This document summarizes an expert talk on emerging therapies for systemic sclerosis. It discusses how scleroderma is now treatable with licensed therapies for pulmonary arterial hypertension and digital ulcers. Guidelines and access to treatments need improvement. Immunosuppression can benefit patients if risks are balanced. Targeted therapies are possible. Three recent clinical trials were encouraging by informing disease mechanisms and supporting therapy advances.

1. Christopher P. Denton PhD FRCP
Professor of Experimental Rheumatology
Royal Free Hospital and UCL Medical School,
London, UK
Emerging therapies for systemic
sclerosis

2. Disclosures
Consultancy:
Actelion, Pfizer, GSK, Sanofi Aventis, Boehringer Ingelheim,
Roche, CSL Behring, Genzyme, Inventiva
Research grant funding:
Actelion, Novartis, CSL Behring
Clinical trial investigator and steering committee :
Pfizer, Actelion, Sanofi-Aventis, MedImmune, United
Therapeutics, Novartis, Celgene, Bayer

3. Overview:
emerging
therapies
• Scleroderma
is
now
treatable
– Licensed
therapies
for
2
major
vascular
complica<ons
PAH
and
DU
– Recommenda<ons
and
guidelines
are
important
– Pathways
to
access
treatments
must
be
developed
• Immunosuppression
is
beneficial
– benefit
and
risk
need
to
be
balanced
• Targeted
approach
to
therapy
is
possible
• Three
recent
clinical
trials
are
encouraging
– Posi<ve
trials
inform
about
disease
mechanism
and
underpin
further
advances
in
therapy

4. dcSSc lcSSc
0 12 24 36 48 60
50
60
70
80
90
100
93%
91%
P=0.534
Disease duration (months)
Survival(%)
Disease onset
1990 -1993 n=234
2000 -2003 n=286
0 12 24 36 48 60
50
60
70
80
90
100
84%
69%P=0.018
Nihtyanova et al, QJM 2010; 103:109-15
Improving survival in systemic sclerosis: a
historical perspective

5. EULAR/EUSTAR
recommenda<ons
for
the
treatment
of
systemic
sclerosis
I
SSc-­‐related
digital
vasculopathy
(RP,
digital
ulcers)
1.
Calcium
channel
blockers
and
iloprost
for
Raynaud’s
2.
Intravenous
prostanoids
(in
par<cular
iloprost)
should
be
considered
for
treatment
of
digital
ulcers
in
SSc
3.
Bosentan
should
be
considered
in
SSc
with
mul<ple
digital
ulcers
II
SSc-­‐PAH
4.
Bosentan
should
be
strongly
considered
to
treat
SSc-­‐PAH
5.
Sildenafil
may
be
considered
to
treat
SSc-­‐PAH
6.
Sitaxentan
is
withdrawn
and
should
not
be
used
for
SSc-­‐PAH
7.
Intravenous
epoprostenol
should
be
considered
for
the
treatment
of
severe
SSc-­‐PAH
III
SSc-­‐related
skin
involvement
8.
Methotrexate
may
be
considered
for
treatment
of
skin
manifesta<ons
of
early
diffuse
SSc
IV
SSc-­‐ILD
9.
Cyclophosphamide
should
be
considered
for
treatment
of
SSc-­‐ILD
V
SRC
10.
ACE
inhibitors
should
be
used
in
the
treatment
of
SRC
11.
Pa<ents
on
steroids
should
be
carefully
monitored
for
SRC
VI
SSc-­‐related
gastrointes<nal
disease
12.
PPI
should
be
used
for
the
treatment
of
SSc-­‐related
gastro-­‐oesophageal
reflux,
13.
Prokine<c
drugs
should
be
used
for
the
management
of
SSc-­‐related
symptoma<c
mo<lity
disturbances
14.
When
malabsorp<on
is
caused
by
bacterial
overgrowth,
an<bio<cs
may
be
useful
in
SSc
Kowal-­‐Bielecka
et
al,
Ann
Rheum
Dis
2009;68:620-­‐628

