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Pulmonary Hypertension associated with Connective Tissue Disease.

The document discusses the prevalence, pathophysiology, diagnosis, and treatment of pulmonary hypertension associated with connective tissue disease (CTD). It highlights the variability in prevalence rates and diagnostic methods, emphasizing the importance of early screening, particularly in high-risk populations such as patients with systemic sclerosis. The findings are supported by various registries and studies, and it outlines recommendations for improving detection and management of pulmonary arterial hypertension in CTD patients.

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Pulmonary Hypertension Overview•
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Introduction to pulmonary hypertension in connective tissue diseases; includes historical context.

Definitions and classification of pulmonary hypertension (PH/PAH) with hemodynamic criteria.

Discussion on prevalence of PH in connective tissue diseases with variances depending on study methods. Data from studies on abnormal echo and RHC prevalence in different connective tissue diseases. Insights from various registries on the prevalence and demographics of CTD-associated pulmonary arterial hypertension.

Detailed statistics of CTD-PAH from various registries, identifying significant patterns in prevalence.

Pathogenetic factors contributing to pulmonary hypertension in connective tissue diseases.

Description of vascular remodeling and how it correlates with pulmonary hypertension.

Identifies various clinical and serological risk factors for developing pulmonary hypertension in scleroderma and lupus.

Analysis of timeframes and prognostic class stratification in systemic sclerosis and PH.

Importance of early diagnosis and screening protocols for pulmonary hypertension in high-risk CTD populations.

Algorithm for diagnosing pulmonary hypertension, emphasizing the necessity of right heart catheterization.

Survival outcomes from major studies comparing CTD-PAH with idiopathic forms and related pathologies.

Current treatment options for pulmonary arterial hypertension, highlighting the importance of early intervention.

Discussion on combination therapy efficacy and the systematic approach to managing PAH in CTD.

Insights into immunosuppressive therapy providing benefits in managing pulmonary hypertension associated with connective tissue diseases.

Final thoughts on the treatment protocols for CTD-PAH, emphasizing the need for personalized management strategies.

