18 aprile 2015 ip malattie reumatiche
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Transcript of 18 aprile 2015 ip malattie reumatiche
Ipertensione
polmonare nelle
malattie reumatiche
Annalisa Fiorella
UO Cardiologia SS Annunziata Taranto
Galiegrave N et al Eur Heart J and Eur Respir J 2009
GaliegraveN et al Eur Heart J and Eur Respir J 2009
Recommendations for PAWP at rest
bull The cutoff for pre-capillary PH should remain at 15 mmHg because this value has been used in almost all clinical trials generating evidence for the safety and efficacy of PAH-targeted therapies in patients fulfilling these criteria
bull Invasive hemodynamics need to be placed in clinical and echocardiographic context with regard to probability of existence of left heart disease
bull The working group recommends zeroing the pressure transducer at the midthoracic line in a supine patient halfway between the anterior sternum and the bed surface This represents the level of the left atrium
Coghlan Arthritis Rheum 2013 Apr65(4)1074-84 doi 101002art37838
bull A mPAP between 21-24 mmHg may be not normal in these cases It has been proposed to use the term of ldquoBorderlinerdquo elevation of PAP
bull ldquoBorderlinerdquo elevation of PAP is frequently observed in Groups 2 and 3 however the meaning of this observation is unknown and has no therapeutic implications
bull ldquoBorderlinerdquo elevation of PAP is also observed in scleroderma patients screened for PH Recent data support that a substantial number of these patients develop manifest PAH in the F-U
ldquoBorderlinerdquo PH
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
Long-term Follow-up of lsquorsquoborderlinersquorsquo PH in Scleroderma
Coghlan Arthritis Rheum 2013 Apr65(4)1074-84 doi 101002art37838
37 had Borderline PAP at baseline
How do we handle ldquoborderlinerdquo PH
bull We recognize ldquoborderlinerdquo elevation of PAP is a hemodynamic definition with mPAP at RHC of 21 to 24 mm Hg
bull In scleroderma Patients we consider ldquoborderlinerdquo elevation of PAP as a risk marker for progression to PHa risk marker for progression to PH
bull Therapeutic implications remain unknown
Task Force recommendations
Coghlan Arthritis Rheum 2013 Apr65(4)1074-84 doi 101002art37838
Galiegrave N et al Eur Heart J and Eur Respir J 2009
1 Pulmonary arterial hypertension
2 PH ass with left heart disease
3 PH ass with lung diseases
4 PH due to chronic TE disease
5 Miscellaneous
35
79
10
15
6
Mixed
PH Epidemiology in an Echo lab (Armadale study)
Gabbay et al Am J Resp Crit Care Med 2007175A713
Prevalence of PH (SPAPgt 40 mmHg) among 4579 pts 105
Pulmonary Arterial Hypertension (group 1)Associated Conditions
1Pulmonary Arterial Hypertension11 Idiopathic PAH12 Heritable PAH121 BMPR2122 ALK-1ENGSMAD9CAV1KCNK3123 Unknown13 Drugs and toxins induced
14 Associated with141 Connective tissue disease142 HIV infection143 Portal hypertension144 Congenital Heart diseases (table)145 Schistosomiasis
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Non-invasive assessment of PH
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
PH PresentPeak TRV
(ms)ePASP (mmHg)
Additional Echo Signs of
PHRE
Unlikely lt28 lt35 No I-B
Possiblelt28 lt35 Yes IIa-C
29 ndash 34 36 ndash 50 NoYes IIa-C
Likely gt34 gt50 NoYes I-B
Table 9 Arbitrary Echo Criteria for estimating the presence of PH based on TRV an assumed RAP of 5 mmHg and additional Echo variables suggestive of PH
Galiegrave N et al Eur Heart J and Eur Respir J 2009
increased velocity of pulmonary valve regurgitation short AcT increased dimensions of RH chambers abnormal shape and function of the IVS increased RV wall thickness and dilated main PA
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
Cateterismo cardiaco destro
Permette di misurare quanto descritto nella definizione funzionale della PAH
mPAP gt25 mmHg a riposo o gt30 mmHg in corso di esercizio
Gaine et al Lancet 1998352719
IP all rsquoEcocardiogramma gt PAPs 30-50 mmHg velocitagrave del rigurgito tricuspidalico di 2834 msec (PADx 5 mmHg)
European Heart Journal 2004 252253
Screening can be effective in identifying earlier disease
1
24
75
12Pa
tie
nts
(
)
63
0
20
40
60
80
100
I II III IV
100
80
60
40
20
0
n = 8(44) n = 5
(28) n = 2
(11)
II III IV
Pa
tie
nts
39
Hachulla E et al Arthritis Rheum 2005 523698-700 Humbert M et al Am J Respir Crit Care Med 2006 1731023-30
No screening With screening
WHO class WHO class
Survival Daily practice vs screening
Humbert Arthritis Rheum 2011 Nov63(11)3522-30
Screening
bull Systemic Sclerosis (10-13)
bull SLE (05-14)
bull MCTD (23-53)
bull RA (lt 1)
bull DM (lt 1)
bull Sjogrenrsquos Syndrome (25 )
bull Undifferentiated and Overlap syndromes
bull Antiphospholipid Syndrome
bull Vasculitis
PAH associated to CTD
1 Pulmonary arterial hypertension
bull Associated with CTD
3 PH due to lung diseasehypoxia
bull Interstitial lung disease (fibrosis)
2PH due to left heart disease
bull Systolicdiastolic dysfunction
bull Valvyular disease
PHin
CTD
PH associated with CTD
Pumonary VascularDisease
InterstitialFibrosis
PAHPH associated to SSc
lcSSc dcSSc
50-90 8-50
Raccomandation for PAH associated with connective tissue disease
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Galiegrave N et al Eur Heart J and Eur Respir J 2009
GaliegraveN et al Eur Heart J and Eur Respir J 2009
Recommendations for PAWP at rest
bull The cutoff for pre-capillary PH should remain at 15 mmHg because this value has been used in almost all clinical trials generating evidence for the safety and efficacy of PAH-targeted therapies in patients fulfilling these criteria
bull Invasive hemodynamics need to be placed in clinical and echocardiographic context with regard to probability of existence of left heart disease
bull The working group recommends zeroing the pressure transducer at the midthoracic line in a supine patient halfway between the anterior sternum and the bed surface This represents the level of the left atrium
Coghlan Arthritis Rheum 2013 Apr65(4)1074-84 doi 101002art37838
bull A mPAP between 21-24 mmHg may be not normal in these cases It has been proposed to use the term of ldquoBorderlinerdquo elevation of PAP
bull ldquoBorderlinerdquo elevation of PAP is frequently observed in Groups 2 and 3 however the meaning of this observation is unknown and has no therapeutic implications
bull ldquoBorderlinerdquo elevation of PAP is also observed in scleroderma patients screened for PH Recent data support that a substantial number of these patients develop manifest PAH in the F-U
ldquoBorderlinerdquo PH
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
Long-term Follow-up of lsquorsquoborderlinersquorsquo PH in Scleroderma
Coghlan Arthritis Rheum 2013 Apr65(4)1074-84 doi 101002art37838
37 had Borderline PAP at baseline
How do we handle ldquoborderlinerdquo PH
bull We recognize ldquoborderlinerdquo elevation of PAP is a hemodynamic definition with mPAP at RHC of 21 to 24 mm Hg
bull In scleroderma Patients we consider ldquoborderlinerdquo elevation of PAP as a risk marker for progression to PHa risk marker for progression to PH
bull Therapeutic implications remain unknown
Task Force recommendations
Coghlan Arthritis Rheum 2013 Apr65(4)1074-84 doi 101002art37838
Galiegrave N et al Eur Heart J and Eur Respir J 2009
1 Pulmonary arterial hypertension
2 PH ass with left heart disease
3 PH ass with lung diseases
4 PH due to chronic TE disease
5 Miscellaneous
35
79
10
15
6
Mixed
PH Epidemiology in an Echo lab (Armadale study)
Gabbay et al Am J Resp Crit Care Med 2007175A713
Prevalence of PH (SPAPgt 40 mmHg) among 4579 pts 105
Pulmonary Arterial Hypertension (group 1)Associated Conditions
1Pulmonary Arterial Hypertension11 Idiopathic PAH12 Heritable PAH121 BMPR2122 ALK-1ENGSMAD9CAV1KCNK3123 Unknown13 Drugs and toxins induced
14 Associated with141 Connective tissue disease142 HIV infection143 Portal hypertension144 Congenital Heart diseases (table)145 Schistosomiasis
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Non-invasive assessment of PH
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
