World Scleroderma Foundation - NICO Congressi World Scleroderma Foundation, has been considering for...
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World Scleroderma Foundation Summer School Thu 23 June - Sun 26 June 2011 Location: Villa Medicea La Ferdinanda & Borgo in Artimino, Florence, Tuscany, Italy Pulmonary Arterial Hypertension (PAH) in Systemic Sclerosis (SSc) - in depth course
Transcript of World Scleroderma Foundation - NICO Congressi World Scleroderma Foundation, has been considering for...
World Scleroderma FoundationSummer School
Thu 23 June - Sun 26 June 2011Location: Villa Medicea La Ferdinanda
& Borgo in Artimino,
Florence, Tuscany, Italy
Pulmonary Arterial Hypertension (PAH)in Systemic Sclerosis (SSc) - in depth course
SUMMARY
Presentation........................................ 5
Programme.......................................... 7
Notes.................................................... 12
Faculty.................................................. 17
Abstract................................................ 23
Location................................................ 121
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ONWorld Scleroderma Foundation
Summer School
Pulmonary Arterial Hypertension (PAH)in Systemic Sclerosis (SSc) - in depth course
Thu 23 June- Sun 26 June 2011Location: Villa Medicea La Ferdinanda & Borgo in Artimino,
Florence, Tuscany, Italy
BackgroundWorld Scleroderma Foundation, has been considering for some time the need for an “in-depth” course to enable rheumatologists to truly expand their knowledge in the field of pulmonary vascular disease, particularly in the pathophysiology and diagnosis with relation to the scleroderma patients they see.
Objectives1. General •Provide a vehicle for expanding expertise (Scleroderma PAH) in the rheumatology
community •Developing future experts and excellence in the field of Scleroderma and pulmonary vascular
disease •Encourage cross speciality (Pulmonology, Cardiology, Connective Tissue Pathology) networking
by involving “highest” experts in the field of PAH •Developing an alumni of experts who can transfer their knowledge and improve skills at a
local country level worldwide2. Specific •Content for this meeting focussed on Scleroderma and pulmonary vascular disease to allow
depth of learning and discussion in this disease area •Interactive format to aid networking and learning •Practical, discussion and plenary to address diversity of learning styles •Use of patients and patient cases to support practical application of learning •Production of materials to enable “excellent” replication 3. Long term •Replicate template and core content to support education and training on Scleroderma PAH
across the global community •Maintaining and increasing size of alumni
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World Scleroderma FoundationSummer SchoolSteering Committee
Alan Tyndall, Dan Furst, Marco Matucci Cerinic
Local Organizing CommitteeSerena Guiducci, Silvia Bellando Randone, Cinzia Pruneti
Board
1. R Abbate (I)2. Y Allanore* (F)3. R Badagliacca (I)4. G Coghlan (UK)5. M Confalonieri (I)6. M D’Alto* (I)7. C Denton (UK)8. O Distler (CH)9. J Easaw* (UK)10. D Furst (USA)11. N Galiè (I)12. L Gargani* (I)13. G F Gensini (I)14. E Hachulla (F)15. S Harari (I)16. D Khanna* (USA)17. O Kowal Bielecka* (PI)
18. E Majno (I)19. M Matucci Cerinic (I)20. A Moggi Pignone (I)21. U Muller Ladner (D)22. M Palazzini (I)23. R Naeije (B)24. H Olschewski (A)25. J Seibold (USA)26. A Tyndall (CH)27. JL Vachiery (B)28. G Valentini (I)29. P Vitulo (I)30. C D Vizza (I)31. R Voswinckel (D)32. F Wigley (USA)
*Tutors
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Scientific Programme
Thursday, June 23rd
15h00- 19h00 • Welcome - The World Scleroderma Foundation Daniel Furst, Marco Matucci Cerinic & Alan Tyndall The University of Florence, Faculty of Medicine Gian Franco Gensini, Dean Az. Ospedaliera Universitaria Careggi Edoardo Majno, General Director • Learning objectives of the course Daniel Furst • Eustar data on PAH (database) (20’) Ulf Mueller Ladner Pre-meeting MCQ test Serena Guiducci & Silvia Bellando Randone
LecturesChairmen: M. Matucci Cerinic & D. Furst
• PH-PAH definition / classification in Systemic Sclerosis (30’) R. Voswinckel • ESR PAH Guidelines (30’) N. Galiè – M. Palazzini • Genetics of PAH and Systemic Sclerosis PAH (30’) Y. Allanore • The screening of Systemic Sclerosis PAH (30’) E. Hachulla • Outcome measures in Systemic Sclerosis PAH (30’) D. Furst • Pathophysiology of lung circulation R. Naeije (30’)
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Friday, June 24th
MORNING
Systemic Sclerosis - CLINICAL ASPECTSChairmen: Y. Allanore & C. Denton
8.30-9.30 Clinical aspects of Systemic Sclerosis PAH: when to suspect? In depth analysis of the symptoms (dyspnea, heart failure) J. Seibold - C. Denton
•Clinical Confounders and Mimics - PAH, PH secondary to ILD, PVOD, LVDD, other causes of dyspnoea
•Clinical Presentations •The Role of History and Physical Examination •Diagnostic Laboratory Testing - Sensitivity, Specificity and Predictive Value - potential integrated
approach •Exercise Testing •A Proposed Algorithm for Early Recognition
9.30-10.30 Heart involvement in Systemic Sclerosis: focus on myocardiopathy and diastolic dysfunction, differential diagnosis of PAH in Systemic Sclerosis G. Valentini - Y. Allanore
•Clinical cases of differential diagnosis from pre capillary PAH will be presented (25 minutes) •Then Systemic Sclerosis cardiomyopathy will be commented: prevalence, subsets at risk, toll for
assessment, outcomes and treatment (25 minutes) •Q/A (10 minutes)
10.30-11.00 BREAK
Chairmen: O. Kowal-Bielecka & D. Khanna11.00-12.00 Lung involvement: prevalence, patterns, imaging subgroup at risk, disproportionate PAH, Differential outcomes of PAH vs Interstitial Lung Disease associated
Otylia Kowal Bielecka (25’)
I. Different forms of lung involvement in Systemic Sclerosis: - Parenchymal = interstitial lung disease - Vascular = obliterative vasculopathy = PH (primary and secondary)
II. Interstitial lung disease: - Definition - Prevalence - Clinical heterogenity - Diagnosis including differential diagnosis with other forms of lung involvemnt (clinical,
PFTs, X-ray, HRCT, biopsy, BAL) - Prognostic factors (severity of ILD=PFTs, HRCT score, hist-pat, BAL, biomarkers) - Treatment
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Dinesh Khanna (25’)
III. PH associated with lung disease in Systemic Sclerosis: - Pathogenesis - Prevalence - Outcomes (worse versus PAH) - Diagnosis (when suspected, screening,) - Treatment
12.00-12.30 LectureChairman: U. Mueller LadnerPAH pathogenesis in Systemic Sclerosis O. Distler
12.30-14.00 LuNCH
AFTERNOON - Practical workshops (movies and practice)Chairmen: S Harari & P Vitulo
14.00-15.00 Pulmonary functional tests and & 6 Minutes Walk test: useful parameters in PAH-SSc? S. Harari •MOVIE- PFTs & 6MWT recorded S. Harari •Interactive discussion
15.00-16.00 Doppler echocardiography: fundamental parameters, parameters useful for the diagnosis and prognosis of PAH, pitfalls D. Vizza - L. Gargani
I part - The anatomy of the heart by echo: parasternal, subcostal and apical windows - Principles of Doppler Echocardiography: The study of blood flow through the heart - How estimate systolic and diastolic pulmonary pressure - How to evaluate right ventricular function (TAPSE) - How to evaluate the presence of pericardial effusion II part- (20’) - The impact of echocardiography in the prognosis of PAH patients - PH, not only PAH in Systemic Sclerosis
16.00-16.30 BREAK
16.30-19.00Chairmen: A. Moggi Pignone & H. OlschewskiThe early diagnosis of PAH in Systemic Sclerosis H. OlschewskiExercise echo, yes or no? A. Pignone •HANDS ON - Doppler echocardiography on patients: R. Badagliacca, L. Gargani, M. D’Alto, J. Easaw, JL. Vachiery •Interactive discussions
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Saturday, June 25th
MORNING
8.30-10.30Chairmen: J. Coghlan & M. D’Alto
• Practical workshops (movies and practice) •RHC how to interpret the results J. Coghlan •MOVIE - Catheterization recorded J. Coghlan
10.30-11.00 BREAK
11.00-13.00 Interactive discussion •HANDS ON- Doppler echocardiography on patients: R. Badagliacca, L. Gargani, M. D’Alto, J. Easaw, JL. Vachiery
13-14.30 LuNCH
AFTERNOON - TREATMENT
14.15-19.00Chairmen: F. Wigley & E. Hachulla •Current view of the treatment of Systemic Sclerosis-PAH & Overall strategy C. Denton • Endothelin Receptor Antagonistis in PAH J. Seibold
•Endothelin in health and disease
• ET receptor function A vs B and receptor plasticity
• Clinical outcomes in Systemic Sclerosis PAH
• Clinical outcomes in other Systemic Sclerosis clinical complications
• Are ERA the “treatment of choice”?
• Supportive care M. Confalonieri • Anti Coagulation, yes or no ? R. Abbate
Break
• Lung Transplantation in PAH P. Vitulo • Prostanoids in PAH F. Wigley • Combination therapy M. D’Alto • PD5 inhibitors in Systemic Sclerosis JL. Vachiery
Lecture:Chairman: O. Distlerupdate on PAH - Future molecular targets JL. Vachiery
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Sunday, June 26th
MORNING
8.30 Post meeting test S. Guiducci & S. Bellando Randone9.00 Difficult cases of Systemic Sclerosis -PAH - presentations by young investigatorssupported by tutorsChairmen: D Khanna & Y Allanore
1. Leslie Ann Saketkoo - Tutor Dinesh Khanna “Pulmonary Vascular Disease in Systemic Sclerosis: Multi-Factorial Contribution and the
Complexities of Management”
2. Barbara Gabrielli - Tutor Marco Matucci Cerinic “Successful pulmonary trasplantation in a young PAH - Systemic Sclerosis man”
3. Tunde Minier - Tutor Luna Gargani “Responder or non-responder?– the influence of pulmonary vasodilator
testing on therapeutic decision-making”
4. Alessandra Vacca - Tutor Yannick Allanore “When aggressive therapy can make a difference”
5. Mike Becker - Tutor Otylia Kowal-Bielecka “ Systemic Sclerosis-PAH - in search of a diagnosis”
6. Iudici Michele - Tutor M. D’alto “A case of Systemic Sclerosis with multifactorial pulmonary hypertension”
11.30 Final remarks and closure of the courseM. Matucci Cerinic, D. Furst, A. Tyndall
11.45 departures
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FACu
LTYRosanna Abbate MD
Professor of Internal MedicineCenter for Atherothombotic DiseasesDepartment of Medical and Surgical Critical Careuniversity of Florence
Yannick AllanoreParis Descartes universityCochin Hospital, Rheumatology A department
Roberto BadagliaccaDipartimento di Scienze Cardiovascolari e Respiratorie,università di Roma Sapienza
Gerry CoghlanConsultant Cardiologist at Royal Free HospitalLocation London,united Kingdom Industry Hospital & Health Care
Silvia Bellando RandoneLocal Organizing Committee
Marco ConfalonieriDirector of the complex structure of the pulmonaryHospitals of Trieste.Professor of respiratory diseases at the universityof Trieste and the university of Modena.
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Christopher Denton Phd FRCPProfessor of Experimental RheumatologyCentre for RheumatologyRoyal Free Hospital and uCL Medical SchoolLondonNW 2QG
Oliver Distler PD Dr. Med.Center of Experimental Rheumatology and Department of Rheumatologyuniversity Hospital Zurich, Switzerland
Jacob EasawConsultant CardiologistSpeciality in Cardiology, Pulmonary Hypertension and EchocardiographyRoyal united Hospital, Bath, united Kindom
Daniel Furst MDDirector of clinical research at the David school ofmedicine at uCLA
Nazzareno GaliéAssociate Professor of Cardiologyuniversity of Bologna
Michele D’AltoChief of Pulmonary hypertension unitDepartment of Cardiology, Second university of Naples,Monaldi Hospital,Naples, Italy
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Gian Franco Gensini Dean of Medicine and Surgery Facultyuniversity of Florence
Eric HachullaDepartment of Internal Medicine, National Reference Centerfor Scleroderma, Claude Huriez Hospital, university of Lille, France.
Serena GuiducciLocal Organizing Committee
Sergio HarariDirector of Operations pulmonology St. Joseph Hospital in Milan
Dinesh Khanna MD, MSAssociate Professor of Medicineuniversity of Michigan Scleroma Program
Luna GarganiCardiology DepartmentG. Monasterio FoundationInstitute of Clinical Physiology, National Research Council of Pisa
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Marco Matucci-Cerinic MD, PhDProfessor of Rheumatology and MedicineDepartment of Medicine, Division of Rheumatology, university of Florence, Italy
Alberto Moggi Pignone Professore Associato di Medicina InternaAz. Ospedaliera universitaria Careggi, Firenze
ulf Mueller-LadnerLehrstuhi für Innere Medizin mit Schwerpunkt Rheumatologie,Justus-Liebig universität Giessen.Arztlicher Direktor, Abteilung für Rheumatologie und KlinischeImmunologie, Kerchoff Klinik
Robert Naeije MD, PhDProfessor of Physiology and Medicine, and Chairmanof the Department of Pathophysiology at the Facultyof Medicine of the Free university of Bruxelles,Consultant at the Pulmonary Hypertension Clinicof Department of Cardiology of the Erasme universityHospital, Bruxelles
Edoardo Majno MDGeneral ManagerCareggi university Hospital
Otylia Kowal Bielecka MDDepartment of Rheumatology and Internal Medicine university in Bialystok, Poland
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James R. SeiboldScleroderma Research Consultants, LLCAvon CT 06001
Alan TyndallProfessor and head of the department ofrheumatogy in the university of Basel
Jean-Luc VachieryHead of the Pulmonary Vascular Diseases and Heart Failure ClinicDepartment of CardiologyCliniques universitaires de Bruxelles - Hôspital Erasmeuniversité Libre de Bruxelles
Gabriele Valentini Professor of Rheumatology at the Seconduniversity of Naples
Massimiliano Palazzini MD, PhDInstitute of Cardiology, university of Bologna, Italy
Horst Olschewskiuniversitätsklinik für Innere MedizinKlinische Abteilung für Pulmonogie
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Robert VoswinkelPulmonary Medicine Specialistuniversity of Giessen Lung CenterMax-Planck-Institute for Heart and Lung Research Kerckhoff-Center for Heart-Thorax and Rheumatic Diseases Giessen/Bad Nauheim Germany
Fred WigleyProfessor of MedicineAssociate Director, Johns Hopkins RheumatologyDirector, Johns Hopkins Scleroderma Center
Carmine Dario VizzaAssociate Professor of Cardiology,university of Rome La Sapienza
Patrizio VituloMedical Director Lung transplant ProgramDirector Pulmonary Hypertension ProgramChief of Pulmonology ServiceISMEET-uPMC
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15h00- 19h00
Eustar data on PAH (database) Ulf Müller-Ladner, MD
The intention of the EUSTAR database (meds/medsonline) is to collect actual live data on SSc patients
and their organ complications on a pn-European or even worldwide setting. In the meantime, more than
100 centers worldwide have contributed data sets of around 10.000 patients addressing all aspects of
SSc. The continuously ongoing database analysis showed that both in limited as well as diffuse SSc, PAH
is much more frequent than expected and contributes significantly to overall morbidity and mortality.
Therefore, the Artimino PAH course is of utmost importance for all physicians diagnosing and treating
SSc to prevent long-term damage and reduction of quality-of-live for PAH-affected SSc patients.
References
Tyndall AJ, Bannert B, Vonk M, Airò P, Cozzi F, Carreira PE, Farge Bancel D, Allanore Y, Müller-Ladner U,
Distler O, Iannone F, Pellerito R, Pileckyte M, Matucci-Cerinic M, Ananieva L, Balbir Gurman A, Damjanov
N, Mueller A, Valentini G, Riemekasten G, Tikly M, Wigley FM, Da Silva JAP, Caramaschi P, Scheja A,
Rozman B, Ton E, Czirják L, Coleiro B, Feierl E, Szucs G, von Mühlen CA, Riccieri V, Novak S, Chizzolini
C, Kotulska A, Denton C, Coelho PC, Kötter I, Simsek I, De la Pena Lefebvre PG, Hachulla E, Seibold JR,
Rednic S, Štork J, Morovic-Vergles J, Walker UA. Causes and risk factors for death in systemic sclerosis – A
study from the EULAR Scleroderma Trials And Research (EUSTAR) data base. Ann Rheum Dis 69, 1809-
1815, 2010
Avouac J, Walker U, Tyndall A, Kahan A, Matucci-Cerinic M, Allanore Y, Miniati I, Muller A, Iannone
F, Distler O, Becvar R, Sierakowsky S, Kowal-Bielecka O, Coelho P, Cabane J, Cutolo M, Shoenfeld Y,
Valentini G, Rovensky J, Riemekasten G, Vlachoyiannopoulos P, Caporali R, Jiri S, Inanc M, Zimmermann
Gorska I, Carreira P, Novak S, Czirjak L, Oliveira Ramos F, Jendro M, Chizzolini C, Kucharz EJ, Richter J,
Cozzi F, Rozman B, Mallia CM, Gabrielli A, Farge D, Kiener HP, Schöffel D, Airo P, Wollheim F, Martinovic
D, Trotta F, Jablonska S, Reich K, Bombardieri S, Siakka P, Pellerito R, Bambara LM, Morovic-Vergles
J, Denton C, Hinrichs R, Van den Hoogen F, Damjanov N, Kötter I, Ortiz V, Heitmann S, Krasowska
D, Seidel M, Hasler P, Van Laar JM, Kaltwasser JP, Foeldvari I, Juan Mas A, Bajocchi G, Wislowska M,
Pereira Da Silva JA, Jacobsen S, Worm M, Graninger W, Kuhn A, Stankovic A, Cossutta R, Majdan M,
Damjanovska Rajcevska L, Tikly M, Nasonov EL, Steinbrink K, Herrick A, Müller-Ladner U, Dinc A, Scorza
R, Sondergaard K, Indiveri F, Nielsen H, Szekanecz Z, Silver RM, Antivalle M, Espinosa IB, García de la
Pena Lefebvre P, Midtvedt O, Launay D, Valesini F, Tuvik P, Ionescu RM, Del Papa N, Pinto S, Wigley F,
Mihai C, Sinziana Capranu M, Sunderkötter C, Jun JB, Alhasani S, Distler JH, Ton E, Soukup T, Seibold J,
Zeni S, Nash P, Mouthon L, De Keyser F, Duruöz MT, Cantatore FP, Strauss G, von Mühlen CA, Pozzi MR,
Eyerich K, Szechinski J, Keiserman M, Houssiau FA, Román-Ivorra JA, Krummel-Lorenz B, Aringer M,
Westhovens R, Bellisai F, Mayer M, Stoeckl F, Uprus M, Volpe A, Buslau M, Yavuz S, Granel B, Valderílio
Feijó A, Del Galdo F, Popa S, Zenone T, Ricardo Machado X, Pileckyte M, Stebbings S, Mathieu A, Tulli
A, Tourinho T, Souza R, Acayaba de Toledo R, Stamp L, Solanki K, Veale D, Francisco Marques Neto J,
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Bagnato GF, Loyo E, Toloza S, Li M, Ahmed Abdel Atty Mohamed W, Cobankara V, Olas J, Salsano F, Oksel
F, Tanaseanu CM, Foti R, Ancuta C, Vonk M, Caramashi P, Beretta L, Balbir A, Chiàla A, Pasalic Simic
K, Ghio M, Stamenkovic B, Rednic S, Host N, Pellerito R, Hachulla E, Furst DE. Characteristics of joint
involvement and relationships with systemic inflammation in systemic sclerosis: results from the EULAR
Scleroderma Trial and Research Group (EUSTAR) database. J Rheumatol 37, 1488-1501, 2010.
