Nailfold capillary density is associated with the
presence and severity of pulmonary arterial
hypertension in systemic sclerosis
H M A Hofstee,
1
A Vonk Noordegraaf,
2
A E Voskuyl,
3
B A C Dijkmans,
3
P E Postmus,
2
Y M Smulders,
1
E H Serne´
1
c An appendix is published
online only at http://ard.bmj.
com/content/vol68/issue2
1
Department of Internal
Medicine, VU University Medical
Centre, Amsterdam, The
Netherlands;
2
Department of
Pulmonary Medicine, VU
University Medical Centre,
Amsterdam, The Netherlands;
3
Department of Rheumatology,
VU University Medical Centre,
Amsterdam, The Netherlands
Correspondence to:
H M A Hofstee, MD,
Department of Internal
Medicine, VU University Medical
Centre, De Boelelaan 1117,
1081 HV, Amsterdam, The
Netherlands; hma.hofstee@
vumc.nl
Accepted 16 March 2008
Published Online First
28 March 2008
ABSTRACT
Objective: The aim of this study was to investigate
whether there are differences in capillary nailfold changes
in patients with systemic sclerosis (SSc) with and without
pulmonary arterial hypertension (PAH), and whether these
changes are associated with PAH severity and disease
specificity.
Methods: Capillary density and loop dimensions were
studied in 21 healthy controls, 20 patients with idiopathic
PAH (IPAH) and 40 patients with SSc. Of the 40 patients
with SSc, 19 had no PAH (SSc–nonPAH) and 21 had PAH
(SSc–PAH), of whom eight had PAH during exercise.
Results: Capillary density was lower in SSc–PAH
compared with patients who had SSc–nonPAH (4.33/mm
vs 6.56/mm respectively, p = 0.001), but loop dimensions
were equal. In comparison with IPAH, patients with SSc–
PAH had reduced capillary density (4.33/mm vs 7.86/mm,
p,0.001) and larger loop dimensions (total width
101.05 mm vs 44.43 mm, p,0.001). Capillary density in
healthy controls (9.87/mm) was significantly higher when
compared with SSc–nonPAH (6.56/mm), SSc–PAH (4.33/
mm) and with IPAH (7.86/mm). No differences in capillary
dimensions were present between healthy controls and
IPAH.
Capillary density correlated with mean pulmonary arterial
pressure (PAP) at rest in SSc–PAH at rest (r = 20.58,
p = 0.039) and IPAH (r = 20.67, p = 0.001).
Conclusions: Reduction of nailfold capillary density, but
not capillary loop dimensions is associated with PAH, and
correlates with the severity of PAH in both SSc and IPAH.
This suggests that either systemic microvascular changes
play a part in the development of PAH, or that PAH itself
contributes to systemic microvascular changes.
Systemic sclerosis (SSc) represents the main con-
nective tissue disease (CTD) associated with
pulmonary arterial hypertension (PAH).
1
PAH
complicates an estimated 12% of patients with
SSc, and is a leading cause of death in this disease.
2
Microvascular dysfunction is considered to be a key
element in the pathogenesis of SSc and its
complications.
3–5
The majority of patients with SSc display
characteristic structural changes of the capillaries
in the nailfold, consisting of reduction in the
number of capillaries (capillary density), and
widening of capillary loops.
6–8
A number of studies
suggest an association between systemic micro-
vascular changes and organ involvement in SSc;
9–11
nevertheless, it is not clear whether systemic
microvascular changes in SSc are associated with
the presence and severity of PAH.
Better knowledge of the association between
nailfold capillary characteristics and PAH in SSc
could be useful both for better understanding of
the pathophysiology of SSc-associated PAH, as
well as for stratification of SSc patients in terms of
PAH risk. Recent developments, including compu-
ter based nailfold video capillaroscopy systems,
have improved the quantitative assessment of
microcirculatory changes such as capillary density
and loop dimensions.
6
The aim of this study was to test the hypothesis
that there are differences in capillary density and
capillary dimensions between patients with SSc–
PAH and SSc–nonPAH, and that these changes are
quantitatively correlated with pulmonary haemo-
dynamic parameters. To test the hypothesis that
these changes are SSc specific, a group of patients
with idiopathic PAH (IPAH), as well as healthy
controls were investigated. Computer-based panor-
ama mosaic video capillaroscopy was used to
display the nailfold capillaries.