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Pulmonary Hypertension in Connective Tissue Disease Sarfraz Saleemi Pulmonary Hypertension Program Section of pulmonary medicine Department of medicine King Faisal Specialist Hospital & Research Center
Outline • Prevalence • Pathophysiology • Screening • Diagnosis • Prognosis • Treatment
Cardiopulmonary complications of CTD Complications Acute lupus pneumonitis Obstructive lung disease Acute reversible hypoxemia Pericardial disease Alveolar hemorrhage Pleural effusion Atelectasis Pleurisy Coronary artery disease Pneumothorax Diaphragmatic dysfunction Pulmonary embolism Diastolic dysfunction Interstitial lung disease Uremic pulmonary edema Myocarditis Valve lesions Recurrent aspiration pneumonia Bronchiectasis and bronchiolitis Pulmonary hypertension
Ibn al-Nafis • Discovered Pulmonary circulation nearly 350 years before Sir William Harvey(1616) of England • Described the purification of blood in the lungs where it was refined in contact with the air inhaled from the outer atmosphere
Badesch D et al. J Am Coll Cardiol. 2009;54:S55-S66. McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619. Hemodynamic Definition of PH/PAH PH PAH Mean PAP ≥25 mmHg PCWP/LVEDP ≤15 mmHg PVR >3 Wood Units Mean PAP ≥25 mm Hg
Classification of Pulmonary Hypertension
LV LA RA RV PT PVOD ILD Pulmonary Hypertension Spectrum in CTD PAH LV systolic or diastolic dysfunction Post-capillary PH CTEPH Multifactorial PH
Prevalence of CTD-PAH Highly variable Lack of consistent epidemiological data Method used for assessing PA pressure Diagnostic tools – Echocardiogram, Right heart catheterization Potential bias concerning the study population – Rheumatologic definitions, criteria etc Geographical variation in the epidemiology of CTD
Prevalence of abnormal Echo in patients with CTD – UNCOVER study
Prevalence of PH in Connective Tissue Disease Disease Echo prevalence RHC prevalence SSc 20-50% 1,2 7.85-12% 3,4 SLE 4-43% 5,6 0.9% 3 RA 20% 7 <0.01% 8 MCTD 50%9 3.4%10 9. Udayakumar N, Int J Cardiol. 2008 Jul 21;127(3):410-2 10. Gunnarson Rheumatology 2013.
Prevalence of PAH in CTD 13% 9.18 % to 18.16 % Range (95% CI) Yang, X., Mardekian, J., Sanders, K.N. et al. Clin Rheumatol (2013) 32: 1519. Prevalence of PH in Connective Tissue Disease (systematic review)
Prevalence of CTD-PAH in general population 2.3 – 10 cases per million Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 2006;173:1023–1030 Connective Tissue Disease–associated Pulmonary Arterial Hypertension in the Modern Treatment Era. Am J Respir Crit Care Med Vol 179. pp 151–157, 2009 An epidemiological study of pulmonary arterial hypertension. Eur Respir J 2007;30:104–109.
REVEAL Registry 2967 patients. Adapted from Badesch DB et al. Chest. 2010;137:376-387. Overall group 1 PAH Associated PH Associated (50.7%) Idiopathic (46.2%) Heritable (2.7%) Pulmonary veno-occlusive (0.4%) Connective tissue/ collagen vascular (49.9%) Congenital heart disease (19.5%) HIV (4.0%) Other (5.5%) Portopulmonary (10.6%) Nearly 25% of group 1 PAH is CTD-related
Prevalence of PH in Connective Tissue Disease CTD-PAH SSc SLE Other Registry 641 62% 17% 21% REVEAL 343 76% 8% 16% UK CTD-PH 188 83% 17% Aspire 103 76% 15% 9% French Chest. 2010;137:376-387 Am J Respir Crit Care Med VOL 179 2009 Eur Respir J. 2012 Apr;39(4):945-55 Eur Respir J. 2012 Apr;39(4):945-55
REVEAL registry CTD-PAH CTD-PAH N=641 SSc-PAH N=399 (62%) SLE-PAH N=110 (17%) Other CTD N=132 (20%)
UK CTD-PH registry (incidental cases January 2001 to January 2006) CTD-PAH n=484 CTD-PAH = 429 SSC 315 (74%) MCTD 36 (8%) SLE 35 (8%) DM/PM 18 (4%) RA 13 (3%) UCTD 9 (2%) Sjogren’s 3 (1%) CTD-PAH = 343 SSC 259 (76%) MCTD 28 (8%) SLE 28 (8%) DM/PM 7 (2%) RA 12 (3%) UCTD 6 (2%) Sjogren’s 3 (1%) PAH on exercise only n=55 PAH due to respiratory disease N=86 Condliffe, Kiely, Peacock, et al.: U.K. CTD-PAH Registry Am J Respir Crit Care Med VOL 179 2009
ASPIRE registry (Sheffield Pulmonary Vascular Disease Unit) (treatment-naive cases diagnosed between 2001 and 2010) Group 1 and 1’ PAH N=600 PAH-CHD=198 PoPH=24 Hemolytic=10 HIV=3 PVOD=2 iPAH N=175 CTD-PAH N=188(31%) SSc-PAH N=156 (83%) Other CTD N=32 (17%) Eur Respir J. 2012 Apr;39(4):945-55
French Registry AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 173 2006 Group 1 PAH N=674 PAH-CHD=76 (11.3%) Anorexogenic=64 (9.5%) PoPH=70 (10.4%) Familial=26 (3.9%) HIV=42 (6.2%) >1 risk factors=29 (4.3%) iPAH N=264(39.2%) CTD-PAH N=103(15.3%) Eur Respir J. 2012 Apr;39(4):945-55 SSc-PAH 76% SLE-PAH 15%
Connective tissue disease-associated pulmonary arterial hypertension in Chinese patients (n=129) Eur Respir J 2014; 44: 963–972 pSS = Primary Sjogren syndrome TA = Takayasu arteritis ASOD = Adult onset Still disease UCTD = undifferentiated CTD pAPS = primary APL syndrome SLE, 49% pSS; 16% TA; 12% MCTD; 9% SSc; 6% RA; 3% AOSD; 2% UCTD; 2% pAPS; 1%
Undiagnosed connective tissue diseases High prevalence in pulmonary arterial hypertension patients • 49 patients (36 females, 13 males) with iPAH were studied for rheumatological re-assessment. • 17 (15 F, 2M) were classified as having a CTD-PH (34.6%) • 12 had SSc (11 F, 1M ) • 2 SLE ( 2 F) • 2 UCTD (1 F, 1M) • 1 SS (1 F). Cavagna et al. Medicine (2016) 95:39
Pathogenesis of PH in CTD Normal pulmonary artery Inflammation Viral infections AECA Cytokines and chemokines release Dendritic cells Mast cells B cells T cells Chemokines / Cytokines / Growth factors Vascular remodeling In situ thrombi Matrix remodeling Endothelia cell dysfunction Smooth muscle cell dysfunction Chronic vasoconstriction Collagen dysfunction Recruitmentof inflammatory cells A B C Clinical and Developmental Immunology Volume 2012, Article ID 854941
Vasoconstrictors Vasodilators Imbalance of vasoconstrictors and vasodilators Endothelin-1 Thromboxane A2 Leukotrienes Serotonin Angiotensin II Platelet activating factor NO PGI2 Vasodilators Antiproliferatives Anticoagulants Vasoconstrictor s Proliferative Procoagulants Pathophysiology of PH
Remodelling Pathophysiology of PH Pulmonary Vascular Disease Pulmonary Vascular Resistance Pulmonary Hypertension Vascular tone Progress of the disease
Normal Pulmonary Artery Medial Hypertrophy Intimal Proliferation Plexiform Lesion In-situ thrombosis
Limited SSc Late age of onset of SSc Raynaud phenomenon Long standing diseae (>5 years) Telangectasia FVC %: DLCO% > 1.6 DLCO <55% predicted Increased NT-proBNP Antibodies (Anti-U1 RNP, Anti- centromere, Anti-nuclear pattern ANA) Absence of anti-Scl 70 antibody Risk factors for PH In Scleroderma
Female gender Isolated reduction in DLCO on PFT Renal disease Cutaneous vasculitis Antiribonuclear proteins Antiphospholipid antibodies Antiendothelial antibodies Risk factors for PH In SLE
Development of pulmonary hypertension in a high-risk population with systemic sclerosis in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) cohort study V.M. Hsu et al. / Seminars in Arthritis and Rheumatism 44( 2014)55–6260 Risk Factors • sPAP >40 mmHg on echocardiogram, • (DLCO) <55% predicted • FVC%/ DLCO% >1.6 • Exercise-induced hypoxemia The time to PH 10% at 2 years 13% at 3 years 25% at 5 years
When to suspect PH in CTD Clinical and Lab finding suggestive of PH Allergology International. 2011;60:405-409 Raised JVP ECG RBBB RVH tall P wave Exertional dyspnea Elevated pro-BNP Hyper- uricemia Para-sternal heave %FVC/ %DLCO >1.4
Dyspnea in SSc patients Dyspnea Lung disease Sedentary life style Cardiac disease Anemia PAH A forgotten killer Chest wall tightness Muscle disease Thromboembolic disease
Survival from diagnosis of patients with isolated SSc-PAH grouped by World Health Organization (WHO) functional class. Am J Respir Crit Care Med Vol 179. pp 151–157, 2009 Cumulativesurvival Years from diagnosis
Badesch DB et al. Chest. 2010;137:376-387 CTD-PAH functional class at diagnosis 7,6 36,7 50,0 5,6 0 20 40 60 80 100 I II III IV Patients(%) FC at Enrollment REVEAL Registry (All Patients) (n=2525) 5,7 32,2 54,9 7,2 0 20 40 60 80 100 I II III IV FC at Enrollment REVEAL Registry (CVD/CTD) (n=639)
Screening – Early diagnosis 1 24 63 12 0 20 40 60 80 100 I II III IV Patients(%) NYHA FC (N=674) Humbert M et al. Am J Respir Crit Care Med. 2006;173:1023-1030. Hachulla E et al. Arthritis Rheum 2005: 52:3792-3800. No Screening 5 44 28 11 0 20 40 60 80 100 I II III IV NYHA FC (N=18) With Screening
PAH: Screening high risk population  Key to early diagnosis – screening high risk populations:  Family members of a patient with familial Pulmonary Arterial Hypertension (FPAH)  Patients with systemic sclerosis (SSc)  Patients with HIV  Patients with chronic liver disease and portal hypertension  International guidelines recommend annual screening with Doppler echocardiography.  Early diagnosis improves outcome • Hachulla E et al Ann Rheum Dis 2004 • Galie N et al. Eur Heart J 2004 • McGoon M et al. Chest 2004
Echocardiographic probability of pulmonary hypertension patients with a suspicion of pulmonary hypertension ESC/ERS 2015 guidelines – Screening
ASIG (Australian Scleroderma Interest Group) Screening algorithm Intern Med J. 2015 Nov;45(11):1134-40. doi: 10.1111/imj.12890
Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study Coghlan JG, et al. Ann Rheum Dis 2013;00:1–10 SSc patients screened = 646 RHC analysis set = 466 SSc patients enrolled = 488 PH N=145(31%) Non-PH N=321(69%) PAH N=87 (19%) Group 2 PH N=30 (6%) Group 3 PH N=27 (6%) Screen failure, n=158 No RHC consent withdrawn N=22