Avouac J, Fransen J, Walker UA, Riccieri V, Smith V, Muller C, Miniati I, Tarner IH, Bellando Randone
S, Cutolo M, Allanore Y, Distler O, Valentini G, Czirjak L, Müller-Ladner U, Furst DE, Tyndall A, Matucci-
Cerinic M for EUSTAR. Preliminary criteria for the Very Early Diagnosis Of Systemic Sclerosis (VEDOSS):
Results of a Delphi consensus study from EULAR scleroderma trials and research group (EUSTAR). Ann
Rheum Dis 70, 476-481, 2011.
Galluccio F, Walker UA, Nihtyanova S, Moinzadeh P, Hunzelmann N, Krieg T, Steen V, Baron M, Sampaio-
Barros P, Kayser C, Nash P, Denton CP, Tyndall A, Müller-Ladner U, Matucci-Cerinic M. Registries in
systemic sclerosis. A worldwide experience. Rheumatology 50, 60-68. 2011.
Beyer C, Distler JH, Allanore Y, Aringer M, Avouac J, Czirják L, Cutolo M, Damjanov N, Del Galdo F, Fligelstone
K, Guiducci S, Kowal-Bielecka O, van Laar JM, Martucci-Cerinic M, Müller-Ladner U, Riemekasten G,
Tarner IH, Tyndall A, Kennedy AT, Valentini G, Vettori S, Walker UA, Denton C, Distler O, and the EUSTAR
Biobanking Group. EUSTAR biobanking: recommendations for the collection, storage and distribution of
biospecimens in scleroderma research. Ann Rheum Dis, in press.
References
1. See actual PAH database data from EUSTAR
2. Compare this to other data published on PAH
3. Estimate the importance of PAH in a large cohort
Biographic Sketch
Prof. Müller-Ladner is Chair for Internal Medicine and Rheumatology at the Justus-Liebig University
Giessen, Germany, and Director of the Department of Rheumatology and Clinical Immunology at the
Kerckhoff-Clinic Bad Nauheim, Germany. Prior to this position, Prof. Müller-Ladner was Head of the
Division of Rheumatology and Clinical Immunology at the University of Regensburg, Germany.
Prof. Müller-Ladner is member of the Executive Committee of the German Society of Rheumatology,
Chairman of the EULAR Scleroderma Trials and Research Network (EUSTAR), member of the Executive
Committee of the German Network for Systemic Sclerosis and the Society of Internal Medicine. He is a
fellow of the American College of Rheumatology, the American Association of Immunologists and the
German Societies for Rheumatology, Internal Medicine, Immunology and Gene Therapy. In addition,
Prof. Müller-Ladner is serving as a consultant to the German Ministry for Health and Education (BMBF),
the German Science Council and the German Research Foundation (DFG). At the latter, he is currently
chairing the National Clinical Studies Program.
Prof. Müller-Ladner has received his medical degree from the University of Tübingen, Germany and
received his internal medicine and rheumatology training at the Universities of Ulm and Regensburg,
Germany. He also performed a 2-year basic research fellowship at the Department of Rheumatology of
the University of Alabama at Birmingham.
Prof. Müller-Ladner has authored and/or coauthored numerous research papers and book chapters on
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journals in the field of clinical immunology, rheumatology and internal medicine as member of the
editorial board.
References
Tyndall AJ, Bannert B, Vonk M, Airò P, Cozzi F, Carreira PE, Farge Bancel D, Allanore Y, Müller-Ladner U,
Distler O, Iannone F, Pellerito R, Pileckyte M, Matucci-Cerinic M, Ananieva L, Balbir Gurman A, Damjanov
N, Mueller A, Valentini G, Riemekasten G, Tikly M, Wigley FM, Da Silva JAP, Caramaschi P, Scheja A,
Rozman B, Ton E, Czirják L, Coleiro B, Feierl E, Szucs G, von Mühlen CA, Riccieri V, Novak S, Chizzolini
C, Kotulska A, Denton C, Coelho PC, Kötter I, Simsek I, De la Pena Lefebvre PG, Hachulla E, Seibold JR,
Rednic S, Štork J, Morovic-Vergles J, Walker UA.
Causes and risk factors for death in systemic sclerosis – A study from the EULAR Scleroderma Trials And
Research (EUSTAR) data base.´
Ann Rheum Dis 69, 1809-1815, 2010
Avouac J, Walker U, Tyndall A, Kahan A, Matucci-Cerinic M, Allanore Y, Miniati I, Muller A, Iannone
F, Distler O, Becvar R, Sierakowsky S, Kowal-Bielecka O, Coelho P, Cabane J, Cutolo M, Shoenfeld Y,
Valentini G, Rovensky J, Riemekasten G, Vlachoyiannopoulos P, Caporali R, Jiri S, Inanc M, Zimmermann
Gorska I, Carreira P, Novak S, Czirjak L, Oliveira Ramos F, Jendro M, Chizzolini C, Kucharz EJ, Richter J,
Cozzi F, Rozman B, Mallia CM, Gabrielli A, Farge D, Kiener HP, Schöffel D, Airo P, Wollheim F, Martinovic
D, Trotta F, Jablonska S, Reich K, Bombardieri S, Siakka P, Pellerito R, Bambara LM, Morovic-Vergles
J, Denton C, Hinrichs R, Van den Hoogen F, Damjanov N, Kötter I, Ortiz V, Heitmann S, Krasowska
D, Seidel M, Hasler P, Van Laar JM, Kaltwasser JP, Foeldvari I, Juan Mas A, Bajocchi G, Wislowska M,
Pereira Da Silva JA, Jacobsen S, Worm M, Graninger W, Kuhn A, Stankovic A, Cossutta R, Majdan M,
Damjanovska Rajcevska L, Tikly M, Nasonov EL, Steinbrink K, Herrick A, Müller-Ladner U, Dinc A, Scorza
R, Sondergaard K, Indiveri F, Nielsen H, Szekanecz Z, Silver RM, Antivalle M, Espinosa IB, García de la
Pena Lefebvre P, Midtvedt O, Launay D, Valesini F, Tuvik P, Ionescu RM, Del Papa N, Pinto S, Wigley F,
Mihai C, Sinziana Capranu M, Sunderkötter C, Jun JB, Alhasani S, Distler JH, Ton E, Soukup T, Seibold J,
Zeni S, Nash P, Mouthon L, De Keyser F, Duruöz MT, Cantatore FP, Strauss G, von Mühlen CA, Pozzi MR,
Eyerich K, Szechinski J, Keiserman M, Houssiau FA, Román-Ivorra JA, Krummel-Lorenz B, Aringer M,
Westhovens R, Bellisai F, Mayer M, Stoeckl F, Uprus M, Volpe A, Buslau M, Yavuz S, Granel B, Valderílio
Feijó A, Del Galdo F, Popa S, Zenone T, Ricardo Machado X, Pileckyte M, Stebbings S, Mathieu A, Tulli
A, Tourinho T, Souza R, Acayaba de Toledo R, Stamp L, Solanki K, Veale D, Francisco Marques Neto J,
Bagnato GF, Loyo E, Toloza S, Li M, Ahmed Abdel Atty Mohamed W, Cobankara V, Olas J, Salsano F, Oksel
F, Tanaseanu CM, Foti R, Ancuta C, Vonk M, Caramashi P, Beretta L, Balbir A, Chiàla A, Pasalic Simic
K, Ghio M, Stamenkovic B, Rednic S, Host N, Pellerito R, Hachulla E, Furst DE. Characteristics of joint
involvement and relationships with systemic inflammation in systemic sclerosis: results from the EULAR
Scleroderma Trial and Research Group (EUSTAR) database. J Rheumatol 37, 1488-1501, 2010.
Lambova S, Hermann W, Müller-Ladner U. Capillaroscopic pattern at the toes of systemic sclerosis
patients – does it “tell” more than those of fingers ? J Clin Rheumatol, in press.
Avouac J, Fransen J, Walker UA, Riccieri V, Smith V, Muller C, Miniati I, Tarner IH, Bellando Randone
S, Cutolo M, Allanore Y, Distler O, Valentini G, Czirjak L, Müller-Ladner U, Furst DE, Tyndall A, Matucci-
Cerinic M for EUSTAR. Preliminary criteria for the Very Early Diagnosis Of Systemic Sclerosis (VEDOSS):
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Results of a Delphi consensus study from EULAR scleroderma trials and research group (EUSTAR). Ann
Rheum Dis 70, 476-481, 2011.
Galluccio F, Walker UA, Nihtyanova S, Moinzadeh P, Hunzelmann N, Krieg T, Steen V, Baron M, Sampaio-
Barros P, Kayser C, Nash P, Denton CP, Tyndall A, Müller-Ladner U, Matucci-Cerinic M Registries in systemic
sclerosis. A worldwide experience. Rheumatology 50, 60-68. 2011.
Lambova S, Müller-Ladner U. Capillaroscopic pattern in systemic sclerosis – an association with processes
of angiogenesis and vasculogenesis. Microvasc Res 80, 534-549, 2010
Beyer C, Distler JH, Allanore Y, Aringer M, Avouac J, Czirják L, Cutolo M, Damjanov N, Del Galdo F, Fligelstone
K, Guiducci S, Kowal-Bielecka O, van Laar JM, Martucci-Cerinic M, Müller-Ladner U, Riemekasten G,
Tarner IH, Tyndall A, Kennedy AT, Valentini G, Vettori S, Walker UA, Denton C, Distler O, and the EUSTAR
Biobanking Group. EUSTAR biobanking: recommendations for the collection, storage and distribution of
biospecimens in scleroderma research. Ann Rheum Dis, in press.
.
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PH-PAH definition / classification in SScRobert Voswinckel
PSystemic sclerosis (SSc) is an autoimmune disease characterized by the deposition of excessive amounts of extracellular matrix components, dysfunction of endothelium and an altered immune tolerance 1. Patients with SSc are at risk of developing pulmonary arterial hypertension (PAH), with estimated prevalence between 8–12% 2, 3, which may lead to right heart failure and death. According to the current guidelines on diagnostics, pulmonary hypertension (PH) in SSc patients is classified in the PAH category, and subclassified in the category of PAH associated with collagen vascular diseases 4. This categorization was based on similarities of clinical and pathological presentation as well as response to therapy. However, differences in clinical outcome between SSc-PAH and other forms of PAH have been noted but have not yet been sufficiently explained. SScPAH has been reported to go along with a worse prognosis than idiopathic PAH (IPAH) 5, 6. In addition, patients with SScPAH present with lower values of transfer factor of the lung for carbon monoxide (TL,CO) than patients with IPAH 7, 8. Although responses to current PAH therapy have been reported to be effective in SScPAH 9, 10, some have reported less favourable responses as compared with IPAH 11–13. These findings suggest that differences might, at least in part, be related to differences in associated vascular lesions. The current knowledge on distinct vascular lesions and the underlying pathogenetic mechanisms will be a part of this presentation.
References
1. Jimenez SA, Derk CT. Following the molecular pathways toward an understanding of the pathogenesis
of systemic sclerosis. Ann Intern Med 2004;140:37–50.
2. Hachulla E, Gressin V, Guillevin L, et al. Early detection of pulmonary arterial hypertension in systemic
sclerosis: a French nationwide prospective multicenter study. Arthritis Rheum 2005;52:3792–
3800.
3. Mukerjee D, St George D, Coleiro B, et al. Prevalence and outcome in systemic sclerosis associated
pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis 2003;62:1088–
1093.
4. Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary
hypertension. Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European
Society of Cardiology (ESC); European Respiratory Society (ERS); International Society of Heart and
Lung Transplantation (ISHLT). Eur Respir J. 2009;34(6):1219-63.
5. Fisher MR, Mathai SC, Champion HC, et al. Clinical differences between idiopathic and scleroderma-
related pulmonary hypertension. Arthritis Rheum 2006;54:3043–3050.
6. Kawut SM, Taichman DB, Archer-Chicko CL, et al. Hemodynamics and survival in patients with
pulmonary arterial hypertension related to systemic sclerosis. Chest 2003;123:344–350.
7. Steen V, Medsger TA Jr. Predictors of isolated pulmonary hypertension in patients with systemic
sclerosis and limited cutaneous involvement. Arthritis Rheum 2003;48:516–522.
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8. Sun XG, Hansen JE, Oudiz RJ, et al. Pulmonary function in primary pulmonary hypertension. J Am
Coll Cardiol 2003;41:1028–1035.
9. Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary
hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann
Intern Med 2000;132:425–434.
10. Badesch DB, Hill NS, Burgess G, et al. Sildenafil for pulmonary arterial hypertension associated with
connective tissue disease. J Rheumatol 2007;34:2417–2422.
11. Girgis RE, Mathai SC, Krishnan JA, et al. Long-term outcome of bosentan treatment in idiopathic
pulmonary arterial hypertension and pulmonary arterial hypertension associated with the
scleroderma spectrum of diseases. J Heart Lung Transplant 2005;24:1626–1631.
12. Mathai SC, Girgis RE, Fisher MR, et al. Addition of sildenafil to bosentan monotherapy in pulmonary
arterial hypertension. Eur Respir J 2007;29:469–475.
13. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension 1. N
Engl J Med 2002;346:896–903.
CME Objective: the participants will be able to
1. Classify different entities of PH based on the current (Dana Point) classification2. Understand the pathogenetic mechanisms involved in vascular remodeling and disease progression
in SSc-PAH3. Identify complications during the course of disease progression and treatment that are observed
with (SSc)-PAH.
Biographic Sketch
R. Voswinckel is a physician researcher with clinical specialization in the filed of pulmonary hypertension,
working in the Pulmonary Vascular Department of the University of Giessen Lung Center and Kerckhoff
Thoracic Center in Germany. He participates in translational and clinical drug development for the
treatment of PAH. He is head of a basic science group at the Max-Planck-Institute for Heart and Lung
Research in Bad Nauheim, Germany, focusing on PAH pathogenesis, progenitor cell contributions and
regenerative lung growth.
Selected Publications
1. Kreymborg K, Uchida S, Gellert P, Schneider A, Boettger T, Voswinckel R, Wietelmann A, Szibor
M, Weissmann N, Ghofrani AH, Schermuly R, Schranz D, Seeger W, Braun T. Identification of right
heart-enriched genes in a murine model of chronic outflow tract obstruction. J Mol Cell Cardiol.
2010 Oct;49(4):598-605.
2. Nikam VS, Schermuly RT, Dumitrascu R, Weissmann N, Kwapiszewska G, Morrell N, Klepetko W, Fink
L, Seeger W, Voswinckel R. Treprostinil inhibits the recruitment of bone marrow-derived circulating
fibrocytes in chronic hypoxic pulmonary hypertension. Eur Respir J. 2010 Dec;36(6):1302-14. Epub
2010 Jun 4.PMID: 20525716 [PubMed - in process]Related citations
3. Udalov S, Dumitrascu R, Pullamsetti SS, Al-tamari HM, Weissmann N, Ghofrani HA, Guenther A,
Voswinckel R, Seeger W, Grimminger F, Schermuly RT. Effects of phosphodiesterase 4 inhibition on
bleomycin-induced pulmonary fibrosis in mice. BMC Pulm Med. 2010 May 5;10:26.
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ACT4. Ghofrani HA, Voswinckel R, Gall H, Schermuly R, Weissmann N, Seeger W, Grimminger F. Riociguat
for pulmonary hypertension. Future Cardiol. 2010 Mar;6(2):155-66. Review.
5. Vallerie V. McLaughlin, Raymond L. Benza, Lewis J. Rubin, Richard N. Channick, Robert Voswinckel,
Victor F. Tapson, Ivan M. Robbins, Horst Olschewski, Melvyn Rubenfire, Werner Seeger. Addition of
Inhaled Treprostinil to Oral Therapy for Pulmonary Arterial Hypertension: A Randomized Controlled
Clinical Trial. J Am Coll Cardiol. 2010 May 4;55(18):1915-22.
