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D-penicillamine therapy and interstitial lung disease in scleroderma. a long-term followup study

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643
D-PENICILLAMINE THERAPY AND INTERSTITIAL
LUNG DISEASE IN SCLERODERMA
A Long-Term Followup Study
LUC S.
DE
CLERCK, JAN DEQUEKER, LUC FRANCX, and MAURITS DEMEDTS
Sequential lung function tests were performed on
17 scleroderma patients who were treated with Dpenicillamine (DP) (total of 66 treatment years) and on
10 control scleroderma patients who were not treated or
were treated with low-dose prednisone (total of 25
treatment years). Cusum plots showed significant differences between the 2 groups in their cumulative changes
in carbon monoxide diffusing capacity (DLco) (P <
0.005) and in DLco/lung volume (P < 0.02). The end
value of the DLco was >lo% lower than the initial
value in 3 of the 17 DP-treated patients versus 5 of the 10
control patients (P < 0.01, Fisher’s exact probability
test); in 3 DP-treated patients and 8 control patients (P
< 0.003, Fisher’s exact probability test), the end value
of the DLcoAung volume was >lo% lower than the
initial value. We conclude that DP has a beneficial effect
on interstitial lung disease in patients with scleroderma.
Scleroderma is a multisystem disease characterized by fibrotic changes in the skin, digital arteries,
and various internal organs, particularly the gastrointestinal tract, heart, kidneys, and lungs (1). Interstitial pulmonary fibrosis is a frequent finding in
scleroderma (2,3) and is a contributing cause of death
in a significant number of patients (4).
From the Divisions of Rheumatology and Pulmonary Medicine, Department of Internal Medicine, University of Leuven,
Pellenberg, Belgium.
Luc S. d e Clerck, MD: Resident in Training, Division of
Rheumatology; Jan Dequeker, MD, PhD, FRCPEd: Professor of
Rheurnatology; Luc Francx, MD: Rheumatologist, St. Elisabeth
Ziekenhuis, Lier, Belgium; Maurits Demedts, MD, PhD: Professor
of Pulmonary Medicine.
Address reprint requests to Prof. Dr. J. Dequeker, Division
of Rheumatology, UZ Pellenberg, B-3041 Pellenberg, Belgium.
Submitted for publication July 8, 1985; accepted in revised
form August 5 , 1986.
Arthritis and Rheumatism, Vol. 30, No. 6 (June 1987)
Treatment with steroids ( 5 ) or colchicine (6) has
no effect on the evolution of lung fibrosis in
scleroderma. D-penicillamine (DP), however, has
been shown by some researchers to stabilize or even
improve pulmonary fibrosis (7,8) and to have a beneficial effect on patient survival, especially in patients
who have scleroderma combined with other connective tissue diseases (9-12). Other investigators, however, question whether DP does indeed have a positive
effect on lung disease in scleroderma (13,14). Moreover, most of the studies of DP treatment in patients
with this disease have been of short-term treatment
and no control subjects were included, or have used
small numbers of patients (15).
A major problem in evaluating the benefit of a
therapy in scleroderma is the lack of objective criteria
for the determination of improvement or deterioration
(15). Carbon monoxide diffusing capacity (DLco) is a
sensitive parameter for the evaluation of pulmonary
involvement in this disease (16); it reflects a reduction
in alveolar membrane diffusion capacity and in pulmonary capillary bed (17). In this report, we describe a
long-term followup study of 17 DP-treated scleroderma patients and 10 control scleroderma patients in
whom the results of sequential lung function tests and
DLco measurements were compared.
PATIENTS AND METHODS
Patients. Of 38 scleroderma patients initially evaluated, 23 were selected for this study. To be included, a
patient had to have received D-penicillamine (DP group) or
steroid therapy or no treatment (control group) for at least 6
months and have had at least 2 lung function measurements,
including DLco, at an interval of 2 6 months. The decision to
treat a patient with DP or with corticosteroids was generally
DE CLERCK ET AL
Table 1. Patient characteristics
Patient no.
