Paolo Fraticelli

Università Politecnica delle Marche

Ospedali Riuniti

ANCONA

Clinica Medica

Ipertensione polmonare e

malattie del tessuto conettivo

•Systemic diseases

•Widespread connective tissue and vascular inflammation

•Autoimmune ethiology

Different (often overlapping) diseases

•Systemic lupus erithematosus

•Rheumatoid arthritis

•Sjogren syndrome

•Polymyositis/dermatomyosisis

•Systemic Sclerosis

•Mixed connective tissue disease

Autoantibodies

Antinuclear antibodies (ANA)

Anti-DNA

Anti-Ro (-SSA)

Anti-La(-SSB)

Anti.Scl-70

Anti-centromere

Anti-U1-RNP

Anti-Jo1

Connective Tissue Diseases

Condizione emodinamica e fisiopatologica comune a molte

malattie e che si associa a sintomi di dispnea, astenia, scarsa

tolleranza allo sforzo, vertigini, sincopi e progressione verso

l’insufficienza cardiaca destra.

Condizione clinica severa caratterizzata da elevata morbilità e

mortalità.

Definizione emodinamica valutata tramite cateterismo cardiaco

in cui si riscontra una Pressione media in arteria polmonare

(PAPm) a riposo 25 mmHg e aumento delle Resistenze

vascolari polmonari (PVR) > 3 unità Wood

Ipertensione polmonare

Definizione emodinamica di Ipertensione Arteriosa

Polmonare al cateterismo destro

Galiè et al., Eur Heart J 2015 (29 Aug)

Ipertensione polmonare pressione arteriosa polmonare (PAP) media rilevata mediante RHC

≥ 25 mmHg a riposo e PVR > 3 Woods units.

PRE-CAPILLARE

• PAP media ≥ 25 mmHg a riposo

• PAWP ≤ 15 mmHg

• CO normale o ridotta

POST-CAPILLARE

• PAP media ≥ 25 mmHg a riposo

• PAWP ≥ 15 mmHg

• CO normale o ridotta

1. IAP

3. IAP sec. a malattia del polmone

4. Malatt. Tromboembolica

5. I meccanismo vario/non chiaro

2. malattia del cuore

5. I meccanismo vario/non chiaro

Fisiopatologia

1. Rimodellamento del letto

vascolare arterioso

polmonare

2. Modificazioni cardiache

secondarie

• Ipertrofia della media

• Ipertrofia/fibrosi intimale

• Ispessimento avventiziale

• Infiltrato infiammatorio perivascolare

• Trombosi in situ

• Lesioni plessiformi

Modificazioni anatomopatologiche della IAP

La classificazione dell’ipertensione polmonare in 5 gruppi

Galiè et al., Eur Heart J 2015 (29 Aug)

La classificazione dell’ipertensione polmonare in 5 gruppi

Epidemiologia

0 20 40 60 80

Gruppo 5

Gruppo 4

Gruppo 3

Gruppo 2

Gruppo 1

6,8

0,6

9,7

78,7

4,2

Gruppi clinici

Gruppo 5

Gruppo 4

Gruppo 3

Gruppo 2

Gruppo 1

Gabbay et al., American Thoracic Society Annual Meeting, 2007 Am J

Resp Crit Care, 2007

Strange et al., Heart 2012; 98(24):1805-1811

Mc Goon Eur Respir Rev 2012; 21: 8-12

PAH

I-PAH 46%

CTD-PAH 25%

Prevalence of PAH in CTDs

Disease Echo prevalence

RHC prevalence/clinically

significant

Systemic sclerosis 20-50% 7.85-12%

SLE 4-43% 0.05-9.3%

MCTD 11-19% 5-16%

PM/DM 11% 0.56%

RA 20% 0.01%

IPAH 1-5/milion

Wigley FM, et al. Arthritis Rheum 2005, 54: 2125-32

Condliffe et al. Am J Respir Crit Care Med. 2009; 179:151-7

Yoshida S. Allergol Int. 2011; 60: 405-409

Clinical and prognostic differences

between IPAH vs CTD-APAH

Chung L, et al. Chest 2010; 138(6):1383–1394

Dada from REVEAL (Registry to Evaluate Early and Long-term Pulmonary

Arterial Hypertension Disease Management)

Patients with SSc-APAH

had a worse survival

compared with different

CTDs

Chung L, et al. Chest 2010; 138(6):1383–1394 Condliffe et al Am J Respir Crit Care Med 2009

PA = pulmonary artery; PASP = pulmonary artery systolic pressure; SSc = systemic sclerosis

Stupi AM, et al. Arthritis Rheum 1986;29:515–24.;

Steen V, et al. Arthritis Rheum 2003;48:516–22.

