THU0016 EPIGENOMIC ANALYSIS OF RA PATIENTS SHOWS DISTINCT BIOLOGICAL PROCESSES ASSOCIATED WITH ANTI-TNF RESPONSE
Authors: A. Julià, A. Gómez, A. Fernández Nebro, F. J. Blanco, A. Erra, S. Sánchez Fernandez, J. Monfort, M. Alperi-López, I. González-Álvaro, R. Garcia de Vicuna, R. Sanmartí, C. Diaz Torne, C. Marras Fernandez Cid, J. Tornero Molina, N. Palau, R. M. Lastra, J. Lladós, S. Marsal
Journal: Annals of the Rheumatic Diseases (2020)

Background: Blocking Tumor Necrosis Factor (TNF) activity is a successful therapeutic approach for approximately 60% of patients with rheumatoid arthritis (RA). To date, however, the biological basis of the lack of efficacy of anti-TNF agents is unknown. Objectives: The objective of present study was to characterize the biological basis of anti-TNF lack of efficacy in RA using an epigenomic data approach in two steps: first, to assess the differential methylation changes between responders and non-responders and second, to use this differential methylation profile in a systems biology approach to infer differential methylated biological modules according to anti-TNF response. Methods: A total of n=68 patients diagnosed with RA according to the ACR-EULAR criteria belonging to 16 Hospitals across Spain were recruited. All patients were &gt;18 years old, with more than 6 months of disease evolution and a baseline disease activity of DAS28 &gt; 3.2. Treatment response was defined according to the EULAR criteria at week 12. Good and moderate responders were aggregated into a single responder group. Genomic DNA was collected at baseline and the methylation profile was assessed using the Illumina Infinium EPIC array, which interrogates 850,000 methylation CpG sites across the genome. Differential Methylation analysis, biological pathway association and the systems Biology approach using Protein-Protein Interaction Networks, were conducted using the R statistical language and the Bioconductor libraries. Results: From 68 anti-TNF treated patients, n=27 (39.7%) were good responders, n=26 (38.2%) moderate responders and n=15 (22.05%) non-responders at week 12 of treatment. Differential methylation analysis identified two distinctive biological profiles associated with the clinical response: responders were associated to interleukin and cytokine production, and non-responders were associated with biological pathways associated to TGF-Beta production and T cell regulation. Using these differentially methylated profiles, epigenetic modules with differentially methylated hotspots between responders and non-responders were also found. Two epigenetic modules with significant enrichment in inflammatory and interleukin production and immune regulatory processes were validated in an independent patient cohort. Conclusion: The epigenetic analysis of whole blood from RA patients using a module-based approach shows reproducible biological mechanisms associated with the response to anti-TNF therapy. Acknowledgments: We would like to thank the clinical researchers and patients participating in the IMID Consortium for their collaboration Disclosure of Interests: Antonio Julià: None declared, Antonio Gómez: None declared, Antonio Fernández Nebro: None declared, Francisco J. Blanco Grant/research support from: Sanofi-Aventis, Lilly, Bristol MS, Amgen, Pfizer, Abbvie, TRB Chemedica International, Glaxo SmithKline, Archigen Biotech Limited, Novartis, Nichi-iko pharmaceutical Co, Genentech, Jannsen Research &amp; Development, UCB Biopharma, Centrexion Theurapeutics, Celgene, Roche, Regeneron Pharmaceuticals Inc, Biohope, Corbus Pharmaceutical, Tedec Meiji Pharma, Kiniksa Pharmaceuticals, Ltd, Gilead Sciences Inc, Consultant of: Lilly, Bristol MS, Pfizer, Alba Erra: None declared, Simon Sánchez Fernandez: None declared, Jordi Monfort: None declared, Mercedes Alperi-López: None declared, Isidoro González-Álvaro Grant/research support from: Roche Laboratories, Consultant of: Lilly, Sanofi, Paid instructor for: Lilly, Speakers bureau: Abbvie, MSD, Roche, Lilly, Rosario Garcia de Vicuna Grant/research support from: BMS, Lilly, MSD, Novartis, Roche, Consultant of: Abbvie, Biogen, BMS, Celltrion, Gebro, Lilly, Mylan, Pfizer, Sandoz, Sanofi, Paid instructor for: Lilly, Speakers bureau: BMS, Lilly, Pfizer, Sandoz, Sanofi, Raimón Sanmartí Speakers bureau: Abbvie, Eli Lilly, BMS, Roche and Pfizer, Cesar Diaz Torne: None declared, Carlos Marras Fernandez Cid: None declared, Jesús Tornero Molina: None declared, Núria Palau: None declared, Raquel M Lastra: None declared, Jordi Lladós: None declared, Sara Marsal: None declared