Sunday, 18 June 2017

Journal of Scleroderma and Related Disorders (JSRD) – Abstracts Volume 1, Scleroderma Awareness Month, Raynaud’s, Rare Disease, 2017, Patient Profiles

JSRD Volume 1 Number 1 January - April 2016, Abstracts
Journal of Scleroderma and Related Disorders (JSRD) – Abstracts Volume 1,
Scleroderma Awareness Month, Raynaud’s, Rare Disease, 2017, Patient Profiles  

Official Journal of World Scleroderma Foundation and The European Scleroderma Trials and Research group (EUSTAR)

Volume 1 Number 1 Abstracts from Congress 

Session 1: Pulmonary involvement

Association between skin gene expression and clinical phenotype in Ssc  

The data suggests ‘intrinsic’ subtype classification may indicate points of SSc disease severity between inflammatory and proliferative intrinsic subtypes.
These results have important implications for clinical trial design.  

Incidences and predictors of organ manifestations in the early course of Ssc: A longitudinal EUSTAR study  

In SSc patients presenting early after Raynaud’s phenomenon onset, approximately half of all incident organ manifestations occur within 2 years.
These results have important implications for clinical trial design, as well as show the essential requirement for an early diagnosis, to prevent potential life threatening damage.    

Antibodies against chemokine receptors CXCR3 and CXCR4 as marker for lung fibrosis in patients with SSc    

The presence of these receptors along with the corresponding autoantibodies are linked with clinical manifestations of SSc, mainly with signs of lung fibrosis and with the progress of the disease. CXCR4 mRNA expression on PBMC was higher in patients with digital ulcers, low lung function, and, in patients with cardiac involvement, compared to those without these manifestations.   

Session 2 Ulcers:   

Role of stimulating antibodies against angiotensin and endothelin receptors in the pathogenesis of SSc 

The presence of the receptor antibodies were dependent on the antibody levels as well as clinical features of their donor. Thereby offering a novel perspective to investigate mechanisms of the disease.   

Sensitivity to change of nailfold videocapillaroscopy (NVC) and relationship with disease progression   

NVC pattern change was observed in 20% of patients with SSc during a follow up of 3 years. NVC has the ability to detect meaningful changes over time associated with markers of disease progression.    

Digital ulcers in SSc: Predictor Factors:  

Late scleroderma pattern in NVC is the best independent risk predictor for new digital ulcers. Biomarkers indicating endothelial dysfunction, serum levels of Endothelin-1, were found to be independent predictors of digital ulcer recurrence in the 3 year follow up.  

Prevention of digital ulcers in SSc: real life data from the DESSIPHER observational study of the EUSTAR group   

History of digital ulcers in the past 24 weeks should trigger an active prevention strategy. Treatment with calcium channel blockers or ace inhibitors alone is associated with 7 fold increased risk of developing new digital ulcer compared to all other treatment arms.   

Lecture 1

Macitentan responsiveness supports the validity of a murine model of pulmonary hypertension in scleroderma associated with altered TGFBETA/BMPRII signalling 
Macitentan prevents and treats the development of hisotological and haemodynamic PH in this mouse model of SSc. This model replicates imbalance seen in PAH-SSc signalling. This model can be useful for experimental therapeutic studies.

Parallel Session 3
Common clinical situations with poor evidence based data: How to manage?   

Data on pregnancy in SSc are limited. IMPRESS is a retrospective study comparing 99 SSc women with general obstetric population.
IMPRESS-2 is still going on, hoping to answer:
Are SSc complications more frequent during pregnancy?
Are some autoantibodies protective for prematurity?
Which is the prematurity impact on children development?

Parallel Session 4

Advances in epigenetics and genetics

Inhibition of phosphodiesterase 4 (PDE4) reduces dermal fibrosis by interfering with the release of pro-fibrotic cytokines from M2-Macrophages  

PDE4 catalyses the breakdown of the second messengers cAMP and cGMP to modulate intracellular effects. PDE4 is mainly expressed in inflammatory cells, and its inhibition leads to reduced inflammatory cell activity.
PDE4 inhibition reduces the release of pro-fibrotic cytokines from M2 macrophages, which leads to decreased fibroblast activation and collagen release.
Rolipram is a lead compound of the PDE4 inhibitor apremilast, which is indicated for treatment of psoriatic arthritis.
These findings prompt the use of PDE4 inhibition clinical studies in SSc patients with inflammation driven fibrosis.    

