Clinical Trials In Systemic Sclerosis Research Articles

Functional disability and other health-related quality-of-life domains: points to consider for clinical trials in systemic sclerosis.

Patients with SSc have the highest mortality among the rheumatic diseases. In addition, SSc is associated with disfigurement, hand contractures, fatigue, poor sleep, severe RP with numbness and tingling of the fingers can lead to decrements in quality of life. This Points to Consider article provides practical considerations for design of trials for functional disability and other health-related quality-of-life issues.

The mechanistic implications of gene expression studies in SSc: Insights from Systems Biology.

Purpose of review Systemic sclerosis (SSc) has been difficult to treat due to disease heterogeneity and an incomplete understanding of the molecular mechanisms underlying pathogenesis. Some patients show improvement on existing or experimental therapies while others show no significant response. Due to these challenges, clinical trials often do not meet their primary clinical endpoints. Here we review the data-driven genomewideapproaches that have recently been employed to characterize the molecular changes observed in SSc patients. Recent findings Understanding an individual patient’s gene expression phenotype or genotype, a cornerstone of personalized medicine, has been proposed to help determine which therapies are most likely to treat their disease. Network and systems biology methods have been applied to the compendium of publicly available SSc data and suggest that there are shared mechanisms driving the disease in different organs. Computational methods have also been applied to meta-analyses of SSc clinical trials. These approaches have led to the prediction of potential combination therapies that target the multiple pathways deregulated in SSc, which can now be tested in the clinic. Summary Data driven methods to analyze compendia of data are providing additional insights into SSc and related conditions. Modern bioinformatics and systems biology are ecosystems of data and code that are growing exponentially. Data integration allows researchers to combine multiple underpowered studies, a concern in a rare disorder such as SSc, for greater gain.

Evaluation and management approaches for scleroderma lung disease.

Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are leading causes of morbidity and mortality in systemic sclerosis (SSc). As symptoms are often under-reported in SSc, early screening of ILD and PAH is of paramount importance, and early treatment may be associated with better clinical outcomes. Serologies are particularly helpful in identifying patients at risk for pulmonary involvement. Pulmonary function testing, high-resolution computed tomography of the chest and echocardiography are important tools in the initial screening of these patients. Extensive research has also led to an improved understanding of the mediators involved in the pathogenesis of ILD and PAH. As a result, there have been significant advances in the development of novel targeted therapeutics and an increase in the number of early-phase clinical trials in SSc.

Quantitative outcome measures for systemic sclerosis-related Microangiopathy – Reliability of image acquisition in Nailfold Capillaroscopy

BackgroundNailfold capillaroscopic parameters hold increasing promise as outcome measures for clinical trials in systemic sclerosis (SSc). Their inclusion as outcomes would often naturally require capillaroscopy images to be captured at several time points during any one study. Our objective was to assess repeatability of image acquisition (which has been little studied), as well as of measurement. Method41 patients (26 with SSc, 15 with primary Raynaud's phenomenon) and 10 healthy controls returned for repeat high-magnification (300×) videocapillaroscopy mosaic imaging of 10 digits one week after initial imaging (as part of a larger study of reliability). Images were assessed in a random order by an expert blinded observer and 4 outcome measures extracted: (1) overall image grade and then (where possible) distal vessel locations were marked, allowing (2) vessel density (across the whole nailfold) to be calculated (3) apex width measurement and (4) giant vessel count. Intra-rater, intra-visit and intra-rater inter-visit (baseline vs. 1week) reliability were examined in 475 and 392 images respectively. A linear, mixed-effects model was used to estimate variance components, from which intra-class correlation coefficients (ICCs) were determined. ResultsIntra-visit and inter-visit reliability estimates (ICCs) were (respectively): overall image grade, 0.97 and 0.90; vessel density, 0.92 and 0.65; mean vessel width, 0.91 and 0.79; presence of giant capillary, 0.68 and 0.56. These estimates were conditional on each parameter being measurable. ConclusionWithin-operator image analysis and acquisition are reproducible. Quantitative nailfold capillaroscopy, at least with a single observer, provides reliable outcome measures for clinical studies including randomised controlled trials.

