Nintedanib Reduces Fibrosis and Blood Vessel Remodeling in Mice with Systemic Sclerosis, Study Shows

Nintedanib alleviated the core manifestations of systemic sclerosis, resulting in a marked improvement in the disease, a study in mice has shown.

The research, published in the Annals of the Rheumatic Diseases, was titled “Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis.”

Approved for idiopathic pulmonary fibrosis (IPF) treatment, nintedanib (sold as Ofev by Boehringer Ingelheim) may be also useful for the treatment of fibrosis in people with systemic sclerosis or SSc.

Systemic sclerosis has a number of manifestations, including vascular remodeling, pulmonary arterial hypertension (PAH), and progressive scarring of skin and organ tissue. Vascular remodeling refers to changes in blood vessel structure, particular narrowing of arteries. This can lead to increases in hypertension, or higher blood pressure.

While there are drugs for treating SSc’s vascular problems, there are no therapies for treating scarring, also known as fibrosis. Nintedanib may be an effective way to treat the fibrosis in SSc, some researchers believe.

Nintedanib blocks multiple cell pathways that lead to fibrosis, clinical trials have shown. And preclinical-trial studies indicate it can alleviate skin fibrosis.

A Phase 3 clinical trial (NCT02597933) is under way to evaluate nintedanib as a treatment for SSc-associated interstitial lung disease. But no studies have addressed its ability to alleviate the vascular manifestations of SSc.

Researchers decided to study the issue with a mouse model of SSc that exhibits the core manifestations of the disease, including fibrosis and vascular remodeling. They administered nintedanib to the mice, then looked at whether it had alleviated their SSc symptoms.

A key finding was that nintedanib reduced the proliferation of the pulmonary vascular smooth muscle cells (PVSMCs) that line the walls of blood vessels. PVSMC multiplication can lead to narrowing of arteries by thickening vessel walls.

Nintedanib not only prevented vessel walls from thickening but also prevented blocked blood vessels, researchers found.

In addition, nintedanib reduced the death of microvascular endothelial cells, whose destruction contributes to narrowing of arteries.

Another important finding was that nintedanib reduced lung, skin and heart fibrosis in the mice, demonstrating that it can treat scarring.

M2 macrophages are a type of immune cell involved in fibrosis. Nintedanib improves fibrosis by lowering macrophage activity, the study suggested. Appearing to bear this out was the fact that researchers found fewer M2 macrophages in the skin of nintedanib-treated mice than in untreated mice.

“Our data provide preclinical evidence that treatment with nintedanib may not only improve fibrosis of skin, lungs and heart, but also ameliorate vascular manifestations as the other major cause of morbidity [disease] and mortality in SSc,” the researchers wrote.

“We also provide evidence that nintedanib may not only exert its antifibrotic effects” by tempering the activity of inflammation-promoting fibroblast cells but also by tempering macrophage activity, they wrote.