Οι βιολογικοί παράγοντες ως θεραπεία των χρόνιων φλεγμονωδών αρθροπαθειών
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Παπαδόπουλος, Χρήστος Γ.
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Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής
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Οι βιολογικές θεραπείες άνοιξαν νέους θεραπευτικούς ορίζοντες στην αντιμετώπιση των χρονιών φλεγμονωδών αρθροπαθειών. Εχει φανεί οτι τα φάρμακα αυτά είναι αποτελεσματικά τόσο στις ανθεκτικές μορφές της ρευματοειδούς αρθρίτιδας όσο και στις οροαρνητικές
σπονδυλαρθροπάθειες, επιτυγχάνοντας σημαντική κλινική βελτίωση αλλά και αναστολή της εξέλιξης των ακτινολογικών βλαβών.
Σκοπός της παρούσης διατριβής ήταν να διερευνηθούν η μακροχρόνια αποτελεσματικότητα, η ασφάλεια (τοξικότητα), ο χρόνος παραμονής (επιβίωση), καθώς και οι λόγοι διακοπής της θεραπείας με βιολογικούς παράγοντες στις χρόνιες φλεγμονώδεις αρθροπάθειες.
Για τις ανάγκες αυτής της διερεύνησης, μελετήθηκαν ιατρικοί φάκελοι ασθενών, διαγνωσμένων με ρευματοειδή αρθρίτιδα (ΡΑ), ψωριασική αρθρίτιδα (ΨΑ) και αγκυλοποιητική σπονδυλίτιδα (ΑΣ), οι οποίοι ελάμβαναν θεραπεία με τους αντι-TNFa βιολογικούς παράγοντες infliximab, adalimumab και etanercept και παρακολουθήθηκαν στα Εξωτερικά Ιατρεία και τη Ρευματολογική Κλινική του Πανεπιστημιακού Νοσοκομείου Ιωαννίνων, κατά τη διάρκεια μιας περιόδου 16 ετών, από τον Οκτώβριο του 1999 έως και το Νοέμβριο του 2015.
Τα δεδομένα σχετικά με τις παραμέτρους εκτίμησης της αποτελεσματικότητας και ασφάλειας συλλέγονταν σε καθορισμένα χρονικά σημεία: κατά την έναρξη της μελέτης, κάθε 6 μήνες κατά τα δύο πρώτα έτη παρακολούθησης και εν συνεχεία κάθε έτος, μέχρι τη συμπλήρωση μιας χρονικής περιόδου 8 ετών για τη ρευματοειδή αρθρίτιδα και 6 ετών για τις σπονδυλαρθροπάθειες (ΨΑ και ΑΣ).
Ειδικότερα, κατά την ένταξη στη μελέτη καταγράφονταν στοιχεία σχετικά με τα δημογραφικά χαρακτηριστικά των ασθενών (ηλικία, φύλο, κ.α.) και σχετικά με το χαρακτήρα και τη βαρύτητα της νόσου (διάρκεια νόσου, λιγότερο ή περισσότερο καταστροφική νόσος, ύπαρξη ή μη συμπτωματολογίας φλεγμονώδους σπονδυλίτιδας, ύπαρξη ή μη θετικού RF, τυχόν προηγηθείσα θεραπεία με άλλο βιολογικό παράγοντα ή DMARDs κ.α.). Σε κάθε εκτίμηση του ασθενούς (ανά 6-μηνο ή έτος) καταγράφονταν η δοσολογία των φαρμάκων, παράμετροι κλινικής και εργαστηριακής εκτίμησης (αριθμός ευαίσθητων και οιδηματωδών αρθρώσεων, ΤΚΕ, CRP κ.α ), καθώς και ειδικοί δείκτες κλινικής ανταπόκρισης, διαφορετικοί για την κάθε νόσο (DAS 28 ΤΚΕ, DAS 28 CRP, SDAI, ACR 20, 50 και 70 και HAQ για τη ΡΑ' DAS 28 ΤΚΕ, DAS 28 CRP, SDAI, τροποποιημένο ACR 20, 50 και 70, PsARC και PASI για την ΨΑ' BASDAI, BASFI και ASAS για την ΑΣ). Καταγράφονταν ακόμη οι ανεπιθύμητες ενέργειες (συμπεριλαμβανομένων των αλλεργικών αντιδράσεων) και άλλα συμβάματα που πιθανώς σχετίζονταν αιτιολογικά με τη βιολογική θεραπεία, οι διαταραχές των εργαστηριακών εξετάσεων, οι νέες νόσοι που εμφανίζονταν, οι χειρουργικές επεμβάσεις που διενεργούνταν κατά τη διάρκεια της βιολογικής αγωγής και η τυχόν διακοπή ή αλλαγή του βιολογικού παράγοντα σε άλλον βιολογικό παράγοντα, καθώς και οι λόγοι διακοπής ή αλλαγής.
Κύριος τελικός στόχος της μελέτης για τους ασθενείς με ΡΑ ήταν ο υπολογισμός του ποσοστού των ασθενών που ανταποκρίθηκαν σύμφωνα με το δείκτη ενεργότητας DAS 28, για την ΨΑ αντίστοιχα με το δείκτη PsARC και για την ΑΣ με το δείκτη BASDAI.
