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Pulmonary involvement in systemic sclerosis scleroderma.

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759
PULMONARY INVOLVEMENT IN
SYSTEMIC SCLEROSIS (SCLERODERMA)
VIRGINIA D. STEEN, GREGORY R. OWENS, GREGORY J. FINO,
GERALD P. RODNAN, and THOMAS A. MEDSGER, JR.
One hundred sixty-five nonsmoking systemic
sclerosis patients were evaluated by pulmonary function
testing. Restrictive lung disease and an isolated reduction of the diffusing capacity of carbon monoxide were
the most frequent abnormalities. Patients with the
CREST syndrome (calcinosis, Raynaud's phenomenon,
esophageal dysmotility, sclerodactyly, and telangiectasias) had a similar frequency and severity of pulmonary
involvement compared with the patients who had diffuse
scleroderma. CREST syndrome patients with restrictive
lung disease rarely had the anticentromere antibody and
had more skin and joint involvement of their hands,
compared with other CREST syndrome patients. Dyspnea and rales were most commonly found in patients
with restrictive lung disease. Fibrosis, shown on chest
radiograph, and pulmonary function abnormalities correlated poorly with each other. Dyspnea was associated
with restrictive disease, and rales were more commonly
found in patients with fibrosis. Patients with a restrictive abnormality had the worst prognosis, with a 5-year
survival rate of 58%, although death from pulmonary
From the Division of Rheumatology and Clinical Immunology andl the Division of Pulmonary Medicine, Department of Medicine, 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.
Virginia D. Steen, MD: Assistant Professor of Medicine;
Gregory R. Owens, MD: Assistant Professor of Medicine; Gregory
J. Fino, MD: Fellow; Thomas A. Medsger, Jr., MD: Professor of
Medicine.
Dr. Rodnan is deceased.
Address reprint requests to Virginia D. Steen, MD, Department of Medicine, 985 Scaife Hall, University of Pittsburgh School
of Medicine, Pittsburgh, PA 15261.
Submitted for publication August 24, 1984; accepted in
revised form January 17, 1985.
Arthritis and Rheumatism, Vol. 28, No. 7 (July 1985)
causes was uncommon. Comparison of these nonsmoking patients with 137 scleroderma patients who smoked,
seen during the same time period, revealed more frequent and severe obstructive changes in smokers. Smoking patients with restrictive lung disease had more
severe disease than nonsmoking patients. The single
breath diffusing capacity for carbon monoxide was
significantly decreased in the patients who smoked
compared with the nonsmokers. These data confirm
that pulmonary function abnormalities are common in
patients with systemic sclerosis including CREST syndrome. Smoking appears to have an additive deleterious
effect on pulmonary function and should be strongly
discouraged.
Pulmonary involvement, characterized by restrictive lung disease and an impaired diffusing capacity for carbon monoxide (DLco), has been recognized
in systemic sclerosis (scleroderma) since Baldwin et al
first described these findings in 1949 (1). Numerous
studies have illustrated the types and frequencies of
pulmonary abnormalities found on roentgenograms
and on pulmonary function testing of systemic sclerosis patients (2-9). Reduced lung volume has been
found in 5-90% of systemic sclerosis patients. An
equally wide distribution is also evident in the measurement of the diffusing capacity (5,7,8). In addition,
obstructive pulmonary involvement, including disease
of both small and large airways, has been identified
(7,8).
The clinical significance of these physiologic
abnormalities remains unclear. Interpretation of earlier studies is difficult because of the small number of
patients, incomplete descriptions of clinical manifestations, and the lack of evaluation of the impact of
STEEN ET AL
760
smoking on pulmonary function. In addition, other
conditions which might affect pulmonary function (including occupational lung disease, Sjogren’s syndrome, overlap disorders, asthma, and congestive
heart failure) were largely ignored.
The present study w a s designed t o examine
pulmonary function in a “pure” population of systemic sclerosis patients. The natural history and systemic
disease correlations of t h e abnormalities, as well as the
effects of smoking o n lung function, are examined.
and/or rapidly progressive renal insufficiency without other
explanation.
