Rheumatology 2017;56:2197–2203

RHEUMATOLOGY doi:10.1093/rheumatology/kex351
Advance Access publication 26 September 2017

Original article
Prognostic significance of computed tomography
criteria for pulmonary veno-occlusive disease in
systemic sclerosis-pulmonary arterial hypertension

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Michelle J. Connolly1, Sharif Abdullah2, Deborah A. Ridout3,
Benjamin E. Schreiber1, Jamanda A. Haddock2 and J. Gerry Coghlan1

Abstract
Objectives. SSc-pulmonary arterial hypertension (SSc-PAH) is associated with worse response to therapy
and survival when compared with idiopathic PAH. It is suggested that the vasculopathy in SSc may
involve postcapillary pulmonary venules resulting in pulmonary veno-occlusive disease (PVOD). This
may underlie the lower gas transfer and worse outcome on therapy. We sought to test whether CT
signs of PVOD (CTS-PVOD) were frequent in SSc-PAH and whether they were associated with pulmonary
oedema on therapy and worse survival.
Methods. CT thorax of 66 SSc patients with precapillary pulmonary hypertension (PH) were blindly scored
by two radiologists for CTS-PVOD (41 or 5 2). Case note and radiograph review determined the presence
of pulmonary oedema on therapy.
Results. Fifty-nine patients (89%) had 41 CTS-PVOD and only 7 (11%) had 52 CTS-PVOD. Pulmonary
oedema on therapy was relatively common in those with 52 CTS-PVOD. On univariate analysis 52
CTS-PVOD were associated with a trend towards worse survival.
Conclusion. CTS-PVOD were less frequent in this SSc-PAH cohort than in previous reports but the
presence of at least two of these signs is associated with pulmonary oedema on therapy and a trend
towards worse survival on univariate analysis.

CLINICAL
SCIENCE
Key words: systemic sclerosis, pulmonary arterial hypertension, computed tomography, systemic sclerosis-
pulmonary arterial hypertension, pulmonary veno-occlusive disease

Rheumatology key messages

. Pulmonary veno-occlusive disease is rare in this population with SSc and pulmonary arterial hypertension.
. One or no CT features of pulmonary veno-occlusive disease denotes survival comparable to idiopathic pulmonary
arterial hypertension.
. Two or more CT features of pulmonary veno-occlusive disease trends towards reduced survival.

1
National Pulmonary Hypertension Service, Royal Free London NHS
Foundation Trust, 2Department of Radiology, Royal Free London NHS
Foundation Trust and 3Population, Policy and Practice Programme,
UCL Great Ormond Street Institute of Child Health, University College
London, London, UK
Submitted 14 February 2017; revised version accepted
16 August 2017
Correspondence to: Michelle J. Connolly, National Pulmonary
Hypertension Service, Royal Free London NHS Foundation Trust,
London NW3 2QG, UK.
E-mail: michelle.connolly@doctors.org.uk
Introduction
Pulmonary veno-occlusive disease (PVOD) is a rare form
of pulmonary hypertension (PH) with a prevalence of
0.1–0.2/million persons per year [1]. It is characterized
histologically by fibrotic occlusion of post-capillary ven-
ules. Pulmonary arterial hypertension (PAH) is a vasculo-
pathy of the precapillary arterioles without severe venous
involvement. While pulmonary vasodilators are generally
well tolerated in PAH and form the mainstay of therapy [2],
their use in PVOD is potentially dangerous, as dilating the
arterial tree in the face of fixed venous obstruction may
precipitate non-cardiogenic pulmonary oedema [3].

