Background Current drugs for rheumatoid arthritis, including the conventional disease-modifying antirheumatic drugs (e.g. methotrexate) and the more recent biologic agents (e.g. TNF inhibitors), have several drawbacks, such as limited clinical efficacy and side effects. In this context, small molecule inhibitors of protein kinases are emerging since they can suppress multiple intracellular signals simultaneously with important roles in the functioning of the immune system. Recent inhibitors of the tyrosine kinases JAK and SYK have demonstrated clinical efficacy in immune disorders.
Objectives We compared the efficacy and safety of inhibiting JAK and SYK individually versus simultaneously, and with the corticosteroid prednisolone and the anti-TNF drug etanercept. We are currently investigating the effect of these small molecules on relevant pathogenic cells.
Methods We used a well-established murine model of chronic (non self-remitting) and destructive arthritis induced by G6PI and both preventive and curative protocols, in which treatment either started the day of immunization or when the disease was submaximal, were assayed. Mice were treated with a selective pan-JAK inhibitor (tofacitinib), a selective SYK inhibitor (PRT2607) or a combination of both, and clinical, immunoinflammatory and histopathological responses were evaluated and compared to prednisolone and etanercept. Moreover, immunotoxicity was evaluated in mice treated for a month under the G6PI arthritis model and TDAR test, as well as in standard in vitro toxicity assays.
Results Dual JAK/SYK inhibition was able to completely prevent the development of arthritis. In a curative protocol, dual inhibition ameliorated up to 90% clinical score, over 90% joint inflammation and 75-85% bone/cartilage erosion, as well as diminished over 90% RANKL and Th1/Th17 cytokine expression. In contrast, single inhibition of JAK or SYK, or treatment with etanercept or prednisolone were less effective, i.e. decreased clinical score by 58, 19, 28 and up to 70%, respectively. Interestingly, dual inhibition was fast-acting, led to disease remission in half of the animals and, in some cases, treatment withdrawal was accompanied by long-lasting amelioration. While daily dual treatment decreased lymphoid organ cellularity and T/B cell counts, these levels were never below those in naïve or prednisolone-treated mice. Red blood cell counts were intact. Dual inhibition decreased regulatory T and NK cell counts to the same extent as single JAK inhibition, without compromising cytotoxic activity. Preliminary work suggests that dual inhibition reduces the inflammatory cytokine cascade and the function of joint cells, such as the activity of osteoclasts to degrade bone.
Conclusions Concurrent JAK and SYK inhibition results in higher efficacy than single kinase inhibition in preventing and treating chronic and severe arthritis without additional immunotoxicity. Thus, therapeutic approaches that block multiple immune signals, such as dual JAK/SYK inhibition, represent a reasonable therapeutic strategy for rheumatoid arthritis, in particular in patients with inadequate response to current treatments. Our data supports the multiplicity of events leading to this heterogeneous and complex disease.
Disclosure of Interest None declared
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