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BACKGROUND: This study aims to assess the impact of sotatercept on exercise tolerance, exercise capacity, and right ventricular function in pulmonary arterial hypertension. METHODS: SPECTRA (Sotatercept Phase 2 Exploratory Clinical Trial in PAH) was a phase 2a, single-arm, open-label, multicenter exploratory study that evaluated the effects of sotatercept by invasive cardiopulmonary exercise testing in participants with pulmonary arterial hypertension and World Health Organization functional class III on combination background therapy. The primary end point was the change in peak oxygen uptake from baseline to week 24. Cardiac magnetic resonance imaging was performed to assess right ventricular function. RESULTS: Among the 21 participants completing 24 weeks of treatment, there was a significant improvement from baseline in peak oxygen uptake, with a mean change of 102.74 mL/min ([95% CIs, 27.72-177.76]; P=0.0097). Sotatercept demonstrated improvements in secondary end points, including resting and peak exercise hemodynamics, and 6-minute walk distance versus baseline measures. Cardiac magnetic resonance imaging showed improvements from baseline at week 24 in right ventricular function. CONCLUSIONS: The clinical efficacy and safety of sotatercept demonstrated in the SPECTRA study emphasize the potential of this therapy as a new treatment option for patients with pulmonary arterial hypertension. Improvements in right ventricular structure and function underscore the potential for sotatercept as a disease-modifying agent with reverse-remodeling capabilities. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03738150. [ABSTRACT FROM AUTHOR]

BACKROUND Pulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension. METHODS We conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro—B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension—Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit. RESULTS A total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, —0.3 to 3.5) in the placebo group. The Hodges—Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, in-creased hemoglobin levels, thrombocytopenia, and increased blood pressure. CONCLUSIONS In patients with pulmonary arterial hypertension who were receiving stable back-ground therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.) [ABSTRACT FROM AUTHOR]

Introduction: Pulmonary arterial hypertension (PAH) is a progressive disease associated with significant morbidity and mortality. Sotatercept is a first-in-class activin signalling inhibitor that acts to restore the balance between the growth-promoting and growth-inhibiting signalling pathways., Methods: This post-hoc, exploratory, pooled analysis combines data from the double-blind placebo periods of the phase 2 PULSAR (NCT03496207) and phase 3 STELLAR (NCT04576988) studies. Both studies were international, multicentre, randomised, double-blind, placebo-controlled trials in patients with PAH. Efficacy and safety parameters common to both studies were analysed., Results: A total of 429 patients were randomised and treated; 237 received sotatercept and 192 received placebo. Adding sotatercept to background PAH therapy for 24 weeks improved exercise capacity (as assessed by 6-min walk distance), pulmonary vascular resistance, World Health Organization functional class, and delayed time to first occurrence of death or clinical worsening event. There were clinically important reductions in both pulmonary and right heart pressures; improvements in right ventricle (RV) size during both systole and diastole; and enhancements in RV contractility and RV-pulmonary artery coupling. The number of patients who experienced at least one adverse event of interest or special interest (increased haemoglobin, thrombocytopenia, bleeding events [mostly epistaxis], increased blood pressure, and telangiectasia) was higher in the sotatercept group than the placebo group., Discussion: This pooled analysis confirms that sotatercept delivers therapeutic benefit across a range of efficacy endpoints and has favourable safety in patients with PAH. Increased duration of follow-up will provide further insight into long-term outcomes of sotatercept in patients with PAH., (Copyright ©The authors 2025.)

