(Chest. 2001;120:796-800.)
© 2001
American College of Chest Physicians
Primary Pulmonary Hypertension Is Not Associated With Scleroderma-Like Changes in Nailfold Capillaries*
Eric L. Greidinger, MD;
Sean P. Gaine, MBBCh, FCCP;
Robert A. Wise, MD, FCCP;
Christy Boling, BA;
Traci Housten-Harris, RN and
Fredrick M. Wigley, MD
*
From the Division of Immunology and Rheumatology (Dr. Greidinger), University of Missouri, Columbia, MO; and the Divisions of Rheumatology (Dr. Wigley and Ms. Boling) and Pulmonary and Critical Care Medicine (Drs. Gaine and Wise and Ms. Housten-Harris), Johns Hopkins University, Baltimore, MD.
Correspondence to: Eric L. Greidinger, MD, MA427 Health Sciences Center, Columbia, MO 65212; e-mail: greidingere{at}health.missouri.edu
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Abstract
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Study objectives: To determine whether primary
pulmonary hypertension (PPH) is associated with scleroderma-like
changes in nailfold capillaries.
Design: Blinded,
prospective, case-control study.
Setting: University
medical centers in Baltimore, MD.
Patients:
Thirty-seven patients with PPH, 15 patients with scleroderma, and 13
healthy control subjects.
Measurements: Subjects
underwent nailfold capillary videomicroscopy of the fourth digits of
both hands. Capillary images were evaluated by two blinded, trained
graders according to standardized criteria for the presence of
scleroderma nailfold changes.
Results: The prevalence
of scleroderma-associated nailfold changes in patients with PPH (1 of
37 patients) was dramatically lower than that in patients with
scleroderma (9 of 15 patients; p < 0.0001). The distribution of
nailfold grades for the PPH patients was indistinguishable from that of
the healthy control subjects.
Conclusion: PPH is not
associated with scleroderma-like vasculopathy of nailfold
capillaries.
Key Words: primary pulmonary hypertension • scleroderma • nailfold capillaroscopy
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Introduction
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Primary
pulmonary hypertension (PPH) is a frequently fatal condition, the
causes of which remain uncertain.1
Mutations of the
BMPR-II gene have been associated with the familial form of
the disease but have been found in only a minority of sporadic
cases.2
Pulmonary hypertension is also a leading
cause of mortality and morbidity in patients with systemic sclerosis
(scleroderma).3
4
Histologic studies of the lung lesions
in patients with PPH demonstrate a diffuse vasculopathy that is similar
to that seen in those with scleroderma.5
6
Some patients
who have received diagnoses of PPH have other features that overlap
with scleroderma, such as Raynaud’s phenomenon and antinuclear
antibodies.7
Moreover, prostaglandin therapy has proved to
be effective both for PPH and for scleroderma-associated pulmonary
hypertension.8
9
Given the similarities between PPH and
scleroderma, the possibility has been raised that cases of PPH
represent a forme fruste of scleroderma.10
Therefore, we
investigated whether PPH also was associated with a form of
extrapulmonary vascular disease that is prominent in patients with
scleroderma.
Examination of the nailfold capillaries has been made popular as a
means of evaluating small blood vessels in the peripheral circulation
in humans.11
Scleroderma-specific nailfold capillary
abnormalities have been identified and have been found to be
consistently distinguishable by a blinded observer.12
The
classic changes observed in the scleroderma are nailfold capillary
dropout with decreased capillary density and giant nailfold
capillaries. The presence of scleroderma-associated nailfold
abnormalities has been associated with progression to scleroderma in a
cohort of patients presenting with Raynaud’s
phenomenon.13
To our knowledge, there have been no
investigations that examine the nailfold capillaries of PPH patients to
determine whether changes comparable to those in patients with
scleroderma are found.
This study examined the nailfold capillaries from PPH patients,
scleroderma patients, and healthy control subjects. The
prevalence of nailfold capillary abnormalities in PPH patients was much
lower than that in scleroderma patients and was not significantly
different from that in healthy control subjects. Thus, the features of
systemic vasculopathy that are seen in scleroderma patients do not
develop in PPH patients.
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Materials and Methods
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Subjects
A cohort of 37 PPH patients, 8 scleroderma patients with
pulmonary hypertension, 8 patients with other forms of secondary
pulmonary hypertension, 7 scleroderma patients without pulmonary
hypertension, and 13 control subjects was recruited between May and
October 1998 at university medical subspecialty clinics in Baltimore,
MD. Consecutive patients attending the clinics were recruited until
enrollment targets were met. Family history was obtained. No known
cases of familial PPH were included in this cohort. Study protocols
were approved by the institutional review board committees for the
clinics from which the patients were recruited.
Clinical Data
Pulmonary hypertension was defined to be present if the
mean pulmonary artery pressure was > 25 mm Hg, as determined by right
heart catheterization, or the estimated right ventricular systolic
pressure was > 35 mm Hg by Doppler cardiac
ultrasonography.14
Patients with pulmonary hypertension
were classified as having PPH if they had no other disease process
known to be associated with pulmonary hypertension.14
The
American Rheumatism Association criteria were used to confirm the
diagnosis of scleroderma.15
Raynaud’s phenomenon was
identified using a standardized questionnaire.16
The
epoprostenol infusion history was determined by chart review.