Epithelial FLI1 deletion induces fibrosis and autoimmunity with downregulation of AIRE – possible roles in SSc pathogenesis  

Investigation of keratinocytes contributing to the development of skin fibrosis.
Deficiency of transcription factor FLI1 in epithelial cells has significance in the pathogenesis of SSc.

Endothelial to Mesenchymal transition (ENDOMT) as a key profibrotic switch in SSc  

Profibrotic myofibroblasts may arise from different sources. Endothelial cells may also exhibit substantial plasticity by undergoing EndoMT where the cell loses its specific markers and acquires mesenchymal cell products such as fibroblast proteins and collagen.
The results show direct evidence that EndoMT may contribute to the development of dermal fibrosis in SSc.

WNT/PCP-Signalling as a β-Catenin-independent pathway to promote fibroblast activation in SSc  
Canonical Wnt/beta-catenin signalling has been identified as a core pathway of fibrosis in SSc. This study aimed at analysing the non-canonical Wnt pathway and the role of Wnt5a in fibrotic diseases.
Wnt5a was found to be a novel mediator of fibroblast activation in SSc. Upregulation of Wnt5a induces fibroblast activation and promotes tissue fibrosis. The pro-fibrotic effects of Wnt5a are independent of canonical Wnt signalling and are mediated by PCP signalling via binding with Ror2 and Ryk receptor and JNK/cJun activation.

Parallel Session 5


Inflammatory cells and stromal sub populations involvement in the myocardial fibrogenesis in systemic sclerosis  

The role of inflammatory and stRomal cells in myocardial remodelling in SSc.
Inflammatory and stRomal cells might play a pivotal role in TGF-b1/Fra-2 driven myocardial remodelling. Targeting of identified key-cellular sources of myocardial fibrogenesis in SSc animal models might serve the basis for developing effective therapies.   

N-Terminal Pro Brain Natriuretic Peptide is a strong predictor of mortality in SSc  
Cardiovascular involvement is a key contributor to mortality. This study investigated whether the cardiac biomarker NT-proBNP could be used for the prognostic assessment in SSc.
The results showed that NT-proBNP is strongly and independently associated with 3 year and 5 year mortality. 125ng/L is confirmed as a threshold value.   

Cardiac biomarkers in primary heart involvement in SSc: NT-proBNP and Troponin T as diagnostic and prognostic biomarkers  

The aim of the study was to identify primary cardiac involvement in SSc patients, defining the role of cardiac troponin T (cTnT) and NT-proBNP.
cTnT and NT-proBNP identify patients with subclinical heart disease and allow to define a poor cardiac outcome and to guide further specialistic imaging and therapy.  

Prognostic role of ventricular ectopic beats in SSc  

Arrhythmias are frequent in SSc and portend a bad prognosis.
Ventricular ectopic beats (VEBs) are frequent in SSc and correlate with cardiac damage; 1190/24h identify patients at high risk of ajor arrhythmic complications. 24h-ECG-Holter should be considered as routine evaluation and could be an additional risk stratification test to select SSc-patients at high risk of sudden cardiac death, in whom an implantable cardioverter defibrillator implantation could represent a potential life saving intervention.

Early detection of cardiac involvement by magnetic resonance: clinical correlations in SSc  

Myocardial fibrosis affects prognosis. Echocardiography is the routine imaging tool to easily detect cardiac involvement, but it is not accurate to detect myocardial fibrosis. Delayed gadolinium enhancement (DE) cardiovascular magnetic resonance (CMR) is superior for myocardial fibrosis assessment.
CMR can detect patterns of reversible (by T2-weighted) and irreversible (by DE) cardiac involvement, often without detectable systolic and diastolic left ventricular dysfunction. The majority of patients with ventricular alterations at ecg Holter monitoring show DE, underlying the potential role of myocardial fibrosis in the genesis of ventricular arrhythmias.
There is an association between a history of ulcers and myocardial fibrosis that may suggest a similar pathological substrate of abnormal vascular function, underlying digital and cardiac complications.

