Evolving Care and Diagnostics in Inflammatory Bowel Diseases : Infliximab Therapy Optimization & Motility-based Crohn's Disease Detection

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http://urn.fi/URN:ISBN:978-951-51-8036-0
Title: Evolving Care and Diagnostics in Inflammatory Bowel Diseases : Infliximab Therapy Optimization & Motility-based Crohn's Disease Detection
Author: Arkko, Anssi
Contributor organization: University of Helsinki, Faculty of Medicine
Doctoral Program in Clinical Research
Helsingin yliopisto, lääketieteellinen tiedekunta
Kliininen tohtoriohjelma
Helsingfors universitet, medicinska fakulteten
Doktorandprogrammet i klinisk forskning
Publisher: Helsingin yliopisto
Date: 2022-05-20
Language: eng
URI: http://urn.fi/URN:ISBN:978-951-51-8036-0
http://hdl.handle.net/10138/342794
Thesis level: Doctoral dissertation (article-based)
Abstract: This thesis presents three studies aiming to improve both medical care and diagnostics for the inflammatory bowel diseases (IBD): Crohn’s disease (CD), ulcerative colitis (UC), and unspecified IBD (IBDU). Biological drugs such as the TNF-α antagonist infliximab (IFX) have presented a major improvement in medicinal care for moderate-to-severe IBD. Not all patients benefit from a particular biological drug, however, and many eventually lose their initial response. The drugs are also costly and carry risks of adverse effects. Early identification of non-response is paramount, as is reacting to changes in drug response during treatment. The aim of study I was to evaluate the utility of fecal calprotectin (F-Calpro) measurements in identifying those benefiting from IFX soon after introduction. Findings with fecal lactoferrin in the task suggested potential for F-Calpro, which is an accurate surrogate for inflammation and state of the intestinal mucosa. In the study, F-Calpro was measured in 36 pediatric IBD patients at baseline and weeks 2 and 6 from IFX introduction. Median F-Calpro declined from initial 1150 μg/g (range 54-6032 μg/g) to 261 μg/g (p < 0.001) by week 2 and normalized (< 100 μg/g) in 37% of the patients. By week 6, there was no additional improvement in F-Calpro (median 345 μg/g) which increased to pretreatment levels or above in 22% of patients. In conclusion, F-Calpro levels normalized rapidly during IFX induction in a third of the patients suggesting complete mucosal healing. The goal in study II was to identify patterns in serum IFX trough levels (S-IFX), which were largely unexplored in pediatric patients at the time. S-IFX levels were seen related to inflammatory burden and changes in dosage accordingly a possible way to improve outcomes. Meanwhile, antibodies-to-infliximab (ATI) were a suggested cause for loss of response. For the study, S-IFX measurements were obtained from 37 pediatric IBD patients. From the induction phase, 48 samples were available and 85 from maintenance. During induction, S-IFX related to the total dose of IFX: children with lower body weight presented lower levels (p < 0.001 at week 2 and p < 0.05 at week 6). During maintenance, dosage decisions were made dependent on clinical assessment. In the study, higher S-IFX levels were achieved through shortening infusion interval (p < 0.005) but not conclusively by dose increase from 5 to 10 mg/kg. ATI were determined in 93 samples (30 patients) and detected in 18 samples from five patients. All samples with undetectable S-IFX (6.8%) presented ATI. High F-Calpro (> 1000 µg/g as opposed to < 1000 µg/g) was associated with lower S-IFX levels (p < 0.005) during induction, but a similar association was not detected during maintenance. In conclusion, body weight and the intensity of intestinal inflammation during induction appeared related to S-IFX levels while infusion intervals seemed related during maintenance therapy. Association with therapeutic response and ATI remained unclear due to study limitations. Current guidelines contrast the findings in study II, indicating that both dose increase and interval reduction are usable in reaching target levels. Therapeutic drug monitoring has been adopted in the guidelines. The added benefit of treatment optimization through monitoring S-IFX over symptoms-based optimization remains a contentious topic, however, and so does the role of ATI in the scheme. In study III the aim was to investigate new tools for diagnostics. Cine series obtained in magnetic resonance enterography (MRE) allow observing bowel motility dynamically. Even healthy-appearing bowel areas may present with aberrant motility related to markers of inflammation and endoscopic findings. Computer vision and machine learning allow quantifying motility faster and more accurately than manual