MATERIALS AND METHODS
Subjects
Between September 2006 and July 2007 consecu-
tive eligible patients with SSc and IPAH were
recruited from the rheumatology and pulmonology
departments of this hospital. The healthy controls
were mainly staff members of the hospital who
volunteered to participate in the study. Because of
the female preponderance in patients with SSc,
only female controls were recruited. All patients
with SSc fulfilled the American College of
Rheumatology criteria for SSc and were subse-
quently divided into a limited (LcSSc) and a diffuse
(DcSSc) cutaneous SSc group according to LeRoy et
al.
12
Patients with IPAH did not have the symp-
toms and signs of CTD and were tested negative
for antinuclear antigen (ANA).
PAH was diagnosed according to the clinical
classification of Venice 2003,
13
with PAH defined as
a mean pulmonary artery pressure (PAP) of
.25 mmHg at rest or .30 mmHg during exercise
as determined by right heart catheterisation.
Exclusion criteria for PAH in patients with SSc
were: (1) patients with SSc with New York Heart
Association (NYHA) class I dyspnoea, and no signs
of PAH at echocardiography and exercise testing;
and (2) patients with SSc with NYHA class II
dyspnoea with normal pressures as determined by
right heart catheterisation at rest and during
exercise. All patients with SSc required a total
lung capacity (TLC) of .70% of predicted, and a
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pO
2
of .60 mmHg at rest. Study protocols were approved by
the local ethics committee.
Exercise testing and right heart catheterisation
Before right heart catheterisation, maximal exercise tolerance
and peak oxygen uptake (VO
2
max) were assessed by an exercise
test on a cycle ergometer. PAPs were taken during right heart
catheterisation. Cardiac output was determined and pulmonary
vascular resistance (PVR) was calculated as the ratio of mean
PAP to cardiac output. Cardiac index is defined as the cardiac
output divided by the body surface area. Haemodynamic
measurements were obtained at baseline and, if at baseline
mean PAP was less than 25 mmHg, while cycling (see the
appendix for further details).
Capillaroscopy
Capillaroscopy and computerised mosaic of the nailfold was
obtained as described previously.
6
For this study, only images
from digit 4 of the non-dominant hand were used. Image quality
was scored as ‘good’ or ‘moderate’. Cases in which only ‘poor’
quality images were available, precluding identification of
capillary architecture, were excluded from this study (see the
online-only appendix for further details). The investigator was
blinded to patient diagnosis and laboratory results; all images
were coded. Capillary density (number of loops per mm) was
calculated by computer from the manually marked loops in the
terminal row. Mean apex, arterial, venous and total capillary
widths of the three to five widest capillaries were measured. In the
case of irregular dilated capillaries, maximal width was measured.
Statistical analysis
Capillary density and dimensions showed a normal distribution
in all categories and are presented as the mean and standard
deviations (SD). Data on the duration of Raynaud’s phenom-
enon and the duration of SSc were positively skewed and are
presented as geometric means and 95% confidence interval of
the back-transformed data after log transformation was
performed. Numerical means of two or more independent
categories were analysed using the Student’s t test or one-way
ANOVA, respectively. Differences between the groups with
respect to capillary density and loop dimensions, were analysed
using analysis of variance with and without adjustment for age
and multiple comparisons (Bonferroni). Categorical variables
were analysed using the x
2
or Fisher’s exact test when
appropriate. Correlation between density and pulmonary
haemodynamic parameters were described using Pearson’s
correlation coefficient. Statistical significance was set at
p,0.05. Results were calculated using computer software
(SPSS, version 15.0 for Windows; SPSS; Chicago, Illinois, USA).
RESULTS
Characteristics of subjects
In one patient with SSc–PAH and one with IPAH, image quality
was poor and these patients were excluded from the analyses.
Characteristics of the 21 healthy controls, 20 patients with
IPAH, 19 with SSc–nonPAH and 21 with SSc–PAH are shown in
table 1.