DETECT nomogram for PH screening in SSC STEP 1 Criteria for Referral to Echo STEP 2 Criteria for Referral to RHC
The DETECT algorithm for PAH screening in SSc patients is a sensitive, non-invasive screening tool, which minimizes missed diagnoses, identifies even mild disease and optimizes resource utilization. SSc patients to be screened Step 1 Non-echo variables FVC/DLCO%, Telangiectasia, ECG–RAD, ACA, pro-BNP, Uric Acid Total risk score >300 No Yes No referral for ECHO Step 2: step1 variable plus 2 echo variables Right atrium area TR velocity Total risk score >35 No Yes No referral for RHC RHC for diagnosis of presence /absence of PAH Coghlan JG, et al. Ann Rheum Dis 2013;00:1–10.
RHC Referral rate Missed PAH Diagnosis 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% DETECT vs Standard screening for PAH-SSc Coghlan JG, et al. Ann Rheum Dis 2013;00:1–10.
DETECT tool http://www.detect-pah.com/
Comparison between screening tools Hao J. et al. Arthritis Res Ther. 2015 Jan 18;17:7.
ESC/ERS 2015 guidelines • Clearly recognized the limitations of relying on TR velocity. • Described single tools for screening. • Described DETECT as a composite tool. • But did not recommend any (more validation is required). Galie N. et al. Eur Heart J. 2016 Jan 1;37(1):67-119.
General recommendations, initial screening evaluation, and frequency of noninvasive tests for early detection of CTD-associated PAH Recommendation Level of evidence All patients with SSc should be screened for PAH Moderate Patients with MCTD or other CTDs with scleroderma features (Scleroderma spectrum) should be screened in a similar manner to patients with SSc Very low Screening is not recommended for asymptomatic patients with MCTD or other CTDs (including SLE, rheumatoid arthritis, inflammatory myositis, Sjögren’s syndrome) without features of scleroderma Low to moderate For unexplained signs and symptoms of PH in patients with MCTD, SLE, or other CTDs without scleroderma features, one may consider the diagnostic algorithm evaluation for PH Moderate All patients with SSc and scleroderma spectrum disorders with a positive results on a noninvasive screen should be referred for RHC High RHC is mandatory for diagnosis of PAH High Vasoreactivity testing is not required for evaluation of PAH in patients CTDs Moderate to high systematic review of the literature – consensus based evidence driven ARTHRITIS & RHEUMATISM Vol. 65, No. 12, December 2013, pp 3194–3201
Recommendation Level of evidence Initial screening evaluation Transthoracic echo PFTs with DLCO NT-proBNP DETECT algorithm if DLCO < 60% predicted and disease duration 3 years or more High High Moderate Moderate Frequency of noninvasive tests Transthoracic echo annually as screening Transthoracic echo if new signs or symptoms develop PFTs with DLCO annually as a screening test PFTs with DLCO if new signs or symptoms develop NT-proBNP if new signs or symptoms develop Low High Low Low Low General recommendations, initial screening evaluation, and frequency of noninvasive tests for early detection of CTD-associated PAH systematic review of the literature – consensus based evidence driven ARTHRITIS & RHEUMATISM Vol. 65, No. 12, December 2013, pp 3194–3201
Diagnostic algorithm Echocardiography NO YES NO YES PH Right heart catheterization sPAP <35 mmHg sPAP 36-50 mmHg sPAP >50 mmHg Other clinical and Lab features Other clinical and Lab features PH suspected PH ruled out (periodic assessment recommended RHC is recommended in all cases of suspected PAH associated with CTD to confirm the diagnosis, determine severity and rule out left heart disease
Stupi AM et al. Arthritis Rheum.1986;29:515-524. Steen VD, Medsger TA Jr. Arthritis Rheum. 2003;48:516-522. Impact of PAH on Survival in Limited SSc Before PAH Therapy SSc with PAH (n=20) (n=106) SSc without PAH (n=287) (n=106) % cumulative survival Follow-up (yr) 0 20 40 60 80 100 1 2 3 4 5
Koh et al, Br J Rheumatol, 1996 Outcome of Scleroderma Patients with Pulmonary Hypertension 0 10 20 30 40 50 60 70 80 90 100 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Years From Diagnosis of PHT PHT Lung Involvement (without PHT) None Survival,%
Survival - ASPIRE registry Eur Respir J 2012; 39: 945–955
Survival – PAH-SSc vs PAH-SLE Condliffe, Kiely, Peacock, et al.: U.K. CTD-PAH Registry AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 179 2009
Survival – CTD-PAH vs ILD-PAH Condliffe, Kiely, Peacock, et al.: U.K. CTD-PAH Registry AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 179 2009
Prognosis of SSc-PAH in major registries Registry Year n Age (yrs) Incident cases (%) WHO FC I&II/III/IV (%) mPAP (mmHg) PVR (dyns.s.cm5) 1 yr survival (%) 3 yr survival (%) UK 2009 259 64 100 16/68/16 42 715 78 47 REVEAL 2010 399 62 18 25/60/15 45 768 82 n/a ASPIRE 2012 156 66 100 19/67/14 43 678 82 52 French 2013 85 65 100 21/67/12 41 680 90 56 PHAROS 2014 131 60 100 56/38/6 36 448 93 75
CTD-PAH vs iPAH Compared to patients with iPAH, patients with CTD-PAH have: • higher mortality • lower 6-minute walk distance • Higher pro-BNP • more right ventricular dysfunction • Poor lung functions • More pericardial disease Rhee et al Arth& Rheum 2015
Factors Role Evidence Age Mean age of diagnosis SSc-PAH ≈10 yrs > IPAH Arthritis Rheum 2006, 54:3043-50 Pulmonary vasculopathy Higher proportion of pulmonary venule involvement in SSc-PAH Eur Respir J 2009, 34:371-9. Right ventricle (RV) Reduced RV contractility Higher NT-proBNP despite less severe pulmonary haemodynamics Respir Res 2008, 9:68. Eur Respir J 2010, 35:95-104 Left ventricle (LV) High prevalence of LV dysfunction ≈1/3 of patients with SSc-PAH have occult LV dysfunction on fluid challenge Ann Rheum Dis 2009, 68:1878-84. Eur Respir J 2013,42:1083-91. Interstitial lung disease (ILD) ILD common in SSc Response to PH therapy in the presence of ILD appears poor Arthritis Rheum 2011, 63:2456-64 Multisystem disease Coexisting renovascular and gastrointestinal disease Antibodies Possible role of autoantibodies Am J Respir Crit Care Med 2010, 181:1285-93 Potential reasons for poorer outcome in SSc-PAH than in IPAH
ECHOCARDIOGRAPHIC PROGNOSTIC MARKERS IN CONNECTIVE TISSUE DISEASE ASSOCIATED PULMONARY HYPERTENSION DIFFER FROM IDIOPATHIC PULMONARY HYPERTENSION J Am Coll Cardiol. 2016;67(13_S):2071-2071. doi:10.1016/S0735-1097(16)32072-1
Treatment of Pulmonary Arterial Hypertension  Currently there is no cure for PAH  Those who start therapy in WHO FC I or II demonstrate a better prognosis than those whose therapy is started in the more advanced stages  By recognizing and treating patients as early as possible, disease progression may be delayed Sitbon O et al. J Am Coll Cardiol 2002
Treatment algorithm 2015 ESC/ERS Guidelines Treatment naive patient PAH confirmed by expert center General measures Supportive therapy Acute vasoreactivity test (I-PAH, H-PAH, D-PAH only) Vasoreactive CCB Therapy Non-vasoreactive (or not IPAH/HPAH/DPAH) Low/intermediate Risk (FC II/III) High Risk (FC IV) Oral Monotherapy Oral Combo Therapy Parenteral Therapy Inadequate response Double/triple sequential therapy . Galie N, ESC/ERS 2015 Guidelines, Alreadyon treatment Inadequate response Lung Transplant European Heart Journal August 29, 2015
Risk assessment in Pulmonary Arterial Hypertension . Galie N, ESC/ERS 2015 Guidelines Estimated1-year mortality LowRisk (<5%) Intermediate (5-10%) High Risk (>10%) Right heart failure No No Yes Progression No Slow Rapid Syncope No Occasional Repeated WHO FC I or II III IV CPET VO2 max >15 Ve/VCO2 <36 VO2 max 11-15 Ve/VCO2 36-45 VO2 max<11 Ve/VCO2 >45 BNP <50 50-300 >300 Hemodynamics RA <8 mmHg CI>2.5 SvO2 >65% RA 8-14 mmHg CI2.0-2.4 SvO2 60-65% RA >14 mmHg CI<2 SvO2 <60%
PAH Therapy: General and supportive  Sodium restriction  Contraception  Vaccination  Oxygen  Diuretics if signs of right heart failure  Anticoagulation  Digoxin if evidence of atrial arrythmias
Humbert M et al. N Engl J Med. 2004;351:1425-1436. Targets for current PAH-specific therapy Big Endothelin Endothelin- converting Enzyme Endothelin Receptor A Endothelin Receptor B Vasoconstriction and Proliferation Endothelin Receptor Antagonists Endothelin-1 Endothelin Pathway Arginine Nitric Oxide Synthase Vasodilatation and Antiproliferation Nitric Oxide cGMP Exogenous Nitric Oxide Phosphodiesterase Type-5 Phosphodiesterase Type-5 Inhibitors Nitric Oxide Pathway Arachidonic Acid Prostacyclin Synthase Vasodilatation and Antiproliferation Prostacyclin cAMP Prostacyclin Derivatives Prostacyclin Derivatives Prostacyclin Pathway sGC stimulators 60 IP receptor agonist
<1995 1995 2001 2002 2004 2005 2007 2009 2013 2015 CCB Anticoagulation Digitalis Diuretics IV Epoprostenol Bosentan SC Treprostenol IV Treprostenol Inhaled Iloprost Sildenafil Ambrisartan Tadalafil Inhaled Treprostinil Macitentan Riociguat Pulmonary Hypertension Treatment Timeline IV Sildenafil Oral Treprostinil Selexipag BREATHE SUPER ARIES PHIRST AIR SERAPHIN PATENT CHEST GRIPHON FREEDOM TIMELINE for PAH targeted therapy
Treatment response in CTD-PH vs iPAH Am J Respir Crit Care Med Vol 192, Iss 9, pp 1111–1117, Nov 1, 2015
Source PAH agent Number of patients Number (%) of CTD-PAH patients Galiè et al (SUPER-1) Sildenafil 278 84 (30) Simonneau et al (PACES) Sildenafil 267 55 (21) Galiè et al (PHIRST) Tadalafil 405 95 (24) Rubin et al20 (BREATHE-1) Bosentan 213 63 (30) Galiè et al (EARLY) Bosentan 185 33 (18) Galiè et al (ARIES) Ambrisentan 393 124 (32) Badesch et al Epoprostenol 111 111 (100) Galiè et al (ALPHABET) Beraprost 130 13 (10) Simonneau et al Treprostinil 469 90 (19) Hiremath et al Treprostinil 44 2 (5) CTD-PAH patients included in major RCTs
