title: Towards patient stratification and treatment in the autoimmune disease lupus erythematosus using a systems pharmacology approach.
abstract: Drug development in Systemic Lupus Erythematosus (SLE) has been hindered by poor translation from successful preclinical experiments to clinical efficacy. This lack of success has been attributed to the high heterogeneity of SLE patients and to the lack of understanding of disease physiopathology. Modelling approaches could be useful for supporting the identification of targets, biomarkers and patient subpopulations with differential response to drugs. However, the use of traditional quantitative models based on differential equations is not justifiable in a sparse data situation. Boolean networks models are less demanding on the required data to be implemented and can provide insights into the dynamics of biological networks. This methodology allows the integration of all the available knowledge into a single framework to evaluate the behavior of the system under different conditions and test hypotheses about unknown aspects of the disease. In this proof-of-concept study, we explored the potential of a systems pharmacology model based on Boolean networks to support drug development in SLE. We focused the analysis on the antigen presentation by the antigen presenting cells (APC) to the T-cells to evaluate the scope of this methodology in a medium size network before full implementation of the whole SLE pathway. The heterogeneity of SLE patients was replicated using this methodology simulating subjects with distinct pathway alterations. A perturbation analysis of the network coupled with clustering analysis showed potential to identify drug targets, optimal combinatorial regimens and subpopulations of responders and non-responders to drug treatment. We propose this approach as a first step towards the development of more quantitative platforms to address the current challenges in drug development for complex diseases.
authors.affiliation: Pharmacometrics & Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona 310890, Spain.
authors.forename: M Leire
authors.initials: ML
authors.lastname: Ruiz-Cerdá
authors.affiliation: Pharmacometrics & Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona 310890, Spain.
authors.forename: Itziar
authors.initials: I
authors.lastname: Irurzun-Arana
authors.affiliation: Pharmacometrics & Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona 310890, Spain; Pharmacy and Pharmaceutical Technology Department, University of Valencia, Valencia, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: González-Garcia
authors.affiliation: Clinical Pharmacology and Pharmacometrics, Janssen Research and Development, LLC, Spring House, PA 19477, USA.
authors.forename: Chuanpu
authors.initials: C
authors.lastname: Hu
authors.affiliation: Clinical Pharmacology and Pharmacometrics, Janssen Research and Development, LLC, Spring House, PA 19477, USA.
authors.forename: Honghui
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Janssen Research and Development, a division of Janssen Pharmaceutica NV, Beerse B-2340, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Vermeulen
authors.affiliation: Pharmacometrics & Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona 310890, Spain. Electronic address: itroconiz@unav.es.
authors.forename: Iñaki F
authors.initials: IF
authors.lastname: Trocóniz
authors.affiliation: Pharmacometrics & Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona 310890, Spain. Electronic address: jdgomez@unav.es.
authors.forename: José David
authors.initials: JD
authors.lastname: Gómez-Mantilla
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology; D016000:Cluster Analysis; D003198:Computer Simulation / Q000639:trends; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology; D010601:Pharmacology, Clinical / Q000379:methods* / Q000639:trends; D049490:Systems Biology / Q000379:methods* / Q000639:trends; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents
keywords: Autoimmune diseases; Clustering analysis; Drug combination optimization; Drug target identification; Perturbation analysis