Τα αποτελέσματα της έρευνας έδειξαν οτι και οι τρεις βιολογικοί παράγοντες που μελετήθηκαν (infliximab, adalimumab και etanercept) φάνηκε να είναι ιδιαίτερα αποτελεσματικοί και στα τρία νοσήματα (ΡΑ, ΨΑ και ΑΣ).
Πιο συγκεκριμένα, μελετώντας αρχικά τους ασθενείς με ΡΑ ως σύνολο - ανεξαρτήτως της βιολογικής αγωγής που ελάμβαναν - διαπιστώθηκε μία στατιστικά σημαντική μείωση τόσο του DAS 28 ΤΚΕ όσο και του DAS 28 CRP εντός του 1ου εξαμήνου, που διατηρήθηκε - και στους δύο δείκτες -μέχρι και το τέλος της παρακολούθησης (8 έτη μετά την έναρξη). Μελετώντας τους ασθενείς με ΡΑ ξεχωριστά ανά φάρμακο φάνηκε μία επίσης πολύ καλή ανταπόκριση και στις τρεις αγωγές, που διατηρήθηκε σε μεγάλο βαθμό μέχρι και το τέλος της μελέτης. Τα ποσοστά ανταπόκρισης σύμφωνα με το ACR 20 στους 12 μήνες ήταν για το infliximab 63%, για το adalimumab 72% και για το etanercept 61,5%. Τα αντίστοιχα ποσοστά στην 8-ετία ήταν 17,8%, 32,4% και 65,4%. Η καλή/μέτρια ανταπόκριση σύμφωνα με το DAS28 CRP στους 12 μήνες ήταν για το infliximab 34,5%/63,8%, για το adalimumab 42,6%/54,1 % και για το etanercept 60,0%/40,0%. Η σύγκριση της αποτελεσματικότητας των τριών φαρμάκων, που έγινε στους ασθενείς με ΡΑ για το πρώτο 18-μηνο θεραπείας, δεν έδειξε υπεροχή κάποιου αντι-TNF έναντι των άλλων.
Εξετάζοντας τους ασθενείς με ΨΑ ως σύνολο - ανεξαρτήτως βιολογικής αγωγής -διαπιστώσαμε, όπως και στην περίπτωση της ΡΑ, μια στατιστικά σημαντική μείωση τόσο του δείκτη DAS 28 ΤΚΕ όσο και του DAS 28 CRP εντός του 1ου εξαμήνου, που διατηρήθηκε - και στους 2 δείκτες - μέχρι και το τέλος της παρακολούθησης (6 έτη μετά την έναρξη). Μελετώντας τους ασθενείς με ΨΑ ξεχωριστά ανά αγωγή φάνηκε μία πολύ καλή ανταπόκριση και στα τρία φάρμακα, που διατηρήθηκε σε μεγάλο βαθμό μέχρι και το τέλος της μελέτης. Τα ποσοστά ανταπόκρισης σύμφωνα με τα κριτήρια ACR 20 ήταν στους 12 μήνες: για το infliximab 73%, για το adalimumab 71,4% και για το etanercept 88,9%. Τα αντίστοιχα ποσοστά για την 8-ετία ήταν 45,9%, 28,6% και 16,7%. Ανάλογη ήταν η ανταπόκριση στους 12 μήνες σύμφωνα με το PsARC: 75,7%, 66,7% και 93,7% αντίστοιχα.
Μελετώντας τους ασθενείς με ΑΣ ως σύνολο - ανεξαρτήτως βιολογικής αγωγής - φάνηκε ότι, ήδη από το 1ο εξάμηνο, το ποσοστό ενεργής νόσου σύμφωνα με το δείκτη BASDAI μειώθηκε από 75,7% στο 22,7%. Σταδιακά, το ποσοστό αυτό μειώθηκε περαιτέρω και στα 6 έτη - όπου και το τέλος της παρακολούθησης - μηδενίστηκε. Το ποσοστό ανταπόκρισης σύμφωνα με το BASDAI στο 1ο εξάμηνο έφτανε το 66,7%, ενώ στην 6-ετία ανταποκρίθηκαν όλοι οι ασθενείς. Αντίστοιχη ήταν η βελτίωση στο χρόνο της CRP. Εξετάζοντας τους ασθενείς με ΑΣ ξεχωριστά ανά αγωγή φάνηκε μία ανάλογη βελτίωση στην πορεία του χρόνου και με τα τρία φάρμακα.
Και οι τρεις βιολογικές θεραπείες βρέθηκε να έχουν ένα αποδεκτό προφίλ ασφάλειας. Κατά τη μελέτη του πληθυσμού ως σύνολο - ανεξαρτήτως νοσήματος - το φάρμακο στο οποίο παρατηρήθηκαν οι περισσότερες ανεπιθύμητες ενέργειες ήταν το infliximab (96,15% των ασθενών) και ακολουθούσαν το adalimumab και το etanercept (71,59% και 68,25% αντίστοιχα). Η συχνότερα εμφανιζόμενη ανεπιθύμητη ενέργεια και για τις τρεις αγωγές ήταν η λοίμωξη, με το μεγαλύτερο ποσοστό να παρατηρείται επίσης στο infliximab (75%), ενώ αρκετά μικρότερο ήταν εκείνο του adalimumab και του etanercept (46,59% και 39,68% αντίστοιχα). Οι συχνότερα εμφανιζόμενες λοιμώξεις ήταν κατα φθίνουσα σειρά: λοίμωξη ανωτέρου αναπνευστικού/κοινό κρυολόγημα, ουρολοίμωξη, λοίμωξη γαστρεντερικού, μυκητίαση δέρματος, επιχείλιος έρπης, πνευμονία, έρπητας ζωστήρας, ιγμορίτιδα και φαρυγγίτιδα. Οι συστηματικές αλλεργικές αντιδράσεις ήταν συχνότερες στο infliximab (33,33%) και πολύ σπανιότερες στο adalimumab και το etanercept (2,27% και 1,59% αντίστοιχα).
