Presentation in WestBengal IRA branch annual meeting 2023

1. Recent update in scleroderma Pulmonary
Hypertension
Dr Ritasman Baisya

2. Points of discussion
• 1. Update in definition
• 2. Advances in pathogenesis
• 3 Risk and screening update
• 4 Medical therapy including immunosuppression
• 5.SSc-PAH with mPAP 21-24 mm Hg
• 6. Subsets of PH in scleroderma – latest opinion
• 7.Future in SSc-PH

3. Abbreviation
• SSc-PAH- Scleroderma pulmonary arerial hypertension
• Lc SSc- Limited cutaneous scleroderma
• Dc SSc – diffuse cutaneous scleroderma
• PH-LHD – PH –left heart disease
• PVOD – pulmonary veno-occlusive disease
• mPAP- mean pulmonary arterial pressure
• PVR- Pulmonary vascular resistance
• WSPH- World symposium pulmonary hypertension

4. Introduction
• SSc-PAH has poor prognosis with 3-year survival of only 52%
• The incidence in LcSSc & DcSSc is 1.25 and 0.4 cases / 100 patient-years
• Mortality remains high despite the availability of PAH-specific therapy
• Survival of patients with SSc-PAH is worse than with idiopathic PAH (IPAH)

5. Potential pulmonary hypertension (PH) classification groups associated with systemic
sclerosis
Haque A, Kiely DG, Kovacs G, et al. Pulmonary hypertension phenotypes in patients with systemic sclerosis. Eur
Respir Rev 2021; 30: 210053

6. Causes of PH in SSc
• Pulmonary arterial vasculopathy ( group 1, pulmonary arterial hypertension)
• PH due to left heart disease (group 2) – PH-LHD
• PH due to lung disease (group 3; ILD , combined fibrosis & emphysema ) – PH-ILD
• Pulmonary veno-occlusive disease ( group 1)
• Chronic thromboembolic PH (group 4)
• Patients with a previous SRC who progress to end-stage chronic kidney disease (
group 5 disease)

7. Changing definitions of PH
• The diagnostic threshold of mPAP mmHg would remain until the sixth WSPH in 2018 where it was
proposed that the threshold be reduced to >20 mmHg
• PVR was incorporated into the definition of PAH at the third WSPH using a threshold of >3 Wood
Units (WU)
• PAH at the fifth WSPH, albeit with the slight change of including patients with a PVR ⩾3 WU (as
opposed to >3 WU)

8. First WSPH Second
WSPH
Third
WSPH
Fourth
WSPH
Fifth
WSPH
Sixth
WSPH
Year 1973 1998 2003 2008 2013 2018
mPAP >25 Not defined >25 >25 >25 >20
PVR in PAH >3 ≥3 >3
PAWP post-
capillary
threshold
>15 >15 >15 >15
Isolated post-
capillary PH
PVR <3, TPG
>12
DPG <7 PVR <3
Combined pre
& post-capillary
PH
PVR > 3, TPG
>12
DPG >7 PVR >3
PH-exercise Discussed
but not
defined
>30 no no no
mPAP 21-24 20 mm Hg
as upper
limit of
normal
recognized
At risk patients
(CTD ) should be
followed closely
Most now
defined as PH ,
mPAP >20 ,
PAWP < 15 but
PVR <3

9. Haque A, Kiely DG, Kovacs G, et al. Pulmonary hypertension phenotypes in patients with systemic sclerosis. Eur Respir
Rev 2021; 30: 210053.