Recommendations for efficacy of drug monotherapy for PAH (group 1) according to WHO functional class
Clinical trials in PAH
SUPER-1: Sildenafil in PAH-CTD
Bosentan for PAH-CTD BREATHE-1 Trial Subgroup analysis Time to clinical worseningSurvival Bosentan Historical group 6MWT = mean difference 43 m in Bosentan group Ann Rheum Dis 2006;65:1336–1340
Ambrisentan for PAH-CTD
Pulmonary vasodilators in CTD-PH PDE-5 inhibitors Kuwana M, Watanabe H, Matsuoka N, et al. BMJ Open 2013;3:e003113 Kuwana M, Watanabe H, Matsuoka N, et al. BMJ Open 2013;3:e003113
Pulmonary vasodilators in CTD-PH Endothelin Receptor Antagonists Kuwana M, Watanabe H, Matsuoka N, et al. BMJ Open 2013;3:e003113
Pulmonary vasodilators in CTD-PH Prostacyclin Analogs Kuwana M, Watanabe H, Matsuoka N, et al. BMJ Open 2013;3:e003113
Pulmonary vasodilators in CTD-PH Kuwana M, Watanabe H, Matsuoka N, et al. BMJ Open 2013;3:e003113
SERAPHIN study - Macitentan Pulido T. et al. N Engl J Med. 2013 Aug 29;369(9):809-18. 224/742 (30.5%) had CTD-PAH HR,0.55; 97.5% CI, 0.39 to 0.76; log-rank P<0.001
GRIPHON study - Selexipag HR, 0.60; 99% CI, 0.46 to 0.78; log rank P<0.001 334/1156 (28.9) had CTD-PAH Sitbon O. et al. N Engl J Med. 2015 Dec 24;373(26):2522-33.
Ambrisentan response in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) A subgroup analysis of the ARIES-E clinical trial. J Am Coll Cardiol. 2009 Nov 17;54(21):1971-81 ARIES-E trial 124 patients with CTD-PAH were evaluated. 62.6%, 57.3%, and 58.2% of CTD-PAH patients treated with ambrisentan exhibited increases in 6MWD at 1-, 2-, and 3- years respectively. At 3 years, 64% of patients were free from clinical worsening . And 76% of patients were still alive. Respir Med. 2016 Aug;117:254-63.
Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2 Humbert M, et al. Ann Rheum Dis 2016;0:1–5 • 443 patients • 111 patients had PAH-CTD (66 SSc,18 SLE; 11 RA 10 MCTD), and 6 unspecified CTD) • Riociguat improved mean 6MWD, WHO FC, PVR, CI. • Improvements in 6MWD and WHO FC persisted at 2 years. • Two-year survival of patients with PAH-CTD was the same as for idiopathic PAH (93%). • Riociguat had a similar safety profile in patients with PAH-CTD to that of the overall population
There is no consensus as to which oral agent should be used as initial therapy
Choice of Initial PAH Therapy Dependent on many factors – Disease severity – Approval status – Route of administration – Side-effect profile – Patient preference – Cost consideration – Physician experience, clinical judgment Barst RJ, et al. J ACC 2009
Association Between Initial Oral Therapy and Outcome in SSc-PAH DATA FROM PHAROS REGISTRY - 98 patients 24=ERA, 59=PDE5, 15=RRA/PDE5 Arthritis Rheumatol. 2016 Mar;68(3):740-8 Percentage of patients with qualifying events for time to clinical worsening Kaplan-Meier curves showing time to clinical worsening At 1 year free of CW ERA=63.0% PDE5=85.9% PDE5+ERA=85.7%
Combination Therapy Upfront + + Drug 1 Drug 2 Drug 2Drug 1 Sequential
Combination Therapy *Half of patients on combination therapy †SERAPHIN, 64% on combination therapy, 5% of patients on prostanoid; PATENT 1, 6%. SGC Stimulators Prostanoids Endothelin Receptor Antagonists Phospho- diesterase Inhibitors TRIUMPH STEP SERAPHIN† TRIUMPH PACES PATENT-1* PATENT-1* PHIRST* SERAPHIN†
Recommendations for efficacy of sequential drug combination therapy for pulmonary arterial hypertension (group 1) according to WHO class Circulation 2009;119:2894–2903 Cardiovasc Ther 2012;30:93–99. Eur Heart J 2006;27:589–595. Eur Respir J 2015;46:405–413.. Eur Respir J 2015;46:414–421. Eur Respir J 2015;46:414–421. PATENT PLUS. Eur Respir J 2015;45:1314–1322. 2015 ESC/ERS Guidelines. European Heart Journal August 29, 2015
Recommendations for efficacy of sequential drug combination therapy for pulmonary arterial hypertension (group 1) according to WHO class SERAPHIN Engl J Med 2013; 369:809–818. (PATENT-1 PATENT-2) N Engl J Med 2013;369:330–340 Humbert M, et al. Ann Rheum Dis 2016;0:1–5 Am Coll Cardiol 2013;62:1101–1102 GRIPHON study. J Am Coll Cardiol 2015;65(Suppl A):A380. Ann Intern Med 2008;149:521–530. J Am Coll Cardiol 2010;55:1915–1922. Am J Respir Crit Care Med 2006;174:1257–1263. Eur Respir J 2006;4:691–694 2015 ESC/ERS Guidelines. European Heart Journal August 29, 2015
Recommendations for efficacy of upfront drug combination therapy for pulmonary arterial hypertension (group 1) according to WHO functional class. Galie` N, et al; Ambition trial New Engl J Med 2015;379(9):834–844 Sitbon O. et al; a pilot study. Eur Respir J 2014;43:1691–1697. Humbert M, et al; BREATHE-2. Eur Respir J 2004;24:353–359. Kemp K, et al; an observational study J Heart Lung Transplant 2012;31:150–158. 2015 ESC/ERS Guidelines. European Heart Journal August 29, 2015
Ambition study Galie E. et al. N Engl J Med. 2015 Aug 27;373(9):834-44. Pooled monotherapy 103/253 (41%) had CTD-PAH Combination therapy 84/247 (34%) had CTD-PAH Outcome Combination (n = 103) Monotherapy (n = 84) Any event, % 21 40 Improvement in 6-minute walking, m 40 12
Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial John Gerry Coghlan, Nazzareno Galiè, Joan Albert Barberà et al. Annals of the Rheumatic Diseases Published Online First: 30 December 2016
Kaplan-Meier curves for the time from randomisation to first adjudicated clinical failure John Gerry Coghlan et al. Ann Rheum Dis doi:10.1136/annrheumdis-2016-210236 (A) CTD-PH (B) SSc-PH
John Gerry Coghlan et al. Ann Rheum Dis doi:10.1136/annrheumdis-2016-210236 (A) CTD-PH (B) SSc-PH
Ambrisentan and Tadalafil Up-front Combination Therapy in Scleroderma-associated Pulmonary Arterial Hypertension Paul M. Hassoun et al. American Journal of Respiratory and Critical Care Medicine Volume 192 Number 9 | November 1 2015 Open labeled – 36 weeks 19 patient with treatment naïve SSc-PH Tadalfil 40 mg plus Abrisartan 10 mg PVR RVmassRVEF
There is no consensus as to which combination should be used
Immunosuppressive therapy in SLE & MCTD-PAH Immuno- suppression Vasodilators ± immunosuppression SLE-PH MCTD-PH Supportive therapy: Diuretics, Oxygen, anticoagulants WHO FC II IV III CI<3.1 III CI>3.1 Clinical and hemodynamic Evaluation 4-6 months Clinical and hemodynamic Evaluation 4-6 months No Response Response Response No Response Maintenance immunosuppression regimen Azathioprine, FK506 Combination vasodilators Stop immunosuppression unless indicated Clinical and Hemodynamic follow up Start vasodilators Stop immunosupp. unless indicated Chest. 2006 Jul;130(1):182-9
Immunosuppressive Therapy in SLE-PAH
CTD-PAH and Lung Transplant • CTD-PAH patients who fail maximum PH therapy are candidates for lung transplant • Associated morbidity and organ dysfunction other than the lung, places them at a significantly increased risk for lung transplant • Esophageal motility disorders and GERD in patients with SSc is contraindicated for transplant • Post-transplant survival is 52–75% at 5 years and to 45–66% at 10 years. • The short and intermediate-term post-lung transplant survival are similar to IPAH and ILD patients requiring lung transplantation. • The frequency of recurrent disease after Lung transplant is low at 1% in a population of 1394 transplant patients. Arthritis Rheum. 2006 Dec; 54(12):3954-61 Radiology 2001;219:503–9. Respiratory Medicine (2013) 107, 2081e2087
Post-transplant Survival Saggar R et al. Eur Respir J. 2010;36:893-900. [Epub 2010 Mar 29.] 0.00 0.25 0.50 0.75 1.00 Survival proportion Time after lung transplant (mo) 0 12 24 36 48 60 SSc IPF
Recommendations for pulmonary arterial hypertension associated with connective tissue disease Arthritis Rheum 2005;52: 3792–3800 DETECT study. Ann Rheum Dis 2014;73:1340–1349 Arthritis Rheum 2008;58:521–531. (COMPERA). Circulation 2014;129: 57–65 2015 ESC/ERS Guidelines. European Heart Journal August 29, 2015
Conclusion • Pulmonary arterial hypertension (PAH) is a common complication of CTD particularly scleroderma • PAH complicating CTD significantly worsens survival and is a leading cause of death in these patients • SSc-PAH carries a significantly worse prognosis compared to other forms of PAH • Treatment of patients with CTD -PAH should follow the same treatment algorithm as in IPAH • Standard PAH-specific therapy is not as effective in CTD-PAH compared to iPAH • Immunosuppressive therapy combined with vasodilator treatment may result in clinical improvement in patients with PAH associated with SLE or MCTD
Conclusion Risk benefit ratio of oral anticoagulation is less favorable in CTD- PAH than in IPAH and should be considered on individual basis. Calcium Channel Blockers are not recommended in CTD-PAH Generalized microangiopathy must take into account when choosing PAH therapy in SSc There is no consensus as to the initial choice of monotherapy or order of combination therapy in treating patients with CTD-PAH. There is a need for a better understanding of underlying mechanisms of CTD-PAH in order to achieve therapeutic goals Arthritis Rheum 2008;58:521–531. Ann Rheum Dis 2008;67:808–814. Circulation 2014;129:57–65.
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Pulmonary Hypertension associated with Connective Tissue Disease.