Ειδικά για τους ασθενείς με ΡΑ τα αποτελέσματα ήταν παρόμοια με εκείνα του συνολικού πληθυσμού. Το μεγαλύτερο ποσοστό ασθενών που εμφάνισαν μία τουλάχιστον ανεπιθύμητη ενέργεια παρατηρήθηκε στο infliximab και ήταν υψηλό (98,65%). Η συχνότερα αναφερόμενη ανεπιθύμητη ενέργεια και για τα τρία φάρμακα ήταν η λοίμωξη, με το μεγαλύτερο ποσοστό να παρατηρειται πα ι στο infliximab (70,27%), έχοντας στατιστικά σημαντική διαφορά από τις δύο άλλες αγωγές. Ομως, σε οτι αφορά τα ποσοστά εμφάνισης των σοβαρών λοιμώξεων τα τρία φάρμακα δεν διεφεραν στατιστικά μεταξύ τους Οι συστηματικές αλλεργικές αντιδράσεις ήταν σημαντικά συχνότερες στο infliximab, με αρκετά υψηλό ποσοστό (39,19%), σπανιότατες στο adalimumab (2,67%), ενω στο etanercept δεν παρατηρήθηκε καμία αλλεργική αντίδραση, ούτε συστηματική ούτε τοπική.
Στα πλήθη των ασθενών με ΨΑ και ΑΣ η συχνότερη ανεπιθύμητη ενέργεια και για τα τρία φάρμακα ήταν και πάλι η λοίμωξη.
To infliximab σε ότι αφορά την εμφάνιση συστηματικών αλλεργικών αντιδράσεων και άλλων συμβαμάτων κατά την έγχυση (εκτός των αλλεργιών), φάνηκε να είναι πολύ καλύτερα ανεκτό στους ασθενείς με ΑΣ συγκριτικά με τους ασθενείς με ΡΑ και ΨΑ (συστηματικές αλλεργικές αντιδράσεις σε ΡΑ και ΨΑ: περίπου 40%, ενώ στην ΑΣ: 17,78% ■ λοιπά συμβάματα κατά την έγχυση σε ΡΑ και ΨΑ. περίπου 10%, ενώ στην ΑΣ: 2,22%).
Τόσο οι ανεπιθύμητες ενέργειες γενικά, όσο και ειδικότερα οι λοιμώξεις και οι συστηματικές αλλερνικές αντιδράσεις, παρουσιάστηκαν με μεγαλύτερη συχνότητα κατά το πρώτο έτος της βιολογικής θεραπείας, εύρημα που επιβάλλει μεγαλύτερη επαγρύπνηση των θεραπόντων ιατρών κατα το
διάστημα αυτό.
Προδιαθεσικός παράγοντας για τη σημαντικά συχνότερη εμφάνιση λοιμώξεων βρέθηκε να είναι η λήψη στεροειδών, μόνον όμως για τους ασθενείς με ΡΑ και μόνο σε εκείνους υπο infliximab. Στους ασθενείς με ΨΑ και ΑΣ - όχι όμως με ΡΑ - ήταν σημαντικά πιθανότερη η εμφάνιση αλλεργικών αντιδράσεων στις γυναίκες συγκριτικά με τους άνδρες.
Καταγράφηκαν 6 περιστατικά ΤΒ λοίμωξης (5 πνευμονικής φυματίωσης και 1 εξωπνευμονικής). Από αυτά, 4 παρουσιάστηκαν στο infliximab, 2 στο adalimumab - μεταξύ των οποίων και η εξωπνευμονική φυματίωση - και κανένα στο etanercept. Εμφανίστηκαν επίσης 3 κακοήθη λεμφώματα (2 στο infliximab, 1 στο adalimumab), ένα περιστατικό σκλήρυνσης κατα πλακας (infliximab), ένα περιστατικό οπτικής νευρίτιδας (adalimumab), ένα περιστατικό επιδείνωσης γνωστής καρδιακής ανεπάρκειας (etanercept) και ένα περιστατικό αναζωπύρωσης ηπατιτιδας Β (infliximab).
Μελετώντας την επιβίωση της αντι-TNFa αγωγής ανά νόσημα για το σύνολο του πληθυσμού - ανεξαρτήτως του φαρμάκου που χορηγήθηκε - είχαμε ένα ποσοστό επιβίωσης της τάξης του 31,8/ο via τη ΡΑ (στο τέλος της 8-ετίας), ενώ τα αντίστοιχα ποσοστά για την ΨΑ και την ΑΣ ήταν 50 /ο και 60 8% (στο τέλος της 6-ετίας). Από τις καμπύλες επιβίωσης φάνηκε να είναι σχετικά υψηλότερη αυτή των ασθενών με ΑΣ, αλλά η διαφορά με τα άλλα δύο νοσήματα δεν ήταν στατιστικά σημαντική.
