Dr. Roberto Machado from the University of Illinois at Chicago presented an update on PAH at a Patient Education Conference on March 15, 2014 hosted by the Scleroderma Foundation, Greater Chicago Chapter.

1. Update on Pulmonary Arterial
Hypertension in Scleroderma
Scleroderma Patient Education Conference
March 15th 2014
Roberto F. Machado, MD
Section of Pulmonary and Critical Care, Allergy and Sleep
University of Illinois at Chicago College of Medicine

2. Interstitial Fibrosis
Potentially treatable;
not currently reversible
Recurrent Aspiration Treatable
Pulmonary Hypertension Treatable within limits
The major clinical issue is defining the relative contribution of
each process and choosing the appropriate therapy.
Scleroderma and the Lung

3. Badesch D et al. J Am Coll Cardiol. 2009;54:S55-S66.
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
Hemodynamic Definition of PH/PAH
PH
PAH
Mean PAP ≥25 mm Hg plus
PCWP/LVEDP ≤15 mm Hg
Mean PAP ≥25 mm Hg
ACCF/AHA includes PVR >3 Wood Units

4. Clinical Classification of Pulmonary
Hypertension (Dana Point)
1. PAH
• Idiopathic PAH
• Heritable
• Drug- and toxin-induced
• Persistent PH of newborn
• Associated with:
−CTD
−HIV infection
−portal hypertension
−CHD
−schistosomiasis
−chronic hemolytic anemia
1’. PVOD and/or PCH
2. PH Owing to Left Heart Disease
• Systolic dysfunction
• Diastolic dysfunction
• Valvular disease
3. PH Owing to Lung Diseases and/or Hypoxia
• COPD
• ILD
• Other pulmonary diseases with mixed
restrictive and obstructive pattern
• Sleep-disordered breathing
• Alveolar hypoventilation disorders
• Chronic exposure to high altitude
• Developmental abnormalities
4. CTEPH
5. PH With Unclear Multifactorial Mechanisms
• Hematologic disorders
• Systemic disorders
• Metabolic disorders
• Others
Simonneau G et al. J Am Coll Cardiol. 2009;54;S43-S54.

5. LV
A
LA
RA
RV
PT
PVOD
ILD
Pulmonary Hypertension (PH) in CTD
PAH
LV systolic or
diastolic dysfunction
↑ LAP

6. Vasculopathy in Scleroderma
• Masson-Trichrome stain of digital artery from
patient with SSc
• Striking fibrotic intimal
hyperplasia
• Adventitial fibrosis
• Arterial lumen severely
compromised

7. Nearly 25% of PAH Is CTD-related:
REVEAL Registry
Based on Venice Clinical Classification (2003); 2967 patients.
Adapted from Badesch DB et al. Chest. 2010;137:376-387.
Overall Associated
Associated
(50.7%)
Idiopathic
(46.2%)
Heritable
(2.7%)
Pulmonary
veno-occlusive
(0.4%)
Connective tissue/
collagen vascular
(49.9%)
Congenital
heart disease
(19.5%)
HIV
(4.0%)
Other
(5.5%)
Drugs/Toxins (10.5%)
Portopulmonary (10.6%)

8. SRC
PAH
GI
PF
Heart
Multi-organ
1972-
1976
1977-
1981
1982-
1986
1987-
1991
1992-
1996
1997-
2001
Changing Patterns of Mortality
in Scleroderma
Steen VD. Ann Rheum Dis. 2007;66:940-944.
PAH p=0.05
GI p=0.43
Heart p=0.26
50
40
30
20
10
0
Year of death
p<0.001(SRC)
p<0.001 (PF)
Frequency(%)

9. Impact of Untreated Lung Disease in
SSc
Koh ET. Br J Rheumatol. 1996;35:989-993.
Survival
(%) Lung involvement (without PH)
(n=73)
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Years from diagnosis of PH
PH (n=17)
No lung disease
(n=138)

