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Pulmonary hypertension in the crest syndrome variant of systemic sclerosis.

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515
PULMONARY HYPERTENSION IN THE CREST
SYNDROME VARIANT OF SYSTEMIC SCLEROSIS
ANGELA M. STUPI, VIRGINIA D. STEEN, GREGORY R. OWENS, E. LEON BARNES,
GERALD P. RODNAN, and THOMAS A. MEDSGER, JR.
Pulmonary hypertension (PHT) occurred in 59
(9%) of 673 systemic sclerosis patients seen between
1963 :and 1983. In 30 patients, all with the CREST
syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias), the
pulmmary hypertension was isolated, i.e., independent
of other pulmonary or cardiac conditions. In 20 patients, isolated PHT was demonstrated by cardiac
catheterization. All had normal or only mildly decreased
lung volumes, and mild or no pulmonary interstitial
fibrosis on chest roentgenogram. In comparison with
287 CREST syndrome patients without PHT, these 20
patients had markedly reduced diffusing capacity for
carbon monoxide (DLco) (mean 39% of predicted normal). In 6 patients, the low DLco antedated clinical
evidence of PHT by 1-6 years. At autopsy there was
marked intimal fibrosis with hyalinization and smooth
muscle hypertrophy in the small- and medium-sized
arteries, without significant parenchymal fibrosis or
inflammation. Patients with isolated PHT did not reFrom the Department of Medicine, Divisions of Rheumatology and Clinical Immunology and Pulmonary Medicine, and
the Deipartment of Pathology, University of Pittsburgh School of
Medicine, Pittsburgh, Pennsylvania.
Supported by grants from the National Institutes of Health
(FR-00056 and AM-21393), the RGK Foundation, Austin, Texas,
and the Arthritis Foundation, Western Pennsylvania Chapter.
Angela M. Stupi, MD: Fellow in Rheumatology; Virginia D.
Steen, MD: Assistant Professor of Medicine; Gregory R. Owens,
MD: Assistant Professor of Medicine; E. Leon Barnes, MD: Associate Professor of Pathology; Thomas A. Medsger, Jr., MD: Professor of Medicine.
Dr. Rodnan is deceased.
Address reprint requests to Dr. Virginia D. Steen, 985
Scaife Hall, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.
Submitted for publication February 21, 1985; accepted in
revised form September 27, 1985.
Arthritiis and Rheumatism, Vol. 29, No. 4 (April 1986)
spond favorably to vasodilators and had a very poor
prognosis, with a 2-year cumulative survival rate of
40%. A DLco <45% of predicted in the absence of
pulmonary interstitial fibrosis may be an important predictor of the subsequent development of isolated PHT.
The CREST syndrome variant of systemic sclerosis (scleroderma) refers to a subset of patients with
restricted skin changes, often limited to the fingers
and/or face, the relatively slow development of visceral involvement, and the presence of serum anticentromere antibody (1,2). (CREST is an acronym for
calcinosis, Raynaud's phenomenon, esophageal
dysmotility, sclerodactyly, telangiectasias.) Pulmonary arterial hypertension, one of the leading causes of
mortality among patients with the CREST syndrome
variant, is most frequently detected at a late stage,
when vascular structural changes are far advanced,
the response to vasodilator and other therapies unsatisfactory, and the prognosis grave (3-5). In order to
identify clinical or laboratory features which correlate
with and might serve as early predictors of this complication, we studied a large series of systemic sclerosis patients with the CREST syndrome, with and
without pulmonary hypertension (PHT).
PATIENTS AND METHODS
Data on all patients with systemic sclerosis evaluated
at the University of Pittsburgh from 1963-1983 were examined for clinical evidence of pulmonary hypertension. Initial
screening criteria were: increased pulmonic sound, right
ventricular enlargement on chest radiograph, or electrocardiographic evidence of right ventricular hypertrophy or right
axis deviation. Cardiac catheterization was performed in
patients with suspected PHT, for the purpose of confirming
the diagnosis or to observe the hemodynamic effects of
STUPI ET AL
5:16
Table 1. The frequency of pulmonary hypertension in subsets of
systemic sclerosis patients seen at the University of Pittsburgh,
1963- 1983
CREST
syndrome
(n = 331)*
Secondary pulmonary hypertension
Parenchymal pulmonary disease
Cardiac disease
Isolated pulmonary hypertension
Catheterization-proven
Clinical evidence only
Diffuse
scleroderma
(n = 342)
14 (4%)
15 (5%)
6
8
30 (9%)
20
10
11
4
0 (0%)
0
0
* CREST syndrome = calcinosis, Raynaud’s phenomenon,
esophageal dysmotility, sclerodactyly, telangiectasias.
vasodilating drugs injected directly into the main pulmonary
artery.