Sotatercept is a breakthrough, first-in-class biologic, recently approved by the Food and Drug Administration (FDA) for the treatment of pulmonary arterial hypertension (PAH). Exposure-response (E-R) analyses and pharmacokinetic/pharmacodynamic (PK/PD) modeling were performed for sotatercept after intravenous and subcutaneous (SC) administrations. Clinical endpoints included 6-minute walk distance (6MWD), pulmonary vascular resistance (PVR), and probability of N-terminal pro-B natriuretic peptide (NT-proBNP) concentrations < 300 pg/mL for efficacy, and hemoglobin (Hgb) for safety from two Phase 1 studies, two Phase 2 studies, and one Phase 3 study. E-R models using nonlinear mixed effect modeling approach were developed for 6MWD and PVR, while Cox proportional hazards model and semi-mechanistic PK/PD model were used for NT-proBNP and Hgb. Covariate analyses were conducted to identify significant predictors of variability for each of these clinical endpoints. Modeling results showed that increasing sotatercept average concentration (C avg ) at week 24 is associated with increased predicted 6MWD, increased probability of NT-proBNP concentration < 300 pg/mL, decreased predicted PVR, and increased Hgb which was clinically manageable. All these responses approached their corresponding plateaus at a C avg range associated with the dose of 0.7 mg/kg Q3W SC. Statistically relevant covariates included age and iron supplementation which slightly increased Hgb-mediated effect for 6MWD, PAH disease duration, and baseline therapy infusion with prostacyclin for PVR, and WHO functional class for NT-proBNP. The magnitudes of the impact of these covariates are not clinically meaningful. Taken together, these results support an appropriate benefit-risk profile for the FDA-approved target dose for sotatercept of 0.7 mg/kg Q3W SC., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: This analysis examined the effects of the activin signaling inhibitor, sotatercept, in pulmonary arterial hypertension (PAH) subgroups stratified by baseline cardiac index (CI)., Methods: Pooled data from PULSAR (N = 106; NCT03496207) and STELLAR (N = 323; NCT04576988) were analyzed using 2 different CI thresholds, <2.0 and ≥2.0 liter/min/m 2 as well as <2.5 and ≥2.5 liter/min/m 2 . Median changes from baseline at week 24 were evaluated using Hodges-Lehmann estimator and least squares (LS) means, with 95% confidence intervals and p-values (significance: p = 0.05). Categorial endpoints and time-to-clinical worsening were analyzed by Cochran-Mantel-Haenszel and Cox model respectively., Results: Of 429 participants, 51 had CI <2.0 and 378 ≥2.0 liter/min/m 2 , while 179 had CI <2.5 and 250 ≥2.5 liter/min/m 2 . Sotatercept significantly improved median 6-minute walk distance (range: 33.9 to 63.7 m: p < 0.001), pulmonary vascular resistance (range: -202.8 to -395.4 dyn•s•cm - 5 ; p ≤ 0.002), and N-terminal pro-B-type natriuretic peptide (range: -317.3 to -1,041.2 pg/ml; p < 0.001) across subgroups. LS means showed reductions in pulmonary and right atrial pressures, decreased right ventricular size, and improved tricuspid annular plane systolic excursion/systolic pulmonary artery pressure. Sotatercept delayed time to first occurrence of death or a worsening event for CI ≥2.5 (hazard ratio [HR] 0.12; p < 0.001), ≥2.0 (HR 0.13; p < 0.001), and <2.5 (HR 0.21; p < 0.001) liter/min/m 2 . Improvements were observed in WHO functional class (all p < 0.050) and ESC/ERS risk scores (all p < 0.001)., Conclusions: Sotatercept demonstrated consistent efficacy and safety across CI subgroups, supporting its use in PAH patients irrespective of baseline cardiac hemodynamics., (Copyright © 2025. Published by Elsevier Inc.)

Sotatercept is a breakthrough, first-in-class biologic, that is FDA-approved for the treatment of pulmonary arterial hypertension (PAH). A population pharmacokinetic (PopPK) model was developed using data from two phase 1 studies in healthy participants, and two phase 2 studies and one phase 3 study in participants with PAH. The pooled sotatercept PK data encompassed single intravenous (IV) or subcutaneous (SC) doses ranging from 0.01 to 3.0 mg/kg, as well as multiple SC doses ranging from 0.03 to 1.0 mg/kg, with PK samples collected up to a maximum of ~150 weeks following Q3W and Q4W dosing regimens. The final PopPK analysis included 350 participants, with 30 and 320 participants receiving sotatercept IV and SC, respectively. A two-compartment model with a first-order absorption rate constant and a linear disposition from central compartment well-described sotatercept PK. The estimated bioavailability