! The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
Michelle J. Connolly et al.
The diagnosis of PVOD in life requires open lung biopsy,
but this is unsafe in most patients with PH. Non-invasive
cross-sectional imaging, for example, CT, is the preferred
diagnostic modality [4]. Resten and colleagues [5] showed
that a triad of radiological findings on CT chest—centrilobu-
lar ground glass opacities, interlobular septal thickening and
lymph node enlargement—were significantly more frequent
in patients with histopathologically confirmed PVOD than in
those with idiopathic, familial or anorexigen-associated PAH
and that these patients had a worse prognosis [6].
PAH complicates up to 12% of cases of SSc and is the
major cause of death in these individuals [7]. Patients with
SSc-PAH have less favourable outcomes despite PAH-
specific therapy than those with idiopathic PAH [8].
A possible explanation is that radiological PVOD is more
common in SSc-PAH than in idiopathic PAH, and thus that
the poorer outcomes may be due in part to unmasking of
PVOD by vasodilator therapy [9]. Histological support for
this concept was provided by Dorfmüller et al. [10] whose
analyses of biopsy samples from four patients with SSc-
PAH demonstrated smooth muscle actin-positive staining
lesions of the preseptal veins, highly suggestive of PVOD.
Günther et al. [11] further reported that >60% of SSc-PAH
patients had two or more CT signs of PVOD (CTS-PVOD)
and that half of these individuals developed pulmonary
oedema following PAH-specific therapies and had worse
survival than did patients with fewer CTS-PVOD.
Our centre manages more than 500 patients with SSc-
PAH. We have observed pulmonary oedema in response
to PAH-specific therapies, but this appears to be uncom-
mon despite routine aggressive use of combination ther-
apy and prostanoids. We therefore wished to explore
more formally the prevalence of radiological and clinical
PVOD in an unselected population.
Methods
Patients
From 500 patients with SSc referred for evaluation to the
National Pulmonary Hypertension Service at the Royal
Free Hospital between 2005 and 2013, 195 were identified
with available chest CT imaging performed either at the
time of diagnosis of PH, or during follow-up where no
interval change in CT findings was found compared with
an available scan from before the diagnosis of PH.
All patients underwent right heart catheterization. All pa-
tients were euvolaemic. Where patients were suspected
of having left heart disease (in particular if the left atrium
was enlarged on transthoracic echocardiography), left
ventricular end diastolic pressure was assessed and/or
cardiac MRI performed to exclude those with postcapil-
lary PH. Patients were excluded from further evaluation if:
mean pulmonary artery pressure (mPAP) was <25 mmHg
(n = 87); pulmonary capillary wedge pressure was
>15 mmHg (n = 3); interstitial lung disease was identified
(n = 34); or the quality of CT imaging was inadequate
(n = 5). Sixty-six patients were included in the final ana-
lysis. Ethical approval and informed patient consent
were not required for this study.
2198
Clinical assessment
Clinical variables recorded at baseline included WHO
functional class and 6 min walk distance (6MWD). One
patient was too unwell to perform the 6MWD, and so a
value of 0 m was recorded. Autoantibody profile, NT-Pro
brain natriuretic peptide (NT-ProBNP) and serum creatin-
ine were noted. Pulmonary function testing was per-
formed. Haemodynamic measurements included mPAP,
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pulmonary capillary wedge pressure, right atrial pressure,
pulmonary vascular resistance and cardiac index.
Evaluation of CT thorax
All patients underwent CT chest using either a Philips
Brilliance 64 (Amsterdam, Netherlands), General Electric
Lightspeed 4 slice (Boston, Massachusetts, United
States) or Toshiba Aquilion Once 320 slice volume scan-
ner (Tokyo, Japan). Scan protocols included volumetric
and non-volumetric high resolution CT scans with supine
inspiratory/expiratory acquisitions and prone inspiratory
acquisitions; CT pulmonary angiography; and volumetric
unenhanced, arterial and portal venous phase scans. Slice
thickness, tube current/kilovoltage, filters and reconstruc-
tion algorithms varied according to the protocol and scan-
ner used. The scans were read by two radiologists: J.A.H.,
a consultant thoracic and general radiologist, and S.A., a
final year subspecialty training registrar in cardiothoracic
imaging. Both were blinded to the pulmonary pressures
and clinical indications for the scans. Each scan was
scored using a system with both quantitative and qualita-
tive components (supplementary Table S1, available at
Rheumatology Online). There was 100% agreement be-
tween the radiologists with respect to the number of
CTS-PVOD in each scan. If there was minor disagreement
with respect to other scan findings, a discussion resulted
in 100% agreement. Owing to the nature of the radio-
logical findings assessed, it was not felt by either radiolo-
gist that the type of scan had any impact upon
interpretation. Five patients were excluded from the
study due to suboptimal imaging such that one or more
of the triad of centrilobular ground glass opacities, inter-
lobular septal thickening and lymph node enlargement
could not be assessed.
Patients were divided into two groups according to the
number of CTS-PVOD (41 or 52). If a patient had >20%
interstitial lung disease, defined as > 20% parenchymal
involvement in the fibrotic process, severe emphysema
or combined pulmonary fibrosis and emphysema, they
were considered to have SSc-PH secondary to lung dis-
ease and were excluded from the analysis. In the absence
of significant radiological lung disease, as long as airways
disease (FEV1 <50%) was not present, then a diagnosis
of SSc-PAH was made.
Treatment
Following a diagnosis of PAH, all patients were com-
menced on PAH-specific therapy, as per multisociety
guidelines. These included phosphodiesterase-5 inhibitors,
endothelin receptor antagonists and prostanoids. Patients
were followed until death or date of censorship. Incidence
www.rheumatology.oxfordjournals.org
 CT signs of PVOD in SSc

