ARTHRITIS & RHEUMATOLOGY Vol. 66, No. 1, January 2014, pp 15–23 DOI 10.1002/art.38202 © 2014, American College of Rheumatology Global Molecular Effects of Tocilizumab Therapy in Rheumatoid Arthritis Synovium Julie Ducreux, 1 Patrick Durez, 2 Christine Galant, 2 Adrien Nzeusseu Toukap, 2 Benoı ˆt Van den Eynde, 3 Fre ´de ´ric A. Houssiau, 2 and Bernard R. Lauwerys 2 Objective. To investigate the global molecular effects of tocilizumab (TCZ) in comparison with meth- otrexate (MTX) treatment in synovial biopsy tissue obtained from patients with previously untreated rheu- matoid arthritis (RA) before therapy (T0) and 12 weeks after the initiation of therapy (T12), and to compare the results with previous gene expression data obtained in synovial biopsy tissue from adalimumab (ADA)– and rituximab (RTX)–treated patients with RA. Methods. Paired synovial biopsy samples were obtained at T0 and T12 from the affected knee of TCZ-treated RA patients and MTX-treated RA patients. Gene expression studies were performed using GeneChip Human Genome U133 Plus 2.0 microarrays, and confirmatory quantitative real-time reverse transcription–polymerase chain reaction experiments were performed on selected transcripts. The effects of TCZ and MTX on synovial cell populations and histo- logic characteristics were assessed by immunohisto- chemistry. Results. Gene expression studies showed that blockade of the interleukin-6 receptor (IL-6R) gene (IL6R) using TCZ induced a significant decrease in the expression of numerous chemokine and T cell activation genes in the RA synovium. These effects strongly corre- lated with the molecular effects of MTX and RTX therapy on RA synovial tissue, but differed from the molecular changes induced by ADA (decreased expres- sion of genes involved in cell proliferation). Conclusion. The molecular similarities between the effects of TCZ, RTX, and MTX therapies in the RA synovium indicate that B cell– and IL-6–dependent pathways play synergistic roles in the pathogenesis of the disease, in particular through activation of T cell responses. Moreover, these results open perspectives for the individualization of therapeutic decisions, based on a better knowledge of the synovial molecular effects of each type of RA therapy. Tocilizumab (TCZ) is a humanized anti–IL-6 receptor (anti–IL-6R) monoclonal antibody that inhibits all IL-6R– and soluble IL-6R (sIL-6R)–mediated sig- nals. TCZ, either as monotherapy or in combination with methotrexate (MTX), is labeled for the treatment of RA patients who have an insufficient response to MTX or other disease-modifying antirheumatic drugs (DMARDs) (1–3). In this study, we investigated the global molecular effects of TCZ therapy in synovial biopsy samples col- lected prospectively from DMARD-naive RA patients at baseline (T0) and 12 weeks after the initiation of TCZ therapy (T12). In parallel, synovial biopsy samples were harvested from DMARD-naive RA patients before and 12 weeks after the initiation of MTX therapy. We previously identified specific molecular pathways that were associated with response to treatment with adali- mumab (ADA) and rituximab (RTX) in RA patients (4,5). In the present study, we sought to determine whether the molecular changes induced in the synovium by treatment with TCZ might overlap with the molecular effects of these other treatments. We found that TCZ significantly down-regulated numerous chemokine genes and genes involved in T cell activation, and Supported by a grant from Roche Belgium. Dr. Ducreux’s work was supported in part by a UCB/Universite ´ catholique de Louvain Chaire sur les Rhumatismes Syste ´miques Fellowship. 1 Julie Ducreux, PhD: Universite ´ Catholique de Louvain, Brussels, Belgium; 2 Patrick Durez, MD, Christine Galant, MD, PhD, Adrien Nzeusseu Toukap, MD, Fre ´de ´ric A. Houssiau, MD, PhD, Bernard R. Lauwerys, MD, PhD: Universite ´ Catholique de Louvain and Cliniques Universitaires Saint-Luc, Brussels, Belgium; 3 Benoı ˆt Van den Eynde, MD, PhD: Ludwig Institute for Cancer Research and de Duve Institute, Brussels, Belgium. Address correspondence to Julie Ducreux, PhD, Po ˆle de Pathologies Rhumatismales, Institut de Recherches Expe ´rimentales et Cliniques, Avenue Hippocrate 10, Bte B2.5390, 1200 Brussels, Bel- gium. E-mail: Julie.Ducreux@uclouvain.be. Submitted for publication May 7, 2013; accepted in revised form September 17, 2013. 15