Background: Targeted therapies have revolutionized the management of immune-mediated inflammatory diseases (IMIDs), however, there is a substantial number of patients who respond poorly to a given drug. There is a big need to understand the factors that are associated with this heterogeneity.

Objectives: The DoCTIS project [1] aims to characterize molecular variation both at the disease and drug-response levels across six different IMIDs.

Methods: We applied single cell RNA sequencing to 360 samples from 176 patients from six prevalent IMIDs -psoriasis, psoriatic arthritis, Crohn’s Disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus- treated with five different drugs targeting TNF, IL12p40, IL6R, BLySS, IL17 and JAK pathways. All patients were analyzed at two time points including baseline and at the week of clinical response creating an immune landscape of more than two million peripheral immune cells.

Results: We found large inter-disease differences both at the compositional and genetic regulatory programs. ScRNA-Seq analysis revealed large differences at the systemic level between the six IMIDs. We found expected findings, like the predominant interferon response signature affecting multiple cell types in SLE, but also novel findings like strong regulatory differences between diseases with a shared genetic risk like Psoriatic Arthritis and Psoriasis. The impact of each drug was found to be largely disease-specific. Furthermore, we found multiple regulatory features associated with the effect of each drug as well the association to response.

Conclusion: The scRNA-Seq atlas developed in DoCTIS provides a unique resource for the understanding of drug response and disease heterogeneity across immune-mediated inflammatory diseases.

REFERENCES: [1] Decision on Optimal Combinatorial Therapies in IMIDS using Systems Approaches (DoCTIS). https://doctis.eu/

Acknowledgements: IMID Consortium.

Disclosure of Interests: Antonio Julià: None declared, Yolanda Guillén: None declared, Juan Angel Patiño Galindo: None declared, Sergio H. Martínez-Mateu: None declared, Paloma Vela Casasempere: None declared, Antonio Fernández Nebro: None declared, Carlos Marras: None declared, Santos Castañeda Bristol-Myers Squibb, Eli Lilly, Bristol-Myers Squibb, Eli Lilly, Jaime Calvo Alén: None declared, Jesús Tornero Molina: None declared, Juan de Dios Cañete Crespillo: None declared, Eugeni Domènech: None declared, 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, and Takeda, AbbVie, Abivax, Boehringer Ingelheim, Bristol Myers Squibb, Dr. Falk Pharma, Eli Lilly, Endpoint Health, Falk, Galapagos, Gilead, Janssen, Landos, Lilly, Materia Prima, PredictImmune, Pfizer, and 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, Parvus Therapeutics, Sanofi, Parvus Therapeutics, Edgar Angelats: None declared, Rick Myers: None declared, Ernest Choy AbbVie, Amgen, Biocon, Biogen, Chugai, Eli Lilly, Fresenus Kabi, Gilead, Janssen, Novartis, Pfizer, Regeneron, Roche, RPharm, and Sanofi, Bio-Cancer, Biogen, Novartis, PFizer, and Sanofi, AbbVie, Amgen, Bristol-Myers Squibb, Chugai, Eli Lilly, Fresenus Kabi, Galapagos, Gilead, Novartis, Pfizer, Regeneron, Roche, RPharm, Sanofi, and UCB Pharma, Sara Marsal UCB, Novartis, Eli Lilly, Abbvie, MSD, Pfizer, Roche, and 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.