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Biomarker analysis from the phase 2b randomized placebo-controlled trial of riociguat in early diffuse cutaneous systemic sclerosis
D. Khanna, F. Kramer, J. Höfler, M. Ghadessi, P. Sandner, Y. Allanore, CP. Denton, M. Kuwana, M. Matucci-Cerinic, JE. Pope, T. Atsumi, R. Bečvář, L. Czirják, E. De Langhe, E. Hachulla, T. Ishii, O. Ishikawa, SR. Johnson, V. Riccieri, E. Schiopu,...
Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu časopisecké články, randomizované kontrolované studie, klinické zkoušky, fáze II
Grantová podpora
Bayer AG and Merck Sharp & Dohme LLC
Merck & Co., Inc.
GlaxoSmithKline
Nippon Shinyaku Co., Ltd
NLK
Free Medical Journals
od 1996 do Před 1 rokem
Open Access Digital Library
od 1996-01-01
Medline Complete (EBSCOhost)
od 1999-01-01 do Před 1 rokem
- MeSH
- biologické markery * krev MeSH
- biopsie MeSH
- difuzní sklerodermie * farmakoterapie patologie MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- fibróza farmakoterapie MeSH
- guanosinmonofosfát cyklický krev metabolismus MeSH
- kůže * patologie účinky léků metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- pyrazoly * terapeutické užití MeSH
- pyrimidiny * terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- randomizované kontrolované studie MeSH
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 Dermatology Gunma University Postgraduate School of Medicine Maebashi Japan
Department of Rheumatology and Immunology Medical School University of Pécs Pécs Hungary
Department of Rheumatology CHU Bordeaux Bordeaux France
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 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
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
Unit of Immunology Rheumatology Allergy and Rare Diseases IRCCS San Raffaele Hospital Milan Italy
Citace poskytuje Crossref.org
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