This document discusses pulmonary hypertension (PH) in patients with connective tissue diseases (CTD). It finds that treatment is less effective for CTD-associated PH (CTD-PAH) compared to idiopathic PAH, with less improvement in walking distance and higher rates of clinical worsening. Combination therapy may be more effective than monotherapy for CTD-PAH. The prognosis of CTD-PAH patients is better if they are short-term responders to treatment or were initially treated with glucocorticoids and immunosuppressants upon PAH and CTD diagnosis. However, treatment outcomes are worse if CTD-PAH patients also have interstitial lung disease. Right ventricular size measured

1. Pulmonary hypertension
in rheumatic diseases
三軍總醫院 風濕免疫過敏科 盧俊吉醫師

2. Pulmonary hypertension classification (2013)
BMJ 2018;360:j5492
Simonneau G, et al. J Am Coll Cardiol 2013;62(25 Suppl):D34-41

3. Pulmonary hypertension classification (2013)
BMJ 2018;360:j5492
Simonneau G, et al. J Am Coll Cardiol 2013;62(25 Suppl):D34-41

4. FI GU RE 1 Algorith
diagnose pulmonary hyp
pulmonary arterial hyper
patients with connective
(CTD). (1) Signs include
sound and peripheral oed
included dyspnoea on re
fatigue, presyncope/sync
palpitations, dizziness an
(2) Sclerodactyly, nail fo
abnormalities and/or scle
autoantibodies. (3) Lymp
enlargement, centrilobula
opacities and/or septal lin
sclerosis; PFT, pulmonar
TTE, transthoracic echoc
proBNP, N-terminal pro-
peptide; RHC, right hear
mPAP, mean pulmonary
BoPAP, borderline pulm
pressure; PAWP, pulmon
pressure; V/Q, ventilation
computed tomography; I
disease; TLC, total lung
pulmonary veno-occlusiv

5. Diagnostic testing algorithm for PAH
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J Am Coll Cardiol 2009;53:1573-1619

6. Methodologies for detecting PAH
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7. Methodologies for detecting PAH
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8. Apical four chamber
view echocardiography
showing severe RV
dilatation and short
axis view showing
flattened D shaped
interventricular
septum.
(F) Ventilation/perfusion scan
showing patchy perfusion defects
(“moth eaten” appearance).
(G) Pulmonary function test
showing isolated moderate
reduction in DLCO with normal
volumes.
(H) Right heart catheterization
data showing severely elevated PA
pressures and pulmonary vascular
resistance with normal pulmonary
capillary wedge pressure (PCWP)
typical of PAH. Cardiac output
(CO) is reduced with normal right
atrial (RA) pressure.
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10. Mechanisms implicated in
pathogenesis of PAH
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11. Mechanisms implicated in
pathogenesis of PAH
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12. Inflammatory and immunological factors
involved in the pathogenesis of CTD-PAH
Experimental Biology and Medicine 2019; 244: 120–131

13. • cDC and monocyte migration toward lung tertiary lymphoid
organs in IPAH and autoimmune disease (AD) patients.
• cDC subset distribution and function in IPAH, CTD-PAH, and Ads.
Front Immunol. 2019 Jan 22;10:11.

14. Involvement of DCs and monocyte in lungs of
IPAH and CTD-PAH patients
Front Immunol. 2019 Jan 22;10:11.

15. The dysregulated immune response asso- ciated with
iPAH or hPAH may be related in part to DC dysfunction
and to increased Th17 immune polarization
CHEST 2015; 147(6):1610-1620

16. • Treg are dysfunctional in patients with IPAH, heritable PAH, and
CTD-PAH
• Circulating leptin is increased in patients with iPAH and SSc-PAH
• Pulmonary endothelial cells dysfunction may lead to altered
Treg cells via excessive leptin secretion
CHEST 2016; 149:1482-1493

17. Pathogenesis of PAH
• Characterization of a cancer-like phenotype in PAH that accounts for the obstructive
pulmonary vasculopathy. This is defined by altered mitochondrial metabolic
function (Warburg metabolism) and mitochondrial dynamic function
(fragmentation). These changes drive cell proliferation and impair apoptosis. They
are downstream from genetic mechanisms, such as BMPR2 mutation, and
epigenetic mechanisms
• PAH is promoted by genetic and epigenetic factors that contribute to disease
pathogenesis. The most common genetic mechanism is mutation of BMPR2
• PAH is in part a disease of altered immunity and increased inflammation. Improved
understanding of the role of chronic inflammation, fibrosis, and immune mediated
mechanisms offers potential therapies to reverse adverse vascular remodeling
• PAH is predominantly a disease of women, although afflicted men have worse
prognosis. There is an emerging appreciation for the importance of sex differences
in the incidence, therapeutic responsiveness, and outcomes of PAH
• Patients with PAH die from right ventricular failure. There is an increasing
recognition of the unique embryologic origins and response to increased afterload
of the right ventricle, and the crucial role that right ventricular adaptation plays,
both in determining prognosis and as a target for therapy. It seems that the
ischemic, metabolically remodeled right ventricle in PAH is an example of
hibernating myocardium

