Dokument: Objektivierung des End-of-Dose Phänomens unter Natalizumab Therapie mittels radiologischer und digitaler Verlaufsmarker
| Titel: | Objektivierung des End-of-Dose Phänomens unter Natalizumab Therapie mittels radiologischer und digitaler Verlaufsmarker | |||||||
| Weiterer Titel: | Objectification of the End-of-Dose Phenomenon During Natalizumab Therapy Using Radiological and Digital Monitoring Markers | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=74741 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20261026-154056-5 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Trautmann, Elaine [Autor] | |||||||
| Dateien: |
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| Beitragende: | Pawlitzki, Marc [Gutachter] Kaschner, Marius [Gutachter] | |||||||
| Stichwörter: | Multiple Sklerose, Natalizumab, End-of-Dose-Phänomen | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | End-of-dose-Phänomene (EOD) unter Natalizumab sind häufig berichtete Beschwerden bei Patienten mit Multipler Sklerose (MS) und werden in der Praxis oftmals als Hinweise für eine subklinische Krankheitsaktivität interpretiert. Unklar ist jedoch, ob EOD tatsächlich mit objektiv messbarer inflammatorischer oder neurodegenerativer Aktivität einhergeht oder primär subjektive Symptome widerspiegeln.
Ziel der Arbeit war es, EOD systematisch zu erfassen und insbesondere im Kontext bildgebender Parameter zu untersuchen. Hierzu wurde ein multimodaler Ansatz gewählt, der klinische, bildgebende und digitale Parameter integriert, um mögliche Zusammenhänge zwischen EOD und zugrunde liegenden Krankheitsprozessen zu identifizieren. In einer prospektiven, monozentrischen Beobachtungsstudie wurden 34 Patienten mit schubförmiger MS unter Natalizumab-Therapie eingeschlossen und über einen Zeitraum von sechs Monaten longitudinal untersucht. Die Datenerhebung umfasste klinische Skalen (EDSS, MSFC), standardisierte Fatigue-Instrumente kontinuierliches Aktivitätsmonitoring mittels Smartwatch sowie umfassende MRT-Analysen. Letztere beinhalteten die Bestimmung der zerebralen Läsionslast, die Analyse diffusionsgewichteter Parameter der weißen Substanz sowie die Quantifizierung der Rückenmarksquerschnittsfläche. EOD wurde vor jeder Applikation mithilfe eines standardisierten Fragebogens erfasst. Insgesamt berichteten 68% der Teilnehmenden von mindestens einem EOD-Ereignis, wobei 39% aller Applikationen mit EOD assoziiert waren. Die bildgebenden Analysen zeigten über den Beobachtungszeitraum eine stabile Krankheitskonstellation. Weder die zerebrale Läsionslast noch die diffusionsgewichteten Parameter der weißen Substanz wiesen signifikante Veränderungen auf oder korrelierten mit der Häufigkeit von EOD. Auch für die Rückenmarksquerschnittsfläche und deren Atrophie ergaben sich keine signifikanten Zusammenhänge mit EOD. Auch auf klinischer Ebene zeigte sich kein Zusammenhang zwischen der EOD-Häufigkeit und dem Behinderungsgrad. Es bestand jedoch eine konsistente Assoziation zwischen EOD und der subjektiven Fatigue-Belastung. Der Applikationsweg beeinflusste die Häufigkeit von EOD, wobei s.c.-behandelte Patienten seltener Symptome berichteten als i.v.-behandelte, während das Dosierungsintervall keinen Effekt zeigte. Zusammenfassend liefern die Ergebnisse keine Hinweise darauf, dass EOD unter NTZ-Therapie Ausdruck einer subklinischen entzündlichen Aktivität oder neurodegenerativer Prozesse sind. Insbesondere die umfassenden MRT-Analysen konnten keine bildgebenden Korrelate identifizieren. Vielmehr sprechen die Befunde dafür, dass EOD primär subjektive, Fatigue-assoziierte Symptomfluktuationen widerspiegeln. Diese Ergebnisse unterstreichen die Bedeutung einer differenzierten klinischen Einordnung von EOD und heben das Potenzial multimodaler, insbesondere multimodaler Verfahren hervor, um subjektive Symptome besser zu charakterisieren und individualisierte Therapieansätze zu unterstützen.End-of-dose (EOD) phenomena under Natalizumab therapy are frequently reported by patients with multiple sclerosis (MS) and are often interpreted in clinical practice as indicators of subclinical disease activity. However, it remains unclear whether EOD is associated with objectively measurable inflammatory or neurodegenerative processes or primarily reflects subjective symptoms. The aim of this study was to systematically assess EOD and to investigate it particularly in the context of imaging parameters. A multimodal approach was applied, integrating clinical, imaging, and digital data to identify potential associations between EOD and underlying disease processes. In a prospective, monocentric observational study, 34 patients with relapsing-remitting MS undergoing natalizumab therapy were included and followed longitudinally over a period of six months. Data collection comprised clinical scales (Expanded Disability Status Scale [EDSS], Multiple Sclerosis Functional Composite [MSFC]), standardized fatigue instruments, continuous activity monitoring via smartwatch, and comprehensive MRI analyses. The latter included assessment of cerebral lesion load, analysis of diffusion-weighted parameters of white matter, and quantification of the spinal cord cross-sectional area. EOD was assessed prior to each administration using a standardized questionnaire. Overall, 68% of participants reported at least one EOD episode, and 39% of all natalizumab administrations were associated with EOD symptoms. Imaging analyses demonstrated a stable disease state over the observation period. Neither cerebral lesion load nor diffusion-weighted parameters of white matter showed significant changes or correlations with EOD frequency. Similarly, no significant associations were found between spinal cord cross-sectional area or its atrophy and EOD or fatigue. At the clinical level, no association was observed between EOD frequency and disability status. In contrast, a consistent association was found between EOD and subjective fatigue burden. The route of administration influenced EOD frequency, with subcutaneously treated patients reporting fewer symptoms than those treated intravenously, whereas dosing interval had no significant effect. In summary, the results provide no evidence that EOD under stable natalizumab therapy reflects subclinical inflammatory activity or neurodegenerative processes. In particular, comprehensive MRI analyses did not identify any imaging correlates. Instead, the findings suggest that EOD primarily reflects subjective, fatigue-associated symptom fluctuations. These results highlight the importance of a differentiated clinical interpretation of EOD and underscore the potential of multimodal approaches, particularly imaging and digital biomarkers, to better characterize subjective symptoms and support individualized therapeutic strategies. | |||||||
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| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 26.10.2026 | |||||||
| Dateien geändert am: | 26.10.2026 | |||||||
| Promotionsantrag am: | 31.05.2026 | |||||||
| Datum der Promotion: | 15.10.2026 |