6. Dahal BK, Cornitescu T, Tretyn A, Pullamsetti SS, Kosanovic D, Dumitrascu R, Ghofrani HA, Weissmann
N, Voswinckel R, Banat GA, Seeger W, Grimminger F, Schermuly RT. Role of epidermal growth factor
inhibition in experimental pulmonary hypertension. Am J Respir Crit Care Med: 181(2): 158-167.
2010
7. Voswinckel R, Reichenberger F, Gall H, Schmehl T, Gessler T, Schermuly RT, Grimminger F, Rubin LJ,
Seeger W, Ghofrani HA, Olschewski H. Metered dose inhaler delivery of treprostinil for the treatment
of pulmonary hypertension. Pulm Pharmacol Ther 2009: 22(1): 50-56.
8. Toshner M, Voswinckel R, Southwood M, Al-Lamki R, Howard LS, Marchesan D, Yang J, Suntharalingam
J, Soon E, Exley A, Stewart S, Hecker M, Zhu Z, Gehling U, Seeger W, Pepke-Zaba J, Morrell NW.
Evidence of dysfunction of endothelial progenitors in pulmonary arterial hypertension. Am J Respir
Crit Care Med 2009: 180(8): 780-787.
9. Laumanns IP, Fink L, Wilhelm J, Wolff JC, Mitnacht-Kraus R, Graef-Hoechst S, Stein MM, Bohle RM,
Klepetko W, Hoda MA, Schermuly RT, Grimminger F, Seeger W, Voswinckel R. The noncanonical WNT
pathway is operative in idiopathic pulmonary arterial hypertension. Am J Respir Cell Mol Biol 2009:
40(6): 683-691.
10. Grimminger F, Weimann G, Frey R, Voswinckel R, Thamm M, Bolkow D, Weissmann N, Muck W, Unger
S, Wensing G, Schermuly RT, Ghofrani HA. First acute haemodynamic study of soluble guanylate
cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J 2009: 33(4): 785-792.
11. Voswinckel R, Reichenberger F, Enke B, Kreckel A, Krick S, Gall H, Schermuly RT, Grimminger F, Rubin
LJ, Olschewski H, Seeger W, Ghofrani HA. Acute effects of the combination of sildenafil and inhaled
treprostinil on haemodynamics and gas exchange in pulmonary hypertension. Pulm Pharmacol Ther
2008: 21(5): 824-832.
12. Schermuly RT, Pullamsetti SS, Kwapiszewska G, Dumitrascu R, Tian X, Weissmann N, Ghofrani HA,
Kaulen C, Dunkern T, Schudt C, Voswinckel R, Zhou J, Samidurai A, Klepetko W, Paddenberg R, Kummer
W, Seeger W, Grimminger F. Phosphodiesterase 1 upregulation in pulmonary arterial hypertension:
target for reverse-remodeling therapy. Circulation 2007: 115(17): 2331-2339.
13. Voswinckel R, Ghofrani HA, Grimminger F, Seeger W, Olschewski H. Inhaled treprostinil [corrected] for
treatment of chronic pulmonary arterial hypertension. Ann Intern Med 2006: 144(2): 149-150.
14. Voswinckel R, Enke B, Reichenberger F, Kohstall M, Kreckel A, Krick S, Gall H, Gessler T, Schmehl
T, Ghofrani HA, Schermuly RT, Grimminger F, Rubin LJ, Seeger W, Olschewski H. Favorable effects
of inhaled treprostinil in severe pulmonary hypertension: results from randomized controlled pilot
studies. J Am Coll Cardiol 2006: 48(8): 1672-1681.
15. Channick RN, Olschewski H, Seeger W, Staub T, Voswinckel R, Rubin LJ. Safety and efficacy of inhaled
treprostinil as add-on therapy to bosentan in pulmonary arterial hypertension. J Am Coll Cardiol
2006: 48(7): 1433-1437.
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ESC 2009 practice guidelines in pulmonary hypertension.Nazzareno Galiè, MD
Pulmonary hypertension (PH) is a haemodynamic and pathophysiological state that can be found in multiple clinical conditions which have been classifi ed into six diagnostic groups with specific histological, clinical, and therapeutic features. Despite possible comparable elevations of pulmonary pressure in the different clinical groups, the underlying mechanisms, the diagnostic approaches, and the prognostic and therapeutic implications are completely different.Group 1, defined as pulmonary arterial hypertension (PAH), includes rare conditions which share comparable clinical and haemodynamic pictures and virtually identical pathological changes in the lung microcirculation.PAH comprises the idiopathic and familial forms and the forms associated with connective tissue diseases, congenital heart defects with systemic-to-pulmonary shunts, portal hypertension, and human immunodefi ciency virus (HIV) infection. A sequential diagnostic approach is suggested to identify and characterize the different types. Three classes of drugs (prostanoids, endothelin-receptor antagonists, phosphodiesterase type-5 inhibitors) have proven to be effective in this severe condition and an evidence-based treatment algorithm is presented. Specific clinical and therapeutic characteristics of each PAH type are also discussed. Lung transplantation is indicated in case of medical treatments failure.Group 2 includes patients with PH due to left heart diseases. In these cases the treatment is addressed to the underlying heart condition and specific medications approved for PAH have not proven to be convincingly effective.Group 3 includes cases of PH due to lung diseases in which the use of specifi c medications approved for PAH is not recommended on the basis of their minimal clinical effi cacy and because they may impair pulmonary gas exchange.Group 4 comprises patients with chronic thromboembolic PH where treatment of choice is pulmonary endarterectomy, and group 5 includes a miscellanea of rare conditions.
References1. Galiè N, Hoeper M, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Klepetko W, Joendeau G, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G. Guidelines on diagnosis and treatment of pulmonary hypertension: The Task Force on Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology and of the European Respiratory Society. Eur Heart J 2009;30:2493-2537
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Screening for pulmonary arterial hypertensionassociated to systemic sclerosis
Eric Hachulla
Pulmonary arterial hypertension (PAH) is a serious complication of systemic sclerosis (SSc), which if untreated, can rapidly lead to right heart failure and death. Specific treatments for PAH are available and can significantly improve the survival prospects of patients, especially for those diagnosed in World Health Organization functional class (WHO FC) II. Registry data from France and the United Kingdom have shown that in those countries, without screening, more than two thirds of SSc-PAH patients are in WHO FC III or IV by the time they are diagnosed. The recognised predisposition of SSc patients to develop PAH as a complication should mean that an optimal screening programme will enable the early diagnosis of PAH in this population. A definitive diagnosis of PAH is only achieved via right heart catheterisation (RHC), but it would be impractical to regularly screen all SSc patients with such an invasive tool. Non-invasive investigations are therefore used and echocardiographic screening is recommended for SSc patients. Screening algorithms using the echocardiographic parameter tricuspid regurgitation velocity and the presence or absence of dyspnoea have successfully detected RHC-confirmed PAH patients in WHO FC II (Figure 1). Earlier diagnosis provides the opportunity for earlier treatment given the hope of a better survival. Due to the possible false positive of Echocardiography, other surrogate markers for suspecting PAH in SSc should be tested as DLCO, NT-pro-BNP and exercise Echocardiography.
Figure 1. PAH screening protocol for SSc patients.
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1. Galiè N, Hoeper MM, Humbert M, et al. 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: 24932537.
2. Hachulla E, Launay D, Yaici A, et al; on behalf of the French PAH-SSc Network. Pulmonary arterial hypertension associated with systemic sclerosis in patients with functional class II dyspnoea: mild symptoms but severe outcome. Rheumatology 2010 Feb 8. [Epub ahead of print]
3. Hachulla E, de Groote P, Gressin V, et al; Itinér AIR-Sclérodermie Study Group. The three-year incidence of pulmonary arterial hypertension associated with systemic sclerosis in a multicenter nationwide longitudinal study in France. Arthritis Rheum 2009;60 : 18311839.
4. Hachulla E, Carpentier P, Gressin V, et al; ItinérAIR-Sclérodermie Study Investigators. Risk factors for death and the 3-year survival of patients with systemic sclerosis: the French ItinérAIR-Sclérodermie study. Rheumatology 2009; 48 :304308.
5. Allanore Y, Borderie D, Avouac J, et al. High N-terminal pro-brain natriuretic peptide levels and low diffusing capacity for carbon monoxide as independent predictors of the occurrence of precapillary pulmonary arterial hypertension in patients with systemic sclerosis. Arthritis Rheum 2008; 58: 284–291.
6. Steen V, Medsger TA Jr. Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum 2003;48:516-22.
CME Objective: the participants will be able to
1. explain why regular screening for PAH is needed in SSc 2. dentify SSc patients at risk of PAH3. use the most effective screening tolls to detect PAH
Biographic Sketch
Eric Hachulla has been Professor of Internal Medicine at the Hospital Claude Huriez, University of Lille
since 1995. He is the Head of one of the Scleroderma National Centre in France. He has published many
papers and carried out clinical research into a variety of topics, mainly in connective tissue diseases. He
is a member of several professional bodies, including the French Society of Internal Medicine, French
Society of Rheumatology, the American College of Rheumatology and EULAR. He is a member of the
educational committee of EUSTAR and of the EULAR online course on rheumatic diseases.
References
Hachulla E, Launay D, Yaici A, Berezne A, de Groote P, Sitbon O, Mouthon L, Guillevin L, Hatron PY,
Simonneau G, Clerson P, Humbert M; French PAH-SSc Network. Pulmonary arterial hypertension
associated with systemic sclerosis in patients with functional class II dyspnoea: mild symptoms but
severe outcome. Rheumatology (Oxford). 2010 May;49(5):940-4
Hachulla E, Carpentier P, Gressin V, Diot E, Allanore Y, Sibilia J, Launay D, Mouthon L, Jego P, Cabane
J, de Groote P, Chabrol A, Lazareth I, Guillevin L, Clerson P, Humbert M; ItinérAIR-Sclérodermie Study
Investigators. Risk factors for death and the 3-year survival of patients with systemic sclerosis: the
French ItinérAIR-Sclérodermie study.Rheumatology (Oxford). 2009 Mar;48(3):304-8.
37
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ACTHachulla E, de Groote P, Gressin V, Sibilia J, Diot E, Carpentier P et al. The three-year incidence of pulmonary
arterial hypertension associated with systemic sclerosis in a multicenter nationwide longitudinal study
in France.
Arthritis Rheum. 2009;60:1831-9.
Hachulla AL, Launay D, Gaxotte V, de Groote P, Lamblin N, Devos P, Hatron PY, Beregi JP, Hachulla E.
Cardiac magnetic resonance imaging in systemic sclerosis: a cross-sectional observational study of 52
patients.Ann Rheum Dis. Ann Rheum Dis. 2009 ; 68 : 1878-84.
Presentation
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Pathophysiology of Pulmonary Arterial HypertensionRobert Naeije
Pulmonary arterial hypertension (PAH) is a disease of the small pulmonary arteriole, which undergo a series of changes including intimal fibrosis, medial hypertrophy, adventitial proliferation, in situ thrombosis, fibrinoid necrosis and plexiform lesions, all leading to a relentless increase in PVR and associated dyspnea-fatigue syndrome. (1). Corresponding functional changes concern ventilation/perfusion (VA/Q) matching), pulmonary artery pressure (Ppa)-flow (Q) relationships, right ventricular (RV) by pressure-volume relationships and the autonomic nervous system.
1. Pulmonary gas exchange.
Patients with PAH present with normal or near-normal arterial PO2, more frequently with decreased arterial PCO2 (2). Hypocapnia, not hypoxemia, has been shown to be an independent predictor of survival in PAH (3). Studies using the multiple inert gas elimination technique have shown that the distribution of VA/Q relationships is characterized by a close to normal matching of ventilation and perfusion, even though there is a shift to a higher than normal mean VA/Q, associated with a decreased efficiency of gas exchange and increased physiologic dead space (VD/VTphys) (4-6). There is minimal or no increased perfusion to lower than normal VA/Q), the low-normal arterial PO2 being essentially to be accounted for by a low mixed venous PO2, consequence of a low cardiac output (4-6). In some patients are hypoxemic because of a right-to-left shunt through a patent foramen ovale (5). In spite of vascular obliteration, the inert gas (or anatomical) dead space remains normal (6).
Patients with PAH hyperventilate at exercise, at rest and even during sleep (2). This is explained by an increase in VD/VTphys and chemosensitivity, like in heart failure (7,8). Increased chemosensitivity is related to a tonic activation of the sympathetic nervous system (7,8).
2. Pulmonary vascular function
The typical hemodynamic profile in PAH is a marked increase in Ppa with a normal left atrial pressure (Pla) and a low-normal Q. Thus increased Ppa reflects an increase in PVR. It is of interest that an increase in Q, for example at exercise or with the administration of a low dose of dobutamine, increases Ppa less that predicted by baseline PVR (9,10). This is explained by persistent recruitment and distension of vessels in spite of widespread remodelling. The flow-dependency of Ppa or PVR in PAH makes difficult the evaluation of the functional state of the pulmonary circulation when cardiac output is increased. In that case, the analysis of multipoint Ppa–Q plots, or the use of a Ppa-Q diagram is preferable to isolated PVR calculations (11).
Right ventricular afterload is determined by a dynamic interaction between pulmonary arterial compliance (Ca) and PVR. Recent studies have demonstrated that the product of Ca and PVR, or time
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constant of the pulmonary circulation, remains constant in all circumstances at a value of approximately 0.7 s (12). This explains why mean Ppa can be predicted from systolic Ppa by multiplying the value by 0.6 and adding 2 mmHg (13). The hyperbolic relationship between Ca and PVR explains why mildly increased PVR may already markedly increase RV afterload because of a proportionally greater decrease in Ca. Normal subjects at exercise present with a mild decrease in PVR but a marked increase in Ca. Patients with PAH at exercise present with a mild or marked increase in PVR and no or minimal further decrease in Ca (14).
3. Right ventricular function
The symptomatology of pulmonary hypertension is explained by a decrease of cardiac output caused by an afterload-induced right ventricular (RV) failure (15). Ventricular function adaptation to afterload is systolic, with secondary diastolic function changes. The compensated RV in pulmonary hypertension has preserved dimensions with increased contractility and eventual hypertrophy. The failing RV uses the Frank-Starling mechanism to maintain flow output, which causes increased dimensions and congestion. The standard hemodynamic evaluation of pulmonary hypertension, with pulmonary vascular pressure and flow measurements, does not capture the determinants of RV pump function. Right ventricular afterload can be measured either as a hydraulic load calculated from spectral analysis of pulmonary artery pressure and flow waves, or, more simply, from a pulmonary arterial elastance defined as a ratio between end-systolic to stroke volume ratio (16). The adequacy of ventricular adaptation to afterload can be assessed by a measurement of systolic function, or end-systolic elastance, as it is matched to arterial elastance. Patients with severe pulmonary hypertension may present with a decreased ratio of elastances, in spite of an adaptative increase in systolic function (17). An alternative approach makes use of the pump function graph, which represents mean RV pressure as a function of stroke volume (18). Patients with systemic sclerosis-associated PAH present with lower pressures at a given stroke volume than those with idiopathic PAH, indicating depressed myocardial systolic function (19).
The importance of RV systolic adaptation to afterload in pulmonary hypertension is underscored by the strong predictive value of survival of echocardiographic indices of systolic function such as the tricuspid annular plane excursion or the isovolumic contraction acceleration or maximal velocity. Echocardiographic measures of increased dimensions and filling pressures of the RV are indicators of heart failure and clinical deterioration. Further studies are needed for a better definition of non invasive imaging measurements of RV-arterial coupling and their functional and biological correlates. 4. The autonomic nervous system
Heart failure has long been known to be associated with neuro-humoral derangements including an increased sympathetic nervous system tone and an activation of rennin-angiotensin-aldosterone signaling. Evaluation of the sympathetic nervous system by measurements of circulating catecholamines produced ambiguous results in PAH until microneurographic recordings disclosed an sympathetic activation of a severity comparable to reported in congestive heart failure (20). These studies also showed a decreased sympathetic activation after atrial septostomy, in spite of hypoxemia, suggesting an “inverse Bainbridge reflex”, that is decreased decreased sympathetic tone related to decreased right atrial stretch (21). Most recently, microneurographic measurements of sympathetic nervous activation were shown to predict decreased survival in PAH (22). These findings offer the rationale for cautious low-dose -blocker therapies in PAH, which are currently being evaluated in clinical trials.
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ACT5. References
1. McLaughlin VV et al. Circulation 2009; 119 : 2250-94.
2. Melot C and Naeije R. Pulmonary vascular diseases. Compr Physiol 2011 ; 1: 593-619
3. Hoeper MM et al. Eur Respir J 2007; 29: 944-50.
4. Dantzker DR et al. J Clin Invest 1979; 64: 1050-5
5. Mélot C et al Chest 1983; 83: 203-7
6. Dantzker DR et al. Am Rev Respir Dis 1984; 130: 412-6
7. Johnson RL, Jr. Circulation 2001; 103 : 916-8.
8. Naeije R and van de Borne P. Eur Respir J 2009 ; 34: 792-4.
9. Kafi SA et al J Am Coll Cardiol 1998; 31: 1372-6.
10. Castelain V et al Am J Respir Crit Care Med 2002; 165: 338-40.
11. Naeije R. Intens Care Med 2003; 29: 526-9.
12. Lankhaar JW et al. Eur Heart J. 2008; 29: 1688-95.
13. Chemla D et al Chest 2004; 126: 1313-7.
14. Bonderman D et al. Chest 2011; 139: 122-7.
15. Champion HC et al. Circulation 2009 ; 120: 992-1007.
16. Chesler NC et al Conf Proc IEEE Eng Med Biol Soc. 2009:177-80.
17. Kuehne T et al. Circulation. 2004; 110: 2010-6
18. Elzinga G and Westerhof N. Circ Res. 1978; 42: 620-8
19. Overbeek MJ et al..Eur Respir J. 2008; 31: 1160-6
20. Velez Roa S et al. Circulation 2004; 110: 1308-12.
21. Ciarka A et al. Chest 2007; 131: 1831-7.
22. Ciarka A et al Am J Respir Crit Care Med 2010; 181: 1269-75.
Biographic Sketch
Robert Naeije, MD, PhD, is Professor of Physiology and Medicine, and Chairman of the Department of
Pathophysiology at the Faculty of Medicine of the Free University of Brussels. He is also Consultant at the
Pulmonary Hypertension Clinic of Department of Cardiology of the Erasme University Hospital, Brussels.