is ~66%; bioavailability, clearance (CL), and central volume (VC) have low to moderate inter-individual variability. Time-varying body weight and baseline albumin concentration were statistically significant predictors of PK; CL and VC were predicted to increase with increasing body weight, while CL was predicted to decrease with increasing baseline albumin concentration. However, the magnitude of covariate effects is not predicted to meaningfully alter the disposition of sotatercept. Altogether, the PopPK modeling results demonstrate favorable PK characteristics (low to moderate variability and typical bioavailability), supporting sotatercept as a SC biological agent for the treatment of patients with PAH., (© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Sotatercept, a soluble fusion protein comprising the extracellular domain of activin receptor type IIA linked to the Fc portion of human IgG1, is a first-in-class activin signaling inhibitor under development for the treatment of pulmonary arterial hypertension (PAH). We evaluated antidrug antibody (ADA) development and determined the effects of immunogenicity on the pharmacokinetics (PKs), efficacy, and safety of sotatercept in STELLAR, a multicenter, double-blind phase III trial (NCT04576988) wherein participants with PAH were randomized 1:1 to receive sotatercept (starting dose 0.3; target dose 0.7 mg/kg) or placebo subcutaneously every 3 weeks in combination with background therapies for ≤ 72 weeks. ADA-positive (ADA-POS) participants were identified and characterized for neutralizing antibodies (NAbs). PKs, efficacy, and safety were evaluated by ADA and NAb status. Of 162 evaluable participants, 42 (25.9%) were ADA-POS through week 24, of whom 11 (6.8%) were also NAb-POS. Median onset of ADAs was 3.29 weeks (interquartile range (IQR): 3.14-6.14), and median duration was 6 weeks (IQR: 3.14-17.86). No clinically meaningful differences were found across subgroups that were ADA-NEG, ADA-POS/NAb-NEG, and ADA-POS/NAb-POS, in terms of PKs (sotatercept trough concentration over time, mean postdose trough concentration at the end of treatment, and clearance), efficacy (changes from baseline in 6-minute walk distance, pulmonary vascular resistance, and N-terminal pro-B-type natriuretic peptide levels), and safety (incidence of hypersensitivity, anaphylactic reactions, and administration site reactions). We conclude that ADA incidence from sotatercept treatment was 25.9% and did not meaningfully affect the PKs, efficacy, or safety of sotatercept in participants with PAH., (© 2023 Merck Sharp & Dohme LLC. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Pulmonary arterial hypertension (PAH) is a rare, progressive disease associated with significant morbidity and mortality. The phase 3 STELLAR trial tested sotatercept plus background therapy (BGT) versus placebo plus BGT. BGT was comprised of mono-, double-, or triple-PAH targeted therapy. Building on STELLAR findings, we employed a population health model to assess the potential long-term clinical impact of sotatercept., Methods: Based on the well-established ESC/ERS 4-strata risk assessment approach, we developed a six-state Markov-type model (low risk, intermediate-low risk, intermediate-high risk, high risk, lung/heart-lung transplant, and death) to compare the clinical outcomes of sotatercept plus BGT versus BGT alone over a lifetime horizon. State-transition probabilities were obtained from STELLAR. Risk stratum-adjusted mortality and lung/heart-lung transplant probabilities were based on COMPERA PAH registry data, and the post-transplant mortality probability was obtained from existing literature. Model outcomes were discounted at 3% annually. Sensitivity analyses were conducted to examine model robustness., Results: In the base case, sotatercept plus BGT was associated with longer life expectancy from model baseline (16.5 vs 5.1 years) versus BGT alone, leading to 11.5 years gained per patient. Compared with BGT alone, sotatercept plus BGT was further associated with a gain in infused prostacyclin-free life years per patient, along with 683 PAH hospitalizations and 4 lung/heart-lung transplant avoided per 1000 patients., Conclusions: According to this model, adding sotatercept to BGT increased life expectancy by roughly threefold among patients with PAH while reducing utilization of infused prostacyclin, PAH hospitalizations, and lung/heart-lung transplants. Real-world data are needed to confirm these findings., Trial Registration: ClinicalTrials.gov identifier, NCT04576988 (STELLAR)., (© 2023. Merck & Co., Inc., Rahway, NJ, USA and its affiliates.)