Predicted normal values for all pulmonary function
tests were from the Intermountain Thoracic Society standards (14). Test results were divided into the following
groups using previously described criteria (12)*:
PATIENTS AND METHODS
Isolated DLco reduction = FVC 280% predicted: FEVI/
FVC 270%; FEF25-75 260% predicted; and DLco <80%
predicted
Patients. All patients with systemic sclerosis who
were evaluated in the Division of Rheumatology and Clinical
Immunology of the University of Pittsburgh during the
period from April 1970 through August 1981 were considered
eligible for the study. Patients were classified as having
systemic sclerosis with diffuse scleroderma if they had any
of the following features: skin thickening of the extremities
both distal and proximal to the elbow, truncal skin thickening, or palpable tendon friction rubs. Tendon friction rubs
occur in 70% of individuals with diffuse scleroderma, compared with only 5% of those with the CREST syndrome
variant (calcinosis, Raynaud’s phenomenon, esophageal
dysmotility, sclerodactyly, and telangiectasias) (10). Patients
were considered to have systemic sclerosis with the CREST
syndrome if their skin involvement was limited to the distal
portions of the extremities (below the elbows) andlor face,
without palpable tendon friction rubs. Although they were
frequently detected, we did not require calcinosis and telangiectasia to be present for classification as CREST syndrome.
Patients were excluded from the initial study if they
had a smoking history of > 1 pack year (i.e., a cumulative
dose of > 1 pack/day for more than 1 year), an occupational
exposure such as coal mining, or any other disorder which
might adversely affect pulmonary function, including Sjogren’s syndrome documented by lip biopsy, asthma, chronic
bronchitis, emphysema, lung cancer, myocardial infarction,
congestive heart failure, or valvular heart disease. All patients evaluated during the same time period who had a
smoking history of >5 pack years were analyzed separately
and compared with the nonsmoking patients.
Each patient had a complete history taken, including
inquiries regarding dyspnea, orthopnea, pleurisy, and chest
pain. A general and specific scleroderma-related physical
examination was performed including detailed assessment of
the degree and extent of skin changes using a semiquantitative method, the total skin score (TSS) (11). As part of a
comprehensive initial evaluation, chest roentgenogram,
electrocardiogram, cineesophagram, small bowel radiographic series, kidney function studies, and complete pulmonary function testing were performed as previously described (12). Criteria used for muscle and gastrointestinal
involvement were those determined by Medsger and Masi
(13). Cardiac involvement was considered to be present if
there was symptomatic pericarditis, an arrhythmia requiring
treatment, or clinical evidence of congestive heart failure.
Renal involvement was defined as malignant hypertension
Normal = FVC 280% predicted; FEVJFVC 270%;
FEF25-75
260% predicted; and DLco 280% predicted
Restrictive = FVC <80% predicted; and FEVJFVC 270%
Obstructive
=
FEVJFVC <70%
Isolated FEFZs-75reduction = FEV 280% predicted; FEVJ
FVC 270%; and FEFzs-75 <60% predicted
Serologic studies were performed, including the test
for antinuclear antibody using rat liver substrate, rheumatoid
factor by latex agglutination reaction, antibody to extractable nuclear antigens (anti-RNP and anti-Sm) by hemagglutination, and anticentromere antibody test using HEp-2 cells
(15).
All clinical and laboratory data obtained were entered and stored in the American Rheumatism Association
Medical Information System computer facility located at
Stanford University, as part of an ongoing systemic sclerosis
databank. Differences between proportions were examined
using chi-square contingency table analysis, and differences
between mean values were determined by Student’s t-test.
Cumulative survival rates were calculated with life table
methods and comparisons made using log-rank tests.
RESULTS
Of t h e 497 systemic sclerosis patients evaluated
from April 1970 through August 1981, 363 had complete pulmonary function tests performed. One hundred ninety-seven were nonsmokers, but 32 of them
were excluded because they had Sjogren’s syndrome.
or complicating pulmonary or cardiac conditions as
described above. Of the remaining 165 nonsmoking
patients, 77 had systemic sclerosis with diffuse scleroderma and 88 had systemic sclerosis with CREST
syndrome. All 77 patients with diffuse scleroderma
and 79% of the CREST syndrome patients fulfilled t h e
American Rheumatism Association criteria for definite
systemic sclerosis (16). Of the I8 patients who did not
fulfill t h e criteria, 2 had all of the 5 CREST features, 8
patients had 4 features, a n d 6 patients had 3 features.
Two patients had only Raynaud’s phenomenon a n d
* FVC = forced vital capacity; FEV, = forced expiratory
volume in 1 second; FEFZ5-75= forced expiratory flow between
25% and 75% of the vital capacity; DLco = single breath diffusing
capacity for carbon monoxide.
