Optimizing biologic therapy in patients with Inflammatory Bowel Diseases

Treatment optimization and tight control have been suggested as important parameters in the management of patients with Inflammatory Bowel Disease (IBD). Towards this direction, the often use of colonoscopy as well as various biomarkers have been suggested.The aim of this thesis is to investigate potential serum or fecal biomarkers,that could reliably, accurately and objectively predict disease activity, assisting the treatment optimization strategy. In this way, a documented, and not only a clinically guided (empirical) approach is applied in treatmentoptimization preserving both drug survival and patient safety.The measurement of infliximab trough levels (IFX-TLs) and antibodies to infliximab (Abs) has been suggested as an important parameter for the optimization of treatment in patients with IBD. In the first part of the thesis we aimed to estimate the patterns overtime of IFX-TLs and Abs in IBD patients on maintenance treatment with IFX. In two consecutive measurements, taken 10 months apart, IFX-TLs showed significantly decreasing patterns associated with an increase of CRP values. This observation may be suggestive of an impending loss of response and highlights the need for treatment intensification when detected. In fact 3 years later upon recording of all treatment modifications made during this period in the same patient group we retrospectively found that the decrease in IFX-TLs was more evident in those who eventually needed treatment optimization (based on clinical, laboratory and endoscopic criteria) in the years to follow than those that did not.Fecal calprotectin (FC) is also a valuable tool with widespread use in IBD demonstrating a favorable positive correlation with disease endoscopic activity. Recently, in support of self-monitoring strategies and distance medicine, smartphone-based home FC tests have been developed showing highaccuracy and good correlation with laboratory ELISA FC measurements. We aimed to compare FC home test with other biomarkers as for their association with endoscopic activity in IBD patients under maintenance treatment with adalimumab. FC home test performed better than all serum biomarkers in predicting endoscopic activity.In conclusion, this thesis describes how the use of inflammatory markers, drug levels and antidrug antibody levels help to optimize the outcome of anti-TNFα therapy in patients with IBD.Η στενότερη παρακολούθηση των ασθενών με Ιδιοπαθείς Φλεγμονώδεις Νόσους του Εντέρου (ΙΦΝΕ) και η βελτιστοποίηση της αγωγής τους επιβάλλεται από το γεγονός ότι οι ασθενείς δεν ρυθμίζονται επαρκώς μόνο βάση των κλινικών συμπτωμάτων. Προς την κατεύθυνση αυτήχρησιμοποιούμε την κολονοσκόπηση σαν εξέταση εκλογής αλλά και άλλους εναλλακτικούς αυτής έμμεσους δείκτες που αντανακλούν την ενεργότητα της νόσου τους λεγόμενους βιοδείκτες. Στόχος της παρούσας διατριβής είναι να διερευνήσει πιθανούς βιοδείκτες, η χρήση των οποίων θα μπορούσε να βοηθήσει στην αξιόπιστη και αντικειμενική εκτίμηση του φλεγμονώδους φορτίου και οι οποίοι θα συνεισφέρουν στη βελτιστοποίηση της θεραπείας σε ασθενείς με ΙΦΝΕ. Με τον τρόπο αυτό επιδιώκεται η τεκμηριωμένη, και όχι μόνο η κλινικά καθοδηγούμενη (εμπειρική), τροποποίηση της θεραπείας διαφυλάττοντας τόσο τα φάρμακα όσο και την ασφάλεια του ασθενή. Η μέτρηση των κυκλοφορούντων επιπέδων του infliximab (IFX-TLs) και των αντισωμάτων έναντι αυτού (Abs) έχει προταθεί σαν σημαντική παράμετρος ρύθμισης της θεραπείας στις ΙΦΝΕ. Στο πρώτο σκέλος της διδακτορικής διατριβής σκοπός ήταν να εκτιμηθεί η αξία των διαδοχικών μετρήσεων των IFX-TLs και Abs στον ορό ασθενών με ΙΦΝΕ υπό αγωγή συντήρησης με IFX. Σε διαδοχικές μετρήσεις που έγιναν με μεσοδιάστημα 10 μηνών τα IFX-TLs παρουσίασαν σημαντική μείωση γεγονός που βρέθηκε να συνοδεύεται με αύξηση των τιμών της CRP. Αυτή η παρατήρηση μπορεί να αποτελεί οιωνό επικείμενης απώλειας της ανταπόκρισης του φαρμάκου και υποδηλώνει την ανάγκη πιθανής εντατικότερης θεραπείας για αποτελεσματικότερο έλεγχο της νόσου όταν εντοπίζεται. Η διαπίστωση αυτή επιβεβαιώθηκε 3 έτη μετά σε καταγραφή όλων των τροποποιήσεων που χρειάστηκε να γίνουν στο διάστημα αυτό στην ίδια ομάδα ασθενών. Φάνηκε αναδρομικά ότι η πτώση στις τιμές των IFX-TLs ήταν πιο έκδηλη σε αυτούς που τελικά χρειάστηκαν βελτιστοποίηση της θεραπείας (βάση κλινικών, εργαστηριακών και ενδοσκοπικών κριτηρίων) στα χρόνια που ακολούθησαν σε σχέση με αυτούς που τελικά δεν χρειάστηκε κάποιου είδους αλλαγή. Η καλπροτεκτίνη κοπράνων (FC) αποτελεί έναν εξίσου αξιόλογο βιοδείκτη με ευρεία χρήση στις ΙΦΝΕ και υπάρχει σημαντική συσχέτιση των τιμών της με την ενδοσκοπική δραστηριότητα της νόσου. Τα τελευταία χρόνια έχει αρχίσει να χρησιμοποιείται η κατ’οίκον μέτρησή της, μέθοδος γρήγορη με αποδεδειγμένη αξιοπιστία αφού έχει δείξει υψηλή ακρίβεια και καλή συσχέτιση με τις αντίστοιχες εργαστηριακές δοκιμασίες. Επιδιώξαμε στο δεύτερο σκέλος της διατριβής να εκτιμήσουμε τη διαγνωστική ικανότητα της κατ’οίκον μετρούμενης FC να προβλέπει την ενδοσκοπικά ενεργό νόσο και να τη συγκρίνουμε με άλλους βιοδείκτες ορού σε ασθενείς υπό θεραπεία συντήρησης με adalimumab. Aποδείχθηκε ότι η κατ’οίκον μετρούμενη FC αποδίδει καλύτερα σε σχέση με τους βιοδείκτες ορού στην πρόβλεψη της ενδοσκοπικά ενεργού νόσου. Συμπερασματικά, οι μελέτες αυτές αναδεικνύουν πώς η χρήση των κυκλοφορούντων επιπέδων των αντι-ΤΝFα, των αντισωμάτων έναντι αυτών και της κατ’οίκον μετρούμενης καλπροτεκτίνης κοπράνων βοηθούν στη βελτιστοποίηση του αποτελέσματος της θεραπείας των αντιTNFα στους ασθενείς με ιδιοπαθή φλεγμονώδη νόσο του εντέρου