Εξετάζοντας την επιβίωση για τις τρεις βιολογικές αγωγές στο σύνολο των ασθενών -ανεξαρτήτως νοσήματος - βρέθηκε ένα ποσοστό επιβίωσης της τάξης του 36,6% για το infliximab, 39 7% για το adalimumab και 60,5% για το etanercept. Ο χρόνος επιβίωσης ήταν κατα μέσο ορο σημαντικά χαμηλότερος για την περίπτωση του infliximab συγκριτικά με το χρόνο επιβίωσης του adalimumab και του etanercept, μεταξύ των οποίων δεν υπήρχε στατιστικά σημαντική διάφορά.
Μελετώντας τέλος την επιβίωση ανάλογα με την αγωγή για κάθε πάθηση ξεχωριστά, το υψηλότερο ποσοστό επιβίωσης καταγράφηκε για το etanercept στους ασθενείς με ΑΣ (88,9%), ενώ το χαμηλότερο στους ασθενείς με ΡΑ και infliximab (20%). Ειδικότερα, στη ΡΑ φάνηκε και πάλι οτι η επιβίωση στο infliximab ήταν σημαντικά χαμηλότερη συγκριτικά με τις δύο άλλες αγωγές, οι οποίες δεν διέφεραν στατιστικά μεταξύ τους (ρ=0,089). Επίσης στη ΡΑ, ως ανεξάρτητοι προγνωστικοί παράγοντες που επιδρούν στο χρόνο επιβίωσης με στατιστική σημαντικότητα βρέθηκαν να είναι το πλήθος των αποτυχημένων DMARDs και η συγχορήγηση μεθοτρεξάτης. Πιο συγκεκριμένα, φάνηκε οτι η επιβίωση σε όσους είχαν αποτυχία σε >3DMARDs και σε όσους δεν ελάμβαναν ΜΤΧ ήταν σημαντικό χαμηλότερη Στις περιπτώσεις της ΨΑ και της ΑΣ δεν φάνηκε να υπάρχουν στατιστικά σημαντικές διαφορές στην επιβίωση μεταξύ των τριών φαρμάκων, ούτε ανεξάρτητοι παράγοντες που να μπορούν να επιδράσουν σημαντικά στο χρόνο επιβίωσης.
Οι συχνότερες αιτίες διακοπής της βιολογικής θεραπείας στο σύνολο του πληθυσμού ήταν η αναποτελεσματικότητα (12,7% επί του αρχικού δείγματος ασθενών) και ακολουθούσαν η συστηματική αλλεργική αντίδραση (11,7%) και η ανεπιθύμητη ενέργεια (9,4%). Οι τρεις παραπανω αίτιες ήταν και οι συχνότερες για όλους τους συνδυασμούς αγωγής - νόσου. Στο σύνολο του πληθυσμού η συχνότερη ανεπιθύμητη ενέργεια που οδήγησε σε διακοπή της βιολογικής θεραπείας ήταν η λοίμωξη απο φυματίωση και ακολουθούσαν η πνευμονία και το ψωριασιόμορφο εξάνθημα. Συμπερασματικά, και οι τρεις βιολογικοί παράγοντες που μελετήθηκαν (infliximab, adalimumab και etanercept) φάνηκε να είναι ιδιαίτερα αποτελεσματικοί και για τα τρία νοσήματα (ΡΑ, ΨΑ, και ΑΣ). Σε ένα σημαντικό ποσοστό των ασθενών η βελτίωση επηλθε απο το πρώτο 6-μηνο της θεραπείας και διατηρήθηκε έως και το τέλος της παρακολούθησης ετη για τη ΡΑ, 6 έτη για την ΨΑ και την ΑΣ). Η σύγκριση της αποτελεσματικότατα των τριών φαρμάκων στους ασθενείς με ΡΑ για τους πρώτους 18 μήνες θεραπείας, δεν έδειξε υπέροχη κάποιου αντι-TNF έναντι των άλλων.
Και οι τρεις αγωγές επέδειξαν ένα αποδεκτό προφίλ ασφάλειας. Στη ρευματοειδή αρθρίτιδα, τόσο οι ανεπιθύμητες ενέργειες γενικά όσο και ειδικότερα οι λοιμώξεις και οι συστηματικές αλλεργικές αντιδράσεις, ήταν σημαντικά συχνότερες στο infliximab. Όμως, για τις σοβαρές λοιμώξεις δεν βρέθηκε στατιστικά σημαντική διαφορά ανάμεσα στα τρία φάρμακα.
Η επιβίωση και για τις τρεις αγωγές ήταν ικανοποιητική, αλλά για το infliximab, στους ασθενείς με ρευματοειδή αρθρίτιδα, βρέθηκε να είναι σημαντικά χαμηλότερη σε σύγκριση με το adalimumab και το etanercept, που δεν διέφεραν στατιστικά μεταξύ τους.