Patients with documented pulmonary hypertension
on cardiac catheterization, as well as those with clinical
evidence of cor pulmonale or pulmonary hypertension found
by noninvasive testing, were classified as having PHT.
Patients with primary cardiac disease, e.g., scleroderma
cardiomyopathy with left ventricular failure or nonsclerodlermatous (rheumatic or atherosclerotic) heart disease,
were considered to have PHT secondary to cardiac causes,
and were therefore excluded from further study. Patients
with severe parenchymal pulmonary interstitial fibrosis on
roentgenogram or restrictive disease on pulmonary function
testing (vital capacity <55% of predicted) were considered
to have PHT secondary to parenchymal pulmonary causes.
All remaining patients with PHT were considered to have
primary disease of the pulmonary arteries or isolated pulmonary hypertension (IPHT).
The following criteria were required for inclusion in
the IPHT group: pulmonary artery mean pressure >20 mm
Hg, pulmonary artery systolic and diastolic pressures
>30/15 mm Hg, mean pulmonary capillary wedge pressure
< I 2 mm Hg, no or mild bibasilar pulmonary interstitial
fibrosis on chest roentgenogram, and normal pulmonary
function or only mild restrictive disease, with forced vital
capacity >60% of predicted normal and forced expiratory
volume in 1 secondiforced vital capacity (FEVI/FVC)
>’70%. Patients with clinical evidence of pulmonary hypertension (cor pulmonale, right ventricular hypertrophy, or
pulmonary hypertension found on noninvasive testing) but
who had not undergone cardiac catheterization were excluded from both study groups and analyzed separately.
Classification of patients as having the CREST syndrome required the presence of puffy fingers or sclerodermatous skin changes limited to the distal portions of the
extremities (fingers, hands, distal forearms) and/or face but
not the trunk, Raynaud’s phenomenon, and either subcutaneous calcification of the digits or multiple telangiectasias of
the digits (2). Patients classified as having diffuse scleroderma had sclerodermatous skin changes of both distal and
proximal extremities and either truncal scleroderma or 1 or
more palpable tendon friction rubs. Patients were divided
into 2 subgroups for comparison: CREST with isolated PHT
(CREST-IPHT) and CREST without PHT (CREST-no-
PHT). The CREST-no-PHT group consisted of CREST
syndrome patients who had neither clinical nor cardiac
catheterization evidence of PHT.
Initial assessment of all patients consisted of a complete history and physical examination, with detailed assessment of skin changes using the total skin score, a
semiquantitative method of measuring the degree and extent
of skin thickening (6). Complete pulmonary function tests,
including spirometry and testing for single breath carbon
monoxide diffusing capacity (DLco) (7), were routinely
performed as part of this initial evaluation. Normal values
were obtained from the Intermountain Thoracic Society
standards (8) and results are presented as percent of predicted. Evidence of other visceral involvement was sought
by electrocardiogram, cineesophagram, small bowel series,
urinalysis, plasma renin activity, serum creatinine, and
creatinine clearance.
Serologic tests were performed in the laboratories of
the University of Pittsburgh School of Medicine Division of
Rheumatology and Clinical Immunology, using standard
techniques. They included tests for antinuclear antibody
using rat liver substrate, anticentromere antibody on HEp-2
cells (9), anti-Scl-70 (lo), anti-RNP by hemagglutination,
rheumatoid factor by latex agglutination, and anti-SS-A and
anti-SS-B by immunodiffusion. Serum complement components (C3 and C4), anti-DNA, and immune complexes by
agarose gel electrophoresis (1 1) were also measured. Microscopic examination of lung parenchyma and blood vessels
was performed on available autopsy specimens.