PH PresentPeak TRV
(ms)ePASP (mmHg)
Additional Echo Signs of
PHRE
Unlikely lt28 lt35 No I-B
Possiblelt28 lt35 Yes IIa-C
29 ndash 34 36 ndash 50 NoYes IIa-C
Likely gt34 gt50 NoYes I-B
Table 9 Arbitrary Echo Criteria for estimating the presence of PH based on TRV an assumed RAP of 5 mmHg and additional Echo variables suggestive of PH
Galiegrave N et al Eur Heart J and Eur Respir J 2009
increased velocity of pulmonary valve regurgitation short AcT increased dimensions of RH chambers abnormal shape and function of the IVS increased RV wall thickness and dilated main PA
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
Cateterismo cardiaco destro
Permette di misurare quanto descritto nella definizione funzionale della PAH
mPAP gt25 mmHg a riposo o gt30 mmHg in corso di esercizio
Gaine et al Lancet 1998352719
IP all rsquoEcocardiogramma gt PAPs 30-50 mmHg velocitagrave del rigurgito tricuspidalico di 2834 msec (PADx 5 mmHg)
European Heart Journal 2004 252253
Screening can be effective in identifying earlier disease
1
24
75
12Pa
tie
nts
(
)
63
0
20
40
60
80
100
I II III IV
100
80
60
40
20
0
n = 8(44) n = 5
(28) n = 2
(11)
II III IV
Pa
tie
nts
39
Hachulla E et al Arthritis Rheum 2005 523698-700 Humbert M et al Am J Respir Crit Care Med 2006 1731023-30
No screening With screening
WHO class WHO class
Survival Daily practice vs screening
Humbert Arthritis Rheum 2011 Nov63(11)3522-30
Screening
bull Systemic Sclerosis (10-13)
bull SLE (05-14)
bull MCTD (23-53)
bull RA (lt 1)
bull DM (lt 1)
bull Sjogrenrsquos Syndrome (25 )
bull Undifferentiated and Overlap syndromes
bull Antiphospholipid Syndrome
bull Vasculitis
PAH associated to CTD
1 Pulmonary arterial hypertension
bull Associated with CTD
3 PH due to lung diseasehypoxia
bull Interstitial lung disease (fibrosis)
2PH due to left heart disease
bull Systolicdiastolic dysfunction
bull Valvyular disease
PHin
CTD
PH associated with CTD
Pumonary VascularDisease
InterstitialFibrosis
PAHPH associated to SSc
lcSSc dcSSc
50-90 8-50
Raccomandation for PAH associated with connective tissue disease
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
GaliegraveN et al Eur Heart J and Eur Respir J 2009
Recommendations for PAWP at rest
bull The cutoff for pre-capillary PH should remain at 15 mmHg because this value has been used in almost all clinical trials generating evidence for the safety and efficacy of PAH-targeted therapies in patients fulfilling these criteria
bull Invasive hemodynamics need to be placed in clinical and echocardiographic context with regard to probability of existence of left heart disease
bull The working group recommends zeroing the pressure transducer at the midthoracic line in a supine patient halfway between the anterior sternum and the bed surface This represents the level of the left atrium
Coghlan Arthritis Rheum 2013 Apr65(4)1074-84 doi 101002art37838
bull A mPAP between 21-24 mmHg may be not normal in these cases It has been proposed to use the term of ldquoBorderlinerdquo elevation of PAP
bull ldquoBorderlinerdquo elevation of PAP is frequently observed in Groups 2 and 3 however the meaning of this observation is unknown and has no therapeutic implications
bull ldquoBorderlinerdquo elevation of PAP is also observed in scleroderma patients screened for PH Recent data support that a substantial number of these patients develop manifest PAH in the F-U
ldquoBorderlinerdquo PH
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
Long-term Follow-up of lsquorsquoborderlinersquorsquo PH in Scleroderma
Coghlan Arthritis Rheum 2013 Apr65(4)1074-84 doi 101002art37838
37 had Borderline PAP at baseline
How do we handle ldquoborderlinerdquo PH
bull We recognize ldquoborderlinerdquo elevation of PAP is a hemodynamic definition with mPAP at RHC of 21 to 24 mm Hg
bull In scleroderma Patients we consider ldquoborderlinerdquo elevation of PAP as a risk marker for progression to PHa risk marker for progression to PH
bull Therapeutic implications remain unknown
Task Force recommendations
Coghlan Arthritis Rheum 2013 Apr65(4)1074-84 doi 101002art37838
Galiegrave N et al Eur Heart J and Eur Respir J 2009
1 Pulmonary arterial hypertension
2 PH ass with left heart disease
3 PH ass with lung diseases
4 PH due to chronic TE disease
5 Miscellaneous
35
79
10
15
6
Mixed
PH Epidemiology in an Echo lab (Armadale study)
Gabbay et al Am J Resp Crit Care Med 2007175A713
Prevalence of PH (SPAPgt 40 mmHg) among 4579 pts 105
Pulmonary Arterial Hypertension (group 1)Associated Conditions
1Pulmonary Arterial Hypertension11 Idiopathic PAH12 Heritable PAH121 BMPR2122 ALK-1ENGSMAD9CAV1KCNK3123 Unknown13 Drugs and toxins induced
14 Associated with141 Connective tissue disease142 HIV infection143 Portal hypertension144 Congenital Heart diseases (table)145 Schistosomiasis
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Non-invasive assessment of PH
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
PH PresentPeak TRV
(ms)ePASP (mmHg)
Additional Echo Signs of
PHRE
Unlikely lt28 lt35 No I-B
Possiblelt28 lt35 Yes IIa-C
29 ndash 34 36 ndash 50 NoYes IIa-C
Likely gt34 gt50 NoYes I-B
Table 9 Arbitrary Echo Criteria for estimating the presence of PH based on TRV an assumed RAP of 5 mmHg and additional Echo variables suggestive of PH
Galiegrave N et al Eur Heart J and Eur Respir J 2009
increased velocity of pulmonary valve regurgitation short AcT increased dimensions of RH chambers abnormal shape and function of the IVS increased RV wall thickness and dilated main PA
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
Cateterismo cardiaco destro
Permette di misurare quanto descritto nella definizione funzionale della PAH
mPAP gt25 mmHg a riposo o gt30 mmHg in corso di esercizio
Gaine et al Lancet 1998352719
IP all rsquoEcocardiogramma gt PAPs 30-50 mmHg velocitagrave del rigurgito tricuspidalico di 2834 msec (PADx 5 mmHg)
European Heart Journal 2004 252253
Screening can be effective in identifying earlier disease
1
24
75
12Pa
tie
nts
(
)
63
0
20
40
60
80
100
I II III IV
100
80
60
40
20
0
n = 8(44) n = 5
(28) n = 2
(11)
II III IV
Pa
tie
nts
39
Hachulla E et al Arthritis Rheum 2005 523698-700 Humbert M et al Am J Respir Crit Care Med 2006 1731023-30
No screening With screening
WHO class WHO class
Survival Daily practice vs screening
Humbert Arthritis Rheum 2011 Nov63(11)3522-30
Screening
bull Systemic Sclerosis (10-13)
bull SLE (05-14)
bull MCTD (23-53)
bull RA (lt 1)
bull DM (lt 1)
bull Sjogrenrsquos Syndrome (25 )
bull Undifferentiated and Overlap syndromes
bull Antiphospholipid Syndrome
bull Vasculitis
PAH associated to CTD
1 Pulmonary arterial hypertension
bull Associated with CTD
3 PH due to lung diseasehypoxia
bull Interstitial lung disease (fibrosis)
2PH due to left heart disease
bull Systolicdiastolic dysfunction
bull Valvyular disease
PHin
CTD
PH associated with CTD
Pumonary VascularDisease
InterstitialFibrosis
PAHPH associated to SSc
lcSSc dcSSc
50-90 8-50
Raccomandation for PAH associated with connective tissue disease
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Recommendations for PAWP at rest
bull The cutoff for pre-capillary PH should remain at 15 mmHg because this value has been used in almost all clinical trials generating evidence for the safety and efficacy of PAH-targeted therapies in patients fulfilling these criteria
bull Invasive hemodynamics need to be placed in clinical and echocardiographic context with regard to probability of existence of left heart disease
bull The working group recommends zeroing the pressure transducer at the midthoracic line in a supine patient halfway between the anterior sternum and the bed surface This represents the level of the left atrium
Coghlan Arthritis Rheum 2013 Apr65(4)1074-84 doi 101002art37838
bull A mPAP between 21-24 mmHg may be not normal in these cases It has been proposed to use the term of ldquoBorderlinerdquo elevation of PAP
bull ldquoBorderlinerdquo elevation of PAP is frequently observed in Groups 2 and 3 however the meaning of this observation is unknown and has no therapeutic implications
