Jocelyn Quistrebert1, Signe Hässler1, Delphine Bachelet1, Cyprien Mbogning1, Anne Musters2, Paul Peter Tak3, Carla Ann Wijbrandts4, Marieke Herenius2, Sytske Anne Bergstra5, Gülşah Akdemir5, Martina Johannesson6, Bernard Combe7, Bruno Fautrel8, Sylvie Chollet-Martin9, Aude Gleizes10, Naoimh Donnellan11, Florian Deisenhammer12, Julie Davidson13, Agnès Hincelin-Mery14, Pierre Dönnes15, Anna Fogdell-Hahn16, Niek De Vries2, Tom Huizinga5, Imad Abugessaisa17, Saedis Saevarsdottir6, Salima Hacein-Bey-Abina18, Marc Pallardy9, Philippe Broët19, Xavier Mariette20. 1. CESP, INSERM UMR 1018, Faculty of Medicine, Paris-Sud University, Paris-Saclay University, UVSQ, Villejuif, France. 2. Amsterdam Rheumatology and Immunology Center, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands. 3. Amsterdam Rheumatology and Immunology Center, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands; GlaxoSmithKline, Stevenage, UK; University of Cambridge, Cambridge, UK; Ghent University, Ghent, Belgium. 4. Amsterdam Rheumatology and Immunology Center, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands; Medical Center Slotervaart, Amsterdam, the Netherlands. 5. Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands. 6. Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. 7. Department of Rheumatology, Lapeyronie Hospital, Montpellier University, Montpellier, France. 8. Department of Rheumatology, AP-HP, Pitié Salpétrière Hospital, Paris, France; UPMC, GRC 08, Pierre Louis Institute of Epidemiology and Public Health, Paris, France. 9. INSERM UMR 996, Faculty of Pharmacy, Paris-Sud University, Paris-Saclay University, Châtenay-Malabry, France. 10. INSERM UMR 996, Faculty of Pharmacy, Paris-Sud University, Paris-Saclay University, Châtenay-Malabry, France; Clinical Immunology Laboratory, AP-HP, Paris-Sud University Hospitals, Le Kremlin Bicêtre Hospital, Le Kremlin Bicêtre, France. 11. IPSEN, Slough, Berkshire, UK. 12. Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. 13. GlaxoSmithKline, Uxbridge, Middlesex, UK. 14. Sanofi, Chilly-Mazarin, France. 15. SciCross AB, Skövde, Sweden. 16. Department of Clinical Neuroscience, Clinical Neuroimmunology, Karolinska Institutet, Stockholm, Sweden. 17. Unit of Computational Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. 18. Clinical Immunology Laboratory, AP-HP, Paris-Sud University Hospitals, Le Kremlin Bicêtre Hospital, Le Kremlin Bicêtre, France; UTCBS, CNRS UMR 8258, INSERM U1022, Faculty of Pharmacy, Paris-Descartes-Sorbonne-Cité University, Paris, France. 19. CESP, INSERM UMR 1018, Faculty of Medicine, Paris-Sud University, Paris-Saclay University, UVSQ, Villejuif, France; AP-HP, Paris-Sud University Hospitals, Paul Brousse Hospital, Villejuif, France; CHU Sainte Justine, Quebec, Canada. 20. INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Paris-Sud University, Paris-Saclay University, Le Kremlin-Bicêtre, France; Department of Rheumatology, AP-HP, Paris-Sud University Hospitals, Le Kremlin Bicêtre Hospital, Le Kremlin-Bicêtre, France. Electronic address: xavier.mariette@aphp.fr.
Abstract
OBJECTIVES: To evaluate the incidence of anti-drug antibody (ADA) occurrences and ADA-related risk factors under adalimumab and infliximab treatment in rheumatoid arthritis (RA) patients. METHODS: The study combined retrospective cohorts from the ABIRISK project totaling 366 RA patients treated with adalimumab (n = 240) or infliximab (n = 126), 92.4% of them anti-TNF naive (n = 328/355) and 96.6% of them co-treated with methotrexate (n = 341/353) with up to 18 months follow-up. ADA positivity was measured by enzyme-linked immunosorbent assay. The cumulative incidence of ADA was estimated, and potential bio-clinical factors were investigated using a Cox regression model on interval-censored data. RESULTS: ADAs were detected within 18 months in 19.2% (n = 46) of the adalimumab-treated patients and 29.4% (n = 37) of the infliximab-treated patients. The cumulative incidence of ADA increased over time. In the adalimumab and infliximab groups, respectively, the incidence was 15.4% (5.2-20.2) and 0% (0-5.9) at 3 months, 17.6% (11.4-26.4) and 0% (0-25.9) at 6 months, 17.7% (12.6-37.5) and 34.1% (11.4-46.3) at 12 months, 50.0% (25.9-87.5) and 37.5% (25.9-77.4) at 15 months and 50.0% (25.9-87.5) and 66.7% (37.7-100) at 18 months. Factors associated with a higher risk of ADA development were: longer disease duration (1-3 vs. < 1 year; adalimumab: HR 3.0, 95% CI 1.0-8.7; infliximab: HR 2.7, 95% CI 1.1-6.8), moderate disease activity (DAS28 3.2-5.1 vs. < 3.2; adalimumab: HR 6.6, 95% CI 1.3-33.7) and lifetime smoking (infliximab: HR 2.7, 95% CI 1.2-6.3). CONCLUSIONS: The current study focusing on patients co-treated with methotrexate for more than 95% of them found a late occurrence of ADAs not previously observed, whereby the risk continued to increase over 18 months. Disease duration, DAS28 and lifetime smoking are clinical predictors of ADA development.
