The tyrosine kinase inhibitor imatinib mesylate suppresses uric acid crystal-induced acute gouty arthritis in mice.

Laurent L Reber,William H Robinson,Philipp Starkl,Jeremy Sokolove,Stephen J Galli,Riccardo Sibilano,Steven Sensarn,Dongmin Kang,Christopher H Contag,Harini Raghu,Stephan Rogalla,Nicolas Gaudenzio,Bianca Balbino,Mindy Tsai

doi:10.1371/journal.pone.0185704

Abstract

Gouty arthritis is caused by the deposition of monosodium urate (MSU) crystals in joints. Despite many treatment options for gout, there is a substantial need for alternative treatments for patients unresponsive to current therapies. Tyrosine kinase inhibitors have demonstrated therapeutic benefit in experimental models of antibody-dependent arthritis and in rheumatoid arthritis in humans, but to date, the potential effects of such inhibitors on gouty arthritis has not been evaluated. Here we demonstrate that treatment with the tyrosine kinase inhibitor imatinib mesylate (imatinib) can suppress inflammation induced by injection of MSU crystals into subcutaneous air pouches or into the ankle joint of wild type mice. Moreover, imatinib treatment also largely abolished the lower levels of inflammation which developed in IL-1R1-/- or KitW-sh/W-sh mice, indicating that this drug can inhibit IL-1-independent pathways, as well as mast cell-independent pathways, contributing to pathology in this model. Imatinib treatment not only prevented ankle swelling and synovial inflammation when administered before MSU crystals but also diminished these features when administrated after the injection of MSU crystals, a therapeutic protocol more closely mimicking the clinical situation in which treatment occurs after the development of an acute gout flare. Finally, we also assessed the efficiency of local intra-articular injections of imatinib-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles in this model of acute gout. Treatment with low doses of this long-acting imatinib:PLGA formulation was able to reduce ankle swelling in a therapeutic protocol. Altogether, these results raise the possibility that tyrosine kinase inhibitors might have utility in the treatment of acute gout in humans.

Highlights

Acute attacks of gout are initiated by the deposition of uric acid and generation of monosodium urate (MSU) crystals in joints
We show that the tyrosine kinase inhibitor imatinib mesylate can suppress ankle swelling and synovial inflammation in a mouse model of MSU crystal-induced acute arthritis
We demonstrated that the tyrosine kinase inhibitor imatinib can suppress MSU crystal-induced inflammation in an air-pouch model and in a model of acute gout

Summary

Introduction

Acute attacks of gout are initiated by the deposition of uric acid and generation of monosodium urate (MSU) crystals in joints. Despite many treatment options for gout, including urate lowering therapy, chronic refractory gout remains a challenging problem, especially in patients with polyarticular and/or tophaceous disease, and can result in functional impairment, joint destruction, and reduced quality of life [2]. Though IL-1 blockade has demonstrated significant utility in prevention of gout flares [3] and in amelioration of symptoms among patients suffering from chronic refractory gout [4], there is still a sizable minority of patients who remain refractory and/or experience breakthrough of gouty inflammation despite these powerful targeted therapies. The FDA declined approval of the anti-IL-1 agent canakinumab, citing safety concerns as well as unconvincing evidence of the agent’s ability to reduce the frequency of gout flares. The FDA panel did agree that there is a serious need for alternative treatment for those patients unresponsive to current therapies [5]

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