6. • Best
prac<ce
documents
available
on
UKSSG
page
of
the
Scleroderma-­‐Royal
Free
website
• Stand-­‐alone
publica<ons
are
emerging
– GI
–
published
–
excellent
North
American
feedback
– Digital
vasculopathy
–
in
press
– Lung
fibrosis
–
for
submission
– Cardiac
–
in
prepara<on
– Renal
–
in
drag
form
UKSSG
Best
prac<ce
project
(2011-­‐14)
h,p://www.scleroderma-­‐royalfree.org.uk/UKSSG.html

7. • Work
started
September
2012
• February
2015
-­‐
submihed
to
BSR
and
first
stage
of
external
peer
review
–
presented
drag
April
2015
• Target
for
comple<on
September
2015
• Scope
and
structure
of
drag
guideline
A. General
approach
to
SSc
management
B. Key
therapies
and
treatment
of
organ
based
disease
C. Service
organiza<on
and
delivery
within
NHS
England
BSR
and
BHPR
guideline
for
the
management
of
systemic
sclerosis

8. Licensed targeted therapies for PAH in
systemic sclerosis
Endothelin receptor
antagonists
Selective
phosphodiesterase
inhibitors
Prostacyclin
analogues
Bosentan*
(approved
2001)
Ambrisentan
Sitaxentan
(withdrawn)
Macitentan
(approved
2013)
Sildenafil
(approved
2005)
Tadalafil
Riociguat
–
guanylate
cyclase
agonist
(approved
2013)
Epoprostenol
Trepros<nil
Iloprost
ET1
NO
cGMP
PGI2
Mechanism
p.o.
p.o.
i.v.,
s.c.,
inh.
*licensed
for
SSc
digital
ulcers
2007

9. Denton CP, et al. Ann Rheum Dis 2008; 67: 1222-8.
Pope J, et al. Presented at the ACR meeting, 2007.
100
80
90
70
60
50
40
30
20
10
0
Patientssurviving(%)
Time from treatment start (weeks)
0 16 32 48 64 80 96 112 128 144 160
Patients at risk 53 51 49 47 45 40 40 32 12 3 0
82% alive at 2 years
92% alive at 48 weeks
TRUST
TRacleer Use in PAH associated with Scleroderma and other
connective Tissue diseases – 3-year survival data
SSc n=42 (80%)
MCTD/overlap n=6 (11%)
SLE n=5 (9%)
mPAP = 40 (+13) mm Hg
PVR = 559.4 (+371.5) dyn/s/cm–5

10. NHS
England
policy
for
DU
in
SSc*
• Sildenafil
• Prostenoids
(iloprost)
• Bosentan
access
for
severe
cases
– Severe
refractory
disease:
persistent
or
progressive
ulcera<on
of
one
or
more
digits
causing
or
threatening
<ssue
loss
despite
op<mal
treatment
with
vasodilators
including
IV
prostanoids
and
oral
sildenafil,
or
– Mul<ple
DUs:
3
or
more
DUs
either
currently
or
occurring
in
the
last
12
months
despite
IV
prostanoids
and
sildenafil.
Challenging
process
(18
months)
with
reduced
access
during
development
compared
with
previous
arrangements
(IFR)
*First
published:
January
2015
Prepared
by
NHS
England
Specialised
Services
Clinical
Reference
Group
for
Specialised
Rheumatology
Published
by
NHS
England,
in
electronic
format
only.