TABLE 1 Patient characteristics according to number of CT signs of pulmonary veno-occlusive disease

SSc-PAH (n = 66)

Variable 0–1 (n = 59) 2–3 (n = 7) P-value

Female, n (%) 53 (90) 6 (86) 0.74

Age, years 62 (12) 69 (6) 0.14
LcSSc, n (%) 52 (88) 7 (100) 0.34

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DcSSc, n (%) 7 (13) 0 (0)
WHO Functional class II, n (%) 9 (15) 0 (0) 0.18
WHO Functional class III, n (%) 45 (76) 5 (71)
WHO Functional class IV, n (%) 5 (9) 2 (29)
6MWD, m 254 (122) 246 (154) 0.86
mPAP, mmHg 39 (11) 38 (8) 0.81
PCWP, mmHg 11 (3) 11 (3) 0.98
RAP, mmHg 9 (5) 11 (7) 0.28
Cardiac index, l/min/m2 2.7 (1) 2.5 (1) 0.48
PVR, dynes/s/cm5 584 (378) 515 (188) 0.64
Aorta saturations, n (%) 94 (3) 90 (6) 0.01
SvO2, n (%) 67 (10) 63 (16) 0.37
NT-proBNP, median (IQR), pmol/l 68 (29–312) 243 (52–819) 0.10
Creatinine, mmol/l 80 (24) 98 (18) 0.03
FEV1, % predicted 84 (19) 75 (19) 0.24
FVC, % predicted 98 (19) 84 (23) 0.08
FEV1/FVC, % predicted 71 (10) 66 (13) 0.32
DLCO, % predicted 45 (11) 41 (18) 0.47
KCO, % predicted 55 (15) 53 (10) 0.80
TLC, % predicted 98 (18) 92 (17) 0.47

Values listed as mean (S.D.) unless otherwise stated. For NT-proBNP the median (inter-quartile range (IQR)) and result of
Mann–Whitney non-parametric test are shown. 6MWD: 6 min walk distance; DLCO: diffusion capacity for carbon monoxide;
FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; KCO: carbon monoxide transfer coefficient; mPAP: mean
pulmonary artery pressure; NT-ProBNP: NT-Pro brain natriuretic peptide; PAH: pulmonary arterial hypertension; PCWP: pul-
monary capillary wedge pressure; PVR: pulmonary vascular resistance; RAP, right atrial pressure; SvO2: mixed venous oxygen
saturation; TLC: total lung capacity.