Imaging patterns of stress perfusion-fibrosis in SSc using cardiovascular magnetic resonance (CMR)  

Perfusion’s defects and consequent fibrosis are major causes of cardiac disease in SSc. By using stress perfusion-fibrosis CMR, the imaging can detect a pattern of heart involvement during various stages of SSc.
Reduction in Myocardial Perfusion Reserve Index (MPRI) is more common in patients with recently diagnosed SSc than myocardial fibrosis identified by late gadolinium enhanced images which in contrast was predominantly noticed in the long standing SSc group. Whether MPRI is an earlier marker of heart involvement in SSc and its implications remain to be determined.   


Current research in immunity / inflammation

Pan PPAR Agonist IVA337 is effective in prevention and treatment of experimental skin fibrosis  

Evidence suggest that peroxisome proliferator-activated receptors (PPARs) play an important role in SSc-related fibrosis and their agonists may become effective therapeutic approaches.
The objective of this study was to determine the expression of PPARs in human fibrotic skin and investigate the effects of IVA337, a pan PPAR agonist, in in vitro and in vivo models of fibrosis.
The findings indicate that simultaneous activation of all three PPAR isoforms exerts a dampening effect on inflammation and fibrosis making IVA337 a potentially effective therapeutic candidate for the treatment of fibrotic diseases.

Multi organ systems biology analysis of systemic sclerosis reveals a macrophage signature associated with disease severity in multiple end-target tissues  

An integrative meta analysis of ten different SSc gene expression datasets that identify common disease drivers and infer sequence of disease progression, was analysed.
A model highlighting the SSc-PF response is thought to be initiated by an interferon response, followed by lipid uptake by lung macrophages that are alternatively activated and may secrete TGFbeta. This model may reflect the process of fibrosis in all SSc end-target tissues. Genes that bridge multiple molecular processes (eg ECM remodelling, apoptosis) have been tested experimentally and shown to be important in animal models of PF. 

TIE2 as a novel factor of peripheral microangiopathy in SSc  

The angiopoietin (ang)/Tie2 system is a key regulator of vascular biology. The stable expression of membrane bound (mb) Tie2 and Ang1 is responsible for vessel stability, whereas Ang2, inducible by VEGF, hypoxia and pro-inflammatory stimuli, acts as an antagonist.
This study investigates the role of ang/Tie2 in the peripheral vasculopathy in SSc including different animal models.
Peripheral microvasculopathy in SSc results from a complex dysregulation of angiogenic signalling networks including VEGF and the Ang/Tie2 system. The Ang/Tie2 system is profoundly disturbed in SSc and might represent an important target for vascular therapeutic approaches.  

The role of IL-17 cytokine family members in SSc skin  

CD4+ Tcells are characteristically present in SSc skin, particularly in perivascular areas. This study investigates the presence and function of cytokines mainly produced by Th17 cells, which numbers are increased in SSc.
Dermal expression of IL-17C(low) and IL-17E(high) idenitifies a fibrosis-specific motif. IL-22 capacitates fibroblast responses to TNF and promotes a pro-inflammatory fibroblast phenotype by favouring TNF-induced keratinocyte activation. 

Estrogens inhibit the profibrotic effects of TGF-Beta and protect from the development of experimental dermal fibrosis  

SSc primarily affects postmenopausal women. This sex bias raises the question of the role of female hormones on SSc phenotype. The aim of this study was to evaluate the effects of estrogens i) in the development of experimental dermal fibrosis, and ii) on the response of dermal fibroblasts to transforming growth factor-β.
The results show a beneficial effect of estrogen in experimental dermal fibrosis. Estrogens reduce TGF-β dependent activation of SSc dermal fibroblasts and estrogen inhibition leads to a more severe experimental dermal fibrosis.
These findings may partly contribute to the occurrence of SSc in postmenopausal women and the greater severity of the disease in men and open avenue to potential hormone therapies.  


