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Objectives: Riociguat is approved for pulmonary arterial hypertension and has antiproliferative, anti-inflammatory and antifibrotic effects in animal models of tissue fibrosis. We evaluated the efficacy and safety of riociguat in patients with early diffuse cutaneous systemic sclerosis (dcSSc) at high risk of skin fibrosis progression., Methods: In this randomised, double-blind, placebo-controlled, phase IIb trial, adults with dcSSc of <18 months' duration and a modified Rodnan skin score (mRSS) 10-22 units received riociguat 0.5 mg to 2.5 mg orally three times daily (n=60) or placebo (n=61). The primary endpoint was change in mRSS from baseline to week 52., Results: At week 52, change from baseline in mRSS units was -2.09±5.66 (n=57) with riociguat and -0.77±8.24 (n=52) with placebo (difference of least squares means -2.34 (95% CI -4.99 to 0.30; p=0.08)). In patients with interstitial lung disease, forced vital capacity declined by 2.7% with riociguat and 7.6% with placebo. At week 14, average Raynaud's condition score had improved ≥50% in 19 (41.3%)/46 patients with riociguat and 13 (26.0%)/50 patients with placebo. Safety assessments showed no new signals with riociguat and no treatment-related deaths., Conclusions: Riociguat did not significantly benefit mRSS versus placebo at the predefined p<0.05. Secondary and exploratory analyses showed potential efficacy signals that should be tested in further trials. Riociguat was well tolerated., Competing Interests: Competing interests: DK reports personal fees from Actelion, grants and personal fees from Bayer AG, grants and personal fees from BMS, grants from Pfizer, personal fees from Arena, personal fees from Eclos Sciences, Inc, personal fees from BI, personal fees from Arena, personal fees from CSL Behring, personal fees from GSK, personal fees from Galapagos, personal fees from Genentech/Roche, personal fees from Corbus, personal fees from Cytori, grants from Horizon, outside the submitted work. OD reports other from Actelion, other from Bayer, other from Boehringer Ingelheim, other from Mitsubishi Tanabe, other from AnaMar, other from ChemonAb, other from espeRare Foundation, other from Genentech/Roche, other from GSK, other from Inventiva, other from Italfarmaco, other from iQvia, other from Lilly, other from Medac, other from MedImmune, other from Pharmacyclics, other from Novartis, other from Pfizer, other from Sanofi, other from Serodapharm, other from UCB, other from Amgen, other from AbbVie, other from Mepha, other from MSD, outside the submitted work. YA reports personal fees from Actelion, personal fees from Bayer AG, grants and personal fees from BMS, grants from Inventiva, personal fees from BI, grants from Roche, grants from Sanofi, outside the submitted work. CPD reports personal fees from Actelion, personal fees from Bayer AG, grants and personal fees from Inventiva, personal fees from BI, personal fees from Roche-Genentech, personal fees from Sanofi Aventis, grants and personal fees from CSL Behring, grants and personal fees from GlaxoSmithKline, outside the submitted work. MK reports grants and personal fees from Actelion, personal fees from Bayer AG, personal fees from Chugai, personal fees from BI, personal fees from Reata, personal fees from Corpus, personal fees from CSL Behring, personal fees from GlaxoSmithKline, personal fees from Mochida, personal fees from Pfizer, personal fees from Nippon Shinyaku, outside the submitted work. MMC reports grants and personal fees from Actelion, grants from Chemomab, grants and personal fees from BMS, grants from Pfizer, grants and personal fees from MSD, grants from Sanipedia, personal fees from Janssen, outside the submitted work. JEP reports personal fees from Actelion, personal fees from Bayer AG, personal fees from BMS, personal fees from AbbVie, personal fees from Lilly, personal fees from Roche, personal fees from Sanofi, personal fees from Merck, personal fees from Novartis, personal fees from Pfizer, personal fees from Sandoz, personal fees from UCB, personal fees from Amgen, outside the