Uncovering combination therapies for Immune-Mediated Inflammatory Diseases through systems biology analysis on longitudinal patient data 3497
Abstract Description Despite advancements in targeted therapies, most patients with immune-mediated inflammatory diseases (IMIDs) fail to achieve sustained remission. Combining existing drugs has the potential to overcome this. We performed bulk and scRNA-Seq analyses of longitudinal blood samples of patients from six IMIDs including rheumatoid arthritis, psoriasis, psoriatic arthritis, Crohn’s disease, ulcerative colitis, and systemic lupus erythematosus. A total of 186 patients were analyzed at the initiation of a targeted therapy and at the time of clinical response. Using a novel systems biology approach, we determined drug pairs with the highest likelihood of synergy. scRNA-Seq data on 2.1 million PBMCs validated the top drug combinations. Our analysis identified anti-TNF and anti-IL6R therapies as highly complementary for RA. This combination mitigated non-responder molecular signatures, generated transcriptional profiles resembling those of healthy individuals, and demonstrated specificity and non-redundancy. The complementarity was validated using independent data. Longitudinal scRNA-Seq analysis of PBMCs corroborated the combinatorial effect, identifying a population of monocytes as key mediators of efficacy. Through systems biology analysis of patient data, we have found that the combination of anti-TNF and anti-IL6R therapies shows significant potential to overcome the current therapeutic ceiling in RA. The drug combination is currently under evaluation in a clinical study. Funding Sources This work was supported by the DocTIS2 project, funded by the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement N° 848028 Topic Categories Computational and Systems Immunology (COMP)
Authors
- Richard H. Myers (ORCID: https://orcid.org/0000-0002-8365-2674)
- Juan D. Cañete (ORCID: https://orcid.org/0000-0003-2606-0573)
- Santos Castañeda (ORCID: https://orcid.org/0000-0002-7748-853X)
- Javier P. Gisbert (ORCID: https://orcid.org/0000-0003-2090-3445)
- Giampiero Girolomoni (ORCID: https://orcid.org/0000-0001-8548-0493)
- Pere Santamaría (ORCID: https://orcid.org/0000-0003-3469-1586)
- Britta Siegmund (ORCID: https://orcid.org/0000-0002-0055-958X)
- Antonio Fernández‐Nebro (ORCID: https://orcid.org/0000-0002-2962-9844)
- Sara Marsal (ORCID: https://orcid.org/0000-0001-5515-3854)
- Sergio H. Martínez-Mateu (ORCID: https://orcid.org/0000-0002-6656-3231)
- Yolanda Guillén (ORCID: https://orcid.org/0000-0001-8673-6470)
- Jaime Calvo‐Alén (ORCID: https://orcid.org/0000-0001-9378-8412)
- María López‐Lasanta (ORCID: https://orcid.org/0000-0002-8462-8406)
- E. J. S. Fonseca (ORCID: https://orcid.org/0000-0001-5975-2467)
- Carlos Marras (ORCID: https://orcid.org/0000-0002-7791-9889)
- Paloma Vela (ORCID: https://orcid.org/0000-0001-8566-5172)
- J.M. Carrascosa (ORCID: https://orcid.org/0000-0003-4266-0771)
- Eugeni Domènech (ORCID: https://orcid.org/0000-0002-2315-7196)
- Holger Heyn (ORCID: https://orcid.org/0000-0002-3276-1889)
- Ernest Choy (ORCID: https://orcid.org/0000-0003-4459-8609)
- Luís Bujanda (ORCID: https://orcid.org/0000-0002-4353-9968)
- Valle García
- Jesús Tornero
- Antonio Juli
Institutions
- University of Verona (IT)
- Hebron University (PS)
- United Nations Industrial Development Organization (AT)
- Hospital Universitario de Guadalajara (ES)
- Hospital Universitario Rey Juan Carlos (ES)
- Vall d'Hebron Institut de Recerca (ES)
- Hospital Universitario Araba (ES)
- National Institute of Genomic Medicine (MX)
- Hospital Universitario Reina Sofía (ES)
- Hospital Universitario de La Princesa (ES)
- Hospital General Universitario de Alicante Doctor Balmis (ES)
- Donostiako Unibertsitate Ospitalea (ES)
- Complexo Hospitalario Universitario A Coruña (ES)
- HudsonAlpha Institute for Biotechnology (US)
- Hospital Universitario Virgen de la Arrixaca (ES)
- Center for Genomic Science (IT)
- Hospital Universitari Germans Trias i Pujol (ES)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Charité - Universitätsmedizin Berlin (DE)
- Cardiff University (GB)
Publication Details
- Journal
- The Journal of Immunology
- Published
- 2025-11-01
- DOI
- https://doi.org/10.1093/jimmun/vkaf283.1293
- Primary Topic
- Rheumatoid Arthritis Research and Therapies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Commission