Background: In the phase 3 STELLAR trial, sotatercept, an investigational first-in-class activin signalling inhibitor, demonstrated beneficial effects on 6-min walk distance and additional efficacy endpoints in pre-treated participants with pulmonary arterial hypertension (PAH)., Methods: This post hoc analysis evaluated data from right heart catheterisation (RHC) and echocardiography (ECHO) obtained from the STELLAR trial. Changes from baseline in RHC and ECHO parameters were assessed at 24 weeks. An analysis of covariance (ANCOVA) model was used to estimate differences in least squares means with treatment and randomisation stratification (mono/double versus triple therapy; World Health Organization functional class II versus III) as fixed factors, and baseline value as covariate., Results: Relative to placebo, treatment with sotatercept led to significant (all p<0.0001 except where noted) improvements from baseline in mean pulmonary artery (PA) pressure (-13.9 mmHg), pulmonary vascular resistance (-254.8 dyn·s·cm -5 ), mean right atrial pressure (-2.7 mmHg), mixed venous oxygen saturation (3.84%), PA elastance (-0.42 mmHg·mL -1 ·beat -1 ), PA compliance (0.58 mL·mmHg -1 ), cardiac efficiency (0.48 mL·beat -1 ·mmHg -1 ), right ventricular (RV) work (-0.85 g·m) and RV power (-32.70 mmHg·L·min -1 ). ECHO showed improvements in tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure ratio (0.12 mm·mmHg -1 ), end-systolic and end-diastolic RV areas (-4.39 cm 2 and -5.31 cm 2 , respectively), tricuspid regurgitation and RV fractional area change (2.04% p<0.050). No significant between-group changes from baseline were seen for TAPSE, heart rate, cardiac output, stroke volume or their indices., Conclusion: In pre-treated patients with PAH, sotatercept demonstrated substantial improvements in PA pressures, PA compliance, PA-RV coupling and right heart function., Competing Interests: Conflict of interest: R. Souza has served as consultant for Acceleron Pharma, Inc., Bayer Healthcare Pharmaceuticals Inc. and Janssen Biotech, Inc. (fees paid to self). D.B. Badesch has received grants/contracts from Acceleron Pharma, Inc., Merck & Co., Inc. (Rahway, NJ, USA), Altavant and United Therapeutics (all paid to institution, clinical trial), received payment as consultant from Acceleron Pharma, Inc., Merck & Co., Inc. (Rahway, NJ, USA) and Aerovate Inc. (paid through institution), and the author's spouse or partner has stock in Johnson & Johnson Health Care Systems Inc. H.A. Ghofrani has served as consultant for Aerovate, Altavant, Bayer Healthcare, Gossamer Bio, Janssen Diagnostics, LLC, Merck & Co., Inc. (Rahway, NJ, USA) and Pfizer (fees paid to self), and is an employee of Justus Liebig University Giessen, Germany. J.S.R. Gibbs has served a consultant for Acceleron Pharma and Merck & Co., Inc. (Rahway, NJ, USA) (fees paid to self), served in data and safety monitoring boards for Actelion Pharmaceuticals, Fundação Bial, GossamerBio and Merck & Co., Inc. (Rahway, NJ, USA) (fees paid to self), served in end point review committee for Actelion Pharmaceuticals, Aerovate, Janssen Biotech, Pfizer Pharma GMBH and United Therapeutics Corporation (fees paid to self), and served as Chair of ERN-Lung Functional Committee Patient Reported Outcomes for ERN Lung. M. Gomberg-Maitland has served as a consultant for Acceleron Pharma and Merck & Co., Inc. (Rahway, NJ, USA), Aerami, Bayer HealthCare Pharmaceuticals Inc., Janssen Biotech, Keros and United Therapeutics Corporation (fees paid to self), has received grant/contract from Aerovate, Altavant, Acceleron Pharma and Merck & Co., Inc. (fees paid to institution), and the author's spouse is an employee of Intellia Therapeutics. V.V. McLaughlin has served as a consultant for Aerami, Aerovate, Altavant, Bayer Healthcare, Caremark, Corvista, Gossamer Bio, Janssen Biotech, Merck & Co., Inc. (Rahway, NJ, USA) and United Therapeutics (fees paid to self), received grants/contracts from Aerovate, Altavant, Gossamer Bio, Janssen Biotech, Merck & Co., Inc. (Rahway, NJ, USA) and Sonovie (paid to institution), served as fiduciary officer, board of directors, for Clene (fees paid to self), and is an employee of the University of Michigan. I.R. Preston has served as a steering committee member for Acceleron Pharma, Liquidia and United Therapeutics (fees paid to self), served as scientific advisory board member for Aerovate, Altavant and Gossamer (fees paid to self), served as consultant for Janssen Global Services, LLC and Respira Therapeutics (fees paid to self), and served as principal investigator for Janssen Global Services, LLC and United Therapeutics (fees paid to self). A.B. Waxman has served as consultant for ARIA-CV, Goassamer, Merck & Co., Inc. (Rahway, NJ, USA) and United Therapeutics Corporation (fees paid to self), received grants/contracts from AI Therapeutics, Inc. (fees paid to self), and served on a data and safety monitoring committee for Insmed, Inc. (fees paid to self). E. Grünig has served as consultant for Actelion Pharmaceuticals (fees paid to self), and served as speaker and/or consultant for Bayer Healthcare, Ferrer, GEBRO, GlaxoSmithKline, Janssen Biotech, Merck Sharp & Dohme (MSD) and