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1 Cover Page The handle holds various files of this Leiden University dissertation. Author: Wietmarschen, Herman van Title: A systems approach to sub-typing of rheumatoid arthritis Date:

2 Samenvatting De huidige geneeskunde richt zich vooral op het bestrijden en managen van ziekten. Ontwikkelingen op dit vlak hebben geleid tot een enorme verlenging van de levensduur van mensen met bijvoorbeeld kanker, hart- en vaatziekten en diabetes. Echter, zoals de vicepresident van GlaxoSmithKline in 2003 al opmerkte, werken 90% van de medicijnen in slechts 30-50% van de patiënten. Er is dus veel ruimte voor verbetering. Een recente ontwikkeling is de gedachte dat medicijnen meer op het individu toegesneden moeten worden. Het is van belang wie welk medicijn krijgt, op welk moment en in welke dosis. De effectiviteit van medicijnen kan enorm verhoogd worden door de juiste categorie patiënten te vinden voor een bepaald medicijn. Voor de ontwikkeling van deze geïndividualiseerde zorg is goede diagnose essentieel. In dit proefschrift staat diagnose centraal. In China heeft zich de afgelopen millennia een geneeswijze ontwikkeld met een meer beschrijvend diagnostisch systeem. Patronen van symptomen hebben een betekenis gekregen en kunnen vertaald worden in een behandeling. In dit proefschrift wordt getracht Chinese kennis van diagnostiek te vertalen naar manieren om de Westerse zorg te optimaliseren. Systeem biologie is bij uitstek een geschikte werkwijze om deze vertaling te bewerkstelligen. Deze benadering berust op het meten van informatie op verschillende niveaus van een systeem, waarbij het meten van metabolieten in bloed en urine in dit proefschrift de nadruk heeft. Deze benadering kan gebruikt worden om biologische verschillen tussen patiënten groepen te vinden en te karakteriseren. In dit proefschrift wordt een systeem biologische benadering gepresenteerd waarbij reumatoïde artritis patiënten kunnen worden ingedeeld in twee groepen op basis van Chinese diagnostische eigenschappen. Metabolomics en genexpressie analyses werden uitgevoerd om mogelijke biologische verschillen tussen deze twee groepen te ontdekken. Hieronder volgt een overzicht van de gepresenteerde hoofdstukken van het proefschrift. Hoofdstuk 2 is een zoektocht naar een visie op geïndividualiseerde geneeskunde en de mogelijkheden om deze visie vorm te geven. Diagnose wordt beschouwd als een sleutelbegrip. Een betere integratie van systeemdenken in de levenswetenschappen en medische wetenschappen wordt voorgesteld, wat uit kan groeien tot een systeemwetenschap. Daarnaast wordt de waarde van het systeemdenken in de Chinese geneeskunde voor de 193

3 ontwikkeling van geïndividualiseerde geneeskunde uitvoerig belicht en worden methoden beschreven voor het integreren van het Chinese denken in de Westerse wetenschap. Metabolomics is naast andere -omics technologieën zoals genomics en proteomics één van de hoekstenen van systeembiologie. In hoofdstuk 3 wordt een overzicht gegeven van het metabolomicsveld vanuit het perspectief van 30 jaar metabolomics ontwikkeling bij TNO. De omslag van een door technologie gedreven ontwikkeling van metabolomics naar een door biologie getrokken ontwikkeling wordt beschreven. Dit alles geïllustreerd met een verscheidenheid aan metabolomics toepassingen en afgesloten met een visie op de rol van metabolomics in het veranderende landschap van de zorg. In hoofdstuk 4 wordt dieper ingegaan op metabole processen die betrokken zijn bij reumatoïde artritis. Een gedetailleerd overzicht wordt gepresenteerd van metabole processen die de afgelopen tientallen jaren beschreven zijn. Een geïntegreerde analyse van de informatie resulteerde in een belangrijke rol voor celdood en vetmetabolisme in reumatoïde artritis. Een andere conclusie van de literatuurstudie was het belang van de dynamiek van bepaalde metabolieten voor het ziekte proces evenals voor de behandeling. Hoofdstuk 5 beschrijft de eerste klinische studie waarin twee subtypen van reumatoïde artritis patiënten worden beschreven die gebaseerd zijn op een Chinese diagnose. De twee subtypen worden gekenmerkt door verschillende genexpressie profielen gemeten in CD4 positieve T-cellen en verschillen in een GC-MS metabolomics analyse van bloed plasma. De studie beschreven in dit hoofdstuk is het eerste bewijs voor biologische verschillen tussen deze twee subgroepen van RA patiënten, gebaseerd op een combinatie van Westerse en Chinese diagnose. Hoofdstuk 6 beschrijft het logische vervolg op de resultaten van hoofdstuk 5, het standaardiseren van de Chinese diagnose waarmee de subtypen van RA patiënten kunnen worden vastgesteld. Hiertoe is een systeemdiagnose-vragenlijst ontwikkeld en toegepast waarmee uitgebreide symptoomprofielen van reumapatiënten zijn verzameld. De grootste variatie in symptoomprofielen tussen de patiënten bleek te corresponderen met de Chinese basis concepten Intern en Extern en de concepten Koude en Hitte. Deze twee algemene indelingen die gebruikt worden in de Chinese diagnose en behandeling bleken dus duidelijk terug te vinden te zijn met deze systeem diagnose vragenlijst. In hoofdstuk 7 wordt een klinische studie beschreven vergelijkbaar met die van hoofdstuk 5. In deze studie werden wederom RA-patiënten ingedeeld in Koude en Hitte typen patiënten op basis van een Chinese diagnose. Daarnaast werd een systeemdiagnose-vragenlijst ingevuld 194

4 door de patiënten. In deze studie werden standaard klinisch chemische bepalingen gedaan op bloedmonsters. Plasma en urine werd geanalyseerd met een globale LC-MS methode. De meest opvallende bevinding was de lagere hoeveelheid van 11 acylcarnitines in de urine van Hitte RA patiënten, in vergelijking met de Koude RA patiënten. Daarnaast werd een lagere hoeveelheid dehydroepiandrosterone sulfate (DHEAS) gevonden in Koude RA patiënten, wat kan duiden op een meer onderdrukte HPA-as functie in deze patiënten. In dit proefschrift wordt laten zien hoe relevante subtypen van reumatoïde artritis patiënten kunnen worden gevonden door te kijken naar Chinese diagnostische kenmerken. Systeemdenken en systeem biologie blijkt een goede methode te zijn om biologische verschillen tussen deze subtypen te vinden en beschrijven. Het indelen van patiëntengroepen in kleinere subgroepen met specifieke kenmerken is een eerste stap richting geïndividualiseerde geneeskunde. In de toekomst kan de response van deze subgroepen op medicatie worden onderzocht en zo nodig de medicatie worden aangepast aan de subgroep. Bovendien kan deze methode helpen met het beschrijven en in kaart brengen van meer subgroepen met ieder een toegesneden behandelstrategie. In een verdere toekomst kan deze methode bijdragen aan het ontwikkelen van een persoonlijk zorg ecosysteem waarin de nadruk ligt op preventie, participatie, en het bevorderen van gezondheid. 195

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