Biological therapies broadened new therapeutic horizons in the treatment of the chronic inflammatory arthropathies. It has been shown that these drugs are effective both for the resistant forms of the rheumatoid arthritis and for the seronegative spondylarthropathies, achieving significant clinical improvement as well as inhibition of radiological lesions progression. The aim of the present doctoral thesis was to investigate the long-term efficacy, the safety (toxicity), the residence time (survival) and the reasons of discontinuation of the therapy with biological agents in chronic inflammatory arthropathies. For this purpose, medical records of patients diagnosed with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), who were under treatment with the anti-TNFa biological agents infliximab, adalimumab and etanercept and were also under the supervision of the Rheumatology Clinic of the University Hospital of loannina during a period of 16 years, from October 1999 up to November 2015 were studied. The data related with the parameters of assessment for the effectiveness and safety were collected at determined time points: at baseline, every six months for the first two years of observation and then annually until the completion of an eight-year period for rheumatoid arthritis and a six-year period for spondylarthropathies (PsA and AS). More specifically, at the beginning of the study, the data that are related to the demographic characteristics of the patients (age, sex, etc.) and the nature and severity of the disease (disease duration, less or more destructive disease, presence or not of inflammatory spondylitis, presence or not of positive RF, any prior therapy with other biologic agent or DMARDs etc) were recorded. In each patient's assessment (every 6 months or a year), the dosage of medications, parameters of clinical and laboratory assessment (number of tender and swollen joints, ESR, CRP etc.) as well as specific indices of clinical response which are different for each disease (DAS 28 ESR, DAS 28 CRP, SDAI, ACR 20 50 and 70 and HAQ for RA; DAS 28 ESR, DAS 28 CRP, SDAI, modified ACR 20, 50 and 70, PsARC and PASI for PsA; BAS DAI, BASFI and ASAS for AS) were recorded. The side effects (including allergic reactions) and other adverse events which were possibly related to the biological treatment disturbances from laboratory tests, appearance of new diseases, surgical operations that were carried out during the biological treatment and any discontinuation or change of the biological agent to another biological agent, including the reasons of this discontinuation or change were also recorded. The primary objective of the present study, as far as the RA patients are concerned, was the calculation of the rate of patients who responded according to the activity index DAS 28, for the PsA patients according to the index PsARC and for the AS patients to the index BASDAI respectively. The results of this study showed that all three biological agents which have been studied (infliximab, adalimumab and etanercept) were proved to be particularly effective in all three diseases More particularly, studying RA patients as a whole at first - regardless of the biological treatment they received - a statistically significant reduction was found in both DAS 28 ESR and DAS 28 CRP in the first six months, that was maintained - on both indices - until the end of the followup (8 years from the beginning). Studying RA patients separately, per medication, a very good response in all three treatments was observed which was sustained up to a great degree until the end of the study. The response rates according to ACR 20 in the twelve months were 63% for infliximab, 72% for adalimumab and 61,5% for etanercept. The response rates in the eight years period were 17,8%, 32,4% and 65,4% respectively. The good/moderate response according to the DAS28 CRP in the twelve months period was 34,5%/63,8% for infliximab, 42,6%/54,1% for adalimumab and 60%/40% for etanercept. The comparison of the effectiveness of the three drugs, which concerned RA patients for the first eighteen month therapy, did not show superiority of any anti-TNF therapy over the others. After examining PsA patients as a whole - regardless of biological treatment - we found out, as in the case of RA patients, a statistically significant reduction in both DAS 28 ESR index and DAS 28 CRP in the first six months, which was maintained - on both indices - until the end of the follow-up (6 years after onset). Studying PsA patients separately, per medication, a very good response to all three drugs, which was sustained up to a great degree until the end of the study was observed. The response rates according to the ACR 20 criteria in the twelve months were 73% for infliximab, 71,4% for adalimumab and 88,9%. for etanercept. The response rates for the eight years were 45,9%, 28,6% and 16,7% correspondingly. There was a similar response in the twelve months period according to PsARC: 75,7%, 66,7% and 93,7% respectively. After studying AS patients as a whole - regardless of biological treatment - it was shown that the percentage of the active disease according to the BASDAI index decreased from 75,7% to 22,7% from the first six months of treatment. Gradually, this percentage was further reduced in the six years period until the end of the attendance, where it was zeroed. The response rate according to the BASDAI for the first six months reached 66,7% while in the six years period all patients responded. There was a similar improvement of CRP during the time. Examining AS patients separately, per medication, a similar improvement was observed over time with all three drugs. All three biological treatments were found to have an acceptable safety profile. Studying the total population - regardless of disease - the drug in which most adverse events were remarked was infliximab (96,15% of patients) followed by adalimumab and etanercept with 71,59% and 68,25% respectively. The most frequently occurring adverse event for all the three treatments was infection, with the greater percentage of which to be remarked to infliximab (75%) while the percentage of adalimumab and etanercept was much lower (46,59% and 39,68% correspondingly). The most frequently occurring infections were, in descending order, upper respiratory