All data were entered into a computer for storage and
analysis using the American Rheumatism Association Medical Information System (ARAMIS) (12). Statistical methods
included the chi-square test for differences between proportions, with Yates’ correction or Fisher’s exact test where
applicable, for small numbers. Comparisons of mean values
were examined using Student’s t-test or the Wilcoxon rank
sum test. Cumulative survival rates were calculated with
Table 2. Demographic and clinical data on systemic sclerosis
patients with CREST syndrome, with and without pulmonary
hypertension at the time of initial evaluation*
CREST-IPHT
(n = 20)
Mean age
% female
% satisfying ARA criteria-!
% with Raynaud’s
phenomenon as first
symptom
Mean duration of Raynaud’s
phenomenon prior to
diagnosis of systemic
sclerosis (years)
Mean disease duration prior
to PHT diagnosis (years)
CREST-no-PHT
(n = 287)
80
85
1OO$
52.5
83
87
68$
10.9
7.2
57.0
13.6
* CREST = calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias; IPHT = isolated pulmonary
hypertension.
t American Rheumatism Association criteria; see ref. 13.
$.
P < 0.01.
5 17
PULMONARY HYPERTENSION IN CREST
life-table methods and comparisons made using logrank
tests.
Table 3. Clinical features in CREST syndrome patients with and
those without pulmonary hypertension, at the time of first
evaluation at the University of Pittsburgh*
RESULTS
Table 1 summarizes the occurrence of pulmonary hypertension in the 673 systemic sclerosis patients seen at the University of Pittsburgh during
1963-1983. Fifty-nine had proven or suspected pulmonary hypertension. There were 29 patients with secondary PHT; 14 had CREST syndrome and 15 had
diffuse scleroderma. Seventeen of these individuals, 8
of whom had cardiac catheterization, had PHT secondary to parenchymal pulmonary causes; 15 had
moderate-to-severe restrictive lung disease due to
systemic sclerosis and 2 had severe chronic obstructive lung disease. Twelve patients (8 with the CREST
variant and 4 with diffuse scleroderma) had PHT
secolndary to cardiac disease. Most of these (6 with
CREST and 1 with diffuse scleroderma) were believed
to have a nonscleroderma etiology of their heart
condition (rheumatic or atherosclerotic heart disease).
Ten of these 12 patients had cardiac catheterization.
There were 30 patients, all with the CREST
syndrome, who had IPHT without other antecedent
pulmonary or cardiac conditions: 20 cases were documented by cardiac catheterization and 10 patients
had only clinical evidence of pulmonary hypertension.
For the purpose of this study, only the 20 catheterization-confirmed CREST-IPHT patients were compared
with1 the group of 287 CREST-no PHT patients. Of
these 20 patients, pulmonary hypertension had been
diagnosed in 6 shortly (1-6 months) before their initial
evaluation in Pittsburgh. Eleven patients were diagnosed as having IPHT at the time of their first visit,
and 3 patients were seen for 1-3 years prior to the
diagnosis of IPHT. Of 228 CREST syndrome patients
from our referral area, there were 22 with IPHT,
yielding an estimated incidence of 10%. Based on our
best estimates, we see 90% of all systemic sclerosis
patilents in the Pittsburgh area.
Demographic data on both patient groups at the
time of their first evaluation in Pittsburgh are shown in
Table 2. There were no significant differences with
regard to age, race, or sex. The CREST-IPHT patients ranged from 28-69 years of age, whereas the
CREST-no-PHT patients had a wider age range
(18-85). Similar proportions of CREST-IPHT and
CREST-no-PHT patients fulfilled ARA preliminary
criteria for classification of definite systemic sclerosis
(13): 85% and 87%, respectively.
IPHT
(n = 20)
NO-PHT
(n = 287)
50
44
100
47
16
95
93
48
16
86
10
55
25
10
6
4
62
20
14
7
63
5
0
73
4
<I
Calcinosis
Peripheral vascular changes
Raynaud’s phenomenon
Digital pitting scars
Digital tip ulcers
Digital telangiectasias
Scleroderma changes
Puffy fingers only
Fingers only
Fingers and hands only
Fingers, hands, and forearms
Total skin score (mean)
Visceral involvement
Gastrointestinal tract
Heart
Kidney
* Except for total skin score, all values represent percent with
positive finding. See Table 2 for definitions.