Of the 19 patients with SSc–nonPAH, 16 had NYHA class I
and no signs of PAH at echocardiography and exercise testing,
and three had NYHA class II with normal PAP. Of the 21
patients with SSc–PAH, 13 had SSc–PAH at rest, and eight had
SSc–PAH during exercise. In 93% (75 of 81) of the cases it was
possible to study digit 4 of the non-dominant hand, digit 3 and 5
were examined in the remaining 2 and 4 cases, respectively. The
healthy controls were significantly younger than patients with
IPAH and SSc. Raynaud’s phenomenon was present in 95% (38
of 40) of the patients with SSc. One patient with IPAH was
considered to have long-standing primary Raynaud’s phenom-
enon, as ANA was negative and there were no other clinical
symptoms and signs of a CTD.
Four patients with IPAH, three with SSc–PAH at rest, and all
patients with SSc–PAH during exercise were without medical
treatment for PAH. The other patients with SSc–PAH at rest
and IPAH used monotherapy or combinations of prostaglandin/
prostacyclin analogous, endothelin receptor antagonists, and
phosphodiesterase-5 inhibitors. No differences in capillary
density were present between treated and non treated patients
with SSc–PAH (4.5 vs 3.9/mm, p = 0.61) and IPAH (7.2 vs 7.9/
mm, p = 0.38),and did not differ between treatment modalities,
although some treatment categories were small.
There were no striking differences between the patients with
SSc–nonPAH and SSc–PAH in time since clinical diagnosis of
SSc, type of SSc (LcSSc or DcSSc) or antibody testing (table 2).
Compared with patients with SSc–PAH, patients with SSc–
nonPAH were less likely to have any sign of pulmonary fibrosis
in the dorsobasal fields on a high resolution computed
tomography scan (p = 0.002), or a diffusing capacity for cardiac
output of less than 70% of predicted (p = 0.009). None of the
patients with IPAH had signs of pulmonary fibrosis on a
computed tomography scan.
Capillary density and dimensions in healthy controls, patients
with idiopathic pulmonary arterial hypertension and systemic
sclerosis subgroups
The main findings on capillary microscopy are reported in
table 3. In comparison with healthy controls, patients with SSc
had reduced capillary density (5.36 vs 9.87/mm, p,0.001) and
larger loop dimensions (total width 101.05 mm vs 43.20 mm,
p,0.001). Capillary density was lower in patients with SSc–
PAH compared with patients with SSc–nonPAH (4.33 vs 6.56/
mm respectively, p = 0.001), but no difference in capillary
density between SSc–PAH at rest or SSc–PAH during exercise
could be detected. Loop dimensions were equal in SSc–nonPAH,
SSc–PAH at rest, and SSc–PAH during exercise. A reduction in
capillary density was also observed in patients with IPAH
compared with healthy controls (7.86 vs 9.87 respectively,
p = 0.009), but no differences in loop dimensions were present
between patients with IPAH and healthy controls. In compar-
ison with patients with SSc–PAH, patients with IPAH had a
higher capillary density (7.86 vs 4.33/mm, p,0.001) and smaller
loop dimensions (44.43 mm vs 109.24 mm, p,0.001). Age was
significantly different between controls, patients with IPAH,
and patients with SSc, but capillary density and loop dimen-
sions were not age related (r = 0.097, p = 0.68 for capillary
density and age). Analysis of differences in capillary density and
loop dimensions between groups with and without adjustment
for age yielded similar results.
Exercise testing and pulmonary haemodynamic parameters
Exercise performances and haemodynamic parameters of
patients with IPAH and SSc–PAH at rest were, as expected,
worse than that of patients with SSc–PAH during exercise as
measured by the cardiac index, mean PAP, PVR, 6 min walking
test (6MWD), VO
2
max, and maximal exercise tolerance
(table 4). Exercise performances between patients with IPAH
and SSc were not different. In comparison with SSc–PAH at
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rest, patients with IPAH had a higher mean PAP (51.3 vs
39.2 mmHg, p = 0.006), but no other differences in haemody-
namic parameters were present. Capillaroscopy was performed
after a median of 5.8 months (range 23 to 48 months) after
right heart catheterisation. Time separation was shorter than
18 months in 90% of the patients.