PULIMONARY INVOLVEMENT IN SCLERODERMA
76 1
Table 1. Subgroups of pulmonary function abnormalities in patients with systemic sclerosis*
Diffuse scleroderma patients
Number of patients (%)
FVC 9% predicted
FEV,/FVC %
DLco % predicted
CREST syndrome patients
Number of patients (%)
FVC % predicted
FEV,/FVC %
DLco % predicted
All
patients
Normal
77
87$
81
83
29 (38)
104
82
101
26 (34)
62
85
69
88
94$
76
77
25 (28)
106
83
99
20 (23)
68
82
71
Isolated
DLco
Isolated
FEF15-75t
6 (8)
97
52
84
14 (18)
93
78
61
2 (2)
87
74
91
14 (16)
99
58
70
23 (26)
100
80
72
6 (7)
95
72
106
Re\trictive Obstructive
~~~~
* DLco
single breath diffusing capacity for carbon monoxide; FEFZ5-75= forced expiratory flow
between 25% and 75% of the vital capacity; FVC = forced vital capacity; FEV, = forced expiratory
volume in 1 second. See Patients and Methods for definitions of pulmonary function abnormalities.
CREST = calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias.
‘r Number of patients too small for statistical tests to be applied.
$ P < 0.01, diffuse scleroderma patients versus CREST syndrome patients.
=
scleroldactyly ; however, their sera showed anticentromere antibodies.
Table 1 describes the patient subgroups based
on results of pulmonary function testing. Thirty-four
percent of the entire patient population (38% of patients with diffuse scleroderma and 28% of patients
with CREST syndrome) had normal pulmonary function. ‘There was no significant difference in the frequency distribution by physiologic group between
diffuse scleroderma and CREST syndrome patients.
And within each subgroup, the pulmonary function
indices were not significantly different between patients with diffuse scleroderma and those with CREST
syndriome. The overall mean FVC percent predicted
was significantly lower in the diffuse scleroderma
patients compared with CREST syndrome patients
(87% versus 94%; P < 0.01). In contrast, CREST
syndrome patients had a lower mean diffusing capacity
than the diffuse scleroderma patients (77% versus
83%). Although not statistically significant, this difference may be important considering that the CREST
patients had a higher FVC and thus less restrictive
disease.
Table 2 summarizes the clinical and laboratory
findings in these pulmonary function subgroups. The
sex distribution was similar in the various groups.
CREST syndrome patients were significantly older
than patients with diffuse scleroderma (mean 50.7
years versus 45.2 years; P < 0.05). As expected,
CREST syndrome patients had a markedly longer
disease duration (mean 12.2 years versus 3.7 years;
P < 0.001). Within each variant, those patients with
restrictive abnormalities had a significantly longer
mean disease duration than those with normal pulmonary findings ( P < 0.05).
The patients with diffuse scleroderma in each of
the 5 pulmonary function subgroups were similar in
most respects, regardless of the form of lung disease.
There were no differences in the frequency of Raynaud’s phenomenon, digital ulcers, arthralgias or arthritis, telangiectasia, calcinosis, or TSS. In all 5
groups, the mean TSS ranged from 29-40 at the time of
study. There was no greater skin thickening of the
chest wall or upper back in patients with restrictive
abnormalities than in the other groups; the mean skin
score for the anterior chest was 1.3 in patients with
restrictive disease and 1.1-1.4 in the other groups.
Visceral involvement at the time of pulmonary function testing was remarkably similar among groups.
Objective evidence of gastrointestinal disease was
commonly present; however, muscle, renal, and cardiac involvement were infrequent (4 patients had been
excluded from the study because of congestive heart
failure). Serologic test results did not predict pulmonary function abnormalities, but rheumatoid factor
was present more often and at higher titers in patients
with restrictive disease than in those with normal
pulmonary function. As expected, anticentromere
antibody was absent in all diffuse scleroderma patients.
