Research News

EULAR Update Targets Organ Involvement in Systemic Sclerosis

Author: Diana Swift
Date Published: May-2017
Source: MedPage Today

In a systematic review–based update of its 2009 recommendations, the European League Against Rheumatism (EULAR) has added two new therapeutic statements addressing organ complications in systemic sclerosis (SSC). These include Raynaud's phenomenon, digital ulcers, pulmonary arterial hypertension, skin and lung disease, scleroderma renal crisis, and gastrointestinal involvement.


Pros and cons of echocardiography in the screening, diagnosis and follow-up of patients with systemic sclerosis pulmonary arterial hypertension – a rheumatologist’s perspective

Author: Murray Baron
Date Published: February-2017
Source: JSRD

Purpose: Our objective was to review the evidence regarding echocardiography in patients with systemic sclerosis (SSc) and possible pulmonary hypertension (PH).

Methods: The literature was reviewed. In addition, a survey was conducted of 315 rheumatologists/internists with a self-declared interest in SSc, to determine their preferred use of echocardiograms.

Results: The most relevant literature findings come from two studies, the DETECT study and one from the Australian Scleroderma Interest Group. In both these studies, it appears that the use of non-echocardiographic variables such as pulmonary function tests (PFTs) and values of serum N-terminal pro-brain natriuretic peptide (NT-proBNP), are adequate on their own in suggesting which patients are at high risk of PH. Echocardiograms added very little information and in fact may confuse the picture by appearing to be normal when in fact underlying PH is present.



Digital ulcers in SSc treated with oral treprostinil: a randomized, double-blind, placebo-controlled study with open-label follow-up

Author: J. Seibold, F. Wigley, E. Schiopu, C. Denton, et al
Date Published: February-2017
Source: JSRD

Methods: The literature was reviewed. In addition, a survey was conducted of 315 rheumatologists/internists with a self-declared interest in SSc, to determine their preferred use of echocardiograms.

Background: Prostacyclins are routinely used to treat vascular features of systemic sclerosis (SSc, scleroderma) but require parenteral infusion or inhalation. This study evaluated the safety and efficacy of oral treprostinil in digital ulcers secondary to SSc. Methods: This was a randomized (1:1) placebo-controlled, multicenter study in adults with SSc and at least one active digital ulcer at entry. Oral treprostinil was administered twice daily and titrated to maximum tolerated dose with clinical assessments at Weeks 5, 10, 15 and 20. The primary endpoint was change in net digital ulcer burden. Secondary outcomes included ulcer healing and prevention, measures of hand function, quality of life, Raynaud phenomenon and global assessments. Simplified data were gathered during open-label follow up.


Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS)

Author: A. Herrick, X. Pan, S. Peytrignet, M. Lunt, R. Hesselstrand, L. Mouthon, A. Silman, E. Brown, L. Czirják, J. Distler, O. Distler, et al
Date Published: February-2017
Source: Annals of the Rheumatic Diseases

Objectives The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches.

Methods This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or ‘no immunosuppressant’. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival.


Immunosuppressive Therapy Helps Systemic Sclerosis Patients With Lung Disease

Author: Patricia Inacio
Date Published: January-2017
Source: Scleroderma News

Levels of the cytokine CXCl4 in the bloodstream drop sharply in response to immunosuppressive therapy, and are associated with improved lung function in systemic sclerosis (SSc) patients with interstitial lung disease (ILD), a study shows. The research, “Changes in plasma CXCL4 levels are associated with improvements in lung function in patients receiving immunosuppressive therapy for systemic sclerosis-related interstitial lung disease,” was published in the journal Arthritis Research & Therapy.


Systematic autoantigen analysis identifies a distinct subtype of scleroderma with coincident cancer

Author: Robert Linda
Date Published: January-2017
Source: Johns Hopkins Rheumatology

A study by Livia Casciola-Rosen, Ph.D. and Aim Shah, M.D. from the Johns Hopkins Division of Rheumatology in collaboration with Steve J. Elledge, Ph.D. and collegues at MIT and Harvard, used cutting-edge technologies to identify a new subgroup of antibodies present in people without classical scleroderma-associated antibodies who develop cancer and scleroderma within a short period of time.