OMT (fees paid to self). G. Kopeć has served as consultant for Acceleron Pharma, Inc. and Janssen Global Services, LLC, on a scientific advisory board (fees paid to self), served as PI in a clinical study for Acceleron Pharma, Inc., Bayer and Janssen Global Services, LLC (fees paid to self), served as a speaker for Bayer, Janssen Global Services, LLC and Merck & Co., Inc. (Rahway, NJ, USA) (fees paid to self), served as investigator for Janssen Global Services, LLC (fees paid to self), and received travel fees from Janssen Global Services, LLC and Merck & Co., Inc. (Rahway, NJ, USA) (paid to self). G. Meyer has served as consultant for Bayer Healthcare and Janssen Biotech (fees paid to self), and received grants/contracts from Bayer Healthcare (paid to institution). K.M. Olsson has served as a consultant for Acceleron Pharma, Inc., Actelion Pharmaceuticals, AOP Orphan, Bayer, Ferrer Pharma, Janssen Global Services, LLC and Merck & Co., Inc. (Rahway, NJ, USA) (fees paid to self). S. Rosenkranz has served as consultant for Abbott Fund, Acceleron Pharma, Inc., Actelion Pharmaceuticals, Aerovate, Altavant, AOP Orphan, AstraZeneca, Bayer, Boehringer Ingelheim, Edwards Lifesciences, Ferrer, Gossamer, Janssen, MSD and United Therapeutics (fees paid to self), and received grants/contracts from Actelion Pharmaceuticals, AstraZeneca, Bayer and Janssen (paid to institution). J. Lin, A.O. Johnson-Levonas and J. de Oliveira Pena are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and own stock/stock shares in Merck & Co., Inc., Rahway, NJ, USA. M. Humbert has served as consultant for Acceleron Pharma, Inc., Aerovate, Altavant, AOP Orphan, Bayer, Chiesi Farmaceutici, Ferrer, Janssen Pharmaceuticals, Merck & Co., Inc. (Rahway, NJ, USA), MorphogenIX and United Therapeutics Corporation (fees paid to self). M.M. Hoeper has served as consultant for Acceleron Pharma, Inc., Actelion Pharmaceuticals, AOP Orphan, Bayer Healthcare, Ferrer, GossamerBio, Janssen Global Services, LLC and Merck & Co., Inc. (Rahway, NJ, USA) (fees paid to self)., (Copyright ©The authors 2023.)

Background: In participants with pulmonary arterial hypertension, 24 weeks of sotatercept resulted in a significantly greater reduction from baseline in pulmonary vascular resistance than placebo. This report characterises the longer-term safety and efficacy of sotatercept in the PULSAR open-label extension. We report cumulative safety, and efficacy at months 18-24, for all participants treated with sotatercept., Methods: PULSAR was a phase 2, randomised, double-blind, placebo-controlled study followed by an open-label extension, which evaluated sotatercept on top of background pulmonary arterial hypertension therapy in adults. Participants originally randomised to placebo were re-randomised 1:1 to sotatercept 0.3 or 0.7 mg·kg -1 (placebo-crossed group); those initially randomised to sotatercept continued the same sotatercept dose (continued-sotatercept group). Safety was evaluated in all participants who received ≥1 dose of sotatercept. The primary efficacy endpoint was change from baseline to months 18-24 in pulmonary vascular resistance. Secondary endpoints included 6-min walk distance and functional class. Two prespecified analyses, placebo-crossed and delayed-start, evaluated efficacy irrespective of dose., Results: Of 106 participants enrolled in the PULSAR study, 97 continued into the extension period. Serious treatment-emergent adverse events were reported in 32 (30.8%) participants; 10 (9.6%) reported treatment-emergent adverse events leading to study discontinuation. Three (2.9%) participants died, none considered related to study drug. The placebo-crossed group demonstrated significant improvement across primary and secondary endpoints and clinical efficacy was maintained in the continued-sotatercept group., Conclusion: These results support the longer-term safety and durability of clinical benefit of sotatercept for pulmonary arterial hypertension., Competing Interests: Conflict of interest: M. Humbert is a consultant and an advisory committee member for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Aerovate, Altavant, AOP Orphan, Bayer, Ferrer, Janssen, Merck & Co., Inc., Rahway, NJ, USA, MorphogenIX and United Therapeutics, and has received research grants for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Janssen, and Merck & Co., Inc., Rahway, NJ, USA. V. McLaughlin is a consultant for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Aerovate, Altavant, Bayer, Caremark LLC, CiVi Bioharma Inc., Corvista, Gossamer Bio, Janssen, Merck & Co., Inc., Rahway, NJ, USA, and United Therapeutics, has received grant(s) from Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Janssen, Sonovie, United Therapeutics, is involved in CME programs for Impact PH and PHA, and on the board of directors for CiVi Biopharma Inc., and for Clene. J.S.R. Gibbs is a consultant and speaker for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Aerovate, Bayer, Complexa, Janssen, Merck & Co., Inc., Rahway, NJ, USA, MSD, Pfizer and United Therapeutics. M. Gomberg-Maitland is a consultant for Altavant, Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Janssen, and