10. Stupi AM et al. Arthritis Rheum.1986;29:515-524.
Steen VD, Medsger TA Jr. Arthritis Rheum. 2003;48:516-522.
Stupi AM et al:
Average PA pressure: 82/35 (50) mm Hg
Average PA resistance: 16 Wood units
Average cardiac index: 2.1 L/min/m2
Impact of PAH on Survival in Limited
SSc Before PAH Therapy
Steen V et al:
Average PASP: 76 mm Hg
SSc with
PAH
(n=20)
(n=106)
SSc without
PAH
(n=287)
(n=106)
%
cumulative
survival
Follow-up (yr)
0
20
40
60
80
100
1 2 3 4 5

11. Summary of Risk Factors for PAH in
Scleroderma
• Long disease duration (usually >8 yr)
• Limited scleroderma > diffuse scleroderma
• Abnormal pulmonary function tests
– low DLCO <55% predicted and FVC %/DLCO % >1.6
• Autoantibody profile
– anticentromere antibody
– antinucleolar pattern on ANA (anti-U3 antibody, which
is not clinically available)

12. Prevalence
~8.0%
Screening for PAH in Scleroderma
Hachulla E et al. Arthritis Rheum. 2005;52:3792-3800.
SSc patients with no severe pulmonary function abnormalities
(N=599; n=29 with known PAH)
Doppler echocardiography (n=570)
VTR <2.5 m/s VTR 2.5–3 m/s VTR >3 m/s
NO DYSPNEA
(or dyspnea explained
by another cause)
DYSPNEA
(not explained
by another cause)
Suspected PAH
(n=33)
No PAH
Right heart catheterization
mPAP at rest <25 mm Hg mPAP at rest ≥25 mm Hg
and PAWP <15 mm Hg
mPAP
during exercise
<30 mm Hg
mPAP
during exercise
≥30 mm Hg
Confirmed PAH
(n=18)
No PAH
(n=15)

13. Latest Recommendations for Screening
and Detection of SSC-Associated PAH
General Evidence-based Guidelines
Khanna D et al. Arthritis Rheum. 2013 Sep 10. doi: 10.1002/art.38172. [Epub ahead of print]
• All patients with SSc should be screened for
PAH
• All SSc and scleroderma-spectrum patients
with a positive non-invasive screen should
be referred for RHC
• RHC is mandatory for diagnosis of PAH

14. Latest Recommendations for Screening
and Detection of SSc-Associated PAH
Khanna D et al. Arthritis Rheum. 2013 Sep 10. doi: 10.1002/art.38172. [Epub ahead of print]
Initial SSc Screening Evaluation
• FT with DLCO (high)
• Transthoracic echocardiogram (TTE) (high)
• NT- Pro BNP (mod)
• DETECT algorithm if DLCO% < 60% and >3 yrs disease duration (mod)
Frequency of Noninvasive Tests
• TTE annually as screening (low); if new signs or symptoms develop (high)
• PFT with DLCO annually as screening (low qual); if new signs or symptoms
develop (low)
• NT-Pro BNP if new signs of symptoms develop (low)

15. Impact of Proactive Screening in
Systemic Sclerosis

16. CTD patients are known to be a high-risk patient population.
Why aren’t they identified earlier than other PAH patients?
*Modified NYHA/WHO functional class.
Badesch DB et al. Chest. 2010;137:376-387.
CVD/CTD Patients Are Often Diagnosed
With More Advanced Symptoms
7.6
36.7
50.0
5.6
0
20
40
60
80
100
I II III IV
Patients(%)
FC* at Enrollment
REVEAL Registry (All Patients)
(n=2525)
5.7
32.2
54.9
7.2
0
20
40
60
80
100
I II III IV
FC* at Enrollment
REVEAL Registry (CVD/CTD)
(n=639)

17. Screening Can Help in Diagnosing the
Disease in an Early Stage
1
24
63
12
0
20
40
60
80
100
I II III IV
Patients(%)
NYHA FC (N=674)
Humbert M et al. Am J Respir Crit Care Med. 2006;173:1023-1030.
Hachulla E et al. Arthritis Rheum 2005: 52:3792-3800.
No Screening
Without screening, the majority of patients were diagnosed in NYHA
FC III or FC IV, and only 24% of patients were in NYHA FC II at diagnosis.
5
44
28
11
0
20
40
60
80
100
I II III IV
NYHA FC (N=18)
With Screening