10. Patient characteristics
• SSc-PAH - Older age group & lower DLCO independent prognostic marker
• The lower DLCO - increased alveolar-capillary block due to overt or covert ILD,
reduced capillary blood volume related to the nature of the pulmonary vasculopathy
or a component of PVOD. .
• Anti-endothelin receptor type A antibodies and anti-angiotensin receptor type-1
antibodies in SSc-PAH
Ramjug S, Hussain N, Hurdman J, Billings C, Charalampopoulos A et al . Idiopathic and Systemic Sclerosis-
Associated
Pulmonary Arterial Hypertension: A Comparison of Demographic, Hemodynamic, and MRI Characteristics and

11. Risk factors
• Anticentromere antibody, anti-RNA-polymerase-III and anti-Th/To antibodies
• Recent studies have suggested that PAH is almost as common in diffuse disease
• A reduced and falling gas transfer (DLCO) is common in patients with SSc-PAH
• Mean DLCO of 52% predicted 4.5 years prior to the diagnosis of PAH

12. Risk stratification strategies
• REVEAL 2.0
• French Pulmonary Hypertension Network (FPHN)
• COMPERA 55
• Swedish Pulmonary Arterial Hypertension Registrar (SPAHR).
• REVEAL LITE 2.0

13. Summary of four registries assessing risk scores
WORLD SYMPOSIUM ON PULMONARY HYPERTENSION | N. GALIÈ ET AL.

14. REVEAL LITE 2.0
• Functional class (FC), vital signs (systolic BP and heart rate), 6MWD , NT-
proBNP, and renal insufficiency (by estimated eGFR ) –
• Simplified method of risk assessment
• REVEAL Lite 2 approximates REVEAL 2.0 at discriminating low,
intermediate, and high risk for 1-year mortality in patients in the REVEAL
registry.
• BNP/NT-proBNP, followed by 6MWD and FC

15. Update in pathogenesis

16. Vasculopathy
• Intimal fibrosis is more common in SSc-PAH ( Overbeek et al. [12] )
• Plexiform lesions were much less common than in patients with IPAH.
• Marked muscular artery intimal fibrosis ( Dorfmüller et al. [11] )
• Increased frequency of pulmonary venous lesions in SSc-PAH
Overbeek MJ, Vonk MC, Boonstra A, et al. Pulmonary arterial hypertension in limited cutaneous systemic sclerosis: a
distinctive vasculopathy. Eur Respir J 2008; 34: 371–379

17. Right ventricle
• Worse RV contractility and coupling of RV contractility with afterload in SSc-PAH (
Tedford et al. )
• NT-proBNP levels in SSc-PAH significantly high (Mathai et al.)
• Increased inflammatory myocardial infiltrate in the SSc-PAH group.
• Sarcomere function (as assessed by the maximum calcium-activated force) was
significantly lower in SSc-PAH
Overbeek MJ, Mouchaers KTB, Niessen HM, et al. Characteristics of interstitial fibrosis and inflammatory cell infiltration
in right ventricles of systemic sclerosis-associated pulmonary arterial hypertension. Int J Rheumatol 2010; 2010:
604615.

18. Inflammation
• More macrophage infiltration in the
right ventricle
• Vasculopathy of the small pulmonary
arteries secondary to inflammation and
fibrosis
• Role of inflammatory mediators
• Abnormalities in Complement
Sydykov A, Mamazhakypov A et al. Inflammatory Mediators Drive Adverse Right Ventricular
Remodeling and Dysfunction and Serve as Potential Biomarkers. Front Physiol. 2018 May 23;9:609

19. • Larger treatment response of patients in functional class (FC) II
compared with FC III

20. Is screening so
important ?
Weatherald J, Montani D, Jevnikar M, et al. Screening for pulmonary arterial hypertension in systemic sclerosis.
Eur Respir Rev 2019; 28: 190023

21. Screening method
• TTE
• Pulmonary function test- FVC , DLCO
• COMPOSITE – ASIG , DETECT
• Cardiac MR
• Nailfold capillariscopy
• Blood biomarkers
• Newer TTE
• Cardiopulmonary testing
• FeNO testing

22. The 2015 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines.*

23. 13 variables were divided into nine non-echocardiographic variables (step 1 ) and four
echocardiographic variables (Step 2).
Sensitivity/specificity for identifying PAH (mPAP ⩾25 mmHg and PAWP ⩽15 mmHg) of
96%/ 48% and 71%/69%, respectively
DETECT identified a significantly higher number of patients with mPAP 21–24 mmHg
(31% versus 17%)