Entelligence Young for Janssen, is part of the advisory committee for United Therapeutics and the data safety monitoring board for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, has received grant(s) and/or reports GW with funds from Altavant, Bayer and United Therapeutics. M.M. Hoeper is a consultant and speaker for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer. I.R. Preston is a consultant for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Pfizer, Respira and United Therapeutics, a steering committee member for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and has received grant(s) from Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Bayer, Complexa, Liquidia, PhaseBio, Tenax and United Therapeutics. R. Souza is an advisory committee member for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA. A.B. Waxman is steering committee member for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Altavant, Gossamer Bio, United Therapeutics, an investigator and/or principal investigator for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Aria-CV and United Therapeutics, and has received grant(s) from Acceleron, a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA. H-A. Ghofrani is a consultant for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Bayer, Gossamer Bio, Jansson, MorphogenIX, MSD and Pfizer. P. Escribano Subias has received consulting fees from Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Janssen, MSD and Gossamer Bio, has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Janssen, MSD, Ferrer, Bayer and AOT, has received support for attending meetings from Janssen and MSD, has received equipment, materials, drugs, medical writing or other services from Janssen, and has participated on data safety monitoring or advisory boards for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway NJ, USA, Janssen, MSD and Gossamer Bio. J. Feldman reports consulting fees from Merck, Aerovate, Altavant, United Therapeutics, Liquidia, Corsair and Janssen. G. Meyer has received payment or honoraria for lectures, presentations, and speakers’ bureaus from Bayer and Janssen and has participated on advisory boards for Bayer and Janssen. D. Montani has received grant(s) from and is a consultant for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Bayer, Chesi, GlaxoSmithKline, MSD and Pfizer. K.M. Olsson is a consultant and speaker for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer. S. Manimaran and J. de Oliveira Pena are employees of Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA. D.B. Badesch is a consultant for Pfizer, is a consultant and advisory committee member for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Altavant, Arena, Bayer, Liquidia, Merck & Co., Inc., Rahway, NJ, USA, United Therapeutics, has received research grant for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Altavant, Arena, Belleraphon, Janssen, Liquidia, Merck & Co., Inc., Rahway, NJ, USA, and United Therapeutics, sits on the data safety monitoring board for United Therapeutics, and is a long-term holder of common stock for Johnson and Johnson., (Copyright ©The authors 2023.)

Background: Pulmonary arterial hypertension is characterized by pulmonary vascular remodeling, cellular proliferation, and poor long-term outcomes. Dysfunctional bone morphogenetic protein pathway signaling is associated with both hereditary and idiopathic subtypes. Sotatercept, a novel fusion protein, binds activins and growth differentiation factors in the attempt to restore balance between growth-promoting and growth-inhibiting signaling pathways., Methods: In this 24-week multicenter trial, we randomly assigned 106 adults who were receiving background therapy for pulmonary arterial hypertension to receive subcutaneous sotatercept at a dose of 0.3 mg per kilogram of body weight every 3 weeks or 0.7 mg per kilogram every 3 weeks or placebo. The primary end point was the change from baseline to week 24 in pulmonary vascular resistance., Results: Baseline characteristics were similar among the three groups. The least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline to week 24 in pulmonary vascular resistance was -145.8 dyn · sec · cm -5 (95% confidence interval [CI], -241.0 to -50.6; P = 0.003). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was -239.5 dyn · sec · cm -5 (95% CI, -329.3 to -149.7; P<0.001). At 24 weeks, the least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline in 6-minute walk distance was 29.4 m (95% CI, 3.8 to 55.0). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was 21.4 m (95% CI, -2.8 to 45.7). Sotatercept was also associated with a decrease in N-terminal pro-B-type natriuretic peptide levels. Thrombocytopenia and an increased hemoglobin level were the most common hematologic adverse events. One patient in the sotatercept 0.7-mg group died from cardiac arrest., Conclusions: Treatment with sotatercept resulted in a reduction in pulmonary vascular resistance in patients receiving background therapy for pulmonary arterial hypertension. (Funded by Acceleron Pharma; PULSAR ClinicalTrials.gov number, NCT03496207.)., (Copyright © 2021 Massachusetts Medical Society.)