submitted work. TA reports grants and personal fees from Astellas, grants and personal fees from Takeda, grants and personal fees from Mitsubishi Tanabe, grants and personal fees from Chugai, grants and personal fees from Daiichi-Sankyo, grants from Otuska, grants from Takeda, grants and personal fees from Pfizer, grants from Alexion, grants from Bayer, grants from Eisai, grants from Bristol-Myers Squibb, grants from Asahi Kasei, personal fees from Ono, personal fees from Sanofi, personal fees from Eli Lilly, outside the submitted work. LC reports personal fees from Actelion, personal fees from Bayer AG, personal fees from BI, personal fees from Roche-Genentech, personal fees from Lilly, personal fees from Medac, personal fees from Novartis, personal fees from Pfizer, outside the submitted work. EH reports grants, personal fees and non-financial support from Actelion, grants, personal fees and non-financial support from Bayer AG, grants, personal fees and non-financial support from GlaxoSmithKline, grants, personal fees and non-financial support from MSD, grants and personal fees from Pfizer, outside the submitted work. TI reports personal fees from Astellas, personal fees from Daiichi-Sankyo, personal fees from Chugai, personal fees from Sanofi, personal fees from AbbVie, personal fees from Bristol-Myers, personal fees from Mitsubishi Tanabe, personal fees from Eisai, personal fees from Janssen, personal fees from Asahi Kasei, personal fees from Ono Pharmaceutical, personal fees from Ayumi Pharmaceutical, personal fees from Pfizer, outside the submitted work. Virginia Steen reports participation in advisory boards, consultancy for economics of scleroderma management, and clinical trials for Bayer; investigator-initiated grant, advisory board, and steering committee (consulting) for CSL Behring; advisory board and site primary investigator (PI) of clinical trial for Roche; site PI of clinical trial for Sanofi; site PI of clinical trial for Immune Tolerance Network; and DSMB for open labs phase 2 trial and site PI for the phase 3 trial for Corbus. ME-T reports consulting fees, speaking fees and honoraria from AbbVie, BMS, Lilly, Medac, MSD, Pfizer, Roche, UCB, outside the submitted work. MW reports employment from Bayer AG, outside the submitted work. KL reports other from StatFinn Oy, outside the submitted work. JdOP reports other from Bayer AG, outside the submitted work. ZY reports other from Bayer HealthCare, outside the submitted work. FK reports other from Bayer AG, outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Objectives: Mortality and worsening of organ function are desirable endpoints for clinical trials in systemic sclerosis (SSc). The aim of this study was to identify factors that allow enrichment of patients with these endpoints, in a population of patients from the European Scleroderma Trials and Research group database., Methods: Inclusion criteria were diagnosis of diffuse SSc and follow-up over 12±3 months. Disease worsening/organ progression was fulfilled if any of the following events occurred: new renal crisis; decrease of lung or heart function; new echocardiography-suspected pulmonary hypertension or death. In total, 42 clinical parameters were chosen as predictors for the analysis by using (1) imputation of missing data on the basis of multivariate imputation and (2) least absolute shrinkage and selection operator regression., Results: Of 1451 patients meeting the inclusion criteria, 706 had complete data on outcome parameters and were included in the analysis. Of the 42 outcome predictors, eight remained in the final regression model. There was substantial evidence for a strong association between disease progression and age, active digital ulcer (DU), lung fibrosis, muscle weakness and elevated C-reactive protein (CRP) level. Active DU, CRP elevation, lung fibrosis and muscle weakness were also associated with a significantly shorter time to disease progression. A bootstrap validation step with 10 000 repetitions successfully validated the model., Conclusions: The use of the predictive factors presented here could enable cohort enrichment