, but it is largely insensitive to worsening in other clinical domains.
Pathology, neuroimaging, and clinical insights support a paradigm shift in our understanding of the biological mechanisms within the CNS that contribute to MS worsening.4, 5 The gradual accumulation of physical and cognitive disability is driven by smouldering pathological processes via biological substrates, which are different from those of acute focal damage and remain an important unmet therapeutic target.6
To date, there is no uniform definition of smouldering disease in MS, nor of its clinical manifestations and pathological substrates. In this context, we previously reviewed the biological perspective of pathological drivers within the CNS responsible for smouldering disease in MS.6 Here, we set out to define clinical and radiological manifestations of smouldering processes, its underlying biology and biomarkers. We provide consensus statements and recommendations to integrate the concept of smouldering disease in MS into clinical practice, to discuss its implications for clinical trial design and regulatory pathways, and to promote research activities to understand better its pathological mechanisms.
Methods
An international panel of 15 MS experts from 8 countries across Europe, the United States, and Canada convened in June 2021 to develop a consensus on smouldering disease in MS. This panel was selected based on clinical experience, scientific background and expertise, and geographical representation. The panel met several times to discuss various aspects of smouldering disease. First, it was debated and eventually agreed, which categories had to be addressed. This led to the identification of key domains in line with panelists’ expertise, which were selected as subjects for subsequent debates and included: definitions, pathological drivers, the role of aging, clinical and paraclinical manifestations, implications for routine clinical practice, clinical trial design, and regulatory pathways. Second, for each category, a leading expert was selected to coordinate the effort of a subgroup of panelists responsible for developing statements related to their respective topic. Finally, the whole panel of experts debated and reached agreement on proposed statements covering each domain. The Delphi method was used to anonymously establish the level of agreement on the 5-point Likert scale (strongly agree, agree, neither agree nor disagree, disagree and strongly disagree) for each statement, and a consensus was defined as ≥75% who strongly agree or agree to each statement. In addition, when voting, experts were given the opportunity to provide anonymous comments on how statements could be potentially modified and improved. The surveys were facilitated independently by a medical consultant using the Welphi online survey platform with 100% involvement of all 15 panelists at every stage of the review. Modifications to statements were made over a maximum of 3 rounds. A total of 41 statements were proposed, with 29 finally reaching consensus (≥75% of agreement), whereas 12 statements were discarded. Among the rejected statements, some did not reach the minimum required threshold of 75% level of agreement, whereas others because of partial overlapping wording were merged and then re-surveyed again to check the level of agreement among panelists. All experts agreed on the full contents of the final statements and recommendations.
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