Professor Naeije has a long publication record of fundamental and clinical research on the pulmonary
circulation. He has served on scientific advisory boards of several randomized controlled trials of new
specific pharmacologic treatments of pulmonary arterial hypertension. He was actively involved in the
Evian (1998), Venice (2003) and Dana Point (2008) world expert consensus conferences on pulmonary
hypertension. Professor Naeije’s current research interests include various pathophysiological and
therapeutic aspects of pulmonary arterial hypertension, and the pathobiology of experimental animal
models of pulmonary hypertension and right hear failure. On the clinical side, his team has developed
original methods for an improved non invasive evaluation of the pulmonary circulation and right
ventricular function, with recent focus on tissue Doppler imaging techniques and exercise stress testing.
His publication list currently reaches 295 peer reviewed articles. Professor Naeije is former chairman of
the Pulmonary Circulation group of the European Respiratory Society, has been member of the editorial
board of the American Journal of Respiratory and Critical Care Medicine and is currently Associate Editor
of the European Respiratory Journal.
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References
1. Naeije R, Mélot C, Mols P, Hallemans R. Reduction in pulmonary hypertension by prostaglandinE1
in decompensated chronic obstructive pulmonary disease. Am Rev Respir Dis 1982; 125 : 1-5.
2. Naeije R, Lipski A, Abramowicz M, Lejeune P, Mélot C, Antoine M, De Smet JM, Leclerc JL, Primo G.
Nature of pulmonary hypertension in congestive heart failure. Effects of cardiac transplantation.
Am J Respir Crit Care Med 1994; 147: 881-7.
3. Abdel Kafi S, Mélot C, Vachiéry JL, Brimioulle S, Naeije R. Partitioning of pulmonary vascular
resistance in primary pulmonary hypertension. J Am Coll Cardiol 1998, 31: 1372-6
4. Rondelet B, Kerbaul F, van Beneden R, Motte S, Fesler P, Hubloue I, Remmelink M, Brimioulle S,
Salmon I, Ketelslegers JM, Naeije R. Signaling molecules in overcirculation-induced experimental
pulmonary hypertension. Effects of sildenafil. Circulation 2004; 110: 2220-5.
5. Kerbaul F, Brimioulle S, Rondelet B, Dewachter C, Hubloue I, Naeije R. How Prostacyclin Improves
Cardiac Output in Acute Right Heart Failure on Pulmonary Hypertension. Am J Respir Crit Care Med.
2007; 175 : 846-50.
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Clinical aspects of SSc PAHChristopher P. Denton
Pulmonary arterial hypertension (PAH; Group 1 PH) occurs in up to 15% of patients with systemic sclerosis (SSc) and can affect both limited and diffuse subsets. It is the commonest and post important form of pulmonary hypertension occurring in SSc but other causes include Group 2 (cardiac disease) and Group 3 (lung disease). Its importance in part is through the availability of disease modifying PAH specific therapies that have emerged over the past decade. In addition other forms such s pulmonary veno-occlusive disease (PVOD) can occur (group 1’). In addition PAH must be considered as a differential diagnosis for breathlessness in SSc for which there are many other causes. This presentation will consider the clinical presentation, diagnosis and differential diagnosis of PAH in SSc and review approaches to diagnosis and investigation of this important complication.
References
1 Hachulla E, Denton CP. Early intervention in pulmonary arterial hypertension associated with
systemic sclerosis: an essential component of disease management. Eur Respir Rev. 2010 Dec
1;19(118):314-20.
2 Nihtyanova SI, Tang EC, Coghlan JG, Wells AU, Black CM, Denton CP. Improved survival in systemic
sclerosis is associated with better ascertainment of internal organ disease: a retrospective cohort
study. QJM. 2010 Feb;103(2):109-15.
3 Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, Elliott CG, Gaine SP,
Gladwin MT, Jing ZC, Krowka MJ, Langleben D, Nakanishi N, Souza R. Updated clinical classification
of pulmonary hypertension. J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S43-54.
4 Hant FN, Herpel LB, Silver RM. Pulmonary manifestations of scleroderma and mixed connective
tissue disease. Clin Chest Med. 2010 Sep;31(3):433-49.
5 Vachiéry JL, Coghlan G. Screening for pulmonary arterial hypertension in systemic sclerosis. Eur
Respir Rev. 2009 Sep 1;18(113):162-9.
CME Objective: the participants will be able to
1. Define the types of pulmonary hypertension occurring in SSc2. Differentiate PAH from other causes of breathlessness in SSc3. Plan systematic investigation and assessment of PAH
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Biographic Sketch
Professor Christopher Denton, Royal Free Hospital and UCL Medical School, UK
Christopher Denton PhD, FRCP, is Professor of Experimental Rheumatology at UCL Medical School and
Consultant Rheumatologist and Joint Director of the Centre for Rheumatology, Royal Free Hospital,
London. He studied medicine at Guy’s Hospital, where he qualified with distinction. He trained in
internal medicine and rheumatology in London and later undertook a PhD in cell biology at UCL and
a Wellcome Trust advanced fellowship in molecular genetics at the M.D. Anderson Cancer Center in
Houston, USA. He leads the UK Scleroderma Study Group (UKSSG), is Treasurer of EUSTAR and Chair-elect
of the Heberden Committee of the BSR. He manages a large cohort of more than 1000 scleroderma
patients and has published extensively on laboratory and clinical aspects of Raynaud’s phenomenon,
connective tissue disease and pulmonary hypertension.
References
1 Hachulla E, Denton CP. Early intervention in pulmonary arterial hypertension associated with
systemic sclerosis: an essential component of disease management. Eur Respir Rev. 2010 Dec
1;19(118):314-20.
2 Valerio CJ, Handler CE, Kabunga P, Smith CJ, Denton CP, Coghlan JG. Clinical experience with
bosentan and sitaxentan in connective tissue disease-associated pulmonary arterial hypertension.
Rheumatology (Oxford). 2010 Nov;49(11):2147-53.
3 Coghlan JG, Pope J, Denton CP. Assessment of endpoints in pulmonary arterial hypertension
associated with connective tissue disease. Curr Opin Pulm Med. 2010 May;16 Suppl 1:S27-34.
4 Nihtyanova SI, Tang EC, Coghlan JG, Wells AU, Black CM, Denton CP. Improved survival in systemic
sclerosis is associated with better ascertainment of internal organ disease: a retrospective cohort
study. QJM. 2010 Feb;103(2):109-15.
5 Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, Elliott CG, Gaine SP,
Gladwin MT, Jing ZC, Krowka MJ, Langleben D, Nakanishi N, Souza R. Updated clinical classification
of pulmonary hypertension. J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S43-54.
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9.30-10.30
Differential diagnosis of systemic sclerosis associated pulmonary arterial hypertension: primary heart involvement.
Yannick Allanore & Gabriele Valentini
Primary myocardial involvement is common in systemic sclerosis (SSc). There is strong evidence that this involvement is related to repeat focal ischemic injury causing irreversible myocardial fibrosis. Clinically evident cardiac involvement is recognized to be a poor prognostic factor; thus pre-clinical identification is highly encouraged. Studies that used conventional echocardiographic measurements report only few patients with depressed left ventricular (LV) contractility, though up to 40% of relaxation abnormalities and possible right ventricular involvement (RV). In contrast, a higher prevalence (10-15%) of reduced LV and/or RV contractility has been observed with new methods, such some modalities of tissue-Doppler echocardiography or magnetic resonance imaging, and a high prevalence of diastolic dysfunction confirmed. Therefore, primary heart disease is a concern in front of a SSc patient with suspected pulmonary hypertension and right heart catheterisation is mandatory to differenciate pre versus post capillary pulmonary hypertension. Pulmonary embolism may also occur in SSc although thrombophilia is not associated specifically with SSc. In this session we will discuss in depth clinical cases and literatu data of differential diagnoses of SSc-PAH related to primary heart disease.
References1. Allanore Y, Meune C, Vonk MC, Airo P, et al, and EUSTAR co-authors. Prevalence and factors associated
with left ventricular dysfunction in the EULAR Scleroderma Trial and Research group (EUSTAR) database of patients with systemic sclerosis.Ann Rheum Dis. 2010 Jan;69(1):218-21
2. Allanore Y, Meune C, Kahan A. Systemic sclerosis and cardiac dysfunction: evolving concepts and diagnostic methodologies. Curr Opin Rheumatol. 2008 Nov;20(6):697-702.
3. Meune C, Avouac J, Wahbi K, et al. Cardiac involvement in systemic sclerosis assessed by tissue-doppler echocardiography during routine care: A controlled study of 100 consecutive patients. Arthritis Rheum. 2008 Jun;58(6):1803-9
4. De Groote P, Gressin V, Hachulla E, et al; ItinerAIR-Scleroderma Investigators. Evaluation of cardiac abnormalities by Doppler echocardiography in a large nationwide multicentric cohort of patients with systemic sclerosis.Ann Rheum Dis. 2008 Jan;67(1):31-6
5. Maione S, Cuomo G, Giunta A, et al. Echocardiographic alterations in systemic sclerosis: a longitudinal study. Semin Arthritis Rheum. 2005 Apr;34(5):721-7
CME Objective: the participants will be able to
1. Know the prevalence and characteristics of primary heart involvement in SSc2. Understand the different mechanisms that can lead to pulmonary hypertension3. Understand the usefulness of the different tools to assess heart involvement in this context
Biographic SketchYannick Allanore got a Professor of Rheumatology position at the Paris Descartes University in Paris in 2008. Professor ALLANORE is the Head of a research group working on the cardiovascular clinical aspects of systemic sclerosis and on pathogenesis, through genetic and cellular biology approaches (INSERM U1016, Cochin Institute). He has published over 160 papers. Professor Allanore is a member of several professional bodies, including the French Rheumatology Society, the American College of Rheumatology and EULAR. He is advisory editor of Arthritis and Rheumatism journal. He is a member of board of the The EULAR Scleroderma Trials and Research group (EUSTAR) and organised the 3rd Eustar Course in Paris in 2009
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11.00-12.00
Interstitial lung disease associated with systemic sclerosisOtylia Kowal-Bielecka
Interstitial lung disease (ILD) is characterized by inflammation and/or fibrosis of the lung parenchyma which eventually lead to impairment of gas exchange, respiratory failure and, subsequently, death. Sensitive diagnostic methods such as high resolution computed tomography (HRCT) of the lungs reveal features of ILD in up to 80-90% of patients with systemic sclerosis (SSc, scleroderma) [1]. However restrictive lung disease, which is associated with worse clinical prognosis, develops in approximately 40% of SSc patients [2].Since ILD is the most frequent pulmonary complication and a major cause of mortality in patients with SSc, regular screening aimed at early identification of parenchymal lung involvement is recommended in scleroderma patients [3-5]. Typical radiological features in HRCT of the lungs together with characteristic clinical picture usually allow reliable diagnosis of SSc-related ILD (SSc-ILD) while histopathological assessment of lung biopsy or analysis of bronchoalveolar lavage are helpful in differential diagnosis with other infiltrating lung diseases such as infections, hypersensitivity pneumonitis or malignancy [4, 6].In view of variable clinical course of SSc-ILD and potential toxicity of therapies used for its treatment, management of SSc-ILD should be designed individually based on regular assessment of prognosis and response to therapy. Severity of lung involvement assessed by pulmonary function tests and fibrosis score on HRCT are best established predictors of worse clinical prognosis in SSc-ILD, but these are usually features of advanced lung disease [2, 7-8]. Identification and validation of new biomarkers to predict and monitor lung involvement is of key importance for optimizing management of and developing new therapies for SSc-ILD [9].Immunosuppressive drugs are considered a cornerstone in treatment of SSc-ILD however, evidence concerning their efficacy is limited. So far only cyclophosphamide has shown statistically significant although clinically modest efficacy in delaying deterioration of vital capacity in symptomatic SSc-ILD [8, 10-11]. Other agents such as mycophenolate mofetil or rituximab showed promising in retrospective analyses or open label clinical trials [12-13]. New therapies aimed at targeting fibrotic pathways are currently under investigation in experimental or early clinical studies.Because of systemic character of SSc and many challenges associated with assessment and treatment decisions, appropriate management of patients with SSc-ILD requires multidisciplinary care involving specialists in rheumatology, radiology, lung diseases and rehabilitation with clinical experience in SSc and ILDs.
References
1. Warrick JH. Bhalla M. Schabel SI. Silver RM. High resolution computed tomography in early scleroderma
lung disease. J Rheumatol. 1991;18:1520-1528.
2. Steen VD, Conte C, Owens GR, Medsger TA Jr. Severe restricitive lung disease in systemic sclerosis.
Arthritis Rheum 1994;37:1283-1289.
3. Tyndall AJ, Bannert B, Vonk M, et al.. Causes and risk factors for death in systemic sclerosis: a study
from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis. 2010;69:1809-
15.
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4. Wells AU, Hirani N. et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration
with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax
2008;63(Suppl V):v1–v58.
5. Khanna D, Kowal-Bielecka O, Khanna PP, et al.. Quality indicator set for systemic sclerosis. Clin Exp
Rheumatol 2011;29 (Suppl 65) S33-S39.
6. Kowal-Bielecka O, Kowal K, Chyczewska E. Utility of bronchoalveolar lavage in evaluation of patients
with connective tissue diseases. Clin Chest Med. 2010;31:423-431.
7. Goh NSL, Desai SR, Veeraraghavan S, et al. Interstitial lung disease in systemic sclerosis: A simple
staging system. Am J Respire Crit Care Med. 2008;177:1248-1254
8. Tashkin DP. Elashoff R. Clements PJ. et al; for Scleroderma Lung Study Research Group. Cyclophosphamide
versus placebo in scleroderma lung disease. N Engl J Med 2006; 354:2655-66.
9. Hant FN, Silver RM. Biomarkers of scleroderma lung disease: recent progress. Curr Rheumatol Rep.
2011;13:44-50.
10. Tashkin DP, Elashoff R, Clements PJ, et al. for Scleroderma Lung Study Research Group. Effects of 1-year
treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease. 1. Am J Respir
Crit Care Med. 2007;176:1026-1034.
11. Kowal-Bielecka O, Landewé R, Avouac J, et al. EULAR recommendations for the treatment of systemic
sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis.
2009;68:620-628.
12. Nihtyanova SI, Brough GM, Black CM, Denton CP. Mycophenolate mofetil in diffuse cutaneous systemic
sclerosis--a retrospective analysis. Rheumatology (Oxford). 2007;46:442-445.
13. Daoussis D, Liossis SN, Tsamandas AC, et al. Experience with rituximab in scleroderma: results from a
1-year, proof-of-principle study. Rheumatology (Oxford). 2010;49:271-80.
CME Objective: the participants will be able to
1. Understand clinical significance of and importance of screen for interstitial lung disease in SSc2. Make diagnosis of interstitial lung disease3. Make treatment decisions based on assessment of prognosis in interstitial lung disease associated with
SSc
Biographic Sketch
Otylia Kowal-Bielecka is an assistant professor in the Department of Rheumatology and Internal Medicine
at Medical University of Bialystok, Poland. She undertook her postdoctoral fellowship at the Center of
Experimental Rheumatology, University of Zurich, and since then she is interested in systemic sclerosis. Her
major research focus is on the pathophysiology and clinical aspects of lung involvement. Dr Kowal-Bielecka
served as a Counselor in the EUSTAR (EULAR Scleroderma Trial and Research) group. She is a member of the
EUSTAR Clinical Committee and the EPOSS (Expert Panel on Outcome Measures in PAH related to Systemic
Sclerosis), a member of the editorial board of Rheumatology, and a board member of the Polish Society of
Rheumatology.
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1. Kowal-Bielecka O, Kowal K, Distler O, Gay S. Leukotrienes and lipoxins in scleroderma interstitial lung
disease – recent insights and potential therapeutic interventions. Nature Clin Prac Rheumatol 2007;3: 43-
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2. Kowal-Bielecka O, Landewé R, Avouac J, et al. EULAR recommendations for the treatment of systemic
sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis
2009;68:620-628.
3. Kowal-Bielecka O, Kowal K, Highland KB, Silver RM. Bronchoalveolar Lavage Fluid in Scleroderma Interstitial
Lung Disease: Technical Aspects and Clinical Correlations: Review of the Literature. Semin Arthritis Rheum.
2010;40:73-88
4. Kowal-Bielecka O, Avouac J, Pittrow D, et al; for EPOSS group. Echocardiography as an outcome measure
in scleroderma-related pulmonary arterial hypertension: a systematic literature analysis by the EPOSS
group. J Rheumatol. 2010;37:105-115.
5. Khanna D, Kowal-Bielecka O, Khanna PP, et al. Quality indicator set for systemic sclerosis. Clin Exp
Rheumatol 2011;29 (Suppl 65) S33-S39.
Presentation
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11.00-12.00
PH associated with lung disease in SSc Dinesh Khanna, MD, MS
Pulmonary disease is the leading cause of morbidity and mortality in patients with systemic sclerosis (SSc)(1). Lung involvement in SSc can be separated into two distinct entities: pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) although many patient have elements of both. Approximately 70% of patients have evidence of ILD on high-resolution computer tomography (HRCT). Dana Point classification for PH has classified PH due to lung diseases (including ILD) as WHO group 3. In recent analyses from different cohorts, patients with PH-ILD have worse survival compared to PAH in patients with SSc. The pathogenetic basis for PH in the setting of ILD is multifactorial and may include fibrotic destruction of the pulmonary vasculature, remodeling due to chronic hypoxia and/or a distinct and diffuse pulmonary vasculopathy similar to that observed in isolated PAH in SSc (2-5). The presentation will discuss the pathogenesis, diagnosis, prevalence, and outcomes in patients with PH-ILD.
