icaro 2015 pah e ctd cavagna

Il sospetto di ipertensione polmonare

nel paziente con connettivite

Dr Lorenzo Cavagna

Department of Rheumatology,

University and IRCCS Foundation Policlinico S. Matteo, Pavia

Alma Ticinensis Universitas

Ospitale di S. Matteo

Guidelines for the diagnosis and treatment of

pulmonary hypertension

Some conditions included in PAH group, although presenting similarities with

IPAH, bear sufficient differences to require specific comments……………………

……..Recognition of these differences is critical because they may influence not only

the diagnostic approach but also the global management of PAH……………..

Galié N, et al. Eur Heart J 2009;30:2493–537.

…………………………








………………………… CONNECTIVE TISSUE DISEASES

An epidemiological study of pulmonary

arterial hypertension

Peacock AJ, et al. Eur Respir J 2007;30:104-9.

French national registry

Scottish hospitalisation records (Scottish Morbidity Record)

Scottish Pulmonary Vascular Unit database

Pulmonary

Arterial

hypertension

Antisynthetase

sindrome

Systemic

sclerosis

UCTD

Mixed connective

tissue disease

Rheumatoid

arthritis

Systemic lupus

erythematosus

PM/DM

Sjogren

sindrome

The wide universe of CTD associated Pulmonary

Arterial Hypertension

1. Systemic sclerosis

2. Systemic lupus erythematosus

3. Mixed connective tissue disease

4. Sjogren syndrome

5. Rheumatoid arthritis

6. Idiopathic inflammatory myopathies

7. Antisynthetase syndrome

The epidemiology of PAH in connective

tissue diseases

Avouac J, et al. J Rheumatol 2010;37:2290-8.

9%

Prevalence of pulmonary hypertension in systemic

sclerosis in European Caucasians and metaanalysis

of 5 studies.

Survival in patients with PAH associated

with SSc from a Swedish single centre:

prognosis still poor and prediction difficult

Humbert M. JACC 2004 Hesselstrand R, et al. Scand J Rheumatol 2011;40:127-32.

“The 1-, 2-, 3-, and 4-year survival rates were 86, 59, 39, and

22%, respectively, from diagnosis of PAH. The hazard ratio for

total mortality in the SSc-PAH group was 3.2 [95% confidence

interval (CI) 1.8-5.7] compared to SSc without PAH (p < 0.001)”

Is the survival different between idiopathic

and SSc related PAH?

Humbert M. JACC 2004 Fisher MR, et al. Arthritis Rheum 2006;54:3043-50.

Survival after diagnosis PAH-SSc Idiopathic-PAH

1 year 87.8 % 95.1 %

3 years 48.9 % 83.6 %

Is there any other difference between

idiopathic and SSc related PAH?

SSc PAH lower mean PAP despite similar levels of cardiac index

Fisher MR, et al. Arthritis Rheum 2006;54:3043-50.

PAH-SSc had more echocardiographic evidence of left heart disease

than patients with IPAH




Does pericardial effusion affects the

survival of patients with SSc related PAH?

Humbert M. JACC 2004

No effusion -------- Effusion present

Time (years)

Logrank p-value = 0.043

1 2 3

100%

75%

50%

25%

0%





PAH-SSc patients are older than IPAH patient (at disease onset)

Is Pulmonary Arterial Hypertension Really a Late

Complication of Systemic Sclerosis?

Hachulla E, et al. Chest 2009;136:1211-9.

SSc associated PAH: key points

• High prevalence and incidence

• Worst survival with respect to iPAH

• Lower mean PAP despite similar levels of cardiac index

• High frequency of pericardial effusion and left hearth disease

• Older age at the onset with respect to iPAH

• Not only a late complication of the disease

Pulmonary arterial hypertension in

systemic sclerosis: the need for early

detection and treatment

Proudman SM, et al. Internal Med J 2007;37:485-94.

• ANNUAL Doppler echocardiography

• PFTs + DLCO

• Biochemical markers (BNP)

Comparison of Brain Natriuretic Peptide (BNP) and NT-proBNP in

Screening for Pulmonary Arterial Hypertension in Patients with

Systemic Sclerosis

Cavagna L, et al. J Rheumatol 2010;37:2064-70.

