Date: Monday, November 9, 2015
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Systemic sclerosis (SSc) is characterised by fibrosis and vascular alterations, both of which account for the high morbidity and mortality of SSc. Although several therapies are in clinical use for the treatment of vascular manifestations, no targeted therapies are yet approved for the treatment of fibrosis.
Stimulators of the soluble guanylate cyclase (sGC) have recently been shown to inhibit transforming growth factor-β signaling. Here, we aimed to demonstrate that Riociguat, the drug candidate for clinical trials in systemic sclerosis (SSc), is effective in experimental fibrosis and to compare its efficacy to that of phosphodiesterase V inhibitors that also increase the intracellular levels of cyclic guanosine monophosphate (cGMP).
The antifibrotic effects of Riociguat and Sildenafil were compared in the tight-skin 1 model, in bleomycin-induced fibrosis and in a model of sclerodermatous chronic graft-versus-host-disease (cGvHD). Doses of 0.1 – 3 mg/kg twice a day for Riociguat and of 3 – 10 mg/kg twice a day for Sildenafil were used. In addition to the antifibrotic effects, the effects on cardiovascular parameters were measured in conscious mice implanted with telemetry devices.
Riociguat dose-dependently reduced skin thickening, myofibroblast differentiation and accumulation of collagen with potent antifibrotic effects at 1 and 3 mg/kg. Riociguat also ameliorated fibrosis of the gastrointestinal tract in the cGvHD model. The antifibrotic effects were associated with reduced phosphorylation of extracellular signal-regulated kinases and effects on cardiovascular parameters. Sildenafil at doses of 3 and 10 mg/kg exerted mild antifibrotic effects that were significantly less pronounced compared with 1 and 3 mg/kg Riociguat.
These data demonstrated potent antifibrotic effects of Riociguat on experimental skin and organ fibrosis. These findings suggest a role for Riociguat for the treatment of fibrotic diseases, especially for the treatment of SSc. A phase II study with Riociguat in patients with diffuse cutaneous systemic sclerosis (dcSSc) is ongoing.
To cite this abstract in AMA style:Sandner P, Dees C, Distler JHW, Beyer C, Distler A, Zhang Y, Palumbo-Zerr K, Schett GA, Soare A, Distler O, Haasbach E. Stimulators of Soluble Guanylate Cyclase (sGC) Inhibit Experimental Skin Fibrosis of Different Aetiologies [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/stimulators-of-soluble-guanylate-cyclase-sgc-inhibit-experimental-skin-fibrosis-of-different-aetiologies/. Accessed March 3, 2021.
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