Riociguat in patients with early diffuse cutaneous systemic sclerosis (RISE-SSc): randomised, double-blind, placebo-controlled multicentre trial

Khanna, Dinesh; Allanore, Yannick; Denton, Christopher P.; Kuwana, Masataka; Matucci‐Cerinic, Marco; Pope, Janet; Atsumi, Tatsuya; Bečvář, Radim; Czirják, László; Hachulla, É.; Ishii, Tomonori; Ishikawa, Osamu; Johnson, Sindhu R.; Langhe, Ellen De; Stagnaro, Chiara; Riccieri, Valeria; Schiopu, Elena; Silver, Richard M.; Smith, Vanessa; Steen, Virginia D.; Stevens, Wendy; Szűcs, Gabriella; Truchetet, Marie-Élise; Wosnitza, M.; Laapas, Kaisa; Pena, Janethe de Oliveira; Yao, Zhen; Krämer, Frank; Distler, Oliver

doi:10.1136/annrheumdis-2019-216823

Cited by 85 publications

(60 citation statements)

References 39 publications

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“…Our results confirm the overall high progressive trajectory for the worsening of mRSS, particularly in the first year of follow-up [ 32 ], whereas FVC showed a more progressive decrease during the three first years. In accordance with previous studies, this result demonstrates the relevance of including early dcSSc patients for RCTs based on mRSS evolution [ 21 , 30 , 38 , 39 ]. In PRESS, approximately 20% of the patients had significant mRSS worsening after 1 year of follow-up.…”

Section: Discussionsupporting

confidence: 92%

Clinical characteristics, visceral involvement, and mortality in at-risk or early diffuse systemic sclerosis: a longitudinal analysis of an observational prospective multicenter US cohort

et al. 2021

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Background Early diffuse cutaneous systemic sclerosis (dcSSc) has the highest case fatality among rheumatic diseases. We report baseline characteristics, current immunosuppressive therapies, progression of skin and internal organ involvement, and mortality in a multicenter prospective cohort from the United States (US) of America. Methods We performed a longitudinal analysis of participants from 12 US centers, from April 2012 to July 2020. All participants had early dcSSc or were at-risk for dcSSc, with ≤2 years since the first non-Raynaud’s phenomenon (RP) symptom. Results Three hundred one patients were included with a baseline median disease duration of 1.2 years since RP and a mean modified skin score of 21.1 units. At baseline, 263 (87.3%) had definite dcSSc and 38 (12.7%) were classified as at-risk; 112 (49.6%) patients were positive for anti-RNA polymerase III antibodies. The median follow-up duration was 24.5 months (IQR = 10.3–40.7 months). One hundred ninety (63.1%) participants were treated with an immunosuppressive therapy, of which mycophenolate mofetil was most used at baseline and follow-up. Of 38 who were classified as at-risk at baseline, 27 (71%) went on to develop dcSSc; these patients were characterized by higher baseline mean HAQ-DI (0.8 versus 0.4, p = 0.05) and higher baseline mRSS (8.8 versus 4.4, p < 0.01) in comparison with those who remained as limited cutaneous SSc. In the overall cohort, 48 participants (21.1%) had clinically significant worsening of skin fibrosis, mainly occurring in the first year of follow-up; 41 (23.3%) had an absolute forced vital capacity decline of ≥10%. Twenty participants (6.6%) died, of which 18 died in the first 3 years of follow-up. Cardiac involvement (33.3%), gastrointestinal dysmotility (22.2%), and progressive interstitial lung disease (ILD) (16.7%) were the main causes of death. Conclusion This US cohort highlights the management of early SSc in the current era, demonstrating progression of skin and lung involvement despite immunosuppressive therapy and high mortality due to cardiac involvement.

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Section: Discussionsupporting

confidence: 92%

Clinical characteristics, visceral involvement, and mortality in at-risk or early diffuse systemic sclerosis: a longitudinal analysis of an observational prospective multicenter US cohort

et al. 2021

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“…Riociguat is soluble guanylate cyclase (sGC) stimulator with potential anti-fibrotic effects and proved efficacy in patients with pulmonary arterial hypertension associated with connective tissue diseases [ 47 ]. A 52 weeks, double-blind, placebo-controlled, multi-centre, randomized phase 2 study was undertaken in early (disease duration ≤ 18 months) dcSSc patients to investigate the potential effects on skin invovlement [ 48 ]. No background immunosuppression was allowed.…”

Section: Resultsmentioning

confidence: 99%

An update on targeted therapies in systemic sclerosis based on a systematic review from the last 3 years

