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Internal Medicine department, Hôpital Cochin, Paris, France
& French National Reference Center for Systemic Scler osis
Inserm U1016, Institut Cochin
Hypertension artHypertension artéérielle rielle pulmonaire associpulmonaire associéée e àà la la ScSScS
Luc Mouthon
� Consultant: Actelion, CSL Behring, Cytheris, GSK, LFB Biotechnologies, Lilly, Pfizer
� Subventions ARMIIC
� Investigateur: Actelion, CSL Behring, Pfizer
� Soutien financier (projets de recherche): Actelion, CSL Behring, GSK, LFB Biotechnologies, Pfizer
Conflits d’intérêt LM
HTAP: définition
Galiè N et coll. Eur Heart J. 2009 & Eur Resp J 2009
DDééfinition hfinition héémodynamique de modynamique de ll’’hypertension pulmonaire hypertension pulmonaire ((cathcathéérréétismetisme droit)droit)
PAP moyenne > 25 PAP moyenne > 25 mmHgmmHg au reposau repos
Pression
Pression
Pression
normale
DDééfinition hfinition h éémodynamique de lmodynamique de l ’’hypertension hypertension artart éérielleriellepulmonaire (pulmonaire ( cathcath éérréétismetisme droit):droit):
-- PAP moyenne > 25 PAP moyenne > 25 mmHgmmHg au reposau reposEtEt-- Pression capillaire pulmonaire < 15 Pression capillaire pulmonaire < 15 mmHgmmHg au reposau repos
Updated clinical classification of pulmonary hypertension(4th PH World Conference – Dana Point, CA – Feb 2008)
Simonneau G, et al. J Am Coll Cardiol 2009.
3. PH due to lung diseases and/or hypoxia3.1. COPD3.2. Interstitial lung diseases3.3. Other pulmonary diseases with mixed restrictive
and obstructive pattern3.4. Sleep-disordered breathing3.5. Alveolar hypoventilation disorders3.6. Chronic exposure to high altitude3.7. Developmental abnormalities
4. Chronic Thromboembolic PH (CTEPH)
5. PH with unclear and/or mulifactorial mechanisms
5.1. Haematological disorders : myeloproliferativedisorders splenectomy.
5.2. Systemic disorders, Sarcoidosis, pulmonary Langerhans cell histiocytosis, LAM, neurofibromatosis, vasculitis
5.3. Metabolic disorders : Glycogen storage disease, Gaucher disease, Thyroid disorders
5.4. Others : tumoral obstruction, fibrosingmediastinitis, chronic renal failure on dialysis.
1. Pulmonary Arterial Hypertension1.1. Idiopathic PAH1.2. Heritable
1.2.1. BMPR21.2.2. ALK1, endoglin (with or w/o HHT)1.2.3. Unknown
1.3. Drugs and toxins induced1.4. Associated with:
1.4.1. Connective tissue diseases1.4.2. HIV infection1.4.3. Portal hypertension1.4.4. Congenital heart diseases1.4.5. Schistosomiasis1.4.6. Chronic haemolytic anemia
1.5. Persistent PH of the newborn
1’. PVOD and PCH
2. PH due to left heart diseases2.1. Systolic dysfunction2.2. Diastolic dysfunction2.3. Valvular disease
Pulmonary arterial hypertension in France : results from a national registry
Humbert M et al. AJRCCM 2006, Feb 2; [Epub ahead of print]
Scleroderma is the first cause of HTTP in CTD
� Lupus : 15 %
� Systemic sclerosis : 76 %
Limited67 %
Diffuse 33 %
Humbert M et al. Am J Respir Crit Care Med 2006;173:1023
PAH IN CONNECTIVE TISSUE DISEASES
Pulmonary vascular remodeling in SSc-PAH
Le Pavec J et al 2010 AJRCCM (in press)
TelangiectasesTelangiectasesTelangiectasesTelangiectases in Scleroderma: A Potential Clinical Marker of in Scleroderma: A Potential Clinical Marker of in Scleroderma: A Potential Clinical Marker of in Scleroderma: A Potential Clinical Marker of Pulmonary Arterial HypertensionPulmonary Arterial HypertensionPulmonary Arterial HypertensionPulmonary Arterial Hypertension
Shah et al. J Shah et al. J Shah et al. J Shah et al. J RheumatolRheumatolRheumatolRheumatol 2010201020102010
Mathai et al. Eur Resp J 2010
NT-proBNP levels are 1) significantly higher in
PAH-SSc than IPAHdespite less severehaemodynamicperturbations,
2) stronger predictors of survival in PAH -SSc,suggesting thatneurohormonalregulation may differbetween PAH-SSc and IPAH.