References
1. Steen VD, Medsger TA, Jr. Changes in causes of death in systemic sclerosis. Ann Rheum Dis 2007.
2. Girgis RE, Mathai SC, Wigley FM, Hassoun PM. Survival in systemic sclerosis-related pulmonary arterial
hypertension in the modern treatment era. Am J Respir Crit Care Med 2009; 180(12):1280-1.
3. Le PJ, Launay D, Mathai SC, Hassoun PM, Humbert M. Scleroderma lung disease. Clin Rev Allergy
Immunol 2011; 40(2):104-16.
4. Mathai SC, Hassoun PM. Pulmonary arterial hypertension associated with systemic sclerosis. Expert
Rev Respir Med 2011; 5(2):267-79.
5. Le PJ, Girgis RE, Lechtzin N, Mathai SC, Launay D, Hummers LK et al. Systemic sclerosis related
pulmonary hypertension associated with interstitial lung disease: Impact of pulmonary arterial
hypertension therapies. Arthritis Rheum 2011.
CME Objective: the participants will be able to
1. Understand the pathogenesis of PH-ILD in SSc.2. Current diagnostic and treatment modalities.
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12.00-12.30
Pathogenesis of pulmonary arterial hypertensionassociated with systemic sclerosis (SSc-PAH)
Oliver Distler
Pulmonary arterial hypertension (PAH) is characterized by occlusion of the pulmonary arteries, resulting in a progressive increase in pulmonary vascular resistance and, ultimately, in cardiac failure. It is a serious complication of scleroderma (SSc), with the prevalence of SSc-PAH estimated to be approximately 8-12%.1 In common with idiopathic PAH (IPAH), histopathological features of SSc-PAH include intimal and medial hyperplasia of the pulmonary arteriole and endothelial dysfunction. As such, therapeutic approaches for SSc-PAH centre around those used in the treatment of IPAH.2 Endothelial dysfunction is understood to play a major role in the pathogenesis of PAH, with resultant functional effects including increased production of endothelin, reduced nitric oxide synthase production and reduced prostacyclin release. Therapeutic agents targeting these three pathways currently represent the mainstay of PAH therapy.SSc-PAH is associated with higher morbidity and mortality and poorer response to therapy compared with IPAH.3,4 One possible explanation for this phenomenon is the existence of additional pathophysiologies as compared to IPAH. Although currently available data are limited by their methodological approaches, there is increasing evidence that the co-existence of pulmonary veno-occlusive disease, inflammatory infiltrates 5,6 and pulmonary fibrotic lesions might contribute to the worse prognosis of SSc-PAH. Based on these data there is an ongoing debate as to whether therapies targeting these pathological features would be more effective in these patients. This review talk will summarize the advances in our understanding of the pathogenesis of SSc –PAH and introduce a number of potential novel therapeutic targets, for example, mediators that act on inflammatory and profibrotic pathways. This includes Tyrosine kinase inhibitors (TKIs), such as imatinib, dasatinib and nilotinib, which target two major profibrotic pathways, transforming growth factor- and platelet-derived growth factor signalling, and have demonstrated anti-fibrotic effects in pre-clinical investigations.7 Serotonin-Inhibitors are other promising candidates for targeting both vascular and fibrotic features of the disease 8. Novel specific animal models resembling features of SSc-PAH such as Fra-2 transgenic mice will further help to identify key pathways in the pathogenesis of SSc-PAH9. These models can also serve for preclinical proof-of concept studies targeting specific molecular and cellular pathways in SSc-PAH.The efficacy of putative therapeutic agents needs to be verified by large, controlled clinical trials. Until such data become available, it remains unclear whether potential new strategies will serve to confer therapeutic advantages to patients with SSc-PAH.
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References 1. Mukerjee D, et al. Ann Rheum Dis 2003;62:1088–93.2. Coghlan J, Handler C. Lupus 2006;15:138–42.3. Fisher MR, et al. Arthritis Rheum 2006;54:3043–50.4. Kawut SM, et al. Chest 2003;123:344–50.5. Overbeek MJ, et al. Eur Respir J 2009;34:371–9.6. Dorfmuller P, et al. Hum Pathol 2007;38:893–902..7. Iwamoto N, et al. Curr Rheumatol Rep 2011, 13:21-7.8. Dees C, et al. J Exp Med 2011 Apr 25. [Epub ahead of print]9. Maurer B, et al. Circulation 2009; 120:2367-2376.
CME Objective: the participants will be able to1. To understand the similarities and differences in the pathophysiology of SSc-PAH and IPAH2. To evaluate the usefulness and limitations of animal models of SSc-PAH3. To appreciate the technical challenges in studying the pathophysiology of SSc-PAH4. To understand the process of identifying novel targets for therapy
Biographic Sketch 1996-2004: Clinical Education and Fellowship Training in Molecular Biology at the Department of Internal Medicine II, Bamberg, Germany (Prof. Dr. H.J. Weiss); at the Department of Internal Medicine I, University of Regensburg, Germany (Prof. Dr. H. Schölmerich); at the Center of Experimental Rheumatology, University Hospital Zurich, Switzerland (Prof. Dr. S. Gay); at the Department of Rheumatology University Hospital Zurich, Switzerland (Prof. Dr. B.A. Michel), and at the Department of Clinical Immunology, University Hospital Zurich, Switzerland; (Prof. Dr. A. Fontana); 2004: Specialization in Internal Medicine; 2005: Habilitation (Venia legendi) for Rheumatology; 2006: Specialization in Rheumatology, Attending Physician (Oberarzt) and Senior Research Group leader at the Department of Rheumatology and Center of Experimental Rheumatology, University Hospital Zurich; Head outpatient clinic for connective tissue diseases and vasculitis; 2009: Leitender Arzt, University Hospital Zurich
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14.00-15.00
PFTs & 6MWT recorded Sergio Harari
A growing body of literature suggests that pulmonary function tests and exercise testing provide diagnostic and prognostic value in interstitial lung diseases in general and in scleroderma lung disease too. Sequential measurements of pulmonary function in patients with scleroderma have shown a remarkable variability in the pulmonary function decline, ranging from an indolent disease with a fairly constant pulmonary function to a rapidly deteriorating condition with loss in both forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO). The ability of initial pulmonary function to predict subsequent pulmonary function loss has received particular attention with variable and conflicting results. The 6-minute walking test (6MWT) is perhaps the most popular of the available exercise tests. The test requires an unobstructed walking path but no exercise equipment and little advanced training to administer. The test evaluates the integrated global response of the pulmonary, cardiovascular and neuromuscular systems but does not provide specific information regarding which system contributes to exercise limitation, which the cardiopulmonary exercise test (CPET) does provide. The 6MWT reflects functional exercise capacity for activities of daily living. Exercise-induced hypoxia can be seen in early interstitial involvement in scleroderma patients even in the absence of pulmonary function abnormalities. Changes in 6MWT has been widely used to assess therapeutic efficacy in pulmonary arterial hypertension clinical trials.
References
1. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement:
guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166: 111–117.
2. Lama VN, Flaherty KR, Toews GB, et al. Prognostic value of desaturation during a 6-minute walk test
in idiopathic interstitial pneumonia. Am J Respir Crit Care Med 2003; 168: 1084–1090.
3. Miyamoto S, Nagaya N, Satoh T, et al. Clinical correlates and prognostic significance of sixminute walk
test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise
testing. Am J Respir Crit Care Med 2000; 161: 487–492.
4. Garin MC, Highland KB, Silver RM, et al. Limitations to the 6-minute walk test in interstitial lung
disease and pulmonary hypertension in scleroderma. J Rheumatol 2009; 36: 330–336.
5. Miyamoto S, Nagaya N, Satoh T, et al. Clinical correlates and prognostic significance of six minute walk
test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise
testing. Am J Respir Crit Care Med 2000; 161: 487–492.
6. Buch MH, Denton CP, Furst DE, et al. Submaximal exercise testing in the assessment of interstitial lung
disease secondary to systemic sclerosis: reproducibility and correlations of the 6-min walk test. Ann
Rheum Dis 2007; 66: 169–173.
7. Villalba WO, Sampaio-Barros PD, Pereira MC, et al. Six-minute walk test for the evaluation of pulmonary
disease severity in scleroderma patients. Chest 2007; 131: 217–222.
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CME Objective: the participants will be able to
1. Provide specific information on diagnostic and prognostic indications of PFT and 6MWT in PAH and ILD in SSC
2. Provide practical indication on PFT and 6MWT; how perform test and interpretation.
Presentation
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15.00-16.00
Doppler echocardiography: fundamental parameters, parameters useful for the diagnosis and prognosis of PAH, pitfalls.
Carmine Dario Vizza & Luna Gargani
Pulmonary arterial hypertension (PAH) is a common cause of morbidity and mortality in systemic sclerosis (SSc). Doppler echocardiography is the non-invasive method of choice to evaluate pulmonary artery systolic pressure (PASP) and should always be performed in the case of suspected PAH. Moreover, echocardiography may provide several variables assessing right and left ventricular systolic and diastolic function, valvular abnormalities and pericardial effusion; a thorough non-invasive hemodynamic evaluation, beyond PASP estimation, including pulmonary vascular resistances and pulmonary capillary wedge pressure, is also possible.
Principal echocardiographic parameters The estimation of PASP is based on the peak velocity of the jet of tricuspid regurgitation. The simplified Bernoulli equation describes the relationship of tricuspid regurgitation peak velocity and the peak pressure gradient of tricuspid regurgitation as 4 x (tricuspid regurgitation peak velocity)2. This equation allows for estimation of right ventricular (RV) pressure, whereas right atrial (RA) pressure is also needed to obtain PASP. RA pressure can be estimated by the diameter and respiratory variation of the inferior vena cava (IVC diameter ≤21 mm that collapses >50% with a sniff suggests normal RA pressure of about 3 mmHg (range 0-5 mm Hg); IVC diameter >21 mm that collapses < 50% with a sniff suggests high RA pressure of 15 mm Hg (range 10-20 mmHg); if IVC diameter and collapse do not fit this paradigm, an intermediate value of 8 mmHg (range 5-10 mmHg) may be used or, preferably, other indices of RA pressure should be integrated to downgrade or upgrade to the normal or high values of RA pressure).Pulmonary vascular resistances (PVR) may be calculated by the following formula: tricuspid regurgitation peak velocity/RV outflow tract time-velocity integral x 10 + .16, although the usefulness of this indirect, non-invasive estimation has not been clearly provided, yet. RV outflow tract time-velocity integral can be assessed by placing the pulsed Doppler sample volume at the RV outflow tract level, recording the systolic Doppler waveform in a parasternal short axis view. Mean pulmonary artery (PA) pressure can be estimated by the Mahan formula, as 79 - (0.45 x acceleration time). Acceleration time (AT) of RV ejection into PA is measured in parasternal short axis view from the same waveform of RV outflow tract time-velocity integral, as the time interval between the waveform leaving the baseline and reaching its peak velocity.
Stroke volume (SV), cardiac output (CO) and cardiac index (CI) determinations can be evaluated by the left ventricle outflow track (LVOT) Doppler method (SV = 0.785 x LVOT diameter squared x time-velocity integral of LVOT flow; CO = SV x heart rate; CI = CO/body surface area). Pulmonary capillary wedge pressure (PCWP) can be derived by the following formula: PCWP = (1.24 x [E/E’]) + 1.9. E/E’ is the ratio of peak early diastolic mitral E velocity to tissue Doppler imaging-derived peak early diastolic E’ velocity at mitral annulus level. These calculations can be easily performed with the
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ACThelp of a web downloadable software for training in cardiovascular hemodynamics. The informatics
infrastructure is available on the web, linking to http://cctrainer.ifc.cnr.it.
Other echocardiographic variables that might raise or reinforce suspicion of PAH independently of tricuspid regurgitation velocity include a short AT, increased dimensions of right heart chambers, abnormal shape and function of the interventricular septum, increased RV wall thickness and dilated main PA, although they tend to occur later in the course of the disease. Earlier signs of RV and LV impairment may be assessed by more recent techniques, such as Tissue Doppler Imaging, strain rate analysis and 3-D evaluation. These techniques are very promising, since they may detect very early cardiac abnormalities, which are often subclinical. However, their role in the management of SSc patients is still debated.
Echocardiography as a clinical tool The main clinical applications of echocardiography in PAH associated to SSc include the screening of patients, the identification of other possible causes of pulmonary hypertension, and the prognostic stratification.
Screening: On the basis of the significant prevalence of PAH in SSc in 2004 the guidelines of the European Society of cardiology strongly recommended the use of Doppler echocardiography for the screening of this population. Because of the high rate of false positive results (cut-off value of tricuspid regurgitation velocity: 2.5 m/sec in symptomatic patients and 2.8 m/sec in asymptomatic patients), the recent guidelines suggest the use of other parameters (a short acceleration time of pulmonary artery flow, increased dimension of right heart chambers) in order to reinforce the suspicion of pulmonary hypertension.
Identification of possible cause of PH: In SSc patients a subtle cause of PH is left ventricular diastolic dysfunction. Doppler-echocardiography allows the assessment of left ventricular diastolic function by the evaluation of mitral valve and pulmonary vein flow (or TDI analysis of mitral valve annulus). As already stated, TDI could give an estimation of PCWP, if this is elevated PH is likely to be secondary to venous hypertension, and specific drugs for PAH should not be used for the risk of pulmonary edema.
Prognostic stratification: Some echocardiographic parameters have demonstrated to have prognostic impact in idiopathic PAH and it is likely that they have a similar importance in PAH associated to SSc. These parameters include:- a decrease in tricuspid annular plane systolic escursion (TAPSE), - the shift of interventricular septum towards left ventricle, evaluated as the left ventricular
eccentricity index (i.e. the relationship of the transversal and longitudinal diameters of left ventricle in parasternal short axis view),
- the right atrial enlargement, evaluated as the right atrium area in a four chamber view,- the presence of pericardial effusion.The TAPSE is related to right ventricular ejection fraction (a parameter of systolic function), while the others are related to the increased right ventricular overload and telediastolic pressure.
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ConclusionDoppler echocardiography is a useful diagnostic tool for the screening, differential diagnosis and prognostic stratification of PAH patients, but only a comprehensive diagnostic work-up including pulmonary function test, high resolution CT scan, ventilation-perfusion scintigraphy, biomarkers, and invasive hemodynamic assessment allows a precise diagnosis and risk stratification of these patients.
References1. Sohn D-W, Chai I-H, Lee D-J, Kim H-C, Kim H-S, Oh B-H, Lee M-M, Park Y-B, Choi Y-S, Seo J-D, Lee
Y-W. Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol. 1997;30:474–480.
2. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, Waggoner AD, Flachskampf FA, Pellikka PA, Evangelisa A. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Eur J Echocardiogr. 2009;10:165-93.
3. Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, Solomon SD, Louie EK, Schiller NB. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr. 2010;23:685-713.
4. Naeije R, Vizza D. Current perspectives modern hemodynamic evaluation of the pulmonary circulation. Application to pulmonary arterial hypertension and embolic pulmonary hypertension. Ital Heart J. 2005;6:784-8.
5. Abbas AE, Fortuin FD, Schiller NB, Appleton CP, Moreno CA, Lester SJ. A simple method for noninvasive estimation of pulmonary vascular resistance. J Am Coll Cardiol. 2003;41:1021-7.
6. Nagueh SF, Middleton KJ, Kopelen HA, Zoghbi WA, Quiñones MA. Doppler tissue imaging: a noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol. 1997;30:1527-33.
7. Serra W, Chetta A, Santilli D, Mozzani F, Dall’Aglio PP, Olivieri D, Cattabiani MA, Ardissino D, Gherli T. Echocardiography may help detect pulmonary vasculopathy in the early stages of pulmonary artery hypertension associated with systemic sclerosis. Cardiovasc Ultrasound. 2010 ;8:25.
8. Bossone E, Rubenfire M, Bach DS, Ricciardi M, Armstrong WF. Range of tricuspid regurgitation velocity at rest and during exercise in normal adult men: implications for the diagnosis of pulmonary hypertension. J Am Coll Cardiol. 1999;33:1662-6.
9. Roule V, Labombarda F, Pellissier A, Sabatier R, Lognoné T, Gomes S, Bergot E, Milliez P, Grollier G, Saloux E. Echocardiographic assessment of pulmonary vascular resistance in pulmonary arterial hypertension. Cardiovasc Ultrasound. 2010;8:21.
10. Dahiya A, Vollbon W, Jellis C, Prior D, Wahi S, Marwick T. Echocardiographic assessment of raised pulmonary vascular resistance: application to diagnosis and follow-up of pulmonary hypertension. Heart. 2010;96:2005-9.
11. Bombardini T, Cini D, Arpesella G, Picano E. WEB downloadable software for training in cardiovascular hemodynamics in the (3-D) stress echo lab. Cardiovasc Ultrasound. 2010;8:48.
12. Mahan G, Dabestani A, Gardin J, Allfie A, Burn C, Henry W. Estimation of pulmonary artery pressure by pulsed Doppler echocardiography. Circulation 1983;68:367.
13. Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC); European Respiratory Society (ERS); International Society of Heart and Lung Transplantation (ISHLT), Galie’ N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA,
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Peacock A, Rubin L, Zellweger M, Simonneau G. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2009;34:1219-63.
CME Objective: the participants will be able to 1. Define the fundamental echocardiographic parameters useful for the diagnosis and prognosis of
PAH. 2. Interpret these parameters and their potential pitfalls within the patient’s clinical picture.3. Distinguish the different impact of these parameters on the prognosis of PAH patients
Biographic Sketch
Carmine Dario Vizza, MD, is Associate Professor of Cardiology in the Department of Cardiovascular
and Respiratory Disease, and Director of the Pulmonary Hypertension Clinic at the University of Rome
La Sapienza. Professor Vizza has published widely in the field of pulmonary vascular physiology,
pulmonary transplantation and pulmonary hypertension. He participated as principal investigator to
several international multicenter randomized study on pulmonary hypertension including ALPHABET,
PHAST, EARLY, PHIRST, COMPASS-1.
He is currently the chairman of the working group on Pulmonary Circulation in the Italian Society of
Cardiology.