Increased frequency of malignancies, and in particular breast cancer, synchronous to the onset of SSc in anti-RNA polymerase III antibodies positive patients: A EUSTAR multicentre study  

Data taken collectively to investigate clinical associations with anti-RNAP SSc, taking into account recent data that demonstrated a link between immune response against cancer cells and the generation of anti-RNAP.
Anti-RNAP are associated with severe clinical manifestations of SSc, and with malignancies synchronous to the onset of SSc (in particular, breast cancer).
These findings have relevant prognostic implications which should guide the monitoring and follow up of these patients. 


Impaired Micronutrient Status In Patients With SSc  
Micronutrients are essential dietary factors involved in numerous metabolic processes, including oxidative stress, collagen synthesis and wound healing, which are also important for the pathogenesis of SSc. Considering the frequent GI involvement and impaired nutritional status, micronutrients were analysed.  

Out 0f 176 patients with SSc:
Almost half (44%) showed a deficiency in at least one of the measured micronutrients.
The most frequent deficit was seen in selenium – 22%
Folic acid 17%
Prealbumin 15%
Nearly a fifth (19%) had multiple deficiencies
There was a significant association between low levels of zin and selenium, prealbumin and folic acid, respectively.

Deficiencies in micronutrients correlate with clinical aspects of the disease. Especially patients with more advanced skin fibrosis are at high risk for an impaired micronutrient status. These results suggest that screening for micronutrients status should be performed in SSc patients.



Phenotypes determined by cluster analysis and their survival in the prospective EUSTAR cohort of patients with SSc  

SSc is classically dichotomized in limited or diffuse cutaneous subsets (lcSSc/dcSSc) associated with different prognosis. However, it appears that SSc is a highly heterogenous disease.
The primary objective of this study was to identify and characterise homogeneous phenotypes in the EUSTAR SSc population using a cluster analysis. The secondary objective is to assess the survival in the different clusters.
This cluster analysis on the largest ever worldwide database of SSc patients showed 5 different clusters characterised by different sex ratio , mRSS, autoantibodies status, joint and organ involvement as well as by a different prognosis.
Although SSc is a heterogeneous disease, this study shows that homogeneous groups beyond the classical limited/diffuse dichotomy can be delineated in this disease.

Low frequency of renal crisis in more than 3100 patients of the German Network for SSc (DNSS)  

Scleroderma rena crisis (SRC) is a rare manifestation but still a medical emergency in patients with SSc. To improve detection and follow-up of patients with SSc, the German Network for Systemic Scleroderma (DNSS) was founded in 2003 implementing a patient registry recording data on diagnosis, organ involvement and therapy in a prospective manner.   
Compared to data collected 10 to 20 years ago, SRC has become a rare complication in SSc with a frequency of less than 2%.
Whereas a number of previously defined risk factors were confirmed, it remains to be shown whcihc factors are protective for the development of SRC.

Guidelines for the rational use of follow-up cardiac echocardiography to screen for pulmonary arterial hypertension (PAH) in SSc  

Clinical practice guidelines recommend screening of all SSc patients for PAH with yearly echocardiograms. However, this may not be cost effective due to its low sensitivity and specificity and the low incidence of PAH in SSc. The prmary objective of this study was to develop a risk prediction score to identify SSc patients who do not need an annual echocardiogram after a baseline echocardiogram.
A simple risk prediction score consisting of DLCO and SOB can identify subjects at risk of PAH in a general SSc population. More than 50% of SSc subjects are at very low risk of PAH and it would be reasonable to defer annual echocardiogram screening in this group, representing large savings in health expenditures. These findings represent the first evidence based risk score for the rational use of echocardiograms in an unselected SSc cohort. 

Determinants of unemployment amongst Australian Scleroderma patients: Results from a large multicentre cohort study  

Work disability is a significant consequence of chronic rheumatic disorders, impacting both the society through indirect costs and the individual and their family through loss of income and social activities, and a negative influence on quality of life. We sought to assess employment status, risk factors for unemployment, and the associations of unemployment with patients’ health related quality of life (HRQOL).
SSc is associated with substantial work disability and poor quality of life. Raising awareness, identifying modifiable risk factors and implementing employment strategies and modifications to work place environments are possible ways of reducing this burden and potentially improving patients’ HRQOL.  