Nailfold Imaging
Nailfold capillary videomicroscopy was performed on the fourth
fingers of both hands by an operator (E.L.G.) who was blinded to the
subjects’ clinical status. Mock infusion pumps were randomly placed on
subjects to blind the operator to their epoprostenol treatment status.
Imaging was performed after at least 30 min of equilibration in a
24°C temperature-controlled room. Immersion oil was applied to the
nailfold before imaging. Recordings were made using a video camera
(model KP-160; Hitachi; Brisbane, CA) and a video recorder
(S-VHS; Panasonic; Secaucus, NJ) mounted on an stereo zoom
microscope (model 52-Tr; Olympus; Melville, NY). Lighting was
supplied by a high-intensity fiber-optic light source. A 5-mm
measurement standard was applied to the digit and was included in each
image.
Grading and Classification of Nailfold Images
As part of the prospective design of the study, the nailfold
recordings were presented in random order to two blinded, trained
graders (F.M.W. and R.A.W.) for classification. The graders both had
participated in a previous multicenter trial performing nailfold
capillary grading17
and had been further trained using a
video atlas to assess for capillary loop enlargement, capillary loop
dropout, capillary density, and tortuous or bushy capillaries. The
graders summarized their assessment of each digit as "scleroderma"
(ie, corresponding to Maricq class II or class III
changes18
), "abnormal but not scleroderma," or
"normal" (Fig 1
). Also, the graders assessed the quality of the images as "good"
(ie, the number and pattern of all nailfold loops clearly
visible over at least a 5-mm span), "fair" (ie, the
number of total loops but not the morphology of all loops clearly
visible over the best 5-mm span), or "poor" (ie, the
number and morphology of loops uncertain over the best 5-mm span). The
blinded graders met to resolve all divergences in grading. Nailfold
scores on the most abnormal hand were used for analysis. For secondary
outcome measures, a single, blinded, trained grader (E.L.G.) evaluated
each nailfold image strictly for capillary density and the presence or
absence of tortuous or bushy capillaries.
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Figure 1.. Representative nailfold videomicroscopy
images from study subjects. Images were obtained from the fourth
fingers of study subjects. Top: normal nailfold
capillaries are shown in which thin, straight, uniformly distributed
loops are present along the nailfold. Middle: abnormal
but not scleroderma nailfold capillaries are shown in which tortuous
and bushy loops are present. The vascular plexus proximal to the
nailfold is prominent. Bottom: scleroderma nailfold
capillaries. The nailfold is oriented as in the top
panel. Enlarged nailfold capillaries and extensive capillary dropout
are present. Two normal capillaries can be seen to the right of the
large dark capillary hemorrhage in the upper part of the field.
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Statistical Analysis
Group means were compared with Student’s t test
results. Independent group proportions were compared using Fisher’s
Exact Test or the 
2 test. Agreement between
test conditions was assessed with the 
statistic.19
Statistical significance was set at p < 0.05. The Bonferroni
correction was used in cases in which multiple comparisons were
performed. Results were calculated using computer software (Prism,
version 3.0 for Windows; Graphpad Software; San Diego, CA; and SPSS,
version 10.0 for Windows; SPSS; Chicago, IL).
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Results
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Clinical Features of the Cohort
This project recruited 52 patients with pulmonary hypertension, 8
additional patients with scleroderma, and 13 healthy control subjects.
Of the 52 subjects with pulmonary hypertension, 37 had PPH, 7 had
scleroderma, and 8 had other forms of secondary pulmonary hypertension.
Of the eight patients recruited who had received a diagnosis of
scleroderma, one also had pulmonary hypertension (transthoracic
echocardiography was performed in every scleroderma patient who was
enrolled except for two who had no clinical signs of pulmonary
hypertension and normal diffusing capacity results on pulmonary
function testing). Clinical characteristics of the patient groups were
compared (Table 1
). A trend toward an older mean age in the scleroderma patients compared
to the healthy control subjects and PPH patients did not reach
significance (p > 0.03). Compared to the healthy control subjects,
more of the scleroderma patients were women (p = 0.005). Raynaud’s
phenomenon was significantly more common in the scleroderma patients
(100%) than in the healthy control subjects (7.7%; p < 0.0001),
the PPH patients (8.1%; p < 0.0001), or the patients with
nonscleroderma secondary pulmonary hypertension (25.0%; p = 0.0003).
Performance of Video Assessment Protocol
Video images of the fourth fingers of both hands for all 73
subjects (146 images) were presented in random order to two blinded
graders. Image-quality assessments were concordant in 87 fingers
(59.6%). The graders’ clinical assessments of each nailfold image
were concordant in 79 fingers (54.1%), and there were only 5 fingers
(3.4%) in which one grader judged the nailfold to be scleroderma while
the other grader judged the nailfold to be normal. Overall, fair
agreement in clinical assessments existed between the two graders for
each digit ( = 0.29).