Correlation of capillary density with NYHA class and
haemodynamic parameters
A lower capillary density was associated with a higher NYHA
class in patients with SSc (p = 0.042 by ANOVA). Capillary
density correlated with mean PAP at rest in SSc–PAH at rest
(r = 20.58, p = 0.039) (fig 1), SSc–PAH during exercise
(r = 20.82, p = 0.013), and IPAH (r = 20.67, p = 0.001) (fig 2).
Capillary density also correlated with PVR at rest in IPAH
(r = 20.60, p = 0.005), and, although not significantly, in SSc–
PAH at rest (r = 20.50, p = 0.08), but not in SSc–PAH during
exercise (r = 20.18, p = 0.69). No correlation between capillary
density and cardiac index or systemic vascular resistance was
observed in the PAH groups.
DISCUSSION
Structural changes in the systemic microcirculation, consisting
of reduction of capillary density and widening of capillary
dimensions, are a hallmark of SSc.
6–8
A novel finding of this
study is that capillary density, but not capillary dimensions,
differs between SSc–PAH and SSc–nonPAH, and correlates with
pulmonary haemodynamic parameters. Interestingly, when
compared with healthy controls, the same is true for patients
with IPAH, a condition not known to be characterised by
systemic microvascular changes. Our data suggest that widen-
ing of capillaries and capillary density reduction represents two
different aspects of systemic microvascular involvement, ie,
widening of capillaries is SSc specific, whereas reduction in
capillary density is a marker of the presence and severity of
PAH.
Few studies have investigated nailfold capillary patterns in
patients with SSc–PAH, with only one study including patients
with IPAH. Two studies used echocardiography and/or right
heart catheterisation to confirm the diagnosis of PAH. One of
these found a significant reduction of capillary density in eight
patients with SSc with PAH in comparison with 12 patients
with SSc without PAH.
14
No pulmonary haemodynamic
parameters were reported in this study. The other study, using
capillary density and qualitative scoring of nailfold patterns,
found no differences in capillary patterns between eight
patients with SSc–nonPAH and seven with SSc–PAH, but
capillary density in these groups was not reported.
15
A third
study, using only right heart catheterisation to diagnose and
exclude the diagnosis of PAH, showed a significant difference
in semi-quantitative scoring of nailfold patterns between
Table 1 Characteristics of controls, patients with IPAH, SSc–nonPAH and SSc–PAH
Controls
(n = 21) IPAH (n = 20)
SSc–nonPAH
(n = 19)
SSc–PAH (n = 21)
PAH rest (n = 13)
PAH exercise
(n = 8)
Age, year (SD) 37.7 (10.7) 46.4 (12.0) 56.0 (10.7) 63.1 (15.6) 62.7 (15.6)*
Female (%) 21 (100) 19 (86) 18 (95) 13 (100) 7 (88){
RP (%) 0 1 (5) 17 (90) 13 (100) 8 (100){
Duration of RP, year
(95% CI)
NA 27 (NA) 6.3 (4.0 to 11.9) 15.3 (10.9 to 21.3) 6.6 (2.7 to 16.3)1
Good/moderate
image quality
20/1 19/1 15/4 12/1 5/3{
IPAH, idiopathic pulmonary arterial hypertension; NA, not applicable; PAH, pulmonary arterial hypertension; RP, Raynaud’s
phenomenon; SSC, systemic sclerosis; SSc–nonPAH, SSc without PAH; SSc–PAH, SSc with PAH.
*Differences significant (p, 0.05) between categories.
{Differences not significant between categories.
{Difference not significant between SSc-non PAH and SSc–PAH.
1Difference significant (p,0.05) between SSc–PAH at rest and SSc-nonPAH; difference not significant between SSc–PAH at rest
and SSc–PAH during exercise.