24. If the ‘Total risk points from Step 1’
is >300 , then to step 2
If the ‘Total risk points
from Step 2’ is >35 , then
to RHC

25. • The Australian Scleroderma Interest Group (ASIG) - pulmonary function tests & NT-proBNP.
• Sensitivity/specificity for identifying PAH of 94%/55% compared with 95%/32% for the
ERS/ESC approach
• Long-term survival was also significantly better in the detection cohort with 64% of patients
still alive at 8 years

26. The Australian Scleroderma Interest Group (ASIG) algorithm.*

27. Nailfold capillaroscopy
• SSc-PAH - severe pattern compared to SSc-no PAH patients ( 73.2% vs 50% )
• SSC-PAH - significantly lower capillary density (5.64 ± 1.9 loops/mm vs 6.5 ± 1.3 loops/
mm )
• SSc-PAH - significantly higher capillary width (55 ± 7 μm vs 35 ± 8 μm ) and mean
number of neo-angiogenesis (N/mm) (1 ± 0.3 vs 0.2 ± 0.22 ).
• Capillary density correlates with symptoms and resting mPAP

28. Newer TTE
• 2D speckle-tracking TTE - novel modality to detect subclinical right ventricular
involvement
• Decreased RV systolic strain rate ( RV-LS) and/or greater RV- dysynchrony (RV-
Dys)
• Although SSc-PAH patients had lower RV-LS and higher RV-Dys than SSc PAH(−)
patients, the differences were not statistically significant
The evaluation of right ventricle dyssynchrony by speckle tracking echocardiography in systemic sclerosis patients .
Murat Demirci MD et al

29. Cardiac magnetic resonance imaging (cMRI)
• Noninvasive imaging modality
• More sensitive than TTE for detecting cardiac abnormalities in patients with SSc
• Ventricular mass index (=right end-diastolic ventricular mass divided by left end-
diastolic ventricular mass) strongly correlated with invasive haemodynamics.
• Pulmonary blood volume can be quantified - early indicator of pulmonary
vascular involvement

30. Blood biomarkers
• Anti-cardiolipin Ab-IgG with SSc-PAH - higher titers increased the likelihood
• igh AT1R & ETAR levels conferred a 4.3 & 3.5-fold higher risk of developing PAH
• CCL21 - elevated years prior to the PAH diagnosis and were associated with survival
after diagnosis
• Growth differentiation factor (GDF)-15- significantly higher serum levels of GDF-15
when compared to SSc –no PAH
• The ongoing PVDomics study may provide novel insights into early pulmonary
vascular disease in SSC

31. • CCL21 levels were higher in patients with SSc and were elevated prior to
the diagnosis of PAH
• When risk at diagnosis was combined with high or low CCL21 level, there
was a significant predictive effect (HR 1.3, 95% CI 1.03-1.60 [P = 0.027]).
• A high CCL21 level was associated with decreased survival (P < 0.001).
Hoffmann-Vold AM,etal . CCL21 as a Potential Serum Biomarker for Pulmonary Arterial
Hypertension in Systemic Sclerosis. Arthritis Rheumatol. 2018 Oct;70(10):1644-1653.

32. Others
• Cardiopulmonary exercise testing (CPET
Peak maximal oxygen consumption (VO2) revealed the highest diagnostic
accuracy (sensitivity 87% and specificity 75% at a threshold level of 13.8 mL/min/kg).
• FE-NO
SSc-PAH patients had lower median (interquartile range) alveolar NO
compared to SSc-no-PAH patients

33. THERAPY

34. Medical therapy in SSc-PAH
• Drugs targeting nitric oxide pathway
• Endothelin-1 receptor antagonist
• Prostacyclin
• Immunosuppression – emerging concept