Age
Sex
Diagnosis*
50
53
50
41
63
50
59
45
47
38
37
50
61
52
54
45
62
50.4 2 7.9
M
F
F
M
F
F
M
M
M
F
M
M
M
F
F
M
M
PSS
PSS
PSS
PSS
PSS
PSS
PSS
PSS
PSS
PSS
PSS
MCTD
PSS
PSS
CREST
PSS
PSS
28
43
62
32
42
30
53
41
54
47
F
MCTD
PSS
PSS
CREST
MCTD
MCTD
PSS
PSS
PSS
PSS
Disease
duration
(years)
Followup
(years)
Smoker
D-penicillamine group
1$
2
3
4
5
6
7
8
94
10
11
12
13
14
15
16$
17$
Mean t SD
Control group
189
19
20
21§
22
23
6bisT
lobis7
14bisgT
16bisSll
Mean 2 SD
43.2
2
F
M
M
F
F
F
F
F
M
11.1
Yes
No
1 .o
26.0
1 .o
15.0
7.0
15.0
1 .o
6.3 2 7.4
1.o
5.5
1.5
7.75
1.5
5.75
3.0
2.0
7.25
11.0
9.25
2.0
5.0
3.75
0.75
5.5
6.25
2.0
4.7 t 3.0
6.0
6.0
7.0
1.5
4.0
0.5
5.0
4.25
17.0
17.0
6.8 2 5.7
4.25
3.5
2.5
6.0
4.0
1.25
5.25
6.5
3.0
9.25
4.6 5 2.3
No
No
Yes
No
Yes
No
No
No
No
Yes
0.5
0.6
9.0
2.0
12.0
2.0
0.5
2.0
11.0
?
No
Yes
No
Yes
Yes
Yes
No
Yes
Yes
Yes
No
No
Yes
Yes
Respiratory
signs/
symptoms
+
+
+
+
-
-
+
+
+
+
+
+
+
+
-
+
+
+
+
-
+
+
+
Treatment
yearst
4.75
1.5
7.75
1.25
4.2
3.0
2.0
6.5
11.0
6.0
2.0
4.25
3.0
0.75
4.0
2.75
2.0
3.9 2 2.7
4.25
1.75
2.5
2.0
2.5
1 .o
1.25
3.25
0.7
6.0
2.5 2 1.6
* PSS = progressive systemic sclerosis; MCTD = mixed connective tissue disease; CREST = calcinosis, Raynaud's phenomenon, esophageal
dysmotility, sclerodactyly, telangiectasias.
t Control patients 18,21,22,23, 14bis,and 16bis were treated with prednisone; the others were treated with nonsteroidal antiinflammatorydrugs
only. Patient 16bis received prednisone for 3.5 years only.
$ Former miner.
§ Deceased.
ll Patients 6bis, lobis, 14bis, and l6bis were the same individualsas patients 6, 10, 14, and 16. Each had had D-penicillaminetreatment withdrawn
because of side effects and was assigned to the control group after a washout period of at least 6 months.
based on the preferences of the supervising medical staB
members, who saw the patients randomly. Patients in the DP
group were followed for a mean of 4.7 years (range
0.75-1 1.O); patients in the control group were followed for a
mean of 4.6 years (range 1.25-6.5). Followup values used in
this study are those recorded at the last followup visit.
Patient characteristics are summarized in Table 1.
The mean (cSD) age in the DP group was 50.4 & 7.9 years,
slightly higher than in the control group (43.2 5 11.1; P =
0.03). The DP group had a higher percentage of males than
did the control group (10 of 17 versus 3 of 10). Fifteen of the
17 patients in the DP group had generalized progressive
systemic sclerosis (PSS) according to the American Rheumatism Association preliminary criteria (18), 1 had the
CREST variant (calcinosis, Raynaud's phenomenon,
esophageal dysmotility, sclerodactyly, telangiectasias), and
1 had an overlap syndrome (mixed connective tissue disease;
MCTD), as described by Sharp et al (19), with mainly
scleroderma features. In the control group, 6 of 10 patients
presented with generalized PSS, 1 with the CREST variant,
and 3 with MCTD, mainly with scleroderma features.