All CREST-IPHT patients had Raynaud’s phenomenon as their initial connective tissue disease
symptom. In contrast, only 68% of CREST-no-PHT
patients had Raynaud’s phenomenon as the first complaint (P < 0.01). Other presenting manifestations in
the no-PHT group included puffy fingers or sclerodactyly (9%), articular complaints (9%), and esophageal dysfunction (3%). The mean ages at disease
onset were similar (42 and 41 years, respectively), and
both groups had prolonged duration of Raynaud’s
phenomenon before the first physician diagnosis of
systemic sclerosis (10.9 and 7.2 years, respectively).
Patients with IPHT thus had Raynaud’s phenomenon
for a mean of 13.6 years (range 2-34) before the
recognition of pulmonary hypertension.
Table 4. Serologic abnormalities in CREST syndrome patients
with and those without pulmonary hypertension, at the time of
first evaluation at the University of Pittsburgh*
IPHT
(n = 20)
NO-PHT
(n = 287)
Antinuclear antibodies
(titer >1:32)
Anticentromere antibodies
(titer >1:40)
7/16 (44%)
93/251 (37%)
8/15 (53%)
63/136 (46%)
i::!z$terlo,ooo~
0/14
1/13 (8%)
2/16 (13%)
30/136 (22%)
9/207 (4%)
32/243 (13%)
>1:
Rheumatoid factor
(titer >1:80)
Or
* See Table 2 for definitions.
0/13
6/79 (8%)
STUPI ET AL
5h8
Other clinical features of systemic sclerosis
present in patients at the time of the first evaluation in
Pittsburgh are listed in Table 3. Calcinosis, ischemic
peripheral vascular findings, and telangiectasias occurred with similar frequency in both groups. The
distribution of skin changes was almost identical, and
the mean total skin score at first evaluation was
similar. Visceral involvement, as defined by the 1971
criteria of Medsger and Masi (14), occurred equally
often in the 2 groups. As expected, “scleroderma renal
crisns” was rare in this population of CREST syndrome patients; it was not found in the IPHT group
and developed in only 1 patient in the comparison
group. Myositis, tenosynovitis with tendon friction
rubs, Sjogren’s syndrome, hypothyroidism, and
trigeminal neuropathy were occasionally encountered,
but none of these features was associated with IPHT.
Table 4 summarizes serologic abnormalities in
the 2 patient groups at the time of initial evaluation.
There were no statistically significant differences.
Anticentromere antibody, a recognized marker for
CREST syndrome, was detected in 53% of the IPHT
group and 46% of the no-PHT patients. Anti-Scl-70
was not found in any of the 14 PHT patients tested, nor
was it present in 6 noncatheterized individuals with
IPHT. High-titer anti-RNP antibodies were identified
in only 1 individual with IPHT.
The most common cardiopulmonary symptom
in the 20 patients at the time of diagnosis of IPHT was
exertional dyspnea. This symptom had been present
for < 1 year prior to the diagnosis of IPHT in 17 of the
20 patients, whereas 2 had a prolonged history of
dyspnea (4 and 6 years). Orthopnea was noted in 7
patients (35%). Sixteen patients (80%) had an accentuated pulmonic component of the second heart sound
on physical examination. Additional features included
a palpable parasternal heave (3 patients) and
auscultatory evidence of tricuspid regurgitation (4
patients). Neither pleuritic chest pain nor pleural friction rub was detected in any of these patients.
Electrocardiographic evidence of right axis deviation was noted in all 20 CREST-IPHT patients, and
all but 1 had evidence of right ventricular hypertrophy
(RVH). The single patient with only right axis deviation also displayed poor R-wave progression, which
may have masked RVH. Echocardiograms confirmed
the presence of right ventricular hypertrophy in 6 of 7
patients studied. Chest roentgenograms were inter-
Table 5. Pulmonary function and chest roentgenogram results in 20 patients with CREST
syndrome and isolated pulmonary hypertension*
FVC, %
predicted
(normal >80)
FEVIIFVC, %
(normal >70)
DLco, %
predicted
(normal 3 0 )
Po2, mm Hg
(normal 3 0 )
Bibasilar
interstitial
fibrosis
12
13
14
15
16
17
18
19
20
68
73
106
69
84
103
91
83
95
NA
79
90
84
89
NA
76
92
92
90
69
77
78
82
82
81
74
81
75
68
NA
75
83
80
73
NA
70
82
83
80
77
26
42
25
20
44
52
NA
47
49
NA
22
43
53
31
NA
32
60
34
51
38
79
73
39
NA
68
NA
83
NA
48
NA
56
NA
75
53
51
50
NA
81
NA
75
0
0
Mild
0
Mild
0
0
0
0
0
Mild
0
0
0
0
0
Mild
0
0
0
Mean
85
78
39
64
Patient
1
2
3
4
5
6
7
8
9
10
11
* CREST = calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias; FVC = forced vital capacity; FEV, = forced expiratory volume in 1 second; DLco = lung
diffusing capacity for carbon monoxide; NA = not available.