35. Sildenafil
• SUPER1 (2007) – change in 6MWD −13 m (placebo), +42 m (20 mg), +36 m
(40 mg), +15 m (80 mg)
• SUPER2 (2011) - After 3 years, the majority of patients (60%) who entered
the SUPER-1 trial improved or maintained their functional status, 46%
maintained or improved 6MWD
• Combination trial - PACES , COMPASS2 ,COMPASS3

36. Tadalafil
• PHIRST-1 - mean placebo-adjusted change in 6MWD +27 m (20 mg), +33 m(40
mg) , a significant decrease in mPAP
• IL-12 signaling & extracellular matrix maintenance were coordinately up- or
down-regulated with treatment, respectively, across all subjects. ( Cheong et al
2017 )
• voltage-gated potassium channels & genes related to innate immunity were
coordinately up-regulated.
Cheong FY, Gower AC, Farber HW. Changes in gene expression profiles in patients with pulmonary arterial
hypertension associated with scleroderma treated with tadalafil. Semin Arthritis Rheum. 2017 Feb;46(4):465-
472

37. • Increase in mean 6MWD, WHO FC, pulmonary vascular resistance and cardiac index.
• The improvement in 6MWT in patients pretreated with an ERAs (53%) as well.
• Improvements in 6MWD and WHO FC persisted at 2 years ( PATENT2)
• Two-year survival of patients with PAH-CTD was the same as for idiopathic PAH (93%)
• Similar safety profile in patients with PAH-CTD to that of the overall population.
Riociguat

38. ERA- Bosentan
• BREATHE1 ( 2002 ) –
1. Change in exercise capacity (6MWT) from baseline to week 16 (primary
endpoint).
2. Difference was not significant in CTD-PAH as other factors contribute
• EARLY (2008) - 6MWT was improved but not significantly versus placebo; PVR
decreased significantly in the former.
• EARLY –extension (2014) - 16.8% of patients had an elevation of hepatic
aminotransferases levels over a median exposure of 51 months

39. Ambrisentan
• (ARIES-C) and their open-label extensions (ARIES-E). (2016)
• The primary endpoint for both studies was change in 6MWT from baseline to
week 12 compared to placebo.
• At one, two, three years, 62.6%, 57.3%, and 58.2% of CTD-PAH patients treated
with ambrisentan exhibited an increase in 6MWT
Fischer A, Denton CP, et al . Ambrisentan response in connective tissue disease associated pulmonary arterial
hypertension (CTD-PAH) – a subgroup analysis of the ARIES-E clinical trial. Respir Med 2016;117:254–63

40. Macitentan
• SERAPHIN trial ( 2013 )
• Composite primary endpoint - death, atrial
septostomy, lung transplantation, initiation of iv
or sc prostanoids, and/or worsening in PAH
• Decreased the risk of the morbidity/ mortality
endpoint by 45% in all patients versus placebo
• The effect was observed regardless of whether the
patient was receiving therapy at baseline

41. Prostanoids
• Iv epoprostenol
• Treprostinil - Analog of epoprostenol which is chemically stable at room temperature
• Inhaled Iloprost
• Selexipag - a non-prostacyclin drug which selectively activates the IP receptor, oral
administration facilitates an early initiation of prostanoid therapy

42. • Exercise capacity was improved in the 41 patients treated with epoprostenol
(median distance walked in six minutes, 362 m at 12 weeks vs. 315 m at base
line),
• Hemodynamics improved at 12 weeks in the epoprostenol treated patients

43. • GRIPHON study PAH-CTD subgroup
• PAH-SSc in 170, PAH-SLE in 82 , mixed CTD/CTD-other in 82.
• PAH-SSc - more impaired at baseline, more progressive disease course.
• Selexipag reduced the risk of composite morbidity/mortality events in patients with PAH-
CTD by 41% (HR 0.59; 95% CI 0.41–0.85).
• Selexipag delayed progression of PAH and was well-tolerated among PAH-CTD patients
2017
Gaine S, Chin K, Coghlan G et al . Selexipag for the treatment of connective tissue disease-associated pulmonary arterial
hypertension. Eur Respir J 2017;50:1602493

