Download Signs of PAH

VASCULAR COMPLICATIONS
OF SYSTEMIC SCLEROSIS
Early Diagnosis of PAH in Systemic
Sclerosis: How Do We Recognize
the Warning Signs?
Joseph C. Shanahan, MD
Assistant Professor, Rheumatology and Immunology
Clinical Director, Duke Scleroderma Research Center
Associate Director, Duke Lupus Clinic
Duke University Medical Center
Durham, North Carolina
VASCULAR COMPLICATIONS
OF SYSTEMIC SCLEROSIS
DISCLOSURE STATEMENT
Joseph C. Shanahan, MD
Grants/research support:
Novartis Pharmaceuticals
Encysive Pharmaceuticals Inc.
Speakers’ bureau:
Actelion Pharmaceuticals US, Inc.
Encysive Pharmaceuticals Inc.
Kaplan-Meier Survival Estimates in
Scleroderma By Organ Involvement
100
Percent Survival
90
80
70
None
60
50
Lung Involvement (without PH)
40
30
20
PAH
10
0
0
1
2
3
4
5
6
7
8
9
Year from PH Diagnosis
Koh ET et al. Br J Rheumatol. 1996;35:989-993.
10
11
12
13
14
Survival in PAH
1.0
0.9
0.8
CHD
0.7
Portopulmonary
0.6
Percent
survival
0.5
PPH
0.4
CTD
0.3
0.2
HIV
0.1
0
0
1
2
3
Years
McLaughlin VV et al. Chest. 2004;126:78S-92S.
4
5
PAH: 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.
Signs and Symptoms of PAH
No early symptoms of PAH
Disease Onset
First Symptoms
End-stage
Symptoms
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
Death
Gaine SP, Rubin LJ. Lancet. 1998;352:719-725.
Erratum in: Lancet. 1999;353:74.
Physical 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 PAH
Pre-symptomatic/
Compensated
CO
PAP
PVR
Symptomatic/
Decompensating
Declining/
Decompensated
Symptom Threshold
Right Heart
Dysfunction
PAP
CO =
PVR
Time
Available Diagnostic Methods
• Clinical predictors of disease
• Pulmonary function tests
• Transthoracic echocardiogram
• Right heart catheterization
• Cardiac MRI and serum BNP
Predictors 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
Function 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 Echo
• Increased sPAP or TR jet
• Right atrial & ventricular
hypertrophy
• Flattening of
intraventricular septum
• Small LV dimension
• Dilated PA
McGoon M et al. Chest. 2004;126:14S-34S.
IVS
RV
LV
RA
LA
Prevalence 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:
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)
Wigley FM et al. Arthritis Rheum. 2005;52:2125-2132.
Total prevalence:
26.7%
• 122 known
• 89 sPAP >40 mm Hg
Scleroderma and PAH
Recommended Screening
Patient newly
diagnosed
with scleroderma
Patient with
existing
diagnosis
of scleroderma
Perform baseline
Annual
echo and PFT
echo and PFT
McGoon M et al. Chest. 2004;126:14S-34S.
Diagnosis of PAH by
Right 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
Gaine et al. Lancet. 1998;352:719.
PAH definition:
• mPAP >25 mm Hg at rest or >30 mm Hg
during exercise
• Normal PCWP <15 mm Hg
• PVR >3 wu
Potential Diagnostic Tools
• Serum brain natriuretic peptide (BNP) and
pro-BNP
• Cardiac MRI
Signs 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.
Early Signs of PAH: Cardiac MRI
• Cardiac MRI measures:
– RV volume and mass,
stroke volume, CO
– myocardial fibrosis
– pulmonary perfusion
QuickTime™ and a
decompressor
cMRI PAH
4chamber.avi
are needed to see this picture.
Early Diagnosis of PAH in SSc:
Concluding Remarks
• Annual screening:
– DLCO
– transthoracic echocardiogram
– serum BNP