  • 1.
    Pulmonary Hypertension in Connective TissueDisease Sarfraz Saleemi Pulmonary Hypertension Program Section of pulmonary medicine Department of medicine King Faisal Specialist Hospital & Research Center
  • 2.
    Outline • Prevalence • Pathophysiology •Screening • Diagnosis • Prognosis • Treatment
  • 3.
    Cardiopulmonary complications ofCTD Complications Acute lupus pneumonitis Obstructive lung disease Acute reversible hypoxemia Pericardial disease Alveolar hemorrhage Pleural effusion Atelectasis Pleurisy Coronary artery disease Pneumothorax Diaphragmatic dysfunction Pulmonary embolism Diastolic dysfunction Interstitial lung disease Uremic pulmonary edema Myocarditis Valve lesions Recurrent aspiration pneumonia Bronchiectasis and bronchiolitis Pulmonary hypertension
  • 4.
    Ibn al-Nafis • DiscoveredPulmonary circulation nearly 350 years before Sir William Harvey(1616) of England • Described the purification of blood in the lungs where it was refined in contact with the air inhaled from the outer atmosphere
  • 5.
    Badesch D etal. J Am Coll Cardiol. 2009;54:S55-S66. McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619. Hemodynamic Definition of PH/PAH PH PAH Mean PAP ≥25 mmHg PCWP/LVEDP ≤15 mmHg PVR >3 Wood Units Mean PAP ≥25 mm Hg
  • 6.
  • 7.
    LV LA RA RV PT PVOD ILD Pulmonary Hypertension Spectrumin CTD PAH LV systolic or diastolic dysfunction Post-capillary PH CTEPH Multifactorial PH
  • 8.
    Prevalence of CTD-PAH Highlyvariable Lack of consistent epidemiological data Method used for assessing PA pressure Diagnostic tools – Echocardiogram, Right heart catheterization Potential bias concerning the study population – Rheumatologic definitions, criteria etc Geographical variation in the epidemiology of CTD
  • 9.
    Prevalence of abnormalEcho in patients with CTD – UNCOVER study
  • 10.
    Prevalence of PHin Connective Tissue Disease Disease Echo prevalence RHC prevalence SSc 20-50% 1,2 7.85-12% 3,4 SLE 4-43% 5,6 0.9% 3 RA 20% 7 <0.01% 8 MCTD 50%9 3.4%10 9. Udayakumar N, Int J Cardiol. 2008 Jul 21;127(3):410-2 10. Gunnarson Rheumatology 2013.
  • 11.
    Prevalence of PAHin CTD 13% 9.18 % to 18.16 % Range (95% CI) Yang, X., Mardekian, J., Sanders, K.N. et al. Clin Rheumatol (2013) 32: 1519. Prevalence of PH in Connective Tissue Disease (systematic review)
  • 12.
    Prevalence of CTD-PAH ingeneral population 2.3 – 10 cases per million Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 2006;173:1023–1030 Connective Tissue Disease–associated Pulmonary Arterial Hypertension in the Modern Treatment Era. Am J Respir Crit Care Med Vol 179. pp 151–157, 2009 An epidemiological study of pulmonary arterial hypertension. Eur Respir J 2007;30:104–109.
  • 13.
    REVEAL Registry 2967 patients. Adaptedfrom Badesch DB et al. Chest. 2010;137:376-387. Overall group 1 PAH Associated PH Associated (50.7%) Idiopathic (46.2%) Heritable (2.7%) Pulmonary veno-occlusive (0.4%) Connective tissue/ collagen vascular (49.9%) Congenital heart disease (19.5%) HIV (4.0%) Other (5.5%) Portopulmonary (10.6%) Nearly 25% of group 1 PAH is CTD-related
  • 14.
    Prevalence of PHin Connective Tissue Disease CTD-PAH SSc SLE Other Registry 641 62% 17% 21% REVEAL 343 76% 8% 16% UK CTD-PH 188 83% 17% Aspire 103 76% 15% 9% French Chest. 2010;137:376-387 Am J Respir Crit Care Med VOL 179 2009 Eur Respir J. 2012 Apr;39(4):945-55 Eur Respir J. 2012 Apr;39(4):945-55
  • 15.
  • 16.
    UK CTD-PH registry (incidentalcases January 2001 to January 2006) CTD-PAH n=484 CTD-PAH = 429 SSC 315 (74%) MCTD 36 (8%) SLE 35 (8%) DM/PM 18 (4%) RA 13 (3%) UCTD 9 (2%) Sjogren’s 3 (1%) CTD-PAH = 343 SSC 259 (76%) MCTD 28 (8%) SLE 28 (8%) DM/PM 7 (2%) RA 12 (3%) UCTD 6 (2%) Sjogren’s 3 (1%) PAH on exercise only n=55 PAH due to respiratory disease N=86 Condliffe, Kiely, Peacock, et al.: U.K. CTD-PAH Registry Am J Respir Crit Care Med VOL 179 2009
  • 17.
    ASPIRE registry (Sheffield PulmonaryVascular Disease Unit) (treatment-naive cases diagnosed between 2001 and 2010) Group 1 and 1’ PAH N=600 PAH-CHD=198 PoPH=24 Hemolytic=10 HIV=3 PVOD=2 iPAH N=175 CTD-PAH N=188(31%) SSc-PAH N=156 (83%) Other CTD N=32 (17%) Eur Respir J. 2012 Apr;39(4):945-55
  • 18.
    French Registry AMERICAN JOURNALOF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 173 2006 Group 1 PAH N=674 PAH-CHD=76 (11.3%) Anorexogenic=64 (9.5%) PoPH=70 (10.4%) Familial=26 (3.9%) HIV=42 (6.2%) >1 risk factors=29 (4.3%) iPAH N=264(39.2%) CTD-PAH N=103(15.3%) Eur Respir J. 2012 Apr;39(4):945-55 SSc-PAH 76% SLE-PAH 15%
  • 19.
    Connective tissue disease-associatedpulmonary arterial hypertension in Chinese patients (n=129) Eur Respir J 2014; 44: 963–972 pSS = Primary Sjogren syndrome TA = Takayasu arteritis ASOD = Adult onset Still disease UCTD = undifferentiated CTD pAPS = primary APL syndrome SLE, 49% pSS; 16% TA; 12% MCTD; 9% SSc; 6% RA; 3% AOSD; 2% UCTD; 2% pAPS; 1%
  • 20.
    Undiagnosed connective tissuediseases High prevalence in pulmonary arterial hypertension patients • 49 patients (36 females, 13 males) with iPAH were studied for rheumatological re-assessment. • 17 (15 F, 2M) were classified as having a CTD-PH (34.6%) • 12 had SSc (11 F, 1M ) • 2 SLE ( 2 F) • 2 UCTD (1 F, 1M) • 1 SS (1 F). Cavagna et al. Medicine (2016) 95:39
  • 22.
    Pathogenesis of PHin CTD Normal pulmonary artery Inflammation Viral infections AECA Cytokines and chemokines release Dendritic cells Mast cells B cells T cells Chemokines / Cytokines / Growth factors Vascular remodeling In situ thrombi Matrix remodeling Endothelia cell dysfunction Smooth muscle cell dysfunction Chronic vasoconstriction Collagen dysfunction Recruitmentof inflammatory cells A B C Clinical and Developmental Immunology Volume 2012, Article ID 854941
  • 23.
    Vasoconstrictors Vasodilators Imbalance of vasoconstrictorsand vasodilators Endothelin-1 Thromboxane A2 Leukotrienes Serotonin Angiotensin II Platelet activating factor NO PGI2 Vasodilators Antiproliferatives Anticoagulants Vasoconstrictor s Proliferative Procoagulants Pathophysiology of PH
  • 24.
    Remodelling Pathophysiology of PH PulmonaryVascular Disease Pulmonary Vascular Resistance Pulmonary Hypertension Vascular tone Progress of the disease
  • 25.
  • 26.
    Limited SSc Late ageof onset of SSc Raynaud phenomenon Long standing diseae (>5 years) Telangectasia FVC %: DLCO% > 1.6 DLCO <55% predicted Increased NT-proBNP Antibodies (Anti-U1 RNP, Anti- centromere, Anti-nuclear pattern ANA) Absence of anti-Scl 70 antibody Risk factors for PH In Scleroderma
  • 27.
    Female gender Isolated reductionin DLCO on PFT Renal disease Cutaneous vasculitis Antiribonuclear proteins Antiphospholipid antibodies Antiendothelial antibodies Risk factors for PH In SLE
  • 28.
    Development of pulmonaryhypertension in a high-risk population with systemic sclerosis in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) cohort study V.M. Hsu et al. / Seminars in Arthritis and Rheumatism 44( 2014)55–6260 Risk Factors • sPAP >40 mmHg on echocardiogram, • (DLCO) <55% predicted • FVC%/ DLCO% >1.6 • Exercise-induced hypoxemia The time to PH 10% at 2 years 13% at 3 years 25% at 5 years
  • 29.
