Pneumo-Reuma senza frontiere

La diagnosi precoce di ipertensione polmonare

XlIL Congresso Italiano della Società Italiana di Reumatologia

Milano 21-24 Novembre 2012

Sergio Harari

U.O. Pneumologia e UTIRServizio di Emodinamica e Fisiopatologia Respiratoria Osp. San Giuseppe - Milano

CTDs

• PAH may complicate a number of autoimmune diseases, such as – Systemic sclerosis– Systemic lupus erythematosus and anti-

phospholipids syndrome– Mixed connective tissue disease– Rheumatoid arthritis

• Most data come from cohorts of SSc patients because PAH is a frequent occurrence in this disease

• • Sergio Harari

MULTIPLE MECHANISMS LEADING TO PH IN CTDs

Due to pulmonary vascular remodeling

PAH

Due to CRDs and/or hypoxemia (lung

fibrosis+++)Hypoxic PH

Due to left-heart disease

Post-capillary PHCTEPH

PH in CTDs

Differential diagnosis of “PH” CTD

Pulmonary arterial hypertension (PAH)

Interstitial lung disease (ILD)

Chronic thromboembolic

pulmonary hypertension (CTEPH)

Others

Myocardialinvolvement

Pulmonaryveno-occlusive

disorder(PVOD)

PH = pulmonary hypertension Sergio Harari

Updated clinical classification of pulmonary hypertension

Galie’ N, et al. Eur Respir J 2009 Sergio Harari

Updated clinical classification of pulmonary hypertension

Galie’ N, et al. Eur Respir J 2009 Sergio Harari

Updated clinical classification of pulmonary hypertension

Galie’ N, et al. Eur Respir J 2009 Sergio Harari

IDIOPATHIC AND SYSTEMIC SCLEROSIS ASSOCIATED PULMONARY ARTERIAL HYPERTENSION

Tamby MC et al. Thorax 2005; 60 : 765-772.Mouthon et al, Eur Resp J 2005; 26:986-8. Tamby MC et al. Eur Resp J 2005

Pathogenesis includesAngiogenesis InflammationAutoimmunity

anti-endothelial cell antibodiesanti-fibroblast antibodies

Perspectives Identification of target antigens Characterisation of function

200

60

40

IPAH

SScPAH

CTD PAH: data from registries

Chung L et al, Chest 2010 Sergio Harari

399 SSc (68%)110 SLE (18%)52 MCTD (9%)28 RA (5%)

SSc PAH

Mukerjee D, et al. ARD 2003 Sergio Harari

• In SSc frequency estimated between 7.5 and 12% (variable between 4 and 38% depending on the study considered)

Lo screening è efficace per diagnosticare la malattia

1%

24%

75%

12%

Pati

en

ts (

%)

63%

100

80

60

40

20

0I II III IV

44%

28%

11%

II III IV

Pati

en

ts (

%)

39%

No screening1 With screening2

WHO FC WHO FC

1Hachulla et al. Arthritis Rheum 2005; 2Humbert et al. Am J Respir Crit Care Med 2006 Sergio Harari

100

80

60

40

20

0

Detection of milder disease with screening

mPAP (mmHg) 49 ± 17 30 ± 9

 

CI (L/min/m2) 2.8 ± 0.7 3.2 ± 1.0

PVR (d.s.cm-5) 1007 ± 615 524 ± 382

Newly

diagnosedPAH

(n=18)

Previously

knownPAH

(n=29)

3.6 ± 0.8

800 ± 320 320 ± 240

Newly

diagnosedPAH(n=5)

Previously

knownPAH

(n=30)

46 ± 13 30 ± 9

3.0 ± 0.8

Systemic Sclerosis1 HIV infection2

1. Hachulla E, et al. Arthritis Rheum 2005;52:3792-800.

2. Sitbon O, et al. Am J Respir Crit Care Med 2008;177:108-13. Sergio Harari

Tempo fra valutazione iniziale e cateterismo

Prognosis of “routine practice” and “detected” PAH-SSc patients

100

90

80

70

60

50

40

30

20

10

0

Su

rviv

al (%

)

1 year 3 years 5 years 8 years

Years of follow-up

100%

75%

31%

25%

17%

81% 73%

64%

Routine practice PAH-SSc

Detected PAH-SSc

p = 0.0037

HR = 4.15 (95% CI 1.47 - 11.71)

Humbert M, et al. Arthritis Rheum 2011; Epub ahead of print. Sergio Harari

PAH: malattia progressiva

Is interstitial lung disease present?

Is pulmonary hypertension present?

Is it clinically significant?

Sergio Harari

Key problems for clinicians

Symptoms misleading

Chest radiography insensitive

Sensitive markers include pulmonary function tests, echocardiography, right heart catheterization Sergio Harari

Is pulmonary hypertension or fibrosis present?

HRCT can sometimes creates its own problems

Is disease clinically significant?

When does a minor abnormality become “disease”?