References 1. Galie N, Humbert M, Vachiery JL, Vizza CD, Kneussl M, Manes A, Sitbon O, Torbicki A, Delcroix M, Naeije R,
Hoeper M, Chaouat A, Morand S, Besse B, Simonneau G. Effects of beraprost sodium, an oral prostacyclin
analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled
trial. J Am Coll Cardiol. 2002 May 1;39:1496-502
2. Vizza CD, Letizia C, Sciomer S, Naeije R, Della Rocca G, Di Roma A, Musaro,S, Quattrucci S, Gaudio C, Battagliese
A, Badagliacca R, D’Erasmo E, Fedele F. Increased plasma levels of adrenomedullin, a vasoactive peptide,
in patients with end-stage pulmonary disease. Regul Pept. 2005 Jan 15;124:187-93.
3. Vizza CD, Letizia C, Badagliacca R, Sciomer S, Poscia R, Della Rocca G, Iacoboni C, Leonardo de L, Quattrucci
S, Dario C, Luigi P, Fedele F. Plasma adrenomedullin and endothelin-1 concentration during low-dose
dobutamine infusion: Relationship between pulmonary uptake and pulmonary vascular pressure/flow
characteristics. Regul Pept. 2006;136:85-91.
4. D’Alto M, Vizza CD, Romeo E, Badagliacca R, Santoro G, Poscia R, Sarubbi B, Mancone M, Argiento P, Ferrante
F, Russo MG, Fedele F, Calabro R. Long term effects of bosentan treatment in adult patients with pulmonary
arterial hypertension related to congenital heart disease (Eisenmenger physiology): safety, tolerability,
clinical, and haemodynamic effect. Heart. 2007;93: 621-5.
5. Vizza CD, Letizia C, Petramala 5.Badagliacca R, Poscia R, Zepponi E, Crescenzi E, Nona A, Benedetti G, Ferrante
F, Sciomer S, Fedele F. Venous endotelin-1 (ET-1) and brain natriuretic peptide (BNP) plasma levels during
6-month bosentan treatment for pulmonary arterial hypertension. Regul Pept. 2008;158:48-53.
6. Gruenig E, Michelakis E, Vachiéry JL, Vizza CD, Meyer FJ, Doelberg M, Bach D, Dingemanse J, Galiè N. Acute
hemodynamic effects of single-dose sildenafil when added to established bosentan therapy in patients
with pulmonary arterial hypertension: results of the COMPASS-1 study. J Clin Pharmacol. 2009;49:1343-52.
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Biographic Sketch
Luna Gargani, MD is a fellow in Cardiology at the G. Monasterio Foundation - Institute of Clinical Physiology,
National Research Council of Pisa. She is accreditated by the European Association of Echocardiography
for transthoracic echocardiography. She is a Member of both the Scientific Initiatives Committee and
the Education and Accreditation Committee of the European Association of Echocardiography.Her main
fields of interest are lung ultrasound and the non-invasive hemodynamic evaluation of pulmonary
circulation. She is member of the Expert Panel of the International Consensus Conference on Pleural and
Lung Ultrasound, and has published some of the landmark papers on this new application of ultrasound.
She is one of the coordinators of the project SECURE on the non-invasive cardiopulmonary evaluation of
patients with systemic sclerosis.
References 1. Caiulo VA, Gargani L, Caiulo S, Fisicaro A, Moramarco F, Latini G, Picano E. Lung ultrasound in bronchiolitis:
comparison with chest X-ray. Eur J Pediatr. 2011 Apr 6. [Epub ahead of print]
2 Gargani L. Lung ultrasound: a new tool for the cardiologist. ardiovasc Ultrasound. 2011 Feb 27;9:6.
3 Bedetti G, Gargani L, Sicari R, Gianfaldoni ML, Molinaro S, Picano E. Comparison of prognostic value of
echographic risk score with the Thrombolysis in Myocardial nfarction (TIMI) and Global Registry in Acute
Coronary Events (GRACE) risk scores in acute coronary syndrome. Am J Cardiol. 2010 Dec 15;106(12):1709-
16.
4 Delle Sedie A, Doveri M, Frassi F, Gargani L, D’Errico G, Pepe P, Bazzichi L, Riente L, Caramella D, Bombardieri
S. Ultrasound lung comets in systemic sclerosis: a useful tool to detect lung interstitial fibrosis. Clin Exp
Rheumatol. 2010 Sep-Oct;28 (5 Suppl 62):S54.
5 ambrik Z, Gargani L, Adamicza A, Kaszaki J, Varga A, Forster T, Boros M, Picano E. B-lines quantify the lung
water content: a lung ltrasound versus lung gravimetry study in acute lung injury. Ultrasound Med Biol.
2010 Dec;36(12):2004-10.
6 Gargani L, Doveri M, D’Errico L, Frassi F, Bazzichi ML, Delle Sedie A, Scali MC, Monti S, Mondillo S, Bombardieri
S, Caramella D, Picano E. Ultrasound lung comets in systemic sclerosis: a chest sonography hallmark of
pulmonary interstitial fibrosis. Rheumatology (Oxford). 2009 Nov;48(11):1382-7.
7 Picano E, Gargani L, Gheorghiade M. Why, when, and how to assess pulmonary congestion in heart failure:
pathophysiological, clinical, and methodological implications. Heart Fail Rev. 2010 Jan;15(1):63-72.
8 Soldati G, Gargani L, Silva FR. Acute heart failure: new diagnostic perspectives for the emergency physician.
Intern Emerg Med. 2008 Mar;3(1):37-41. Epub 2008 Feb 9.
9 Gargani L, Frassi F, Soldati G, Tesorio P, Gheorghiade M, Picano E.
10. Ultrasound lung comets for the differential diagnosis of acute cardiogenic dyspnoea: a comparison with
natriuretic peptides. Eur J Heart Fail. 2008 Jan;10(1):70-10: Frassi F, Gargani L, Tesorio P, Raciti M, Mottola
G, Picano E. Prognostic value of extravascular lung water assessed with ultrasound lung comets by chest
sonography in patients with dyspnea and/or chest pain. J Card Fail. 2007 Dec;13(10):830-5
11. Gargani L, Lionetti V, Di Cristofano C, Bevilacqua G, Recchia FA, Picano E. Early detection of acute lung injury
uncoupled to hypoxemia in pigs using ultrasound lung comets. Crit Care Med. 2007 Dec;35(12):2769-74.
12. Soldati G, Copetti R, Gargani L. [Lung sonography for the cardiologist]. G Ital Cardiol (Rome). 2007 Mar;8
(3):139-47.
13. Frassi F, Gargani L, Gligorova S, Ciampi Q, Mottola G,
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The early diagnosis of PAH in SSHorst Olschewski
Pulmonary arterial hypertension (PAH) is a devastating disease of the small pulmonary arteries and leads to impaired right ventricular function, decreased exercise capacity and eventually death. Current guidelines define PAH as a mean pulmonary arterial pressure (MPAP) > 25 mmHg at rest or > 30 mmHg during exercise 1. According to measurements in healthy individuals, normal resting MPAP is 14.0±3.3 mmHg 2. The clinical relevance of MPAP values in the upper normal range is unknown. Previous studies on chronic obstructive pulmonary disease and lung fibrosis suggested that resting MPAP > 17 mmHg may be associated with adverse events and reduced survival 3-5. Idiopathic PAH is very rarely diagnosed with MPAP values below 35 mmHg, because symptoms are unspecific and diagnostic tools like echocardiography are expensive and not available to the general population. In contrast, scleroderma patients are often in close contact with physicians and health personal and have a much better access to diagnostic tools. This is the main reason why not only echocardiography but also right heart catheter investigations have been performed in scleroderma patients with MPAP levels below 25 mmHg. This level may be elevated as compared to normal controls but does not meet the criteria of PAH and has been called “borderline pulmonary hypertension”, although the prognostic and therapeutic consequence have not been established. We and others have shown that borderline pulmonary pressures are associated with diminished exercise tolerance 6, 7. In an English long-term observation, scleroderma patients with borderline pulmonary pressures often progressed within 2-3 years into manifest PAH despite targeted therapy and had an impaired prognosis 8. In a small case series we found that targeted PAH treatment in scleroderma with borderline pulmonary pressures reversed the trend for increasing pulmonary pressures at rest and exercise (published as abstract, ERS 2010), suggesting that very early therapy in scleroderma patients should be addressed in controlled randomized prospective studies.
CME Objective: the participants will be able to 1. understand the association between pulmonary pressure and pulmonary vascular resistance 2. understand pulmonary hemodynamics during exercise 3. understand the clinical problem of early PAH in scleroderma
Biographic Sketch Horst K. Olschewski, MD, PhD, is Professor of Pulmonology at the Medical University of Graz, Austria and Director of the Div. of Pulmonology with Respiratory Care Unit, Sleep Laboratory and Infectious Diseases Service at the LKH University Hospital. He is specialized in Pulmonology, Internal Medicine, Infectiology and Intensive Care Medicine. Following his medical training, he continued his studies on the interaction of temperature regulation and circulation at the Physiological Institute of the Medical Faculty, Justus-Liebig-University Giessen, Germany. He then became resident in Internal Medicine before specialising in Pulmonology and Intensive Care Medicine. He has been lead author
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of German guidelines for pulmonary hypertension and an active participant in Task Forces on Pulmonary Hypertension of the European Society of Cardiology and European Respiratory Society and the German Consensus Conference. He is President of the Austrian Society of Pneumology and principle investigator in multiple international studies on PAH. References 1. Galie N, Hoeper MM, Humbert M et al. 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(20):2493-2537.
2. Kovacs G, Berghold A, Scheidl S, Olschewski H. Pulmonary arterial pressure during rest and exercise in healthy subjects: a systematic review. Eur Respir J 2009; 34(4):888-894.
3. Hamada K, Nagai S, Tanaka S et al. Significance of pulmonary arterial pressure and diffusion capacity of the lung as prognosticator in patients with idiopathic pulmonary fibrosis. Chest 2007; 131(3):650-656.
4. Kessler R, Faller M, Fourgaut G, Mennecier B, Weitzenblum E. Predictive factors of hospitalization for acute exacerbation in a series of 64 patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 159(1):158-164.
5. Weitzenblum E, Hirth C, Ducolone A, Mirhom R, Rasaholinjanahary J, Ehrhart M. Prognostic value of pulmonary artery pressure in chronic obstructive pulmonary disease. Thorax 1981; 36(10):752-758.
6. Kovacs G, Maier R, Aberer E et al. Borderline Pulmonary Arterial Pressure is Associated with Decreased Exercise Capacity in Scleroderma. Am J Respir Crit Care Med 2009.
7. Tolle JJ, Waxman AB, Van Horn TL, Pappagianopoulos PP, Systrom DM. Exercise-induced pulmonary arterial hypertension. Circulation 2008; 118(21):2183-2189.
8. Condliffe R, Kiely DG, Peacock AJ et al. Connective tissue disease-associated pulmonary arterial hypertension in the modern treatment era. Am J Respir Crit Care Med 2009; 179(2):151-157.
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Exercise echo, yes or no?A. Moggi Pignone
Pulmonary hypertension is the main cause of death in SSc and a crucial point is represented by the delay between the first clinical signs/symptoms and the definitive diagnosis; the clinical consequence is the pivotal importance to reach an early diagnosis, possibly in the early phases of the disease, when we can better optimize our therapeutic strategies.In this perspective have to be interpreted the study on exercise induced pulmonary arterial hypertension, in the attempt to identifie a preclinc conditions before the appearance of pulmonary hypertension at rest.In SSc many Authors already demonstrated a significant percentage of patients, without pulmonary hypertension at rest, that developed during physical activity abnormal elevation of pulmonary pressure in contrast with the physiological behaviour of healthy populations, inducing to hypothesize this aspect as an early, mild and clinical relevant phase of PH spectrum.The real significance of exercise-induced PAH is still in discussion and further studies on larger population are warranted to confirm these preliminary data and to verify with an adeguate follow-up if Ex-echo may have a real predictive value for PAH developing at rest.
a) Short Profile and literature about PH.In SSc many Authors already demonstrated a significant percentage of patients, without pulmonary hypertension at rest, that developed during physical activity abnormal elevation of pulmonary pressure in contrast with the physiological behaviour of healthy populations, inducing to hypothesize this aspect as an early, mild and clinical relevant phase of PH spectrum.The real significance of exercise-induced PAH is still in discussion and further studies on larger population are warranted to confirm these preliminary data and to verify with an adeguate follow-up if Ex-echo may have a real predictive value for PAH developing at rest. Prof .Alberto Moggi Pignone, Associate Professor of Internal Medicine, is Director of Internal Medicine Unit 3 in the University of Medicine of Florence since 2002.He has the postgraduate in Rheumatology and in Internal Medicine and his specific interests have been focused since many years on connective tissue diseases and in particular on Systemic Sclerosis (SSc). During the last ten years the problem of Pulmonary Hypertension (PH) in SSc represented the main specific interest of his clinical research with the effort to reach a diagnosis of PH possibly in the early phases of the disease, when a pharmacolgical treatment still has some chance to really interfere with the physiopatological process of SSc and to modify the clinical course ant the prognosis of such patients.In this perspective must be interpretated his studies on exercise induced pulmonary arterial hypertension in patients affected with SSc but still without the presence of PH at rest; indeed, the potential evidence of an early and reversible dysfunction of pulmonary vascular bed could open new interesting frontiers in the treatment of PH.
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Robertson L, Pignone A et al: Pulmonary arterial hypertension in systemic sclerosis: diagnostic pathway and therapeutic approach.Ann Rheum Dis 2005; Jun 64: 804-807.Disler O, Pignone A. Pulmonary arterial hypertension and rheumatic diseases: from diagnosis to treatment.Rheumatology (Oxford) 2006; Oct 45: 22-5.Pignone A, del Rosso A et al: Reduced circulating levels of angiotensin (1-7) in Systemic Sclerosis: a new pathway in the dysregulation of endothelin-dependent vascular tone control.Ann Rheum Dis 2007; Oct 66(10): 1305-1310.Pignone A, Mori F et al: Exercise Doppler echocardiography identifies preclinic asymptomatic pulmonary hypertension in systemic sclerosis.Ann N Y acad Sci 2007; June: 291-304.
b) A summary of presentation:• The prognostic impact of PAH in SSc, also compared with Idiopathic PAH;• The problem of the delay between the first clinical signs/symptoms of PAH and the definitive diagnosis, including either rheumatological than other pathological conditions; the crucial importance of an early diagnosis of PH.• The concept of “vascular reserve” in SSc, involving many organs such as heart, kidneys and
lung.• An introduction on the concept of “exercise induced PAH”, with its definition and significance.• A short history about the “conflictual approach “ to the concept of exercise induced PAH by the European and American Guidelines on PH.• a brief review of the main studies on exercise PAH, either in SSc than in many other non rheumatological pathologies.• A summary about our clinical opinion and experience on exercise induced PAH, about our published data on this topic and about future directions of our clinical research.• Conclusions and thanks
c) References about PH:R Livi, L Teghini, A Pignone et al: Renal function is impaired in patients with systemic sclerosis without clinical signs of kidney involvement.Ann Rheum Dis 2002; 61: 682-686.Bossone E et al: Pulmonary arterial hypertension: the key role of echocardiography.Chest 2005;127: 1836-1843.Marwick TH. Progress in stress echocardiography: application of stress echocardiography to the evaluation of non coronary heart diseases.Eur J Echocardiography 2000; 1: 171-179.Sadaniantz A et al: Miscellaneous use of exercise echocardiography in patients with chronic pulmonary disease or congenital heart defect.Echocardiography 2004; 5: 477-484.Grunig E et al . Stree Doppler Echocardiography in relatives of patients with idiopathic and familial pulmonary arterial hypertension: results of a multicenter European analysis of pulmonary artery pressure response to exercise and hypoxia.Circulation 2009;119: 1747-1757.
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Tolle JJ et al: Exercise induced pulmonary arterial hypertensionCirculation 2008; 118: 2183-2189.Pignone A et al: Exercise Doppler echocardiography identifies asymptomatic pulmonary hypertension in systemic sclerosis.Ann N Y Acad Sci 2007Steen V et al: Exercise induced pulmonary arterial hypertension in patients with Systemic Sclerosis.Chest 2008; 134: 146-151.Kovacs GR et al: Early recognition of pulmonary arterial hypertension in patients with connective tissue diseases using exercise stree-echocardiography, cardiopulmonary exercise test and right heart catheterisation.Eur Resp J 2007; 30: 1803.Kovacs G et al: Borderline pulmonary arterial pressure is associated with decreased exercise capacity in scleroderma.Am J Respir Cri Care Med 2009; 180: 881-886.D’Alto M et al: Inappropriate exercise-induced increase in pulmonary artery pressure in patients with systemic sclerosis.Heart 2011; 97: 112-117.
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Practical WorkshopGerry Coghlan
Dr Gerry Coghlan is an interventional cardiologist and pulmonary hypertension specialist at the Royal Free Hospital in London. The pulmonary hypertension service at the Royal Free is one of eight designated centers in the UK and provides leadership in the field of connective tissue disease associated pulmonary hypertension. With Professor Denton he has pioneered joint rheumatology and pulmonary hypertension care delivery, including one stop screening and diagnosis of scleroderma associated pulmonary hypertension, goal oriented therapy for systemic sclerosis associated PAH and outreach services to deliver expert centre levels of care around the country. With Dr B Schreiber and Professor Abrahams he has developed a translational research program. The unit is heavily involved in multinational studies, and he is the principle investigator for the DETECT study to establish the optimal nature of screening programs in scleroderma associated PH.