OBJECTIVES: To evaluate the incidence of anti-drug antibody (ADA) occurrences and ADA-related risk factors under adalimumab and infliximab treatment in rheumatoid arthritis (RA) patients. METHODS: The study combined retrospective cohorts from the ABIRISK project totaling 366 RApatients treated with adalimumab (n = 240) or infliximab (n = 126), 92.4% of them anti-TNF naive (n = 328/355) and 96.6% of them co-treated with methotrexate (n = 341/353) with up to 18 months follow-up. ADA positivity was measured by enzyme-linked immunosorbent assay. The cumulative incidence of ADA was estimated, and potential bio-clinical factors were investigated using a Cox regression model on interval-censored data. RESULTS: ADAs were detected within 18 months in 19.2% (n = 46) of the adalimumab-treated patients and 29.4% (n = 37) of the infliximab-treated patients. The cumulative incidence of ADA increased over time. In the adalimumab and infliximab groups, respectively, the incidence was 15.4% (5.2-20.2) and 0% (0-5.9) at 3 months, 17.6% (11.4-26.4) and 0% (0-25.9) at 6 months, 17.7% (12.6-37.5) and 34.1% (11.4-46.3) at 12 months, 50.0% (25.9-87.5) and 37.5% (25.9-77.4) at 15 months and 50.0% (25.9-87.5) and 66.7% (37.7-100) at 18 months. Factors associated with a higher risk of ADA development were: longer disease duration (1-3 vs. < 1 year; adalimumab: HR 3.0, 95% CI 1.0-8.7; infliximab: HR 2.7, 95% CI 1.1-6.8), moderate disease activity (DAS28 3.2-5.1 vs. < 3.2; adalimumab: HR 6.6, 95% CI 1.3-33.7) and lifetime smoking (infliximab: HR 2.7, 95% CI 1.2-6.3). CONCLUSIONS: The current study focusing on patients co-treated with methotrexate for more than 95% of them found a late occurrence of ADAs not previously observed, whereby the risk continued to increase over 18 months. Disease duration, DAS28 and lifetime smoking are clinical predictors of ADA development.
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Authors: Signe Hässler; Delphine Bachelet; Julianne Duhaze; Natacha Szely; Aude Gleizes; Salima Hacein-Bey Abina; Orhan Aktas; Michael Auer; Jerôme Avouac; Mary Birchler; Yoram Bouhnik; Olivier Brocq; Dorothea Buck-Martin; Guillaume Cadiot; Franck Carbonnel; Yehuda Chowers; Manuel Comabella; Tobias Derfuss; Niek De Vries; Naoimh Donnellan; Abiba Doukani; Michael Guger; Hans-Peter Hartung; Eva Kubala Havrdova; Bernhard Hemmer; Tom Huizinga; Kathleen Ingenhoven; Poul Erik Hyldgaard-Jensen; Elizabeth C Jury; Michael Khalil; Bernd Kieseier; Anna Laurén; Raija Lindberg; Amy Loercher; Enrico Maggi; Jessica Manson; Claudia Mauri; Badreddine Mohand Oumoussa; Xavier Montalban; Maria Nachury; Petra Nytrova; Christophe Richez; Malin Ryner; Finn Sellebjerg; Claudia Sievers; Dan Sikkema; Martin Soubrier; Sophie Tourdot; Caroline Trang; Alessandra Vultaggio; Clemens Warnke; Sebastian Spindeldreher; Pierre Dönnes; Timothy P Hickling; Agnès Hincelin Mery; Matthieu Allez; Florian Deisenhammer; Anna Fogdell-Hahn; Xavier Mariette; Marc Pallardy; Philippe Broët Journal: PLoS Med Date: 2020-10-30 Impact factor: 11.069