Survival and organ involvement in patients with limited cutaneous SSc and anti-topoisomerase antibodies: more like lcSSc or dcSSc? 
SSc has two main subtypes based on skin involvement: limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous systemic sclerosis (dcSSc). LcSSc is associated with anti-centromere antibodies (ACA) and a mild course whereas dcSSc is associated with anti-topoisomerase (ATA) and a severe course.
However, ATA can also be present in lcSSc, but little is known about this subgroup and the course of disease concerning survival and organ involvement. If it is possible to improve subclassification of SSC patients and to improve recognition of high risk patients, those patients can be screened more tightly and receive treatment to prevent organ involvement and premature death.
lcSSc ATA positive subjects do not resemble lcSSc ATA negative subjects or dcSSc ATA positive subjects, but have a different course of disease regarding survival an organ involvement. This could be the first step in the development of risk stratification for lcSSc ATA positive patients and the development of a new subclassification for SSc patients.  


Experimental Models of Scleroderma

UPAR-deficient mice: A novel experimental model of delayed cutaneous wound healing to explore SSc related digital ulcers  

Digital ulcers are a painful complication of SSc. Their treatment is challenging, and therapeutic options are limited. The development of animal models of SSc related ulcers would help to screen drugs with potential benefit.   

Urokinase-type plasminogen activator receptor (u.PAR) knock out mice was recently described as a good model of peripheral microvasculopathy and skin fibrosis. The objective of this work was to assess the wound healing process on uPAR-KO mice in comparison with uPAR-KO mice in comparison with uPAR-wt mice.  

SSc related digital ulcers are very handicapping and lead to a decrease in the quality of life of patients. Here we showed that u.PAR-KO mice presented a delayed wound healing process, making this model a good model to explore new pharmacological strategies in the treatment of these ulcers. Further experiments with this novel experimental model should be proposed to screen potential drugs that would enhance the wound healing process.

GL12 as a target for antifibrotic therapies in preclinical models of SSc  

Hedgehog signalling plays a crucial role in the pathogenesis of SSc. Besides canonical hedgehog signalling with Smoothened (Smo)-dependent activation of Glitranscription factors, Gli can be activated independently of classical hedgehog ligands and receptors (non canonical pathways).  

The aim of the present study was to characterise the role of non-canonical hedgehog signalling in SSc and to address the efficacy of direct Gli-inhibitors that target simultaneously canonical and non-canonical hedgehog pathways.  

These results characterise Gli2 as a central mediator of fibroblast activation in SSc and as a potential target for anti-fibrotic therapies. We demonstrate that Gli2 is activated in SSc not only by canonical, but also by TGF-β dependent, non-canonical pathways. Genetic and pharmacologic inhibition of Gli2 ameliorates fibrosis in murine models of dermal and pulmonary fibrosis in preventative and therapeutic settings. These finding may have translational implications as non selective inhibitors of Gli2 are already in clinical use and selective inhibitors are currently developed.  

Small peptides derived from MET receptor Tyrosine Kinase as new therapeutic approach for the treatment of SSc  
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 several motifs demonstrating antifibrotic effects in lung and skin fibroblasts. 
MET-derived peptides demonstrate antifibrotic effects by counteracting Smad-dependent fibrogenic pathways. Cell-protective effects of MET-derived peptides 1403 and 1404 in AEC are based on inhibition of caspase-3-induced apoptosis. MET-derived peptides should be considered as potential therapeutic agents for SSc and other fibrosing diseases.

CM-101, A novel monoclonal antibody blocking CCL24 ameliorates experimental SSc and Idiopathic Pulmonary Fibrosis (IPF)   
SSc and IPF share in part, common pathogenic pathways in the genesis of tissue fibrosis. Chemokines have been sporadically reported to be expressed in these disorders. Previously we have shown that the CCL24/CCR3 pathway is significantly expressed in affected SSc skin tissues and in the lungs of IPF patients. A novel monoclonal antibody (mAb) against human CCl24 was shown to attenuate chemokine induced fibroblast and inflammatory cell migration in vitro. Aim: to test CM-101 in two models of SSc and IPF induced either by subcutaneous or intratracheal instillation of bleomycin (BLM).
CM-101, a novel mAb blocking CCL24 is effective in reducing skin thickness and lung fibrosis in two murine models of experimental SSc and IPF respectively.