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.)

Purpose: Systemic sclerosis is a rare multi-organ autoimmune rheumatic disease, resulting in progressive fibrosis of the skin/internal organs. This study aimed to understand the impact of diffuse cutaneous systemic sclerosis symptoms and disease burden from the patient's perspective., Methods: This was a mixed methodology, market research study involving ethnography, structured interviews, video diaries, and patient tasks. Patients had been diagnosed with diffuse cutaneous systemic sclerosis for ⩾ 6 months and were recruited via healthcare professionals or patient associations (France, Italy, the United Kingdom, and the United States). Patients filmed short (~15 min) daily video diaries about their lives over 7 days and participated in ethnographic sessions, patient tasks, and structured video interviews. In Germany and Spain, patients participated in 60-min telephone interviews., Results: Twenty-three patients (mean age: 54 years; 83% women; minimum disease duration: 6 months) participated in the study. Time to diagnosis was prolonged, as patients overlooked their symptoms and some healthcare professionals attributed symptoms to other causes. Patients rarely received additional information or support services at diagnosis. Importantly, although patients were aware of the seriousness of organ involvement, they reported that skin changes, pain, and fatigue impaired their ability to perform routine tasks. Patients had a high prescription treatment burden (mean: 10 tablets/day; up to >25 tablets/day) with additional non-prescription medication taken for other comorbidities. Treatment discontinuation was common due to side effects. Patients experienced diffuse cutaneous systemic sclerosis as a loss of independence and self-esteem. Moreover, patients tended to have small support networks, and emotional support services were not offered as standard care., Conclusion: Patients with diffuse cutaneous systemic sclerosis had high treatment and disease burdens, with skin changes, pain, and fatigue profoundly affecting their lives. There is an unmet need for patient information at the time of diagnosis and emotional support services throughout the patient's journey with diffuse cutaneous systemic sclerosis. Based on the results of this study, we provide recommendations for improving diffuse cutaneous systemic sclerosis care., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: D.K. consults for Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Cytori, CSL Behring, EMD Merck-Serono, Genentech/Roche, GlaxoSmithKline, Genkyotex, Sanofi-Aventis, UCB, Actelion, and Gilead; has stock options in Eicos Sciences; and has received research grants from National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health/National Institute of Allergy and Infectious Diseases, Bayer, Bristol-Myers Squibb, and Pfizer. Y.A. consults for Actelion, Bayer, Roche/Genentech, Inventiva, Medac, Pfizer, Sanofi, Servier, and UCB; and has received research grants from Bristol-Myers Squibb, Roche/Genentech, Inventiva, Pfizer, Sanofi, and Servier. C.P.D. consults for Bayer, Roche, GlaxoSmithKline, Actelion, Inventiva, CSL Behring, Takeda, Merck-Serono, MedImmune, and Biogen; and has received research grants from Actelion, GlaxoSmithKline, Novartis, and CSL Behring. M.M.-C. consults for Actelion, GlaxoSmithKline, Pfizer, and Bristol-Myers Squibb. J.P. consults for and/or has research grants with Actelion, Bayer, BMS Merck, Pfizer, and Roche. B.H. is an employee of Bayer AG. S.D. is an employee of Blueprint Partnership. J.d.O.P. has been an employee of Bayer US LLC. O.D. has been a consultant for Genentech/Roche, 4D Science GmbH, Actelion, Active Biotech, Bayer, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, EpiPharm, Ergonex, espeRare Foundation, GlaxoSmithKline, Inventiva, Lilly, Mitsubishi Tanabe, Medac, MedImmune, Pfizer, Pharmacyclics, Serodapharm, and Sinoxa; and has received research funding from Actelion, Bayer, Boehringer Ingelheim, Ergonex, Pfizer, and Sanofi. O.D. has a patent for mir-29 for the treatment of systemic sclerosis., (© The Author(s) 2019.)

