Systemic sclerosis Hadi poormoghim professor of Rheumatology.
Early Diagnosis of PAH in Systemic Sclerosis: How Do We Recognize the Warning Signs?
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Transcript of Early Diagnosis of PAH in Systemic Sclerosis: How Do We Recognize the Warning Signs?
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.
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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
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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