bull ldquoBorderlinerdquo elevation of PAP is also observed in scleroderma patients screened for PH Recent data support that a substantial number of these patients develop manifest PAH in the F-U
ldquoBorderlinerdquo PH
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
Long-term Follow-up of lsquorsquoborderlinersquorsquo PH in Scleroderma
Coghlan Arthritis Rheum 2013 Apr65(4)1074-84 doi 101002art37838
37 had Borderline PAP at baseline
How do we handle ldquoborderlinerdquo PH
bull We recognize ldquoborderlinerdquo elevation of PAP is a hemodynamic definition with mPAP at RHC of 21 to 24 mm Hg
bull In scleroderma Patients we consider ldquoborderlinerdquo elevation of PAP as a risk marker for progression to PHa risk marker for progression to PH
bull Therapeutic implications remain unknown
Task Force recommendations
Coghlan Arthritis Rheum 2013 Apr65(4)1074-84 doi 101002art37838
Galiegrave N et al Eur Heart J and Eur Respir J 2009
1 Pulmonary arterial hypertension
2 PH ass with left heart disease
3 PH ass with lung diseases
4 PH due to chronic TE disease
5 Miscellaneous
35
79
10
15
6
Mixed
PH Epidemiology in an Echo lab (Armadale study)
Gabbay et al Am J Resp Crit Care Med 2007175A713
Prevalence of PH (SPAPgt 40 mmHg) among 4579 pts 105
Pulmonary Arterial Hypertension (group 1)Associated Conditions
1Pulmonary Arterial Hypertension11 Idiopathic PAH12 Heritable PAH121 BMPR2122 ALK-1ENGSMAD9CAV1KCNK3123 Unknown13 Drugs and toxins induced
14 Associated with141 Connective tissue disease142 HIV infection143 Portal hypertension144 Congenital Heart diseases (table)145 Schistosomiasis
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Non-invasive assessment of PH
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
PH PresentPeak TRV
(ms)ePASP (mmHg)
Additional Echo Signs of
PHRE
Unlikely lt28 lt35 No I-B
Possiblelt28 lt35 Yes IIa-C
29 ndash 34 36 ndash 50 NoYes IIa-C
Likely gt34 gt50 NoYes I-B
Table 9 Arbitrary Echo Criteria for estimating the presence of PH based on TRV an assumed RAP of 5 mmHg and additional Echo variables suggestive of PH
Galiegrave N et al Eur Heart J and Eur Respir J 2009
increased velocity of pulmonary valve regurgitation short AcT increased dimensions of RH chambers abnormal shape and function of the IVS increased RV wall thickness and dilated main PA
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
Cateterismo cardiaco destro
Permette di misurare quanto descritto nella definizione funzionale della PAH
mPAP gt25 mmHg a riposo o gt30 mmHg in corso di esercizio
Gaine et al Lancet 1998352719
IP all rsquoEcocardiogramma gt PAPs 30-50 mmHg velocitagrave del rigurgito tricuspidalico di 2834 msec (PADx 5 mmHg)
European Heart Journal 2004 252253
Screening can be effective in identifying earlier disease
1
24
75
12Pa
tie
nts
(
)
63
0
20
40
60
80
100
I II III IV
100
80
60
40
20
0
n = 8(44) n = 5
(28) n = 2
(11)
II III IV
Pa
tie
nts
39
Hachulla E et al Arthritis Rheum 2005 523698-700 Humbert M et al Am J Respir Crit Care Med 2006 1731023-30
No screening With screening
WHO class WHO class
Survival Daily practice vs screening
Humbert Arthritis Rheum 2011 Nov63(11)3522-30
Screening
bull Systemic Sclerosis (10-13)
bull SLE (05-14)
bull MCTD (23-53)
bull RA (lt 1)
bull DM (lt 1)
bull Sjogrenrsquos Syndrome (25 )
bull Undifferentiated and Overlap syndromes
bull Antiphospholipid Syndrome
bull Vasculitis
PAH associated to CTD
1 Pulmonary arterial hypertension
bull Associated with CTD
3 PH due to lung diseasehypoxia
bull Interstitial lung disease (fibrosis)
2PH due to left heart disease
bull Systolicdiastolic dysfunction
bull Valvyular disease
PHin
CTD
PH associated with CTD
Pumonary VascularDisease
InterstitialFibrosis
PAHPH associated to SSc
lcSSc dcSSc
50-90 8-50
Raccomandation for PAH associated with connective tissue disease
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
bull A mPAP between 21-24 mmHg may be not normal in these cases It has been proposed to use the term of ldquoBorderlinerdquo elevation of PAP
bull ldquoBorderlinerdquo elevation of PAP is frequently observed in Groups 2 and 3 however the meaning of this observation is unknown and has no therapeutic implications
bull ldquoBorderlinerdquo elevation of PAP is also observed in scleroderma patients screened for PH Recent data support that a substantial number of these patients develop manifest PAH in the F-U
ldquoBorderlinerdquo PH
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
Long-term Follow-up of lsquorsquoborderlinersquorsquo PH in Scleroderma
Coghlan Arthritis Rheum 2013 Apr65(4)1074-84 doi 101002art37838
37 had Borderline PAP at baseline
How do we handle ldquoborderlinerdquo PH
bull We recognize ldquoborderlinerdquo elevation of PAP is a hemodynamic definition with mPAP at RHC of 21 to 24 mm Hg
bull In scleroderma Patients we consider ldquoborderlinerdquo elevation of PAP as a risk marker for progression to PHa risk marker for progression to PH
bull Therapeutic implications remain unknown
Task Force recommendations
Coghlan Arthritis Rheum 2013 Apr65(4)1074-84 doi 101002art37838
Galiegrave N et al Eur Heart J and Eur Respir J 2009
1 Pulmonary arterial hypertension
2 PH ass with left heart disease
3 PH ass with lung diseases
4 PH due to chronic TE disease
5 Miscellaneous
35
79
10
15
6
Mixed
PH Epidemiology in an Echo lab (Armadale study)
Gabbay et al Am J Resp Crit Care Med 2007175A713
Prevalence of PH (SPAPgt 40 mmHg) among 4579 pts 105
Pulmonary Arterial Hypertension (group 1)Associated Conditions
1Pulmonary Arterial Hypertension11 Idiopathic PAH12 Heritable PAH121 BMPR2122 ALK-1ENGSMAD9CAV1KCNK3123 Unknown13 Drugs and toxins induced
14 Associated with141 Connective tissue disease142 HIV infection143 Portal hypertension144 Congenital Heart diseases (table)145 Schistosomiasis
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Non-invasive assessment of PH
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
PH PresentPeak TRV
(ms)ePASP (mmHg)
Additional Echo Signs of
PHRE
Unlikely lt28 lt35 No I-B
Possiblelt28 lt35 Yes IIa-C
29 ndash 34 36 ndash 50 NoYes IIa-C
Likely gt34 gt50 NoYes I-B
Table 9 Arbitrary Echo Criteria for estimating the presence of PH based on TRV an assumed RAP of 5 mmHg and additional Echo variables suggestive of PH
Galiegrave N et al Eur Heart J and Eur Respir J 2009
increased velocity of pulmonary valve regurgitation short AcT increased dimensions of RH chambers abnormal shape and function of the IVS increased RV wall thickness and dilated main PA
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
Cateterismo cardiaco destro
Permette di misurare quanto descritto nella definizione funzionale della PAH
mPAP gt25 mmHg a riposo o gt30 mmHg in corso di esercizio
Gaine et al Lancet 1998352719
IP all rsquoEcocardiogramma gt PAPs 30-50 mmHg velocitagrave del rigurgito tricuspidalico di 2834 msec (PADx 5 mmHg)
European Heart Journal 2004 252253
Screening can be effective in identifying earlier disease
1
24
75
12Pa
tie
nts
(
)
63
0
20
40
60
80
100
I II III IV
100
80
60
40
20
0
n = 8(44) n = 5
(28) n = 2
(11)
II III IV
Pa
tie
nts
39
Hachulla E et al Arthritis Rheum 2005 523698-700 Humbert M et al Am J Respir Crit Care Med 2006 1731023-30
No screening With screening
WHO class WHO class
Survival Daily practice vs screening
Humbert Arthritis Rheum 2011 Nov63(11)3522-30
Screening
bull Systemic Sclerosis (10-13)
bull SLE (05-14)
bull MCTD (23-53)
bull RA (lt 1)
bull DM (lt 1)
bull Sjogrenrsquos Syndrome (25 )
bull Undifferentiated and Overlap syndromes
bull Antiphospholipid Syndrome
bull Vasculitis
PAH associated to CTD
1 Pulmonary arterial hypertension
bull Associated with CTD
3 PH due to lung diseasehypoxia
bull Interstitial lung disease (fibrosis)
2PH due to left heart disease
bull Systolicdiastolic dysfunction
bull Valvyular disease
PHin
CTD
PH associated with CTD
Pumonary VascularDisease
InterstitialFibrosis
PAHPH associated to SSc
lcSSc dcSSc
50-90 8-50
Raccomandation for PAH associated with connective tissue disease
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Long-term Follow-up of lsquorsquoborderlinersquorsquo PH in Scleroderma