Changes in plasma CXCL4 levels are associated with improvements in lung function in patients receiving immunosuppressive therapy for systemic sclerosis-related interstitial lung disease

Author: E. Volkmann, D. Tashkin, M. Roth, P. Clements, D. Khanna, D. Furst, M. Mayes, J. Charles, C. Tseng, R. Elashoff and S. Assassi
Date Published: January-2017
Source: Arthritis Research & Therapy

Increased circulatory levels of the chemokine CXCL4 have been associated with the presence of interstitial lung disease (ILD) in an observational study of patients with systemic sclerosis (SSc). The purpose of the present study was to evaluate the relationship between baseline CXCL4 level and extent of ILD in the context of a randomized controlled trial and to determine whether changes in CXCL4 levels in response to immunosuppression are associated with future progression of SSc-ILD.


Gene Activity Predicts Progression of Autoimmune Disease, Researchers Find

Author: Jennie Dusheck
Date Published: December-2016
Source: Stanford Medicine

New research provides additional evidence that rituximab, a B-cell depletion therapy, improves lung fibrosis and reduces skin thickening in patients with systemic sclerosis (SSc).

Stanford researchers and their collaborators have found a way to tell whether patients with systemic sclerosis were improving during drug treatment a year before a standard clinical test could. Researchers at the Stanford University School of Medicine and six other institutions have designed a new diagnostic tool for a rare and deadly autoimmune disease that affects the skin and internal organs.


Systematic Autoantigen Analysis Identifies a Distinct Subtype of Scleroderma with Coincident Cancer

Author: George J. Xu, Ami A. Shahf, Mamie Z. Li, Qikai Xu, Antony Rosen, Livia Casciola-Rosen, and Stephen J. Elledge
Date Published: November-2016
Source: PNAS

In this study, we created a barcoded whole-genome ORF mRNA display library and combined it with phage-immunoprecipitation sequencing to look for autoantibodies in sera from patients with scleroderma who also had coincident cancer without a known autoantibody biomarker. Using these two technologies, we found that 25% of these patients had autoantibodies to RNA Binding Region Containing 3 (RNPC3) and multiple other components of the minor spliceosome. There was evidence of intra- and intermolecular epitope spreading within RNPC3 and the complex. These combined technologies are highly effective for rapidly discovering autoantibodies in patient subgroups, which will be useful tools for patient stratification and discovery of pathogenic pathways.


Many Systemic Sclerosis Patients with Raynaud’s Syndrome Soon Develop Other Conditions

Author: Joana Fernandes, PHD
Date Published: October-2016
Source: Scleroderma News

Patients with systemic sclerosis and Raynaud’s syndrome have a high risk of developing other organ complications within two years after the onset of Raynaud’s, according to a study published in the journal PLoS One. The authors reported that these complications mainly occur in the skin, gastrointestinal tract, lungs, heart, kidneys and prostate. The study, “Incidences and Risk Factors of Organ Manifestations in the Early Course of Systemic Sclerosis: A Longitudinal EUSTAR Study,” was conducted by Veronika Jaeger and her colleagues from the University Hospital Basel in Switzerland.


PAH Medications, Tracleer and Opsumit, Seen to Block Fibrosis in Systemic Sclerosis in Early Study

Author: Joana Fernandes, PHD
Date Published: October-2016
Source: Scleroderma News

Two approved treatments for pulmonary arterial hypertension — Tracleer (bosentan) and Opsumit (macitentan) — can block a molecular pathway that promotes fibrosis in systemic sclerosis (SSc), and may be a potential therapy for these patients as well, according to an early study. The study, “Bosentan And Macitentan Prevent The Endothelial-To-Mesenchymal Transition (Endomt) In Systemic Sclerosis: In Vitro Study,” was published in the journal Arthritis Research & Therapy.