Recent Advances in the Optimization of Anti-TNF Treatment in Patients with Inflammatory Bowel Disease

Despite the evolution in inflammatory bowel disease (IBD) management during the last 20 years owing to the advent of new advanced therapies, anti-TNF agents still remain the cornerstone of therapy for both Crohn’s disease and ulcerative colitis. However, this does not only secure favorable outcomes for patients considering the progressive disease character and the high likelihood of primary or secondary loss of response. Therefore, trying to reach a better treatment approach and maximize the benefits anti-TNF agents offer, optimization strategies should be examined. It has been indicated that optimizing treatment with anti-TNF enhances drug efficacy and has been associated with improved disease outcomes and a complication-free disease course. From this perspective, we aim to provide an overview of currently available data and recent advances in the practices of anti-TNF treatment optimization. Special focus has been given to the role of therapeutic drug monitoring (TDM), as well as the utility of combining anti-TNF with an immunomodulator and the treat-to-target approach

Effect of antinuclear antibodies on pharmacokinetics of anti-TNF therapy in patients with inflammatory bowel disease

Purpose The detection of antinuclear antibodies (ANA) in serum of patients with inflammatory bowel disease (IBD) has been associated with a worse response to anti-TNF therapy and the development of cutaneous or arthritic manifestations. The aim of this study was to investigate a possible association of serum ANA with infliximab (IFX) and adalimumab (ADA) trough levels (TLs) and anti-drug antibodies in IBD patients treated with IFX or ADA. Methods Consecutive IBD patients under maintenance therapy with IFX or ADA in whom there was at least one available measurement of anti-TNF TLs, antibodies to IFX or ADA, and ANA in serum were included. The correlation of ANA positivity with demographics, clinical characteristics, treatment, TLs and anti-drug antibodies, of all patients was analyzed. Results One hundred two IBD patients under maintenance therapy with IFX or ADA were enrolled. Of these, 53 (52%) were ANA positive with 28 (27.5%) positive also to anti-ds-DNA in serum. In the univariate analysis ANA positivity was found to be correlated with age (P = 0.008), female gender (P = 0.03), duration of treatment (P = 0.06), arthralgias (P = 0.04) and TLs (P = 0.005). However, in multivariate logistic regression analysis only age and TLs remained significantly associated with the presence of ANA positivity (P = 0.04 and P = = 0.006, respectively). No significant association of ANA positivity with the development of cutaneous or rheumatological manifestations was found. Conclusions In IBD patients under maintenance therapy with anti-TNF ANA positivity is associated with lower TLs. The clinical significance of this finding remains to be defined in future larger prospective studies

Mucocutaneous manifestations in patients with inflammatory bowel disease: a decade study from a Greek cohort