How to suspect PAH in SSc

Meune C, et al. Arthritis Rheum 2011;63:2790-6.

Cochin RPS=0.0001107 x age + 0.0207818 x (100-FVC) + 0.04905 x (150- DLCO/AV)

Prediction of pulmonary hypertension related to systemic sclerosis by

an index based on simple clinical observations

Patients in the highest quintile of Cochin RPS were >35-fold more

likely to develop PH during follow-up than patients in the lowest

quintiles.

The mean Cochin RPS was 1.39±0.56 (range -2.03 to 2.03) in 176 low-,

2.48±0.28 (range 2.04 to 2.98) in 176 intermediate-, and 3.57±0.45

(range 2.98 to 4.77) in 88 high-risk patients.

How to suspect PAH in SSc

D’Alto M, et al. Heart 2011;97:112-7.

Inappropriate exercise-induced increase in pulmonary artery pressure

in patients with systemic sclerosis

controls

SSc

Log-rank p <0.05

PAPS <18 mmHg

PAPS ≥18 mmHg

Stress Doppler echocardiography in systemic sclerosis: evidence for a

role in the prediction of pulmonary hypertension.

Variabile Hazard Ratio IC 95% p

PAPS 1.2 1.03-1.4 <0.05

ILD 4.6 0.37-57.3 ns

RPS (5th quintile) 16.2 1.3-201 <0.05

E/A 0.35 0.26-4.5 ns

TAPSE 0.7 0.5-1.3 ns

Adapted from: Codullo V, et al. Arthritis Rheum 2013;65:2403–11.

Evidence-based detection of pulmonary arterial hypertension in

systemic sclerosis: the DETECT study

Coghlan JG, et al. Ann Rheum Dis 2014;73:1340-1349

Adults with SSc at increased risk of PAH (SSc for >3 years and

predicted pulmonary diffusing capacity for carbon monoxide <60%)

underwent a broad panel of non-invasive assessments followed by

diagnostic right heart catheterisation (RHC). Univariable and

multivariable analyses selected the best discriminatory variables for

identifying PAH. After assessment for clinical plausibility and

feasibility, these were incorporated into a two-step, internally validated

detection algorithm. Nomograms for clinical practice use were

developed.

Evidence-based detection of pulmonary arterial hypertension in

systemic sclerosis: the DETECT study

Coghlan JG, et al. Ann Rheum Dis 2014;73:1340-1349

The novel, evidence-based DETECT algorithm for PAH detection in

SSc is a sensitive, non-invasive tool which minimises missed diagnoses,

identifies milder disease and addresses resource usage.

http://detect-pah.com/pah-risk-

calculator/calculator-step-1

How to confirm PAH in SSc

Right Heart Catheterization

Launay D, et al. Chest. 2011 Apr 7. [Epub ahead of print]

What about ILD related PH?

How to discriminate?

In case of pre-capillary PAH,

FVC/DLCO ratio > 1.6 is an excellent

predictor of development of PH in SSc

Steen VD, et al Arthritis Rheum 1992;35:765-70.

PAH and PH in SSc

a “long lung question”

“idiopathic”

PAH?

ILD related

PH?

Increase of PAPs in SSc patients with ILD

1. Systemic sclerosis

2. Systemic lupus erythematosus (0.5-14%)

3. Mixed connective tissue disease (up to 38%)

4. Sjogren syndrome (rare)

5. Rheumatoid arthritis (rare)

6. Idiopathic inflammatory myopathies (rare)

PAH in connective tissue diseases

Kahler CM, et al. Rheumatology 2006;45(S3):11-3.

Is the survival different between idiopathic

and CTDs related PAH?

Humbert M. JACC 2004 Fisher MR, et al. Arthritis Rheum 2006;54:3043-50.

Survival after

diagnosis

PAH-SLE PAH –SS Idiopathic-PAH

1 year 87.8 % 73% 95.1 %

3 years 45% 66% 83.6 %

5 years 17% 68%

Factors associated with pulmonary

hypertension appearence in patients with CTDs

Vegh J, et al. Scand J Immunol 2006;64:69-76.

Launay D, et al. Medicine 2007;86:299-315.

Galiè N, et al. Lupus 2005;14:713-7.

Tanaseanu C, et al. Eur J Med Res 2007 ;12:145-51.