of pulmonary oedema following initiation of therapy was
determined by case note and radiography review.
Survival data
Survival data were collected on all patients and were drawn
from the National Health Service Primary Care Mortality
Database, an online database that is updated monthly and
holds mortality data for each deceased patient in England
and Wales. The censorship date was 1 March 2015.
Statistical analysis
Statistical analysis was performed using an unpaired
Student’s t test to compare mean values between
groups (41 CTS-PVOD vs 52 CTS-PVOD), and the chi-
square test was used to compare categorical data be-
tween groups. For skewed data, such as NT-ProBNP
and right atrial pressure, we used a logarithm transform-
ation to satisfy the normality assumption of the statistical
methods. Data are presented as the mean (S.D.), or fre-
quency (percentage) unless otherwise stated. Survival
status was evaluated using the Kaplan–Meier method.
Univariate Cox regression analysis was used to compare
survival between the two groups and also to evaluate sep-
arately survival for European Society of Cardiology/
European Respiratory Society determinants of prognosis
[12]. A multiple Cox regression model was performed
to adjust the comparison between the two groups for
the effect of known risk factors including age and sex.
P < 0.05 was considered significant.
Results
Demographic data at baseline
Demographic and clinical characteristics of SSc-PAH pa-
tients with 41 CTS-PVOD (n = 59) and SSc-PAH with 52
CTS-PVOD (n = 7) are shown in Table 1. The mean age of all
patients was 63 (12) years (range 34–83 years). The majority
(89%) were female. Limited cutaneous SSc was present in
89% and the remainder had diffuse SSc.
Functional and serological characteristics
WHO functional class, 6MWD and the results of pulmon-
ary function tests are shown in Table 1. The majority were
functional class III with no difference between the 41
CTS-PVOD and 52 CTS-PVOD groups. The mean
6MWD was 253 (124) m, again with no difference between
groups. Analysis of pulmonary function shows that there
was a non-significantly lower FVC in those with 52 CTS-

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Michelle J. Connolly et al.

PVOD and that gas transfer, while numerically lower, was
not reduced in those with 52 CTS-PVOD. Median NT-
ProBNP and creatinine tended to be higher in patients
with 52 CTS-PVOD.
Cardiac catheter data
Haemodynamic parameters were very similar between
Analysis of CT thorax
Radiographic characteristics of SSc-PAH patients are
shown in supplementary Table S2, available at
Rheumatology Online. The mean pulmonary artery diam-
eter was similar between the two groups, at 31 mm. Four
patients (7%) with 41 CTS-PVOD and three patients
(43%) with 52 CTS-PVOD had pleural effusions, making
this the only radiological sign that was more prevalent in

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groups (Table 1). The mPAP in the total population was
39 (11) mmHg with a mean wedge of 11 (3) mmHg.
Cardiac index was preserved at 2.7 (1.0) l/min/m2.
Patients with 52 CTS-PVOD were more hypoxic than
those with 41 CTS-PVOD (P < 0.01).
Prevalence of individual CTS-PVOD
Forty-eight patients (73%) exhibited no CTS-PVOD.
Eleven patients (17%) had one CT feature of PVOD, six
patients (9%) had two CTS-PVOD and just one patient
(2%) exhibited all three CTS-PVOD. With respect to indi-
vidual CT features of PVOD: 13 patients (20%) had lymph
node enlargement, 10 (15%) had interlobular septal
thickening and three (5%) had centrilobular ground glass
opacities.
patients with 52 CTS-PVOD (P < 0.01). Fifteen patients
(25%) with 41 CTS-PVOD and four patients (57%) with
52 CTS-PVOD had pericardial effusions but this differ-
ence did not reach statistical significance (P = 0.08).
Dilatation of the oesophagus was common across the
entire population with a prevalence ranging from 22 to
43%, but no significant difference was noted with respect
to number of CTS-PVOD (P = 0.22).
Incidence of pulmonary oedema following vasodilator
therapy
The overall incidence of pulmonary oedema on PAH-
specific therapy was low at 6%. The baseline parameters
and disease course of these four patients are shown in
Table 2. Fifty-nine patients with 41 CTS-PVOD received

TABLE 2 Characteristics and disease course of patients who developed pulmonary oedema on therapy