A novel antibody blocking CCL24/CCR3 reduces chemokinesis of immune cells and the transition of fibroblasts to myofibrobalsts in SSc  
In SSc the contribution of inflammation, fibrosis and endothelial dysfunction is significant to the evolution of the disease. Chemokines have been shown to be involved in this process and some have been circumstantially associated with the pathogenesis of SSc. Usually, CCL24 and its receptor CCR3 are potent chemokines that are principally investigated in allergic reactions. Aim: to perform a preliminary evaluation of the role of the CCL24/CCR3 pathway in SSc either in vivo and in vitro and verify the role of a new monoclonal antibody against CCL24 in interfering with some fundamental mechanisms of SSc pathogenesis.
CCL24 levels are significantly higher in SSc sera and this chemokine is also expressed along with its receptor in affected SSc skin tissues. In vitro, a humanised blocking antibody to the CCL24 attenuates chemokinesis of immune cells and reduces fibroblast to myofibroblast transition. This novel monoclonal antibody might represent a new therapeutic strategy for SSc patients.  

Effects of Nintedanib on fibrotic and vascular manifestations in preclinical models of SSc  

Nintedanib is a powerful inhibitor that inhibits PDGF-, FGFR-, VEGFR-receptors and Src kinases activity simultaneously. It has been approved for the treatment of idiopathic pulmonary fibrosis (IPF). The aim of this study was to evaluate the effects of nintedanib on fibrotic manifestations in preclinical models of SSc as well as on vascular manifestations in the fos-related-antigen-2 (Fra2) model.   
Nintedanib inhibits fibroblasts activation and exerts anti-fibrotic effects in several complementary mouse models of SSc. Nintedanib also ameliorates SSc-like vascular features in Fra2-tg mice. These preclinical findings might have direct implications for the upcoming phase III clinical trial with nintedanib in SSc.

M2-shifted mice recapitulate dermal and pulmonary remodelling  

Characteristics of SSc includes excessive fibrosis and microvascular abnormalities. Several lines of recent evidence showed that monocytes were actively involved in pathogenic process of SSc through differentiating into alternatively activated (M2) rather than classically activated (M1) phenotype. We accidentally found that mice transgenic (TG) for Fra-1, one of AP-1 components, developed thickening of lung interstitium and narrowing of the lumen of pulmonary arteries. Interestingly, it has been reported that Fra-1 TG mice represent resistance to dextran sulfate sodium-induced colitis by suppression of monocyte differentiation into M1 phenotype. The aim is to investigate whether M2-shfted monocytes promote fibrotic phenotype using Fra-1 TG mice.
M2-shifted environment in Fra-1 TG mice promote dermal and pulmonary remodelling, resembling histologically to skin sclerosis, interstitial lung disease, and pulmonary arterial hypertension typically observed in patients with SSc.

NOX4  is a crucial mediator of TGF-BETA1-Induced Fibroblast activation of dermal fibroblasts – novel findings from in vitro  and in vivo scleroderma research  
Members of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) family are emerging as important players in a number of fibrotic diseases. We recently hypothesized that Nox4 could be a promising target for the treatment of SSc.
The findings strongly suggest that Nox4 is a promising candidate for clinical trials n SSc patients using Nox-subtype-specific NADPH inhibitors.  


Outcome Measures

Prediction of Improvement in Skin Fibrosis in Diffuse Cutaneous SSc – A EUSTAR analysis  
The course of skin fibrosis varies widely across patients with dcSSc. An overall tendency towards improvement has been observed, but its determining factors are sill unknown. Recognising those patients prone to improve could avoid unnecessary use of therapy. Moreover, excluding ‘spontaneous improvers’ could support cohort enrichment in clinical trials in skin fibrosis. In this study we aim to identify predictors for improvement of skin fibrosis over 1 year in patients with dcSSc.
According to these evidence based data, dcSSc patients with high baseline mRSS and absence of tendon friction rubs are most likely to experience improvement of skin fibrosis within 1 year, under standard of care.
Therefore they should be considered for exclusion from trial recruitment and perhaps also not seleceted for treatment (at least as long as the drug of choice has been shown to induce regression). Conversely, focus for treatment intervention and recruitment in clinical trials in skin fibrosis should shift to at risk patients with low to moderate skin fibrosis. 

