Background: Targeted therapies have failed to provide sustained disease remission in most patients with immune-mediated inflammatory diseases (IMIDs). Combining existing drugs has the potential to overcome this therapeutic ceiling.

Objectives: To analyse longitudinal cohorts of patients showing very opposite response to a given drug to reveal essential insights into the most effective drug combinations for clinical practice.

Methods: As part of the European DocTIS Consortium [1], we conducted RNA-Seq analyses of blood transcriptomes from a longitudinal cohort of 186 patients across six prevalent immune-mediated inflammatory diseases: rheumatoid arthritis, psoriasis, psoriatic arthritis, Crohn’s disease, ulcerative colitis, and systemic lupus erythematosus. Patients were selected based on their extreme clinical responses to therapy. Using a novel systems biology approach to assess the complementarity of targeted drug pairs, we identified likely synergistic combinations for specific IMIDs. Furthermore, single-cell RNA-Seq (scRNA-Seq) data from peripheral blood mononuclear cells (PBMCs) were analyzed to validate the complementarity of these drugs and to elucidate their mechanisms of action.

Results: From a total of 60 drug combinations analyzed, our findings highlight that anti-TNF therapy and anti-IL6R receptor therapy (tocilizumab) are highly complementary for the treatment of RA. This combination was found to mitigate the non-response signature, leading to a signature closer to that of healthy individuals. The observed effects were therapy-specific (non-redundant), and consistent through baseline and follow-up time points, and validated using independent patient data. Analysis of longitudinal scRNA-Seq data from PBMCs corroborated the significant combinatorial effect of the two drugs, and supported the mediation of the effect in a subpopulation of classical monocytes. This cell population was found to be functionally related to inflammatory macrophages in the synovial membrane of RA.

Conclusion: Using a systems biology approach on longitudinal patient data, we have identified anti-TNF and anti-IL6R as a powerful drug combination with which to reach remission in RA. The efficacy of this therapeutic combination will be evaluated in a clinical study.

REFERENCES: [1] www.doctis.eu .

Acknowledgements: IMID Consortium.

Disclosure of Interests: Antonio Julià: None declared, Ernest Choy AbbVie, Amgen, Biocon, Biogen, Chugai, Eli Lilly, Fresenus Kabi, Giled, Janssen, Novartis, Pfizer, Regeneron, Roche, RPharm, Sanofi, Bio-Cancer, Biogen, Novartis, Pfizer, Sanofi, AbbVie, Amgen, Bristol-Myers Squibb, Chugai, Eli Lilly, Fresenus Kabi, Galapagos, Gilead, Novartis, Pfizer, Regeneron, Roche, RPharm, Sanofi, UCB Pharma, María América López Lasanta Abbvie, UCB, Galápagos, Pfizer, Nordic Pharma, Abbvie, UCB, Galápagos, Pfizer, Nordic Pharma, Paloma Vela Casasempere Abbvie, Abbvie, GSK, Lilly, GSK, GSK, Abbvie, Roche, Novartis, Lilly, AstraZeneca, Pfizer, Antonio Fernández Nebro: None declared, Santos Castañeda Bristol-Myers Squibb, Eil Lilly, Merck, Roche, UCB, Merck, Pfizer, UCB, Bristol-Myers Squibb, Eli Lilly, Merck, Roche, Carlos Marras: None declared, Jaime Calvo Alén: None declared, Jesús Tornero Molina: None declared, Juan de Dios Cañete Crespillo: None declared, Eugeni Domènech Some of the following: Abbvie, Adacyte Therapeutics, Biogen, Celtrion, Ferring, Galapagos, Gilead, Goodgut, Janssen, Kern Pharma, Lilly, MSD, Pfizer, Roche, Samsung, Takeda, Tillots, Some of the following: Abbvie, Adacyte Therapeutics, Biogen, Celtrion, Ferring, Galapagos, Gilead, Goodgut, Janssen, Kern Pharma, Lilly, MSD, Pfizer, Roche, Samsung, Takeda, Tillots, Some of the following: Abbvie, Adacyte Therapeutics, Biogen, Celtrion, Ferring, Galapagos, Gilead, Goodgut, Janssen, Kern Pharma, Lilly, MSD, Pfizer, Roche, Samsung, Takeda, Tillots, Javier P. Gisbert: None declared, Jose M Carrascosa: None declared, Eduardo Fonseca: None declared, Luis Bujanda Fernández de Pierola: None declared, Valle García Sánchez: None declared, Britta Siegmund AbbVie, AlfaSigma, BMS, CED Service GmbH, Dr. Falk Pharma, Eli Lilly, MSD, Ferring, Galapagos, Janssen, Pfizer, Takeda, AbbVie, Abivax, Boehringer Ingelheim, Bristol-Myers Squibb, Dr. Falk Pharma, Eli Lilly, Endpoint Health, Galapagos, Gilead, Janssen, Landos, Lilly, Materia Prima, PredictImmune, Pfizer, Takeda, Pfizer, Giampiero Girolomoni AbbVie, Almirall, Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli-Lilly, Leo Pharma, Merck Serono, Novartis, Pfizer, Pierre Fabre, Samsung bioepis and Sanofi, Almirall, Amgen, Bristol-Myers Squibb, Eli-Lilly, Leo Pharma, Merck Serono, Novartis, Pfizer, Samsung bioepis and Sanofi, Pfizer, Holger Heyn Mirxes, Moderna, Nanostring, Omniscope, Singularity, Omniscope, Laura Jimenez: None declared, Pere Santamaría Parvus Therapeutics, Sanofi, Parvus Therapeutics, Edgar Angelats: None declared, Rick Myers: None declared, Yolanda Guillén: None declared, Sergio H. Martínez-Mateu: None declared, Sara Marsal UCB, Novartis, Lilly, Abbvie, MSD, Pfizer, Roche, Sanofi.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.