Global Molecular Effects of Tocilizumab Therapy in Synovial Biopsies of Early Rheumatoid Arthritis Patients

Ducreux, Julie [UCL] Nzeusseu Toukap, Adrien [UCL] Galant, Christine [UCL] Houssiau, Frédéric [UCL] Durez, Patrick [UCL] Lauwerys, Bernard [UCL]

(eng) Background/Purpose: Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disease that is characterized by the presence of inflammatory cytokines, including interleukin-6 (IL-6). Here, we investigated the global molecular effects of Tocilizumab, an approved humanized anti-IL6 Receptor antibody, versus Methotrexate therapy, in synovial biopsy samples collected prospectively in early RA before and 12 weeks after administration of the drug. The results were compared with our previous data, generated in prospective cohorts of Adalimumab- and Rituximab-treated (Methotrexate- and anti-TNF-resistant, respectively) RA patients. Methods: Paired synovial biopsy samples were obtained from the affected knee of early RA patients before and 12 weeks after initiation of Tocilizumab (n=12) or Methotrexate (n=8) therapy. SDAI remission criteria were computed prospectively before, 3 months and 6 months after administration of the drugs and patients’ responses were defined according to their SDAI remission status at 6 months. Gene expression studies were performed using GeneChip Human Genome U133 Plus 2.0 arrays. Quantitative real-time reverse transcriptase-polymerase chain reaction (qPCR) experiments were performed to confirm the differential expression of selected transcripts. Results: We found that Tocilizumab induces a significant down-regulation of genes included in specific pathways: cytokines & chemokines (e.g. IL-6, IL-7, IL-22, CCL8, CCL11, CCL13, CCL19, CCL20), and T cell activation. By contrast, Tocilizumab induces a significant up-regulation of genes associated with healing processes. These effects are significantly more pronounced as compared to Methotrexate, Rituximab, or Adalimumab therapies. By opposition to the effects of Adalimumab, Tocilizumab therapy does not induce a decreased expression of genes involved in cell proliferation. Real-time qPCR experiments confirmed the differential expression of several transcripts belonging to these pathways. Gene expression studies further identified genes differentially expressed at baseline according to SDAI remission status at 6 months. In Methotrexate-treated patients, genes involved in myeloid cell function predict remission, whereas the presence of a mesenchymal cell development signature predicts absence of remission. By opposition, in Tocilizumab-treated patients, genes involved in myeloid cell differentiation predict absence of remission, whereas genes involved in ras-dependent cell proliferation predict remission at 6 months. Conclusion: Tocilizumab displays distinct molecular effects on synovial biopsies of RA patients. These results open perspectives for the individualization of therapeutic decisions, based on the identification of specific molecular profiles in individual patients.