Response to Biologic Drugs in Patients With Rheumatoid Arthritis and Antidrug Antibodies

JAMA network open - Tập 6 Số 7 - Trang e2323098
Samuel Bitoun1, Signe Hässler2,3,4, David Ternant5, Natacha Szely6, Aude Gleizes7,8,9, Christophe Richez10, Martin Soubrier11, Jérôme Avouac12, Olivier Brocq13, Jérémie Sellam14, Niek de Vries15, T. Huizinga16, Elizabeth C. Jury17, Jessica Manson18, Claudia Mauri19, Andrea Matucci20, Salima Hacein Bey Abina7,9, Denis Mulleman5, Marc Pallardy6, Philippe Broët4, Xavier Mariette1, Françis Berenbaum21, Philippe Dieudé21, Philippe Bertin21, Maxime Dougados21, Corinne Miceli‐Richard21, Aleth Pedriger21, Hubert Marotte21, A. Cantagrel21, Olivier Vittecoq21, Thierry Lequere21, Alain Saraux21, René-Marc Flipo21, Jean Sibilia21, Jacques Eric Gottenberg21, B. Combe21, Jacques Morel21, Daniel Wendling21, Carin Verhoef21, M van Rijswijk21, Michael T. Nurmohamed21, Alessandra Vultaggio21
1Rheumatology Department, Université Paris-Saclay, Institut National de la Santé et de la Recherche Médicale (INSERM) U1184, Hôpital Bicêtre, Assistance Publique–Hôpitaux de Paris (APHP), Fédération Hospitalo Universitaire Cancer and Autoimmunity Relationships, Paris, France
2APHP, Hôpital Pitié Salpêtrière, Biotherapy (CIC-BTi), Paris, France
3INSERM Unité Mixte de Recherche (UMR) 959, Immunology-Immunopathology-Immunotherapy (i3), Sorbonne Université, Paris, France
4Université Paris-Saclay, INSERM U1018, Centre de Recherche en Epidémiologie et Santé des Populations, Paris, France
5EA6295 NanoMedicines and NanoProbes, University of Tours, Tours, France
6Université Paris-Saclay, INSERM, Inflammation, Microbiome, Immunosurveillance, Faculty of Pharmacy, Paris, France
7Clinical Immunology Laboratory, Groupe Hospitalier Universitaire Paris-Saclay, Hôpital Bicêtre, APHP, Paris, France
8Unité de Formation et de Recherche de Pharmacie, Université Paris-Saclay, Paris, France
9Université Paris Cité, Centre National de la Recherche Scientifique, INSERM, Unité des Technologies Chimiques et Biologiques pour la Santé, Paris, France
10Rheumatology Department, Centre Hospitalier Universitaire (CHU) de Bordeaux-GH Pellegrin, Bordeaux, France
11Rheumatology Department, CHU Gabriel-Montpied, Clermont-Ferrand, France
12Rheumatology Department, Hôpital Cochin, APHP, Centre-Université de Paris Cité, Paris, France
13Rheumatology Department, Hôpital Princesse Grâce de Monaco, Monaco
14Rheumatology Department, Hôpital Saint-Antoine, APHP, Sorbonne University, INSERM UMR 938, Paris, France
15Rheumatology and Clinical Immunology, Amsterdam UMC, AMC University of Amsterdam, Amsterdam, the Netherlands
16Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands
17Centre for Rheumatology Research, University College London, London, England
18Department of Rheumatology, University College London Hospital, London, England
19Division of Infection, Immunity and Transplantation, University College London, London, England
20Department of Immunology, Azienda Ospedaliero Universitaria Careggi, Florence, Italy
21for the ABIRISK Consortium

Tóm tắt

ImportanceThere are conflicting data on the association of antidrug antibodies with response to biologic disease–modifying antirheumatic drugs (bDMARDs) in rheumatoid arthritis (RA).ObjectiveTo analyze the association of antidrug antibodies with response to treatment for RA.Design, Setting, and ParticipantsThis cohort study analyzed data from the ABI-RA (Anti-Biopharmaceutical Immunization: Prediction and Analysis of Clinical Relevance to Minimize the Risk of Immunization in Rheumatoid Arthritis Patients) multicentric, open, prospective study of patients with RA from 27 recruiting centers in 4 European countries (France, Italy, the Netherlands, and the UK). Eligible patients were 18 years or older, had RA diagnosis, and were initiating a new bDMARD. Recruitment spanned from March 3, 2014, to June 21, 2016. The study was completed in June 2018, and data were analyzed in June 2022.ExposuresPatients were treated with a new bDMARD: adalimumab, infliximab (grouped as anti–tumor necrosis factor [TNF] monoclonal antibodies [mAbs]), etanercept, tocilizumab, and rituximab according to the choice of the treating physician.Main Outcomes and MeasuresThe primary outcome was the association of antidrug antibody positivity with EULAR (European Alliance of Associations for Rheumatology; formerly, European League Against Rheumatism) response to treatment at month 12 assessed through univariate logistic regression. The secondary end points were the EULAR response at month 6 and at visits from month 6 to months 15 to 18 using generalized estimating equation models. Detection of antidrug antibody serum levels was performed at months 1, 3, 6, 12, and 15 to 18 using electrochemiluminescence (Meso Scale Discovery) and drug concentration for anti-TNF mAbs, and etanercept in the serum was measured using enzyme-linked immunosorbent assay.ResultsOf the 254 patients recruited, 230 (mean [SD] age, 54.3 [13.7] years; 177 females [77.0%]) were analyzed. At month 12, antidrug antibody positivity was 38.2% in patients who were treated with anti-TNF mAbs, 6.1% with etanercept, 50.0% with rituximab, and 20.0% with tocilizumab. There was an inverse association between antidrug antibody positivity (odds ratio [OR], 0.19; 95% CI, 0.09-0.38; P < .001) directed against all biologic drugs and EULAR response at month 12. Analyzing all the visits starting at month 6 using generalized estimating equation models confirmed the inverse association between antidrug antibody positivity and EULAR response (OR, 0.35; 95% CI, 0.18-0.65; P < .001). A similar association was found for tocilizumab alone (OR, 0.18; 95% CI, 0.04-0.83; P = .03). In the multivariable analysis, antidrug antibodies, body mass index, and rheumatoid factor were independently inversely associated with response to treatment. There was a significantly higher drug concentration of anti-TNF mAbs in patients with antidrug antibody–negative vs antidrug antibody–positive status (mean difference, −9.6 [95% CI, −12.4 to −6.9] mg/L; P < 001). Drug concentrations of etanercept (mean difference, 0.70 [95% CI, 0.2-1.2] mg/L; P = .005) and adalimumab (mean difference, 1.8 [95% CI, 0.4-3.2] mg/L; P = .01) were lower in nonresponders vs responders. Methotrexate comedication at baseline was inversely associated with antidrug antibodies (OR, 0.50; 95% CI, 0.25-1.00; P = .05).Conclusions and RelevanceResults of this prospective cohort study suggest an association between antidrug antibodies and nonresponse to bDMARDs in patients with RA. Monitoring antidrug antibodies could be considered in the treatment of these patients, particularly nonresponders to biologic RA drugs.

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JAMA network open

Tập 6 Số 7

e2323098

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