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dc.contributor.advisorGoll, Rasmus
dc.contributor.authorJohnsen, Kay-Martin
dc.date.accessioned2024-05-23T12:31:27Z
dc.date.available2024-05-23T12:31:27Z
dc.date.embargoEndDate2029-06-20
dc.date.issued2024-06-20
dc.description.abstractUlcerøs kolitt (UC) er en kronisk tarmsykdom kjennetegnet med betennelse i tykktarmen som forårsaker symptomer som magesmerter, blodig avføring og diaré. Å forstå årsakene til UC er utfordrende og involverer en kompleks blanding av faktorer som immunsystemproblemer, eksponering for mikrober og genetiske påvirkninger. Et gjennombrudd i UC-behandling kom med anti-tumor nekrose faktor (anti-TNF) medisiner. Denne behandlingen har ført til betydelig bedring i behandlingen med tanke på å oppnå kontroll på tarmbetennelsen. Personlig medisin, tilpasning av behandling basert på markører for å forutsi sykdomforløp vil være til stor nytte for å vurdere hvordan behandlingen skal tilpasses den enkelte pasient. I de tidlige stadiene av sykdommen følges vanligvis en gradvis opptrapping av behandling for å oppnå kontroll på betennelse. På grunn av risiko for at mange vil overbehandles startes man ikke i motsatt ende med den mest effektive behandlingen for så å trappe ned. Dette kan igjen føre til at noen pasienter opplever lengre perioder med høy betennelse og forverring av sykdommen før man får trappet opp. Nåværende retningslinjer favoriserer ofte vedlikeholds behandling på ubestemt tid grunnet manglende kriterier for å stoppe anti-TNF-behandling. Fraværet av biomarkører og begrenset kunnskap om hvordan terapi endrer sykdomsforløpet bidrar til denne utfordringen. Å innføre behandlingsalgoritmer med biomarkører som kan bidra til å velge det riktige tidspunktet for å avslutte dyr målrettet behandling, kan gjøre denne type behandlinger både mere tilgjengelig samt og redusere bivirkninger. På samme måte vil biomarkører være til stor nytte om de kan forutsi hvilke pasienter som vil være i behov for anti-TNF behandling, og dermed kunne starte med den mest effektive behandlingen for så å trappe ned. Tidlig kontroll på betennelse vil sannsynligvis også bedre prognosene. Avhandlingen konkluderer med at tidlig og intensiv behandling, spesielt med anti-TNF behandling kan bidra til å raskt oppnå sykdomskontroll. Langsiktige resultater antyder en endring mot en mildere sykdomsgrad, muligens er normalisering av TNF-uttrykk i tarmslimhinnen en viktig markør for dette. Avslutning av anti-TNF-behandling er gjennomførbart for de fleste, og for de som for oppbluss vil re oppstart med anti-TNF behandling ha god effekt for de fleste. Biomarkører, spesielt TNF-uttrykk i tarmslimhinnen kombinert med mikroskopiundersøkelse av prøver fra tarmslimhinnen kan bidra til å identifisere pasienter som er egnet for tidlig oppstart med målrettet behandling.en_US
dc.description.abstractUlcerative colitis (UC) is a chronic inflammation of the colon that causes symptoms such as abdominal pain, bloody stools, and diarrhea. Understanding the causes of UC, an inflammatory bowel disease (IBD), is challenging and involves a complex interplay of factors such as immune system issues, exposure to microbes, and genetic influences. A breakthrough in UC treatment came with targeted therapies like anti-tumor necrosis factor (anti-TNF) medications. This treatment has significantly improved the management of intestinal inflammation. Personalized medicine, tailoring treatment based on biomarkers to predict disease progression, would be beneficial in assessing how treatment should be customized for each patient. In the early stages of the disease, a gradual escalation of treatment is typically followed to gain control over inflammation. Due to the risk of overtreating, the most effective treatment is not initiated immediately and then tapered down. This, in turn, may lead to some patients experiencing prolonged periods of high inflammation and worsening of the disease before treatment escalation. The lack of tools to select suitable patients is a challenge. Current guidelines often favor indefinite maintenance treatment due to the absence of criteria to discontinue anti-TNF treatment. The lack of biomarkers and limited knowledge of how therapy alters the course of the disease contribute to this challenge. The high cost of IBD treatment is a significant challenge for healthcare and a burden for patients in terms of frequent hospital visits and side effects. Introducing treatment algorithms with biomarkers that can help choose the right time to discontinue expensive targeted therapy can make such treatments more accessible and reduce side effects. Similarly, biomarkers would be beneficial if they could predict which patients will need anti-TNF treatment, enabling the initiation of the most effective treatment followed by tapering. Early control of inflammation will likely improve prognoses. The thesis concludes that early and intensive treatment, especially with infliximab, can contribute to achieving rapid disease control. Long-term results suggest a shift toward a milder disease course, possibly with the normalization of TNF expression in the intestinal lining as a key marker. Discontinuation of anti-TNF treatment is feasible for most, and for those experiencing relapses, re-treatment with the same medication is effective. Biomarkers, especially mucosal TNF expression combined with histological assessment, can help identify patients suitable for early initiation of targeted treatment.en_US
dc.description.doctoraltypeph.d.en_US
