In Silico Strategies for Prospective Drug Repositionings

The discovery of new drugs is one of pharmaceutical research's most exciting and challenging tasks. Unfortunately, the conventional drug discovery procedure is chronophagous and seldom successful; furthermore, new drugs are needed to address our clinical challenges (e.g., new antibiotics, new anticancer drugs, new antivirals).Within this framework, drug repositioning—finding new pharmacodynamic properties for already approved drugs—becomes a worthy drug discovery strategy.Recent drug discovery techniques combine traditional tools with in silico strategies to identify previously unaccounted properties for drugs already in use. Indeed, big data exploration techniques capitalize on the ever-growing knowledge of drugs' structural and physicochemical properties, drug–target and drug–drug interactions, advances in human biochemistry, and the latest molecular and cellular biology discoveries.Following this new and exciting trend, this book is a collection of papers introducing innovative computational methods to identify potential candidates for drug repositioning. Thus, the papers in the Special Issue In Silico Strategies for Prospective Drug Repositionings introduce a wide array of in silico strategies such as complex network analysis, big data, machine learning, molecular docking, molecular dynamics simulation, and QSAR; these strategies target diverse diseases and medical conditions: COVID-19 and post-COVID-19 pulmonary fibrosis, non-small lung cancer, multiple sclerosis, toxoplasmosis, psychiatric disorders, or skin conditions

Translational Aspects of Behçet’s Disease

__abstract__ De ziekte van Behçet is een multi-factoriele (auto)inflammatoire vascilitis die vooral voorkomt bij mensen uit landen van de Middellandse Zee gebied en langs de voormalige zijderoute naar het Verre Oosten, er zijn ongeveer 600 patiënten in Nederland. Algemeen wordt aangenomen dat omgevings- en genetische factoren een rol spelen bij het ontstaan van de ziekte. Echter, zowel de epidemiologie als de pathofysiologie zijn onduidelijk, studieresultaten spreken elkaar soms tegen. In dit proefschrift wordt de veronderstelling dat de prevalentie van BD afneemt na migratie ter discussie gesteld, verder wordt voor het eerst epidemiologische data van een Nederlands cohort gepresenteerd. Vervolgens worden nieuwe genetische associaties gepresenteerd waaronder een beschermende relatie met NOD2 varianten en een verhoogd risico bij IL12A varianten. Veel inflammatoire cytokines zijn betrokken bij de ziekte van Behçet, weefsel expressie lijkt relevanter dan serum cytokine niveaus. Tot slot worden de nieuwe inzichten vertaald naar nieuwe behandelmodaliteiten. TNF-α blokkers en andere biologicals hebben een duidelijke plaats in de behandeling van refractaire ziekte

Detection of interstitial lung disease in rheumatoid arthritis: diagnostic tests and prognostic value