Cavagna L, et al. Arthritis Care Res (Hoboken)

2011;63:633-4.

1. Anti-U1 RNP autoantibodies (MCTD)

2. AECA (MCTD)

3. Anti-Ro/SSA antibodies (Sjogren syndrome, SLE)

4. Anti-U3 RNP (SSc)

5. Anti-fibrillarina (SLE)

6. Anti-Jo1

1. Anticardiolipin and antiB2GPI antibodies

2. ILD

PAH

PH

• 28 patients (13 SLE, 8 MCTD, 5 lSSc, 1 dSSc, 1 RA) with PAH

– Monthly I.V. CTX bolus (600 mg/m2) for at least 3 months

– Metilprednisolone 0.5-1 mg/kg/day P.O. (22 out of 28)

Immunosuppressive therapy in connective tissue

diseases-associated pulmonary arterial hypertension

Sanchez O, et al. Chest 2006;130:182-9.

Immunosuppressive therapy in connective tissue

diseases-associated pulmonary arterial hypertension

Sanchez O, et al. Chest 2006;130:182-9.

Immunosuppressive therapy in lupus and Mixed

connective tissue disease associated pulmonary

arterial hypertension

Jais X, et al. Arthritis Rheum 2008;58:521-31.

“PAH associated with SLE or MCTD may respond to a

treatment combining cyclophosphamide and

glucocorticoids. Patients who could benefit from this

immunosuppressive therapy could be those who have less

severe disease at baseline. For patients with more severe

disease, pulmonary vasodilators should be started,

possibly in combination with immunosuppressants.”







……In CTD associated PAH, symptoms and clinical presentation are very similar to

those of IPAH and occasional patients thought to have IPAH can be identified as

having an associated CTD……………………….


TAKE CARE

“symptoms and signs of CTDs are frequently pleiotropic

and not always easily recognizable/associable, so that

CTD diagnosis can be challenging”

Pleurisy

Dry eye

Dry mouth

Alopecia

Arthralgias

Oral ulcers

Photosensitivity

Sclerodactily Raynaud’s phenomenon

Teleangectasias

UNDIAGNOSED CONNECTIVE TISSUE DISEASES IN

PULMONARY ARTERIAL HYPERTENSION (PAH)

PATIENTS: BASELINE AND FOLLOW-UP RESULTS

FROM A PAH REFERRAL CENTRE

Cavagna L, et al. Submitted

CTDs represent the second cause of PAH after idiopathic forms in the registries up to

now available.

Up to now prevalence data of CTD associated PAH raise from the regular follow-up of

patients with established diagnosis of CTD.

In the case of SSc, new criteria have been released in 2013 and PAH is one of the new

items included, recognizing the fact that this manifestation could represent the onset of

the disease as the first non Raynaud’s symptom

No data reported the prevalence of undiagnosed CTDs in patients with precapillary

hypertension.

Background

The study was aimed to evaluate the prevalence of undiagnosed

CTDs among patients referring to a tertiary cardiology centre with

right heart catheterization (RHC)-confirmed PAH, without previous

rheumatology referral and diagnosed/suspected for iPAH.

Objective

The first 50 patients with precapillary-PAH confirmed at right heart

catheterization (RHC), consecutively assessed after 2009 at the

Cardiology Division of the University Hospital of Pavia, without

previous CTD diagnosis, rheumatology referral, or the occurrence

of other conditions explaining PAH, were evaluated for the

occurrence of CTDs.

Methods

Assessment:

• CTD simptoms/signs/previous laboratory results

• Nailfold capillaroscopy, chest computed tomography (HR and

angiographic technique)

• ANA (indirect immunofluorescence), anti-ENA (ELiA), anti-

dsDNA (indirect immunofluorescence) and antiphospholipids

(ELISA) antibodies (double positivity required in all cases).