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Current view of the treatment of SSc-PAH & Overall strategyChristopher P. Denton
There has been tremendous progress over the past 15 years in management of PAH associated with connective tissue disease (PAH-CTD). A major advance in management was the use of oral agents for SSc and other CTD associated PAH cases in the pivotal clinical trials that led to licensing of treatments. The first oral therapy developed was an endothelin receptor antagonist bosentan. Later other related drugs were tested as well as PDEi inhibitors. As well as being given by the intravenous route prostacyclin was assessed by subcutaneous, inhaled and most recently by the oral route with encouraging results. Thus there are now a substantial number of licensed therapies of PAH associated with SSc and the number is increasing. However in many cases the outcome of PAH appears to be worse in those cases associated with CTD, and especially SSc, than in equivalently severe cases of iPAH. There are a number of potential explanations for this but it does suggests that this group of PAH casers present a particular treatment challenge. There are now licensed therapies for FCII and FCIII and these should be initiated at diagnosis. One of the oral agents is initiated as an initial therapy. Although some recommendations favour an ETRA as initial therapy in CTD there is no strong evidence for superiority and it is entirely reasonable to start either a PDE5i or ETRA . Current evidence suggests that selective or non-selective ETRA may be similarly effective in PAH-CTD based upon recent cohort data from our centre. Finally, if major progression to FC IV occurs then patients will be considered for intravenous prostacylin analogue therapy. Licensed agents include epoprostenol and treprostinil. Recommendations for cases that are diagnosed at FC IV generally include intravenous epoprostenol. This is certainly the optimum current therapy for iPAH but less data are available for SSc associated PAH and some centres advocate combination oral therapy for SSc-PAH that is diagnosed in this functional class.
References:1. Valerio CJ, Handler CE, Kabunga P, Smith CJ, Denton CP, Coghlan JG. Clinical experience with
bosentan and sitaxentan in connective tissue disease-associated pulmonary arterial hypertension. Rheumatology (Oxford). 2010 Nov;49(11):2147-53.
2. Hachulla E, Denton CP. Early intervention in pulmonary arterial hypertension associated with systemic sclerosis: an essential component of disease management. Eur Respir Rev. 2010 Dec 1;19(118):314-20.
3. Mathai SC, Hassoun PM. Therapy for pulmonary arterial hypertension associated with systemic sclerosis. Curr Opin Rheumatol. 2009 Nov;21(6):642-8.
4. Barst RJ, Gibbs JS, Ghofrani HA, Hoeper MM, McLaughlin VV, Rubin LJ, Sitbon O, Tapson VF, Galiè N. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S78-84.
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ACTCME Objective: the participants will be able to
1. Plan treatment strategy for PAH in SSc2. Understand the principles of goal-directed therapy3. Evaluate clinical progression and monitor PAH specific therapy in SSc cases
Biographic sketch Professor Christopher Denton, Royal Free Hospital and UCL Medical School, UKChristopher Denton PhD, FRCP, is Professor of Experimental Rheumatology at UCL Medical School and Consultant Rheumatologist and Joint Director of the Centre for Rheumatology, Royal Free Hospital, London. He studied medicine at Guy’s Hospital, where he qualified with distinction. He trained in internal medicine and rheumatology in London and later undertook a PhD in cell biology at UCL and a Wellcome Trust advanced fellowship in molecular genetics at the M.D. Anderson Cancer Center in Houston, USA. He leads the UK Scleroderma Study Group (UKSSG), is Treasurer of EUSTAR and Chair-elect of the Heberden Committee of the BSR. He manages a large cohort of more than 1000 scleroderma patients and has published extensively on laboratory and clinical aspects of Raynaud’s phenomenon, connective tissue disease and pulmonary hypertension.
References
1. Hachulla E, Denton CP. Early intervention in pulmonary arterial hypertension associated with systemic sclerosis: an essential component of disease management. Eur Respir Rev. 2010 Dec 1;19(118):314-20.
2. Valerio CJ, Handler CE, Kabunga P, Smith CJ, Denton CP, Coghlan JG. Clinical experience with bosentan and sitaxentan in connective tissue disease-associated pulmonary arterial hypertension. Rheumatology (Oxford). 2010 Nov;49(11):2147-53.
3. Coghlan JG, Pope J, Denton CP. Assessment of endpoints in pulmonary arterial hypertension associated with connective tissue disease. Curr Opin Pulm Med. 2010 May;16 Suppl 1:S27-34.
4. Nihtyanova SI, Tang EC, Coghlan JG, Wells AU, Black CM, Denton CP. Improved survival in systemic sclerosis is associated with better ascertainment of internal organ disease: a retrospective cohort study. QJM. 2010 Feb;103(2):109-15.
5. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, Elliott CG, Gaine SP, Gladwin MT, Jing ZC, Krowka MJ, Langleben D, Nakanishi N, Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S43-54.
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Supportive careMarco Confalonieri
Supportive care is a treatment given to prevent, control, or relieve complications and side effects and to improve the patient’s comfort and quality of life. Supportive medicine is often misunderstood, but may play a key role in caring for PAH patients. Palliative care may be a part of supportive care, considered as an active, total care of patients whose diseases are not fully responsive to curative treatment, with regard to symptom control as top concern. The goal of both supportive care and palliative care is to achieve the best quality of life for patients and families. Supportive care for patients with pulmonary hypertension includes: oral anticoagulants, diuretics, digoxin, continuous long-term O2 therapy, pulmonary rehabilitation. Patients with PAH have also increased susceptibility to pulmonary infections, which are poorly tolerated. Such infections, therefore, need to be recognized and treated promptly. Furthermore, pregnancy is contraindicated as it is associated with an increased rate of deterioration of health and death in these patients. Specific treatment for pulmonary hypertension without supoortive care is not possible today. Furthermore, evalutaion of the effectiveness of supportive care is mandatory such as for curative care drugs. To evaluate response to the care of patients with systemic sclerosis and pulmonary hypertension there have been steady efforts to develop a combined response index by an Expert Panel on Outcome Measures in PAH related to Systemic Sclerosis (EPOSS) specifically dedicated to measure effect in treatment of pulmonary arterial hypertension of systemic sclerosis (PAH-SSc). EPOSS conducted a Delphi process and judged quality of life/activities of daily living as major domain to evaluate response to treatment either supportive and curative. Finally, complex workup of patients with pulmonary hypertension is usually coordinated at Referral Pulmonary Hypertension Centers, but current workup is necessarily multisciplinary for patients with pulmonary hypertension of any origin.
References1. Galiè N, et al. Guidelines for the diagnosis and treatment of puylmonary hypertension. European
Heart Journal (2009) 30, 2493–25372. Khanna D, et al. Measures of response in clinical trials of systemic sclerosis: the Combined
Response Index for Systemic Sclerosis (CRISS) and Outcome Measures in Pulmonary Arterial Hypertension related to Systemic Sclerosis (EPOSS). J Rheumatol 2009 ;36:2356-61.
CME Objective: the participants will be able to 1. Understand the goal of supportive care for patients with pulmonary hypertension2. To check concerning symptoms and the need for supportive care3. To assess results of supportive care for patients with systemic sclerosis and pulmonary
hypertension
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Prof. M. Confalonieri is the Director of the Pneumology Unit at the University Hospital of Cattinara, Trieste, Italy. The Pneumology Unit of Trieste is a referral Center for pulmonary hypertension and a referral Center for diffuse parenchymal lung disease too.Prof. Confalonieri teaches at the Trieste’s School of Medicine. He’s Authors of more than 200 papers on the principal scientific journals (The Lçancet, JAMA, Annals of Internal Medicine, American Journal of respiratory and Critical Care Medicine, Thorax, Chest, European Respiratory Journal, etc.). He’s a member of the American Thoracic Society, the European Respiratory Society, the American College of Chest Physician, and the Italian Association of Hospital Pneumologists (AIPO).
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Coagulation, yes or no?Rosanna Abbate
In pulmonary arterial hypertension (PAH), thrombosis and thromboembolism occurs as a consequence of pulmonary microvasculopathy with a change of pulmonary vascular microenviroment toward a procoagulant, prothrombotic and antifibrinolytic pattern (Grünig E, Hamostaseologie 2008). In particular a role of thrombin in autoimmune-mediated tissue injury and fibrosis in SSc-interstitial lung disease related to PAH has been demonstrated (Ludwicka-Bradley A., Semin Arthritis Rheum 2010), and an association between ACL and PAH and endothelial injury has been provided (Assous N., Clinical and Experimental Rheumatology 2005).There is clear rationale for a treatment with anticoagulation. Several agents are commonly used in the treatment of PAH despite relatively little controlled trial data. In uncontrolled studies anticoagulation therapy improved the prognosis of patients with idiopathic and other forms of PAH (Johnson S.R., Eur Respir J 2006). Warfarin use in scleroderma (SSc)-associated pulmonary arterial hypertension (PAH) and idiopathic PAH (IPAH) remains controversial.Data from observational studies suggest that anticoagulation therapy may be an effective intervention in pulmonary arterial hypertension. However, given the methodological limitations and the small number of existing observational studies, a randomised controlled trial is needed in order to definitively address this important clinical issue (Johnson S.R., Eur Respir J 2006).
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Lung Transplantation in PAHPatrizio Vitulo
Lung transplantation (LTx) remains an important cure for patients with endstage PAH. However, fewer patients are progressing to LTx since the medical management of PAH continues to improve. The criteria for LTx referral and active listing for an IPAH patient continue to evolve given the available combination therapy , so these patients require particular attentionand close follow-up. Early post-LTx outcomes for IPAH remain poorer than those for other patient populations.For many patients with systemic connective tissue diseases, the presence of significant extrapulmonary comorbidities limits the availability of this therapeutic option and increases the risk for complications when transplantation is performed.
ReferencesOrens JB, Estenne M, Arcasoy S, et al. International guidelines for the selection of lung transplant candidates: 2006 update--a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2006;25:745-55Shitrit D, Amital A, Peled N, et al. Lung transplantationin patients with scleroderma: case series, review of the literature, and criteria for transplantation.Clin Transplant 2009;23(2):178–83.Lee JC, Ahya VN. Lung transplantation in autoimmune diseases. Clin Chest Med. 2010 Sep;31(3):589-603.Blondeau K, Mertens V, Vanaudenaerde BA, et al.Gastro-oesophageal reflux and gastric aspiration in lung transplant patients with or without chronic rejection. Eur Respir J 2008; 31(4):707–13.
CME Objective: the participants will be able to 1. know the current selection criteria for lung transplant in patients with PH2. know the contraindications for lung transplantation in patients with PH3. know the results of lung transplantation for patients with PH
Biographic Sketche-mail [email protected] AND TRAINING1987: University of Pavia (110/110 cum laude) MD Degree1992: Specialty in Respiratory Diseases, University of Pavia (50/50)APPOINTMENTS AND POSITIONS2005-2011 Senior Attending, Chief of Pulmonology, Medical Director of IsMeTT Lung Transplant ProgrammDirector of IsMeTT Pulmonary Hypertension ProgramIsMeTT (Istituto Mediterraneo dei Trapianti e Terapie ad Alte Specializzazione)Via Tricomi 1, 90127 Palermo, Italy2003-04
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Chief of Lung Transplant Follow-up Unit, Respiratory Disease Inst., Lung Transplant Program, IRCCS “Policlinico S. Matteo”, University of Pavia, Pavia, I1993-2004 Consultant Pulmonologist, Div. of Pulmonology , “IRCCS Policlinico S. Matteo”, University of Pavia , I1994-2004 Senior Consultant Pulmonologist of the Lung Transplant Program IRCCS “Policlinico S. Matteo”, Pavia, I 2001-2004: Professor, Specialty School of Respiratory Diseases, University of Pavia, I2009-2010 Professor , Specialty School of Pediatrician, University of Messina, ISKILLSExperienced in the selection of lung transplant candidates affected by: COPD, lung fibrosis, cystic fibrosis, pulmonary hypertension.Experienced in the management of lung transplant follow-up .Experienced in operative rigid broncoscopy (dilatation, laser treatment, stent application)Experienced in diagnosis and treatment of pulmonary arterial hypertension
References Marrone G, Mamone G, Luca A, Vitulo P et al. The role of 1.5T cardiac MRI in the diagnosis, prognosis and management of pulmonary arterial hypertension. Int J Cardiovasc Imaging. 2010 Aug;26(6):665-81. Bertani A, Grossi P, Vitulo P et al. Successful lung transplantation in an HIV- and HBV-positive patient with cystic fibrosis. Am J Transplant. 2009 Sep;9(9):2190-6. Meloni F, Salvini R, Bardoni AM, Passadore I, Solari N, Vitulo P et al. Bronchoalveolar lavage fluid proteome in bronchiolitis obliterans syndrome: possible role for surfactant protein A in disease onset. J Heart Lung Transplant. 2007 Nov;26(11):1135-43.Snell GI, Valentine VG, Vitulo P et al. Everolimus versus azathioprine in maintenance lung transplant recipients: an international, randomized, double-blind clinical trial. Am J Transplant. 2006 Jan;6(1):169-77.PubMed PMID: 16433771.Gerna G, Vitulo P et al. Impact of human metapneumovirus and humancytomegalovirus versus other respiratory viruses on the lower respiratory tractinfections of lung transplant recipients. J Med Virol. 2006 Mar;78(3):408-16.Erratum in: J Med Virol. 2008 Oct;80(10):1869.