Table 2 Clinical, immunological and pulmonary findings in 40 patients with SSc
SSc–nonPAH
(n = 19)
SSc–PAH (n = 21)
PAH rest (n = 13)
PAH exercise
(n = 8)
Time since clinical diagnosis of SSc, year (95% CI) 3.7 (1.3–10.7) 2.8 (1.6–5.0) 4.2 (1.6–27.8)*
Limited cutaneous SSc/diffuse cutaneous SSc 17/2 12/1 7/1{
Antinuclear antibody (%) 17 (90) 13 (100) 7 (88){
Anticentromere antibody (%) 11 (58) 7 (54) 1 (13){
Anti-topoisomerase antibody (%) 2 (11) 0 3 (38){
Anti-RNP antibody (%) 0 3 (23) 1 (13){
Pulmonary fibrosis in the dorsobasal fields of the lungs
on HRCT thorax (%)
4 (21) 8 (62) 8 (100){
Total lung capacity % of predicted (SD) 96.8 (8.4) 91.1 (10.3) 91.8 (13.9)*
Diffusing capacity for cardiac output ,70% of predicted (%) 8 (42) 12 (86) 6 (75){
HRCT, high-resolution computed tomography; PAH, pulmonary arterial hypertension; SSc, systemic sclerosis;
SSC–nonPAH, patients with SSc but no PAH; SSC–PAH, patients with SSc and PAH.
*Differences not significant between categories (ANOVA).
{Differences not significant between categories (x
2
).
{Differences significant (p,0.05) between categories (x
2
).
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SSc–nonPAH and SSc–PAH but, again, capillary density was not
assessed in this study.
16
Only one of these studies included
patients with IPAH and reported no differences in capillary
density and capillary patterns between 13 healthy controls and
37 patients with IPAH.
15
In the present study, a reduction of capillary density was
observed in both SSc–PAH and, albeit to a milder extent, in
IPAH. However, the explanation for capillary density reduction
may not be the same for both disorders. For SSc, it is generally
presumed that structural changes in the systemic (micro)circu-
lation precede changes in the pulmonary circulation, as systemic
microvascular changes may precede SSc development by many
years.
15
Hence, nailfold capillary abnormalities might well
reflect what is going on in the pulmonary circulation. This
may not be true for all capillary abnormalities, because most
patients with SSc demonstrate nailfold capillary abnormalities,
whereas only a minority develop PAH. The present study
Table 3 Mean capillary density and dimensions. All between group comparisons for differences adjusted for age and multiple comparisons
Controls (n = 21) IPAH (n = 20)
SSc–nonPAH
(n = 19)
SSc–PAH (n = 21)
Controls
versus
SSc–
nonPAH
SSc–
nonPAH
versus
SSc–PAH
SSc–PAH
exercise
versus
SSc–PAH
rest
Controls
versus
IPAH
IPAH versus
SSc–PAH
PAH rest (n = 13) PAH exercise (n = 8) p Value p Value p Value p Value p Value
Loops/mm, mean (SD) 9.87 (1.38) 7.86 (1.11) 6.56 (2.78) 4.23 (1.77) 4.49 (1.24) ,0.001 0.001 0.966 0.009 ,0.001
Apex width, mean (SD) 17.03 (3.73) 19.98 (6.92) 40.62 (25.50) 39.46 (18.34) 42.83 (18.50) 0.001 1.000 1.000 1.000 0.001
Arterial width, mean (SD) 13.21 (2.32) 13.04 (3.34) 28.62 (16.53) 27.56 (10.62) 30.39 (14.35) ,0.001 1.000 1.000 1.000 ,0.001
Venous width, mean (SD) 15.32 (2.96) 16.01 (4.66) 35.80 (20.52) 38.25 (18.46) 44.23 (19.25) ,0.001 1.000 1.000 1.000 ,0.001
Total width, mean (SD) 43.20 (5.90) 44.43 (9.02) 93.68 (48.77) 103.36 (35.15) 114.53 (43.69) ,0.001 0.662 1.000 1.000 ,0.001
IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; SSc, systemic sclerosis; SSC–nonPAH, patients with SSc but no PAH; SSC–PAH, patients with SSc and PAH.
