Khanna, Dinesh; Kramer, Frank; Höfler, Josef; Ghadessi, Mercedeh; Sandner, Peter; Allanore, Yannick; Denton, Christopher P; ... Distler, Oliver; + view all Khanna, Dinesh; Kramer, Frank; Höfler, Josef; Ghadessi, Mercedeh; Sandner, Peter; Allanore, Yannick; Denton, Christopher P; Kuwana, Masataka; Matucci-Cerinic, Marco; Pope, Janet E; Atsumi, Tatsuya; Bečvář, Radim; Czirják, László; De Langhe, Ellen; Hachulla, Eric; Ishii, Tomonori; Ishikawa, Osamu; Johnson, Sindhu R; Riccieri, Valeria; Schiopu, Elena; Silver, Richard M; Smith, Vanessa; Stagnaro, Chiara; Steen, Virginia; Stevens, Wendy; Szücs, Gabriella; Truchetet, Marie-Elise; Wosnitza, Melanie; Distler, Oliver; - view fewer (2024) Biomarker analysis from the phase 2b randomized placebo-controlled trial of riociguat in early diffuse cutaneous systemic sclerosis. Rheumatology 10.1093/rheumatology/keae150. (In press).

Text BA25482 RISE SSc Biomarkers_accepted for UCL upload.pdf - Accepted Version Access restricted to UCL open access staff until 10 March 2025. Download (996kB)

Abstract

OBJECTIVE: To examine disease and target engagement biomarkers in the RISE-SSc trial of riociguat in early diffuse cutaneous systemic sclerosis and their potential to predict the response to treatment. METHODS: Patients were randomized to riociguat (n = 60) or placebo (n = 61) for 52 weeks. Skin biopsies and plasma/serum samples were obtained at baseline and week 14. Plasma cyclic guanosine monophosphate (cGMP) was assessed using radio-immunoassay. Alpha smooth muscle actin (αSMA) and skin thickness were determined by immunohistochemistry, mRNA markers of fibrosis by qRT-PCR in skin biopsies, and serum CXC motif chemokine ligand 4 (CXCL-4) and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) by enzyme-linked immunosorbent assay. RESULTS: By week 14, cGMP increased by 94 ± 78% with riociguat and 10 ± 39% with placebo (p < 0.001, riociguat vs placebo). Serum sPECAM-1 and CXCL-4 decreased with riociguat vs placebo (p = 0.004 and p = 0.008, respectively). There were no differences in skin collagen markers between the 2 groups. Higher baseline serum sPECAM-1 or the detection of αSMA-positive cells in baseline skin biopsies were associated with a larger reduction of modified Rodnan skin score from baseline at week 52 with riociguat vs placebo (interaction P-values 0.004 and 0.02, respectively). CONCLUSION: Plasma cGMP increased with riociguat, suggesting engagement with the nitric oxide-soluble guanylate cyclase-cGMP pathway. Riociguat was associated with a significant reduction in sPECAM-1 (an angiogenic biomarker) vs placebo. Elevated sPECAM-1 and the presence of αSMA-positive skin cells may help to identify patients who could benefit from riociguat in terms of skin fibrosis. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02283762.

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