Coghlan Arthritis Rheum 2013 Apr65(4)1074-84 doi 101002art37838
37 had Borderline PAP at baseline
How do we handle ldquoborderlinerdquo PH
bull We recognize ldquoborderlinerdquo elevation of PAP is a hemodynamic definition with mPAP at RHC of 21 to 24 mm Hg
bull In scleroderma Patients we consider ldquoborderlinerdquo elevation of PAP as a risk marker for progression to PHa risk marker for progression to PH
bull Therapeutic implications remain unknown
Task Force recommendations
Coghlan Arthritis Rheum 2013 Apr65(4)1074-84 doi 101002art37838
Galiegrave N et al Eur Heart J and Eur Respir J 2009
1 Pulmonary arterial hypertension
2 PH ass with left heart disease
3 PH ass with lung diseases
4 PH due to chronic TE disease
5 Miscellaneous
35
79
10
15
6
Mixed
PH Epidemiology in an Echo lab (Armadale study)
Gabbay et al Am J Resp Crit Care Med 2007175A713
Prevalence of PH (SPAPgt 40 mmHg) among 4579 pts 105
Pulmonary Arterial Hypertension (group 1)Associated Conditions
1Pulmonary Arterial Hypertension11 Idiopathic PAH12 Heritable PAH121 BMPR2122 ALK-1ENGSMAD9CAV1KCNK3123 Unknown13 Drugs and toxins induced
14 Associated with141 Connective tissue disease142 HIV infection143 Portal hypertension144 Congenital Heart diseases (table)145 Schistosomiasis
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Non-invasive assessment of PH
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
PH PresentPeak TRV
(ms)ePASP (mmHg)
Additional Echo Signs of
PHRE
Unlikely lt28 lt35 No I-B
Possiblelt28 lt35 Yes IIa-C
29 ndash 34 36 ndash 50 NoYes IIa-C
Likely gt34 gt50 NoYes I-B
Table 9 Arbitrary Echo Criteria for estimating the presence of PH based on TRV an assumed RAP of 5 mmHg and additional Echo variables suggestive of PH
Galiegrave N et al Eur Heart J and Eur Respir J 2009
increased velocity of pulmonary valve regurgitation short AcT increased dimensions of RH chambers abnormal shape and function of the IVS increased RV wall thickness and dilated main PA
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
Cateterismo cardiaco destro
Permette di misurare quanto descritto nella definizione funzionale della PAH
mPAP gt25 mmHg a riposo o gt30 mmHg in corso di esercizio
Gaine et al Lancet 1998352719
IP all rsquoEcocardiogramma gt PAPs 30-50 mmHg velocitagrave del rigurgito tricuspidalico di 2834 msec (PADx 5 mmHg)
European Heart Journal 2004 252253
Screening can be effective in identifying earlier disease
1
24
75
12Pa
tie
nts
(
)
63
0
20
40
60
80
100
I II III IV
100
80
60
40
20
0
n = 8(44) n = 5
(28) n = 2
(11)
II III IV
Pa
tie
nts
39
Hachulla E et al Arthritis Rheum 2005 523698-700 Humbert M et al Am J Respir Crit Care Med 2006 1731023-30
No screening With screening
WHO class WHO class
Survival Daily practice vs screening
Humbert Arthritis Rheum 2011 Nov63(11)3522-30
Screening
bull Systemic Sclerosis (10-13)
bull SLE (05-14)
bull MCTD (23-53)
bull RA (lt 1)
bull DM (lt 1)
bull Sjogrenrsquos Syndrome (25 )
bull Undifferentiated and Overlap syndromes
bull Antiphospholipid Syndrome
bull Vasculitis
PAH associated to CTD
1 Pulmonary arterial hypertension
bull Associated with CTD
3 PH due to lung diseasehypoxia
bull Interstitial lung disease (fibrosis)
2PH due to left heart disease
bull Systolicdiastolic dysfunction
bull Valvyular disease
PHin
CTD
PH associated with CTD
Pumonary VascularDisease
InterstitialFibrosis
PAHPH associated to SSc
lcSSc dcSSc
50-90 8-50
Raccomandation for PAH associated with connective tissue disease
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
How do we handle ldquoborderlinerdquo PH
bull We recognize ldquoborderlinerdquo elevation of PAP is a hemodynamic definition with mPAP at RHC of 21 to 24 mm Hg
bull In scleroderma Patients we consider ldquoborderlinerdquo elevation of PAP as a risk marker for progression to PHa risk marker for progression to PH
bull Therapeutic implications remain unknown
Task Force recommendations
Coghlan Arthritis Rheum 2013 Apr65(4)1074-84 doi 101002art37838
Galiegrave N et al Eur Heart J and Eur Respir J 2009
1 Pulmonary arterial hypertension
2 PH ass with left heart disease
3 PH ass with lung diseases
4 PH due to chronic TE disease
5 Miscellaneous
35
79
10
15
6
Mixed
PH Epidemiology in an Echo lab (Armadale study)
Gabbay et al Am J Resp Crit Care Med 2007175A713
Prevalence of PH (SPAPgt 40 mmHg) among 4579 pts 105
Pulmonary Arterial Hypertension (group 1)Associated Conditions
1Pulmonary Arterial Hypertension11 Idiopathic PAH12 Heritable PAH121 BMPR2122 ALK-1ENGSMAD9CAV1KCNK3123 Unknown13 Drugs and toxins induced
14 Associated with141 Connective tissue disease142 HIV infection143 Portal hypertension144 Congenital Heart diseases (table)145 Schistosomiasis
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Non-invasive assessment of PH
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
PH PresentPeak TRV
(ms)ePASP (mmHg)
Additional Echo Signs of
PHRE
Unlikely lt28 lt35 No I-B
Possiblelt28 lt35 Yes IIa-C
29 ndash 34 36 ndash 50 NoYes IIa-C
Likely gt34 gt50 NoYes I-B
Table 9 Arbitrary Echo Criteria for estimating the presence of PH based on TRV an assumed RAP of 5 mmHg and additional Echo variables suggestive of PH
Galiegrave N et al Eur Heart J and Eur Respir J 2009
increased velocity of pulmonary valve regurgitation short AcT increased dimensions of RH chambers abnormal shape and function of the IVS increased RV wall thickness and dilated main PA
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
Cateterismo cardiaco destro
Permette di misurare quanto descritto nella definizione funzionale della PAH
mPAP gt25 mmHg a riposo o gt30 mmHg in corso di esercizio
Gaine et al Lancet 1998352719
IP all rsquoEcocardiogramma gt PAPs 30-50 mmHg velocitagrave del rigurgito tricuspidalico di 2834 msec (PADx 5 mmHg)
European Heart Journal 2004 252253
Screening can be effective in identifying earlier disease
1
24
75
12Pa
tie
nts
(
)
63
0
20
40
60
80
100
I II III IV
100
80
60
40
20
0
n = 8(44) n = 5
(28) n = 2
(11)
II III IV
Pa
tie
nts
39
Hachulla E et al Arthritis Rheum 2005 523698-700 Humbert M et al Am J Respir Crit Care Med 2006 1731023-30
No screening With screening
WHO class WHO class
Survival Daily practice vs screening
Humbert Arthritis Rheum 2011 Nov63(11)3522-30
Screening
bull Systemic Sclerosis (10-13)
bull SLE (05-14)
bull MCTD (23-53)
bull RA (lt 1)
bull DM (lt 1)
bull Sjogrenrsquos Syndrome (25 )
bull Undifferentiated and Overlap syndromes
bull Antiphospholipid Syndrome
bull Vasculitis
PAH associated to CTD
1 Pulmonary arterial hypertension
bull Associated with CTD
3 PH due to lung diseasehypoxia
bull Interstitial lung disease (fibrosis)
2PH due to left heart disease
bull Systolicdiastolic dysfunction
bull Valvyular disease
PHin
CTD
PH associated with CTD
Pumonary VascularDisease
InterstitialFibrosis
PAHPH associated to SSc
lcSSc dcSSc
50-90 8-50
Raccomandation for PAH associated with connective tissue disease
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Galiegrave N et al Eur Heart J and Eur Respir J 2009
1 Pulmonary arterial hypertension
2 PH ass with left heart disease
3 PH ass with lung diseases
4 PH due to chronic TE disease
5 Miscellaneous
35
79
10
15
6
Mixed
PH Epidemiology in an Echo lab (Armadale study)
Gabbay et al Am J Resp Crit Care Med 2007175A713
Prevalence of PH (SPAPgt 40 mmHg) among 4579 pts 105
Pulmonary Arterial Hypertension (group 1)Associated Conditions
1Pulmonary Arterial Hypertension11 Idiopathic PAH12 Heritable PAH121 BMPR2122 ALK-1ENGSMAD9CAV1KCNK3123 Unknown13 Drugs and toxins induced
14 Associated with141 Connective tissue disease142 HIV infection143 Portal hypertension144 Congenital Heart diseases (table)145 Schistosomiasis
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Non-invasive assessment of PH
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
PH PresentPeak TRV
(ms)ePASP (mmHg)
Additional Echo Signs of
PHRE
Unlikely lt28 lt35 No I-B
Possiblelt28 lt35 Yes IIa-C
29 ndash 34 36 ndash 50 NoYes IIa-C
Likely gt34 gt50 NoYes I-B