Development of a disease damage index in systemic sclerosis using consensus and data driven methods 
As there is currently no index for quantifying organ damage in SSc, we sought to develop a disease damage index in SSc (SSc-DI) reflective of mortality and morbidity for use in interventional and observational studies.
Conclusions: ]the combined use of consensus and data driven methods has enabled development of a preliminary weighted Damage Index reflective of mortality and morbidity. By the time of the World SSc Congress 2016, further consensus will have been achieved at a face-to-face working group meeting at ACR ASM in San Francisco. 

EUSTAR task force for the development of a revised activity criteria for SSc  
SSc is a polymorphic disease and defining disease activity in SSc cannot be done using a single variable. In 2001, the European Scleroderma Study Group (EScSG) identified 11 disease activity variables and developed a preliminary activity index. Its criterion validity is supported by several studies although some limitations were raised including a questionable face validity of hypocomplementemia. Here we present the results of a EUSTAR study devoted to the optimisation of a validated SSc activity index. Our objective was to identify a validated set of activity criteria.
A revised SSc activity index has been developed that performs better than the previous activity index.

Complementary Value of ELF Test and NT-PROBNP in reflecting fibrosis and vasculopathy in SSC  
The ELF test and its components (PIIINP, TIMP-1 and HA) have been shown to correlate with skin, lung and overall fibrosis and not with any vascular manifestation of SSc. On the contrary, NT-proBNP has been suggested to be useful for stratification of SSc patients, especially to identify those at risk of pulmonary hypertension.
Aims of this study were: a. to validate ELF score and its single analytes on an independent cohort of scleroderma patients; b. to evaluate whether NT-proBNP could provide additional value to the development of a SSc- specific algorithm.
The findings validate the value of ELF score in a second independent cohort of 250 SSc sera and suggest that NT-proBNP has a cpmlementary value correlating with other aspects of the disease such as PAH and heart severity.
Longitudinal multicentres are warranted to determine the sensitivity to change and the predictive value of these biomarkers in SSc patients and to build up a new combined scleroderma specific algorithm including markers of fibrosis and vasculopathy. 

The Scleroderma Fibrotic Score: A useful serum test in the diagnosis of early scleroderma  
VEDOSS (Very Early Diagnosis of Systemic Sclerosis) is an international study aimed to identify, in patients at risk of SSc, factors predictive of progression and internal organ involvement.
The data indicates that the SSc score is a simple serum test that can be used in patients with Raynaud’s Phenomenon to aid in the early diagnosis of SSc. Furthermore, the identification of VEDOSS patients with high SSc score test even in the absence of internal organ involvement can be used in intervention trials aimed to prevent further disease progression.  

Very early and early SSc patients in the Spanish Scleroderma Registry (RESCLE) Cohort  
SSc is a complex disease difficult to diagnose at subclinical stages.
Very early SSc (presence of specific SSc autoantibodies and / or nailfold capillaries with scleroderma pattern) and Early SSc or pre-SSc (very early SSc characteristics plus at least one of the following: reduced lower esophageal sphincter pressure, reduced diffusing lung capacity for carbon monoxide or diastolic abnormalities at B-mode echocardiography, and / or digital ulcers, pitting scars, telangiecatasias, calcinosis or arthritis.
Early SSc can evolve into definite SSc within a short-term follow up more frequently than very early SSc. A thorough internal organ evaluation is mandatory in patients with RP and positive ANA, nailfold abnormalities or both to identify patients at risk for developing SSc over time.

From VEDOSS to established SSc diagnosis according to the new ACR/EULAR 2013 classification criteria: A capillaroscopic survey  

Nailfold Capillaroscopy (NC) is a diagnostic and sensitive tool in order to investigate Raynaud’s Phenomenon (RP) that is the hallmark of both SSc and Very Early Diagnosis of ScS (VEDOSS) patients. Thus NC is largely used in patients with these conditions and NC specific abnormalities have become a minor criteria in ACR/EULAR SSc Criteria in 2013.
Our study shows a progression of NC changes during the evolution of early SSc. Moreover we identified some NC features, such as higher NC score ad larger apex width, whose presence at the very early diagnosis of SSc may suggest its development in an established disease, thus underlying the relevance of specific NC abnormalities as predictive risk factor.    