519
PULIMONARY HYPERTENSION IN CREST
Table 6. Hemodynamic data on 20 patients with CREST syndrome and isolated pulmonary
hypertension*
Systolicldiastolic
(normal <30/15)
Mean
(normal <20)
Pulmonary vascular
resistance,
dynes/second/cm-5
(normal 60-140)
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
65/20
75/40
68/35
85/40
120138
81/33
120150
60135
90130
80125
85/40
98/37
83/30
65/35
100/40
84/33
90145
60130
64/33
70135
35
55
50
55
63
50
70
45
50
40
50
63
50
45
65
43
55
40
44
42
466
587
465
2,167
2,042
1,516
1,723
1,214
1,312
605
2,424
2,664
705
NA
1,620
711
NA
625
990
1,593
1.52
2.34
4.70
1.36
2.40
2.61
1.47
2.19
1.55
3.19
0.89
1.16
2.98
NA
0.98
2.01
3.00
1.90
2.10
2.25
Mean
82/35
50
1,301
2.14
Pulmonary artery pressure, mm Hg
Patient
1
Cardiac index,
liters/minute/m2
(normal 2.8-3.5)
* See Table 5 for definitions.
pretetl as showing right ventricular enlargement in 18
of 20 IPHT patients (90%). The radiographs also
showed prominent enlargement of the main and proximal pulmonary artery in 14 of the 20 patients.
Table 5 details the pulmonary function and
chest roentgenographic data in the 20 IPHT patients at
the time of diagnosis of IPHT. Spirometry revealed
that 6 of 18 IPHT patients studied had a slightly
reduced FVC ( 4 0 % of predicted), but 5 of these
patients had normal results on chest roentgenogram.
Only 1 patient had radiographic evidence of mild
pulmonary interstitial fibrosis and marginally reduced
vital capacity (79% of predicted). All but 1 IPHT
patient had a normal FEVJFVC. In contrast, the
diffusing capacity for carbon monoxide (DLco) was
abnormal ( 4 0 % of predicted) in all patients. In most
instances, the DLco was extremely low, with a mean
value of 39% of predicted. Arterial Poz was decreased
in 1 1 of 13 IPHT patients tested.
A summary of the hemodynamic data at the
time of diagnosis of IPHT is presented in Table 6.
Right heart catheterization showed markedly elevated
pulmonary artery pressure in all patients, ranging
from 60-120 mm Hg (systolic) and 20-50 mm Hg
(diastolic). The mean pulmonary artery pressure in the
20 CREST-IPHT patients was 50 mm Hg. As expected, pulmonary vascular resistance was uniformly
elevated.
All 20 IPHT patients and 254 no-PHT patients
had results of both a chest roentgenogram and a
simultaneous electrocardiogram reported. Comparison of the cardiopulmonary findings in these 2 groups
is shown in Table 7. The frequency of interstitial
fibrosis was similar. Right ventricular enlargement was
seen infrequently on chest radiographs of the no-PHT
patients, and when present it was associated with left
ventricular enlargement in all cases. Electrocardiographic evidence of right ventricular hypertrophy was
absent in no-PHT patients, although 9 of the 254
examined patients had right bundle branch block. The
most impressive difference was in the DLco, where
the mean values were strikingly disparate. In individuals with IPHT, the mean DLco was 39% of predicted,
compared with 84% of predicted in those without
pulmonary hypertension ( P < 0.001). Eleven of 17
IPHT patients (65%) had a DLco <45% of predicted.
In contrast, only 21 of 165 no-PHT patients (13%) had
a DLco <45% of predicted ( P < 0.01).
