Please cite this article in press as: Sigaux J, et al. Immunogenicity of tocilizumab in patients with rheumatoid arthritis. Joint Bone Spine (2016), http://dx.doi.org/10.1016/j.jbspin.2016.04.013 ARTICLE IN PRESS G Model BONSOI-4423; No. of Pages 7 Joint Bone Spine xxx (2016) xxx–xxx Available online at ScienceDirect www.sciencedirect.com Original article Immunogenicity of tocilizumab in patients with rheumatoid arthritis Johanna Sigaux a,b,c,1 , Moustafa Hamze d,1 , Claire Daien e,f , Jacques Morel e,f , Roman Krzysiek g,h,i , Marc Pallardy j , Bernard Maillere d , Xavier Mariette a,b,c,2 , Corinne Miceli-Richard a,b,c,∗,2 a Service de rhumatologie, hôpital de Bicêtre, hôpitaux universitaires Paris Sud, Assistance publique–Hôpitaux de Paris, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre, France b Inserm U1184, université Paris Sud, 91400 Orsay, France c Labex LERMIT, 94270 Le Kremlin-Bicêtre, France d CEA, iBiTecS, service d’ingénierie moléculaire des protéines (SIMOPRO), Labex LERMIT, Labex VRI, 91191 Gif-sur-Yvette, France e Département de rhumatologie, CHU Lapeyronie, 371, avenue du Doyen-Gaston-Giraud, 34295 Montpellier cedex, France f Université de Montpellier, 39, rue Université, 34295 Montpellier cedex, France g Laboratoire d’immunologie, hôpitaux universitaires Paris Sud, Assistance publique–Hôpitaux de Paris, 94270 Le Kremlin-Bicêtre, France h UMR 996, 92140 Clamart, France i Labex LERMIT, 92140 Clamart, France j UMR996, faculté de pharmacie, 92290 Châtenay-Malabry, France a r t i c l e i n f o Article history: Accepted 13 April 2016 Available online xxx Keywords: Immunogenicity Tocilizumab Rheumatoid arthritis a b s t r a c t Objective: The immunogenicity of tocilizumab (TCZ) has been poorly studied. We assessed the immuno- genicity of TCZ and serum TCZ trough levels in rheumatoid arthritis (RA) patients and the preexisting TCZ-specific CD4+ T cell repertoire in healthy controls. Methods: Anti-drug antibodies (ADAs) to TCZ and serum TCZ trough levels in RA patients were assessed at different times by ELISA. Frequencies of naive anti-TCZ CD4+ precursors were studied in healthy controls. Results: In total, 91 samples from 40 RA patients were analyzed: 21 patients within the first 6 months after treatment initiation and 19 during follow-up after a mean TCZ treatment duration of 21 ± 13 months. None of the 91 samples showed persistent ADAs to TCZ. Only 3 RA patients showed transient and low titers of anti-TCZ ADAs. Serum TCZ trough levels were associated with neither patient characteristics (gender, body mass index) nor disease activity and were identical for patients with and without co- treatment with methotrexate. Three of 9 healthy donors showed preexisting TZC-specific CD4+ T cells at a low level. Conclusion: Serum TCZ trough levels were not affected by patient characteristics. The occurrence of ADAs to TCZ was a rare event. Because healthy donors show the same frequency of naive TCZ-specific and infliximab-specific CD4+ T cell precursors, the low prevalence of ADAs to TCZ might result from interleukin-6 blockade. © 2016 Published by Elsevier Masson SAS on behalf of Soci ´ et ´ e franc ¸ aise de rhumatologie. 1. Introduction Currently, 9 different biologic therapies are approved for the treatment of rheumatoid arthritis (RA): 7 inhibitors of pro- inflammatory cytokines (5 targeting tumor necrosis factor alpha ∗ Corresponding author. Service de rhumatologie, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, Assistance Publique–Hôpitaux de Paris, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France. E-mail address: corinne.miceli@aphp.fr (C. Miceli-Richard). 1 Equal contribution to this work. 2 Equal contribution to this work. [TNF], one interleukin 1 [IL-1] and one IL-6) as well as T- and B-lymphocyte–targeting agents (abatacept and rituximab, respectively). All anti-TNF biologic agents (infliximab [IFX], adal- imumab, etanercept, golimumab and certolizumab) are implicated in the formation of anti-drug antibodies (ADAs) [1–6]. Neverthe- less, ADAs to etanercept are absent or are detected at low levels [4,7,8]. Thus, the immunogenicity profiles of biologic agents can vary highly depending on their molecular design. The ADA response, as for all immunoglobulin G (IgG) responses, is a T cell–dependent process and therefore relies on the activa- tion of helper CD4+ T lymphocytes specific to the biological agents. CD4+ T lymphocytes are educated in the thymus, and the dele- tion of autoimmune T cells by self-peptides is one of the main http://dx.doi.org/10.1016/j.jbspin.2016.04.013 1297-319X/© 2016 Published by Elsevier Masson SAS on behalf of Soci ´ et ´ e franc ¸ aise de rhumatologie.