Background We sought to investigate the prevalence of mucocutaneous manifestations (MCM) and potential associations with clinical characteristics in Greek patients with IBD. Methods This was a retrospective observational single-center study. Patients with IBD diagnosis attending a tertiary referral hospital in Heraklion, Crete, from January 2010 to January 2020 were included. Data were extracted with relevant medical information from the IBD registry. Standard statistical tests, descriptive statistics tests, chi-square, Pearson correlation and multivariate analysis tests were performed, using IBM SPSS Statistics 25. Results A total of 806 IBD patients were included in the study: 463 (57.4%) males, 441 (54.7%) Crohn’s Disease, 352 (43.7%) ulcerative colitis and 13 (1.6%) IBD unclassified (IBD-U). Mean age was 50.67 +/- 17.67 years, mean age of IBD diagnosis 36.67 +/- 16.53 years and mean disease duration 13.65 +/- 9.89 years. The prevalence of MCM was 171/806 (21.2%), 9.65% in ulcerative colitis and 30.84% in CD. The presence of MCM was significantly correlated with younger age of IBD diagnosis, longer IBD duration, CD diagnosis, inflammatory behavior and ileal or ileocolonic location of CD, extensive colitis in ulcerative colitis, intestinal manifestations (EIMs) and treatment with immunosuppressant or anti-TNFa. The development of MCM was independently associated with the presence of other EIMs odds ratio (OR), 4.03 [95% confidence interval (CI), 2.60-6.24; P < 0.001] and treatment with immunosuppressant (OR, 1.87; 95% CI, 01.14-3.07; P = 0.013) or anti-TNFa (OR = 2.47; 95% CI, 1.59-3.84; P < 0.01). Conclusions In our study, about one-fifth of IBD patients developed MCM that was more frequently present in CD than in ulcerative colitis

Real-World Use and Adverse Events of SARS-CoV-2 Vaccination in Greek Patients with Inflammatory Bowel Disease

Since inflammatory bowel disease (IBD) patients were excluded from vaccine authorization studies, limited knowledge exists regarding perceptions and unfavorable effects of COVID-19 vaccination in this group. We aimed to investigate the real-world use and adverse events (AEs) of COVID-19 vaccines in Greek IBD patients. Fully vaccinated IBD patients followed in Greek centers were invited to participate. All patients filled out an anonymous online survey concerning the vaccination program, which included information regarding demographics, clinical characteristics, treatment, vaccination perceptions and potential AEs. Overall, 1007 IBD patients were included. Vaccine hesitancy was reported by 49%. Total AEs to vaccination were reported by 81% after dose 1 (D1) and 76% after dose 2 (D2), including isolated injection site reactions (36% and 24% respectively). Systemic AEs were more common after D2 (51%, D2 vs. 44%, D1, p < 0.0001). Very few patients reported new onset abdominal symptoms (abdominal pain 4% (D1), 6% (D2) and diarrhea 5% (D1), 7% (D2)). There were no serious AEs leading to emergency room visit or hospitalization. In multivariate analysis, AEs occurrence was positively associated with young age and female gender (p < 0.0005 for both doses), whereas inactive disease was negatively associated with AE in D1 (p = 0.044). SARS-CoV-2 vaccination in Greek IBD patients demonstrated a favorable and reassuring safety profile

Real-World Use and Adverse Events of SARS-CoV-2 Vaccination in Greek Patients with Inflammatory Bowel Disease

Since inflammatory bowel disease (IBD) patients were excluded from vaccine authorization studies, limited knowledge exists regarding perceptions and unfavorable effects of COVID-19 vaccination in this group. We aimed to investigate the real-world use and adverse events (AEs) of COVID-19 vaccines in Greek IBD patients. Fully vaccinated IBD patients followed in Greek centers were invited to participate. All patients filled out an anonymous online survey concerning the vaccination program, which included information regarding demographics, clinical characteristics, treatment, vaccination perceptions and potential AEs. Overall, 1007 IBD patients were included. Vaccine hesitancy was reported by 49%. Total AEs to vaccination were reported by 81% after dose 1 (D1) and 76% after dose 2 (D2), including isolated injection site reactions (36% and 24% respectively). Systemic AEs were more common after D2 (51%, D2 vs. 44%, D1, p < 0.0001). Very few patients reported new onset abdominal symptoms (abdominal pain 4% (D1), 6% (D2) and diarrhea 5% (D1), 7% (D2)). There were no serious AEs leading to emergency room visit or hospitalization. In multivariate analysis, AEs occurrence was positively associated with young age and female gender (p < 0.0005 for both doses), whereas inactive disease was negatively associated with AE in D1 (p = 0.044). SARS-CoV-2 vaccination in Greek IBD patients demonstrated a favorable and reassuring safety profile

Implementation and short-term adverse events of anti-SARS-CoV-2 vaccines in inflammatory bowel disease patients: an international web-based survey

International audienc