The CREST syndrome patients with restrictive
abnormalities shown by pulmonary function testing
had more severe scleroderma than those CREST syndrome patients with normal pulmonary function. They
STEEN ET AL
762
Table 2. Clinical and laboratory features of systemic sclerosis patients according to pulmonary
function abnormalities*
Diffuse scleroderma patients
Mean age
Duration of symptoms (years)
Total skin score (mean)
Arthralgiadarthritis (%)
Contractures (%)
Gastrointestinal tract
involvement (%)
ANA (%)
Rheumatoid factor (%)
Anticentromere antibody (%)
CREST syndrome patients
Mean age
Duration of symptoms (years)
Total skin score (mean)
Arthralgiadarthritis (%)
Contractures (%)
Gastrointestinal tract
involvement (%)
ANA (%)
Rheumatoid factor (9%)
Anticentromere antibody (%)
~
~
Isolated
All
patients
Normal
Restrictive
Obstructive
DLco
45.2t
3.7$
36
79
85
67
47.7
3.0t
35
82
79
65
41 .O
3.9t
40
76
96
85
44.1
2.8
32
80
100
20
40.0
4.5
36
64
79
69
56
21
0
57
11
0
63
38
0
40
20
0
54
15
0
0
50
0
50.7t
12.2$
8
44
43
70
48.7
9.2t
59
48
209:
73
53.6
15.81
55.1
55
659
74
16.1
5
27
38
69
48.4
11.8
8
35
30
61
60.9
10.4
11
33
83
83
51
38
49
61
36
50
44
40
10
23
62
71
62
38
73
67
33
104
56.8
20.9
29
100
100
50
100
~
* ANA = antinuclear antibody. See Table 1 for other definitions.
t P < 0.05, diffuse scleroderma patients versus CREST syndrome patients.
< 0.001, diffuse scleroderma patients versus CREST syndrome patients.
P < 0.01, diffuse scleroderma patients versus CREST syndrome patients.
$P
§
had a longer disease duration and a higher TSS with
more skin thickening of the fingers and hands than
other CREST subgroup patients. None of them had
skin thickening proximal to the elbows or on the trunk.
A higher prevalence of digital contractures was also
present. Rheumatoid factor was found with similar
frequency in all CREST subgroups, but patients with
restrictive lung disease seldom had anticentromere
antibody (10%). In all other groups, anticentromere
antibody was present in 50% or more of the CREST
syndrome patients.
Chest radiographs revealed 2 significant findings which have been previously reported (12). Sixtyseven percent of the CREST patients had calcified
granulomata compared with only 14% of diffuse
scleroderma patients. Patients with calcified granulomata did not have a higher frequency of radiographic
evidence of subcutaneous calcinosis in other locations. The presence of such calcified pulmonary lesions was not associated with prolonged disease; in
fact, individuals with the CREST syndrome with calcified granulomata had a significantly shorter mean
duration of symptoms than patients with CREST syndrome without this finding (12.5 years versus 17 years;
P < 0.05). Superior rib notching was found exclusively
in patients with diffuse scleroderma (16%). Affected
individuals did not have any significant differences in
disease duration, total skin score, anterior chest or
upper back skin thickening, presence of Raynaud’s
phenomenon, arthritis, or subcutaneous calcification
compared with patients with diffuse scleroderrna without rib notching. Those with rib notching did have
distal phalangeal tuft resorption more frequently (71%
versus 27%; P < 0.05).
Table 3 summarizes the clinical pulmonary findings in the nonsmoking study group. Patients with
restrictive disease had significantly more frequent
Table 3. Clinical pulmonary findings in patients with systemic
sclerosis classified by pulmonary function abnormality*
Dyspnea (%)
Bibasilar “dry” rales (%)
Fibrosis on radiograph (5%)
Mean Po, (mm Hg)
Normal
function
(n = 54)
Isolated
DLco
(n = 37)
Restrictive
(n = 46)
26t
8$
149
90
40
14
23
83
671
44$
485
84
~
* DLco = single breath diffusing capacity for carbon monoxide.
t P < 0.05.
< 0.01.
9 P < 0.001.
$P
PULIMONARY INVOLVEMENT IN SCLERODERMA
symptoms and signs of pulmonary involvement when
compared with patients who had normal pulmonary
function. Individuals with isolated DLco reduction
had an intermediate frequency of these findings. Only
48% of patients with restrictive abnormalities had
inters1itial changes consistent with pulmonary fibrosis
on chest roentgenogram, but 14% of patients with
normal pulmonary function had pulmonary fibrosis.
Less than one-fourth of patients with isolated reduced
DLco had abnormal findings shown on chest roentgenograms.
This lack of correlation between the chest radiogralph and pulmonary function test results prompted us to compare findings in 4 groups of patients to
deterrnine whether the chest radiograph or the pulmonary function tests more closely predicted outcome.
