Presented during the XIX National Congress of Internal Medicine - Bologna 2014 Author: Riccardo Scagliola, MD

1. BENEFIT IN OUTCOME MEASURES INDUCED BY
BOSENTAN AMONG PATIENTS WITH SYSTEMIC
SCLEROSIS-ASSOCIATED PULMONARY ARTERIAL
HYPERTENSION: RESULTS OF A 5-YEAR
CARDIOLOGIC ASSESSMENT
Dott. Riccardo Scagliola
Clinica di Malattie
dell’Apparato Cardiovascolare e UTIC
IRCCS A.O.U. San Martino-IST - Genova
10 maggio 2014

2. The author has declared no conflicts of interest

3. Hemodynamic and pathophysiological condition defined as
an increase in mean pulmonary arterial pressure
(mPAP) ≥ 25 mmHg at rest
as assessed by right heart catheterization (RHC)
Prevalence: 15-25 cases / million adults
Incidence: 2-4 new cases / million adults / year
Poor prognosis - mean survival without therapy: 2.8 years
o Pre-capillary PH: PCWP ≤ 15 mmHg
o Post-capillary PH PCWP > 15 mmHg
(PCWP: Post-capillary Wedge Pressure)
PULMONARY HYPERTENSION (PH)
MILD 25-35 mmHg
MODERATE 36-45 mmHg
SEVERE > 45 mmHg
ESC Guidelines 2009

4. PH CLINICAL CLASSIFICATION
Geneva
1973
Evian
1998
Venice
2003
Dana Point
2008
Nice
2013
• Group 1: PAH (Pulmonary Arterial Hypertension)
• Group 2: PH due to left heart disease
• Group 3: PH due to lung disease and/or hypoxia
• Group 4: Chronic TromboEmbolic Pulmonary Hypertension
(CTEPH)
• Group 5: PH with unclear and multifactorial mechanisms

5. Normal
Pulmonary
Artery
Medial
Hypertrophy
Intimal
Proliferation
In-situ
thrombosis
Plexiform
Lesion

6. high flow
low resistance
low flow
high resistance
VASCULAR REMODELING
Adapted from Gaine S. JAMA 2002
Normal PAH

7. Time
Increasing PVR
Preclinical Symptomatic /
stable
Progressive /
declining
Level
Cardiac
output
at rest
Pulmonary
pressure
Cardiac
output at
peak
exercise
PATHOPHISIOLOGY

8. PATHOGENESIS
 ET-1
 NO
 Prostacyclin (PGI2)
 5-HT e 5-HTT
 RAA system
 H1 histone
 Ca²⁺ and K⁺ channels
 Growth factors
(PDGF; TGF-β; VEGF)
Humbert M. N Engl J Med 2004;351:1425-36

9. Vascular remodelling
• Smooth muscle cells blood vessels
• Fibroblasts
Fibrosis
• Fibroblastic proliferation
•  E.C. Matrix proteins
•  Production of collagenase
Inflammation
•  Vasal permeability
•  Neutrophiles/mastcells
• Promotion of cellular adhesion
 citokynes
Hipertrophy
• Cardiovascular/
vascular
Vasoconstriction
• Direct or by other vasoconstrictor
systems (i.e. RAA system;
sympathetic nervous system)
ET-1
Rubin LJ, et al. Expert Opin Investig Drugs 2002;11:991–1002.
Clozel M. J Cardiovasc Pharmacol 2000;35 (Suppl):65–8.
ET-1 = endothelin-1
ET-1: a key-role in CTD-PAH

10. o CTD: 10-30% of pt with PAH
o Prevalence of PAH in SSc: 7-15%
o Increase of ET-1 levels in SSc BAL
in early SSc cutaneous lesions and in SSc lungs
CTD Prevalence of PAH (%) References
Systemic Sclerosis 12-33%
Mukerjee D et al AnnRheumDis
2003
Morelli S et al AnnRheumDis 1995
MCTD 8-23%
Hosoda Y et al J Rheumatol 1987
Kondo H et all ArthrRheum 2001
LES 2-14% Simson JS et al JRheumatol 1989
Sjogren Syndrome 2-4%
Dawson JK et al Rheumatology
2000
Reumathoid arthritis 6-21% Gonzales C et al Seminars 2004
PAH associated with connective
tissue diseases (CTD-PAH)
AMNCO – Pulmonary Hypertension – BARI, 26 Gennaio 2008
Denton and Black. Rheum Dis Clin N
America 2003: 335-49.