Denne ph.d. omhandlede diagnostiske og prognostiske undersøgelser ved leddegigt (RA), den mest udbredte af de autoimmune sygdomme. Gennem årene, er behandlingsmuligheder og overlevelsen hos personer med leddegigt forbedret. Der er dog fortsat en overdødelighed, og en stor bidrager til overdødeligheden er lungefibrose (også kaldet RA-ILD). Fem år efter diagnosen RA-ILD er stillet, er 40% af patienterne døde, og gennemsnitsoverlevelsen er 7,4 år. Det anbefales, at man screener RA-patienter for luftvejssymptomer mhp. opsporing af RA-ILD. Der er imidlertid ingen evidens bag anbefalingerne, og screening for luftvejssymptomer er ikke en fast del af den af kliniske vurdering ved RA. Ultralydsskanning af lungerne (LUS) har potentiale til at finde RA-ILD, men det mangler at blive efterprøvet ude i klinikkerne.Der er tilkommet flere behandlingsmuligheder for kroniske inflammatoriske sygdomme (CID’s), så som leddegigt. Omkring 1/3 af CID’s opnår ikke en tilstrækkelig positiv behandlingseffekt af biologisk medicin. Biologisk medicin er heller ikke uden bivirkninger, og der findes ingen validerede metoder til at forudsige behandlingsrespons. Microfibrillarassociated protein 4 (MFAP4) er en lovende biomarkør for aktivinflammation og fibrose aktivitet. MFAP4 er ikke efterprøvet som biomarkør for lungesygdom ved leddegigt og ej heller som biomarkør for at forudsige behandlingsrespons ved opstart af biologisk medicinering.Studie 1 og 2 undersøgte den diagnostiske præcision af LUS til at opspore lungefibrose hos personer med leddegigt, der har selekterede luftvejssymptomer. LUS havde en god sensitivitet og negativ prædiktiv værdi.Studie 3 undersøgte den diagnostiske præcision af et velkendt spørgeskema vedrørende oplevet åndenød (MRC) samt biomarkøren MFAP4 til at opspore nedsat lungefunktion hos personer med ny-diagnosticeret leddegigt, som ikke er opstartet i behandling endnu. Overordnet havde hverken MRC eller den ujusterede MFAP4-analyse en god sensitivitet eller specificitet. Ved en analyse, justeret for alder, biologisk køn og rygerstatus, havde MFAP4 ≥ 29.0 U/ml en association til nedsat lungefunktion.Studie 4 undersøgte den prognostiske værdi af at have høje MFAP4-niveauer i blodet, for at få et positivt behandlingsrespons hos personer med en kronisk inflammatorisk sygdom (leddegigt, psoriasisgigt, psoriasis, rygsøjlegigt, Chron’s sygdom og colitis ulcerosa). Hovedresultaterne viste, at høje MFAP4-niveauer i blodet var associeret med en positiv behandlingsrespons, når der justeres for CID, alder, biologisk køn, rygerstatus og BMI.This was a PhD on diagnostic tests and prognostic value in rheumatoid arthritis (RA), the most common autoimmune disease. Treatment options for patients with RA and overall survival have improved over the years. However, there is still increased mortality in RA, largely due to respiratory diseases such as RA-associated interstitial lung disease (RA-ILD). RA-ILD has a 40% mortality rate after 5 years, with a median survival of 7.4 years after diagnosis. It is generally recommended to screen RA for respiratory symptoms to detect ILD. However, this is currently not evidence-based nor routinely applied in clinics. Thoracic ultrasound has also been suggested as a promising tool for the early detection of RA-ILD, but had yet to be tested in a clinical setting.Treatment options for chronic inflammatory diseases (CIDs) such as RA have increased. It is estimated that about one-third of patients with CIDs who start on biologics will not respond to the treatment. Biological therapy is expensive and can have side effects. There are currently no validated methods of predicting treatment response. Microfibrillar- associated protein 4 (MFAP4) is a promising biomarker of inflammation and fibrotic activity; however, its role in detecting lung disease in RA, as well as predicting treatment response, has not beenevaluated.Papers 1 and 2 investigated the diagnostic accuracy of thoracic ultrasound (TUS) in detecting ILD in RA with pre-defined respiratory symptoms. The results revealed that TUS is a promising tool for detecting ILD, with a high sensitivity and negative predictive value.Paper 3 investigated the diagnostic accuracy of an established questionnaire on perceived dyspnoea, using the Medical Research Council (MRC) dyspnoea scale, and MFAP4 in detecting respiratory impairment in newly diagnosed and treatment-naïve RA. Overall, MRC and the crude analysis of MFAP4 showed neither a high sensitivity nor specificity. However, when adjusting for age, sex and smoking status, there was a correlation of MFAP4 ≥ 29.0 U/ml for detecting respiratory impairment.Paper 4 investigated the prognostic value of high MFAP4 levels on positive treatment outcomes in patients with CIDs (RA, psoriatic arthritis, psoriasis, Axial Spondyloarthritis, Crohn’s disease, and ulcerative colitis) who were about to initiate or switch biological therapy. The main results showed that when adjusting for CID, age, sex, smoking and BMI, high MFAP4 had the potential to predict a positive treatment outcome with biological therapy in most CIDs.</div