Four patients (patients 6, 10, 14, and 16) served as
their own controls. In these patients, DP had to be withdrawn because of side effects (proteinuria or severe skin
rash). After a washout period of at least 6 months, the
patients were assigned to the control group and were designated as patients 6bis, lobis, 14bis, and 16bis.
The DP group and the control group were comparable in disease duration prior to therapy, length of followup
period, and duration of treatment. Three PSS patients in the
DP group and none in the control group were in an early
progressive phase of the disease. Most of the patients were
in a plateau phase. Definite congestive heart failure was
present in 2 patients, 1 in the DP group and 1 in the control
group. Overt pulmonary hypertension, confirmed by
catheterization or autopsy, was present in 2 patients in the
DP group and 2 in the control group. Indirect electrocardiographic andlor radiologic signs of pulmonary hypertension
DP IN SCLERODERMA LUNG DISEASE
Table 2.
645
Lung function parameters on each patient, at start and end of study*
DLcoILV (%)
Patient no.
D-penicillamine group
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Mean 5 SD
Control group
18
19
20
21
22
23
6bis
lObis
l4bis
16bis
Mean & SD
DLco (%)
FEVIIFVC) (%)
TLC (%)
Start
End
Start
End
Start
End
Start
End
68
95
90
99
52
65
101
59
72
71
68
76
13
57
76
57
96
70
26
97
49
56
65.2 22.9
64
86
13
52
92
76
87
109
54
86
57
74
75.3 t 23.7
65
97
84
68
68
113
79
34
56
106
91
49
117
68
70
55
80
76.5 & 22.9
96
46
65
95
89
69
31
56
90
68
57
79
26
82
45
59
93
96
59
83
130
75
93
98
93
48
84
130
80
95
92
110
80
75
114
74
60
75
85
70
73
86
58
64
59
71
82
65
74
76
73
78
72
68
86
85
74
66
86
52
47
25
63
79
57
76
73
72
84
72
71.8 2 16.1
68.5 2 16.1
96
99
100
62
138
124
105
106
61
62
95.3 t 26.4
39
84
80
77
121
110
111
95
51
41
80.9 2 2 9 3
80
94
63
20
59
88
82
89
29
56
66.0 & 25.0
90
88
97
76
40
65
72
82
69
72
91
90
*
* DLco
65.7
5
99
21.2
115
83
76
122
73
46
108
92
85
89.9 4 21.6
106
86
80
87.8 8.5
26.5
75
92
68
38
47
67
80
79
46
97
68.9 19.98
71
85
74
40
61
78
69
77
38
98
69.1 ? 18.7t
32
74
59
31
81
95
77
76
16
40
58.1
2
*
46
*
79
78
66
69
60
86
71
78
81
75.8 t 9.2
75.2 i 16.1
total lung capacity; FEV, forced expiratory volume in 1 second;
= carbon monoxide diffusing capacity; LV = lung volume; TLC
forced vital capacity.
t P < 0.05 versus D-penicillamine group.
j: P < 0.05 versus starting value.
5 P < 0.01 versus D-penicillamine group.
=
were present in 3 patients who received DP and in 2 control
patients.
The median dosage of DP was 750 mg/day (range
2504,250). Three patients in the DP group were taking
prednisone (7.5, 20, and 20 mg/day, respectively). In the
control patients who received prednisone, the median dosage was 12.5 mg/day (range 7.5-35). The majority of the
patients in both groups were taking nonsteroidal antiinflammatory agents as needed. Two patients in the DP group and
2 in the control group were taking colchicine. Three patients
in the control group and 1 in the DP group were taking
antimitotics. There was a higher percentage of smokers in
the DP group, and 3 patients in this group had formerly
worked as miners (patients 1, 16, and 17). One control
patient was a former miner (patient 16bis).
Pulmonary function tests. Vital capacity (VC) and
forced expiratory volume in 1 second (FEVI) were measured
with a water spirometer. Functional residual capacity, residual volume, and total lung capacity (TLC) were determined
by the closed circuit helium dilution technique (10-minute
equilibrium).The DLco was determined by the single-breath
CO method described by Ogilvie et a1 (20), and was corrected for serum hemoglobin (21) and for lung volume
(DLcoIlung volume [LV]). All measurements were performed according to the standardization recommendations
of the European Community for Coal and Steel (ECCS), and
related to the reference values adopted by the ECCS (22).