    When to suspectPH in CTD Clinical and Lab finding suggestive of PH Allergology International. 2011;60:405-409 Raised JVP ECG RBBB RVH tall P wave Exertional dyspnea Elevated pro-BNP Hyper- uricemia Para-sternal heave %FVC/ %DLCO >1.4
  • 30.
    Dyspnea in SScpatients Dyspnea Lung disease Sedentary life style Cardiac disease Anemia PAH A forgotten killer Chest wall tightness Muscle disease Thromboembolic disease
  • 31.
    Survival from diagnosisof patients with isolated SSc-PAH grouped by World Health Organization (WHO) functional class. Am J Respir Crit Care Med Vol 179. pp 151–157, 2009 Cumulativesurvival Years from diagnosis
  • 32.
    Badesch DB etal. Chest. 2010;137:376-387 CTD-PAH functional class at diagnosis 7,6 36,7 50,0 5,6 0 20 40 60 80 100 I II III IV Patients(%) FC at Enrollment REVEAL Registry (All Patients) (n=2525) 5,7 32,2 54,9 7,2 0 20 40 60 80 100 I II III IV FC at Enrollment REVEAL Registry (CVD/CTD) (n=639)
  • 33.
    Screening – Earlydiagnosis 1 24 63 12 0 20 40 60 80 100 I II III IV Patients(%) NYHA FC (N=674) Humbert M et al. Am J Respir Crit Care Med. 2006;173:1023-1030. Hachulla E et al. Arthritis Rheum 2005: 52:3792-3800. No Screening 5 44 28 11 0 20 40 60 80 100 I II III IV NYHA FC (N=18) With Screening
  • 34.
    PAH: Screening highrisk population  Key to early diagnosis – screening high risk populations:  Family members of a patient with familial Pulmonary Arterial Hypertension (FPAH)  Patients with systemic sclerosis (SSc)  Patients with HIV  Patients with chronic liver disease and portal hypertension  International guidelines recommend annual screening with Doppler echocardiography.  Early diagnosis improves outcome • Hachulla E et al Ann Rheum Dis 2004 • Galie N et al. Eur Heart J 2004 • McGoon M et al. Chest 2004
  • 35.
    Echocardiographic probability ofpulmonary hypertension patients with a suspicion of pulmonary hypertension ESC/ERS 2015 guidelines – Screening
  • 36.
    ASIG (Australian SclerodermaInterest Group) Screening algorithm Intern Med J. 2015 Nov;45(11):1134-40. doi: 10.1111/imj.12890
  • 37.
    Evidence-based detection ofpulmonary arterial hypertension in systemic sclerosis: the DETECT study Coghlan JG, et al. Ann Rheum Dis 2013;00:1–10 SSc patients screened = 646 RHC analysis set = 466 SSc patients enrolled = 488 PH N=145(31%) Non-PH N=321(69%) PAH N=87 (19%) Group 2 PH N=30 (6%) Group 3 PH N=27 (6%) Screen failure, n=158 No RHC consent withdrawn N=22
  • 38.
    DETECT nomogram forPH screening in SSC STEP 1 Criteria for Referral to Echo STEP 2 Criteria for Referral to RHC
  • 39.
    The DETECT algorithmfor PAH screening in SSc patients is a sensitive, non-invasive screening tool, which minimizes missed diagnoses, identifies even mild disease and optimizes resource utilization. SSc patients to be screened Step 1 Non-echo variables FVC/DLCO%, Telangiectasia, ECG–RAD, ACA, pro-BNP, Uric Acid Total risk score >300 No Yes No referral for ECHO Step 2: step1 variable plus 2 echo variables Right atrium area TR velocity Total risk score >35 No Yes No referral for RHC RHC for diagnosis of presence /absence of PAH Coghlan JG, et al. Ann Rheum Dis 2013;00:1–10.
  • 40.
    RHC Referral rate Missed PAH Diagnosis 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% DETECT vs Standard screening for PAH-SSc Coghlan JG, et al. Ann Rheum Dis 2013;00:1–10.
  • 41.
  • 42.
    Comparison between screeningtools Hao J. et al. Arthritis Res Ther. 2015 Jan 18;17:7.
  • 43.
    ESC/ERS 2015 guidelines •Clearly recognized the limitations of relying on TR velocity. • Described single tools for screening. • Described DETECT as a composite tool. • But did not recommend any (more validation is required). Galie N. et al. Eur Heart J. 2016 Jan 1;37(1):67-119.
  • 44.
    General recommendations, initialscreening evaluation, and frequency of noninvasive tests for early detection of CTD-associated PAH Recommendation Level of evidence All patients with SSc should be screened for PAH Moderate Patients with MCTD or other CTDs with scleroderma features (Scleroderma spectrum) should be screened in a similar manner to patients with SSc Very low Screening is not recommended for asymptomatic patients with MCTD or other CTDs (including SLE, rheumatoid arthritis, inflammatory myositis, Sjögren’s syndrome) without features of scleroderma Low to moderate For unexplained signs and symptoms of PH in patients with MCTD, SLE, or other CTDs without scleroderma features, one may consider the diagnostic algorithm evaluation for PH Moderate All patients with SSc and scleroderma spectrum disorders with a positive results on a noninvasive screen should be referred for RHC High RHC is mandatory for diagnosis of PAH High Vasoreactivity testing is not required for evaluation of PAH in patients CTDs Moderate to high systematic review of the literature – consensus based evidence driven ARTHRITIS & RHEUMATISM Vol. 65, No. 12, December 2013, pp 3194–3201
  • 45.
    Recommendation Level of evidence Initialscreening evaluation Transthoracic echo PFTs with DLCO NT-proBNP DETECT algorithm if DLCO < 60% predicted and disease duration 3 years or more High High Moderate Moderate Frequency of noninvasive tests Transthoracic echo annually as screening Transthoracic echo if new signs or symptoms develop PFTs with DLCO annually as a screening test PFTs with DLCO if new signs or symptoms develop NT-proBNP if new signs or symptoms develop Low High Low Low Low General recommendations, initial screening evaluation, and frequency of noninvasive tests for early detection of CTD-associated PAH systematic review of the literature – consensus based evidence driven ARTHRITIS & RHEUMATISM Vol. 65, No. 12, December 2013, pp 3194–3201
  • 46.
    Diagnostic algorithm Echocardiography NO YESNO YES PH Right heart catheterization sPAP <35 mmHg sPAP 36-50 mmHg sPAP >50 mmHg Other clinical and Lab features Other clinical and Lab features PH suspected PH ruled out (periodic assessment recommended RHC is recommended in all cases of suspected PAH associated with CTD to confirm the diagnosis, determine severity and rule out left heart disease
  • 47.
    Stupi AM etal. Arthritis Rheum.1986;29:515-524. Steen VD, Medsger TA Jr. Arthritis Rheum. 2003;48:516-522. Impact of PAH on Survival in Limited SSc Before PAH Therapy SSc with PAH (n=20) (n=106) SSc without PAH (n=287) (n=106) % cumulative survival Follow-up (yr) 0 20 40 60 80 100 1 2 3 4 5
  • 48.
    Koh et al,Br J Rheumatol, 1996 Outcome of Scleroderma Patients with Pulmonary Hypertension 0 10 20 30 40 50 60 70 80 90 100 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Years From Diagnosis of PHT PHT Lung Involvement (without PHT) None Survival,%
  • 49.
    Survival - ASPIREregistry Eur Respir J 2012; 39: 945–955
  • 50.
    Survival – PAH-SScvs PAH-SLE Condliffe, Kiely, Peacock, et al.: U.K. CTD-PAH Registry AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 179 2009
  • 51.
    Survival – CTD-PAHvs ILD-PAH Condliffe, Kiely, Peacock, et al.: U.K. CTD-PAH Registry AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 179 2009
  • 52.