Table 4 Cardiopulmonary findings in 41 patients with PAH
IPAH
(n = 20)
SSc–PAH (n = 21)
PAH rest
(n = 13)
PAH exercise
(n = 8)
Cardiac index in l/min per m
2
,
mean (SD)
at rest 2.9 (0.8) 2.9 (0.7) 3.8 (0.8)*
during exercise 4.1 (2.6)
Mean PAP in mmHg, mean (SD)
at rest 51.3 (14.4){ 39.2 (9.8){ 17.9 (3.8)*
during exercise 36.5 (4.7)
Pulmonary vascular resistance at
rest in dyne s/cm
5
, mean (SD)
737.7 (321.9) 567.2 (261.3) 158.3 (79.9)*
6MWD % of predicted, mean (SD) 77.0 (18.7) 73.6 (29.1) 92.7 (9.1){
VO
2
max in ml/kg per min,
mean (SD)
13.5 (3.2) 10.7 (6.5) 16.9 (3.7)*
Maximum exercise tolerance % of
predicted, mean (SD)
49.6 (17.0) 41.5 (17.9) 74.4 (17.9)*
6MWD, 6 min walking test; IPAH, idiopathic pulmonary arterial hypertension; PAH,
pulmonary arterial hypertension; PAP, pulmonary arterial pressure; SSc, systemic
sclerosis; SSC–PAH, patients with SSc and PAH.
*Differences significant (p,0.05) between IPAH vs SSc–PAH exercise and between
SSc–PAH rest vs SSc–PAH exercise.
{Differences significant (p,0.05) between IPAH vs SSc–PAH rest.
{Differences not significant between categories (ANOVA).
Figure 1 Correlation between capillary density and mean pulmonary
arterial pressure (PAP) in patients with systemic sclerosis and
pulmonary arterial hypertension at rest.
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suggests that only capillary density is associated with the
presence of PAH and is a marker of disease severity in SSc. In
IPAH, disturbed structure or function of the systemic (micro)-
circulation is not considered to be a central feature. However,
relatively mild abnormalities of systemic endothelial function
(ie, brachial artery flow-mediated vasodilation) have recently
been observed in IPAH,
17
suggesting that IPAH may not be
strictly limited to the pulmonary vascular bed. If indeed the
systemic circulation is mildly affected in IPAH, this might
explain the relatively mild degree of capillary density reduction
seen in our patients. Therefore, another explanation for the
more pronounced capillary reduction in SSc–PAH could be that
PAH itself amplifies the already present reduction of capillary
density in SSc. Finally, it is conceivable that, both in SSc–PAH
and in IPAH, neurohumoral activation due to compromised
cardiac function causes systemic microvascular dysfunction.
However, this would be at odds with recent observations
showing increased rather than decreased nailfold capillary
density in patients with heart failure.
18
In addition, we found
no association between capillary density and cardiac index or
systemic vascular resistance in our patients with PAH.
A computer-based panorama mosaic video capillaroscopy was
used in this study to display a detailed image of a large part of the
nailfold, that allows precise measurements of capillary density
and loop dimensions. Furthermore, a diagnosis of PAH was
confirmed by right heart catheterisation. However, although we
feel that in patients with SSc with NYHA class I, and no signs of
PAH at echocardiography and exercise testing, a diagnosis of PAH
was reasonably excluded, right heart catheterisation remains the
gold standard. Therefore, some subclinically PAH could not be
fully excluded in this group. In addition, the group of patients
with SSc–PAH during exercise was quite small.
From a pathophysiological viewpoint, our study sheds more
light on the involvement of the microcirculation in SSc–PAH
and IPAH, although subsequent research is needed to delineate
whether the disturbances in the microcirculation are causal or
consequential to PAH. From a clinical viewpoint, it is
interesting to note that a simple, non-invasive tool, such as
nailfold capillary microscopy is potentially capable of identify-
ing patients with PAH.
Acknowledgements: The software to create the panorama mosaic images was
received as a license agreement from the University of Manchester (UK). We would
like to thank A L Herrick, MD, PhD (University of Manchester, Hope Hospital, Salford,
UK), T Moore (Hope Hospital, Salford, UK) and P D Allen, PhD (University of
Manchester, UK) for their kind support.
Competing interests: None.