18. Mitochondrial fragmentation in PAH
BMJ 2018;360:j5492

19. Epigenetic mechanisms in PAH
• DNA methylation—DNA methylation involves the covalent attachment
of a methyl group to cytosine residues in CpG dinucleotide sequences.
Methylation occurs in CpG rich regions of the genome known as CpG
islands. These CpG islands are usually near the gene promoters, and
their hypermethylation interferes with gene transcription
• Histone acetylation—The modification of histones influences the
transcriptional activity of genes through
the regulation of their accessibility to transcription
factors. Histone acetylation, which is associated with increased
transcriptional activity, is carried out by histone acetyltransferases and
reversed by histone deacetylases
• Production of micro-RNA—miRs are encoded by intronic DNA and
regulate gene expression through RNA interference. Short (20-22
nucleotide) segments of RNA bind to complementary sequences in the
3′-untranslated region of mRNA, leading to mRNA degradation or the
repression of translation. As a single miR holds the potential to bind and
regulate multiple gene targets, these molecules can serve as “master
regulators” for programs of targeted gene expression

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21. Right ventricular changes in PAH
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22. Treatment for PAH
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26. Treatment for PAH was less effective in CTD-PAH
compared with IPAH in terms of increasing 6MWD

27. Treatment was less effective in reducing
the occurrence of clinical worsening in
CTD-PAH versus IPAH

28. Combination therapy confer preferable therapeutic efficacy than
monotherapy in patients with CTD-PAH: a more remarkable
reduction in the risk of clinical worsening and a probable
improvement of exercise capacity
Combination vs. monotherapy in CTD-associated PAH / J. Pan et al.
Fig. 2. Forest plot of effect of combination therapy on combined clinical worsening compared with the monotherapy .
Fig. 4. Forest plot of effect of combination therapy on change in 6-minute walk distance (6MWD) compared with the monotherapy .
Fig. 2. Forest plot of effect of combination therapy on combined clinical worsening compared with the monotherapy .
Fig. 3. The funnel plots of the clinical worsening (a) and 6-minute walk distance (6MWD) ( b).
Clin Exp Rheumatol. 2018;36:1095-1102

30. Cumulative rates free of PAH-related death were
better in short-term responders than non-responders
Circ J 2018; 82: 546–554

31. Cumulative rates free of PAH-related death were best
in patients with a simultaneous diagnosis of PAH and
CTD who were treated initially with a combination of
glucocorticoids and immunosuppressants
Circ J 2018; 82: 546–554

32. cal stage of group 1’ (PVOD), group 2 or group 3 PH
which would not be indicated or even be relatively con-
traindicated for PAH-specific therapy.63
9 | COEXI STENCE OF
I NTERSTI TI AL L UNG DI SEASE
Interstitial lung disease (ILD) is frequently detected by high-
resolution computed tomography of the chest in patients with
CTD-PAH, particularly with SSc-PAH, there was, however,
no consensus on the definition of moderate-to-severe ILD to
shown in another cohort study.51
Given thehigh-mortality rate
and the possible unwanted effect of aggressive vasodilation
through an increase of ventilation-perfusion mismatch, the
treatment regimen for SSc-PAH coexisting ILD, particularly
moderate-to-severe ILD, may differ from that for other PAH
but needsfurther studiesto beestablished.
10 | CONCL USI ON
As discussed above, recent studies have clarified that CTD-
PAH has several distinctive aspects from other PAH,
T A BL E 2 The regimen of immunosuppressive therapy (IT) for pulmonary arterial hypertension associated with connective tissue diseases in
previous studies
Ref. No. Year CTD subtype Glucocorticoidsa
IVCY VD
Response
to IT only
Response
to IT + VD
53 2006 SLE, MCTD 0.5-1.0 mg/kg/d of
PSL 500 mg of mPSL pulse
600 mg/m2
, monthly, ≥3 mo 0/21 8/21 N/A
54 2007 SS 30-60 mg/d of PSL 600 mg/m2
, monthly, 3-6 mo 1/3 1/2 0/1
55 2008 SLE, MCTD 0.5-1.0 mg/kg/d of PSL 600 mg/m2
, monthly, 6 mo 7/23 8/16 4/7
56 2011 SLE, MCTD, SS 1.0 mg/kg/d of PSL 500 mg, every 1-3 mo, 12-18 mo 12/12 N/A 10/12
57 2015 SLE 0.5-1.0 mg/kg/d of PSL 500-1000 mg/m2
, monthly, 6 mo 20/24 0/4 11/20
58 2017 SLE, MCTD, SS 60 mg/d of PSL 600 mg/m2
, monthly, 6 mo 4/8 4/4 4/4
SLE, systemic lupus erythematosus; MCTD, mixed connective tissue disease; SS, primary Sj€ogren’s syndrome; PSL, prednisolone; mPSL, methylprednisolone;
IVCY, intravenous cyclophosphamide; VD, vasodilators.
a
Initial dose.
• The optimal regimen of immunosuppressive therapy
remains to be established
• Responders to immunosuppressive therapy tended to
concomitantly receive vasodilators
Eur J Clin Invest. 2018;48:e12876.

33. Experimental Biology and Medicine 2019; 244: 120–131

34. Right ventricular end-diastiolic dimension index
(RVEDDI) evaluated by cardiac MR could serve as a
significant predictor of mortality in PAH-CTD

36. Thanks for your attention