Six IPHT patients had pulmonary function testing performed 1-6 years before confirmation of IPHT.
STUPI ET AL
520
Table 7. Cardiopulmonary findings in CREST syndrome patients
with and those without pulmonary hypertension*
-~
IPHT
(n = 20)
NO-PHT
(n = 287)
~
19/20 (95)t
Dyspnea, no. (%)
Chest roentgenogram
Bibasilar fibrosis, no. (%)
4/20 (20)
Right ventricular enlargement, no. (%) 18/20 (90)t
Electrocardiogram
Right ventricular hypertrophy,
19/20 ( 9 3 7
no. (%)
Pulmonary function tests
85
FVC, mean % predicted
FEVdFVC. mean %
78
39t
DLC~
11/17 (65)$
Mean % predicted
<45% of oredicted, no. (%)
Arterial Po2 (mm Hg)
64$
93/287 (32)t
77/254 (30)
16/254 (6)t
01254 (0)t
83
78
84t
211165 (13)$
1
-
76$
* IPHT = isolated pulmonary hypertension; see Table 5 for other
definitions.
t P < 0.001.
f P < 0.01.
At that time, all had normal results of spirometry and
lung radiographs, but a strikingly reduced DLco,
ranging from 3140% (mean 44%) of predicted normal.
These individuals were followed for 10-72 months
(mean 34) prior to the appearance of clinically apparent IPHT. Two additional IPHT patients who did not
undergo catheterization had reductions in DLco of
similar magnitude 2-3 years prior to the diagnosis of
PHT.
Of the 21 no-PHT patients with DLco <45% of
predicted, this reduction was attributable to other
cardiac or pulmonary disorders in 12 instances and
was isolated in 9. Five of these 9 patients have had
repeat pulmonary function tests performed 1S-6 years
later. Their values for the diffusing capacity all improved during this time, from a mean of 39% to a mean
of 73%. Eight remain free of symptoms or findings of
PHT a mean of 5.5 years after the initial evaluation.
One patient died suddenly at home of unknown
causes.
Of the 20 patients with isolated pulmonary
hypertension studied, only 1 remains alive. In general,
death was attributed to cor pulmonale. However, 6
patients died suddenly, presumably because of cardiac
arrhythmias or pulmonary emboli. Figure 1 illustrates
the cumulative survival rate in the 2 patient groups,
calculated from the time of the first evaluation in
Pittsburgh. The IPHT group had a 2-year survival rate
of 40%, compared with 88% in the no-PHT group (P <
0.001). The longest survival from the discovery of this
complication has been 5.6 years. A similar mortality
rate was found for the 10 noncatheterized PHT patients; 9 have died within 2 years of diagnosis. Survival
was not correlated with the level of pulmonary artery
pressure or the severity of the reduction in diffusing
capacity.
Lung tissue taken at autopsy was available for
histologic study in 13 patients (Table 8). Five types of
vascular changes were observed: smooth muscle
hyperplasia, intimal fibrosis, hyalinization, myxoid
change, and adventitial fibrosis. In some vessels, 2 or
more of these changes were noted.
Vascular abnormalities were observed in all 6 of
the IPHT patients from whom such autopsy material
was available. These were most conspicuous in small
pulmonary arteries, but were occasionally seen in
larger arteries as well. Pulmonary veins and bronchial
arteries were relatively spared. The most common
vascular changes in IPHT were smooth muscle
hyperplasia (2 to 3-t) and intimal fibrosis (1 to 3+),
which were seen in all 6 cases. Smooth muscle
hyperplasia produced the most severe degree of luminal narrowing and was judged to be the most important marker of pulmonary hypertension.
It was impossible to determine if isolated
intimal fibrosis was the cause or the effect of hypertension. However, patients with isolated pulmonary
-1
CREST without
pulmonary hypertension
100
a
>
>
(n=287)
-\
*O
"
I
CREST with isolated
~
1
2
3
4
5
YEARS OF FOLLOW-UP FROM INITIAL VISIT
Figure 1. Survival of systemic sclerosis patients with the CREST
syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly , telangiectasias): patients with isolated pulmonary hypertension and patients without pulmonary hypertension.