11. PATIENTS
137 hemodynamic DG
↓
51 pt: PAH (group 1)
↓
22 pt: SSc-PAH
n = 22
F/M = 18/4
Mean age (years) = 70,4 ± 8,6
(range: 57-87)
Mean age at DG = 67 ± 9
(range: 48-83)
Respiratory comorbidities:
- COPD: 3 pt (14%) - ILD: 6 pt (27%)
23%
29%
18%
15%
8% 7%
Final dyagnosis
Pulmonary Hipertension
NO PH
Group 1 (PAH)
Group 2
Group 3
Group 4
Group 5

12. o CLINICAL EVALUATION
- World Health Organization Functional Class (WHO-FC)
o INSTRUMENTAL ANALISIS
- 2D ECHO
systolic Pulmonary Arterial Pressure (sPAP)
Tricuspid Annular Plane Systolic Excursion (TAPSE)
- Right Heart Catetherization (RHC)
o EXERCISE CAPACITY
- Six-minute walking distance test (6MWD)
o BIOCHEMICAL ANALYSIS
- NT-proBNP
- Antibody profyle
METHODS

13. RESULTS
(statistical analisis)
Retrospective analisis
5-years dedicated service
(2008 - 2013)
o U.O. C. Malattie
Apparato Cardiovascolare
o U.O. C. Medicina Interna
Orientamento Immunologico
58 SSc patients:
• SSc - PAH (n=22)
• SSc - no PAH (n=36)
SSc – PAH
(n=22)
SSc – no PAH
(n=36) p
Age (years) 70,4 ± 8,6 66,8 ± 14,6 n.s.
Age at diagnosis (years) 67 ± 9 65,2 ± 14 n.s.
F/M 18/4 34/2 n.s.
lcSSc (%) 17 (77,3%) 15 (41,6%) p = 0,0082
dcSSc (%) 4 (18,2%) 19 (52,8%) p = 0,0090
SSc ‘sine Scleroderma’
(%)
- 1 (2,8%)
Overlap syndromes (%) 1 (2,8%) 1 (2,8%) n.s.
WHO-FC I 1 (4,5%) 11 (30,5%) p = 0,0177
II 12 (54,6%) 23 (63,9%) n,s,
III 9 (40,9%) 2 (5,6%) p = 0,0009
NT-proBNP (ng/l) 6224,9 ± 9063 872,6 ± 1713 p = 0,0389
6MWD (m) 365 ± 153 412 ± 96 p = 0,0025
CR10 Borg dyspnea score 6,9 ± 1,1 4 ± 0,9 p = 0,0001
Echo sPAP (mmHg) 64 ± 20 41 ± 9,6 p = 0,0001
TAPSE (mm) 19,3 ± 5,3 21,9 ± 4,3 n.s.
RHC mPAP (mmHg) 36 ± 13 -
PCW (mmHg) 10 ± 5 -
PVR (dyn·s/cm5) 449 ± 36 -
PAD (mmHg) 8 ± 4 -
CO (l/min/m2) 2,6 ± 1 -

14. BASELINE MEASURES:
SSc-PAH vs SSc-no PAH patients
-4000
-2000
0
2000
4000
6000
8000
10000
SSc - PAH SSc - no PAH
NT-proBNP (ng/l)
P = 0,0389
0
100
200
300
400
500
600
SSc - PAH SSc - no PAH
6MWD - Walking distance (m)
P = 0,0025
0
20
40
60
80
100
SSc - PAH SSc - no PAH
ECHO PAPs (mmHg)
P = 0,0001
o Increase of estimated echocardiographic sPAP value (p = 0,0001)
o Reduction of walking distance at the 6MWD (p = 0,0025)
o Increase of CR10 Borg dyspnea score value (p = 0,0001)
o Increase of NT-proBNP plasmatic levels (ng/ml) (p = 0,0389)

15. BASELINE WHO-FC
4,5%*
30,5%*
54,6%
63,9%
40,9%*
5,6%*
0%
20%
40%
60%
80%
100%
SSc - PAH group SSc - no PAH group
WHO-FC I WHO-FC II WHO-FC III
*χ²-test: p < 0,01
SSc - PAH (n=22)
WHO - FC
o I = 1 pt (4,5%)
o II = 12 pt (54,6%)
o III = 9 pt (40,9%)
SSc - no PAH (n=36)
WHO - FC
o I = 11 pt (30,5%)
o II = 23 pt (63,9%)
o III = 2 pt (5,6%)

