VASCULAR COMPLICATIONSOF SYSTEMIC SCLEROSIS

Early Diagnosis of PAH in Systemic Sclerosis: How Do We Recognize

the Warning Signs?

Joseph C. Shanahan, MD Assistant Professor, Rheumatology and ImmunologyClinical Director, Duke Scleroderma Research Center

Associate Director, Duke Lupus ClinicDuke University Medical Center

Durham, North Carolina

VASCULAR COMPLICATIONSOF SYSTEMIC SCLEROSIS

DISCLOSURE STATEMENT

Joseph C. Shanahan, MD

Grants/research support: Novartis PharmaceuticalsEncysive Pharmaceuticals Inc.

Speakers’ bureau:Actelion Pharmaceuticals US, Inc. Encysive Pharmaceuticals Inc.

Kaplan-Meier Survival Estimates in Kaplan-Meier Survival Estimates in Scleroderma By Organ InvolvementScleroderma By Organ Involvement

Koh ET et al. Br J Rheumatol. 1996;35:989-993.

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Year from PH Diagnosis

Per

cen

t S

urv

ival

PAHPAH

Lung Involvement (without PH)Lung Involvement (without PH)

NoneNone

14

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5

Percent survival

Survival in PAHSurvival in PAH

McLaughlin VV et al. Chest. 2004;126:78S-92S.

CHD

Portopulmonary

PPH

CTD

HIV

Years

PAH: Clinical DefinitionPAH: Clinical Definition

• Increased mean pulmonary arterial pressure (mPAP) – mPAP >25 mm Hg at rest, or– >30 mm Hg during exercise

• Normal PCWP (<15 mm Hg)• Often associated with end-organ pathology

– pulmonary vasculopathy– right ventricle hypertrophy

Gaine SP, Rubin LJ. Lancet. 1998;352:719-725. Erratum in: Lancet. 1999;353:74.

No early symptoms of PAH

Annual screening in high-risk populations mandatory

Progressive dyspnea on exertion, fatigue, palpitations, chest pain, dizziness, syncope, coughing

Symptoms and signs of right heart failure,

edema, ascites

Disease Onset

First Symptoms

End-stage Symptoms

Signs and Symptoms of PAHSigns and Symptoms of PAH

Death

Gaine SP, Rubin LJ. Lancet. 1998;352:719-725. Erratum in: Lancet. 1999;353:74.

Physical Examination: Signs of PAHPhysical Examination: Signs of PAH

• Loud pulmonic valve closure (P2)

• Early systolic ejection click

• TR murmur

• Right-sided fourth heart sound

• Right ventricular heave

• Jugular venous distention

• Peripheral edema, ascites

McGoon M et al. Chest. 2004;126:14S-34S.

Schematic Progression of PAHSchematic Progression of PAH

Time

PAP

PVR

CO

Pre-symptomatic/ Compensated

Symptomatic/ Decompensating

Symptom Threshold

Right Heart Right Heart DysfunctionDysfunction

Declining/ Decompensated

CO =PAP

PVR

Available Diagnostic MethodsAvailable Diagnostic Methods

• Clinical predictors of disease

• Pulmonary function tests

• Transthoracic echocardiogram

• Right heart catheterization

• Cardiac MRI and serum BNP

Predictors of PAH in SclerodermaPredictors of PAH in Scleroderma

• Predictors of development:– autoantibodies:

• anti-U3 RNP• anti-B23 (nucleolar antigen susceptible to cleavage

by granzyme B only in endothelial cells)

• Predictors of progression to severe PH– later age at onset (>47 yr)– limited cutaneous disease– DLCO <50% predicted

Steen V, Medsger TA. Arthritis Rheum. 2003;48:516-522.Ulanet DB et al. Arthritis Rheum. 2003;49:85-92.Chang B et al. J Rheumatol. 2006;33:204-206.

