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. α-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 two groups. Higher baseline serum sPECAM-1 or the detection of αSMA-positive cells in baseline skin biopsies was 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.

Clinical Research Innovation and Education Center Tohoku University Sendai Japan

Department of Allergy and Rheumatology Nippon Medical School Graduate School of Medicine Tokyo Japan

Department of Clinical Internal Anesthesiological and Cardiovascular Sciences Sapienza University of Rome Rome Italy

Department of Dermatology Gunma University Postgraduate School of Medicine Maebashi Japan

Department of Internal Medicine and Clinical Immunology Referral Centre for Centre for Rare Systemic Autoimmune Diseases North and North West of France CHU Lille University of Lille Inserm U1286 INFINITE Institute for Translational Research in Inflammation Lille France

Department of Internal Medicine Ghent University Belgium and Department of Rheumatology Ghent University Hospital Belgium and Unit for Molecular Immunology and Inflammation VIB Inflammation Research Center Ghent Belgium

Department of Rheumatology and Immunology Medical School University of Pécs Pécs Hungary

Department of Rheumatology CHU Bordeaux Bordeaux France

Department of Rheumatology Endocrinology and Nephrology Faculty of Medicine and Graduate School of Medicine Hokkaido University Sapporo Japan

Department of Rheumatology St Vincent's Hospital Melbourne Melbourne VIC Australia

Department of Rheumatology University Hospital Zurich University of Zurich Zurich Switzerland

Department of Rheumatology University of Debrecen Debrecen Hungary

Division of Medicine Centre for Rheumatology University College London London UK

Division of Rheumatology and Immunology Medical University of South Carolina Charleston SC USA

Division of Rheumatology Department of Experimental and Clinical Medicine University of Firenze Florence Italy

Division of Rheumatology Department of Medicine Georgetown University Medical Center Washington DC USA

Division of Rheumatology Department of Medicine Toronto Western Hospital University Health Network Mount Sinai Hospital University of Toronto Toronto Scleroderma Research Program Toronto ON Canada

Division of Rheumatology Medical College of Georgia at Augusta University Augusta GA USA

Division of Rheumatology Schulich School of Medicine University of Western Ontario London ON Canada

Division of Rheumatology University of Michigan Ann Arbor MI USA

Institute of Rheumatology Department of Rheumatology 1st Faculty of Medicine Charles University Prague Czech Republic

Laboratory of Tissue Homeostasis and Disease Skeletal Biology and Engineering Research Center Division of Rheumatology Department of Development and Regeneration KU Leuven University Hospitals Leuven Leuven Belgium

Research and Development Pharmaceuticals Bayer AG Wuppertal Germany

Rheumatology A Department Cochin Hospital APAP Paris Descartes University Paris France

Rheumatology Unit Department of Clinical and Experimental Medicine University of Pisa Pisa Italy

Staburo GmbH Munich Germany

Unit of Immunology Rheumatology Allergy and Rare Diseases IRCCS San Raffaele Hospital Milan Italy

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ClinicalTrials.gov
NCT02283762