Efficacy of mycophenolate mofetil (MMF) versus oral cyclophosphamide (CYC) on skin thickness in the scleroderma lung study   

A randomised controlled trial comparing MMF vs oral CYC in patients with symptomatic scleroderma-related interstitial lung disease (SLS II), assessing the modified Rodnan skin score (mRSS).
In the SLS II, 2 year of daily MMF and 1-year of CYC was associated with clinically important improvements in mRSS in the diffuse cutaneous subset at 24 months. These data support use of MMF or CYC for management of skin fibrosis in ealry diffuse cutaneous SSc.    

Baseline Characteristics and treatment choices in patients with early diffuse cutaneous systemic sclerosis (ESOS Co-hort)   

ESOS (European Scleroderma Observational Study) is a prospective observational study to compare effectiveness of different immunosuppressants currently used by clinicians treating early diffuse cutaneous systemic sclerosis (dcSSc).
Here we report baseline characteristics of the study cohort and compare these between the 4 different treatment protocols (methotrexate, mycophenolate mofetil, cyclophosphamide, and ‘no immunosuppressant’).
The short disease duration of the ESOS cohort suggests that patients with early disease (and therefore likely to progress) have been enrolled. Baseline characteristics were analysed and several potential confounders were identified: these will be taken into account in the longitudinal analysis examining treatment response. Our findings underscore the high disease burden of patients with early dcSSc in terms of internal organ involvement and functional impact.    

Inhibition of myeloid-associated gene expression in skin biopsy samples of systemic sclerosis patients treated with Tocilizumab  

SSc is a progressive, debilitating disease with limited treatment options. IL-6 has been implicated in disease pathogenesis. Tocilizumab (TCZ), an IL-6Rα inhibitor, was evaluated in the 2-year faSScinate study, a randomised, double blind, placebo controlled trial. At week 24 (primary end point), favourable trends in skin score for TCZ were detected though the primary skin score end point was not met. In addition, smaller declines in FVC were observed in the TCZ-treated patients.  
Of the 86 genes selected for follow-up expression analysis, 75 were, on average, significantly overexpressed in SSc patients compared with healthy volunteers. Analysis of genes significantly downregulated after TCZ treatment and stable or increased with placebo identified a subset of 14 genes highly enriched for myeloid-associated genes, including genes associated with M2 macrophages.
All 14 genes were overexpressed in SSc patients compared with healthy volunteers. No effect of TCZ on the fibrosis and IFN pathways was detected. Serum levels of the M2 macrophage chemokine CCL18 revealed a rapid and sustained decrease from elevated levels in the TCZ group close to levels in healthy controls but not in placebo controls.
The effect of TCZ on myeloid-associated genes may reflect inhibition and/or depletion of skin-infiltrating macrophages. In addition, the effect of TCZ on CCL18 (RNA and protein), CD163, MS4A4A, and MSR1 suggests a specific inhibitory effect of TCZ on M2 macrophages, which are known to promote fibrosis and inflammation.
These findings represent a potential novel mode of action for TCZ in SSc, which will be further investigated in the upcoming phase 3 study of TCZ in SSc.   

Treating scleroderma of the face and hands with fat and stromal vascular fraction 

Since 2009, we have treated with fat and StRomal Vascular Fraction systemic sclerosis patients.
We conclude that microfat grafting on the face is efficient to treat functional and aesthetic disorders. The injection of stRomal vascular fraction in fingers triggers an obvious functional improvement in everyday life activities. Two randomised clinical trials are underway in France and USA.
Overall, these safe and minimally invasive techniques provide an important benefit in terms of aesthetic and functional improvements.    

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June 2017 Total

Living the dream hoping for a cure

#SclerodermaFreeWorld #RaynaudsFreeWorld
#RareDisease #Hope #Belief 

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Thanks to USA patient Sharon Esposito for sharing her wonderful creativity

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#SclerodermaFreeWorld #RaynaudsFreeWorld
#RareDisease #Hope #Belief

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