Stupi AM, et al:

Average PA pressure 82/35 (50) mmHg

Average PA resistance 16 Wood units

Average cardiac index 2.1 L/min/m2

Steen V, et al:

Average PASP 76 mmHg

Survival in limited scleroderma

with and without PAH

0

20

40

60

80

100

% C

um

ula

tive

su

rviv

al

1 2 3 4 5

Follow up (Years)

(n=287) (n=106)

(n=106)

(n=20)

SSc without PAH

SSc with PAH

A B C

iPAH

SSc

Kidney Lung Heart

Vasculopathy in scleroderma and idiopathic PAH

However compared to iPAH:

therapeutic responses are less favourable in SSc-PAH

the outcome is worse in SSc-PAH patients

NT-proBNP much higher Mathai et al. Eur Resp J. 2010

Overbeek et al Eur Respir J 2009

Dorfmüller et al Hum Pathol 2007

Pulmonary arterial hypertension

in limited cutaneous scleroderma

with PAH

Presence of intimal fibrosis of both arteries/arterioles

and veins/venules

Presence of PVOD-like pattern in some cases

Absence of plexiform lesions

Arterial and venous remodelling not restricted to

areas of lung fibrosis

Distinctive features compared with idiopathic PAH

• Human pulmonary artery smooth muscle cells acquired a synthetic phenotype

characterized by higher growth rate, migratory activity, gene expression of type I

collagen α1 chain in vitro when stimulated with PDGF and autoantibodies

against PDGF receptor, but not with normal IgG.

• less expression of markers characteristic of the contractile phenotype such as

smooth muscle-myosin heavy chain and smooth muscle-calponin

• Phenotypic change is mediated by increased generation of reactive oxygen

species (ROS) and expression of NOX4 and mTORC1.

• NOX4 silencing reduce SSc-IgG effects

• rapamicine reduce SSc-IgG effects

Svegliati S, et al. Front Immunol. 2017 Feb 8;8:75. 0

10

20

30

40

50

60

70

Sti

mu

lati

on

in

dex

(%

)

IG N

IG SSc

Agonistic anti-PDGF receptor autoantibodies from Patients with

systemic sclerosis impact human Pulmonary artery smooth

Muscle cells Function In Vitro

PAH p=0.05

GI p=0.43

Heart p=0.26

SRC

PAH

GI

PF

Heart

Fre

qu

en

cy (

%)

0

10

20

30

40

50

p<0.001 (SRC)

p<0.001 (PF)

1972-6 1977-81 1982-6 1987-91 1992-6 1997-2001

Causes of death in

scleroderma

Death (years)

Steen VD, Medsger TA, 2007

Launay D et al. Chest 2011;140;1016-1024;

Patients with SSc with PH-ILD have a different phenotype

and a worse prognosis than those with SSc and PAH.

Condliffe et al Am J Respir Crit Care Med 2009

PAH-SSc

PAH-ILD-SSc

Log-rank X2 = 8.83

p < 0.01

0 1 2 3 4 5 6 7 0

25

50

75

Survival in Years

Perc

en

t su

rviv

al

Mathai et al. Arthritis Rheum 2009

SSc-PAH SSc-ILD-PH

Pathophysiology of Pulmonary hypertension

in pulmonary fibrosis Vascular ablation

Chronic hypoxic vasoconscriction

Intermittent nocturnal hypoxia

Inflammatory response within the pulmonary vasculature specific to the

underlying disease and coagulation cascade

Underexpression of angiogenic factors (e.g. vascular endothelial growth

factor and platelet endothelial cell adhesion molecule)

Factors affecting vascular tone (e.g. angiotensin-converting enzyme and

endothelin-1)

Overxpression of inflammatory (e.g. phospholipase A2) and remodelling

genes.