11. 1Hoyles et al Arthritis Rheum 2006; 54:3962-70
Cyclophosphamide for lung fibrosis in SSc
• Fibrosing alveolitis in scleroderma trial (FAST)1 monthly intravenous
cyclophosphamide 600mg/m2 for 6 months followed by (po) azathioprine,
or placebo in 45 patients
– Over 12 months FVC change favoured active treatment (p=0.04, BMI corrected –
uncorrected p=0.08)
FAST primary outcome: FVC
p=0.08
2.44
2.46
2.48
2.50
2.52
2.54
2.56
2.58
2.60
2.62
2.64
baseline 3 months 6 months 9 months 12months
Months from baseline
AbsoluteFVC(meanateachtimepoint)
ACTIVE PLACEBO
– Magnitude of difference 5.5% (4.8% adjusted)
• active arm improved (+2.5 % predicted)
• placebo arm worsened (-3.0 % predicted)

12. Agreed
pathway
for
UK
pa<ents
to
be
evaluated
for
autologous
stem
cell
transplanta<on

13. Concept of targeted therapy in systemic sclerosis
Varga, J., Denton et al. (2015) Systemic sclerosis
Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.2
Pathway Process Organ

14. Emerging molecular therapies for SSc
Candidate therapy Target pathway
• Bosentan, macitentan ETA/ETB receptor
• Ambrisentan ETA receptor
• Selexipag IP receptor agonist
• Riociguat cGMP agonist
• Infliximab, Adalimumab TNFα ligand
• Etanercept TNFα ligand
• Rituximab CD20
• Basiliximab IL-2Rα
• MLM-1202 CCR2
• Efalizumab LFA1/ICAM-1
• Abatacept CTLA4
• AIMSPRO® (HCS) MSH, IL10, CCL2
• Tocilizumab IL-6R
• ACT12339 LPA1
• Imatinib, Dasatinib, Nilotinib c-Abl, c-Kit, PDGF
• CAT-192 TGFβ1
• GC-1008 TGFβ1,-β2,-β3
• FG-3019 CCN2
• P144 TGFβ1 (topical)
• Anti-αvβ6 integrin TGFβ activation
• Pirfenidone TNFα, IL1β, TGFβ
• Nintedanib (BIBF1120) VEGF,PDGF,FGF
VascularInflammatoryFibrotic

15. Targeting the IL-6 axis in diffuse systemic sclerosis
1
8
0
1
2
0
6
0
0
1
0
0
8
0
6
0
4
0
2
0
0
Disease
duraNon
(months)
Number
at
risk
High
Low
15
5
3
1
24
15
5
1
IL-­‐6
serum
level
at
presenta<on
predicts
survival
Survival
%
p=0.02,
Log
rank
analysis
high
Low
IL-­‐6
Khan
et
al.
Ann
Rheum
Dis.
2012;71:1235-­‐42.
X200
vascular
Immunostaining
IL-­‐6
in
dcSSc
skin
X200
fibroblast
IL-­‐6
(pg/ml)
Controls
50
40
30
20
10
0
dcSSc
High
plts
dcSSc
Normal
plts
lcSSc
*
IL-­‐6
serum
level
in
SSc
50403020100
40
30
20
10
0
IL-6 (pg/ml)
MRSSat36months
r=0.86
p<0.01
IL-­‐6
serum
level
at
presenta<on
predicts
skin
score
at
36
months

16. Conclusions
• Treatment
of
scleroderma
is
improving
• Established
treatments
are
being
used
in
beher
ways
e.g.
immunosuppression
• Licensed
drugs
are
available
for
specific
complica<ons
• Access
to
treatment
requires
co-­‐ordinated
and
persistent
efforts
of
medical
teams,
pa<ents
and
pa<ent
organisa<ons
• Recent
clinical
suggest
more
targeted
skin
treatments
are
likely
to
emerge
over
the
next
few
years
• New
scleroderma
lung
fibrosis
trials
are
being
planned

17. Many thanks to ….
• Our patients
• The “Scleroderma team” at Royal Free
• Research Funders
• Colleagues in many institutions and organisations
• UKSSG colleagues
• International collaborators – EUSTAR, SCTC and FESCA, WSF
Arthritis Research UK, Raynaud’s and Scleroderma Association (UK), Wellcome Trust (UK),
Nuffield Foundation, Scleroderma Society (UK), Rosetrees Trust, Scleroderma Research
Foundation (USA), MRC, EULAR, Royal Free Charity