PULMONARY HYPERTENSION IN CREST
Table 8. Pulmonary histologic findings at autopsy in CREST
syndrome patients with and those without pulmonary hypertension*
IPHT
= 6)
(n
NO-PHT
(n = 7)
Blood vessels
Smooth muscle hyperplasia
Intimal fibrosis
Hyalinization
Myxoid change
Adventitial fibrosis
Parenchyma
Fibrosis
Inflammation
6’r
0
6$
4
2
2
5§
0
0
1
27
0
5#
0
* IPHT
= isolated pulmonary hypertension. All vascular changes in
LPHT patients were diffuse. All vascular changes in no-PHT patients
were focal and confined to areas of parenchymal fibrosis.
t 2 + , 4 patients; 3 + , 2 patients. 0 = absent; 3 + = severe.
$ 1 + , 2 patients; 2 + , 3 patients; 3 + , 1 patient. 0 = absent; 3 + =
severe.
8 1 + , I patient; 2 + , 3 patients; 3 + , I patient. 0 = absent; 3 + =
severe.
ll 1 + , 1 patient; 3 + focal, 1 patient. 0 = absent; 3 + = severe.
# All 2-3 + focal. 0 = absent; 3 + = severe.
hypertension were more likely to have intimal fibrosis
with concomitant smooth muscle hyperplasia which
was noted diffusely throughout the lung sections,
rathler than focally or limited to an area of parenchymal fibrosis. There was no evidence of fibrinoid necrosis, vasculitis, or inflammation.
Vascular changes in the no-PHT group were
limiled to the areas of fibrosis and consisted of mild to
severe intimal fibrosis ( 5 patients) and mild adventitial
fibrosis ( 1 patient). None exhibited smooth muscle
hyperplasia. Figures 2A and B show representative
pholomicrographs of pulmonary arteries from a noP H l patient and an IPHT patient, respectively.
DISCUSSION
It is generally agreed that pulmonary hypertension occurs with increased frequency in patients with
connective tissue diseases, especially systemic sclerosis. Although pulmonary vascular histologic changes
have been recognized in systemic sclerosis since the
work of Krause in 1924 (15), the first series of patients
with PHT was reported by Sackner et a1 in 1964 (16).
In their group of 33 systemic sclerosis patients who
underwent cardiac catheterization, 18 had experienced
an episode of right heart failure or had clinical evidence of right ventricular hypertrophy, and 9 had
elev,ated pulmonary artery pressure. Additional cases
were described and discussed in detail by others
(3,1;7-20).
The prevalence of pulmonary hypertension in
52 1
systemic sclerosis has been estimated to be as high as
33% by Ungerer et a1 (20), who prospectively studied
49 patients who had undergone cardiac catheterization. Sixteen of these persons were considered to have
pulmonary hypertension (8 definite, 8 borderline). In
our study, a lower proportion, 59 of 673 systemic
sclerosis patients (9%), had convincing clinical evidence of either isolated or secondary PHT; however,
we did not attempt to identify patients with marginally
elevated pulmonary artery pressure.
Disparities between the results of pulmonary
function tests and roentgenographic and pathologic
abnormalities in patients with systemic sclerosis have
been well-documented (7,21,22). Of particular interest
has been the poor correlation between the presence
and severity of PHT and the presence of interstitial
fibrosis. Sixteen of our 20 IPHT patients had no
radiographic evidence of pulmonary interstitial fibrosis, and 4 of 6 autopsied subjects with IPHT had
neither roentgenographic nor histologic evidence of
interstitial fibrosis. However, all of these individuals
studied had markedly diminished diffusing capacity.
Of Sackner’s 8 patients with PHT who had
pulmonary function studies performed, 7 had only a
mild reduction in vital capacity (16). In their study of
autopsied patients, Young and Mark (22) reported that
5 of 8 patients with severe pulmonary arterial disease
had only slight or no microscopic evidence of interstitial fibrosis, and 3 of these 5 had no interstitial fibrosis
on chest roentgenogram. Each of these latter 3 patients had a course similar to that of our patients, with
rapid deterioration and death within a few months.
Some patients with systemic sclerosis have
pulmonary vascular lesions without clinical evidence
of pulmonary hypertension (22,23). Germain et al (24)
and Ungerer et a1 (20) have both documented mild
elevations of pulmonary artery pressure in scleroderma patients. Correlation of clinical and pathologic
findings earlier in the disease course, with specialized
pulmonary testing and appropriate followup, will be
required to determine the significance of these results.