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Prostanoids in PAHFredrick M. Wigley
The endothelium is a metabolically active tissue that, under normal circumstances, regulates regional blood flow, transportation of nutrients, regulating coagulation and fibrinolysis, and migration of blood cells while maintaining an antithrombotic lining in the vasculature. These important biologic functions are achieved through production of a complex array of molecules including vasodilators (e.g., nitric oxide and prostacyclin), vasoconstrictors (e.g., endothelin-1 and platelet-activating factor), and cell adhesion molecules (e.g., selectins and integrins). One theory of pathogenesis suggests that early in scleroderma, the homeostatic function of endothelium is disrupted by endothelial cell activation and/or injury. The exact cause of endothelial cell injury is unknown, but it may involve infectious, immunologic, ischemia-reperfusion, and apoptotic pathways. As a consequence of injury the evidence suggest that there is a deficiency in prostacyclin production in scleroderma.Prostaglandins are potent vasodilators that have proven to be efficacious in Raynaud’s phenomenon. Prostacyclin and its analogs (e.g. epoprostenol) are potent vasodilators that acts on the endothelial cells to activate membrane-bound adenylate cyclase to increase cyclic adenosine monophosphate(AMP); it also can potentially provide “protection” to the endothelium because favorable properties of prostacyclin include antiproliferative effects on smooth muscle cells and inhibition of platelet aggregation.Prostaglandin therapy has proven helpful for the pulmonary vascular disease and associated PAH. Epoprostenol, a synthetic prostacyclin, was the first therapy approved by the USA FDA in 1995 for the treatment of PAH. Epoprostenol sodium is formulated for IV delivery and is now available as Flolan (unstable at room temperature) and Veletri (extended stability at room temperatures). There is also a generic preparation. These agents have the same potential clinically. Similar to epoprostenol is treprostinil (stable at room temperature) formulated to be delivered subcutaneously (SQ) or if not tolerated by the SQ route it can be delivered IV. An inhaled formulation of teprostinil (Tyvaso) has recently been approved by the FDA. Like epoprostenol and treprostinil, iloprost is a prostacyclin analog that can be delivered IV. It is marketed under the brand name Ventavis for inhalation therapy in PAH. Oral formulations of prostaglandin analogs are under development (treprostinil) and have been used in Japan and Korea (beraprost {Procyclin}). Initial studies in patients with scleroderma were small open-labeled showing that continuous infusion of prostacyclin improved quality of life and functional status. A open trial in 16 patients showed improvement in pulmonary vascular resistance (PVR) (>25%) in over 80% of patients and improved symptoms and exercise tolerance in all patients. Improved mean PA pressure, reduced PVR and improved cardiac output was also demonstrated in short term studies. Similar benefit was seen in patients with PH and interstitial lung disease. In an open, randomized, controlled trial of epoprostenol (n=55) versus conventional therapy (n=56) in patients with scleroderma with moderate to severe isolated PAH, Badesch et al. demonstrated improved exercise capacity compared with conventional therapy and also several measures of cardiopulmonary hemodynamics at 12 weeks. A Cochrane review concluded that IV prostacyclin improves exercise tolerance, functional status and improves
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hemodynamics. It is unclear whether prostacyclin improves survival in patients with scleroderma with PAH in that long-term controlled studies are not available. A long term follow-up of patients treated with epoprostenol was reported by Badesch et al. They found survival for one year was about 70% and second year about 50%; and it remained about 50% for year three and four of the follow-up. A study of PAH under therapy with epoprostenol defined several predictors of poor outcome. These included older age of onset, WHO classification at any time of IV, and scleroderma. It is clear that despite improved short term status with prostacyclin therapy that the disease state of scleroderma increases the risk for poor outcome.There is evidence that inhaled iloprost, inhaled trepostinil, and subcutaneous or intravenous treprostinil are also effective in patients with pulmonary hypertension (either idiopathic or associated with connective tissue disease). Patients receiving these prostacyclin analogs had significant improvements in 6- min walk tests and dyspnoea index. The most common side effect of subcutaneous infusion of treprostinil is pain at the infusion site, which occurred in 85% of patients who were treated with trepostinil, and therefore the subcutaneous route has not become a popular mode of delivering prostaglandins.Beraprost, an oral prostacyclin, is reported to help mild to moderate PAH, but its benefit may not be long-lasting. New oral preparations (treprostinil) are under study. New prostacyclin receptor agonist drugs are important approaches for the future
References1. Menon N, McAlpine L, Peacock AJ, Madhok R. The acute effects of prostacyclin on pulmonary
hemodynamics in patients with pulmonary hypertension secondary to systemic sclerosis. Arthritis Rheum. 1998 Mar;41(3):466-9.PMID: 9506575
2. Parameswaran K, Purcell I, Farrer M, Holland C, Taylor IK, Keaney NP. Acute effects of nebulised epoprostenol in pulmonary hypertension due to systemic sclerosis. Respir Med. 1999 Feb;93(2):75-8. PMID: 10464856
3. Farber HW, Graven KK, Kokolski G, Korn JH. Pulmonary edema during acute infusion of epoprostenol in a patient with pulmonary hypertension and limited scleroderma. J Rheumatol. 1999 May;26(5):1195-6. PMID: 10332990
4. Klings ES, Hill NS, Ieong MH, Simms RW, Korn JH, Farber HW. Systemic sclerosis-associated pulmonary hypertension: short- and long-term effects of epoprostenol (prostacyclin). Arthritis Rheum. 1999 Dec;42(12):2638-45. PMID: 10616012
5. Gugnani MK, Pierson C, Vanderheide R, Girgis RE. Pulmonary edema complicating prostacyclin therapy in pulmonary hypertension associated with scleroderma: a case of pulmonary capillary hemangiomatosis. Arthritis Rheum. 2000 Mar;43(3):699-703. PMID: 10728766
6. Badesch DB, Tapson VF, McGoon MD, Brundage BH, Rubin LJ, Wigley FM, Rich S, Barst RJ, Barrett PS, Kral KM, Jöbsis MM, Loyd JE, Murali S, Frost A, Girgis R, Bourge RC, Ralph DD, Elliott CG, Hill NS, Langleben D, Schilz RJ, McLaughlin VV, Robbins IM, Groves BM, Shapiro S, Medsger TA Jr. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med. 2000 Mar 21;132(6):425-34. PMID: 10733441
7. Fishman AP. Epoprostenol (prostacyclin) and pulmonary hypertension. Ann Intern Med. 2000 Mar 21;132(6):500-2. PMID: 10733452
8. Klings ES, Farber HW. Epoprostenol for pulmonary hypertension in scleroderma. Ann Intern Med. 2000 Jul 18;133(2):158. PMID: 10896643
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2. PMID: 10988225 10. Strange C, Bolster M, Mazur J, Taylor M, Gossage JR, Silver R. Hemodynamic effects of
epoprostenol in patients with systemic sclerosis and pulmonary hypertension.Chest. 2000 Oct;118(4):1077-82. PMID: 11035680
11. Paramothayan NS, Lasserson TJ, Wells AU, Walters EH. Prostacyclin for pulmonary hypertension. Cochrane Database Syst Rev. 2002;(3):CD002994. Review. Update in: Cochrane Database Syst Rev. 2003;(2):CD002994. PMID: 12137667
12. Bendayan D, Shitrit D, Kramer MR. Combination therapy with prostacyclin and tadalafil for severe pulmonary arterial hypertension: a pilot study. Respirology. 2008 Nov;13(6):916-8. PMID: 18811891
13. Galiè N, Brundage BH, Ghofrani HA, Oudiz RJ, Simonneau G, Safdar Z, Shapiro S, White RJ, Chan M, Beardsworth A, Frumkin L, Barst RJ; Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009 Jun 9;119(22):2894-903. Epub 2009 May 26. PMID: 19470885
14. Barst RJ, Gibbs JS, Ghofrani HA, Hoeper MM, McLaughlin VV, Rubin LJ, Sitbon O, Tapson VF, Galiè N. Updated evidence-based treatment algorithm in pulmonary arterial hypertension.J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S78-84. Review. PMID: 19555861
15. Kunieda T, Nakanishi N, Matsubara H, Ohe T, Okano Y, Kondo H, Nishimura M, Shirato K, Tanabe N, Homma S, Yoshida S, Inokuma S, Kodama M, Koike T, Hishida H. Effects of long-acting beraprost sodium (TRK-100STP) in Japanese patients with pulmonary arterial hypertension. Int Heart J. 2009 Jul;50(4):513-29.PMID: 19609055
16. Badesch DB, McGoon MD, Barst RJ, Tapson VF, Rubin LJ, Wigley FM, Kral KM, Raphiou IH, Crater GD. Longterm survival among patients with scleroderma-associated pulmonary arterial hypertension treated with intravenous epoprostenol. J Rheumatol. 2009 Oct;36(10):2244-9. Epub 2009 Sep 1. PMID: 19723905
17. Mathai SC, Hassoun PM. Therapy for pulmonary arterial hypertension associated with systemic sclerosis. Curr Opin Rheumatol. 2009 Nov;21(6):642-8. Review. PMID: 19667994
18. Delcroix M, Spaas K, Quarck R. Long-term outcome in pulmonary arterial hypertension: a plea for earlier parenteral prostacyclin therapy. Eur Respir Rev. 2009 Dec 1;18(114):253-9. Review. PMID: 20956150
19. Krug S, Sablotzki A, Hammerschmidt S, Wirtz H, Seyfarth HJ. Inhaled iloprost for the control of pulmonary hypertension. Vasc Health Risk Manag. 2009;5(1):465-74. Review.PMID: 19475782
20. Launay D, Sitbon O, Le Pavec J, Savale L, Tchérakian C, Yaïci A, Achouh L, Parent F, Jais X, Simonneau G, Humbert M. Long-term outcome of systemic sclerosis-associated pulmonary arterial hypertension treated with bosentan as first-line monotherapy followed or not by the addition of prostanoids or sildenafil. Rheumatology (Oxford). 2010 Mar;49(3):490-500. Epub 2009 Dec 16. PMID: 20015974
21. Ramani GV, Park MH. Update on the clinical utility of sildenafil in the treatment of pulmonary arterial hypertension. Drug Des Devel Ther. 2010 May 25;4:61-70. Review. PMID: 20531962
22. McLaughlin VV, Benza RL, Rubin LJ, Channick RN, Voswinckel R, Tapson VF, Robbins IM, Olschewski H, Rubenfire M, Seeger W. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010 May 4;55(18):1915-22. PMID: 20430262
23. Mathier MA, McDevitt S, Saggar R. Subcutaneous treprostinil in pulmonary arterial hypertension:
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Practical considerations. J Heart Lung Transplant. 2010 Nov;29(11):1210-7. Epub 2010 Sep 19. PMID: 20855220
24. Homma S. Dose-dependent reduction in pulmonary vascular resistance with epoprostenol in pulmonary arterial hypertension. Circ J. 2010 Oct;74(10):2062-3. Epub 2010 Sep 11. Review. No abstract available. PMID: 20838003
25. Rich S, Pogoriler J, Husain AN, Toth PT, Gomberg-Maitland M, Archer SL. Long-term effects of epoprostenol on the pulmonary vasculature in idiopathic pulmonary arterial hypertension. Chest. 2010 Nov;138(5):1234-9. PMID: 21051399
26. Barst R. How has epoprostenol changed the outcome for patients with pulmonary arterial hypertension? Int J Clin Pract Suppl. 2010 Nov;64 (168):23-32. doi: 10.1111/j.1742-1241.2010.02525.x. Review. PMID: 20939843
27. Barst R. How has epoprostenol changed the outcome for patients with pulmonary arterial hypertension? Int J Clin Pract Suppl. 2010 Nov;64 (168):23-32. doi: 10.1111/j.1742-1241.2010.02525.x. Review. PMID: 20939843
28. Nadler ST, Edelman JD. Inhaled treprostinil and pulmonary arterial hypertension. Vasc Health Risk Manag. 2010 Dec 3;6:1115-24. PMID: 21191432
29. Chaumais MC, Jobard M, Huertas A, Vignand-Courtin C, Humbert M, Sitbon O, Rieutord A, Montani D. Pharmacokinetic evaluation of continuous intravenous epoprostenol. Expert Opin Drug Metab Toxicol. 2010 Dec;6(12):1587-98. Review. PMID: 21077785
30. Walkey AJ, Fein D, Horbowicz KJ, Farber HW. Differential response to intravenous prostacyclin analog therapy in patients with pulmonary arterial hypertension. Pulm Pharmacol Ther. 2011 Jan 18. [Epub ahead of print] PMID: 21251994
31. Gessler T, Seeger W, Schmehl T. The potential for inhaled treprostinil in the treatment of pulmonary arterial hypertension. Ther Adv Respir Dis. 2011 Feb 7. [Epub ahead of print] PMID: 21300738
32. Levin YD, White RJ. Novel therapeutic approaches in pulmonary arterial hypertension: Focus on tadalafil. Drugs Today (Barc). 2011 Feb;47(2):145-56. PMID: 21431102
33. Ewert R, Gläser S, Bollmann T, Schäper C. Inhaled iloprost for therapy in pulmonary arterial hypertension. Expert Rev Respir Med. 2011 Apr;5(2):145-52. PMID: 21510725
34. Vachiéry JL. Prostacyclins in pulmonary arterial hypertension: the need for earlier therapy.Adv Ther. 2011 Apr;28(4):251-69. Epub 2011 Mar 29. PMID: 21455725
35. Safdar Z. Treatment of pulmonary arterial hypertension: The role of prostacyclin and prostaglandin analogs. Respir Med. 2011 Jun;105(6):818-27. Epub 2011 Jan 26. PMID: 21273054
CME Objective: the participants will be able to 1. Understand the role of prostanoids in the pathogenesis of PAH in scleroderma2. To appreciate the current evidence for the use of prostanoids in PAH in scleroderma3. To review the current recommendations for the use of prostanoids in PAH in scleroderma
Biographic Sketch
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Director in the Division of Rheumatology. He has specialized in scleroderma for over 30 years and has had interest in clinical research. Many of his research studies are related to scleroderma lung disease and pulmonary hypertension. He formally established in 1991 and now is the Director of The Johns Hopkins Scleroderma Center; a program that provides the resources to perform clinical and basic science research with an emphasis on translational research related to scleroderma. Currently, the Center has over 2,600 patients in a comprehensive prospectively collected database.
References 1. Schachna L, Wigley FM, Chang B, White B, Wise RA, Gelber AC. Age and risk of pulmonary
arterial hypertension in scleroderma. Chest. 2003 Dec;124(6):2098-104.2. Wigley FM, Lima JA, Mayes M, McLain D, Chapin JL, Ward-Able C. The prevalence of undiagnosed
pulmonary arterial hypertension in subjects with connective tissue disease at the secondary health care level of community-based rheumatologists (the UNCOVER study). Arthritis Rheum. 2005 Jul;52(7):2125-32.
3. Chang B, Schachna L, White B, Wigley FM, Wise RA. Natural history of mild-moderate pulmonary hypertension and the risk factors for severe pulmonary hypertension in scleroderma. J Rheumatol. 2006 Feb;33(2):269-74.
4. Badesch DB, McGoon MD, Barst RJ, Tapson VF, Rubin LJ, Wigley FM, Kral KM, Raphiou IH, Crater GD. Longterm survival among patients with scleroderma-associated pulmonary arterial hypertension treated with intravenous epoprostenol. J Rheumatol. 2009 Oct;36(10):2244-9.
5. Campo A, Mathai SC, Le Pavec J, Zaiman AL, Hummers LK, Boyce D, Housten T, Champion HC, Lechtzin N, Wigley FM, Girgis RE, Hassoun PM. Hemodynamic predictors of survival in scleroderma-related pulmonary arterial hyper tension. Am J Respir Crit Care Med. 2010 Jul 15;182(2):252-60.
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Combination therapyMichele D’Alto
The term combination therapy describes the simultaneous use of more than one PAH-specific class of drugs (ERAs, phosphodiesterase type-5 inhibitors and prostanoids). Combination therapy has become the standard of care in many PAH centres, although long-term safety and efficacy have not yet been amply explored. Numerous case series have suggested that various drug combinations appear to be safe and effective (1-4).Results of a few RCTs evaluating combination therapy for PAH have been published. The relatively small BREATHE-2 study (5) showed a trend to a better haemodynamic effect of the initial combination epoprostenol-bosentan as compared to epoprostenol alone. The STEP-1 study (6) addressed the safety and efficacy of 12 weeks therapy with inhaled iloprost in addition to bosentan and found a marginal increase in the post-inhalation 6 min walk distance by 26 m (P = 0.051). When measured at pre-inhalation, the placebo-corrected improvement in 6 min walk distance was 19 m (P = 0.14). There was no improvement in pre-inhalation haemodynamics in the iloprost group after 12 weeks of treatment, but time to clinical worsening was significantly prolonged in the iloprost group (0 events vs. 5 events in the placebo group; P = 0.02). In contrast, another RCT, COMBI, which also studied the effects of inhaled iloprost added to bosentan, was stopped prematurely after a planned futility analysis did not show an effect on 6 min walking distance or time to clinical worsening (7).Two other RCTs on combination therapy have been concluded: TRIUMPH (8) and PACES (9). TRIUMPH studied the effects of inhaled treprostinil in patients already treated with bosentan or sildenafil. The primary endpoint, change in 6MWT at peak exposure, improved by 20 m compared with placebo (P ,0.0006). At trough exposure, i.e. after .4 h post-inhalation, the difference was 14 m in favour of the treprostinil group (P <0.01). There were no significant differences in Borg dyspnoea index, functional class, and time to clinical worsening. The PACES trial addressed the effects of adding sildenafil to epoprostenol in 267 PAH patients. The most pertinent findings of this study were significant improvements after 12 weeks in 6MWT and time to clinical worsening. Of note, seven deaths occurred in this trial, all in the placebo group.Additional data from RCTs are available for the combination of ERAs and phosphodiesterase type-5 inhibitors. In the subgroup of patients enrolled in the EARLY study (10) (bosentan in WHO-FC II PAH patients) who were already on treatment with sildenafil, the haemodynamic effect of the addition of bosentan was comparable with that achieved in patients without background sildenafil treatment. In the PHIRST study (11) the combination of tadalafil and bosentan resulted in an improvement of exercise capacity of borderline statistical significance (subgroup analysis). There are many open questions regarding combination therapy, including the choice of combination agents, the optimal timing [initial combination (in naive patients) or sequential combination (according to the response to the first drug)], when to switch, and when to combine. When combination therapy is considered, patients should be treated within clinical trials or registries whenever possible. Combination therapy of established PAH drugs is recommended for patients not
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responding adequately to monotherapy, but combination therapy should be instituted by expert centres only. Whether the response to monotherapy is sufficient or not can only be decided on an individual basis. This is judged in an individual patient who, despite monotherapy and optimized background treatment, has an inadequate clinical response.
References1. Ghofrani HA, Rose F, Schermuly RT, Olschewski H, Wiedemann R, Kreckel A, Weissmann N,
Ghofrani S, Enke B, Seeger W, Grimminger F. Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J Am Coll Cardiol 2003;42:158–164.
2. Hoeper MM, Faulenbach C, Golpon H, Winkler J, Welte T, Niedermeyer J. Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J 2004;24:1007–1010.
3. Hoeper M, Taha N, Bekjarova A, Spiekerkoetter E. Bosentan treatment in patients with primary pulmonary hypertension receiving non-parenteral prostanoids. Eur Respir J 2003;22:330–334.
4. Mathai SC, Girgis RE, Fisher MR, Champion HC, Housten-Harris T, Zaiman A, Hassoun PM. Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension. Eur Respir J 2007;29:469–475.
5. Humbert M, Barst RJ, Robbins IM, Channick RN, Galie N, Boonstra A, Rubin LJ, Horn EM, Manes A, Simonneau G. Combination of bosentan with epoprostenol
6. McLaughlin VV, Oudiz RJ, Frost A, Tapson VF, Murali S, Channick RN, Badesch DB, Barst RJ, Hsu HH, Rubin LJ. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med 2006;174:1257–1263.
7. Hoeper M, Leuchte H, Halank M, Wilkens H, Meyer FJ, Seyfarth HJ, Wensel R, Ripken F, Bremer H, Kluge S, Hoeffken G, Behr J. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. Eur Respir J 2006;4:691–694.
8. McLaughlin V, Rubin L, Benza RL, Channick R, Vosswinkel R, Tapson V, Robbins I, Olschewski H, Seeger W. TRIUMPH I: efficacy and safety of inhaled treprostinil sodium in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 2009;177:A965.
9. Simonneau G, Rubin L, Galie N, Barst RJ, Fleming T, Frost A, Engel PJ, Kramer MR, Burgess G, Collings L, Cossons N, Sitbon O, Badesch BD, for the Pulmonary Arterial Hypertension combination Study of Epoprostenol and Sildenafil (PACES) Study Group. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension. Ann Intern Med 2008;149:521–530.
10. Galie` N, Rubin LJ, Hoeper M, Jansa P, Al-Hiti H, Meyer GMB, Chiossi E, Kusic-Pajic A, Simonneau G. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 2008;371:2093–2100.
11. Galie` N, Brundage B, Ghofrani A, Oudiz R, Simonneau G, Safdar Z, Shapiro RS, White J, Chan M, Beardsworth A, Frumkin LR, Barst R. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009;119:2894–2903.
CME Objective: the participants will be able to 1. Knowing how to perform a correct severity evaluation.2. Understanding the correct timing for starting the association therapy.3. Knowing the long term results of association therapy.
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NWorld Scleroderma Foudation Summer School,
from June the 23rd to June the 26th , 2011
Location, Villa Medicea “ La Ferdinanda”, Artimino, Tuscany, Italy
The villa was constructed in 1596 on a design by Bernardo Buontalenti,by order of the Great Duke Ferdinando I
Map of walking distance from the Villa Medicea and the Antique Artimino Village
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June, 23rd 2011
Guests Arrival in the early afternoon.
Meeting in “Salone del Toro”
Hotel accommodation
Hotel accommodation is in the antique village of Artimino,which is a renovation of the historical farm building with the connecting Patron housing.
Each Apartment/Room has an independent entrance.
Breakfast is served in the closed building of the “Cantina del Redi”,10 mts walking distance, just outside the “Borgo” main entrance.
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Social Events
Dinner of June the 23rd at Cantina del Redi : The “Cantina del Redi” is an Wine restaurant situated in the village of Artimino and conserves the walls of a secular castle of mediaeval origin
CANTINA DEL REDI, the outside terrace
CANTINA DEL REDI, the inside room
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Dinner of June the 24th at Biagio Pignatta Restaurant. The “Ser Biagio Pignatta” name deriving from the first butler of the Great Duke Ferdinando I
Biagio Pignatta Restaurant, the outside area
Biagio Pignatta the interior Gazebo with panoramic view to Florence St. Joan fireworks
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Dinner of June the 25th in Sala del Leone (Hall of the Lion, noble floor),inside the Villa Medicea “La Ferdinanda”
Villa Medicea La Ferdinanda, the outside area
SALONE DEL LEONE, noble floor, dinner mis en place
Organizing Secretariat
Mrs Cinzia PrunetiMeeting Planner
[email protected] www.nicocongressi.it
office +39 055 8797796 - +39 055 8777875mobile +39 348 4764651
World Scleroderma Foundation is grateful toPzifer for the unrestricted support
and Esaote for providing the ultrasound machines