Table 9 Arbitrary Echo Criteria for estimating the presence of PH based on TRV an assumed RAP of 5 mmHg and additional Echo variables suggestive of PH
Galiegrave N et al Eur Heart J and Eur Respir J 2009
increased velocity of pulmonary valve regurgitation short AcT increased dimensions of RH chambers abnormal shape and function of the IVS increased RV wall thickness and dilated main PA
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
Cateterismo cardiaco destro
Permette di misurare quanto descritto nella definizione funzionale della PAH
mPAP gt25 mmHg a riposo o gt30 mmHg in corso di esercizio
Gaine et al Lancet 1998352719
IP all rsquoEcocardiogramma gt PAPs 30-50 mmHg velocitagrave del rigurgito tricuspidalico di 2834 msec (PADx 5 mmHg)
European Heart Journal 2004 252253
Screening can be effective in identifying earlier disease
1
24
75
12Pa
tie
nts
(
)
63
0
20
40
60
80
100
I II III IV
100
80
60
40
20
0
n = 8(44) n = 5
(28) n = 2
(11)
II III IV
Pa
tie
nts
39
Hachulla E et al Arthritis Rheum 2005 523698-700 Humbert M et al Am J Respir Crit Care Med 2006 1731023-30
No screening With screening
WHO class WHO class
Survival Daily practice vs screening
Humbert Arthritis Rheum 2011 Nov63(11)3522-30
Screening
bull Systemic Sclerosis (10-13)
bull SLE (05-14)
bull MCTD (23-53)
bull RA (lt 1)
bull DM (lt 1)
bull Sjogrenrsquos Syndrome (25 )
bull Undifferentiated and Overlap syndromes
bull Antiphospholipid Syndrome
bull Vasculitis
PAH associated to CTD
1 Pulmonary arterial hypertension
bull Associated with CTD
3 PH due to lung diseasehypoxia
bull Interstitial lung disease (fibrosis)
2PH due to left heart disease
bull Systolicdiastolic dysfunction
bull Valvyular disease
PHin
CTD
PH associated with CTD
Pumonary VascularDisease
InterstitialFibrosis
PAHPH associated to SSc
lcSSc dcSSc
50-90 8-50
Raccomandation for PAH associated with connective tissue disease
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
1 Pulmonary arterial hypertension
2 PH ass with left heart disease
3 PH ass with lung diseases
4 PH due to chronic TE disease
5 Miscellaneous
35
79
10
15
6
Mixed
PH Epidemiology in an Echo lab (Armadale study)
Gabbay et al Am J Resp Crit Care Med 2007175A713
Prevalence of PH (SPAPgt 40 mmHg) among 4579 pts 105
Pulmonary Arterial Hypertension (group 1)Associated Conditions
1Pulmonary Arterial Hypertension11 Idiopathic PAH12 Heritable PAH121 BMPR2122 ALK-1ENGSMAD9CAV1KCNK3123 Unknown13 Drugs and toxins induced
14 Associated with141 Connective tissue disease142 HIV infection143 Portal hypertension144 Congenital Heart diseases (table)145 Schistosomiasis
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Non-invasive assessment of PH
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
PH PresentPeak TRV
(ms)ePASP (mmHg)
Additional Echo Signs of
PHRE
Unlikely lt28 lt35 No I-B
Possiblelt28 lt35 Yes IIa-C
29 ndash 34 36 ndash 50 NoYes IIa-C
Likely gt34 gt50 NoYes I-B
Table 9 Arbitrary Echo Criteria for estimating the presence of PH based on TRV an assumed RAP of 5 mmHg and additional Echo variables suggestive of PH
Galiegrave N et al Eur Heart J and Eur Respir J 2009
increased velocity of pulmonary valve regurgitation short AcT increased dimensions of RH chambers abnormal shape and function of the IVS increased RV wall thickness and dilated main PA
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
Cateterismo cardiaco destro
Permette di misurare quanto descritto nella definizione funzionale della PAH
mPAP gt25 mmHg a riposo o gt30 mmHg in corso di esercizio
Gaine et al Lancet 1998352719
IP all rsquoEcocardiogramma gt PAPs 30-50 mmHg velocitagrave del rigurgito tricuspidalico di 2834 msec (PADx 5 mmHg)
European Heart Journal 2004 252253
Screening can be effective in identifying earlier disease
1
24
75
12Pa
tie
nts
(
)
63
0
20
40
60
80
100
I II III IV
100
80
60
40
20
0
n = 8(44) n = 5
(28) n = 2
(11)
II III IV
Pa
tie
nts
39
Hachulla E et al Arthritis Rheum 2005 523698-700 Humbert M et al Am J Respir Crit Care Med 2006 1731023-30
No screening With screening
WHO class WHO class
Survival Daily practice vs screening
Humbert Arthritis Rheum 2011 Nov63(11)3522-30
Screening
bull Systemic Sclerosis (10-13)
bull SLE (05-14)
bull MCTD (23-53)
bull RA (lt 1)
bull DM (lt 1)
bull Sjogrenrsquos Syndrome (25 )
bull Undifferentiated and Overlap syndromes
bull Antiphospholipid Syndrome
bull Vasculitis
PAH associated to CTD
1 Pulmonary arterial hypertension
bull Associated with CTD
3 PH due to lung diseasehypoxia
bull Interstitial lung disease (fibrosis)
2PH due to left heart disease
bull Systolicdiastolic dysfunction
bull Valvyular disease
PHin
CTD
PH associated with CTD
Pumonary VascularDisease
InterstitialFibrosis
PAHPH associated to SSc
lcSSc dcSSc
50-90 8-50
Raccomandation for PAH associated with connective tissue disease
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Pulmonary Arterial Hypertension (group 1)Associated Conditions
1Pulmonary Arterial Hypertension11 Idiopathic PAH12 Heritable PAH121 BMPR2122 ALK-1ENGSMAD9CAV1KCNK3123 Unknown13 Drugs and toxins induced
14 Associated with141 Connective tissue disease142 HIV infection143 Portal hypertension144 Congenital Heart diseases (table)145 Schistosomiasis
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Non-invasive assessment of PH
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
PH PresentPeak TRV
(ms)ePASP (mmHg)
Additional Echo Signs of
PHRE
Unlikely lt28 lt35 No I-B
Possiblelt28 lt35 Yes IIa-C
29 ndash 34 36 ndash 50 NoYes IIa-C
Likely gt34 gt50 NoYes I-B
Table 9 Arbitrary Echo Criteria for estimating the presence of PH based on TRV an assumed RAP of 5 mmHg and additional Echo variables suggestive of PH
Galiegrave N et al Eur Heart J and Eur Respir J 2009
increased velocity of pulmonary valve regurgitation short AcT increased dimensions of RH chambers abnormal shape and function of the IVS increased RV wall thickness and dilated main PA
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
Cateterismo cardiaco destro
Permette di misurare quanto descritto nella definizione funzionale della PAH
mPAP gt25 mmHg a riposo o gt30 mmHg in corso di esercizio
Gaine et al Lancet 1998352719
IP all rsquoEcocardiogramma gt PAPs 30-50 mmHg velocitagrave del rigurgito tricuspidalico di 2834 msec (PADx 5 mmHg)
European Heart Journal 2004 252253
Screening can be effective in identifying earlier disease
1
24
75
12Pa
tie
nts
(
)
63
0
20
40
60
80
100
I II III IV
100
80
60
40
20
0
n = 8(44) n = 5
(28) n = 2
(11)
II III IV
Pa
tie
nts
39
Hachulla E et al Arthritis Rheum 2005 523698-700 Humbert M et al Am J Respir Crit Care Med 2006 1731023-30
No screening With screening
WHO class WHO class
Survival Daily practice vs screening
Humbert Arthritis Rheum 2011 Nov63(11)3522-30
Screening
bull Systemic Sclerosis (10-13)
bull SLE (05-14)
bull MCTD (23-53)
bull RA (lt 1)
bull DM (lt 1)
bull Sjogrenrsquos Syndrome (25 )
bull Undifferentiated and Overlap syndromes
bull Antiphospholipid Syndrome
bull Vasculitis
PAH associated to CTD
1 Pulmonary arterial hypertension
bull Associated with CTD
3 PH due to lung diseasehypoxia
bull Interstitial lung disease (fibrosis)
2PH due to left heart disease
bull Systolicdiastolic dysfunction
bull Valvyular disease
PHin
CTD
PH associated with CTD
Pumonary VascularDisease
InterstitialFibrosis
PAHPH associated to SSc
lcSSc dcSSc
50-90 8-50
Raccomandation for PAH associated with connective tissue disease
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Non-invasive assessment of PH
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
PH PresentPeak TRV
(ms)ePASP (mmHg)
Additional Echo Signs of
PHRE
Unlikely lt28 lt35 No I-B
Possiblelt28 lt35 Yes IIa-C
29 ndash 34 36 ndash 50 NoYes IIa-C
Likely gt34 gt50 NoYes I-B
Table 9 Arbitrary Echo Criteria for estimating the presence of PH based on TRV an assumed RAP of 5 mmHg and additional Echo variables suggestive of PH
Galiegrave N et al Eur Heart J and Eur Respir J 2009
increased velocity of pulmonary valve regurgitation short AcT increased dimensions of RH chambers abnormal shape and function of the IVS increased RV wall thickness and dilated main PA