45. Combination therapy
In most of the studies , study drug is compared to placebo , head to head trial is
lacking
Having worse prognosis , upfront or rapid sequential combination therapy with ERA
and PDE5i is needed

46. Primary endpoint - time to the first clinical failure
event
Initial combination therapy reduced the risk of
clinical failure versus pooled monotherapy in
each subgroup including SSc-PAH (0.44 (0.22 to
0.89)).
Peripheral oedema, which was reported more
frequently
2017

47. Forest plot of time to first occurrence of clinical failure, clinical worsening, death, hospitalisation, disease progression
and unsatisfactory long-term clinical response (ULTCR) in the (systemic sclerosis-pulmonary arterial hypertension
population. Post hoc figures. The HR is for combination versus pooled monotherapy.

48. AMBITION - Upfront combination therapy
• Enrolled ‘upfront’ prior to any therapy
• More favorable treatment cohort, where a more ‘vascular’ profile
• Impressive positive response to combination therapy that delivered the
treatment effect
• Neither AE-related discontinuation rates nor SAE rates were increased
• There is a synergistic effect of combination therapy in the SSc subgroup.

49. Others
• BREATHE2 (2004) –
Bosentan/ Placebo + Epoprostenol – 5 SSC-PAH
Bosentan group more improvement in TPR ( by RHC ) at 16 week
• PACES (2008) –
Sildenafil/ placebo + epoprostenol -32 SSc-PAH
Increase of 29 m in 6MWT in Sildenafil group at 16 week

50. Others
COMPASS2 (2015)–
Bosentan / Placebo + Sildenafil -88
Primary end point event – composite mortality/morbidity , no difference
COMPASS 3 (2010) - Initial bosentan , then add on sildenafil , more add-on
achieved target
RESPITE (2017) – switching to Riociguat after inadequate response to PDE5i

51. Comparison of iPAH groupings and connective tissue disease (CTD) populations. Forest plot summarising overall
treatment effect on hazard ratio for event-driven long-term trials including combination PAH therapy in SSc

52. • ATPAHSS-O trial ( ambrisentan and tadalafil upfront combination therapy in SSc-PAH)
• Both RV systolic function and RV diastolic function improved
• Combination therapy was associated with a significant improvement in both RV and
LV function as assessed by CMR-derived strain and strain rate .
2018

53. TRITON ,2021
• Newly diagnosed, treatment-naive patients with PAH
• Initial triple (macitentan, tadalafil, and selexipag) versus initial double
(macitentan, tadalafil, andplacebo) oral therapy
• At week 26, both treatment strategies reduced PVR, increased 6MWT , reduced
NT-proBNP with no significant difference
• Risk for disease progression less in triple therapy
Chin KM, Sitbon O, Doelberg M, Feldman J, et al Three- Versus Two-Drug Therapy for Patients
With Newly Diagnosed Pulmonary Arterial Hypertension. J Am Coll Cardiol. 2021 Oct
5;78(14):1393-1403

54. • Eleven RCTs (1,267 with CTD-PAH) and 19 registries (4,008 with CTD-PAH) were included
• 36% reduction in the risk of clinical morbidity/ mortality events in CTD-PAH patients (HR
0.64, 95% CI 0.51, 0.81; P < 0.001)
• The survival rate was lower in CTD-PAH patients compared to all PAH patients
• survival rate in CTD-PAH patients treated primarily after 2010 was higher than that in CTD-
PAH patients treated before 2010

56. The Joint Task Force for
the Diagnosis and
Treatment of Pulmonary
Hypertension of the
European Society of
Cardiology (ESC) and the
European Respiratory
Society (ERS)
recommendation for CTD-
PAH