SSc PAH: risk factors

Steen V. J Clin Rheumatol 2005 Sergio Harari

Predictors of PAH in SSc

Allanore Y et al, A&R 2008 Cavagna L et al, J Rheumatol 2010

Sergio Harari

The relationship between DLCO and the development of SSc-associated PAH. Serial falls in DLCO are predictive of the development of future PAH, suggesting that DLCO monitoring

could form part of a screening strategy for PAH in SSc. Redrawn from Steen et al.51 DLCO, diffusion capacity for carbon monoxide; PAH, pulmonary arterial hypertension; SSc,

systemic sclerosis.

Lau E M et al. Eur Heart J 2011;32:2489-2498

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2011. For permissions please email: journals.permissions@oup.com

Functional class (NYHA/WHO)

Biochemical markers (uric acid, BNP, TnT/I)

Echocardiography (PE, Tei index, RV-LV function)

Exercise studies (6-min walk test, CPET)

Hemodynamic variables (RAP, CO, SvO2)

Sergio Harari

NON INVASIVE MARKERS OF PAH PROGNOSIS

Biological markers of disease

severity

Uric acid

B-type naturetic

peptide

Cardiac troponin T

ASSESSMENT OF PAH SEVERITYBIOLOGICAL MARKERS

Nagaya N, et al. Am J Respir Crit Care Med 1999; 160:478-492Nagaya N, et al. Am J Respir Crit Care Med 1999; 160:478-492

* p < 0.05 vs control& class II

+ p < 0.05 vs control, class II & class III

Control(n = 30)

NYHA II(n = 5)

NYHA III(n = 72)

NYHA IV(n = 13)

Control(n = 30)

NYHA II(n = 5)

NYHA III(n = 72)

NYHA IV(n = 13)

Ser

um

uri

c ac

id l

evel

s (m

g/d

l)

*

0

2

4

6

8

10

12S

eru

m u

ric

acid

lev

els

(mg

/dl) +

*

0

2

4

6

8

10

12

ASSESSMENT OF PAH SEVERITYURIC ACID

0

20

40

60

80

100

0 2 4 6 8 10 12

0

20

40

60

80

100

0 2 4 6 8 10 12

Su

rviv

al (

%)

Time (years)

Male Female

8.9 mg/dl

< 8.9 mg/dl (median)

6.49 mg/dl

< 6.4 mg/dl(median)

ASSESSMENT OF PAH SEVERITYURIC ACID

Nagaya N, et al. Am J Respir Crit Care Med 1999; 160:478-492 Sergio

Harari

Nagaya N, et al. Circulation 2000; 102:865-70. Sergio Harari

Baseline BNP Follow-up BNP

100

80

60

40

20

0

0 12 24 36 48

BNP < 150 pg/ml

BNP 150 pg/ml

Time (months)

Su

rviv

al r

ate

(%) 100

80

60

40

20

0

0 12 24 36 48

BNP < 180 pg/ml

BNP 180 pg/ml

Time (months)

ASSESSMENT OF PAH SEVERITYNATRIURETIC PEPTIDES

Torbicki A, et al. Circulation 2003 Sergio Harari

ASSESSMENT OF PAH SEVERITYTROPONIN T

Miyamoto et al. AJRCCM 2000; 161:487-492 Sergio Harari

ASSESSMENT OF PAH SEVERITYEXERCISE : 6-MIN WALK TEST

ASSESSMENT OF PAH SEVERITYEXERCISE : 6-MIN WALK TEST

Miyamoto et al. AJRCCM 2000; 161:487-492 Sergio Harari

Wensel et al. Circulation 2002; 106:319-324 Sergio Harari

ASSESSMENT OF PAH SEVERITYCARDIO-PULMONARY EXERCISE TESTING

Is exercise capacity impaired and is it consistent with symptoms?

Is exercise impairment related to lung disease alone or do other conditions contribute?

What physiological mechanisms contribute to exercise impairment?

Prescription of exercise training program or oxygen during exercise

Med Clin N Am 1990; 4:634 Sergio Harari

Uses of exercise testing in lung disease

Criteri per diagnosi di PH dalla misurazione della velocità di flusso del rigurgito tricuspidale

CARDIAC ECHO DOPPLER SCREENING FOR PAH IN SYSTEMIC SCLEROSIS

• CTD-APAH patients have– better hemodynamics but higher prevalence of

pericardial effusion– lower 6-MWD– Higher BNP levels– Lower DLCO

• SSc-APAH vs other CTDs have– Similar hemodynamics but– Higher BNP and lower DLCO

Sergio Harari

Cateterismo destro

Why is PH/PAH-SSc so difficult to treat?

• Older patients• Interstitial lung disease• Left ventricular diastolic dysfunction• Right ventricular diastolic dysfunction• More severe structural vasculopathy• Key outcome measures may differ

(6 MWT-RHC ?)• More inflammation Sergio

Harari

Take home messages• PAH may frequently complicate CTDs• Among CTDs, Systemic Sclerosis-associated

PAH represents a unique phenotype for clinical presentation and outcome

• Screening of PAH is mandatory in SSc patients at any time of the disease course

• A big effort is needed in identifying the earliest predictors of this complication in order to make the most of the new therapeutic armamentarium

• A multidisciplinary management may improve diagnosis and outcome

Sergio Harari

http://www.pulmonaryrarediseases.com