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.)

Objective: To gain insight into clinical practice regarding referral, early diagnosis and other aspects of the management of patients with dcSSc in Europe and the USA., Methods: Semi-structured interviews were conducted with 84 rheumatologists (or internal medicine physicians) and 40 dermatologists in different countries (the UK, France, Germany, Italy, Spain and the USA). Physicians were asked to identify key steps in the patient pathway relating to patient presentation, diagnosis and referral, in addition to other treatment and follow-up processes., Results: The interviewed physicians reported that late presentation with dcSSc was common, with some patients presenting to primary care physicians after symptoms had persisted for up to 1 year. Awareness of dcSSc is reported to vary widely among primary care physicians. Final diagnosis, generally following guideline-based recommendations, was by rheumatologists in most cases (or internal medicine physicians in France) and they remained responsible for global patient management, with lesser involvement in diagnosis and management by dermatologists. Specialist centres were not well defined and did not exist in all countries., Conclusion: Patients and primary healthcare providers can be unaware of the symptoms of dcSSc, therefore presentation and referral to specialist care are often late. Thus, improved awareness among patients and primary care physicians is necessary to facilitate earlier referral and diagnosis. Once referred, more consistent use of the modified Rodnan skin score at diagnosis and follow-up may help to monitor disease progression. Furthermore, establishing specialist centres may help to promote such changes and improve patient care.

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/.)

RISE-SSc is a randomized, double-blind, placebo-controlled phase 2 study investigating the efficacy and safety of riociguat in patients with diffuse cutaneous systemic sclerosis (dcSSc). Based on positive results from riociguat trials in patients with pulmonary hypertension and chronic thromboembolic pulmonary hypertension in combination with the known antiproliferative and antifibrotic effects seen in animal models, patients with SSc may benefit from treatment with riociguat. Patients with SSc meeting the ACR/EULAR systemic sclerosis classification criteria with diffuse cutaneous SSc (dcSSc) subset per LeRoy criteria, and a disease duration of less than or equal to 18 months will be randomized to placebo or riociguat 0.5 mg (up-titrated to a maximum dose of 2.5 mg TID over 10 weeks) and maintained on therapy for a total of 52 weeks. During the first 10 weeks of the long-term extension phase, placebo subjects will be up-titrated on riociguat, and all patients will be followed for up to 6 years. The primary endpoint of change in modified Rodnan skin score (mRSS) from baseline will be assessed at 52 weeks, as will be secondary endpoints such as mRSS progression and regression rates, patient quality of life, digital ulcer burden, and change in forced vital capacity and carbon monoxide diffusing capacity. This review will further define the clinical rationale for the use of riociguat in the treatment of SSc and provide details on study protocol, design, and outcome reporting., Trial Registration: Clinicaltrials.gov identifier: NCT02283762., (Copyright © 2016. Published by Elsevier Ltd.)

Purpose: To compare the anatomical structure and the presence of growth factors and cytokines of amniotic membrane preserved in glycerol/MEM (1:1) or undiluted dimethyl sulfoxide through electron microscopy., Methods: Amniotic membrane preserved in glycerol/MEM (1:1) or undiluted dimethyl sulfoxide were processed for transmission and scanning electron microscopy. As control, freshly collected amniotic membrane was fixed and processed for electron microscopy. The cytokines and growth factors assessed were: TGF-beta (transforming growth factor beta); TGF-beta activ (activated transforming growth factor beta); EGF (epidermal growth factor); FGF-4 (fibroblast growth factor 4); bFGF (basic fibroblast growth factor); IL-4 (interleukin 4); PGE2 (prostaglandin E2); IL-10 (interleukin 10); KGF (keratinocyte growth factor); HGF (hepatocyte growth factor)., Results: Amniotic membrane from the control group showed intact epithelium, with surface microvilli and junctional complexes between the cells and the basal membrane. Glycerol/MEM preserved amniotic membrane had similar aspect to the control, with higher epithelial cells. Those amniotic membranes preserved in dimethyl sulfoxide disclosed less intercellular junction and detachment of the epithelium from the basal membrane. The cytokines and growth factors did not disclose significant differences, except for FGF-4, bFGF, PGE2 and KGF., Conclusions: Amniotic membrane preserved in glycerol/MEM showed a better tissue structure, with less detachment of the epithelium from the basal membrane, in comparison to undiluted dimethyl sulfoxide. The majority of the growth factors and cytokines were kept with both techniques of preservation.