57. SSc with mPAP 21–24 mm Hg
• The majority of patients had a PVR < 3 U
• A risk of hemodynamic progression and
functional impairment
the use of an mPAP threshold
of >20 mmHg and a PVR
threshold of ⩾2 WU is likely to
be a superior approach

58. Key observational studies in systemic sclerosis (SSc) patients with mean
pulmonary arterial pressure (mPAP) 21–24 mmHg
Study Year Patie
nts
PVR Remarks
Coghlan el al 2018 21 2.4 33% patients ( DETECT cohort ) developed PAH within 2
year
VALERIO et al 2018 86 2.3 mPAP 21–24 mmHg (HR 3.7) and TPG ⩾11 mmHg (HR
7.9) predicted development of PAH (both p<0.001)
Xanthouli et al 2019 28 2.5 Compared with 123 patients with mPAP ⩽20 mmHg,
21–24 mmHg group had lower 6MWD (414±100 m
versus 488±101 m

59. • Mildly elevated mPAP at rest between 21 and 24 mmHg and/or > 30 mmHg during
low-dose exercise
• Ambri vs placebo
• After 6 months, the two groups did not differ in the primary endpoint (ambri , mPAP −
1 ± 6.4 mmHg vs. placebo − 0.73 ± 3.59 mmHg at rest, p = 0.884)
• Three patients from the placebo group but none of the ambrisentan group progressed
to PAH

60. SSc-PVOD
• An association with SSc has also been recognized
• Occlusive venous intimal fibrous thickening
• PVOD can involve the pulmonary arterial, capillary and venous bed,
• The sixth WSPH defined a new classification PAH with overt features of
venous/capillaries (PVOD/PCH) involvement
• Significantly reduced DLCO and radiologically by septal lines, centrilobular
ground-glass changes and mediastinal lymphadenopathy
Günther S, Jaïs X, Maitre S, et al. Computed tomography findings of pulmonary venoocclusive disease in
scleroderma patients presenting with precapillary pulmonary hypertension. Arthritis Rheum 2012; 64: 2995–3005.

61. Observational studies in SSC-PVOD
• Günther S et al –
• HRCT images for 26 SSc patients with pre-capillary PH- septal lines in 89%, centrilobular ground-
glass opacities in 46% and mediastinal lymphadenopathy in 58%.
• The presence of ⩾2 radiographic signs was associated with subsequent pulmonary oedema
following commencement of PAH-specific therapy
• DORFMÜLLER et al. study –
• Pulmonary vein and venule obstructive lesions were present in 75% of CTD-PAH patients but only
17% of the IPAH group
• 50% of the CTD patients had developed pulmonary oedema following commencement of PAH-
specific therapy

62. • PVOD in 15 out of 18 patients with SSc-PH-ILD who had undergone lung
transplantation
• PVOD pattern was classified as absent (0), mild (1+) or moderate–severe (2+)
• Pulmonary veins and venules : intimal thickening, obstructive fibrous luminal septa or
recanalisation & arterialisation of pulmonary veins.
Gupta S, Gupta A, Rehman S, et al. Pulmonary veno-occlusive disease is highly prevalent in scleroderma patients
undergoing lung transplantation. ERJ Open Res 2019; 5: 00168-2018

63. PVOD should be considered if clinical deterioration occurs following commencement of PAH-specific therapy
Survival in PVOD is poor and early transplant referral in suitable patients is recommended
Pulmonary vein in a patient with SSc-
PVOD depicting a partially arterialised
vein (blue arrow) and intimal fibrosis
(red arrow) consistent with changes of
PVOD.