Variable Patient 1 Patient 2 Patient 3 Patient 4

Age, years 74 73 65 80
Sex Female Female Female Female
Disease subset Limited SSc Limited SSc Limited SSc Limited SSc
Autoantibody Anti-centromere Anti-centromere Anti-centromere Anti-centromere
WHO functional class III III III III
6MWD, m 0 132 198 289
NT-ProBNP, pmol/l 591 221 518 52
Creatinine, mmol/l 114 94 121 80
mPAP, mmHg 45 46 42 25
PCWP, mmHg 13 10 6 12
RAP, mmHg 18 8 11 4
PVR, dynes/s/cm5 640 655 655 217
Cardiac index, l/min/m2 2.3 2.0 2.6 2.9
SvO2, % 54 54 66 79
Arterial sats, % 97 87 95 85
DLCO, % 35 36 36 37
Initial therapy Sildenafil + bosentan Bosentan Tadalafil Sildenafil
Lymph node enlargement No No No Yes
Centrilobular ground glass No No Yes Yes
opacities
Interlobular septal No Yes Yes Yes
thickening
Survival, months 10 15 32 34
Disease course Pulmonary oedema Pulmonary oedema Orthopnoea and PND Pulmonary oedema
when bosentan when bosentan after ambrisentan on sildenafil
added increased to added. Remained
125 mg twice daily stable on tadalafil
but pulmonary
oedema when
bosentan added

6MWD, 6 min walk distance; DLCO, diffusion capacity for carbon monoxide; mPAP, mean pulmonary artery pressure; NT-
ProBNP, NT-Pro brain natriuretic peptide; PCWP, pulmonary capillary wedge pressure; PND, paroxysmal nocturnal dyspnoea;
PVR, pulmonary vascular resistance; RAP, right atrial pressure; SvO2, mixed venous oxygen saturation.

2200 www.rheumatology.oxfordjournals.org
 CT signs of PVOD in SSc

PAH-specific therapy. Of these, two (3%) developed pul-
monary oedema. Seven patients with 52 CTS-PVOD
received PAH-specific therapy; two of these (29%) de-
veloped pulmonary oedema (P = 0.008). With regard to
the four patients who developed clinical PVOD, one
received sildenafil only, one received bosentan only and
two received oral combination therapy. The median time
between starting PAH-specific therapy and the develop-
features of PVOD had a mean non-adjusted survival of
2.8 years.
On univariate analysis 52 CTS-PVOD was associated with
a trend towards worse survival (hazard ratio (HR) = 2.57, 95%
CI: 0.97, 6.80; P = 0.06; Table 4). However on multivariable
analysis, when European Society of Cardiology/European
Respiratory Society prognostic risk factors are also con-
sidered, 52 CTS-PVOD is not associated with worse survival

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ment of pulmonary oedema was 31 days (range 30–90 (HR = 1.03, 95% CI: 0.30, 3.48; P = 0.97; Table 5).
days). Management of pulmonary oedema included ad-
mission for intravenous diuresis and withdrawal of PAH-
specific therapies. Discussion
This blinded retrospective analysis of the CT scans of 66
Prostanoid therapy
unselected patients with SSc-PAH sought to determine
A total of seven patients (11%) had or developed at least whether CTS-PVOD are common and whether they pre-
one of the pre-specified criteria for prostanoid therapy, dict pulmonary oedema on therapy and worse survival.
one at the time of diagnosis. Six patients were in the We found that radiological signs of PVOD were less
41 CTS-PVOD group and one was in the 52 CTS-
PVOD group. None of these patients developed clinical
PVOD in response to prostanoid therapy.
FIG. 1 Effect of number of CT features of pulmonary
veno-occlusive disease on survival
Autoantibody status
The results of autoantibody status are shown in Table 3.
The commonest autoantibody in those with 41 CTS-
PVOD and in those with 52 CTS-PVOD was anti-
centromere. This was the autoantibody present in all
four patients with clinical PVOD. However, given that
ACAs were also present in 58% of patients without clinical
PVOD, no association between autoantibody status and
PVOD can be drawn from this study (P = 0.10).

