Session Type: Poster Session (Monday)
Session Time: 9:00AM-11:00AM
Background/Purpose: Interstitial lung disease (ILD) is a key driver of mortality in patients with systemic sclerosis (SSc). In lack of approved treatment it constitutes a high unmet medical need. Nintedanib is approved for the treatment of idiopathic pulmonary fibrosis. A recently completed Phase III clinical trial including patients with SSc-ILD (SENSCIS®) showed that nintedanib slows the loss of pulmonary function by 44% in patients with SSc-ILD relative to placebo, as measured by annual rate of decline in FVC over 52 weeks. Mycophenolate mofetil (MMF), an immunosuppressant acting on T and B lymphocytes is used in the clinical practice to treat patients with SSc.
Aim: To compare the activity of nintedanib and MMF in transgenic (tg) FRA2 mice a model of SSc-ILD
Methods: FRA2 mice at an age of 9 weeks were treated with MMF at 100 or 150 mg/kg qd or nintedanib 50 mg/kg bid and were sacrificed at an age of 16 weeks. Histological changes of pulmonary fibrosis were quantified by Ashcroft Scoring. In addition, whole lung sections were stained with Sirius Red and fibrotic area was determined using ImageJ. The amount of collagen protein in skin samples was determined via hydroxyproline assay. The degree of luminal occlusion of pulmonary arteries was examined histologically. The percentage of proliferating vascular smooth muscle cells was evaluated by triple staining for DAPI (nuclear staining), Ki67 (proliferation marker) and SM22. The percentage of apoptotic endothelial cells in the skin of mice was determined by double staining for CD31 (endothelial cells) and caspase 3 (apoptosis).
Results: Nintedanib effectively ameliorated pulmonary fibrosis in FRA2 tg mice and reduced the fibrotic area, the Ashcroft scores and the hydroxyproline content as compared to vehicle-treated FRA2 tg mice. In contrast, treatment of FRA2 tg mice with MMF at doses of 100 mg/kg or 150 mg/kg qd had only mild antifibrotic effects that did not yield statistically significant effects across the three different outcomes.
Treatment with nintedanib also ameliorated remodeling of the pulmonary arteries and significantly reduced the number of occluded pulmonary vessels, the number of proliferating vascular smooth muscle cells and the number of apoptotic endothelial cells. No effect on the remodeling of pulmonary arteries was observed with MMF.
Conclusion: In the FRA2 mouse model of SSc-ILD nintedanib ameliorates pulmonary fibrosis, proliferation of pulmonary vascular smooth muscle cells and apoptosis of microvascular endothelial cells. In contrast, MMF has minor effects on pulmonary fibrosis and no effects on vascular manifestations.
To cite this abstract in AMA style:Trin-Minh T, Zhang Y, Distler J, Wollin L. The Effect of Nintedanib versus Mycopheolate Mofetil in the FRA2 Mouse Model of Systemic Sclerosis Associated Interstitial Lung Disease [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/the-effect-of-nintedanib-versus-mycopheolate-mofetil-in-the-fra2-mouse-model-of-systemic-sclerosis-associated-interstitial-lung-disease/. Accessed December 4, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-effect-of-nintedanib-versus-mycopheolate-mofetil-in-the-fra2-mouse-model-of-systemic-sclerosis-associated-interstitial-lung-disease/