system infection/common cold, urinary tract infection, gastrointestinal infection, skin mycosis, cold sores, pneumonia, herpes zoster, sinusitis, and pharyngitis. The systemic allergic reactions were more frequent to infliximab (33,33%) and much less frequent to adalimumab and etanercept (2,27% and 1,59% respectively). Especially for RA patients, the results were similar to those of the total population. The greater percentage of the patients who had experienced at least one adverse event was under the treatment with infliximab and it was a high one (98,65%). The most frequently reported adverse event for all three drugs was the infection, whose highest rate was observed in infliximab again (70,27%) and having a statistically significant difference from the other two regimens. However, there was not any statistical difference among the three drugs as far as the occurrence of serious infections is concerned. The systemic allergic reactions were significantly more frequent in infliximab with a fairly high percentage (39,19%), a rare one in adalimumab (2,67%) while in etanercept no allergic reaction was observed, neither systemic nor local. In the samples of PsA and AS patients, the most common adverse event for all three drugs was also infection. Infliximab, as far as the appearance of systemic allergic reactions and other events during infusion (except for allergies) is concerned, appeared to be much better tolerated in AS patients than in RA and PsA patients (systemic allergic reactions in RA and PsA: approximately 40% while in AS: 17,78%; other events during infusion in RA and PsA: about 10% while in AS: 2,22%). Both adverse events in general and infections and systemic allergic reactions in particular have been occurred more frequently during the first year of the biological treatment. This fact requires more attention by physicians during this period. As predisposing factor for the significantly more frequent occurrence of the infections was found to be the steroids’ intake but only for RA patients and only for those who were under the treatment with infliximab. For the PsA and AS patients - but not for the RA ones - the occurrence of allergic reactions in women in comparison with men was significantly more likely to appear. Six incidents with TB infection were recorded (5 of pulmonary TB and 1 of extrapulmonary). From all these, 4 appeared in infliximab, 2 in adaiimumab, including extrapulmonary TB and none in etanercept. Also, 3 malignant lymphomas appeared (2 in infliximab and 1 in adaiimumab), 1 incident of multiple sclerosis (infliximab), 1 incident of optic neuritis (adaiimumab), 1 incident of aggravation of heart failure (etanercept) and 1 incident of reactivation of hepatitis B (infliximab). Studying the survival of anti-TNFa treatment in all three diseases for the whole population -regardless of the administered drug - a survival rate of 31,8% for RA (at the end of the 8-year period) was found while the respect rates for PsA and AS were 50% and 60,8% (at the end of the 6-year period). From the survival curves it seemed that AS patients had a relatively higher survival rate but the difference with the other two diseases was not statistically significant. Examining the survival for three biological treatments in all patients - regardless of disease - a survival rate of 36,6% for infliximab, 39,7% for adaiimumab and 60,5% for etanercept was observed. The survival time was on average significantly lower for the case of infliximab in comparison with the survival time of adaiimumab and etanercept, between which there was no a statistically significant difference. Finally, while studying the survival from the point of view of the treatment for each disease separately, the highest survival rate for etanercept in the AS patients was recorded (88,9%) whereas the lower survival rate in RA patients using infliximab was also recorded (20%). Particularly in RA, it was also shown that the survival for the infliximab was significantly lower in comparison with the two other treatments that were not statistically different between them (p=0,089). Also RA patients, as independent prognostic factors which influence the survival time with statistical significance, were found to be the number of failed DMARDs and the co-administration of methotrexate as well. More specific, it seemed that the survival for those who had failed to > 3DMARDs and those who had not received MTX was significantly lower. In the case of PsA and AS, it didn’t seem to be statistically significant differences in the survival among the three drugs nor independent factors that can significantly affect the survival time. The most common reasons for the discontinuation of the biological treatment for the whole population were ineffectiveness (12,7% of the original patient sample) and followed by systemic allergic reaction (11,7%) and adverse event (9,4%). The above three reasons were also the most common for all combinations between treatment and disease. In the total population, the most common adverse event which resulted in the discontinuation of the biological therapy was tuberculosis infection, followed by pneumonia and psoriasiform rash. In conclusion, it was shown that all three biological agents that have been studied (infliximab, adaiimumab and etanercept) are particularly effective for the three diseases (RA, PsA and AS). In a significant percentage of patients, improvement occurred since the first six months of the treatment and it was maintained until the end of the surveillance (8 years for RA, 6 years for PsA and AS). The comparison of the effectiveness of the three drugs, which concerned RA patients for the first eighteen month therapy, did not show superiority of any anti-TNF therapy over the others. All three drugs showed an acceptable safety profile. In heumatoid arthritis, both adverse events in general and infections and systemic allergic reactions in particular were significantly more frequent in infliximab. However, for serious infections, a statistically significant difference between the three drugs was not found. Survival for all three treatments was satisfactory but in infliximab, in patients with rheumatoid arthritis, was found to be significantly lower compared with adaiimumab and etanercept, which had not any difference between them statistically.