The patient groups included: (a) no fibrosis on radiographic examination, no restrictive disease; (b) no
fibrosis, but restrictive disease; (c) fibrosis present, no
restrictive disease; and (d) fibrosis with restrictive
disease (Table 4). Dyspnea and rales were most frequent in patients with both fibrosis and restrictive
disease, and these individuals had the worst 5-year
survival rate. Dyspnea correlated best with restrictive
disease ( P < 0.05), and the presence of rales correlated
more closely with radiographic evidence of fibrosis
( P = 0.08). Patients with only 1 of the 2 abnormalities
more frequently had dyspnea and rales than patients
with normal values on both tests (P < 0.001). Their 5year <survivalwas only slightly reduced from that of
patierits with normal results of both tests. Only when
both abnormalities were present was the survival time
significantly decreased (P < 0.01). Interestingly, the
diffusing capacity was similar in all groups.
Figure 1 shows the 5-year cumulative survival
763
100
w
1
I-
a
LT
90
1
a
LT
05
80
p c 0.0
3
v)
9-
70
2I
60
I-
0 Normal PFTs (n=54)
I)
0
s
50
A Isolated DLCO reduction (n=37)
A Obstructive and abnormal Fef25-75 (n=28)
0 Restrictive PFTs (n=46)
0'
I
I
I
1
2
3
4
5
YEARS OF FOLLOW-UP FROM
PULMONARY FUNCTION TESTS (PFTs)
1
Figure 1. Cumulative survival rates in systemic sclerosis patients
with specific pulmonary function abnormalities, from the time of
testing. See Table 1 for definitions.
rates from the time of pulmonary function testing, for
the various groups of systemic sclerosis patients with
specific pulmonary function abnormalities. Patients
with an obstructive pattern and an isolated FEF25-75
reduction were combined. Those patients with normal
pulmonary function had the best cumulative survival,
>90% at 5 years. Patients who had restrictive abnormalities had the worst prognosis, with a 5-year cumulative survival of 58%. Patients with an isolated DLco
reduction or obstructive disease had an intermediate
survival, which was significantly worse than that of
Table 4. Pulmonary findings according to combinations of radiographic evidence of fibrosis and
restrictive lung disease
Dyspnea (%)*
Bibasilar rales (%)*
FVC % predicted (%)
DLco % predicted (%)
Cumulative survival
5 years from
time of pulmonary
function testing (%)
I
No fibrosis,
no restrictive
disease
(n = 95)
No fibrosis,
restrictive
disease
(n = 25)
Fibrosis, no
restrictive
disease
(n = 23)
Fibrosis,
restrictive
disease
(n = 21)
29
5
91
87
84t
68
22
61
81
66
50
30
85
84
72
71
57
57
88
45t
* All groups significantly different from the no fibrosis, no restrictive disease group, P < 0.01. See
Table 1 for definitions.
t P < 0.01.
STEEN ET AL
764
Table 5.
Comparison of pulmonary function abnormalities in 165 nonsmoking and 137 smoking patients with systemic sclerosis*
Normal
Number (%)
FVC % predicted
FEVJFVC
DLco % predicted
Cumulative survival
5 years from
time of pulmonary
function testing ("6)
Restrictive
Obstructive
Isolated DLco
All patients
NS
S
NS
S
NS
S
NS
S
NS
S
54 (33)
92
82
100
96t
24(18)
94
79
101
76t
46 (28)
67t
83
39(28)
59t
82
61t
71
20 (12)t
93t
70t
82t
69
39 (28)t
80t
59t
69t
62
37 (22)
84t
82t
70t
73
33 (24)
93t
78t
57t
87
165
91
78t
80t
75
137
81
74t
71t
74
57
77t
* NS = nonsmoking patients; S = smoking patients. See Table 1 for other definitions.
t P < 0.05, nonsmoking patients versus smoking patients
patients with normal findings. Twenty-seven percent
of the 37 deaths were directly related to pulmonary
problems. Seven patients died of pulmonary hypertension, and 2 patients died as a direct result of pulmonary fibrosis. However, in most cases, deaths were
attributable to other causes, including gastrointestinal
( 5 patients), cardiac (6 patients), or renal (5 patients)
disease. Seven patients died of causes not related to
scleroderma.