dc.description.popularabstractUlcerative colitis (UC) is a chronic inflammation of the colon that causes symptoms such as abdominal pain, bloody stools, and diarrhea. Understanding the causes of UC, an inflammatory bowel disease (IBD), is challenging and involves a complex interplay of factors such as immune system issues, exposure to microbes, and genetic influences. A breakthrough in UC treatment came with targeted therapies like anti-tumor necrosis factor (anti-TNF) medications. This treatment has significantly improved the management of intestinal inflammation. Personalized medicine, tailoring treatment based on biomarkers to predict disease progression, would be beneficial in assessing how treatment should be customized for each patient. In the early stages of the disease, a gradual escalation of treatment is typically followed to gain control over inflammation. Due to the risk of overtreating, the most effective treatment is not initiated immediately and then tapered down. This, in turn, may lead to some patients experiencing prolonged periods of high inflammation and worsening of the disease before treatment escalation. The lack of tools to select suitable patients is a challenge. Current guidelines often favor indefinite maintenance treatment due to the absence of criteria to discontinue anti-TNF treatment. The lack of biomarkers and limited knowledge of how therapy alters the course of the disease contribute to this challenge. The high cost of IBD treatment is a significant challenge for healthcare and a burden for patients in terms of frequent hospital visits and side effects. Introducing treatment algorithms with biomarkers that can help choose the right time to discontinue expensive targeted therapy can make such treatments more accessible and reduce side effects. Similarly, biomarkers would be beneficial if they could predict which patients will need anti-TNF treatment, enabling the initiation of the most effective treatment followed by tapering. Early control of inflammation will likely improve prognoses. By performing a colonoscopy, which involves the use of a flexible tube equipped with a camera, it is possible to obtain tissue samples from the colon and assess the expression levels of signaling molecules critical to the inflammatory process. A key molecule in this context is tumor necrosis factor (TNF). The research presented in this thesis includes measurements of TNF and other signaling molecules within the intestinal lining. Additionally, the progression of the disease in patients has been monitored over an extended period. This longitudinal observation aims to explore ways to optimize treatment strategies, identify biomarkers that can predict disease course, and enhance our understanding of the course of the disease of UC. The thesis concludes that early and intensive treatment, especially with infliximab, can contribute to achieving rapid disease control. Long-term results suggest a shift toward a milder disease course, possibly with the normalization of TNF expression in the intestinal lining as a key marker. Discontinuation of anti-TNF treatment is feasible for most, and for those experiencing relapses, re-treatment with the same medication is effective. Biomarkers, especially mucosal TNF expression combined with histological assessment, can help identify patients suitable for early initiation of targeted treatment.en_US
dc.description.sponsorshipHelse Nord ID: SFP-50-04, SFP-888-09 and SFP-1136-13.en_US
dc.identifier.urihttps://hdl.handle.net/10037/33602
dc.language.isoengen_US
dc.publisherUiT The Arctic University of Norwayen_US
dc.publisherUiT Norges arktiske universiteten_US
dc.relation.haspartPaper I: Johnsen, K.M., Goll,R., Hansen, V., Olsen, T., Rismo, R., Heitmann, R., Gundersen, M.D., Kvamme, J.M., Paulssen, E.J., Kileng, H., Johnsen, K. & Florholmen, J. (2017). Repeated intensified infliximab induction - results from an 11-year prospective study of ulcerative colitis using a novel treatment algorithm. <i>European Journal of Gastroenterology and Hepatology, 29</i>(1), 98-104. Full text not available in Munin due to publishers restrictions. Published version available at: <a href=https://doi.org/10.1097/MEG.0000000000000753>https://doi.org/10.1097/MEG.0000000000000753</a>. <p> <p>Paper II: Florholmen, J.R. Johnsen, K-M., Meyer, R., Olsen, T., Moe, Ø.K., Tandberg, P., Gundersen, M.D., Kvamme, J-M., Johnsen, K., Løitegård, T., Raschpichler, G., Vold, C., Sørbye, S.W. & Goll, R. (2020). Discovery and validation of mucosal TNF expression combined with histological score - a biomarker for personalized treatment in ulcerative colitis. <i>BMC Gastroenterology, 20</i>, 321. Also available in Munin: <a href=https://hdl.handle.net/10037/20609>https://hdl.handle.net/10037/20609</a>. <p> <p>Paper III: Johnsen, K-M., Florholmen, J., Gundersen, M., Sørbye, S. & Goll, R. (2022). Prediction of long-term remission in patients following discontinuation of anti-TNF therapy in ulcerative colitis: a 10 year follow up study. <i>BMC Gastroenterology, 22</i>, 459. Also available in Munin: <a href=https://hdl.handle.net/10037/27930>https://hdl.handle.net/10037/27930</a>.en_US
dc.rights.accessRightsembargoedAccessen_US
dc.rights.holderCopyright 2024 The Author(s)
dc.subjectUlcerative colitisen_US
dc.subjectanti-tnfen_US
dc.subjectbiological therapyen_US
dc.subjectbiomarkeren_US
dc.titleTowards personalized medicine in ulcerative colitis. Long-term follow-up after biological treatment and prediction of clinical outcomesen_US
dc.typeDoctoral thesisen_US
dc.typeDoktorgradsavhandlingen_US


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