Survival
Patients presenting with 52 CTS-PVOD had a trend
toward more rapid progression to death than did pa-
tients with 41 CTS-PVOD (Fig. 1). At the time of censor-
ing, 32 patients had died and 34 were still alive. SSc-
PAH patients with 41 feature of PVOD had a mean non-
adjusted survival of 5.9 years. SSc-PAH patients with 52 CTS, CT signs; PAH: pulmonary arterial hypertension.

TABLE 3 Autoantibody profiles according to number of TABLE 4 Effect of CT signs of pulmonary veno-occlusive
CT signs of pulmonary veno-occlusive disease disease and prognosis determinants on survival

SSc-PAH (n = 66) CTS-PVOD and ERS/ESC

prognosis determinant HR (95% CI) P-value
Autoantibody 0–1 (n = 59) 2–3 (n = 7) P-value
CTS-PVOD, 52 vs 41 2.57 (0.97, 6.80) 0.06
ANA negative 3 (5) 0 (0) 0.54 WHO functional class
Anti-centromere 36 (61) 5 (71) 0.59 III vs II 2.38 (0.56, 10.14) 0.24
Anti-U3-RNP 8 (14) 1 (14) 0.95 IV vs II 13.38 (2.55, 70.21) <0.01
Anti-RNA polymerase 7 (12) 1 (14) 0.85 6MWD, per 50 m 0.75 (0.64, 0.89) <0.01
Anti-Ro/SSA 5 (8) 0 (0) 0.42 NT-ProBNP, logs 1.82 (1.36, 2.42) <0.001
Anti-nRNP 5 (8) 0 (0) 0.42 Right atrial pressure, logs 1.93 (0.89, 4.17) 0.10
Anti-Scl 70 2 (3) 0 (0) 0.62 Cardiac index 0.63 (0.39, 1.01) 0.06
Anti-PM-Scl 1 (2) 0 (0) 0.73 SvO2 0.97 (0.94, 0.99) 0.02
Spindle proteins 1 (2) 0 (0) 0.73
Anti-ThRNP 0 (0) 1 (14) 0.73 6MWD: 6 min walk distance; CTS-PVOD: CT signs of pulmonary
veno-occlusive disease; ERS: European Respiratory Society;
Values are given as n (%). PAH: pulmonary arterial hyper- ESC: European Society of Cardiology; NT-ProBNP: NT-Pro brain
tension; RNP, ribonucleoprotein. natriuretic peptide; SvO2: mixed venous oxygen saturation.

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Michelle J. Connolly et al.

TABLE 5 Effect of CT signs of pulmonary veno-occlusive CTS-PVOD developed pulmonary oedema on therapy.
disease, age, sex and prognosis determinants on survival Günther et al. [11] reported a higher incidence (50%) of
pulmonary oedema in response to PAH-specific therapy
among their 16 patients with at least two radiographic
CTS-PVOD, ESC/ERS
prognosis determinant, signs of PVOD. This difference between our findings
age and sex HR (95% CI) P-value may be due to the small sample size and differences in
therapeutic aggression. In terms of prostanoid use, half
CTS-PVOD, 52 vs 41 1.03 (0.30, 3.48) 0.97 the patients in the study of Günther et al. [11] who de-
Age, years 1.05 (1.01, 1.10) 0.014