64. SSc-PH-LHD
• Greater levels of fibrosis at endomyocardial biopsy
• Greater tendency of heart failure
• Patients diagnosed with SSc-PAH may have co-existing LHD or occult PH-LHD.
• Increased endothelin-1, inflammatory cellular infiltrate , reduced NO -induced
vasodilation - additional pulmonary vasculopathy
• This state is termed combined pre- and post-capillary PH (CpcPH) and is defined
as mPAP >20 mmHg, PAWP >15 mmHg and PVR ⩾3 WU

65. • The commonest form of SSc-PH-LHD is that associated with heart failure with
preserved ejection fraction (SSc-PH-HFpEF)
• Patients with SSc-PH-HFpEF had higher body mass index, mPAP and PAWP and
larger left atria but similar TPG to patients with SSc-PAH. Survival in SSc-HFpEF,
when adjusted for haemodynamics, was inferior
• Anti-PAH therapy mostly fail in all studies
Bourji KI, Kelemen BW, Mathai SC, et al. Poor survival in patients with scleroderma and pulmonary hypertension due to
heart failure with preserved ejection fraction. Pulm Circ 2017; 7: 409–420.

66. • At 6 months, there was no improvement with placebo, but sildenafil mediated
significant improvements in mPAP (−42.0±13.0%) and RV function.
Guazzi M, Vicenzi M, Arena R, et al. Pulmonary hypertension in heart failure with preserved ejection fraction: a target of
phosphodiesterase-5 inhibition in a 1-year study. Circulation 2011; 124: 164–174

67. SSc-PH-ILD
• ILD occurs within the first 3 years from diagnosis in DcSSc while it develops later
in LcSSc
• No data validating the optimal threshold of lung involvement to differentiate SSc-
PH-ILD from SSc-PAH.
• The presence of any ILD , fibrosis extent >5% plus total lung capacity (TLC) or FVC
< 70%
• Combined fibrosis and emphysema - increased risk of PH.

68. Survival
• Meta-analysis in 2013 demonstrated 3-year survival of 56% in SSc-PAH and 35% in
SSc-PH-ILD
• MATHAI et al. - Independent prognostic factors to be a diagnosis of SSc-PH-ILD, the
presence of DcSSc, PVR index and DLCO.
• Response to PAH-specific therapies appears to be reduced in SSc-PH-ILD.
• Poorer survival , lower frequency of improvement in WHO FC in SSc-PH-ILD
• Best therapy is still a debate
Le Pavec J, Girgis RE, Lechtzin N, et al. Systemic sclerosis-related pulmonary hypertension associated with
interstitial lung disease: Impact of pulmonary arterial hypertension therapies. Arthritis Rheum 2011; 63: 2456–
2464.

69. • Inhaled Treprostinil (ultrasonic, pulsed-delivery nebulizer ) in up to 12 breaths
(total, 72 μg) four times daily, or placebo.
• At week 16, the least-squares mean difference change in 6MWD was 31.12 m
(95% CI - 16.85 to 45.39; P<0.001)
• There was a reduction of 15% in NT-proBNP levels from baseline with an increase
of 46% with placebo
2021 INCREASE study
Waxman A, Restrepo-Jaramillo R, Thenappan T, et al. Inhaled treprostinil in pulmonary hypertension due to interstitial lung
disease. N Engl J Med 2021; 384: 325–334.

70. Immunosuppression

71. • MMF therapy can alleviate thickening of pulmonary arterial walls and inhibit
abnormal vascular remodeling, and the
• MPA concentrations which demonstrated efficacy in this study are within clinical
applicable range
• SPAP, RVI, levels of expression of bFGF in serum & lung homogenates,
alveolar arterial wall thickness, and the number of muscular
arteries decreased
Zheng Y, Li M, Zhang Y, Shi X, Li L, Jin M. The effects and mechanisms of mycophenolate mofetil
on pulmonary arterial hypertension in rats. Rheumatol Int. 2010 Jan;30(3):341-8

72. • 57 SSc-PAH - two infusions of 1,000 mg rituximab or placebo
• Week 24, the adjusted mean change in 6MWD favored the treatment arm (23.6 6 11.1 m vs. 0.5 6
9.7 m; P = 0.12).
• Week 48 were also considered, the estimated change in 6MWD at Week 24 was 25.5 6 8.8 m for
rituximab and 0.4 6 7.4 m for placebo (P = 0.03)
• Low levels of RF (rheumatoid factor), IL-12, and IL-17 were sensitive and specific as favorable
predictors of a rituximab response as measured by an improved 6MWD
DESIRE , LANCET
2021