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
Cateterismo cardiaco destro
Permette di misurare quanto descritto nella definizione funzionale della PAH
mPAP gt25 mmHg a riposo o gt30 mmHg in corso di esercizio
Gaine et al Lancet 1998352719
IP all rsquoEcocardiogramma gt PAPs 30-50 mmHg velocitagrave del rigurgito tricuspidalico di 2834 msec (PADx 5 mmHg)
European Heart Journal 2004 252253
Screening can be effective in identifying earlier disease
1
24
75
12Pa
tie
nts
(
)
63
0
20
40
60
80
100
I II III IV
100
80
60
40
20
0
n = 8(44) n = 5
(28) n = 2
(11)
II III IV
Pa
tie
nts
39
Hachulla E et al Arthritis Rheum 2005 523698-700 Humbert M et al Am J Respir Crit Care Med 2006 1731023-30
No screening With screening
WHO class WHO class
Survival Daily practice vs screening
Humbert Arthritis Rheum 2011 Nov63(11)3522-30
Screening
bull Systemic Sclerosis (10-13)
bull SLE (05-14)
bull MCTD (23-53)
bull RA (lt 1)
bull DM (lt 1)
bull Sjogrenrsquos Syndrome (25 )
bull Undifferentiated and Overlap syndromes
bull Antiphospholipid Syndrome
bull Vasculitis
PAH associated to CTD
1 Pulmonary arterial hypertension
bull Associated with CTD
3 PH due to lung diseasehypoxia
bull Interstitial lung disease (fibrosis)
2PH due to left heart disease
bull Systolicdiastolic dysfunction
bull Valvyular disease
PHin
CTD
PH associated with CTD
Pumonary VascularDisease
InterstitialFibrosis
PAHPH associated to SSc
lcSSc dcSSc
50-90 8-50
Raccomandation for PAH associated with connective tissue disease
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Non-invasive assessment of PH
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
PH PresentPeak TRV
(ms)ePASP (mmHg)
Additional Echo Signs of
PHRE
Unlikely lt28 lt35 No I-B
Possiblelt28 lt35 Yes IIa-C
29 ndash 34 36 ndash 50 NoYes IIa-C
Likely gt34 gt50 NoYes I-B
Table 9 Arbitrary Echo Criteria for estimating the presence of PH based on TRV an assumed RAP of 5 mmHg and additional Echo variables suggestive of PH
Galiegrave N et al Eur Heart J and Eur Respir J 2009
increased velocity of pulmonary valve regurgitation short AcT increased dimensions of RH chambers abnormal shape and function of the IVS increased RV wall thickness and dilated main PA
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
Cateterismo cardiaco destro
Permette di misurare quanto descritto nella definizione funzionale della PAH
mPAP gt25 mmHg a riposo o gt30 mmHg in corso di esercizio
Gaine et al Lancet 1998352719
IP all rsquoEcocardiogramma gt PAPs 30-50 mmHg velocitagrave del rigurgito tricuspidalico di 2834 msec (PADx 5 mmHg)
European Heart Journal 2004 252253
Screening can be effective in identifying earlier disease
1
24
75
12Pa
tie
nts
(
)
63
0
20
40
60
80
100
I II III IV
100
80
60
40
20
0
n = 8(44) n = 5
(28) n = 2
(11)
II III IV
Pa
tie
nts
39
Hachulla E et al Arthritis Rheum 2005 523698-700 Humbert M et al Am J Respir Crit Care Med 2006 1731023-30
No screening With screening
WHO class WHO class
Survival Daily practice vs screening
Humbert Arthritis Rheum 2011 Nov63(11)3522-30
Screening
bull Systemic Sclerosis (10-13)
bull SLE (05-14)
bull MCTD (23-53)
bull RA (lt 1)
bull DM (lt 1)
bull Sjogrenrsquos Syndrome (25 )
bull Undifferentiated and Overlap syndromes
bull Antiphospholipid Syndrome
bull Vasculitis
PAH associated to CTD
1 Pulmonary arterial hypertension
bull Associated with CTD
3 PH due to lung diseasehypoxia
bull Interstitial lung disease (fibrosis)
2PH due to left heart disease
bull Systolicdiastolic dysfunction
bull Valvyular disease
PHin
CTD
PH associated with CTD
Pumonary VascularDisease
InterstitialFibrosis
PAHPH associated to SSc
lcSSc dcSSc
50-90 8-50
Raccomandation for PAH associated with connective tissue disease
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
PH PresentPeak TRV
(ms)ePASP (mmHg)
Additional Echo Signs of
PHRE
Unlikely lt28 lt35 No I-B
Possiblelt28 lt35 Yes IIa-C
29 ndash 34 36 ndash 50 NoYes IIa-C
Likely gt34 gt50 NoYes I-B
Table 9 Arbitrary Echo Criteria for estimating the presence of PH based on TRV an assumed RAP of 5 mmHg and additional Echo variables suggestive of PH
Galiegrave N et al Eur Heart J and Eur Respir J 2009
increased velocity of pulmonary valve regurgitation short AcT increased dimensions of RH chambers abnormal shape and function of the IVS increased RV wall thickness and dilated main PA
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
Cateterismo cardiaco destro
Permette di misurare quanto descritto nella definizione funzionale della PAH
mPAP gt25 mmHg a riposo o gt30 mmHg in corso di esercizio
Gaine et al Lancet 1998352719
IP all rsquoEcocardiogramma gt PAPs 30-50 mmHg velocitagrave del rigurgito tricuspidalico di 2834 msec (PADx 5 mmHg)
European Heart Journal 2004 252253
Screening can be effective in identifying earlier disease
1
24
75
12Pa
tie
nts
(
)
63
0
20
40
60
80
100
I II III IV
100
80
60
40
20
0
n = 8(44) n = 5
(28) n = 2
(11)
II III IV
Pa
tie
nts
39
Hachulla E et al Arthritis Rheum 2005 523698-700 Humbert M et al Am J Respir Crit Care Med 2006 1731023-30
No screening With screening
WHO class WHO class
Survival Daily practice vs screening
Humbert Arthritis Rheum 2011 Nov63(11)3522-30
Screening
bull Systemic Sclerosis (10-13)
bull SLE (05-14)
bull MCTD (23-53)
bull RA (lt 1)
bull DM (lt 1)
bull Sjogrenrsquos Syndrome (25 )
bull Undifferentiated and Overlap syndromes
bull Antiphospholipid Syndrome
bull Vasculitis
PAH associated to CTD
1 Pulmonary arterial hypertension
bull Associated with CTD
3 PH due to lung diseasehypoxia
bull Interstitial lung disease (fibrosis)
2PH due to left heart disease
bull Systolicdiastolic dysfunction
bull Valvyular disease
PHin
CTD
PH associated with CTD
Pumonary VascularDisease
InterstitialFibrosis
PAHPH associated to SSc
lcSSc dcSSc
50-90 8-50
Raccomandation for PAH associated with connective tissue disease
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
PH PresentPeak TRV
(ms)ePASP (mmHg)
Additional Echo Signs of
PHRE
Unlikely lt28 lt35 No I-B
Possiblelt28 lt35 Yes IIa-C
29 ndash 34 36 ndash 50 NoYes IIa-C
Likely gt34 gt50 NoYes I-B
Table 9 Arbitrary Echo Criteria for estimating the presence of PH based on TRV an assumed RAP of 5 mmHg and additional Echo variables suggestive of PH
Galiegrave N et al Eur Heart J and Eur Respir J 2009
increased velocity of pulmonary valve regurgitation short AcT increased dimensions of RH chambers abnormal shape and function of the IVS increased RV wall thickness and dilated main PA
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
Cateterismo cardiaco destro
Permette di misurare quanto descritto nella definizione funzionale della PAH
mPAP gt25 mmHg a riposo o gt30 mmHg in corso di esercizio
Gaine et al Lancet 1998352719
IP all rsquoEcocardiogramma gt PAPs 30-50 mmHg velocitagrave del rigurgito tricuspidalico di 2834 msec (PADx 5 mmHg)
European Heart Journal 2004 252253
Screening can be effective in identifying earlier disease
1
24
75
12Pa
tie
nts
(
)
63
0
20
40
60
80
100
I II III IV
100
80
60
40
20
0
n = 8(44) n = 5
(28) n = 2
(11)
II III IV
Pa
tie
nts
39
Hachulla E et al Arthritis Rheum 2005 523698-700 Humbert M et al Am J Respir Crit Care Med 2006 1731023-30
No screening With screening
WHO class WHO class
Survival Daily practice vs screening
Humbert Arthritis Rheum 2011 Nov63(11)3522-30
Screening
bull Systemic Sclerosis (10-13)
bull SLE (05-14)
bull MCTD (23-53)
bull RA (lt 1)
bull DM (lt 1)
bull Sjogrenrsquos Syndrome (25 )
bull Undifferentiated and Overlap syndromes
bull Antiphospholipid Syndrome
bull Vasculitis
PAH associated to CTD
1 Pulmonary arterial hypertension
bull Associated with CTD
3 PH due to lung diseasehypoxia
bull Interstitial lung disease (fibrosis)
2PH due to left heart disease
bull Systolicdiastolic dysfunction
bull Valvyular disease
PHin
CTD
PH associated with CTD
Pumonary VascularDisease
InterstitialFibrosis
PAHPH associated to SSc
lcSSc dcSSc
50-90 8-50
Raccomandation for PAH associated with connective tissue disease
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Hoeper et allJacc Vol 62 No 25 Suppl D 2013