    Prognosis of SSc-PAHin major registries Registry Year n Age (yrs) Incident cases (%) WHO FC I&II/III/IV (%) mPAP (mmHg) PVR (dyns.s.cm5) 1 yr survival (%) 3 yr survival (%) UK 2009 259 64 100 16/68/16 42 715 78 47 REVEAL 2010 399 62 18 25/60/15 45 768 82 n/a ASPIRE 2012 156 66 100 19/67/14 43 678 82 52 French 2013 85 65 100 21/67/12 41 680 90 56 PHAROS 2014 131 60 100 56/38/6 36 448 93 75
  • 53.
    CTD-PAH vs iPAH Comparedto patients with iPAH, patients with CTD-PAH have: • higher mortality • lower 6-minute walk distance • Higher pro-BNP • more right ventricular dysfunction • Poor lung functions • More pericardial disease Rhee et al Arth& Rheum 2015
  • 54.
    Factors Role Evidence AgeMean age of diagnosis SSc-PAH ≈10 yrs > IPAH Arthritis Rheum 2006, 54:3043-50 Pulmonary vasculopathy Higher proportion of pulmonary venule involvement in SSc-PAH Eur Respir J 2009, 34:371-9. Right ventricle (RV) Reduced RV contractility Higher NT-proBNP despite less severe pulmonary haemodynamics Respir Res 2008, 9:68. Eur Respir J 2010, 35:95-104 Left ventricle (LV) High prevalence of LV dysfunction ≈1/3 of patients with SSc-PAH have occult LV dysfunction on fluid challenge Ann Rheum Dis 2009, 68:1878-84. Eur Respir J 2013,42:1083-91. Interstitial lung disease (ILD) ILD common in SSc Response to PH therapy in the presence of ILD appears poor Arthritis Rheum 2011, 63:2456-64 Multisystem disease Coexisting renovascular and gastrointestinal disease Antibodies Possible role of autoantibodies Am J Respir Crit Care Med 2010, 181:1285-93 Potential reasons for poorer outcome in SSc-PAH than in IPAH
  • 55.
    ECHOCARDIOGRAPHIC PROGNOSTIC MARKERSIN CONNECTIVE TISSUE DISEASE ASSOCIATED PULMONARY HYPERTENSION DIFFER FROM IDIOPATHIC PULMONARY HYPERTENSION J Am Coll Cardiol. 2016;67(13_S):2071-2071. doi:10.1016/S0735-1097(16)32072-1
  • 56.
    Treatment of PulmonaryArterial Hypertension  Currently there is no cure for PAH  Those who start therapy in WHO FC I or II demonstrate a better prognosis than those whose therapy is started in the more advanced stages  By recognizing and treating patients as early as possible, disease progression may be delayed Sitbon O et al. J Am Coll Cardiol 2002
  • 57.
    Treatment algorithm 2015 ESC/ERSGuidelines Treatment naive patient PAH confirmed by expert center General measures Supportive therapy Acute vasoreactivity test (I-PAH, H-PAH, D-PAH only) Vasoreactive CCB Therapy Non-vasoreactive (or not IPAH/HPAH/DPAH) Low/intermediate Risk (FC II/III) High Risk (FC IV) Oral Monotherapy Oral Combo Therapy Parenteral Therapy Inadequate response Double/triple sequential therapy . Galie N, ESC/ERS 2015 Guidelines, Alreadyon treatment Inadequate response Lung Transplant European Heart Journal August 29, 2015
  • 58.
    Risk assessment inPulmonary Arterial Hypertension . Galie N, ESC/ERS 2015 Guidelines Estimated1-year mortality LowRisk (<5%) Intermediate (5-10%) High Risk (>10%) Right heart failure No No Yes Progression No Slow Rapid Syncope No Occasional Repeated WHO FC I or II III IV CPET VO2 max >15 Ve/VCO2 <36 VO2 max 11-15 Ve/VCO2 36-45 VO2 max<11 Ve/VCO2 >45 BNP <50 50-300 >300 Hemodynamics RA <8 mmHg CI>2.5 SvO2 >65% RA 8-14 mmHg CI2.0-2.4 SvO2 60-65% RA >14 mmHg CI<2 SvO2 <60%
  • 59.
    PAH Therapy: Generaland supportive  Sodium restriction  Contraception  Vaccination  Oxygen  Diuretics if signs of right heart failure  Anticoagulation  Digoxin if evidence of atrial arrythmias
  • 60.
    Humbert M etal. N Engl J Med. 2004;351:1425-1436. Targets for current PAH-specific therapy Big Endothelin Endothelin- converting Enzyme Endothelin Receptor A Endothelin Receptor B Vasoconstriction and Proliferation Endothelin Receptor Antagonists Endothelin-1 Endothelin Pathway Arginine Nitric Oxide Synthase Vasodilatation and Antiproliferation Nitric Oxide cGMP Exogenous Nitric Oxide Phosphodiesterase Type-5 Phosphodiesterase Type-5 Inhibitors Nitric Oxide Pathway Arachidonic Acid Prostacyclin Synthase Vasodilatation and Antiproliferation Prostacyclin cAMP Prostacyclin Derivatives Prostacyclin Derivatives Prostacyclin Pathway sGC stimulators 60 IP receptor agonist
  • 61.
    <1995 1995 20012002 2004 2005 2007 2009 2013 2015 CCB Anticoagulation Digitalis Diuretics IV Epoprostenol Bosentan SC Treprostenol IV Treprostenol Inhaled Iloprost Sildenafil Ambrisartan Tadalafil Inhaled Treprostinil Macitentan Riociguat Pulmonary Hypertension Treatment Timeline IV Sildenafil Oral Treprostinil Selexipag BREATHE SUPER ARIES PHIRST AIR SERAPHIN PATENT CHEST GRIPHON FREEDOM TIMELINE for PAH targeted therapy
  • 62.
    Treatment response inCTD-PH vs iPAH Am J Respir Crit Care Med Vol 192, Iss 9, pp 1111–1117, Nov 1, 2015
  • 63.
    Source PAH agentNumber of patients Number (%) of CTD-PAH patients Galiè et al (SUPER-1) Sildenafil 278 84 (30) Simonneau et al (PACES) Sildenafil 267 55 (21) Galiè et al (PHIRST) Tadalafil 405 95 (24) Rubin et al20 (BREATHE-1) Bosentan 213 63 (30) Galiè et al (EARLY) Bosentan 185 33 (18) Galiè et al (ARIES) Ambrisentan 393 124 (32) Badesch et al Epoprostenol 111 111 (100) Galiè et al (ALPHABET) Beraprost 130 13 (10) Simonneau et al Treprostinil 469 90 (19) Hiremath et al Treprostinil 44 2 (5) CTD-PAH patients included in major RCTs
  • 64.
    Recommendations for efficacyof drug monotherapy for PAH (group 1) according to WHO functional class
  • 65.
  • 66.
  • 67.
    Bosentan for PAH-CTD BREATHE-1Trial Subgroup analysis Time to clinical worseningSurvival Bosentan Historical group 6MWT = mean difference 43 m in Bosentan group Ann Rheum Dis 2006;65:1336–1340
  • 68.
  • 69.
    Pulmonary vasodilators inCTD-PH PDE-5 inhibitors Kuwana M, Watanabe H, Matsuoka N, et al. BMJ Open 2013;3:e003113 Kuwana M, Watanabe H, Matsuoka N, et al. BMJ Open 2013;3:e003113
  • 70.
    Pulmonary vasodilators inCTD-PH Endothelin Receptor Antagonists Kuwana M, Watanabe H, Matsuoka N, et al. BMJ Open 2013;3:e003113
  • 71.
    Pulmonary vasodilators inCTD-PH Prostacyclin Analogs Kuwana M, Watanabe H, Matsuoka N, et al. BMJ Open 2013;3:e003113
  • 72.
    Pulmonary vasodilators inCTD-PH Kuwana M, Watanabe H, Matsuoka N, et al. BMJ Open 2013;3:e003113
  • 73.
    SERAPHIN study -Macitentan Pulido T. et al. N Engl J Med. 2013 Aug 29;369(9):809-18. 224/742 (30.5%) had CTD-PAH HR,0.55; 97.5% CI, 0.39 to 0.76; log-rank P<0.001
  • 74.
    GRIPHON study -Selexipag HR, 0.60; 99% CI, 0.46 to 0.78; log rank P<0.001 334/1156 (28.9) had CTD-PAH Sitbon O. et al. N Engl J Med. 2015 Dec 24;373(26):2522-33.
  • 75.
    Ambrisentan response inconnective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) A subgroup analysis of the ARIES-E clinical trial. J Am Coll Cardiol. 2009 Nov 17;54(21):1971-81 ARIES-E trial 124 patients with CTD-PAH were evaluated. 62.6%, 57.3%, and 58.2% of CTD-PAH patients treated with ambrisentan exhibited increases in 6MWD at 1-, 2-, and 3- years respectively. At 3 years, 64% of patients were free from clinical worsening . And 76% of patients were still alive. Respir Med. 2016 Aug;117:254-63.
  • 76.
    Riociguat for thetreatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2 Humbert M, et al. Ann Rheum Dis 2016;0:1–5 • 443 patients • 111 patients had PAH-CTD (66 SSc,18 SLE; 11 RA 10 MCTD), and 6 unspecified CTD) • Riociguat improved mean 6MWD, WHO FC, PVR, CI. • Improvements in 6MWD and WHO FC persisted at 2 years. • Two-year survival of patients with PAH-CTD was the same as for idiopathic PAH (93%). • Riociguat had a similar safety profile in patients with PAH-CTD to that of the overall population