To assess the consistency of nailfold capillary changes, the grades for
the right hand were compared with the left hand for all 73 study
subjects (Table 2
). Fair agreement was noted in the assessments of the paired hands for
each patient ( = 0.37). All analyses were repeated with patients
classified by their least abnormal hand, their right hand, or their
left hand, and they did not significantly differ from those presented
using the most abnormal hand.
PPH vs Scleroderma Nailfold Comparisons
The prevalence of nailfold grades was compared between groups
using the 2 x 3 2 test (Table 3
). The healthy control subjects and the PPH patients each were clearly
different from the scleroderma patients in nailfold grading results
(2 test, p = 0.002 and p < 0.0001,
respectively) and were not significantly different from each other. The
mean nailfold capillary density was also lower in the scleroderma
patients (mean [± SD], 25.9 ± 12.8 loops per 5 mm) than
in the healthy control subjects (mean, 36.5 ± 8.7 loops per 5 mm;
p = 0.019) or the PPH patients (mean, 41.2 ± 10.7 loops per 5 mm;
p < 0.0001). The only PPH patient with nailfolds that graded as
scleroderma had a history of recent-onset Raynaud’s phenomenon.
Nailfold grading was not different in scleroderma patients with
pulmonary hypertension (normal, 1 of 8 patients; abnormal not
scleroderma, 2 of 8 patients; scleroderma, 5 of 8 patients) compared to
scleroderma patients without pulmonary hypertension (normal, 0 of 7
patients; abnormal not scleroderma, 3 of 7 patients; scleroderma, 4 of
7 patients). Overall, nailfold grade prevalence also was not affected
by epoprostenol treatment status (Table 4
). No differences in nailfold capillary density were observed between
epoprostenol-treated and untreated subgroups of PPH patients or
scleroderma patients (not shown). Bushy or tortuous capillaries tended
to be more prevalent in the nailfolds of PPH patients who had been
treated with epoprostenol (76.2%) than in those of untreated PPH
patients (50.0%; p = 0.027 [Fisher’s Exact Test]). The prevalence
of bushy or tortuous capillaries was > 85% in the nailfolds of both
treated and untreated scleroderma patients.
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Discussion
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While PPH and scleroderma share pulmonary vessel abnormalities and
some clinical features, this study found no evidence that cases of PPH
are a forme fruste of scleroderma. Using previously validated criteria
for the evaluation of nailfold capillary images and a blinded
case-control study design, PPH was not associated with scleroderma-like
extrapulmonary vasculopathy in the digital bed. The results of nailfold
capillary microscopy of patients with PPH were substantially different
from those of scleroderma patients and were indistinguishable from
those of healthy control subjects. Only 1 of 37 patients who had
received diagnoses of PPH showed scleroderma-like nailfold
abnormalities. This patient also had severe Raynaud’s phenomenon.
The proportion of scleroderma patients with classic nailfold changes
observed in the current study (9 of 15 patients; 60%) is similar to
that in an earlier study20
of videomicroscopy on the
fourth digit nailfolds of scleroderma patients in which 43% of
patients had classic nailfold changes. The presence in our cohort of
one scleroderma patient who both graders agreed had normal capillary
morphology on one hand and classic scleroderma changes on the
contralateral hand emphasizes that inspection of multiple nailfolds be
performed before concluding that scleroderma nailfold changes are
absent. In an earlier trial21
of nailfold microscopy,
classic nailfold changes were also inconsistent in the fingers of
scleroderma patients. Dilated capillaries were present in 42% of
digits, markedly decreased capillary density was present in 38%, and
avascular areas were present in 26%.
In addition to its immediate vasodilatory effects on the pulmonary
vasculature, epoprostenol gradually reduces pulmonary vascular
resistance with prolonged infusion, presumably due to the remodeling of
pulmonary vessels.22
Our study noted an increased
prevalence of tortuous and bushy capillaries after PPH patients had
received epoprostenol therapy. Although this difference was not
statistically significant, the trend of differences is of interest.
Additional studies will be needed to establish whether epoprostenol
therapy leads to the remodeling of nailfold capillary vessels.
Epoprostenol infusion is known to be an effective treatment for
Raynaud’s phenomenon.23
This study provides evidence that PPH and scleroderma are distinct
entities, even though they lead to similar histologic lesions in the
pulmonary vascular bed. The presence of clear-cut scleroderma nailfold
changes in a patient with pulmonary hypertension should lead to a high
index of suspicion for a scleroderma-spectrum disorder.
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Acknowledgements
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The authors are grateful to Dr. Lewis J. Rubin for
his key roles in the conception of this study and in patient
recruitment.
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Footnotes
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Abbreviations: PPH = primary pulmonary hypertension
Dr. Greidinger is supported by the National Institutes of Health K08
Award No. AI01842 and by a University of Missouri Research Board Award.
Received for publication December 14, 2000.
Accepted for publication April 6, 2001.
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Abstract
Introduction