Targeted Therapy for Scleroderma Fibrosis

Author: Sara R. Schoenfeld, MD, & Flavia V. Castelino, MD
Date Published: October-2016
Source: The Rheumatologist

Scleroderma, or systemic sclerosis (SSc), is an autoimmune disease characterized by vasculopathy and fibrosis. Although relatively rare, with a prevalence in North America of approximately 300 per 1 million people, SSc is associated with significant morbidity and high rates of mortality.1 Patients with scleroderma have four times greater mortality than age- and sex-matched controls, with the majority of deaths related to interstitial lung disease (ILD) and pulmonary hypertension (PH).2


Structural organization of the inactive X chromosome in the mouse

Author: Luca Giorgetti, Bryan R. Lajoie, Ava C. Carter, Mikael Attia, Ye Zhan, Jin Xu, Chong Jian Chen, Noam Kaplan, Howard Y. Chang, Edith Heard & Job Dekker
Date Published: July-2016
Source: Nature

X-chromosome inactivation (XCI) involves major reorganization of the X chromosome as it becomes silent and heterochromatic. During female mammalian development, XCI is triggered by upregulation of the non-coding Xist RNA from one of the two X chromosomes. Xist coats the chromosome in cis and induces silencing of almost all genes via its A-repeat region1, 2, although some genes (constitutive escapees) avoid silencing in most cell types, and others (facultative escapees) escape XCI only in specific contexts3. A role for Xist in organizing the inactive X (Xi) chromosome has been proposed4, 5, 6. Recent chromosome conformation capture approaches have revealed global loss of local structure on the Xi chromosome and formation of large mega-domains, separated by a region containing the DXZ4 macrosatellite.


Systemic sclerosis: The need for structured care

Author: Kathleen Morrisroe, Tracy Frech, Janine Schniering, Britta Maurer, Mandana Nikpour
Date Published: July-2016
Source: Clinical Rheumatology

Autoimmune connective tissue diseases (CTDs) have a propensity to affect multiple organ systems as well as physical function, quality of life, and survival. Their clinical heterogeneity, multisystem involvement, and low worldwide prevalence present challenges for researchers to establish a study design to help better understand the course and outcomes of CTDs.

Systemic sclerosis (SSc) is a notable example of a CTD, wherein longitudinal cohort studies (LCS) have enabled us to elucidate disease manifestations, disease course, and risk and prognostic factors for clinically important outcomes, by embedding research in clinical practice. Nevertheless, further efforts are needed to better understand SSc especially with regard to recognizing organ involvement early, developing new therapies, optimizing the use of existing therapies, and defining treatment targets.


Platelets induce thymic stromal lymphopoietin production by endothelial cells: Contribution to human systemic sclerosis fibrosis

Author: Marie-Elise Truchetet MD-PhD1, Béatrice Demoures, Jorge E. Guimaraes, Anne Bertrand, Paôline Laurent1, Valérie Jolivel1, et al
Date Published: July-2016
Source: Arthritis & Rheumatology

Objective To investigate the relationship between vascular damage and fibrosis in systemic sclerosis (SSc), we tested the hypothesis that platelets contribute to skin fibrosis via the activation of dermal microvascular endothelial cells and subsequent production of pro-fibrotic mediators.

Methods A total of 203 SSc patients and 30 healthy donors (HDs) were prospectively enrolled between 2012 and 2015 at the University Hospital of Bordeaux. Immunohistochemistry and immunofluorescence analyses were performed on skin biopsies from 18 SSc patients and 5 HDs. Serum TSLP levels were measured (ELISA) in the entire cohort. Human dermal microvascular endothelial cells and fibroblasts were purified from biopsies. Extracellular matrix production by cultured fibroblasts was assessed by RT-qPCR.