73. Zamanian, Badesch, Chung, et al.: Rituximab for Treatment of SSc-associated PAH

74. Anticoagulant
• Current guidelines do not recommend anticoagulation in patients with SSc-PAH
and other CTD-PAH
• It may be considered on an individual basis and in the presence of thrombophilic
predisposition
• An Australian multicenter RCT SPHInx evaluating the administration of apixaban
vs. placebo in SSc-PAH is currently ongoing.

75. Calderone A, Stevens W, Prior D, et al. Multicentre randomised placebo-controlled trial of oral anticoagulation with apixaban in
systemic sclerosis-related pulmonary arterial hypertension

76. Future

77. Tocilizumab
PEP - Change from baseline pulmonary vascular resistance to end of study at 6
months

78. Ifetroban
• 34 patients
• Adverse events primary end point
• FVC , DLCO change , MRSS - secondary endpoints

79. • Bardoxolone methyl
• It induces the nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor
that regulates antioxidant proteins, and suppresses activation of the pro-inflammatory
factor NF-κB
• Phase 2 LARIAT – improved 6MWD , CTD-ILD also included
• Phase 3 CATALYST ongoing ,excluding moderate to evere anemia in CTD-PAH

80. Stem cell therapy
• SAPPHIRE seeks to establish the efficacy and safety of repeated monthly dosing of
autologous EPCs transfected with human eNOS (heNOS) in patients with
symptomatic severe PAH on available PAH-targeted medical therapy.
• ALlogeneic Cardiosphere-derived Stem Cells (CDCs) for Pulmonary Hypertension
therApy .

81. Interventional study
• Therapeutic Intra-Vascular UltraSound system (TROPHY study) - PAH in WHO FC
III on stable double combination therapy other than parenteral PGI (TIVUS)
• Pulmonary artery denervation
• PA denervation (+sildenafil)

82. Prognosis

83. Galiè N et al 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension:. Eur Respir
J. 2015 Oct;46(4):903-75.

84. Suggested assessment and timing for the follow-up of patients
with PAH
Galiè N et al 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension:. Eur Respir
J. 2015 Oct;46(4):903-75.

85. • PAH accounted for 52% of all deaths , mostly in 1 year
• Survival in 160 patients with incident SSc-PAH at 1, 3, 5, and 8 years was 95%, 75%, 63%, and
49%, respectively.
• Men , diffuse disease , systolic pulmonary artery pressure (PAP) on ECG , mean PAP
on right heart catheterization , 6-min walk distance , and DLCO significantly affected
survival
• An association between serum autoantibodies and survival in patients with SSc-PAH
was not identified in the PHAROS cohort

86. • Patient survival of advanced PAH remains poor at 5 years despite
treatment advances.
• NYHA- FC remains one of the most important predictors of future survival.
• These observations reinforce the importance of continuous monitoring of
FC in patients with PAH
Farber HW, Miller DP, Poms AD et al . Five-Year outcomes of patients enrolled in the REVEAL
Registry. Chest. 2015 Oct;148(4):1043-54.

87. Take home message
• SSC-PH - worse prognosis than IPAH , FC is helpful predictor of prognosis
• PAH , PH-LHD, PH-ILD, PVOD , CTEPH = SSc-PH
• Diffuse SSc has similar PH risk , ILD is a significant contributor
• Early appropriate screening needed – DETECT , ASIG , 2D TTE
• Cardiac MR , NFC , CPET , blood biomarkers – new screening tools
• Pulmonary artery vasculopathy + right ventricle involvement including inflammation
• Upfront combination – tadalafil + Ambrisentan ( AMBITION )
• Rituximab – Role in SSc PAH ( DESIREs)
• FUTURE is promising .

88. THANK YOU