Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment
- Ntari, Lydia Biomedcode Hellas SA, Vari, Greece
- Nikolaou, Christoforos Institute for Bioinnovation, Biomedical Sciences Research Center Alexander Fleming, Vari, Greece
- Kranidioti, Ksanthi Biomedcode Hellas SA, Vari, Greece
- Papadopoulou, Dimitra Institute for Bioinnovation, Biomedical Sciences Research Center Alexander Fleming, Vari, Greece
- Chouvardas, Panagiotis Department of Medical Oncology, Inselspital, University Hospital and University of Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Meier, Florian Division of Rheumatology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany; Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology TMP, Frankfurt am Main, German
- Geka, Christina Biomedcode Hellas SA, Vari, Greece
- Denis, Maria C Biomedcode Hellas SA, Vari, Greece
- Karagianni, Niki Biomedcode Hellas SA, Vari, Greece
- Kollias, George ORCID Institute for Bioinnovation, Biomedical Sciences Research Center Alexander Fleming, Vari, Greece; Department of Physiology and Joint Rheumatology Program, School of Medicine, National and Kapodistrian University of Athens, Greece
English
Abstract
Background
Medications for Rheumatoid Arthritis (RA) have emerged in the last two decades, including Disease Modifying Antirheumatic Drugs (DMARDs) and biologics. However, there is no known cure, since a significant proportion of patients remain or become non-responders to current therapies. The development of new mode-of-action treatment schemes involving combination therapies could prove successful for the treatment of a greater number of RA patients.
Methods
We investigated the effect of the Tyrosine Kinase inhibitors (TKIs) dasatinib and bosutinib, on the human TNF-dependent Tg197 arthritis mouse model. The inhibitors were administered either as a monotherapy or in combination with a subtherapeutic dose of anti-hTNF biologics and their therapeutic effect was assessed clinically, histopathologically as well as via gene expression analysis and was compared to that of an efficient TNF monotherapy.
Results
Dasatinib and, to a lesser extent, bosutinib inhibited the production of TNF and proinflammatory chemokines from arthritogenic synovial fibroblasts. Dasatinib, but not bosutinib, also ameliorated significantly and in a dose-depended manner both the clinical and histopathological signs of Tg197 arthritis. Combination of dasatinib with a subtherapeutic dose of anti-hTNF biologic agents, resulted in a synergistic inhibitory effect abolishing all arthritis symptoms. Gene expression analysis of whole joint tissue of Tg197 mice revealed that the combination of dasatinib with a low subtherapeutic dose of Infliximab most efficiently restores the pathogenic gene expression profile to that of the healthy state compared to either treatment administered as a monotherapy.
Conclusion
Our findings show that dasatinib exhibits a therapeutic effect in TNF-driven arthritis and can act in synergy with a subtherapeutic anti-hTNF dose to effectively treat the clinical and histopathological signs of the pathology. The combination of dasatinib and anti-hTNF exhibits a distinct mode of action in restoring the arthritogenic gene signature to that of a healthy profile. Potential clinical applications of this combination therapy may provide an interesting alternative to high-dose anti-hTNF monotherapy and increase the number of patients responding to treatment.
Medications for Rheumatoid Arthritis (RA) have emerged in the last two decades, including Disease Modifying Antirheumatic Drugs (DMARDs) and biologics. However, there is no known cure, since a significant proportion of patients remain or become non-responders to current therapies. The development of new mode-of-action treatment schemes involving combination therapies could prove successful for the treatment of a greater number of RA patients.
Methods
We investigated the effect of the Tyrosine Kinase inhibitors (TKIs) dasatinib and bosutinib, on the human TNF-dependent Tg197 arthritis mouse model. The inhibitors were administered either as a monotherapy or in combination with a subtherapeutic dose of anti-hTNF biologics and their therapeutic effect was assessed clinically, histopathologically as well as via gene expression analysis and was compared to that of an efficient TNF monotherapy.
Results
Dasatinib and, to a lesser extent, bosutinib inhibited the production of TNF and proinflammatory chemokines from arthritogenic synovial fibroblasts. Dasatinib, but not bosutinib, also ameliorated significantly and in a dose-depended manner both the clinical and histopathological signs of Tg197 arthritis. Combination of dasatinib with a subtherapeutic dose of anti-hTNF biologic agents, resulted in a synergistic inhibitory effect abolishing all arthritis symptoms. Gene expression analysis of whole joint tissue of Tg197 mice revealed that the combination of dasatinib with a low subtherapeutic dose of Infliximab most efficiently restores the pathogenic gene expression profile to that of the healthy state compared to either treatment administered as a monotherapy.
Conclusion
Our findings show that dasatinib exhibits a therapeutic effect in TNF-driven arthritis and can act in synergy with a subtherapeutic anti-hTNF dose to effectively treat the clinical and histopathological signs of the pathology. The combination of dasatinib and anti-hTNF exhibits a distinct mode of action in restoring the arthritogenic gene signature to that of a healthy profile. Potential clinical applications of this combination therapy may provide an interesting alternative to high-dose anti-hTNF monotherapy and increase the number of patients responding to treatment.
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