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Early Diagnosis of PAH in Systemic Sclerosis: How Do We Recognize the Warning Signs?

VASCULAR COMPLICATIONS OF SYSTEMIC SCLEROSIS. Early Diagnosis of PAH in Systemic Sclerosis: How Do We Recognize the Warning Signs?. Joseph C. Shanahan, MD

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Early Diagnosis of PAH in Systemic Sclerosis: How Do We Recognize the Warning Signs?

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  1. VASCULAR COMPLICATIONSOF SYSTEMIC SCLEROSIS Early Diagnosis of PAH in Systemic Sclerosis: How Do We Recognizethe Warning Signs? Joseph C. Shanahan, MD Assistant Professor, Rheumatology and ImmunologyClinical Director, Duke Scleroderma Research CenterAssociate Director, Duke Lupus ClinicDuke University Medical CenterDurham, North Carolina

  2. 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.

  3. Kaplan-Meier Survival Estimates in Scleroderma By Organ Involvement 100 90 80 None 70 60 Percent Survival 50 Lung Involvement (without PH) 40 30 PAH 20 10 0 14 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Year from PH Diagnosis Koh ET et al. Br J Rheumatol. 1996;35:989-993.

  4. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Survival in PAH CHD Portopulmonary Percent survival PPH CTD HIV 0 1 2 3 4 5 Years McLaughlin VV et al. Chest. 2004;126:78S-92S.

  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.

  6. Signs and Symptoms of PAH No early symptoms of PAH Annual screening in high-risk populations mandatory Disease Onset Progressive dyspnea on exertion, fatigue, palpitations, chest pain, dizziness, syncope, coughing First Symptoms Symptoms and signs of right heart failure, edema, ascites End-stage Symptoms Death Gaine SP, Rubin LJ. Lancet. 1998;352:719-725. Erratum in: Lancet. 1999;353:74.

  7. 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.

  8. Schematic Progression of PAH Pre-symptomatic/ Compensated Symptomatic/ Decompensating Declining/ Decompensated CO Symptom Threshold Right Heart Dysfunction PAP PVR PAP Time CO = PVR

  9. Available Diagnostic Methods • Clinical predictors of disease • Pulmonary function tests • Transthoracic echocardiogram • Right heart catheterization • Cardiac MRI and serum BNP

  10. 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.

  11. 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.

  12. IVS RV LV RA LA 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.

  13. 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: • Total prevalence: • 26.7% • 122 known • 89 sPAP >40 mm Hg Wigley FM et al. Arthritis Rheum. 2005;52:2125-2132.

  14. Scleroderma and PAHRecommended Screening Patientnewly diagnosed with scleroderma Patient with existing diagnosis of scleroderma Performbaselineecho and PFT Annual echo and PFT McGoon M et al. Chest. 2004;126:14S-34S.

  15. Diagnosis of PAH byRight 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 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.

  16. Potential Diagnostic Tools • Serum brain natriuretic peptide (BNP) and pro-BNP • Cardiac MRI

  17. 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.

  18. Early Signs of PAH: Cardiac MRI • Cardiac MRI measures: • RV volume and mass, stroke volume, CO • myocardial fibrosis • pulmonary perfusion cMRI PAH 4chamber.avi

  19. Early Diagnosis of PAH in SSc: Concluding Remarks • Annual screening: • DLCO • transthoracic echocardiogram • serum BNP

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