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Anti-CD20 therapies for multiple sclerosis: current status and future perspectives.

ABSTRACT: Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease affecting the central nervous system (CNS), often characterized by the accumulation of irreversible clinical disability over time. During last years, there has been a dramatic evolution in several key concepts of immune pathophysiology of MS and in the treatment of this disease. The demonstration of the strong efficacy and good safety profile of selective B-cell-depleting therapies (such as anti-CD20 monoclonal antibodies) has significantly expanded the therapeutic scenario for both relapsing and progressive MS patients with the identification of a new therapeutic target. The key role of B cells in triggering MS disease has been also pointed out, determining a shift from the traditional view of MS activity as largely being 'T-cell mediated' to the notion that MS-related pathological processes involve bi-directional interactions between several immune cell types, including B cells, both in the periphery and in the CNS. This review provides an updated overview of the involvement of B cells in the immune pathophysiology and pathology of MS. We summarize the rationale regarding the use of anti-CD20 therapies and the results of the main randomized controlled trials and observational studies investigating the efficacy and safety profile of rituximab, ocrelizumab, ofatumumab and ublituximab. Suggestions regarding vaccinations and management of MS patients during COVID-19 pandemic with anti-CD20 therapies are also discussed. Finally, therapies under investigation and future perspectives of anti-CD20 therapies are taken into consideration.

SUBMITTER: Margoni M

PROVIDER: S-EPMC8356891 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Development of effective treatments requires understanding of disease mechanisms. For diseases of the central nervous system (CNS), such as multiple sclerosis (MS), human pathology studies and animal models tend to identify candidate disease mechanisms. However, these studies cannot easily link the identified processes to clinical outcomes, such as MS severity, required for causality assessment of candidate mechanisms. Technological advances now allow the generation of thousands of biomarkers in living human subjects, derived from genes, transcripts, medical images, and proteins or metabolites in biological fluids. These biomarkers can be assembled into computational models of clinical value, provided such models are generalizable. Reproducibility of models increases with the technical rigor of the study design, such as blinding, control implementation, the use of large cohorts that encompass the entire spectrum of disease phenotypes and, most importantly, model validation in independent cohort(s). To facilitate the growth of this important research area, we performed a meta-analysis of publications (n = 302) that model MS clinical outcomes extracting effect sizes, while also scoring the technical quality of the study design using predefined criteria. Finally, we generated a Shiny-App-based website that allows dynamic exploration of the data by selective filtering. On average, the published studies fulfilled only one of the seven criteria of study design rigor. Only 15.2% of the studies used any validation strategy, and only 8% used the gold standard of independent cohort validation. Many studies also used small cohorts, e.g., for magnetic resonance imaging (MRI) and blood biomarker predictors, the median sample size was <100 subjects. We observed inverse relationships between reported effect sizes and the number of study design criteria fulfilled, expanding analogous reports from non-MS fields, that studies that fail to limit bias overestimate effect sizes. In conclusion, the presented meta-analysis represents a useful tool for researchers, reviewers, and funders to improve the design of future modeling studies in MS and to easily compare new studies with the published literature. We expect that this will accelerate research in this important area, leading to the development of robust models with proven clinical value.

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Anti-CD20 therapies for multiple sclerosis: current status and future perspectives.

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