Campochiaro

Allanore

2021

Arthritis Res Ther

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New molecular mechanisms that can be targeted with specific drugs have recently emerged for the treatment of systemic sclerosis (SSc) patients. Over the past 3 years, the achievement of one large phase 3 trial has led to the approval by drug agencies of the first drug licenced for SSc-related interstitial lung disease. Given this exciting time in the SSc field, we aimed to perform a systemic literature review of phase 1, phase 2 and phase 3 clinical trials and large observational studies about targeted therapies in SSc. We searched MEDLINE/PubMed, EMBASE, and ClinicalTrials.gov for clinical studies from 2016 with targeted therapies as the primary treatment in patients with SSc for skin or lung involvement as the primary clinical outcome measure. Details on the study characteristics, the trial drug used, the molecular target engaged by the trial drug, the inclusion criteria of the study, the treatment dose, the possibility of concomitant immunosuppression, the endpoints of the study, the duration of the study and the results obtained were reviewed. Of the 973 references identified, 21 (4 conference abstracts and 17 articles) were included in the systematic review. A total of 15 phase 1/phase 2 clinical trials, 2 phase 3 clinical trials and 2 observation studies were analysed. The drugs studied in phase 1/phase 2 studies included the following: inebilizumab, dabigatran, C-82, pomalidomide, rilonacept, romilkimab, tocilizumab, tofacitinib, pirfenidone, lenabasum, abatacept, belimumab, riociguat, SAR100842 and lanifibranor. All but 3 studies were performed in early diffuse SSc patients with different inclusion criteria, while 3 studies were performed in SSc patients with interstitial lung disease (ILD). Phase 3 clinical trials investigated nintedanib and tocilizumab. Nintedanib was investigated in SSc-ILD patients whereas tocilizumab focused on early diffuse SSc patients with inflammatory features. Two observational studies including > 50 patients with rituximab as the targeted drug were also evaluated. All these studies offer a real hope for SSc patients. The future challenges will be to customize patient-specific therapeutics with the goal to develop precision medicine for SSc.

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“…Another drug which recently was brought back to attention in ILD is tocilizumab, an anti-IL6 receptor antibody, which has been investigated in two randomized controlled trials for systemic sclerosis (SSc) [ 27 , 28 , 29 , 30 ]. Therein, both FVC decline in SSc-ILD and serum CCL18 levels were reduced significantly with tocilizumab [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic Variation in CCL18 Gene Influences CCL18 Expression and Correlates with Survival in Idiopathic Pulmonary Fibrosis—Part B

Caliskan

Seeliger

Jäger

et al. 2020

JCM

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Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality. CC-chemokine ligand 18 (CCL18) is predictive of survival in IPF. We described correlation of CCL18 serum levels with the genotype of rs2015086 C > T polymorphism the CCL18-gene, which was associated with survival in a pre-antifibrotic cohort (Part-A). Herein (Part-B), we aimed to validate these findings and to study the effects of antifibrotics. Two cohorts were prospectively recruited, cohort-A (n = 61, pre-antifibrotic) and cohort B (n = 101, received antifibrotics). Baseline CCL18 serum level measurement by enzyme-linked immunosorbent assay (ELISA, serially in cohort B) and genotyping of rs2015086 was performed and correlated with clinical outcomes. The CT genotype was present in 15% and 31% of patients. These patients had higher CCL18 levels compared to the TT-genotype (cohort-A: 234 vs. 115.8 ng/mL, p < 0.001; cohort B: 159.5 vs. 120 ng/mL, p = 0.0001). During antifibrotic therapy, CCL18 increased (p = 0.0036) regardless of rs2015086-genotype and antifibrotic-agent. In cohort-A, baseline CCL18-cutoff (>120 ng/mL) and CT-genotype were associated with mortality (p = 0.041 and p = 0.0051). In cohort-B, the CCL18-cutoff (>140 ng/mL) was associated with mortality (p = 0.003) and progression (p = 0.004), but not the CT/CC-genotype. In conclusion, we validated the correlation between rs2015086-genotype and CCL18 serum levels, which was predictive of (progression-free)-survival in two prospective validation cohorts.

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Riociguat in patients with early diffuse cutaneous systemic sclerosis (RISE-SSc): randomised, double-blind, placebo-controlled multicentre trial

Cited by 85 publications

References 39 publications

Clinical characteristics, visceral involvement, and mortality in at-risk or early diffuse systemic sclerosis: a longitudinal analysis of an observational prospective multicenter US cohort

Clinical characteristics, visceral involvement, and mortality in at-risk or early diffuse systemic sclerosis: a longitudinal analysis of an observational prospective multicenter US cohort

An update on targeted therapies in systemic sclerosis based on a systematic review from the last 3 years

Genetic Variation in CCL18 Gene Influences CCL18 Expression and Correlates with Survival in Idiopathic Pulmonary Fibrosis—Part B

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