Nintedanib reduces pulmonary fibrosis in a model of rheumatoid arthritis-associated interstitial lung disease

Abstract

Rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD) develops in ~20% of patients with RA. SKG mice, which are genetically prone to development of autoimmune arthritis, develop a pulmonary interstitial pneumonia that resembles human cellular and fibrotic nonspecific interstitial pneumonia. Nintedanib, a tyrosine kinase inhibitor approved for treatment of idiopathic pulmonary fibrosis, has been shown to reduce the decline in lung function. Therefore, we investigated the effect of nintedanib on development of pulmonary fibrosis and joint disease in female SKG mice with arthritis induced by intraperitoneal injection of zymosan (5 mg). Nintedanib (60 mg·kg·day via oral gavage) was started 5 or 10 wk after injection of zymosan. Arthritis and lung fibrosis outcome measures were assessed after 6 wk of treatment with nintedanib. A significant reduction in lung collagen levels, determined by measuring hydroxyproline levels and staining for collagen, was observed after 6 wk in nintedanib-treated mice with established arthritis and lung disease. Early intervention with nintedanib significantly reduced development of arthritis based on joint assessment and high-resolution μ-CT. This study impacts the RA and ILD fields by facilitating identification of a therapeutic treatment that may improve both diseases. As this model replicates the characteristics of RA-ILD, the results may be translatable to the human disease.

Treatment of Rheumatoid Arthritis-Associated Interstitial Lung Disease: Lights and Shadows

“…Nintedanib is approved for the treatment of IPF, it has been shown to slow down the decrease in FVC and to reduce the number of AE [189]. In vitro, nintedanib demonstrated its efficacy in reducing both pulmonary fibrosis and joint disease in female SKG mice with RA [192].…”

Nintedanib in patients with systemic sclerosis-associated interstitial lung disease: A Japanese population analysis of the SENSCIS trial

“…SSc-ILD is considered to share similar pathophysiology with idiopathic pulmonary fibrosis (IPF) in terms of the underlying fibrotic cascade [14], but the clinical course and pathologic findings differ [15]. Nintedanib is a tyrosine kinase inhibitor that has demonstrated anti-fibrotic, antiinflammatory, and vascular remodelling effects in several animal models resembling aspects of SSc, SSc-ILD, and other fibrosing ILDs [16][17][18][19][20][21][22], suggesting that nintedanib modulates processes fundamental to the progression of fibrosis. Nintedanib has been shown to reduce the rate of decline in FVC in patients with IPF and SSc-ILD [23,24], and has been approved for treatment of patients with IPF in more than 65 countries and to slow the rate of decline in pulmonary function in patients with SSc-ILD in the United States and for treatment of SSc-ILD in Japan [25].…”

Progressive fibrosing interstitial lung disease associated with systemic autoimmune diseases

“…The mechanism of action of pirfenidone remains unclear, but it has been shown to reduce the proliferation of fibroblasts and myofibroblasts and to inhibit ECM synthesis and deposition [84,85]. Nintedanib has demonstrated anti-fibrotic, anti-inflammatory, and vascular remodelling effects in several animal models resembling aspects of fibrosing ILDs [72,[86][87][88][89][90][91][92][93]. In Fra2 mice, a model of the fibrotic and vascular manifestations of SSc, nintedanib reduced hydroxyproline levels and myofibroblast counts in the lung, as well as reducing the thickening of the walls of pulmonary arteries [90].…”

“…In Fra2 mice, a model of the fibrotic and vascular manifestations of SSc, nintedanib reduced hydroxyproline levels and myofibroblast counts in the lung, as well as reducing the thickening of the walls of pulmonary arteries [90]. In transgenic SKG mice, a model resembling aspects of RA-ILD, nintedanib reduced hydroxyproline levels and α-smooth muscle actin staining in the lungs [93].…”