with patients at risk for overall disease worsening in SSc clinical trials., Competing Interests: Competing interests: MOB declares no conflict of interest. OD has had consultancy relationships with Actelion, Bayer, Biogen Idec, Boehringer Ingelheim, ChemomAb, espeRare foundation, Genentech/Roche, GSK, Inventiva, Italfarmaco, Lilly, medac, MedImmune, Mitsubishi Tanabe Pharma, Pharmacyclics, Novartis, Pfizer, Sanofi, Sinoxa and UCB in the area of potential treatments of scleroderma and its complications. OD has received research funding from Actelion, Bayer, Boehringer Ingelheim, Mitsubishi Tanabe Pharma and Roche in the area of potential treatments of scleroderma and its complications. OD has a patent for mir-29 licensed for the treatment of systemic sclerosis. DK has consultancy relationships and/or has received grant/research support from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Genentech/Roche, NIH, Pfizer, Sanofi-Aventis Pharmaceuticals, Actelion Pharmaceuticals US, ChemomAb, Corbus, Covis, Cytori, Eicos, EMD Serono, Gilead, GlaxoSmithKline, and UCB Pharma. He is a shareholder of Eicos. CPD has consultancy relationships with and/or has received speakers’ bureau fees from Actelion Pharmaceuticals US, Bayer AG, GlaxoSmithKline, CSL Behring, Merck Serono, Roche Pharmaceuticals, Genentech and Biogen IDEC Inc., Inventiva, Sanofi-Aventis Pharmaceuticals and Boehringer Ingelheim. JEP has consultancy relationships with and/or has received grant/research support from Actelion, Bayer AG, Bristol-Myers Squibb, Merck, Pfizer Inc. and Roche. MM-C has consultancy relationships and/or has received grant/research support from Pfizer, Bristol-Myers Squibb, Actelion, UCB Pharma, Bayer, ChemomAb, Genentech/Roche, Inventiva and Lilly. YA has consultancy relationships with and/or has received grant/research support from Actelion, Pharmaceuticals US, Bayer AG, Bristol-Myers Squibb, Inventiva, Medac, Pfizer Inc., Roche Pharmaceuticals, Genentech and Biogen IDEC Inc., Sanofi-Aventis Pharmaceuticals and Servier. JdOP and JC are employees of Bayer. NTG has nothing to disclose., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Objectives: To determine whether progressive skin fibrosis is associated with visceral organ progression and mortality during follow-up in patients with diffuse cutaneous systemic sclerosis (dcSSc)., Methods: We evaluated patients from the European Scleroderma Trials and Research database with dcSSc, baseline modified Rodnan skin score (mRSS) ≥7, valid mRSS at 12±3 months after baseline and ≥1 annual follow-up visit. Progressive skin fibrosis was defined as an increase in mRSS >5 and ≥25% from baseline to 12±3 months. Outcomes were pulmonary, cardiovascular and renal progression, and all-cause death. Associations between skin progression and outcomes were evaluated by Kaplan-Meier survival analysis and multivariable Cox regression., Results: Of 1021 included patients, 78 (7.6%) had progressive skin fibrosis (skin progressors). Median follow-up was 3.4 years. Survival analyses indicated that skin progressors had a significantly higher probability of FVC decline ≥10% (53.6% vs 34.4%; p<0.001) and all-cause death (15.4% vs 7.3%; p=0.003) than non-progressors. These significant associations were also found in subgroup analyses of patients with either low baseline mRSS (≤22/51) or short disease duration (≤15 months). In multivariable analyses, skin progression within 1 year was independently associated with FVC decline ≥10% (HR 1.79, 95% CI 1.20 to 2.65) and all-cause death (HR 2.58, 95% CI 1.31 to 5.09)., Conclusions: Progressive skin fibrosis within 1 year is associated with decline in lung function and worse survival in dcSSc during follow-up. These results confirm mRSS as a surrogate marker in dcSSc, which will be helpful for cohort enrichment in future trials and risk stratification in clinical practice., Competing Interests: Competing interests: OD has obtained research support from Bayer, Sanofi, Ergonex, Boehringer Ingelheim, Actelion and Pfizer. He is a scientific consultant for 4D Science, Actelion, Active Biotec, Bayer, BiogenIdec, BMS, Boehringer