Update on Pulmonary Arterial Hypertension in Scleroderma

Scleroderma Patient Education ConferenceMarch 15th 2014

Roberto F. Machado, MD

Section of Pulmonary and Critical Care, Allergy and Sleep

University of Illinois at Chicago College of Medicine

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

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

PAHMean PAP ≥25 mm Hg plusPCWP/LVEDP ≤15 mm Hg

Mean PAP ≥25 mm Hg

ACCF/AHA includes PVR >3 Wood Units

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.

LV

A LA

RA

RV

PT

PVOD

ILD

Pulmonary Hypertension (PH) in CTD

PAH

LV systolic ordiastolic dysfunction

↑ LAP

Vasculopathy in Scleroderma

• Masson-Trichrome stain of digital artery from patient with SSc

• Striking fibrotic intimal hyperplasia

• Adventitial fibrosis

• Arterial lumen severely compromised

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%)Congenitalheart disease (19.5%)

HIV (4.0%)

Other (5.5%)

Drugs/Toxins (10.5%)

Portopulmonary (10.6%)

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=0.05GI p=0.43Heart p=0.26

50

40

30

20

10

0

Year of death

p<0.001(SRC)

p<0.001 (PF)

Fre

quen

cy (

%)

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)

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 HgAverage PA resistance: 16 Wood unitsAverage 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

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)

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 Hgand PAWP <15 mm Hg

mPAPduring exercise

<30 mm Hg

mPAPduring exercise

≥30 mm Hg

Confirmed PAH(n=18)

No PAH(n=15)

Latest Recommendations for Screening and Detection of SSC-Associated PAHGeneral 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

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)

Impact of Proactive Screening in Systemic Sclerosis

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

I II III IV0

20

40

60

80

100

7.6

36.7

50.0

5.6

FC* at Enrollment

Pa

tien

ts (

%)

REVEAL Registry (All Patients)(n=2525)

I II III IV0

20

40

60

80

100

5.7

32.2

54.9

7.2

FC* at Enrollment

REVEAL Registry (CVD/CTD)(n=639)

Screening Can Help in Diagnosing the Disease in an Early Stage

I II III IV0

20

40

60

80

100

1

24

63

12

NYHA FC (N=674)

Pa

tien

ts (

%)

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 NYHAFC III or FC IV, and only 24% of patients were in NYHA FC II at diagnosis.

I II III IV0

20

40

60

80

100

5

44

28

11

NYHA FC (N=18)

With Screening

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

Prognosis of “Routine Practice” and “Detection” PAH-SSc Patients

100

80

60

40

20

0

Surv

ival (%

)

1 3 5 8

Years of follow-up

100%

75%

31%25%

17%

81% 73%

64%

Routine practice PAH-SSc

Detection PAH-SSc

p=0.0037HR=4.15

(95% CI 1.47–11.71)

Adapted from Humbert M et al. Arthritis Rheum. 2011;63:3522-3530.

Treatment for Scleroderma-associated PAH

cGMP

cAMP

Vasoconstriction and proliferation

Endothelin receptor A

Exogenous nitric oxide

Endothelin-receptor

antagonists

Endothelin receptor B

Phosphodiesterase type 5 inhibitor

Vasodilationand antiproliferation

Phosphodiesterase type 5

Vasodilationand antiproliferation

Prostacyclin derivatives

Nitric Oxide

Endothelin-1

Pre-proendothelin

L-arginine

Prostaglandin I2

L-citrulline

Nitric OxidePathway

EndothelinPathway

ProstacyclinPathway

Endothelial cells

Proendothelin

Endothelial cells

Arachidonic acid

Smooth muscle cells

Prostacyclin (prostaglandin I2)

Smooth muscle cells

PAH Treatment: Targeting Known Pathophysiological Pathways

ProstacyclinsEpoprostenol, Treprostinil

Iloprost (inhaled)

PDE-5 InhibitorsSildenafil, Tadalafil

SGC StimulatorRiociguat

Endothelin Receptor AntagonistsBosentan, Ambrisentan ,

Macitentan

Adapted from Humbert M et al. N Engl J Med. 2004;351:1425-1436.

Combination Therapy

*Half of patients on combination therapy†SERAPHIN, 64% on combination therapy, 5% of patients on prostanoid; PATENT 1, 6%.

SGC Stimulators Prostanoids

EndothelinReceptor

Antagonists

Phospho-diesteraseInhibitors

TRIUMPH STEPSERAPHIN† TRIUMPH

PACES

PATENT-1*

PATENT-1*

?

?

???

PHIRST*SERAPHIN†

Morrell, N. W. et al. JACC 2009; 54(1 Suppl):S20-31.

Some Cellular Processes Implicated in the Pathogenesis of PAH

Am J Respir Crit Care Med, 2014 http://www.atsjournals.org/doi/abs/10.1164/rccm.201308-1543PP

Treatment for PAH: The Pipeline

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

Survivalproportion

Time after lung transplant (mo)0 12 24 36 48 60

SScIPF

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

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