Box and whisker plots of the N-terminal pro-brain natriuretic peptide (NT-proBNP) levels measured in IPAH and PAH-SScpatients.
Disproportionate elevation of N -terminal pro-brain natriureticpeptide in SSc-related pulmonary hypertension
PAHPAH--SScSSc: : PrevalencePrevalence
7.85%�mPAP > 25 mmHg at rest or > 30 at exercise pulmonarycapillary < 14 mmHg
Diffuse or limited c SSc
599�Prospective�Multicentric�2002-3
Hachulla et al2005France
12 %�mPAP > 25 mmHg at rest or > 30 at exercise pulmonarycapillary < 14 mmHg
Diffuse or limited c SSc
722�Prospective�Monocentric�1998 to 2002
D Mukerjee, 2003UK
13%�PAPs > 30 mmHg Doppler Echo
Diffuse or limited c SSc
152�Prospective�Monocentric�1992 to 1997
AJ MacGregor, 2001UK
4,9%�PAPm >25 and cap m <12 mmHg upon RHC, or�Ps VD > 35 mmHg (echo)� or RV dilatation, P or T insufficiency, or paradoxicalseptum motion upon echo
Diffuse or limitedcutaneousSSc
344�Prospective�Monocentric�1978 to 1994
ET Koh 1996Canada
35%�PAPs >30 mmHg Doppler Echo
Diffuse or limited c SSc
34�Prospective�Monocentric
R. Battle 1996USA
17%�VIT > 2,5 m/s Doppler EchoSSc and MCTD
71�Prospective�Monocentric�1988 to 1991
I. Murata 1992Japan
16%�Mean PAP >20 mmHg and mean PCP <12 mmHg (right heart catheterization)
Proximal SScand CREST
49� Prospective�Monocentric�1973 to 1979
RG Ungerer 1983USA
PAH prevalence
PAH definitionSSc profileNumber of patients
MethodologyReference
VIT > 3 m/s(~ sPAP > 45 mmHg)
VIT
VIT < 2.5 m/s(~ sPAP < 30 mmHg)
VIT 2.5-3 m/s(~sPAP 30-45 mmHg)
No dyspneaor dyspnea related toanother cause
Dyspnea (notrelated to other causes)
No PAHPAH echography
�
Right cardiac catheterisation
Cardiac EchoDopplerPAH definition
Hachulla et al. Arthritis Rheum 2005
Cardiac catheterisation (n=33)
• PAH : 18 • [mPAP > 25 mmHg at rest or > 30 mmHg
at exercise with PAwP < 15 mmHg]– 25-35 mmHg: 14– 35-45 mmHg: 3– 45 mmHg: 1
• Post-capillary “venous”pulmonary hypertension: 3 (10%)
• No PAH : 12 => 6 with mPAP > 20 mmHg
Hachulla et al. Arthritis Rheum 2005
HTP pré capillaire
PAPm≥ 25 mmHg1
PAPO ≤ 15 mmHg1
PAPd – PAPO > 10 mmHg²
HTP post capillaire passive
PAPm≥ 25 mmHg1
PAPO > 15 mmHg1
GTP ≤ 12 mmHg1
PAPd – PAPO ≤ 10 mmHg²
HTP prHTP préé et post capillaireet post capillaireDDééfinitionfinition
1. Galiè N et al. Eur Respir J 20092. Chemla D et al. Eur Respir J 2002
Courtesy X Jais
Estimated incidence of pulmonary hypertension during the 3-year followup period*
Hachulla et al. Arthritis Rheum 2009
Changes in causes of Systemic Sclerosis relateddeaths between 1972 and 2001
Steen et Medsger. Ann Rheum Dis 2007
Medsger et al. J Rheum 1996
PAH in SSc: prognosis
PAH complicating Connective Tissue Diseases
SSc-PAH
iPAH
Hassoun et al. Semin Respir Crit Care Med 2009
The impact of comorbidities
• Age
• Myocardial involvement
• Musculoskeletal involvement
• Pulmonary fibrosis
• Pulmonary Veno-Occlusive Disease
SSc-PAH: why a so bad prognosis?
� Multivariate analysis, factors associated with increased death:� Left ventricular dysfunction� Pericardial effusion
Fisher et al. Arthritis Rheum 2006
Right ventricular function in SSc-PAH
� SSc-PAH has a poorer exercise capacity and worse prognosisthan those reported in other types of PAH.
