Abstract
BackgroundNew medications for Rheumatoid Arthritis (RA) have emerged in the last 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.MethodsWe 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.ResultsDasatinib 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-dependent 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.ConclusionOur 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 combination therapies with kinase inhibitors and anti-TNF agents may provide an interesting alternative to high-dose anti-hTNF monotherapy and increase the number of patients responding to treatment.
Highlights
New medications for Rheumatoid Arthritis (RA) have emerged in the last decades, including Disease Modifying Antirheumatic Drugs (DMARDs) and biologics
Dasatinib suppresses the arthritogenic phenotype of Tg197‐derived SFs more efficiently than bosutinib We investigated the effect of dasatinib and bosutinib on synovial fibroblasts, the key cellular orchestrators of both human [22, 23] and Tg197
Dasatinib, and, to a lesser degree, bosutinib greatly reduced the levels of CCL5 and CCL20, two chemokines that have been associated with synovial activation [26, 27], reaching levels of inhibition similar to the ones observed with Infliximab treatment (Fig. 1b, c)
Summary
New medications for Rheumatoid Arthritis (RA) have emerged in the last decades, including Disease Modifying Antirheumatic Drugs (DMARDs) and biologics. Despite the therapeutic potential of such medications a subset of RA patients may not tolerate or may be resistant to certain treatments, while the issue of treatment-related side effects, including the higher risk of infections due to immunosuppression, remain important complications [4]. To address such issues, combination therapies have become an attractive therapeutic approach, as combining drugs targeting different pathogenic pathways has shown improved effectiveness compared to monotherapies [5]
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