Review: Frontiers of Antifibrotic Therapy in Systemic Sclerosis

Although fibrosis is becoming increasingly recognized as a major cause of morbidity and mortality in modern societies, targeted anti-fibrotic therapies are still not approved for most fibrotic disorders. However, intense research over the last decade has improved our understanding of the underlying pathogenesis of fibrotic diseases. We now appreciate fibrosis as the consequence of a persistent tissue repair responses, which, in contrast to normal wound healing, fails to be effectively terminated. Profibrotic mediators released from infiltrating leukocytes, activated endothelial cells and degranulated platelets may predominantly drive fibroblast activation and collagen release in early stages, whereas endogenous activation of fibroblasts due epigenetic modifications and biomechanical or physical factors such as stiffening of the extracellular matrix and hypoxia may play pivotal role for disease progression in later stages. In the present review, we discuss novel insights into the pathogenesis of fibrotic diseases using systemic sclerosis (SSc) as example for an idiopathic, multisystem disorder. We set a strong translational focus and predominantly discuss approaches with very high potential for rapid transfer from bench-to-bedside. We highlight the molecular basis for ongoing clinical trials in SSc and also provide an outlook on upcoming trials. This article is protected by copyright. All rights reserved.

Standardization of the modified Rodnan skin score for use in clinical trials of systemic sclerosis.

The modified Rodnan skin score (mRSS) is a measure of skin thickness and is used as a primary or secondary outcome measure in clinical trials of systemic sclerosis (scleroderma). This state-of-art review provides a historical perspective of the development of the mRSS, summarizes the performance of mRSS as an outcome measure, provides guidance on assessing mRSS, and makes recommendations for incorporation of the mRSS into clinical trials.

A Functional Genomic Meta-Analysis of Clinical Trials in Systemic Sclerosis: Toward Precision Medicine and Combination Therapy

Systemic sclerosis is an orphan, systemic autoimmune disease with no FDA-approved treatments. Its heterogeneity and rarity often result in underpowered clinical trials making the analysis and interpretation of associated molecular data challenging. We performed a meta-analysis of gene expression data from skin biopsies of patients with systemic sclerosis treated with five therapies: mycophenolate mofetil, rituximab, abatacept, nilotinib, and fresolimumab. A common clinical improvement criterion of-20% or-5 modified Rodnan skin score was applied to each study. We applied a machine learning approach that captured features beyond differential expression and was better at identifying targets of therapies than the differential expression alone. Regardless of treatment mechanism, abrogation of inflammatory pathways accompanied clinical improvement in multiple studies suggesting that high expression of immune-related genes indicates active and targetable disease. Our framework allowed us to compare different trials and ask if patients who failed one therapy would likely improve on a different therapy, based on changes in gene expression. Genes with high expression at baseline in fresolimumab nonimprovers were downregulated in mycophenolate mofetil improvers, suggesting that immunomodulatory or combination therapy may have benefitted these patients. This approach can be broadly applied to increase tissue specificity and sensitivity of differential expression results.

Multi-arm group sequential designs with a simultaneous stopping rule.

Multi‐arm group sequential clinical trials are efficient designs to compare multiple treatments to a control. They allow one to test for treatment effects already in interim analyses and can have a lower average sample number than fixed sample designs. Their operating characteristics depend on the stopping rule: We consider simultaneous stopping, where the whole trial is stopped as soon as for any of the arms the null hypothesis of no treatment effect can be rejected, and separate stopping, where only recruitment to arms for which a significant treatment effect could be demonstrated is stopped, but the other arms are continued. For both stopping rules, the family‐wise error rate can be controlled by the closed testing procedure applied to group sequential tests of intersection and elementary hypotheses. The group sequential boundaries for the separate stopping rule also control the family‐wise error rate if the simultaneous stopping rule is applied. However, we show that for the simultaneous stopping rule, one can apply improved, less conservative stopping boundaries for local tests of elementary hypotheses. We derive corresponding improved Pocock and O'Brien type boundaries as well as optimized boundaries to maximize the power or average sample number and investigate the operating characteristics and small sample properties of the resulting designs. To control the power to reject at least one null hypothesis, the simultaneous stopping rule requires a lower average sample number than the separate stopping rule. This comes at the cost of a lower power to reject all null hypotheses. Some of this loss in power can be regained by applying the improved stopping boundaries for the simultaneous stopping rule. The procedures are illustrated with clinical trials in systemic sclerosis and narcolepsy. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Bosentan For Digital Ulcers in Patients With Systemic Sclerosis: Single Center Experience.