� This appears related to a relative RV failure, explained by alteredcontractility and maybe also decreased pulmonary arterialcompliance.
Overbeek et al. ERJ 2008
Survival of PAH -SSc versus ILD -PH-SSc
Mathai et al. A & R 2009
Fibrous remodeling of the pulmonary venoussystem in PAH associated with CTD
SSc-PAH: treatment
� Preventive measures
� Conventionnal medical treatment (02 -diuretics - anticoagulants)
� Calcium blockers
� Epoprostenol continuous infusion
� Endothelin receptor antagonists
� Lung transplantation
� New strategies
Humbert, Sitbon, Simonneau. N Engl J Med 2004; 351:1425-36
Grossesse contre-indiquée (I-C)Vaccination antigrippale et antipneumococcique (I-C)Réhabilitation (IIa-B)Soutien psychologique (IIa-C)Éviter les efforts excessifs (III-C)
Diurétiques (I-C)Oxygène (I-C)Anticoagulants oraux• HTAPi, héritable ou associée àdes anorexigènes (IIa-C)• HTAP associées (IIb-C)Digoxine (IIb-C)
Mesures générales
Avis d’experts (I-C)
Test de vasoréactivitéHTAPi (I-C) – HTAP associées (IIb-C)
POSITIF NEGATIF
TRAITEMENT INITIAL
RecommandationPreuve
Classe fonctionnelleII
Classe fonctionnelle III
Classe fonctionnelle IV
AmbrisentanBosentanSildenafil
Ambrisentan, BosentanSitaxentan, SildenafilEpoprosténol i.v.Iloprost inhalé
Epoprosténol i.v.
Tadalafil*
Sitaxentan
Tadalafil* Téprostinil s.c, inhalé*
Iloprost i.v.*Téprostinil i.v.*
Ambrisentan, BosentanSitaxentan, Sildenafil, Tadalafil*Iloprost inhalé, i.v.*Téprostinil s.c, inhalé*Traitements combinés
Béraprost*
I-A
I-B
IIa-C
IIb-B
Classefonctionnelle I-III
ICs (I-C)
Réponse maintenue (CF I-II)
OUI NON
Maintien des ICs
REPONSE CLINIQUE INADEQUATE
REPONSE CLINIQUE INADEQUATE
Combinaison thérapeutique séquencée(IIa-B)ERAs
Prostanoïdes IPDE5
Atrioseptostomie (I-C) et/ou Transplantation
pulmonaire (I-C)
* Molécules ne disposant pas à ce jour d’une AMM en France dans le traitement de l’HTAP
PAD > 15 mmHg ou IC ≤ 2,0 L/min/m 2Hémodynamique
PAD < 8 mmHg et IC ≥ 2,5L/min/m 2
Épanchement péricardiqueTAPSE < 1,5 cm
EchocardiographiePas d’épanchement péricardique
TAPSE > 2,0 cm
Très élevé et croissantBNP/NT-proBNP
(taux plasmatiques)Normal ou quasi-normal
VO2max < 12 ml/min/kgÉpreuve d’effort
cardiopulmonaireVO2max > 15 ml/min/kg
< 300 mTest de marche
de 6 minutes> 500 m (fonction de l’âge)
IVClasse fonctionnelle
(OMS)I, II
OuiSyncopeNon
RapideProgressionLente
OuiSignes cliniques
d’insuffisance ventriculaire droite
Non
Mauvais pronostic (1)Déterminants du pronostic (1)Bon pronostic (1)
1. Galiè N et coll. Guidelines for the diagnosis and treatment of pulmonary hypertension: The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30:2493-537.
Lung transplantation� 29 SSc patients vs 70 patients with IPF and 38 with IPAH
� End point: death.
� During 2 years of followup, 11 patients with scleroderma (38%), 23 with
IPF (33%), and 14 with IPAH (37%) died.
� Cumulative survival at 6 months posttransplantation was 69% in the
scleroderma group compared with 80% in the IPF group (log-rank P =
0.21) and 79% in the IPAH group (P = 0.38). Cumulative survival at 2 years
was comparable (64%).
Schachna L. et al. Arthritis Rheum 2006
Conclusions
�8-12% of SSc patients develop PAH
�Incidence of PAH in SSc: 0.6%
�Detection: echodardiography
�Comfirmation: Right heart catheterization
(treshold….)
�Prognosis: reserved
�Impact of comorbidities
�Lower efficacy of treatments than observed in
idiopathic PAH
�Efficacy of Immunosuppressants in PAH-SLE/MCTD
