9. Prevalence of PAH in SSc ReferenceMethodologyDiagnosisPAH prevalence Mukerjee; 2003, UK n = 722, single center Prospective 1998-2002 RHC12% Hachulla; 2005, France n = 599, multi-center Prospective, cross sectional RHC8% Phung; 2009, Australia n = 184, single center Prospective, cross sectional RHC13% Vonk; 2009, Netherlands n = 819, multi-center Prospective 2005-2007 RHC9,9% RHC: Right heart catheterization. 1. Mukerjee D, et al. Ann Rheum Dis 2003; 62:1088-93. 2. Hachulla E, et al. Arthritis Rheum 2005; 52:3792-800. 3. Phung S, et al. Intern Med J 2009; 39:682-91, 4. Vonk MC, et al. Ann Rheum Dis 2009; 68:961-5

10. Diagnosis of PAH  PAH is defined as – mPAP ≥ 25 mmHg at rest, assessed by right heart catheterization – Pulmonary capillary wedge pressure ≤ 15 mmHg – PVR > 3 Wood units (240 dyn∙sec/cm 5 ) Galiè N, et al. Eur Heart J 2009; 30:2493-537. McLaughlin VV, et al. Circulation 2009; 119:2250-94. mPAP: Mean pulmonary arterial pressure.

14. Existing screening recommendations Proposed criteria for referral for right heart catheterization ESC / ERS 1 TR velocitysPAPAdditional signs of PH on echo SymptomsSSc > 3.4 m/s> 50 mmHgYes / No 2.9  3.4 m/s37  50 mmHg Yes / NoYes ≤ 2.8 m/s≤ 36 mmHgYes ACCF / AHA 2 High right ventricular systolic pressure or right heart chamber enlargement on echocardiography ACCP 3 Clinical suspicion of PAH: echocardiography to evaluate level of right ventricular systolic pressure and abnormalities (right atrium or right ventricle enlargement and pericardial effusion) Dana Point 4 No recommendation ESC / ERS, European Society of Cardiology / European Respiratory Society; ACCF / AHA, American College of Cardiology Foundation / American Heart Association; ACCP, American College of Chest Physicians 1 Galiè et al. Eur Heart J 2009; 2 McLaughlin et al. J Am Coll Cardiol 2009; 3 Badesch et al. Chest 2007; 4 Badesch et al. J Am Coll Cardiol 2009. TR, tricuspid regurgitant jet; sPAP, pulmonary artery systolic pressure; PH, pulmonary hypertension

16. Background  PAH is the leading cause of death in SSc patients 1,2  Screening may lead to earlier diagnosis and intervention and thus to improved outcomes  Current screening is based on consensus rather than robust evidence  No single laboratory test is shown to be adequate PAH, pulmonary arterial hypertension; SSc, systemic sclerosis 1 Steen and Medsger. Ann Rheum Dis 2007; 2 Tyndall et al. Ann Rheum Dis 2010.

17. Rationale  TR velocity is main basis of ESC / ERS screening recommendations but – Does not accurately reflect invasive pressures 1,2 – Is not present in all patients 1 – PAH symptoms as additional criteria are open to interpretation  False positives are common particularly in ILD  No systematic right heart catheterization (RHC) in any screening study to date – Missed diagnoses rate (false negatives) could never be calculated 1 Fisher et al. Am J Respir Crit Care Med 2009; 2 Parent et al. N Engl J Med 2011. ILD, interstitial lung disease; RHC, right heart catheterization

18. Objective of DETECT  To develop an evidence-based screening algorithm for PAH in SSc patients  Minimize the number of missed PAH diagnoses  Optimize the use of screening modalities  Optimize the use of diagnostic RHC

19. Design and methodology  Patient population – Aged ≥ 18 years – SSc of > 3 years’ duration from first non-Raynaud feature – DLCO < 60% of predicted  Prospective cross-sectional study design – RHC performed in all patients following collection of all other data  Demographics, medical history, physical exam, serum lab, pulmonary function tests, ECG, echocardiography DLCO, diffusing capacity of the lung for carbon monoxide; ECG, electrocardiography

21. Patient disposition SSc patients screened n = 646 RHC analysis set n = 466 Screen failures (n = 158) No RHC (n = 22) PH: n = 145* (31%) mPAP ≥ 25 mmHg Non-PH: n = 321 (69%) mPAP < 25 mmHg WHO group 1 PH (PAH): n = 87 (19%) PCWP ≤ 15 mmHg WHO group 2 PH (left heart disease): n = 30 (6%) PCWP > 15 mmHg WHO group 3 PH (lung disease / hypoxia): n = 27 (6%) PCWP ≤ 15 mmHg FVC < 60% or 60  70% + HRCT not available or ‘moderate  severe’ *PH classification not possible in one patient due to a missing pulmonary capillary wedge pressure (PCWP). mPAP, mean pulmonary arterial pressure; WHO, World Health Organization; FVC, forced vital capacity; HRCT, high resolution computed tomography

22. Patient demographics and characteristics Non-PH (n = 321)PAH (n = 87) Male16.625.6 Age, years54.7 ± 11.861.1 ± 9.8 SSc Duration, months Diffuse / limited / mixed or overlap 130.2 ± 96.1 36.5 / 54.3 / 9.2 163.0 ± 130.3 20.9 / 70.9 / 8.1 6MWD, m*412.5 ± 107.2389.7 ± 106.6 WHO functional class I/II vs. III/IV83.7 / 16.364.4 / 35.6 DLCO % predicted48.0 ± 9.243.3 ± 10.5 Right heart catheterization mPAP, mmHg PCWP, mmHg PVR, dyn·sec/cm 5 Cardiac index, L/min/m 2 17.6 ± 3.8 8.5 ± 3.6 145.4 ± 64.6 3.0 ± 0.7 32.5 ± 8.3 10.3 ± 3.2 370.6 ± 225.8 2.9 ± 0.6 Data are mean ± standard deviation or %; *n = 243 / 66. 6MWD, 6-minute walk distance; PVR, pulmonary vascular resistance