This study aims to investigate the effects of bosentan on the prevention and treatment of digital ulcers in systemic sclerosis (SSc) patients. The study included 30 patients (4 males, 26 females; mean age 49.6±15.4 years; range 23 to 71 years) diagnosed with SSc and treated with bosentan for digital ulcers. Bosentan was administered to all patients for a mean of 14±10.3 months. All SSc cases were refractory to calcium channel antagonists or angiotensin II inhibitors. The diagnosis of SSc was based on the American College of Rheumatology criteria and patients were classified as limited or diffuse cutaneous SSc according to the LeRoy classification. Mean disease duration was 8.8±8.0 years and mean duration of digital ulcers was 29.4±6.6 months. Under the bosentan treatment, eight patients (26.7%) developed new digital ulcers; all of these patients had diffuse cutaneous SSc. Health Assessment Questionnaire scores improved after 12 months and 24 months of treatment (p<0.001). Three patients (10%) developed pulmonary arterial hypertension under bosentan treatment [two patients (6.6%) had SSc-associated pulmonary arterial hypertension and one patient (3.3%) had interstitial fibrosis-associated pulmonary arterial hypertension]. The anti-centromere antibody positive patients were predominantly classified as limited cutaneous SSc. Of the patients positive for anti-topoisomerase-1 antibodies, a high proportion was classified as diffuse cutaneous SSc. Pulmonary fibrosis was most frequent in the anti-topoisomerase-1 antibody subset. New digital ulcers developed mainly in the anti-topoisomerase-1 antibody positive patients. Bosentan may be used either alone or in combination with other treatments when digital ulcers worsen and may be expected to suppress the development of new ulcers and severe pain. Further preclinical studies are required shedding light on the etiopathogenesis of SSc and larger clinical trials are needed for more definitive treatment strategies.

247 A Pilot Study Using High-Frequency Ultrasound to Measure Digital Ulcers as an Outcome Measure in Systemic Sclerosis Clinical Trials

247 A Pilot Study Using High-Frequency Ultrasound to Measure Digital Ulcers as an Outcome Measure in Systemic Sclerosis Clinical Trials

Molecular stratification and precision medicine in systemic sclerosis from genomic and proteomic data.

The goal of this review is to summarize recent advances into the pathogenesis and treatment of systemic sclerosis (SSc) from genomic and proteomic studies. Intrinsic gene expression-driven molecular subtypes of SSc are reproducible across three independent datasets. These subsets are a consistent feature of SSc and are found in multiple end-target tissues, such as skin and esophagus. Intrinsic subsets as well as baseline levels of molecular target pathways are potentially predictive of clinical response to specific therapeutics, based on three recent clinical trials. A gene expression-based biomarker of modified Rodnan skin score, a measure of SSc skin severity, can be used as a surrogate outcome metric and has been validated in a recent trial. Proteome analyses have identified novel biomarkers of SSc that correlate with SSc clinical phenotypes. Integrating intrinsic gene expression subset data, baseline molecular pathway information, and serum biomarkers along with surrogate measures of modified Rodnan skin score provides molecular context in SSc clinical trials. With validation, these approaches could be used to match patients with the therapies from which they are most likely to benefit and thus increase the likelihood of clinical improvement.

Systemic sclerosis and localized scleroderma--current concepts and novel targets for therapy.

Systemic sclerosis (SSc) is a chronic autoimmune disease with a high morbidity and mortality. Skin and organ fibrosis are key manifestations of SSc, for which no generally accepted therapy is available. Thus, there is a high unmet need for novel anti-fibrotic therapeutic strategies in SSc. At the same time, important progress has been made in the identification and characterization of potential molecular targets in fibrotic diseases over the recent years. In this review, we have selected four targeted therapies, which are tested in clinical trials in SSc, for in depths discussion of their preclinical characterization. Soluble guanylate cyclase (sGC) stimulators such as riociguat might target both vascular remodeling and tissue fibrosis. Blockade of interleukin-6 might be particularly promising for early inflammatory stages of SSc. Inhibition of serotonin receptor 2b signaling links platelet activation to tissue fibrosis. Targeting simultaneously multiple key molecules with the multityrosine kinase-inhibitor nintedanib might be a promising approach in complex fibrotic diseases such as SSc, in which many partially independent pathways are activated. Herein, we also give a state of the art overview of the current classification, clinical presentation, diagnostic approach, and treatment options of localized scleroderma. Finally, we discuss whether the novel targeted therapies currently tested in SSc could be used for localized scleroderma.

New ACR EULAR guidelines for systemic sclerosis classification.

The American College of Rheumatology and European League Against Rheumatism classification criteria for systemic sclerosis are a significant advancement in the field. This article describes the innovative, rigorous, criteria development strategy that was used. The new criteria build upon previous criteria by incorporating important elements (proximal scleroderma, sclerodactyly, digital pits, pulmonary fibrosis, Raynaud's phenomenon, and scleroderma specific autoantibodies). The new criteria add emphasis to the vasculopathic manifestations, and include the early manifestation of puffy fingers. Together, these enhancements have resulted in a shift in the conceptual framework of the disease for the next generation. The new criteria have improved sensitivity and specifically, particularly among cases with early disease, mild disease, or limited disease. The ability to classify more cases, at an earlier stage, may confer the opportunity to intervene and prevent disease progression. Undoubtedly, this will lead to a paradigm shift in the conduct of clinical trials in systemic sclerosis.