18. Values are mean ± SD.
Humbert M et al. Arthritis Rheum. 2011;63:3522-3530.
Hemodynamics at PAH-SSc Diagnosis:
“Routine Practice” and “Detection”
Patients
Routine Practice
(n=16)
Detection
(n=16) p
RAP (mm Hg) 10 ± 5 6 ± 3 0.020
mPAP (mm Hg) 49 ± 11 34 ± 10 0.0004
mPAWP (mm Hg) 9 ± 4 10 ± 3 0.28
Cardiac output (L/min) 3.59 ± 1.10 5.96 ± 1.51 <0.0001
Cardiac index (L/min/m2) 2.37 ± 0.81 3.42 ± 0.92 0.0028
PVRI (dynes.s.cm-5.m-2) 1500 ± 602 613 ± 400 <0.0001

19. Prognosis of “Routine Practice” and
“Detection” PAH-SSc Patients
100
80
60
40
20
0
Survival(%)
1 3 5 8
Years of follow-up
100%
75%
31%
25%
17%
81% 73%
64%
Routine
practice
PAH-SSc
Detection
PAH-SSc
p=0.0037
HR=4.15
(95% CI 1.47–11.71)
Adapted from Humbert M et al. Arthritis Rheum. 2011;63:3522-3530.

20. Treatment for
Scleroderma-associated PAH

21. cGMP
cAMP
Vasoconstriction
and proliferation
Endothelin
receptor A
Exogenous
nitric oxide
Endothelin-
receptor
antagonists
Endothelin
receptor B
Phosphodiesterase
type 5 inhibitor
Vasodilation
and antiproliferation
Phosphodiesterase
type 5
Vasodilation
and antiproliferation
Prostacyclin
derivatives
Nitric Oxide
Endothelin-1
Pre-proendothelin
L-arginine
Prostaglandin I2
L-citrulline
Nitric Oxide
Pathway
Endothelin
Pathway
Prostacyclin
PathwayEndothelial cells
Proendothelin
Endothelial cells
Arachidonic acid
Smooth muscle cells
Prostacyclin (prostaglandin I2)
Smooth muscle cells
PAH Treatment: Targeting Known
Pathophysiological Pathways
Prostacyclins
Epoprostenol, Treprostinil
Iloprost (inhaled)
PDE-5 Inhibitors
Sildenafil, Tadalafil
SGC Stimulator
Riociguat
Endothelin Receptor Antagonists
Bosentan, Ambrisentan ,
Macitentan
Adapted from Humbert M et al. N Engl J Med. 2004;351:1425-1436.

22. Combination Therapy
*Half of patients on combination therapy
†SERAPHIN, 64% on combination therapy, 5% of patients on prostanoid; PATENT 1, 6%.
SGC
Stimulators
Prostanoids
Endothelin
Receptor
Antagonists
Phospho-
diesterase
Inhibitors
TRIUMPH
STEP
SERAPHIN† TRIUMPH
PACES
PATENT-1*
PATENT-1*
?
?
???
PHIRST*
SERAPHIN†

23. Morrell, N. W. et al. JACC 2009; 54(1 Suppl):S20-31.
Some Cellular Processes Implicated in the
Pathogenesis of PAH

24. Am J Respir Crit Care Med, 2014 http://www.atsjournals.org/doi/abs/10.1164/rccm.201308-1543PP
Treatment for PAH: The Pipeline

25. Post-transplant Survival
Saggar R et al. Eur Respir J. 2010;36:893-900. [Epub 2010 Mar 29.]
0.00
0.25
0.50
0.75
1.00
Survival
proportion
Time after lung transplant (mo)
0 12 24 36 48 60
SSc
IPF

26. Long-term Management
• PH therapies are not curative
– long-term progression should be anticipated
• Re-assess patients frequently and have high
index of suspicion for progression
• Escalate level of care if treatment response
inadequate or progression encountered

27. Summary
• Approximately 1 in 8 SSc patients develops PAH
• Early detection of and intervention in PAH are
critical to delaying onset of right heart failure
• Multiple medical therapies are available but CTD-
associated PAH can be less responsive and
challenging to treat
– combination therapy is becoming the mainstay
• We continue to study new targets that we hope will
reverse the progressive nature of the disorder