This document summarizes information about pulmonary arterial hypertension (PAH) in patients with connective tissue diseases (CTDs). It discusses several key points: - PAH is most prevalent in systemic sclerosis (SSc), occurring in up to 9% of patients. Survival is worse for PAH associated with SSc compared to idiopathic PAH. - Early detection of PAH in SSc is important and can be aided by annual screening with echocardiography, pulmonary function tests, and biomarkers like BNP/NT-proBNP. Stress echocardiography may also help predict PAH. - The DETECT study developed a validated two-step algorithm using non-invasive tests to identify PAH in high

1. 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

2. 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.
…………………………

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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.

9. Survival in patients with PAH associated
with SSc from a Swedish single centre:
prognosis still poor and prediction difficult
Humbert M. JACC 2004Hesselstrand 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)”

10. 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 %

11. 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.

12. PAH-SSc had more echocardiographic evidence of left heart disease
than patients with IPAH
Is there any other difference between
idiopathic and SSc related PAH?
Fisher MR, et al. Arthritis Rheum 2006;54:3043-50.

13. Is there any other difference between
idiopathic and SSc related PAH?
Fisher MR, et al. Arthritis Rheum 2006;54:3043-50.

14. 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%
Fisher MR, et al. Arthritis Rheum 2006;54:3043-50.

15. Is there any other difference between
idiopathic and SSc related PAH?
Fisher MR, et al. Arthritis Rheum 2006;54:3043-50.
PAH-SSc patients are older than IPAH patient (at disease onset)

16. Is Pulmonary Arterial Hypertension Really a Late
Complication of Systemic Sclerosis?
Hachulla E, et al. Chest 2009;136:1211-9.

17. 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

18. 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)

19. 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.

20. 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.

21. 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

22. 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.

23. 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.

24. 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.

25. 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.

26. 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

28. How to confirm PAH in SSc
Right Heart Catheterization

29. Launay D, et al. Chest. 2011 Apr 7. [Epub ahead of print]
What about ILD related PH?

30. 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.

31. PAH and PH in SSc
a “long lung question”
“idiopathic”
PAH?
ILD related
PH?
Increase of PAPs in SSc patients with ILD

32. 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.

33. 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%

34. 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

35. • 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.

36. Immunosuppressive therapy in connective tissue
diseases-associated pulmonary arterial hypertension
Sanchez O, et al. Chest 2006;130:182-9.

37. 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.”

38. 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……………..
……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……………………….
Galié N, et al. Eur Heart J 2009;30:2493–537.

39. 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

40. 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

41. 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

42. 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

43. 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

44. 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

45. 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

46. 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

47. § 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

48. 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.

49. 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

50. Results

51. 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.