Methods

Patients assessed: 50 (37 females, 13 males)

Patients enrolled: 49 (36 females, 13 males)

One patient one refused rheumatology assessment and thus withdrew

from the study

Results

Patients with confirmed idiopathic PAH:

• 32 (21 F, 11 M)

Patients with new diagnosis of CTD associated PAH:

• 17 (15 F, 2 M)

• 12 SSc (11 F, 1 M)

• 2 SLE (2 F)

• 2 UCTD (1 F, 1 M)

• 1 SS (F)

Results

§ Scleroderma pattern late: 5 patients, Scleroderma pattern active: 5 patients. * Scleroderma pattern late

All CTD (17

patients)

SSc associated

PAH

(12 patients)

Other-CTDs associated

PAH (5 patients)

Idiopathic PAH

(32 patients)

Raynaud’s phenomenon 10 10 0 0

Scleroderma pattern (nailfold

capillaroscopy)

11 10§ 1* 0

ANA + (> 1/160 IFI) 16 11 5 8

Anticentromere antibodies 9 9 0 0

Anti-Ro antibodies 4 2 2 1

Antiphospholipid antibodies or LAC 3 1 2 2

Teleangectasias 6 6 0 0

Sclerodactyly 6 6 0 0

Dysphagia 7 7 0 0

Pitting scars 1 1 0 0

Arthritis-arthralgias 3 1 2 0

Low degree ILD (Kazerooni score < 3) 3 2 1 0

Oral ulcers 2 0 2 0

Photosensitivity 3 1 2 0

Dry eye or mouth/Schirmer’s test and

scialometry +

3/2 1/0 2/2 0

Serositis 2 1 1 0

Fever 1 0 1 0

Alopecia 11 0 1 2

Low platelet and WBC 1 0 1 1

SSc associated

PAH (12

patients)

P

value*

Confirmed iPAH

(32 patients)

P value* All CTD associated

PAH (17 patients)

Female, n (%) 11 (91.7) 0.13 21 (65.6) 0.10 15 (88.2)

Age (years), median (IQR) 73 (64.5-76.5) 0.01 58 (46.5-73) 0.24 67 (55-76)

Delay between dyspnea onset and

first RHC (months), median

(IQR)

8.5 (6-14.5) 0.14 6 (3.5-9) 0.21 8 (6-12)

NYHA class at at first RHC , n

(%)

I/II 6 (50) 0.50 20 (62.5) 1.00 10 (58.8)

III/IV 6 (50) 12 (37.5) 7 (41.2)

BNP levels (pg/ml) at first RHC,

median (IQR)

267.5 (202.5-667) 0.19 214 (104-432) 0.81 215 (73-471)

Creatinine clearance

(ml/min/1.73 m2) at first RHC,

median (IQR)

74.9 (59.6-86.1) 0.03 93.6 (62.8- 106.8) 0.11 82.7 (63.7-94.6)

mean PAPs (mmHg) at first

RHC, median (IQR)

47 (29-54) 0.23 47.5 (34-57) 0.12 44 (30-53)

cardiac index (L/min/m2) at first

RHC, median (IQR)

2.25 (1.79-2.85) 0.90 2.28 (1.84, 2.56) 0.77 2.27 (1.84, 2.7)

pulmonary vascular resistances

(dyne*sec*cm-5) at first RHC

878 (705-1125) 0.47 791 (512.7-987) 0.88 748 (516-1028)

* with respect to confirmed iPAH.

ANA positivity was associated with a sensitivity of 94% (95%CI

71.3-99.9%) and a specificity of 78.1% (60-90.7%) for a

diagnosis of CTD-associated-PAH, while Raynaud’s

phenomenon was associated with a sensitivity of 83.3%

(95%CI 51.6-97.9%) and a specificity of 100% (90.5-100%) for

a diagnosis of SSc-associated-PAH

Results

Results

Conclusions

Our results showed a high prevalence of undiagnosed CTDs, particularly

SSc, in patients with iPAH and without a previous rheumatological assessment. All

patients in our series with Raynaud’s phenomenon were diagnosed with SSc. The

reported prevalence of Raynaud’s phenomenon in iPAH ranges from 5 to 30% of

cases and this might be accounted by the high prevalence of an undiagnosed

rheumatic disease in these cohorts. ANA positivity is another factor that may help

clinicians in the assessment of the patients, frequently without overt signs of CTD.

Our data stress the importance of a rheumatological assessment in PAH, especially

because of the unfavourable prognostic impact of an associated SSc in these patients.

icaro 2015 pah e ctd cavagna

Health & Medicine

diagnosis of pah

sscpah group

epidemiology of pah

ssc related pah

global management of

ssc pah lower mean pap

connective tissue diseases

eur heart j