Panagiotu et al. Eur Respir Rev 2017

Corte T, Wort S, Wells A. Sarcoidosis Vasc Diffus Lung Dis 2009

Sajkov D and McEvoy RD. Prog Cardiovasc Dis 2009

PH due to PVOD

• Probably underrecognized in CTDs, particularly in SSc

• Differentiating PVOD from PAH can be clinically challenging

• The high prevalence of veno-occlusive disease in SSc may

explain, in part, the refractoriness to targeted PAH therapy in

some patients.

• PAH therapy can actually precipitate severe pulmonary edema.

• Preferential involvement of small pulmonary veins together with patchy capillary

proliferation vs predominant involvement of small pulmonary arteries in PAH.

• Chest HRCT is characterized by the triad of mediastinal lymphadenopathy,

smooth interlobular septal thickening, and centrilobular ground glass opacities

• Very low DLCO and severe hypoxemia

• Features suggestive of PVOD have been found in as many as two-thirds of

patients who are classified as “SSc-PAH” based on postmortem histological

examination. Montani et al. Eur Respir J 2009

Gunter et al. Arthrits Rheum 2012

Molecular pathways

Leucocyte

recruitment

and cytokine

release

Inflammatory

pathway

e.g. RANTES,

fractalkine

Vasoconstriction Cell

proliferation

e.g.

IL-13

IL-14

PDE-5

inhibitor

NO

L-arginine

Vasodilation and

antiproliferation

cGMP

Exogenous

NO

NOS

PDE-5

Endothelin-1

Arachidonic acid

Prostaglandin I2

Prostacyclin

derivates

PGI2

cAMP

Vasodilation

and antiproliferation

ETA = endothelin-A receptor; ETB = endothelin-B receptor; ETRA = endothelin receptor antagonist; NOS = nitric oxide synthase;

cGMP = cyclic guanosine monophosphate; cAMP = cyclic adenosine monophosphate; PDE-5 = phosphodiesterase type 5; IL = interleukin

Endothelial

cells

Smooth

muscle

cells

ETB

Preproendothelin

Proendothelin

ETA ETB

Vasodilation

and antiproliferation

ETRAs

• Dispnea

• Edemi declivi

• Turgore giugulare

• Epatomegalia da stasi

• Cianosi

• Ipossiemia/normo-ipocapnia

• Poliglobulia

• Iperuricemia

• BNP o NT-proBNP aumentato

Il sospetto clinico

Pazienti giovani senza patologie

cardio-polmonari note.

Pazienti con patologie cardio-

polmonari note (scompenso

cardiaco, BPCO, fibrosi

polmonare, connettiviti, ecc) che

peggiorano in mainera

ingiustificata o “sproporzionata”

al quadro clinico-strumentale

della malattia sottostante.

ECG

• P polmonare

• Deviazione assiale dx

• BBdx

• Ipertrofia ventricolare dx

Ecocardiografia

Galiè et al., Eur Heart J 2015 (29 Aug)

Ecocardiografia

TAPSE, TDI e Strain VD: indici con

maggiore sensibilità come

screening tool

Bonderman D et al. Eur Respir J 2011

Funzionalità respiratoria

• DLCO ridotta nella totalità dei pazienti

• DLCO < 45% associata a outcome peggiore.

• FVC e FEV 1 e altri indici spirometrici se alterati indicativi di una

patologia polmonare.