Table 5 compares pulmonary function abnormalities in the 165 nonsmoking systemic sclerosis
patients versus the 137 systemic sclerosis patients who
were smokers. There were significantly more males in
the smoking group (38% versus 9%; P < 0.001), but
age and disease duration were similar in the 2 groups.
Obstructive changes were more than twice as common
in smokers as in nonsmokers (28% versus 12%; P <
0.05), and there were fewer smokers with normal
pulmonary function test results (18% versus 33%).
Smokers had a significantly decreased FEV,/FVC
ratio and DLco compared with nonsmokers. The FVC
was similar in both groups, but smokers with restrictive changes had significantly decreased FVC compared with the nonsmokers ( P < 0.05). Compared with
the nonsmokers, the DLco was significantly decreased in smokers who had any of the physiologic
abnormalities.
DISCUSSION
Pulmonary involvement is an integral component of systemic sclerosis. In the literature, the frequency of pulmonary function abnormalities has varied widely from 60% (17) to 100% (2,5). Although some
authors have suggested that pulmonary abnormalities
are rare or infrequent in patients who have the CREST
syndrome variant of systemic sclerosis (18,19), we
previously described a prevalance of 37% of CREST
syndrome patients with roentgenographic pulmonary
fibrosis (10) and separate development of pulmonary
arterial hypertension (20) in this condition. In our
recent review (12) of 165 nonsmoking systemic sclerosis patients, we found 1 or more pulmonary function
abnormalities in 62% of patients with diffuse scleroderma and 72% of patients with the CREST syndrome.
The frequency of these abnormalities in patients with diffuse scleroderma may have been low
because it represented a survey of early disease (mean
3.7 years) only in nonsmoking patients. There was no
significant difference in the frequency of the different
physiologic patterns determined by pulmonary function testing in these 2 systemic sclerosis variants.
Within each physiologic subgroup, the mean values of
the individual pulmonary function parameters were
not significantly different for patients with diffuse
scleroderma or with CREST syndrome. These results
suggest that the frequency and severity of pulmonary
involvement are similar in diffuse scleroderma and
CREST syndrome.
As expected, the duration of symptoms in
CREST syndrome patients was significantly longer
than in those with diffuse scleroderma. In both groups,
persons with restrictive abnormalities or an abnormal
DLco had a longer disease duration than did those
with normal pulmonary function findings. In the diffuse scleroderma group, disease duration for the isolated DLco group was even longer than for those with
a restrictive pattern. Patients studied within the first 2
years of their disease were equally distributed between
the normal, restrictive, and isolated DLco reduction
groups. This suggests that an isolated reduction of
diffusing capacity is not the earliest, or most sensitive,
defect of pulmonary function, as has been generally
believed.
Early investigators believed thoracic encasement by tight skin played a role in the etiology of lung
PULMONARY INVOLVEMENT IN SCLERODERMA
involvement (21). Others could not find any correlation between thoracic skin changes and reduced lung
volumes (4,22). Our findings confirm that thoracic
(anterior chest and upper back) skin changes are not
associated with pulmonary dysfunction of any specific
type.
The high frequency of calcified granulomata on
the clhest roentgenograms of CREST syndrome patients was not surprising considering the prominence
of subcutaneous calcinosis in the extremities of these
patients. Surprisingly, calcifications in these 2 locations were not correlated. This would suggest different
mechanisms or inciting factors for the 2 types of
calcium deposition. In contrast, the association between rib notching and digital tuft resorption in patients with diffuse scleroderma may reflect a common
tendency for bone loss.
Idiopathic pulmonary fibrosis has been associated with the presence of serum rheumatoid factor
(23), and we found this occurrence in patients with
diffuse scleroderma, but not in those with CREST
syndrome. Others have found a correlation between
lung involvement in systemic sclerosis and antinuclear
antibodies, in particular anti-Scl-70 (24). We were
unable to demonstrate any such relationship in these
patients with pulmonary involvement. Only a small
number of patients in this series had anti-Scl-70 antibody tests performed. However, in a more recent
series of our patients, anti-Scl-70 was significantly
correlated with both pulmonary fibrosis and restrictive
disease (25). As previously noted, the anticentromere
antibody in CREST syndrome patients is associated
with significantly less restrictive disease and radiographic evidence of interstitial fibrosis (24,26). Obstruct ive disease and isolated DLco reduction had no
serologic associations.