Stimulators of soluble guanylate cyclase (sGC) inhibit experimental skin fibrosis of different aetiologies

ObjectivesStimulators of the soluble guanylate cyclase (sGC) have recently been shown to inhibit transforming growth factor-β signalling. Here, we aimed to demonstrate that riociguat, the drug candidate for clinical trials...

Twenty-two points to consider for clinical trials in systemic sclerosis, based on EULAR standards.

SSc is clinically and aetiopathogenically heterogeneous. Consensus standards for more uniform trial design and selection of outcome measures are needed. The objective of this study was to develop evidence-based points to consider (PTCs) for future clinical trials in SSc. Thirteen international SSc experts experienced in SSc clinical trial design were invited to participate. One researcher with experience in systematic literature review and three trainees were also included. A systematic review using PubMed and the Cochrane Central Register of Controlled Trials was conducted and PTCs when designing clinical trials in SSc were developed. As part of that development we conducted an Internet-based Delphi exercise regarding the main points to be made in the consensus statement. Consensus was defined as achieving a median score of ≥7 of 9. By consensus, the experts decided to develop PTCs for each individual organ system. The current document provides a unifying outline on PTCs regarding general trial design, inclusion/exclusion criteria and analysis. Consensus was achieved regarding all the main points of the PTCs. Using European League Against Rheumatism suggestions for PTCs, a general outline for PTCs for controlled clinical trials in SSc was developed. Specific outlines for individual organ systems are to be published separately. This general outline should lead to more uniform and higher-quality trials and clearly delineate areas where further research is needed.

SAT0219 Shear-Wave Elastography: A New Imaging Method for Evaluating Scleroderma Skin

BackgroundSkin involvement is of major clinical and prognostic relevance in systemic sclerosis (SSc) and is often the primary outcome in clinical trials in SSc. Nevertheless, a fully validated, objective and...

Treating skin and lung fibrosis in systemic sclerosis: a future filled with promise?

Systemic sclerosis (SSc) is a rare autoimmune disorder characterized by immune activation, vascular damage and an excessive accumulation of extracellular matrix proteins in the skin and internal organs. Despite its high morbidity and increased mortality, currently available treatment options for fibrotic manifestations of SSc remain limited and their clinical antifibrotic effects are borderline. In this review, novel insights from recently published clinical trials in SSc on treatment concepts such as mycophenolate mofetil, oral type I collagen, recombinant human relaxin and autologous hematopoietic stem cell transplantation are discussed. In the past decade the most significant progress in this field has been made by the identification of a large number of cellular and molecular key players in the pathogenesis of fibrotic disease manifestations. This has led to the identification of novel candidates as molecular targets for treatment of fibrotic diseases. On the basis of their level of evidence from preclinical studies and based on the availability of first clinical results, the most promising targets are presented including inhibitors of B-cells, tyrosine kinases, 5-hydroxytryptamin receptors, interleukin-6 and Wnt signalling.

OP0156 Epigenetic Silencing of Endogenous WNT Inhibitors Contributes to the Aberrant Activation of Canonical WNT Signaling in Systemic Sclerosis

BackgroundAberrant activation of the Wnt pathway with decreased expression of endogenous antagonists has recently been characterized as central pathomechanism in systemic sclerosis (SSc). Epigenetic alterations have been shown to contribute...

Application of Biomarkers to Clinical Trials in Systemic Sclerosis

Important clinical advances in the treatment of systemic sclerosis have been made, yet fibrotic disease remains largely untreatable. Optimal design of clinical trials to test new therapeutics for fibrotic disease features has suffered from dual difficulties in patient selection and patient evaluation. Patient selection for entry into trials for treatment of interstitial lung disease and/or skin fibrosis is challenged by the natural history of the disease, which stabilizes in some patients while relentlessly progressing in others, and our lack of good clinical markers to distinguish between these trajectories. Patient evaluation is made difficult, particularly in skin disease, by the inherent difficulty in quantifying the extent of disease. Biomarkers hold the potential to solve many of these problems as surrogate outcome measures and as markers for disease progression. Identified biomarkers may have the potential to graduate to surrogate outcome singly or, more likely, in combination. Predictive biomarkers are still largely unknown.

The transcription factor JunD mediates transforming growth factor β-induced fibroblast activation and fibrosis in systemic sclerosis

ObjectivesTransforming growth factor β (TGFβ) has been identified as a key player in fibrotic diseases. However, the molecular mechanisms by which TGFβ activates fibroblasts are incompletely understood. Here, the role...