Clinical characteristics and predictors of gangrene in patients with systemic sclerosis and digital ulcers in the Digital Ulcer Outcome Registry: a prospective, observational cohort

Author: Daniel Rosenberg, Barbara Schwierin and Marco Matucci-Cerinic Yannick Allanore, Christopher P Denton, Thomas Krieg, Peter Cornelisse
Date Published: June-2016
Source: Annals of the Rheumatic Diseases

Digital vasculopathy in systemic sclerosis (SSc) consists of a spectrum of Raynaud’s phenomenon (RP), digital ulcers (DUs), critical digital ischaemia and escalation to gangrene. The complications of severe digital vasculopathy often require hospital-based management with intravenous therapies and surgery.1–3 Although gangrene is not infrequent in the clinic, data on the prevalence and implications of gangrene in patients with SSc are scarce.


Potential beneficial role for endothelin in scleroderma vasculopathy: inhibition of endothelial apoptosis by type B endothelin-receptor signaling

Author: Yongqing Wang, Nezam Altorok, Bashar Kahaleh
Date Published: June-2016
Source: Scleroderma Journal

Microvascular endothelial cell (MVEC) apoptosis is considered to be a key event in the pathogenesis of systemic sclerosis (SSc), an increased expression of endothelin-1 (ET1) is also well recognized in the disease. ET1 is thought to exert deleterious effects on the vasculature by virtue of its known vasospastic, proliferative and fibrotic effects, yet ET1 can act as a survival factor for a variety of cells, including MVEC. The aim of this study is to investigate if ET1 signaling protects SSc-MVECs from apoptosis.


An Open-label, Phase II Study of the Safety and Tolerability of Pirfenidone in Patients with Scleroderma-associated Interstitial Lung Disease: the LOTUSS Trial

Author: Dinesh Khanna, Carlo Albera, Aryeh Fischer, Nader Khalidi, Ganesh Raghu, Lorinda Chung, Dan Chen, Elena Schiopu, Margit Tagliaferri, James R. Seiboldand Eduard Gorina
Date Published: June-2016
Source: The Journal of Rheumatology

Systemic sclerosis-associated interstitial lung disease (SSc-ILD) shares a number of clinical features and pathogenic mechanisms with idiopathic pulmonary fibrosis (IPF). This study was designed to evaluate the tolerability of the IPF treatment pirfenidone in SSc-ILD. The known gastrointestinal, skin, and liver adverse events (AE) of pirfenidone are of importance given the involvement of these organs in SSc.


Frequency of circulating topoisomerase-I-specific CD4 T cells predicts presence and progression of interstitial lung disease in scleroderma

Author: A. Fava, R. Cimbro, F. Wigley, Q. Liu, A. Rosen and F. Boin
Date Published: May-2016
Source: BioMed Central

Scleroderma is an antigen-driven T cell-mediated autoimmune disease. Presence of anti-topoisomerase-I antibodies is associated with pulmonary fibrosis and predicts increased mortality. Characterization of autoreactive T lymphocytes may shed light on disease pathogenesis and serve as a biomarker for disease activity. Here, we aimed to quantify and functionally characterize circulating topoisomerase I (topo-I)-specific CD4+ T cells and to define their association with presence and progression of interstitial lung disease (ILD) in patients with scleroderma.


O27 Subcutaneous Tocilizumab in Adults with Systemic Sclerosis: 24 and 48 Week Safety and Efficacy Data from the Fasscinate Trial

Author: C. Denton, D. Khanna, A. Jahreis, J. van Laar, et al
Date Published: May-2016
Source: Oxford Journals Rheumatology

Background: Interleukin-6 (IL-6) appears to play a key role in the pathogenesis of SSc, a debilitating disease with limited treatment options. Methods: A double-blind, placebo-controlled, phase 2, proof-of-concept study of the efficacy and safety of the IL-6 receptor inhibitor tocilizumab (TCZ) (weekly s.c. injection; TCZ 162 mg vs placebo for 48 weeks) in patients ≥18 years of age with active SSc. The primary end point was a mean change in the modified Rodnan skin score (mRSS) from baseline at week 24. Change in the mRSS at week 48, patient-reported outcomes (PROs) and pulmonary function (week 48) were exploratory measures.


