1. 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

2. 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.

3. Kaplan-Meier Survival Estimates in Scleroderma 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 012345678910111213 Year from PH Diagnosis Percent Survival PAH Lung Involvement (without PH) None 14

4. 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 012345 Percent survival Survival in PAH McLaughlin VV et al. Chest. 2004;126:78S-92S. CHD Portopulmonary PPH CTD HIV Years

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. 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 PAH 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 (P 2 ) 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 Time PAP PVR CO Pre-symptomatic/ Compensated Symptomatic/ Decompensating Symptom Threshold Right Heart Dysfunction Declining/ Decompensated CO = PAP 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. Signs 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 LA RA IVS 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: 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 (%) ≥30282 (42.2) ≥35158 (23.6) ≥4089 (13.3) ≥4545 (6.7) ≥5020 (3.0) ≥606 (0.9) Total prevalence: 26.7% 122 known 89 sPAP >40 mm Hg

14. Scleroderma and PAH Recommended Screening Annual echo and PFT Patient with existing diagnosis of scleroderma Perform baseline echo and PFT Patient newly diagnosed with scleroderma McGoon M et al. Chest. 2004;126:14S-34S.

15. 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 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

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

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