sclerodermia e ipertensione polmonare
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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: [email protected]
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