Clinical Trial Design Issues in Systemic Sclerosis: an Update

Author: Jessica K. Gordon, Robyn T. Domsic
Date Published: May-2016
Source: Springer Link

Systemic sclerosis (scleroderma, SSc) is a multisystem disease characterized by vasculopathy, autoimmunity, and fibrosis. SSc has the highest disease-related mortality rate among the rheumatologic illnesses. In the USA, there remains no FDA-approved therapy. As our understanding of SSc pathogenesis improves, targeted therapies interrupting key pathways and mediators will be studied in clinical trials. However, clinical trials in SSc are fraught with challenges. Validated clinical outcome measures do not exist for all disease manifestations. It can be difficult to discern disease activity from damage. SSc is highly heterogeneous, with multiple different phenotypes, and predicting who will have progressive disease is not currently well understood. Biomarkers are in early stages of development and do not represent surrogate outcomes at this time.


M10, a caspase cleavage product of the hepatocyte growth factor receptor, interacts with Smad2 and demonstrates antifibrotic properties in vitro and in vivo.

Author: Atanelishvili I, Shirai Y, Akter T, Buckner T, Noguchi A, Silver RM, Bogatkevich G
Date Published: April-2016
Source: Translational Research

Hepatocyte growth factor receptor, also known as cellular mesenchymal-epithelial transition factor (c-MET, MET), is an important antifibrotic molecule that protects various tissues, including lung, from injury and fibrosis. The intracellular cytoplasmic tail of MET contains a caspase-3 recognition motif "DEVD-T" that on cleavage by caspase-3 generates a 10-amino acid peptide, TRPASFWETS, designated as "M10". M10 contains at its N-terminus the uncharged amino acid proline (P) directly after a cationic amino acid arginine (R) which favors the transport of the peptide through membranes. M10, when added to cell culture medium, remains in the cytoplasm and nuclei of cells for up to 24 hours.


Esophageal dilatation and interstitial lung disease in systemic sclerosis: a cross-sectional study

Author: C. Richardson, R. Agrawal, J. Lee, O. Almagor, R. Nelson, J. Varga, M. Cuttica, J. D′Amico Dematte, R. Chang, M. Hinchcliff,
Date Published: February-2016
Source: Science Direct

A patulous esophagus on high-resolution computed tomography (HRCT) of the thorax is frequently observed in patients with systemic sclerosis (SSc). Microaspiration has been purported to play a role in the development and progression of SSc interstitial lung disease (ILD), but studies examining the role of microaspiration in SSc-ILD have yielded conflicting results. This study was conducted to determine the association between esophageal diameter and SSc-ILD.


The crowded crossroad to angiogenesis in systemic sclerosis: where is the key to the problem?

Author: Mirko Manetti, Serena Guiducci and Marco Matucci-Cerinic
Date Published: January-2016
Source: Arthritis Research & Therapy

Dysregulated expression of several proangiogenic and antiangiogenic factors has been implicated in the dysfunction of angiogenesis in systemic sclerosis (SSc). Into this complex scenario comes the study recently published in Arthritis Research & Therapy by Hirigoyen et al. [1], who report new data implicating an inhibitory splice variant of vascular endothelial growth factor (VEGF)-A, namely VEGF165b, in the inhibition of angiogenesis by platelets in SSc. These findings are part of an intriguing chain of data as several studies have shown that VEGF-A, one of the most potent promoters of angiogenesis, is markedly increased in SSc skin and circulation despite clear evidence of an insufficient angiogenic response [2, 3].


Treprostinil iontophoresis improves digital blood flow during local cooling in systemic sclerosis

Author: Florence Gaillard-Bigot, Matthieu Roustit, Sophie Blaise, et al
Date Published: January-2016
Source: Microcirculation

Severe Raynaud's syndrome and digital ulcers are the most prevalent manifestations of systemic sclerosis (SSc) peripheral microvascular disease. We tested whether treprostinil iontophoresis on the finger pad of patients with SSc would improve digital blood flow during hand cooling.