23. DETECT: statistical analyses – variable selection Final Multivariable regression across groups Multivariable regression within groups of variables Expert selection: Clinically relevant and feasible variables Descriptive statistics and univariable regression Demographic and clinical parameters (n = 68) Serum tests (n = 13) ECG parameters (n = 3) Echocardiographic parameters (n = 28) 112 variables 8 variables

24. DETECT: The 8 variables in the final screening algorithm Non-PHPAHP-value*ROC AUC (95% CI) FVC % pred. / DLCO % pred.1.8 ± 0.52.2 ± 0.7< 0.0010.715 (0.656, 0.774) Current or past telangiectasias67.987.4< 0.0010.597 (0.554, 0.641) Serum ACA positive25.250.0< 0.0010.624 (0.564, 0.684) Serum NTproBNP, log 10 (pg/mL) 2.1 ± 0.5 (230.0 ± 538.6) 2.4 ± 0.5 (516.4 ± 805.0) < 0.0010.675 (0.609, 0.742) Serum urate, mg/100 mL4.7 ± 1.55.9 ± 1.5< 0.0010.719 (0.659, 0.779) Right axis deviation # on ECG3.413.30.0010.549 (0.511, 0.587) Right atrium area, cm 2 13.4 ± 4.717.1 ± 6.2< 0.0010.712 (0.650, 0.773) TR velocity, m/s2.4 ± 0.63.0 ± 0.8< 0.0010.795 (0.737, 0.853) Data are mean ± standard deviation or %; *Wald  2 test; # QRS axis ≥ 90  ; ROC AUC, area under the receiver operating characteristic curve; ACA, anticentromere antibody; NTproBNP, N-terminal pro-brain natriuretic peptide

25. DETECT: The 8 variables in the final screening algorithm Non-PHPAHP-value*ROC AUC (95% CI) Step 1 0.844 (0.795, 0.898) FVC % pred. / DLCO % pred.1.8 ± 0.52.2 ± 0.7< 0.0010.715 (0.656, 0.774) Current or past telangiectasias67.987.4< 0.0010.597 (0.554, 0.641) Serum ACA positive25.250.0< 0.0010.624 (0.564, 0.684) Serum NTproBNP, log 10 (pg/mL) 2.1 ± 0.5 (230.0 ± 538.6) 2.4 ± 0.5 (516.4 ± 805.0) < 0.0010.675 (0.609, 0.742) Serum urate, mg/100 mL4.7 ± 1.55.9 ± 1.5< 0.0010.719 (0.659, 0.779) Right axis deviation # on ECG3.413.30.0010.549 (0.511, 0.587) Step 2 0.881 (0.824, 0.923) Right atrium area, cm 2 13.4 ± 4.717.1 ± 6.2< 0.0010.712 (0.650, 0.773) TR velocity, m/s2.4 ± 0.63.0 ± 0.8< 0.0010.795 (0.737, 0.853) Data are mean ± standard deviation or %; *Wald  2 test; # QRS axis ≥ 90  ; ROC AUC, area under the receiver operating characteristic curve; ACA, anticentromere antibody; NTproBNP, N-terminal pro-brain natriuretic peptide

26. DETECT: two-step screening algorithm PAH and non-PH patients (n = 408) RHC True PAH positive (n = 69) False PAH positive (n = 129) YES (n = 198) No referral to RHC True PAH negative (n = 68) False PAH negative (n = 1) NO (n = 69) No referral to echo True PAH negative (n = 50) False PAH negative (n = 2) NO (n = 52) YES (n = 304) Step 1 6 non-echo variables Total risk points > 300? Missing data (n = 52) ROC AUC = 0.844 (95% CI, 0.795, 0.898) Step 2 Total risk points from Step 1 2 echo variables Total risk points > 35? Missing data (n = 37) ROC AUC = 0.881 (95% CI, 0.824, 0.923) The DETECT algorithm PPV: 69/198 = 35% Missed PAH: 3/72 = 4% RHC referral: 198/319 = 62%

27. DETECT: comparison of two-step algorithm with current guidelines RHC referral rate Missed PAH diagnoses Overall sensitivity Overall specificity Overall PPV Overall NPV DETECT algorithm 62%4%96%48%35%98% ESC / ERS guidelines* 40%29%71%69%40%89% * Evaluated in 371 DETECT patients with available data for screening variables defined in the guidelines PPV, positive predictive value; NPV, negative predictive value

28. DETECT: limitations  Results obtained in a high-risk SSc population – SSc of > 3 years’ duration – Inclusion criterion DLCO < 60% – More RHC compared to ESC guidelines (62%-40%)  Cross-sectional design – Frequency of screening cannot be recommended

29. DETECT: conclusions  The two-step evidence-based DETECT algorithm – Is a sensitive, non-invasive screening tool for detection of PAH in SSc patients – Minimizes missed diagnoses – Identifies PAH earlier in a mildly symptomatic population – Addresses resource utilization of RHC  The DETECT algorithm has the potential to revise standards of care in SSc patients