REFERENCES
1. Coghlan JG, Handler C. Connective tissue associated pulmonary arterial
hypertension. Lupus 2006;15:138–42.
2. Mukerjee D, St George D, Coleiro B, Knight C, Denton CP, Davar J, et al. Prevalence
and outcome in systemic sclerosis associated pulmonary arterial hypertension:
application of a registry approach. Ann Rheum Dis 2003;62:1088–93.
3. Herrick AL. Vascular function in systemic sclerosis. Curr Opin Rheumatol
2000;12:527–33.
4. Denton CP, Black CM. Targeted therapy comes of age in scleroderma. Trends
Immunol 2005;26:596–602.
5. LeRoy EC. Systemic sclerosis. A vascular perspective. Rheum Dis Clin North Am
1996;22:675–94.
6. Anderson ME, Allen PD, Moore T, Hillier V, Taylor CJ, Herrick AL. Computerized
nailfold video capillaroscopy—a new tool for assessment of Raynaud’s phenomenon.
J Rheumatol 2005;32:841–8.
7. Meli M, Gitzelmann G, Koppensteiner R, Amann-Vesti BR. Predictive value of nailfold
capillaroscopy in patients with Raynaud’s phenomenon. Clin Rheumatol
2006;25:153–8.
8. Cutolo M, Sulli A, Pizzorni C, Accardo S. Nailfold videocapillaroscopy assessment of
microvascular damage in systemic sclerosis. J Rheumatol 2000;27:155–60.
9. Maricq HR, Spencer-Green G, LeRoy EC. Skin capillary abnormalities as indicators of
organ involvement in scleroderma (systemic sclerosis), Raynaud’s syndrome and
dermatomyositis. Am J Med 1976;61:862–70.
10. Groen H, Wichers G, ter Borg EJ, van der Mark TW, Wouda AA, Kallenberg CG.
Pulmonary diffusing capacity disturbances are related to nailfold capillary changes in
patients with Raynaud’s phenomenon with and without an underlying connective
tissue disease. Am J Med 1990;89:34–41.
11. Caramaschi P, Canestrini S, Martinelli N, Volpe A, Pieropan S, Ferrari M, et al.
Scleroderma patients nailfold videocapillaroscopic patterns are associated with
disease subset and disease severity. Rheumatology (Oxford) 2007;46:1566–9.
12. LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, et al.
Scleroderma (systemic sclerosis): classification, subsets and pathogenesis.
J Rheumatol 1988;15:202–5.
13. Galie N, Torbicki A, Barst R, Dartevelle P, Haworth S, Higenbottam T, et al.
Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task
Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European
Society of Cardiology. Eur Heart J 2004;25:2243–78.
14. Ong YY, Nikoloutsopoulos T, Bond CP, Smith MD, Ahern MJ, Roberts-Thomson PJ.
Decreased nailfold capillary density in limited scleroderma with pulmonary
hypertension. Asian Pac J Allergy Immunol 1998;16:81–6.
15. Greidinger EL, Gaine SP, Wise RA, Boling C, Housten-Harris T, Wigley FM. Primary
pulmonary hypertension is not associated with scleroderma-like changes in nailfold
capillaries. Chest 2001;120:796–800.
16. Ohtsuka T, Hasegawa A, Nakano A, Yamakage A, Yamaguchi M, Miyachi Y. Nailfold
capillary abnormality and pulmonary hypertension in systemic sclerosis. Int J Dermatol
1997;36:116–22.
17. Wolff B, Lodziewski S, Bollmann T, Opitz CF, Ewert R. Impaired peripheral endothelial
function in severe idiopathic pulmonary hypertension correlates with the pulmonary
vascular response to inhaled iloprost. Am Heart J 2007;153:1088–7.
18. Houben AJ, Beljaars JH, Hofstra L, Kroon AA, De Leeuw PW. Microvascular
abnormalities in chronic heart failure: a cross-sectional analysis. Microcirculation
2003;10:471–8.
Figure 2 Correlation between capillary density and mean pulmonary
arterial pressure (PAP) in idiopathic pulmonary arterial hypertension.
Extended report
Ann Rheum Dis 2009;68:191–195. doi:10.1136/ard.2007.087353 195
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