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Rizikové faktory vzniku a průběhu léčby zánětlivých střevních onemocnění u dětí
Název práce v češtině: Rizikové faktory vzniku a průběhu léčby zánětlivých střevních onemocnění u dětí
Název v anglickém jazyce: Risk factors of manifestation and course of treatment of inflammatory bowel disease in children
Klíčová slova: predikce, zánětlivá střevní onemocnění, léčba, diagnostika
Klíčová slova anglicky: prediction, inflammatory bowel disease, treatment, diagnostics
Akademický rok vypsání: 2016/2017
Typ práce: disertační práce
Jazyk práce: čeština
Ústav: Pediatrická klinika (13-350)
Vedoucí / školitel: doc. MUDr. Ondřej Hradský, Ph.D.
Řešitel: skrytý - zadáno a potvrzeno stud. odd.
Datum přihlášení: 28.10.2016
Datum zadání: 28.10.2016
Datum potvrzení stud. oddělením: 28.10.2016
Datum a čas obhajoby: 13.09.2021 14:00
Datum odevzdání elektronické podoby:17.06.2021
Datum odevzdání tištěné podoby:18.06.2021
Datum proběhlé obhajoby: 13.09.2021
Oponenti: MUDr. Dana Ďuricová, Ph.D.
  doc. MUDr. Zuzana Havličeková, Ph.D.
 
 
Seznam odborné literatury
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Předběžná náplň práce
Typická Crohnova choroba (CD), Crohnovská kolitida zasahující pouze tlusté střevo, atypická ulcerózní kolitida (UC) a typická UC s kontinuálně rozloženým zánětlivým postižením tlustého střeva jsou v současné době vnímány jako makroskopicky i mikroskopicky se od sebe lišící formy zánětlivých střevních onemocnění (IBD). Výskyt těchto imunitně podmíněných onemocnění celosvětově narůstá v rámci dospělé i dětské populace. Ačkoliv je do jisté míry znám podíl genetického pozadí a faktorů vnějšího prostřední na vznik těchto onemocnění, přesná příčina rozvoje IBD není stále určena. Komplexní péče vyžaduje precizní a co nejlépe daty podpořený přístup vedoucí k minimalizaci rizika komplikovaného průběhu onemocnění a rozvoji s onemocněním a/nebo léčbou asociovaných komplikací.

Hlavním cílem práce je identifikace nových prediktivních faktorů zasahujících do jednotlivých oblastí péče o dětské pacienty s IBD. Spektrum klinických situací, řešených v rámci této práce zahrnuje možnost predikce diagnózy, obecně komplikovaného průběhu onemocnění, odpovědi na konkrétní terapeutický režim, rozvoj nežádoucích účinků asociovaných se zvoleným terapeutickým postupem a adherence pacienta k léčbě. Část prací byla provedena v retrospektivním designu, část jako prospektivní observační studie, dvě z původních prací vznikly jako multicentrické mezinárodní projekty.

Za nejdůležitější výstup práce lze považovat vytvoření predikčního modelu k individuálnímu odhadu času do relapsu u dětských pacientů s CD na léčbě thiopuriny. Dále jsme vytvořili modely predikující hladinu metabolitů azathioprinu, která odráží vhodnost dávkování léku nebo adherenci pacienta k jeho užívání. Nově byl nalezen optimální cut-off pro hladinu metabolitů azathioprinu, který predikuje dosažení žádoucích hladin infliximabu. Identifikovali jsme infliximab, ve srovnání s adalimumabem, jako prediktor rozvoje kožních nežádoucích účinků u dětských pacientů s IBD. Ukázali jsme, že míra tkáňové exprese CD30+ buněk je silným prediktivním faktorem klasifikace onemocnění do jednoho z typů IBD. Naopak možnost klinického využití nebyla prokázána u stanovení hladin tkáňového kalprotektinu (CPT) a fekálního CPT časně po zahájení indukce výlučnou enterální výživou. Upozornili jsme na limitované klinické využití domácích testů ke stanovení hladin fekálního CPT.

Výsledky jednotlivých studií lze shrnout jako získání souboru nových informací, na základě kterých lze předem odhadnout určitý jev, jehož včasné ovlivnění, nebo lépe jehož předejití přispívá k lepší kontrole onemocnění u dětských pacientů s diagnózou IBD. Díky nově identifikovaným možnostem predikce konkrétních klinických otázek je odpověď na ně informovanější a lze tak předpokládat větší přesnost při rozhodování.
Předběžná náplň práce v anglickém jazyce
Typical Crohn's disease (CD), Crohn's colitis, typical and atypical ulcerative colitis (UC) are currently perceived as different forms of inflammatory bowel disease (IBD). The incidence of IBD is increasing worldwide in both the adult and paediatric populations. Although the role of genetic background and environmental factors in the development of these diseases is known to some extent, the exact cause of IBD has still not been determined. Comprehensive care requires a precise and data-driven approach to minimize the risk of complicated disease course and the development of disease-related and/or treatment-associated complications.

The main goal of this work is to identify new predictive factors affecting individual areas of care of paediatric patients with IBD. The range of clinical situations addressed in this work includes the possibility of predicting the diagnosis, the generally complicated disease course, the response to a particular therapeutic regimen, the development of side effects associated with the therapeutic procedure and the patient's adherence to the treatment. Part of the original works was done in a retrospective design, part as prospective observational studies and two of the original works were realized as multicentre international projects.

The most important outcome of the work can be considered the creation of a predictive model of estimation of individual time to relapse in paediatric patients with CD on thiopurine treatment. We also developed models predicting the level of azathioprine metabolites, which reflect the suitability of the drug dosage or the patient's adherence to its use. An optimal cut-off of the level of azathioprine metabolites, which predicts the achievement of the effective infliximab levels, has been found. We identified infliximab, compared to adalimumab, as a predictor of the development of skin side effects in paediatric IBD patients. We have shown that the tissue expression level of CD30+ cells is a strong predictive factor of classifying the disease into one of the IBD types. In contrast, the possibility of clinical usefulness has not been demonstrated in the determination of tissue calprotectin (CPT) levels and faecal CPT levels obtained early after initiation of treatment with exclusive enteral nutrition. We indicated the limited clinical use of home tests to determine faecal CPT levels.

The results of individual studies can be summarized as the acquisition of a set of new information, on the basis of which it is possible to predict a certain phenomenon, the early influence or prevention of which, contributes to better disease control. Thanks to the newly identified possibilities of predicting specific clinical questions, the answer to them is more informed and it is possible to assume greater accuracy in decision-making process.
 
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