Renal vascular lesions without clinical evidence
of functional impairment of the kidney have also been
reported (25). Interestingly, pulmonary arterial and
malignant systemic hypertension rarely occur in the
same patient because of their strong association with
CREST syndrome and diffuse scleroderma, respectively (1,5,22). The physiologic or environmental precipitating events of PHT and “scleroderma renal
STUPI ET AL
522
A
B
Figure 2. A, Normal small pulmonary artery from a patient with CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal
dysmotility, sclerodactyly, telangiectasias) and no pulmonary hypertension. B, Small pulmonary artery from a patient with CREST syndrome
and isolated pulmonary hypertension. Note the marked degree of smooth muscle hyperplasia, with almost total obliteration of the lumen.
(Hematoxylin and eosin stained, original magnification X 500.)
crisis” are completely unknown, although both pulmonary and renal “Raynaud’s phenomenon” have been
described (26-28).
The malignant nature of this form of pulmonary
arterial hypertension in systemic sclerosis is evidenced by its markedly accelerated course and decreased patient survival. Eighteen of our 30 patients
died within 2 years of the diagnosis of this complication. Many of them had undergone a trial of 1 or more
vasodilators administered directly into the pulmonary
artery during right heart catheterization. Although in
some there was transient reduction in the mean pulmonary artery pressure and/or pulmonary vascular
resistance, no oral therapy altered the downhill
course. In our experience, PHT patients have survival
rates that are even worse than those in patients with
renal crisis (29). Peters-Golden et a1 (30) found a
markedly decreased survival rate for patients with a
DLco <40% of predicted normal, although the pres-
ence or absence of PHT and the cause of death were
frequently not known.
Systemic sclerosis patients at greatest risk for
developing IPHT are those with the CREST syndrome
variant. This relationship was first noted by Trell and
Lindstrom (17). Salerni et a1 (3) subsequently described 10 CREST syndrome patients with PHT, 6 of
whom are included in the present study. Young and
Mark (22) and Ungerer et a1 (20) also noted a correlation between PHT and CREST syndrome. Unfortunately, the presence of serum antibodies was not
predictive of IPHT. Anticentromere antibodies were
found with similar frequency in the CREST-PHT and
CREST-no-PHT patients. Anti-Scl-70, a sclerodermaspecific antibody associated with pulmonary fibrosis
(31), was not found in any of the IPHT patients. There
are also reports of PHT in patients with Raynaud’s
phenomenon but without other features of systemic
sclerosis (32-35), 1 of whom had anticentromere anti-
PULMONARY HYPERTENSION IN CREST
body (35). These cases may represent a forme fruste of
systemic sclerosis.
Pulmonary hypertension has been described in
mixed connective tissue disease (36,37). The most
frequent histologic findings are very similar to those
we have described in systemic sclerosis, although true
vasculitis of the pulmonary arteries has also been
observed (36). Only 1 of our patients had high-titer
serum anti-RNP antibodies, and on lung biopsy her
pulmonary vessels showed typical intimal fibrosis and
smooth muscle hypertrophy.
Other than the presence of long-standing
Raynaud’s phenomenon in IPHT patients, no clinical,
laboratory, or serologic abnormalities predicted this
outcome, except the DLco. A diffusing capacity reduction of a marked degree (<45% of predicted)
antedated all other findings in all 6 of our patients who
had been followed prior to the diagnosis of PHT. This
is consistent with the findings of Ungerer et a1 (20). In
our recent survey of pulmonary function test results in
consecutive nonsmoking systemic sclerosis patients,
isolated reduction of diffusing capacity was common,
occurring in 22% of patients (7). However, an isolated
DLco of <45% of predicted occurred only rarely (5%)
in patients without pulmonary hypertension.
We suggest that CREST syndrome patients
withkout obvious pulmonary fibrosis who have a markedly decreased diffusing capacity should be considered
to be at increased risk for PHT. Cardiac catheterization and long-term followup will be required to determine whether these individuals already have or will
develop PHT. Earlier identification of patients with
this serious complication may then allow testing of
new, potentially effective therapeutic interventions
before irreversible pulmonary arterial changes occur.
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