  • 77.
    There is noconsensus as to which oral agent should be used as initial therapy
  • 78.
    Choice of InitialPAH Therapy Dependent on many factors – Disease severity – Approval status – Route of administration – Side-effect profile – Patient preference – Cost consideration – Physician experience, clinical judgment Barst RJ, et al. J ACC 2009
  • 79.
    Association Between InitialOral Therapy and Outcome in SSc-PAH DATA FROM PHAROS REGISTRY - 98 patients 24=ERA, 59=PDE5, 15=RRA/PDE5 Arthritis Rheumatol. 2016 Mar;68(3):740-8 Percentage of patients with qualifying events for time to clinical worsening Kaplan-Meier curves showing time to clinical worsening At 1 year free of CW ERA=63.0% PDE5=85.9% PDE5+ERA=85.7%
  • 80.
  • 81.
    Combination Therapy *Half ofpatients on combination therapy †SERAPHIN, 64% on combination therapy, 5% of patients on prostanoid; PATENT 1, 6%. SGC Stimulators Prostanoids Endothelin Receptor Antagonists Phospho- diesterase Inhibitors TRIUMPH STEP SERAPHIN† TRIUMPH PACES PATENT-1* PATENT-1* PHIRST* SERAPHIN†
  • 82.
    Recommendations for efficacyof sequential drug combination therapy for pulmonary arterial hypertension (group 1) according to WHO class Circulation 2009;119:2894–2903 Cardiovasc Ther 2012;30:93–99. Eur Heart J 2006;27:589–595. Eur Respir J 2015;46:405–413.. Eur Respir J 2015;46:414–421. Eur Respir J 2015;46:414–421. PATENT PLUS. Eur Respir J 2015;45:1314–1322. 2015 ESC/ERS Guidelines. European Heart Journal August 29, 2015
  • 83.
    Recommendations for efficacyof sequential drug combination therapy for pulmonary arterial hypertension (group 1) according to WHO class SERAPHIN Engl J Med 2013; 369:809–818. (PATENT-1 PATENT-2) N Engl J Med 2013;369:330–340 Humbert M, et al. Ann Rheum Dis 2016;0:1–5 Am Coll Cardiol 2013;62:1101–1102 GRIPHON study. J Am Coll Cardiol 2015;65(Suppl A):A380. Ann Intern Med 2008;149:521–530. J Am Coll Cardiol 2010;55:1915–1922. Am J Respir Crit Care Med 2006;174:1257–1263. Eur Respir J 2006;4:691–694 2015 ESC/ERS Guidelines. European Heart Journal August 29, 2015
  • 84.
    Recommendations for efficacyof upfront drug combination therapy for pulmonary arterial hypertension (group 1) according to WHO functional class. Galie` N, et al; Ambition trial New Engl J Med 2015;379(9):834–844 Sitbon O. et al; a pilot study. Eur Respir J 2014;43:1691–1697. Humbert M, et al; BREATHE-2. Eur Respir J 2004;24:353–359. Kemp K, et al; an observational study J Heart Lung Transplant 2012;31:150–158. 2015 ESC/ERS Guidelines. European Heart Journal August 29, 2015
  • 85.
    Ambition study Galie E.et al. N Engl J Med. 2015 Aug 27;373(9):834-44. Pooled monotherapy 103/253 (41%) had CTD-PAH Combination therapy 84/247 (34%) had CTD-PAH Outcome Combination (n = 103) Monotherapy (n = 84) Any event, % 21 40 Improvement in 6-minute walking, m 40 12
  • 86.
    Initial combination therapywith ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial John Gerry Coghlan, Nazzareno Galiè, Joan Albert Barberà et al. Annals of the Rheumatic Diseases Published Online First: 30 December 2016
  • 88.
    Kaplan-Meier curves forthe time from randomisation to first adjudicated clinical failure John Gerry Coghlan et al. Ann Rheum Dis doi:10.1136/annrheumdis-2016-210236 (A) CTD-PH (B) SSc-PH
  • 89.
    John Gerry Coghlanet al. Ann Rheum Dis doi:10.1136/annrheumdis-2016-210236 (A) CTD-PH (B) SSc-PH
  • 90.
    Ambrisentan and TadalafilUp-front Combination Therapy in Scleroderma-associated Pulmonary Arterial Hypertension Paul M. Hassoun et al. American Journal of Respiratory and Critical Care Medicine Volume 192 Number 9 | November 1 2015 Open labeled – 36 weeks 19 patient with treatment naïve SSc-PH Tadalfil 40 mg plus Abrisartan 10 mg PVR RVmassRVEF
  • 91.
    There is noconsensus as to which combination should be used
  • 92.
    Immunosuppressive therapy inSLE & MCTD-PAH Immuno- suppression Vasodilators ± immunosuppression SLE-PH MCTD-PH Supportive therapy: Diuretics, Oxygen, anticoagulants WHO FC II IV III CI<3.1 III CI>3.1 Clinical and hemodynamic Evaluation 4-6 months Clinical and hemodynamic Evaluation 4-6 months No Response Response Response No Response Maintenance immunosuppression regimen Azathioprine, FK506 Combination vasodilators Stop immunosuppression unless indicated Clinical and Hemodynamic follow up Start vasodilators Stop immunosupp. unless indicated Chest. 2006 Jul;130(1):182-9
  • 93.
  • 94.
    CTD-PAH and LungTransplant • CTD-PAH patients who fail maximum PH therapy are candidates for lung transplant • Associated morbidity and organ dysfunction other than the lung, places them at a significantly increased risk for lung transplant • Esophageal motility disorders and GERD in patients with SSc is contraindicated for transplant • Post-transplant survival is 52–75% at 5 years and to 45–66% at 10 years. • The short and intermediate-term post-lung transplant survival are similar to IPAH and ILD patients requiring lung transplantation. • The frequency of recurrent disease after Lung transplant is low at 1% in a population of 1394 transplant patients. Arthritis Rheum. 2006 Dec; 54(12):3954-61 Radiology 2001;219:503–9. Respiratory Medicine (2013) 107, 2081e2087
  • 95.
    Post-transplant Survival Saggar Ret al. Eur Respir J. 2010;36:893-900. [Epub 2010 Mar 29.] 0.00 0.25 0.50 0.75 1.00 Survival proportion Time after lung transplant (mo) 0 12 24 36 48 60 SSc IPF
  • 96.
    Recommendations for pulmonaryarterial hypertension associated with connective tissue disease Arthritis Rheum 2005;52: 3792–3800 DETECT study. Ann Rheum Dis 2014;73:1340–1349 Arthritis Rheum 2008;58:521–531. (COMPERA). Circulation 2014;129: 57–65 2015 ESC/ERS Guidelines. European Heart Journal August 29, 2015
  • 97.
    Conclusion • Pulmonary arterialhypertension (PAH) is a common complication of CTD particularly scleroderma • PAH complicating CTD significantly worsens survival and is a leading cause of death in these patients • SSc-PAH carries a significantly worse prognosis compared to other forms of PAH • Treatment of patients with CTD -PAH should follow the same treatment algorithm as in IPAH • Standard PAH-specific therapy is not as effective in CTD-PAH compared to iPAH • Immunosuppressive therapy combined with vasodilator treatment may result in clinical improvement in patients with PAH associated with SLE or MCTD
  • 98.
    Conclusion Risk benefit ratioof oral anticoagulation is less favorable in CTD- PAH than in IPAH and should be considered on individual basis. Calcium Channel Blockers are not recommended in CTD-PAH Generalized microangiopathy must take into account when choosing PAH therapy in SSc There is no consensus as to the initial choice of monotherapy or order of combination therapy in treating patients with CTD-PAH. There is a need for a better understanding of underlying mechanisms of CTD-PAH in order to achieve therapeutic goals Arthritis Rheum 2008;58:521–531. Ann Rheum Dis 2008;67:808–814. Circulation 2014;129:57–65.
  • 99.