Journal
of Scleroderma and Related Disorders (JSRD) – Abstracts Volume 1
June
Scleroderma Awareness Month 2017
Raynaud's, Autoimmune Rare Disease. 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
Conclusions:
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
Conclusions:
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
Conclusions:
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
Conclusions:
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
Conclusions:
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:
Introduction:
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
Conclusions:
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
Conclusions:
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?
Introduction:
Data on pregnancy in SSc are
limited. IMPRESS is a retrospective study comparing 99 SSc women with general
obstetric population.
Conclusions:
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
Introduction:
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.
Conclusions:
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
Introduction:
Investigation of keratinocytes
contributing to the development of skin fibrosis.
Conclusions:
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
Introduction:
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.
Conclusions:
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
Introduction:
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.
Conclusions:
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
CARDIAC
Inflammatory
cells and stromal sub populations involvement in the myocardial fibrogenesis in
systemic sclerosis
Introduction:
The role of inflammatory and
stRomal cells in myocardial remodelling in SSc.
Conclusions:
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
Introduction:
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.
Conclusions:
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
Introduction:
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.
Conclusions:
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
Introduction:
Arrhythmias are frequent in
SSc and portend a bad prognosis.
Conclusions:
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
Introduction:
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.
Conclusions:
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)
Introduction:
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.
Conclusion:
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.
PARALLEL
SESSION 6
Current research in immunity / inflammation
Pan
PPAR Agonist IVA337 is effective in prevention and treatment of experimental
skin fibrosis
Introduction:
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.
Conclusions:
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
Introduction:
An integrative meta analysis
of ten different SSc gene expression datasets that identify common disease
drivers and infer sequence of disease progression, was analysed.
Conclusions:
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
Introduction:
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.
Conclusion:
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
Introduction:
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.
Conclusion:
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
Introduction:
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.
Conclusion:
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.
LECTURE
3
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
Introduction:
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.
Conclusion:
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.
LECTURE
4
Impaired Micronutrient Status In Patients
With SSc
Introduction:
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.
Results:
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.
Conclusion:
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.
SESSION
8
ROUND TABLE SSc REGISTRIES IN THE WORLD
Phenotypes
determined by cluster analysis and their survival in the prospective EUSTAR
cohort of patients with SSc
Introduction:
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.
Conclusion:
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)
Background:
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.
Conclusions:
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
Introduction:
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.
Conclusions:
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
Introduction:
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).
Conclusion:
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.
LECTURE
5
Survival and organ involvement in patients
with limited cutaneous SSc and anti-topoisomerase antibodies: more like lcSSc
or dcSSc?
Introduction:
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.
Conclusions:
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.
PARALLEL
SESSION 9
Experimental Models of Scleroderma
UPAR-deficient
mice: A novel experimental model of delayed cutaneous wound healing to explore
SSc related digital ulcers
Introduction:
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.
Conclusion:
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
Introduction:
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.
Conclusions:
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
Introduction:
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.
Conclusions:
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)
Introduction:
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).
Conclusions:
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
Introduction:
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.
Conclusions:
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
Introduction:
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.
Conclusion:
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
Introduction:
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.
Conclusions:
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
Introduction:
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.
Conclusions:
The findings strongly suggest
that Nox4 is a promising candidate for clinical trials n SSc patients using
Nox-subtype-specific NADPH inhibitors.
PARALLEL
SESSION 10
Outcome Measures
Prediction
of Improvement in Skin Fibrosis in Diffuse Cutaneous SSc – A EUSTAR analysis
Introduction:
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.
Conclusions:
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
Introduction:
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
Introduction:
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.
Conclusions:
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
Introduction:
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.
Conclusions:
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
Introduction:
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.
Conclusions:
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
Introduction:
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.
Conclusions:
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
Introduction:
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.
Conclusions:
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.
SESSION
11
EMERGING THERAPIES
Efficacy
of mycophenolate mofetil (MMF) versus oral cyclophosphamide (CYC) on skin
thickness in the scleroderma lung study
Introduction:
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).
