Journal
FRONTIERS IN NEUROLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fneur.2021.650530
Keywords
multiple sclerosis; natalizumab (TYSABRI); natalizumab concentration; neurofilament light (NFL) chain; recurrence of disease activity; cessation of natalizumab; alpha-4 integrin expression; alpha-4 integrin receptor saturation
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Funding
- Else Kroner Forschungskolleg Dresden
- open access publication funds of the SLUB/TU Dresden
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The study found that a portion of RRMS and SPMS patients experienced disease activity recurrence after discontinuing Natalizumab treatment. Concentrations of free and cell-bound Natalizumab, as well as alpha 4-integrin receptor saturation, decreased over time while alpha 4-integrin expression increased. sNfL levels were associated with disease activity recurrence and could serve as an early predictive marker.
Background: Natalizumab (NAT) is a high-efficacy treatment for relapsing remitting multiple sclerosis (RRMS). However, it is associated with an increased risk of progressive multifocal leukoencephalopathy that sometimes requires treatment cessation with a risk of returning disease activity. The aim of this study was to characterize the pharmacokinetics and -dynamics as well as neurodestruction marker serum neurofilament light chain (sNfL) in patients with RRMS and secondary progressive MS (SPMS) stopping NAT in correlation to clinical data. Methods: In this study, 50 RRMS and 9 SPMS patients after NAT cessation were included. Five RRMS patients on NAT treatment holiday were evaluated. Clinical and radiological disease activity were systemically assessed by frequent exams after NAT stop. Free NAT concentration, cell bound NAT, alpha 4-integrin expression and alpha 4-integrin-receptor saturation as well as immune cell frequencies were measured for up to 4 months after NAT withdrawal. Additionally, sNfL levels were observed up to 12 months in RRMS and up to 4 months in SPMS patients. Results: NAT cessation was associated with a return of disease activity in 38% of the RRMS and 33% of the SPMS patients within 12 and 7 months, respectively. Concentration of free and cell bound NAT as well as alpha 4-integrin-receptor saturation decreased in the RRMS and SPMS patients whereas alpha 4-integrin expression increased over time. NAT induced increase of lymphocytes and its subsets normalized and a non-significant drop of NK and Th17 T-cells counts could be detected. All RRMS patients showed physiological sNfL levels Conclusions: We demonstrate the reversibility of NAT pharmacodynamic and -kinetic markers. sNfL levels are associated with the recurrence of disease activity and can also serve as an early marker to predict present before onset of clinical or radiological disease activity on the individual level.
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