Ingelheim, ChemoAb, EpiPharm, Ergonex, espeRare foundation, Genentech/Roche, GSK, Inventiva, Lilly, Medac, MedImmune, Pharmacyclics, Pfizer, Serodapharm and Sinoxa, and has a patent licensed on mir-29 for the treatment of systemic sclerosis. DK has consultancy relationships and/or has received grant/research support from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Genentech/Roche, NIH, Pfizer, Sanofi-Aventis Pharmaceuticals, Actelion Pharmaceuticals US, Chemomab, Corbus, Covis, Cytori, Eicos, EMD Serono, Gilead, GlaxoSmithKline and UCB Pharma. He is a shareholder of Eicos. CPD has consultancy relationships with and/or has received speakers’ bureau fees from Actelion Pharmaceuticals US, Bayer AG, GlaxoSmithKline, CSL Behring, Merck-Serono, Roche Pharmaceuticals, Genentech and Biogen IDEC Inc., Inventiva, Sanofi-Aventis Pharmaceuticals and Boehringer Ingelheim. JEP has consultancy relationships with and/or has received grant/research support from Actelion, Bayer AG, Bristol-Myers Squibb, Merck, Pfizer Inc. and Roche. MM-C has consultancy relationships and/or has received grant/research support from Pfizer, Bristol-Myers Squibb, Actelion, UCB Pharma, Bayer, ChemomAb, Genentech/Roche, Inventiva and Lilly. YA has consultancy relationships with and/or has received grant/research support from Actelion, Pharmaceuticals US, Bayer AG, Bristol-Myers Squibb, Inventiva, Medac, Pfizer Inc., Roche Pharmaceuticals, Genentech and Biogen IDEC Inc., Sanofi-Aventis Pharmaceuticals and Servier. JdOP and JC are employees of Bayer. WW, SJ and NG have nothing to disclose., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The 12-week, phase III Pulmonary Arterial hyperTENsion sGC-stimulator Trial (PATENT)-1 study investigated riociguat in patients with pulmonary arterial hypertension (PAH). Here, we present a prospectively planned analysis of the safety and efficacy of riociguat in the subgroup of patients with PAH associated with connective tissue disease (PAH-CTD)., Methods: Patients with PAH-CTD were further classified post hoc as having PAH associated with systemic sclerosis or PAH-other defined CTD. In PATENT-1, patients received riociguat (maximum 2.5 or 1.5 mg three times daily) or placebo. Efficacy endpoints included change from baseline in 6-minute walking distance (6MWD; primary endpoint), haemodynamics and WHO functional class (WHO FC). In the long-term extension PATENT-2, patients received riociguat (maximum 2.5 mg three times daily); the primary endpoint was safety and tolerability., Results: In patients with PAH-CTD, riociguat increased mean 6MWD, WHO FC, pulmonary vascular resistance and cardiac index. Improvements in 6MWD and WHO FC persisted at 2 years. Two-year survival of patients with PAH-CTD was the same as for idiopathic PAH (93%). Riociguat had a similar safety profile in patients with PAH-CTD to that of the overall population., Conclusions: Riociguat was well tolerated and associated with positive trends in 6MWD and other endpoints that were sustained at 2 years in patients with PAH-CTD., Trial Registration Numbers: PATENT-1 (NCT00810693), PATENT-2 (NCT00863681)., Competing Interests: MH has received grants or fees for congress participation, advisory and expert board meetings, and/or research from Actelion, Bayer, GSK, Novartis and Pfizer, all related to the development of drugs in the field of pulmonary hypertension. CPD has been a consultant to Bayer, Roche, GSK, Actelion, Inventiva, CSL Behring, Takeda, Merck-Serono, MedImmune and Biogen. He has received research grants from Actelion, GSK, Novartis and CSL Behring. JGC has received consultancy fees and honoraria from Actelion, GSK, Bayer, United Therapeutics, Endotronics and Pfizer, and unrestricted grants from Actelion, and GSK. J-GH has received fees for participation in advisory boards from Bayer. CDV has received grants or fees for congress participation, advisory boards and research from Actelion, Bayer, GSK, Lilly, Pfizer, and UTEL. AB and CM are employees of Bayer Pharma AG. JdOP is an employee of Bayer HealthCare Pharmaceuticals., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)