• PaO2 ridotta

• PaCO2 normale o ridotta

• PaCO2 aumentata nelle COPD

• Elevata prevalenza di IP nelle OSAS

(monitoraggio respiratorio)

Sun XG, et al. J Am Coll Cardiol 2003

Trip T et al. Eur Resp J 2013

Hoeper MM et al. Eur Resp J 2007

Ipertensione polmonare ed indici funzionali

DLCO: ridotta per ▪ alveolite

▪ fibrosi

▪ danno del microcircolo polmonare

▪ alterazione ventilazione/perfusione

FVC: marcatore pattern ventilatorio restrittivo associato a fibrosi

Behr et al.: Rheumatology 2008 RATIO: FVC%/DLCO%

▪ RATIO > 2: suggestiva di ipertensione arteriosa polmonare isolata

▪ RATIO < 1,4: suggestiva di ipertensione arteriosa polmonare

associata ad interstiziopatia polmonare Gupta. Rheumatology 2004

RATIO > 1.8 correla con PAPs > 36-51 mmHg Steen VD. J Clin Rheumatol 2005

van Laar et al. Drugs 2007

popolazione generale

RATIO (FVC%/DLCO%)

PA

sP

(m

mH

g)

p<.0005

r² = 0,118

Fraticelli et al unpublished

Ratio correlate with PAPs

popolazione generale

DLCO%

PA

sP

(m

mH

g)

p<.001

r² = 0,105

All patients

No correlation in Scl70+ patients

RATIO (FVC%/DLCO%)

p<.5

PA

sP

(m

mH

g)

r² = 0,007

pts. anti-Scl-70 +

DLCO%

PA

sP

(m

mH

g)

p<.2

r² = 0,034

Fraticelli et al unpublished

pts. anti-centromere +

DLCO%

p<.1

PA

Ps (

mm

Hg)

r² = 0,086

pz. anti-centromero +

p<.0007

RATIO (FVC%/DLCO%) P

AP

s (

mm

Hg

)

r² = 0,431

Ratio correlate with PAPs

in anti-centromere+ patients

Curva ROC per PAPs ≥ 51 mmHg in pazienti con SSc

sottoposti a RHC

1-specificità

sen

sib

ilit

à

AUC=0,789

1,698

RATIO

DLco

DLco/VA

Sens 75%

Spec 80%

BNP and NT-proBNP in CTDs-PAH

NT-proBNP levels have been shown to correlate with hemodynamics

and prognosis (Mukerjee et al. Respir Med 2003, Williams et al. Eur Hearth J 2006)

Combination of high NT-proBNP level and low Dlco have been

suggested to be useful in the diagnosis and follow up of SSc-PAH

patients (Allanore et al. Arthritis Rheum 2008)

Elevated levels does not help differentiate left from right ventricular

dysfuntion, and is less helpful when there is a known left heart disease

(Mukerjee et al. Respir Med 2003)

Normal levels does not exclude an early PH (Warwick et al. Eur Respir J

2008)

SSc-PH compared with IPAH exibit disproportionate high levels of NT-

proBNP, despite similar hemodynamics (Mathai et al. Eur Respir J 2010)

Surrogate of severity and response to therapy in PH (Dimitroulas et al.

Semin Arthr Rheum 2010).

Imaging

Imaging

HRCT

Imaging

Scintigrafia polmonare Angio-TC

Escludere CTPH

(LES, APL)

Potential benefit of earlier diagnosis:

importance of screening

1. Advantage over IPAH patients (well known disease and potential

developement of PAH)

2. Recommended screening programmes and guidelines offer earlier

diagnosis

1. Novel therapeutic approaces that can influence survival when early

established

Annual transthorcic echocardiogram

Pulmonary function tests every 6-12 months

ECG

Serum BNP or NT-proBNP EPOSS-OMERACT guidelines

1. clinical (progressive dyspnoea over the past 3 months,

unexplained dyspnoea, worsening of WHO dyspnoea functional

class, any finding on physical examination suggestive of elevated

right heart pressures and any sign of right heart failure),

2. echocardiography (systolic pulmonary artery pressure >45 mm

Hg and right ventricle dilation)

3. pulmonary function tests (diffusion lung capacity for carbon

monoxide <50% without pulmonary fibrosis).

three domains:

Expert consensus for performing right heart catheterisation for

suspected pulmonary arterial hypertension in systemic

sclerosis: a Delphi consensus study with cluster analysis.

Avouac J, Huscher D, Furst DE, Opitz CF, Distler O, Allanore Y; for the EPOSS

group.