17. o Oral active non-selective ET-1A and
ET-1B ERA and the first molecule of its class
that was synthesized
o Started in patients in WHO-FC II-III
o Starting at dose of 62,5 mg x 2/die for 4
weeks, followed by 125 mg x 2/die
o Clinical (WHO-FC), instrumental (2D-ECHO),
functional (6MWD) and hemodynamic
(RHC) benefit
o Also indicated to treat active digital ulcers
and to prevent the development of new
digital ulcers among SSc patients.
BOSENTAN
ESC Guidelines 2009

18. o History of digital ulcers: 30-35% of SSc pt
o Active digital ulcers: 15-25% of SSc pt
o First case report: 1995
o BREATHE-1 and BREATHE-2:
Bosentan Randomized Trial of Endothelin-receptor Antagonist THErapy
o RAPIDS-1 and RAPIDS-2:
RAndomized placebo-controlled study on Prevention of Ischemic Digital Ulcers
in Scleroderma
‘’ Bosentan prevents the occurrence of new digital ulcers and long term trials
underlines how the ERA Bosentan speed the healing of active digital ulcers’’
Digital ulcers in SSc
Humbert M, Cabane J. Rheumatology 2003;42:191-193

19. OUTCOME MEASURES
SSc-PAH patients (n=22)
Bosentan treatment (2008→2013)
o Reduction of echocardiographic estimated sPAP from 67,7 mmHg
± 18,5 to 57,9 mmHg ± 13,5 (p = 0,0021)
o Increase of walking distance at the 6MWD from 365 m ± 153
to 376,2 m ± 132,4 (p = n.s.)
o Stable CR10 Borg dyspnea score value from 7,1 ± 0,8 to 6,9 ± 1
(p = n.s.)

20. WHO – FC sPAP (mmHg) 6MWD (m) CR10 Borg dyspnea
score
T0 T5 p value T0 T5 p value T0 T5 p value T0 T5 p value
Bosentan (n=16) 1,8 ± 0,7 1,6 ± 0,7 n.s.
42,7
mmHg
± 5
36,8
mmHg
± 3,6
p =
0,0340
412 m ±
96
497,3 m
± 66
p =
0,0131
4,1 ± 1 3,2 ± 0,7
p =
0,0082
Untreated
patients (n=20)
1,7 ± 0,4 2,3 ± 0,5
p =
0,0002
41,5
mmHg
± 7,6
42,8
mmHg
± 6,8
n.s.
478,5 m
± 97,1
404 m
± 101,2
p =
0,0441
4 ± 0,8 4,1 ± 0,6 n.s.
OUTCOME MEASURES
SSc-no PAH patients (n=36)

21. TAKE HOME MESSAGE (1)
o PAH: a late complication of SSc: a multisystemic connective
tissue disease with multiple organ involvement
o Identified risk factors: limited skin disease or CREST syndrome,
anti-centromere antibodies, disease duration ≥ 8-10 years, late
onset of SSc, reduced nailfold capillary density and elevated
serum NT-proBNP
o PAH is characterized by a worse clinical, instrumental and
prognostic impact on the quality of life, severe disability and a
reduction of any exercise tolerance among SSc patients

22. TAKE HOME MESSAGE (2)
o Bosentan treatment is correlated with the evidence of benefit in
outcome measures not only among SSc-PAH patients but also
among SSc-no PAH patients for the management of other signs
of disease, such as digital ulcers
o Bosentan treatment improves systemic vascular function,
producing beneficial effects not only to digital microcirculation
but also to other vascular districts, such as pulmonary
circulation. A pre-clinic treatment may suggest a potential
protective effect to pulmonary circulation in patients with
systemic sclerosis

23. o Oral active non-selective ET-1A and ET-1B ERA
o cp 10 mg
o 18 October 2013: FDA approved Macitentan for
treatment of adults PAH
o 20 December 2013: EMA approved Macitentan
for treatment of adults PAH
o SERAPHIN clinical trial
(Study with an Endothelin Receptor Antagonist in Pulmonary
Arterial Hypertension to Improve Clinical Outcome)
‘’…in conclusion, macitentan significantly reduced
morbidity and mortality among patients with
pulmonary arterial hypertension…’’
MACITENTAN
N Engl J Med 2013;369:809 - 818

24. GRAZIE PER L’ATTENZIONE