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veloped pulmonary oedema were receiving them, while
Sex, male; female 1.61 (0.44, 5.81) 0.47
only one of our patients with 52 CTS-PVOD did.
WHO functional class
III vs II 2.17 (0.47, 9.91) 0.32
Several clinical trials have examined the effect of prosta-
IV vs II 5.41 (0.82, 35.78) 0.08 noids on PAH cohorts that include SSc-PAH [14–16] and
6MWD, per 50 m 0.87 (0.69, 1.10) 0.25 these have reported pulmonary oedema as an infrequent
NT-ProBNP, logs 1.40 (0.94, 2.05) 0.09 event in the SSc-PAH population.
Right atrial pressure, logs 0.97 (0.32, 2.96) 0.96 On univariate analysis, 52 CTS-PVOD was associated
Cardiac index 1.23 (0.53, 2.86) 0.63 with a trend towards worse outcome; however, as this
SvO2 1.0 (0.95, 1.06) 0.88 subgroup was older and had higher baseline NT-
ProBNP, the trend was non-significant on multivariable
6MWD: 6 min walk distance; CTS-PVOD: CT signs of pul- analysis. What cannot be determined from the current
monary veno-occlusive disease; ERS: European Respiratory study is whether older SSc patients are more likely to de-
Society; ESC: European Society of Cardiology; NT-ProBNP: velop PVOD and whether the presence of venous exten-
NT-Pro brain natriuretic peptide; SvO2: mixed venous
sion of the vasculopathy increases right ventricular strain,
oxygen saturation.
hence causing a greater elevation of NT-ProBNP.
We identified four patients, two with 41 CTS-PVOD
common in SSc-PAH than previous reports suggest. Two and two with 52 CTS-PVOD, who developed clinical
or more CT signs of PVOD were associated with a rela- PVOD, that is, pulmonary oedema in response to vaso-
tively greater incidence of pulmonary oedema on therapy dilator therapy. The clinical characteristics of these pa-
compared with patients with none or one CT sign of tients are shown in Table 2. While it is not possible to
PVOD. There is a trend towards reduced survival in pa- draw robust conclusions based on a very small number
tients with 52 CT features of PVOD; however, this was of patients, it is noteworthy that these four patients had
not an independent predictor when other risk factors are lower DLCO than did those without clinical PVOD. Patient
4 in Table 2 is notable for having a relatively low mPAP
considered. The data presented suggest that a subpopu-
and NT-ProBNP, a 6MWD that was greater than the mean
lation with survival comparable to idiopathic PAH can be
distance walked by all patients, but hypoxaemia and low
identified: those with 41 CTS-PVOD. Among such pa-
DLCO. Therefore we cautiously suggest that hypoxic pa-
tients 5-year survival exceeds 50% and pulmonary
tients with poor gas transfer should evoke a greater clin-
oedema on therapy is rare.
ical suspicion of the possibility of developing PVOD.
Günther et al. [11] evaluated the CT scans of 26 patients
with SSc-PAH referred to their transplant service because Limitations
of an inadequate response to therapy. Hence they were
studying a selected group of non-responders. In their The current study may be underpowered and this may
explain the lack of a significant effect of the presence of
report, 62% of patients had at least two CTS-PVOD
52 CTS-PVOD on survival. Only a small number of pa-
whereas in our study only 11% did. The demographic,
tients had 52 CTS-PVOD, and thus the association
clinical and haemodynamic characteristics of the two
between such findings and overt pulmonary oedema
populations are similar, intriguingly with the exception of
cannot be explored robustly. Finally, only a minority of
better performance on the 6 min walk test [329 (89) m (in
our patients were treated with prostanoids, and we do
that study) vs 253 (124) m in our population].
not have histological diagnoses of PVOD. However all pa-
Rajaram and colleagues [13] evaluated CT pulmonary
tients were followed to death and evidence of PVOD was
angiograms of 95 patients with SSc-PAH and found that
rare even as disease progressed.
36% had centrilobular ground glass opacities, a quarter
had lymph node enlargement and over a fifth had inter-
lobular septal thickening. These findings contrast with Supplementary data
ours, but interestingly, patients with idiopathic PAH had Supplementary data are available at Rheumatology Online.
a greater frequency of centrilobular ground glass opacities
and interlobular septal thickening than did patients with
Acknowledgements
SSc-PAH. Taken together, it does not appear that CTS-
PVOD are more common in SSc-PAH than in idiopathic We are grateful to Professor Christopher Denton and Dr
PAH. Mahmood Ahmed, both of the Royal Free London NHS
All patients in our study received PAH-specific therapy. Foundation Trust, for critical appraisal of the manuscript
Twenty-nine per cent of our patients with at least two and assistance with data collection, respectively.

2202 www.rheumatology.oxfordjournals.org

Funding: This study was funded by The Royal Free Charity.
Disclosure statement: The authors have declared no
conflicts of interest.
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