Biological therapies broadened new therapeutic horizons in the treatment of the chronic inflammatory arthropathies. It has been shown that these drugs are effective both for the resistant forms of the rheumatoid arthritis and for the seronegative spondylarthropathies, achieving significant clinical improvement as well as inhibition of radiological lesions progression. The aim of the present doctoral thesis was to investigate the long-term efficacy, the safety (toxicity), the residence time (survival) and the reasons of discontinuation of the therapy with biological agents in chronic inflammatory arthropathies. For this purpose, medical records of patients diagnosed with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), who were under treatment with the anti-TNFa biological agents infliximab, adalimumab and etanercept and were also under the supervision of the Rheumatology Clinic of the University Hospital of loannina during a period of 16 years, from October 1999 up to November 2015 were studied. The data related with the parameters of assessment for the effectiveness and safety were collected at determined time points: at baseline, every six months for the first two years of observation and then annually until the completion of an eight-year period for rheumatoid arthritis and a six-year period for spondylarthropathies (PsA and AS). More specifically, at the beginning of the study, the data that are related to the demographic characteristics of the patients (age, sex, etc.) and the nature and severity of the disease (disease duration, less or more destructive disease, presence or not of inflammatory spondylitis, presence or not of positive RF, any prior therapy with other biologic agent or DMARDs etc) were recorded. In each patient's assessment (every 6 months or a year), the dosage of medications, parameters of clinical and laboratory assessment (number of tender and swollen joints, ESR, CRP etc.) as well as specific indices of clinical response which are different for each disease (DAS 28 ESR, DAS 28 CRP, SDAI, ACR 20 50 and 70 and HAQ for RA; DAS 28 ESR, DAS 28 CRP, SDAI, modified ACR 20, 50 and 70, PsARC and PASI for PsA; BAS DAI, BASFI and ASAS for AS) were recorded. The side effects (including allergic reactions) and other adverse events which were possibly related to the biological treatment disturbances from laboratory tests, appearance of new diseases, surgical operations that were carried out during the biological treatment and any discontinuation or change of the biological agent to another biological agent, including the reasons of this discontinuation or change were also recorded. The primary objective of the present study, as far as the RA patients are concerned, was the calculation of the rate of patients who responded according to the activity index DAS 28, for the PsA patients according to the index PsARC and for the AS patients to the index BASDAI respectively. The results of this study showed that all three biological agents which have been studied (infliximab, adalimumab and etanercept) were proved to be particularly effective in all three diseases More particularly, studying RA patients as a whole at first - regardless of the biological treatment they received - a statistically significant reduction was found in both DAS 28 ESR and DAS 28 CRP in the first six months, that was maintained - on both indices - until the end of the followup (8 years from the beginning). Studying RA patients separately, per medication, a very good response in all three treatments was observed which was sustained up to a great degree until the end of the study. The response rates according to ACR 20 in the twelve months were 63% for infliximab, 72% for adalimumab and 61,5% for etanercept. The response rates in the eight years period were 17,8%, 32,4% and 65,4% respectively. The good/moderate response according to the DAS28 CRP in the twelve months period was 34,5%/63,8% for infliximab, 42,6%/54,1% for adalimumab and 60%/40% for etanercept. The comparison of the effectiveness of the three drugs, which concerned RA patients for the first eighteen month therapy, did not show superiority of any anti-TNF therapy over the others. After examining PsA patients as a whole - regardless of biological treatment - we found out, as in the case of RA patients, a statistically significant reduction in both DAS 28 ESR index and DAS 28 CRP in the first six months, which was maintained - on both indices - until the end of the follow-up (6 years after onset). Studying PsA patients separately, per medication, a very good response to all three drugs, which was sustained up to a great degree until the end of the study was observed. The response rates according to the ACR 20 criteria in the twelve months were 73% for infliximab, 71,4% for adalimumab and 88,9%. for etanercept. The response rates for the eight years were 45,9%, 28,6% and 16,7% correspondingly. There was a similar response in the twelve months period according to PsARC: 75,7%, 66,7% and 93,7% respectively. After studying AS patients as a whole - regardless of biological treatment - it was shown that the percentage of the active disease according to the BASDAI index decreased from 75,7% to 22,7% from the first six months of treatment. Gradually, this percentage was further reduced in the six years period until the end of the attendance, where it was zeroed. The response rate according to the BASDAI for the first six months reached 66,7% while in the six years period all patients responded. There was a similar improvement of CRP during the time. Examining AS patients separately, per medication, a similar improvement was observed over time with all three drugs. All three biological treatments were found to have an acceptable safety profile. Studying the total population - regardless of disease - the drug in which most adverse events were remarked was infliximab (96,15% of patients) followed by adalimumab and etanercept with 71,59% and 68,25% respectively. The most frequently occurring adverse event for all the three treatments was infection, with the greater percentage of which to be remarked to infliximab (75%) while the percentage of adalimumab and etanercept was much lower (46,59% and 39,68% correspondingly). The most frequently occurring infections were, in descending order, upper respiratory system infection/common cold, urinary tract infection, gastrointestinal infection, skin mycosis, cold sores, pneumonia, herpes zoster, sinusitis, and pharyngitis. The systemic allergic reactions were more frequent to infliximab (33,33%) and much less frequent to adalimumab and etanercept (2,27% and 1,59% respectively). Especially for RA patients, the results were similar to those of the total population. The greater percentage of the patients who had experienced at least one adverse event was under the treatment with infliximab and it was a high one (98,65%). The most frequently reported adverse event for all three drugs was the infection, whose highest rate was observed