Several authors have noted the lack of correlation hetween symptoms, physical findings, and chest
radiographs (7,17). Although patients with restrictive
disease have significantly more dyspnea, rales, and
fibrosis on chest radiograph, overall our study confirms that these standard measures of pulmonary disease correlate poorly with each other. Pathologic
studies have suggested that histologic evidence of
interstitial fibrosis is far more common than either the
roentgenogram or pulmonary function tests would
suggest (27). This may account for the finding that 27
(29%) of our systemic sclerosis patients had symptoms
and/or rales but did not have fibrosis on roentgenogram or restrictive abnormalities of pulmonary function. The latter findings may be identified only after
765
additional followup time has elapsed. Based on the
data presented in this study, we conclude that pulmonary function tests are the most sensitive predictors of
symptoms. The finding of dry bibasilar rales correlates
more closely with the chest radiograph. Only when
both the chest roentgenogram and the pulmonary
function results were abnormal was there reduced
survival.
The survival characteristics in this population
are similar to those described by Medsger and Masi
(13). Lung involvement independent of cardiac and/or
renal disease was clearly associated with decreased
survival. In this study, CREST syndrome patients had
a slightly longer survival from the time of pulmonary
function testing than did diffuse scleroderma patients
in each physiologic category, but the trend was the
same. Patients with any of the pulmonary function
abnormalities had a significantly decreased survival at
5 years compared with those who had normal pulmonary function (Figure l ) , although those patients with
restrictive disease had the worst prognosis. This remains true even when those patients with pulmonary
hypertension, a complication known to cause a markedly shortened life span, are excluded. Only 9 of the 33
deaths were due to lung involvement, and 7 of these
were attributed to pulmonary hypertension without an
important contribution by pulmonary fibrosis. Thus,
only 2 patients died of causes directly related to
pulmonary fibrosis, 5.7 and 4.3 years after onset of
lung involvement.
Several authors (6,9,28) have reported serial
pulmonary function test evaluations of systemic sclerosis patients and have found very slow progression of
the abnormalities seen on pulmonary function tests.
Although we did not address this issue, the paucity of
deaths attributable to pulmonary fibrosis is in keeping
with this observation or with the possibility that no
progression occurs.
There is a small percentage (12%) of nonsmoking systemic sclerosis patients who have obstructive
disease which appears to be due to systemic sclerosis,
since other obvious causes of obstructive disease have
been excluded. The increased frequency of obstructive disease in the smoking patients is not surprising.
Although there was not an increased frequency of
restrictive disease in smoking patients, they had more
severe involvement as manifested by significantly decreased FVC and DLco compared with the nonsmoking patients with restrictive disease. These findings
suggest an additive deleterious effect of smoking,
associated with increased severity of restrictive dis-
STEEN ET AL
766
ease. Smoking patients who had an isolated DLco
reduction also had a significantly lower DLco than
their nonsmoking counterparts.
The etiology of this additive deleterious effect
of smoking on pulmonary function is speculative.
Since vascular abnormalities may play a role in the
fibrosis of systemic sclerosis, further damage may
occur from smoking, which is also associated with
vascular disease. Local inflammatory mechanisms inciting fibrosis may also be involved since increased
numbers of macrophages, polymorphonuclear leukocytes, and eosinophils are found by bronchoalveolar
lavage in individuals who smoke (29). The vasoconstrictive effects of nicotine may be influencing the
diffusing capacity in these patients. One might also
expect a higher frequency of pulmonary artery hypertension in smoking patients. There were 7 such patients in the nonsmoking group (4%) and 10 in the
smoking group (7%). Although these data suggest that
smoking does increase the risk of pulmonary hypertension, the numbers are too small to make conclusions.
We have described the types of lung involvement in systemic sclerosis patients with both the
diffuse scleroderma and CREST syndrome variants. A
variety of physiologic disturbances in lung function
were identified. Symptoms and findings were common
at the time of first evaluation, but correlated poorly
with pulmonary function abnormalities and fibrosis
shown on chest radiograph. Survival is decreased
when any pulmonary function abnormality is present.
Smoking causes increased obstructive disease and
more severe restrictive disease in patients with systemic sclerosis, and should be strongly discouraged.
ACKNOWLEDGMENTS
We wish to thank Dr. David Herbert for reviewing
chest radiographs, Sandy Blair for excellent assistance with
computer retrieval, and Beverly Knasko and Joan Neitznick
for expert secretarial assistance.
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