Conclusions:
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)
Introduction:
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’).
Conclusions:
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
Introduction:
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.
Results:
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.
Conclusions:
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
Introduction:
Since 2009, we have treated with
fat and StRomal Vascular Fraction systemic sclerosis patients.
Conclusions:
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.
To view the current issue of the JSRD, Click here
To read more about why I chose ‘Patient Profiling and
Research’ as the focus of my 2017 campaign, Click here
Why Research and Patient Profiles? Scleroderma Awareness
Month 2017, Raynaud's, Rare Autoimmune Disease, Click here
INDEX to Scleroderma
Awareness 2016 Campaign, Click here
June 2016.
To read my articles:
Rare Disease Day 2018, Research - Taking Part in Clinical Trials, Click here
March Autoimmune Disease Awareness Month 2018, Click here
Global patient video, Click here
Becoming a Patient Research Ambassador for the NIHR, Click here
If we only had more RESEARCH investment for Scleroderma, Raynaud's, Autoimmune Rare Disease, Click here
The Pandora’s Box of the rare autoimmune disease
Scleroderma, Raynaud's and Cancer, Click here
World Scleroderma Day 29th June 2017, Click here
Why Global Collaboration is important to the Rare Disease Patient, Click here
RARE DISEASE DAY:
Rare Disease Day 2018 – Research, Taking
Part in Clinical Trials. Scleroderma, Raynaud's, Autoimmune Rare Disease, Click here
2016 Rare Disease Day Patient Voice
2016 Rare Disease Day Patient Voice
Rare
Disease Day is a fantastic opportunity for the entire rare disease
community to shine a spotlight on their reality, combining as one unified
voice. Where, at least one commonality presides –
Medical
Research provides the brightest light
for the illumination of the rare disease
patients’ plight.
I
highlighted other areas of medical research interest within Week 3 of my Patient Profiles Campaign for Scleroderma Awareness Month 2017.
VIDEO
VIDEO
Although
rare disease patients are few in number, eg. 2.5 million scleroderma patients
worldwide, (the World Scleroderma Foundation), the commonalities and golden
hallmark for each rare disease patient are the same:
Early Diagnosis
Expert Specialist Centres
Access to Innovative Medicines
Where MEDICAL RESEARCH investment
is VITAL.
Research
is the key. Abstracts from 2016 World Congress, Click here
The Family Day at the Scleroderma Unit, The Royal
Free Hospital is taking place on the 19th May 2018. Browse the
program, here
This year, I am celebrating 20 years of being a
patient at this world leading expert specialist research centre.
 |
| Sept 2017 |
I am eternally grateful to the global scleroderma
trail blazers Dame Prof Black and Prof Chris Denton, whose commitment and
dedication to unlocking the scleroderma enigma, is nothing other than,
superhuman.
I am truly humbled and inspired by their work
ethic. I am wholly appreciative for Prof Denton’s continued medical expertise
and support, especially during my barrister qualifying years, 1997 -
2004.
1st March 2004, I qualified as a self
employed practising barrister. Further to having been told in 1997, by my
diagnosing doctor, that I was looking at a 15month prognosis.
I very much hope to utilise my professional skills
and qualifications along with my patient experience, to help achieve the
#SclerodermaFreeWorld dream, hoping to improve understanding and best practice,
in the meantime.
For latest updates follow:
Facebook Page:
Twitter: @SclerodermaRF @RaynaudsRf
Google Plus: RaynaudsSclerodermaAwarenessGlobalPatients
#SclerodermaFreeWorld
#RaynaudsFreeWorld
#ADAM #Scleroderma
#Raynauds
#RareDisease
Living the dream, scleroderma style.
Please DONATE to help
fund medical research at The Scleroderma Unit,The Royal Free Hospital, London.
100% of your monies will be used for medical
research purposes only. No wages or admin costs. Thank You.
#HOPE
Last Update: April 2018
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