in infliximab again (70,27%) and having a statistically significant difference from the other two regimens. However, there was not any statistical difference among the three drugs as far as the occurrence of serious infections is concerned. The systemic allergic reactions were significantly more frequent in infliximab with a fairly high percentage (39,19%), a rare one in adalimumab (2,67%) while in etanercept no allergic reaction was observed, neither systemic nor local. In the samples of PsA and AS patients, the most common adverse event for all three drugs was also infection. Infliximab, as far as the appearance of systemic allergic reactions and other events during infusion (except for allergies) is concerned, appeared to be much better tolerated in AS patients than in RA and PsA patients (systemic allergic reactions in RA and PsA: approximately 40% while in AS: 17,78%; other events during infusion in RA and PsA: about 10% while in AS: 2,22%). Both adverse events in general and infections and systemic allergic reactions in particular have been occurred more frequently during the first year of the biological treatment. This fact requires more attention by physicians during this period. As predisposing factor for the significantly more frequent occurrence of the infections was found to be the steroids’ intake but only for RA patients and only for those who were under the treatment with infliximab. For the PsA and AS patients - but not for the RA ones - the occurrence of allergic reactions in women in comparison with men was significantly more likely to appear. Six incidents with TB infection were recorded (5 of pulmonary TB and 1 of extrapulmonary). From all these, 4 appeared in infliximab, 2 in adaiimumab, including extrapulmonary TB and none in etanercept. Also, 3 malignant lymphomas appeared (2 in infliximab and 1 in adaiimumab), 1 incident of multiple sclerosis (infliximab), 1 incident of optic neuritis (adaiimumab), 1 incident of aggravation of heart failure (etanercept) and 1 incident of reactivation of hepatitis B (infliximab). Studying the survival of anti-TNFa treatment in all three diseases for the whole population -regardless of the administered drug - a survival rate of 31,8% for RA (at the end of the 8-year period) was found while the respect rates for PsA and AS were 50% and 60,8% (at the end of the 6-year period). From the survival curves it seemed that AS patients had a relatively higher survival rate but the difference with the other two diseases was not statistically significant. Examining the survival for three biological treatments in all patients - regardless of disease - a survival rate of 36,6% for infliximab, 39,7% for adaiimumab and 60,5% for etanercept was observed. The survival time was on average significantly lower for the case of infliximab in comparison with the survival time of adaiimumab and etanercept, between which there was no a statistically significant difference. Finally, while studying the survival from the point of view of the treatment for each disease separately, the highest survival rate for etanercept in the AS patients was recorded (88,9%) whereas the lower survival rate in RA patients using infliximab was also recorded (20%). Particularly in RA, it was also shown that the survival for the infliximab was significantly lower in comparison with the two other treatments that were not statistically different between them (p=0,089). Also RA patients, as independent prognostic factors which influence the survival time with statistical significance, were found to be the number of failed DMARDs and the co-administration of methotrexate as well. More specific, it seemed that the survival for those who had failed to > 3DMARDs and those who had not received MTX was significantly lower. In the case of PsA and AS, it didn’t seem to be statistically significant differences in the survival among the three drugs nor independent factors that can significantly affect the survival time. The most common reasons for the discontinuation of the biological treatment for the whole population were ineffectiveness (12,7% of the original patient sample) and followed by systemic allergic reaction (11,7%) and adverse event (9,4%). The above three reasons were also the most common for all combinations between treatment and disease. In the total population, the most common adverse event which resulted in the discontinuation of the biological therapy was tuberculosis infection, followed by pneumonia and psoriasiform rash. In conclusion, it was shown that all three biological agents that have been studied (infliximab, adaiimumab and etanercept) are particularly effective for the three diseases (RA, PsA and AS). In a significant percentage of patients, improvement occurred since the first six months of the treatment and it was maintained until the end of the surveillance (8 years for RA, 6 years for PsA and AS). The comparison of the effectiveness of the three drugs, which concerned RA patients for the first eighteen month therapy, did not show superiority of any anti-TNF therapy over the others. All three drugs showed an acceptable safety profile. In heumatoid arthritis, both adverse events in general and infections and systemic allergic reactions in particular were significantly more frequent in infliximab. However, for serious infections, a statistically significant difference between the three drugs was not found. Survival for all three treatments was satisfactory but in infliximab, in patients with rheumatoid arthritis, was found to be significantly lower compared with adaiimumab and etanercept, which had not any difference between them statistically.
Description
Keywords
Βιολογικοί παράγοντες, TNF-α αναστολείς, Ινφλιξιμάμπη, Ετανερσέπτη, Ανταλιμουμάμπη, Χρόνιες φλεγμονώδεις αρθροπάθειες, Ρευματοειδής αρθρίτιδα, Ψωριασική αρθρίτιδα, Αγκυλοποιητική σπονδυλίτιδα, Ανεπιθύμητες ενέργειες, Επιβίωση φαρμάκων, Biological agents, TNF-α inhibitors, Infliximab, Etanercept, Adalimumab, Chronic inflammatory, Arthropathies, Rheumatoid arthritis, Psoriatic arthritis, Ankylosing spondylitis, Adverse events, Drug survival
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Ψωριασική αρθρίτιδα, Ρευματοειδής αρθρίτιδα
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el
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Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής
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Δρόσος, Αλέξανρος
Examining committee
Δρόσος, Αλέξανδρος
Βούλγαρη, Παρασκευή
Αλαμάνος, Ιωάννης
Λιάμης, Γεώργιος
Τσιάρα, Σταυρούλα
Χριστοδούλου, Δημήτριος
Γαϊτάνης, Γεώργιος
Βούλγαρη, Παρασκευή
Αλαμάνος, Ιωάννης
Λιάμης, Γεώργιος
Τσιάρα, Σταυρούλα
Χριστοδούλου, Δημήτριος
Γαϊτάνης, Γεώργιος
General Description / Additional Comments
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Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής
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Βιβλιογραφία : σ. 338-381
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421 σ.