methods. Still, earlier quantification systems have required manual effort. The goal in study III was to devise a fully automatic system for motility quantification and detecting CD in cine MRE. Three datasets with CD and non-CD cases were constructed from cine series extracted from free-breathing MREs conducted in two imaging centers in a seven-year period. The datasets were formed primarily according to repetition time (which translates to series length). Dataset 1 cine series were acquired with the repetition time of 425.5 ms. The repetition times in datasets 2 and 3 were shorter at 193.1 ms and 143.1 ms, respectively. Neural networks were taught to generate regions of interest (ROI) of small-bowel, all-bowel, and non-bowel regions. Full image-ROI was also tested. The standard deviation of Jacobians over the given ROIs was used as a surrogate for motility and converted to numerical indices. A binary logistic regression classifier gave an estimated probability of CD. Performance was evaluated through receiver-operating characteristics analysis. The highest mean area-under-the-curve (AUC) score of 0.78 was achieved using the full image-ROI with dataset 1. The best AUC scores for the other two datasets were only 0.54 and 0.49. In conclusion, the system detected CD in MRE studies with longer cine series showing potential for primary bowel disorder diagnostics. Larger ROIs and utilizing all available cine series yielded slight performance improvements. In summary, this thesis presents two studies with then-preliminary results on optimizing IFX treatment through F-Calpro and S-IFX measurements and one later study into potential advancements in diagnostics through automatic quantification of bowel motility. Evidence on the utility of F-Calpro and S-IFX has mounted, though some points remain unsettled. Meanwhile, the potential of automatic bowel motility analysis is only starting to be discovered.Tulehdukselliset suolistosairaudet ovat lapsilla ja aikuisilla voimakkaasti yleistyneitä sairauksia, joiden hoidossa infliksimabilla ja muilla niin kutsutuilla biologisilla lääkkeillä on saavutettu ennennäkemättömiä tuloksia. Tehon kääntöpuolena on kohonnut infektioriski ja korkea hinta, eivätkä kaikki potilaat saa ryhmän lääkkeistä pitkäaikaista hyötyä. Hoidon kohdentaminen ja yksilöiminen ovatkin tärkeitä tavoitteita biologisten lääkkeiden käytössä. Tulehduksellisten suolistosairauksien tunnistamisessa vuorostaan uudet tekoälysovellukset voivat avata uusia mahdollisuuksia kuvantamisen saralla. Yhtenä päätuloksista käytetyssä aineistossa suoliston tulehdusasteesta kertovan ulosteen kalprotektiinitason todettiin laskevan voimakkaasti jo infliksimabihoidon alkuvaiheessa. Tällä perusteella kalprotektiinimittauksia voisi käyttää jo varhaisessa vaiheessa infliksimabihoidon kohdentamisessa siitä hyötyviin henkilöihin. Tutkimuksessa kartoitettiin myös veren lääkepitoisuuksia lapsipotilailla hoidon alku- ja ylläpitovaiheessa johtaen toiseen päätuloksista. Liian matalien lääkeainepitoisuuksien on ajateltu voivan selittää osalla potilaista todettavia heikkoja hoitotuloksia. Tutkimusaineistossa lääkepitoisuuden nostamisessa tehokkainta näytti olevan lääkkeen annosteluvälin lyhentäminen annoskoon nostamisen sijaan, mutta myöhemmät tutkimukset ovat osoittaneet molemmat strategiat hyviksi lähestymistavoiksi. Toinen mahdollinen syy heikkoihin hoitotuloksiin voi olla elimistön infliksimabille muodostamat vasta-aineet. Osassa tapauksista määritettiinkin samalla vasta-aineiden määrä. Tämä osoittautui korkeaksi tapauksissa, joissa lääkeaineen pitoisuus oli matala. Kyseisillä potilailla löydös näytti olevan yhteydessä heikkoon hoitotulokseen. Yhdessä tuoreempien tutkimustulosten kanssa löydökset kalprotektiinista ja lääkepitoisuusmittauksista ovat johtaneet tehokkaampaan ja turvallisempaan lääkehoitoon. Väitöskirjatutkimuksessa tutkittiin myös ensimmäistä kertaa mahdollisuutta tunnistaa yksi tulehduksellisista suolistosairauksista, Crohnin tauti, automaattisesti. Crohnin tautiin liittyy suolten liikkeiden hidastumista. Ilmiötä on mahdollista mitata magneettikuvauksen avulla, mikä on käsin epätarkkaa ja hidasta. Erilaisia tietokonesovelluksia on kehitelty avuksi tehtävään, mutta tähän asti nämäkään eivät ole täysin vapauttaneet käsin tehtävästä työstä. Väitöskirjatutkimuksessa luotiin automaattinen järjestelmä, joka kykenee erottamaan Crohnin tautia sairastavat muista aikuispotilaista varhainen kehitysvaihe huomioiden hyvällä menestyksellä. Samalla tutkittiin erilaisia järjestelmän toteutustapoja jatkokehityksen pohjaksi.
Subject: lääketiede
Rights: Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty.


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