Ann Rheum Dis 2013.

right heart catheterisation

Galiè et al. Eur Respir J 2015; 46: 903-75

Stress doppler echocardiography in systemic sclerosis: evidence for a role in

the prediction of pulmonary hypertension Codullo V et al. Arthritis Rheum 2013

Clinical and echocardiographic correlations of exercise-induced pulmonary

hypertension in systemic sclerosis: a multicenter study Gargani l. et al Am Heart J. 2013;165(2):200-7

• May represent an early, clinically relevant phase of PAH.

• A hemodynamic evaluation of SSc-associated PH patients during

exercise may allow for earlier diagnosis

• No current consensus on the hemodinamic definition of exercise PH.

Exercise-induced pulmonary hypertension

Pulmonary arterial hypertension therapy may be safe and effective in patients

with SSc and borderline pulmonary artery pressure Kovacs G et al. Arthritis Rheum 2012, 64:1257-62

“Borderline PH”

and

risk to develop overt PH

mPAP 21<24 (HR 3.7 p< 0.001)

+

Transpulmonary gradient (mPAP–PAWP) > 11 mmHg (HR 7.9 p< 0.001)

Mortality within 3 years 18%

Patients with mPAP 21<24 mmHg require close monitoring

Valerio CJ, Schreiber BE, Handler CE, et al. Borderline mean pulmonary artery

pressure in patients with systemic sclerosis: transpulmonary gradient predicts risk of

developing pulmonary hypertension. Arthritis Rheum 2013;65:1074-84.

0 10 20 30 40 50 60

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

mPAP < 32 mm Hg

mPAP > 45 mm Hg

Time (months)

mPAP 32-44 mm Hg

Survival curves for 148 SSc patients

with PAH devided into tertiles

Mukerjee et al 2003

mPAP values at presentation and survival

0.0

0.2

0.4

0.6

0.8

1.0

0.00 1.00 2.00 3.00 4.00 5.00 6.00

Years from diagnosis

41

176

42

38

122

19

20

64

10

14

35

4

6

19

2

1 WHO I/II

4 WHO III

1 WHO IV

Patients at risk

IV

III

I-II

p < 0.001

Survival from diagnosis of patients with isolated

SSc-PAH grouped by WHO functional class

Condliffe et al Am J Resp Crit Care Med 2009

Launay D et al. Chest 2011;140;1016-1024;

•Age

•Pericardial effusion

•Left ventricular disfunction

•Low 6MWT

•High mPAP

•High PVR

•NYHA III-IV

predictive of a poor outcome in

PH-ILD

Survival and prognostic factors in systemic sclerosis-associated

pulmonary hypertension: a systematic review and meta-analysis

Lefevre G et al. Arthritis & Rheum 2013.

DOI 10.1002/art.38029

The hazard ratio for death was

3.02 (95% CI 1.91, 4.78) for

systolic pulmonary artery

pressure > 36mmHg in SSc

patients

The hazard ratio for death was

4.94 (95% CI 2.66, 9.17) for DLCO

<64% of predicted in SSc

patients

La valutazione del paziente

Follow-up ogni 3-6 mesi Galiè et al., Eur Heart J 2015 (29 Aug)

Conclusioni

• L’ipertensione arteriosa polmonare è una complicanza non

rara nei pazienti affetti da CTDs

• La sopravvivenza è strettamente correlata alla diagnosi

precoce ad all’inizio di una terapia specifica

• È necessario uno stretto monitoraggio dei pazienti

• Necessaria una valutazione integrata e polispecialistica per

una corretta gestione del paziente

• Necessità di estendere le conoscenze nel campo della

fisiopatologia dei fenomeni vascolari e fibrotici della malattia

Risk factors for pulmonary arterial

hypertension in systemic sclerosis

Limited variant (92%)

Usually considered a late complication (disease duration > 10 years)

Late age of onset of SSc

Severe Raynaud’s phenomenon and digital ulceration and

teleangectases

Low DLco

Anti-centromere and U3-RNP (anti-Scl-70 apparently protecive)

Early onset (within 5 years worse prognosis and no difference

between limited and diffuse SSc)