Cateterismo cardiaco destro
Permette di misurare quanto descritto nella definizione funzionale della PAH
mPAP gt25 mmHg a riposo o gt30 mmHg in corso di esercizio
Gaine et al Lancet 1998352719
IP all rsquoEcocardiogramma gt PAPs 30-50 mmHg velocitagrave del rigurgito tricuspidalico di 2834 msec (PADx 5 mmHg)
European Heart Journal 2004 252253
Screening can be effective in identifying earlier disease
1
24
75
12Pa
tie
nts
(
)
63
0
20
40
60
80
100
I II III IV
100
80
60
40
20
0
n = 8(44) n = 5
(28) n = 2
(11)
II III IV
Pa
tie
nts
39
Hachulla E et al Arthritis Rheum 2005 523698-700 Humbert M et al Am J Respir Crit Care Med 2006 1731023-30
No screening With screening
WHO class WHO class
Survival Daily practice vs screening
Humbert Arthritis Rheum 2011 Nov63(11)3522-30
Screening
bull Systemic Sclerosis (10-13)
bull SLE (05-14)
bull MCTD (23-53)
bull RA (lt 1)
bull DM (lt 1)
bull Sjogrenrsquos Syndrome (25 )
bull Undifferentiated and Overlap syndromes
bull Antiphospholipid Syndrome
bull Vasculitis
PAH associated to CTD
1 Pulmonary arterial hypertension
bull Associated with CTD
3 PH due to lung diseasehypoxia
bull Interstitial lung disease (fibrosis)
2PH due to left heart disease
bull Systolicdiastolic dysfunction
bull Valvyular disease
PHin
CTD
PH associated with CTD
Pumonary VascularDisease
InterstitialFibrosis
PAHPH associated to SSc
lcSSc dcSSc
50-90 8-50
Raccomandation for PAH associated with connective tissue disease
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Cateterismo cardiaco destro
Permette di misurare quanto descritto nella definizione funzionale della PAH
mPAP gt25 mmHg a riposo o gt30 mmHg in corso di esercizio
Gaine et al Lancet 1998352719
IP all rsquoEcocardiogramma gt PAPs 30-50 mmHg velocitagrave del rigurgito tricuspidalico di 2834 msec (PADx 5 mmHg)
European Heart Journal 2004 252253
Screening can be effective in identifying earlier disease
1
24
75
12Pa
tie
nts
(
)
63
0
20
40
60
80
100
I II III IV
100
80
60
40
20
0
n = 8(44) n = 5
(28) n = 2
(11)
II III IV
Pa
tie
nts
39
Hachulla E et al Arthritis Rheum 2005 523698-700 Humbert M et al Am J Respir Crit Care Med 2006 1731023-30
No screening With screening
WHO class WHO class
Survival Daily practice vs screening
Humbert Arthritis Rheum 2011 Nov63(11)3522-30
Screening
bull Systemic Sclerosis (10-13)
bull SLE (05-14)
bull MCTD (23-53)
bull RA (lt 1)
bull DM (lt 1)
bull Sjogrenrsquos Syndrome (25 )
bull Undifferentiated and Overlap syndromes
bull Antiphospholipid Syndrome
bull Vasculitis
PAH associated to CTD
1 Pulmonary arterial hypertension
bull Associated with CTD
3 PH due to lung diseasehypoxia
bull Interstitial lung disease (fibrosis)
2PH due to left heart disease
bull Systolicdiastolic dysfunction
bull Valvyular disease
PHin
CTD
PH associated with CTD
Pumonary VascularDisease
InterstitialFibrosis
PAHPH associated to SSc
lcSSc dcSSc
50-90 8-50
Raccomandation for PAH associated with connective tissue disease
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
European Heart Journal 2004 252253
Screening can be effective in identifying earlier disease
1
24
75
12Pa
tie
nts
(
)
63
0
20
40
60
80
100
I II III IV
100
80
60
40
20
0
n = 8(44) n = 5
(28) n = 2
(11)
II III IV
Pa
tie
nts
39
Hachulla E et al Arthritis Rheum 2005 523698-700 Humbert M et al Am J Respir Crit Care Med 2006 1731023-30
No screening With screening
WHO class WHO class
Survival Daily practice vs screening
Humbert Arthritis Rheum 2011 Nov63(11)3522-30
Screening
bull Systemic Sclerosis (10-13)
bull SLE (05-14)
bull MCTD (23-53)
bull RA (lt 1)
bull DM (lt 1)
bull Sjogrenrsquos Syndrome (25 )
bull Undifferentiated and Overlap syndromes
bull Antiphospholipid Syndrome
bull Vasculitis
PAH associated to CTD
1 Pulmonary arterial hypertension
bull Associated with CTD
3 PH due to lung diseasehypoxia
bull Interstitial lung disease (fibrosis)
2PH due to left heart disease
bull Systolicdiastolic dysfunction
bull Valvyular disease
PHin
CTD
PH associated with CTD
Pumonary VascularDisease
InterstitialFibrosis
PAHPH associated to SSc
lcSSc dcSSc
50-90 8-50
Raccomandation for PAH associated with connective tissue disease
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Screening can be effective in identifying earlier disease
1
24
75
12Pa
tie
nts
(
)
63
0
20
40
60
80
100
I II III IV
100
80
60
40
20
0
n = 8(44) n = 5
(28) n = 2
(11)
II III IV
Pa
tie
nts
39
Hachulla E et al Arthritis Rheum 2005 523698-700 Humbert M et al Am J Respir Crit Care Med 2006 1731023-30
No screening With screening
WHO class WHO class
Survival Daily practice vs screening
Humbert Arthritis Rheum 2011 Nov63(11)3522-30
Screening
bull Systemic Sclerosis (10-13)
bull SLE (05-14)
bull MCTD (23-53)
bull RA (lt 1)
bull DM (lt 1)
bull Sjogrenrsquos Syndrome (25 )
bull Undifferentiated and Overlap syndromes
bull Antiphospholipid Syndrome
bull Vasculitis
PAH associated to CTD
1 Pulmonary arterial hypertension
bull Associated with CTD
3 PH due to lung diseasehypoxia
bull Interstitial lung disease (fibrosis)
2PH due to left heart disease
bull Systolicdiastolic dysfunction
bull Valvyular disease
PHin
CTD
PH associated with CTD
Pumonary VascularDisease
InterstitialFibrosis
PAHPH associated to SSc
lcSSc dcSSc
50-90 8-50
Raccomandation for PAH associated with connective tissue disease
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Survival Daily practice vs screening
Humbert Arthritis Rheum 2011 Nov63(11)3522-30
Screening
bull Systemic Sclerosis (10-13)
bull SLE (05-14)
bull MCTD (23-53)
bull RA (lt 1)
bull DM (lt 1)
bull Sjogrenrsquos Syndrome (25 )
bull Undifferentiated and Overlap syndromes
bull Antiphospholipid Syndrome
bull Vasculitis
PAH associated to CTD
1 Pulmonary arterial hypertension
bull Associated with CTD
3 PH due to lung diseasehypoxia
bull Interstitial lung disease (fibrosis)
2PH due to left heart disease
bull Systolicdiastolic dysfunction
bull Valvyular disease
PHin
CTD
PH associated with CTD
Pumonary VascularDisease
InterstitialFibrosis
PAHPH associated to SSc
lcSSc dcSSc
50-90 8-50
Raccomandation for PAH associated with connective tissue disease
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
bull Systemic Sclerosis (10-13)
bull SLE (05-14)
bull MCTD (23-53)
bull RA (lt 1)
bull DM (lt 1)
bull Sjogrenrsquos Syndrome (25 )
bull Undifferentiated and Overlap syndromes
bull Antiphospholipid Syndrome
bull Vasculitis
PAH associated to CTD
1 Pulmonary arterial hypertension
bull Associated with CTD
3 PH due to lung diseasehypoxia
bull Interstitial lung disease (fibrosis)
2PH due to left heart disease
bull Systolicdiastolic dysfunction
bull Valvyular disease
PHin
CTD
PH associated with CTD
Pumonary VascularDisease
InterstitialFibrosis
PAHPH associated to SSc
lcSSc dcSSc
50-90 8-50
Raccomandation for PAH associated with connective tissue disease
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
1 Pulmonary arterial hypertension
bull Associated with CTD
3 PH due to lung diseasehypoxia
bull Interstitial lung disease (fibrosis)
2PH due to left heart disease
bull Systolicdiastolic dysfunction
bull Valvyular disease
PHin
CTD
PH associated with CTD
Pumonary VascularDisease
InterstitialFibrosis
PAHPH associated to SSc
lcSSc dcSSc
50-90 8-50
Raccomandation for PAH associated with connective tissue disease
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Pumonary VascularDisease
InterstitialFibrosis
PAHPH associated to SSc
lcSSc dcSSc
50-90 8-50
Raccomandation for PAH associated with connective tissue disease
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Raccomandation for PAH associated with connective tissue disease
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Hachulla et al Arthritis Rheum 2005523792
599 patients
29 had known PAH
570 screened for PAH
The ItineacuterAIR-Scleacuterodermie study
18 (54) PAH confirmed
3 pts (9) PH + LVD 12 (36) pts no PH
RHC
45 ECHO False Positive
33 suspected PAH on Echo
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Evidence-based detection of pulmonary arterialhypertension in systemic sclerosis the DETECT
study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 1