Early Signs of PAH: Pulmonary Early Signs of PAH: Pulmonary Function TestsFunction Tests

• Diffusing capacity (DLCO)– reduced years before diagnosis of PAH– strongest predictive value in patients

with developing isolated PAH (without interstitial lung disease)

– in patients with decreased FVC, a rising FVC/diffusing capacity ratio (>1.4-1.8) increases likelihood of PAH

Steen V, Medsger TA. Arthritis Rheum. 2003;48:516-522.Steen VD et al. Arthritis Rheum. 1992;35:765-770.

Signs Indicative of PH on EchoSigns Indicative of PH on Echo

• Increased sPAP or TR jet• Right atrial & ventricular

hypertrophy• Flattening of

intraventricular septum• Small LV dimension• Dilated PA

LV

RV

LARA

IVS

McGoon M et al. Chest. 2004;126:14S-34S.

Prevalence of PAH in SScPrevalence of PAH in SSc• Patients ≥18 yr old, meeting ACR criteria for SSc, or 3 of 5

features of CREST, or Alarcon-Segovia criteria for MCTD

• 815 patient charts retrospectively analyzed for PAH; 122 (15%) had existing diagnosis

• 669 patients without diagnosis of PAH were eligible for echo:

Wigley FM et al. Arthritis Rheum. 2005;52:2125-2132.

Estimated RVSP by Doppler Echo in (n=669) With Unknown PAH Status (the Prospective Group)

ERVSP (mm Hg) No. of patients (%)

≥30 282 (42.2)

≥35 158 (23.6)

≥40 89 (13.3)

≥45 45 (6.7)

≥50 20 (3.0)

≥60 6 (0.9)

Total prevalence: 26.7%•122 known•89 sPAP >40 mm Hg

Scleroderma and PAHScleroderma and PAHRecommended ScreeningRecommended Screening

Annual

echo and PFT

Patient with existing

diagnosisof scleroderma

Perform baseline

echo and PFT

Patient newlydiagnosed

with scleroderma

McGoon M et al. Chest. 2004;126:14S-34S.

PAH definition:• mPAP >25 mm Hg at rest or >30 mm Hg

during exercise• Normal PCWP <15 mm Hg• PVR >3 wu

Gaine et al. Lancet. 1998;352:719.

Diagnosis of PAH byDiagnosis of PAH byRight Heart CatheterizationRight Heart Catheterization

• Gold standard to confirm diagnosis–echo may underestimate

pulmonary pressures–echo can miss

congenital anomalies–echo may underestimate

LV disease• Only proven tool to

accurately assess hemodynamic response to treatment–repeat catheterization

indicated before changing therapy

Potential Diagnostic ToolsPotential Diagnostic Tools

• Serum brain natriuretic peptide (BNP) and pro-BNP

• Cardiac MRI

Signs of PAH: Serum BNPSigns of PAH: Serum BNP• Biology

– released by cardiac myocytes stimulated by increased filling pressures

– during conditions of ventricular dysfunction, BNP maintains renal function and Na balance by antagonizing RAAS

• Clinical utility– screening for PAH in SSc population without primary cardiac

disease:• sensitivity=90%, specificity=90%• positive predictive value=69%• negative predictive value=96%

– monitoring therapy:• reduction in BNP levels paralleled reduced RV mass in

sildenafil trial

Hargett CW, Tapson VF. Sem Resp Crit Care Med. 2005;26:385-393.Allanore Y et al. Arthritis Rheum. 2003;48:3503-3508.Wilkins MR et al. Am J Respir Crit Care Med. 2005;171:1292-1297.

cMRI PAH 4chamber.avi

Early Signs of PAH: Cardiac MRIEarly Signs of PAH: Cardiac MRI

• Cardiac MRI measures:– RV volume and mass,

stroke volume, CO– myocardial fibrosis– pulmonary perfusion

QuickTime™ and a decompressor

are needed to see this picture.

Early Diagnosis of PAH in SSc: Early Diagnosis of PAH in SSc: Concluding RemarksConcluding Remarks

• Annual screening:– DLCO– transthoracic echocardiogram– serum BNP