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Nomograms for practical application of the DETECT algorithm STEP 2
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Evidence-based detection of pulmonary arterial
hypertension in systemic sclerosis the DETECT study
Coghlan JG Ann Rheum Dis 2013 May 18 [E-pub ahead of print]
Missed PAH cases
DETECT algorithm
4
ECHO-based approachESC-ERS guidelines
29
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
How effective are drugs in connective tissue disease
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
The PAH-CTD subgroup represents about the 25 of the entire PAH population included in RCTs being the second largest group after IPAH
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EXERCISE CAPACITY
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
LOCF Analysis Mean plusmn 95 confidence interval IPAH n=176 PAH-CTD n=91
IPAH
PAH-CTD
Change from Baseline in 6MWD in IPAH and PAH-CTD long-term response
Years
Chan
ge in
6M
WD
(m)
Impr
ovem
ent
-40
-20
0
20
40
60
80
00 05 10 15 20
Pulido T et al American Thoracic Society Annual Meeting 2009 [Abstract]
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Meta-analysis of 6MWD in RCTs
Avouac J et al Ann Rheum Dis 200867808ndash14
CTD subset of patients
Whole population of PAH patients
ndash05 0 05 10 15 20
Sildenafil 80 mg TID
Sildenafil 40 mg TID
Sildenafil 20 mg TID
Bosentan 250 mg BID
Bosentan 125 mg BID
Effect size
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
PACES-1 study improvements in 6MWD
ITT = intention-to-treat LOCF = last observation carried forward 1 Simonneau G et al Ann Intern Med 2008149521ndash30 2 Unpublished data subgroup analysis Burgress G et al
Chan
ge in
6M
WD
(m)
Sildenafil TID +IV epoprostenol (n=27)
Placebo + IV epoprostenol (n=25)
p= ns
0
5
10
15
20
25
30
35
+35
+96
CTD subgroup (LOCF)2
-10
0
10
20
30
40
50
Baseline 4 8 12 16
Study time week
Mea
n ch
ange
from
bas
elin
e (9
5 C
I) m Sildenafil + IV epoprostenol
Placebo + IV epoprostenol
Overall cohort (ITT)1
p lt0001
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
SPECIFIC EFFECTS OF PAH-TREATMENTS
IN PAH-CTD SUBGROUP
AS REPORTED IN CLINICAL STUDIES
EFFECTS ON OUTCOME
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
PAH-CREST (n = 18)
0
20
40
60
80
100
0 12 24 36 48 60 72
PPH (n = 36)
(Mois)
P = 00005 test du Log-Rank (Mantel-Cox)
Sur
vie
act u
arie
lle
()
(23)
(6)
(11)
(2)
(9)
(1)
Humbert M et al Eur Respir J 1999 Jun13(6)1351-6
Epoprostenol in PAH-CTD outcome
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Time to Clinical Worsening
Time (Wks)
Even
t-Fr
ee s
urvi
val (
)
0
25
50
75
100
0 4 8 12 16 20 24 28
p = 00015
p = 00038
89
63
(n = 144)(n = 69)
(n = 35)(n = 13)
Bosentan
Placebo100
25
50
75
0
Time (Wks)0 4 8 12 16 18
9079
(n = 33)
(n = 14)
B1 ITT Population B1 SSc Subpopulation
Bosentan on PAH-CTD analysis of TCW in Breathe-1 study
Rubin L et al NEJM 2002
p = ns
Even
t-Fr
ee s
urvi
val (
)
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Macitentan
Comments on the published data
bull In the RCTs the improvement of 6MWD is consistently lower in patients with CTD-PAH as compared to IPAH
bull Also the outcome of CTD-PAH patients seems to be worse as compared to the outcome in IPAH
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
CASO CLINICO
bull Donna 53 anni
bull Da circa 10 anni fenomeno di Raynaud
bull Giunge allrsquoosservazione pneumologica per tosse secca e da alcuni anni dispnea per sforzi moderati
bull Agli esami generali Lieve aumento di VES e szlig1 e szlig2 globuline
bull Obiettivitagrave nei limiti
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Prove di funzionalitagrave respiratoria
bull Spirometria nel range della normalitagrave
bull Ostruzione piccole vie aeree
bull DLCO lieve riduzione (59)
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Visita reumatologica
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Nulla di significativo
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
RX Torace
Non lesioni infilatrative parenchimaliNormale la distribuzione del circolo polmonareLiberi i seni costo-frenici
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Cardiologia
Giunge alla nostra osservazione per ecocardiogramma di screening su prescrizione reumatologica
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Obiettivitagrave
bull Riferisce dispnea per sforzi moderati
bull Obiettivitagrave op murmure vescicolare diffuso su tutto lrsquoambito polmonare Oc toni ritmici validi Polsi normoisosfigmici
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Elettrocardiogramma
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
ECOCARDIOGRAMMA
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
ECOCARDIOGRAMMA
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
6 Minute Wolking Test
bull distanza percorsa 510 metri senza interruzioni
bull SpO2 inizio test 95 in aa
bull PA inizio test 16080 mmHg
bull fc inizio test 73 bpm
bull SpO2 fine test 90 in aa
bull PA fine test 15080 mmHg
bull fc inizio test 68 bpm
bull Scala di Borg 3
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Pulmonary Arterial Hypertension in France Results from a National Registry
Am J Respir Crit Care Med Vol 173 pp 1023ndash1030 2006
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Cateterismo destroDate
Baseline
HR (bmin) 95
RAP (mmHg) 7
mPAP (mmHg) 32
PWP (mmHg) 10
BP sd (mmHg) 12155
CI (lminm2) 31
PVR (RU) 43
SVR (RU) 127
Art O2 99
PA O2 783
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Galiegrave N et al Eur Heart J and Eur Respir J 2009
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Bosentan dapprima 625 mg x 2 successivamente 125 x 2 sia per lrsquoipertensione polmonare che per le ulcere digitali
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Why is PHPAH-SSc so difficult to treat
bull Older patients
bull Interstitial lung disease
bull Left ventricular diastolic dysfunction
bull Right ventricular diastolic dysfunction
bull More severe structural vasculopathy and poorly known pathobiology
bull Key outcome measures may differ
bull Poor recognition in the community
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Comments
bull Appropriate diagnosis of the type of PH is
required in CTD patients
bull Echo screening for the detection of PH is
recommended in symptomatic patients with CTD
bull RHC is indicated in all cases of suspected PH to
confirm the diagnosis
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Comments
bull In patients with PAH associated with CTD the
same treatment algorithm as in patients with
IPAH is recommended
bull The efficacy of the specific PAH treatment is
less long-lasting in PAH ndash CTD as compared to
IPAH
bull The use of PAH-specific drug therapy is not
recommended in patients with PH due to lung
Diseases or PH due to left heart disease
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
bull Despite progresses PAH-CTD remains a severe condition (worst prognosis among all PAH clinical types)
bull PAH approved drugs are less effective in patients with PAH-CTD and a more aggressive implementation of combination therapy may be required
bull The role of upfront combination therapy and early triple combination therapy in this subset of patients should be explored
bull Listing for lung transplantation should not be delayed in particular in young patients
Final comments
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
Multi-disciplinary team are requested because of
multiple comorbidities
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella
UO Complessa Medicina InternaSS AnnunziataDirettore Dott F SogariServizio di PneumologiaDott G DrsquoAlagniDottssa ScodittiServizio di Ecografia internisticaDott V Le Grazie
Struttura complessadi Radiologia SS AnnunziataDirettore M RestaDottssa MC Resta
Struttura complessa di Medicina NucleareDirettore F LaurieroDott S Di RosaDott P Moda
Ambulatorio ReumatologiaDott A MarsicoDott Semeraro
UO Complessa CardiologiaSS Annunziata Dirett V RussoS LanzoneS GerundaA Fiorella