During the followup, only changes in functional
parameters that were 210% from the baseline values were
considered to represent improvement or deterioration.
Chest radiographs. Chest radiographs were reviewed
by 2 independent observers who were unaware of the
patients’ clinical conditions.
Statistical analysis. The Mann-Whitney U-test was
used for comparison between groups. Paired data were
evaluated by the Wilcoxon matched pairs, signed rank test.
The Fisher exact probability test was used for categorical
data. Cumulative changes were evaluated by regression
analysis and by the Welch test (23). P values less than or
equal to 0.05 were considered significant.
FVC
=
646
DE CLERCK ET AL
DLCO
(%f
loom-
- - - y v
p cO.M)5
80
SCLERODERMA
- 0 PENlClLLAHlNE
zol
.......... CONTROL NO TREATMENT
-
CONTROL CORTlCOSTEROlDS
0
OLCOl VL
(%I
80
..?..$
a'..
0
I
10
o;
~
'%
o;
I
I
GO
50
I
60
Treatment- years
1
70
Figure 1. Cumulative changes in the carbon monoxide diffusing capacity (DLCO) and in the
DLCOholume of the lung (VL) in D-penicillarnine (DP)-treated and control scleroderma
patients. The segments between 2 open circles represent 1 patient, and the solid circles
represent additional measuring points for that patient. The slope of the line joining the origin
and the endpoint is the weighted mean slope of the individual segments. The difference between
the DP and control groups is represented graphically by the curve designated a. Treatrnentyears represents total patient years of followup. See Results for further details.
RESULTS
Respiratory symptoms (mostly dyspnea on exertion) and/or respiratory signs (crackles) were present
in nearly 70% of the patients in both groups (Table 1).
There was no overall change in respiratory signs and
symptoms during therapy.
Chest radiographs were carefully interpreted by
an experienced pneumologist. No patient in the Dpenicillamine group and only 1 patient in the control
group had normal findings on initial chest radiographs.
(More detailed radiologic information is available and
can be obtained from the authors upon request.)
The most frequent abnormalities were reticular
and micronodular fibrosis. Five patients presented
with calcified nodules (1 of them had CREST syndrome, 1 was an former miner, and 1 had had miliary
tuberculosis). Followup radiographs showed a progression of the interstitial fibrosis in only 4 patients (1
in the DP group and 3 in the control group); Two
patients in the control group had slight radiologic
DP IN SCLERODERMA LUNG DISEASE
TLC
647
(O/o)
120
F E V I I VC (%I
SCLEROOERHA
- 0 PENlClLLAMlNE
....... CONTROL NO TREATWENT
-
120
40
t:
I
CONTROL CORTICOSTEROIDS
I
I
I
I
I
I
I
10
20
30
40
so
60
70
Treatment- years
Figure 2. Cumulative changes in the total lung capacity (TLC) and in the forced expiratory volume in 1 secondhital
capacity (FEVJVC) in D-penicillamine-treated and control scleroderma patients. See Figure 1 and Results for further
details.
regression of their reticular markings, but this could be
attributed to diminished heart failure in 1, and possibly
both, of them. In 2 DP-treated patients, the disease
evolved to hyperinflation with decreased lung markings. No patient had marked pleural effusions, but in 6,
an obliteration of the costodiaphragmatic sinus was
present. Only 1 patient had radiologic evidence of
diaphragmatic paralysis. Two patients presented with
markedly decreased lung volumes seen radiographically; these could generally be related to the degree of
interstitial fibrosis and did not indicate diaphragmatic
paralysis.
Initial lung function parameters (Table 2) generally did not differ significantly between the DP group
and the control group, except that TLC was higher in
the DP group (89.9% versus 68.9%, P < 0.01) and
DLco/LV was higher in the control group (95.3%
versus 15.3%, P < 0.05).
Followup tests revealed no significant difference in any lung function parameter in the D-penicillamine group, whereas in the control group, the
DLco/LV clearly deteriorated (P < 0.05) (Table 2).
The same trend was present for DLco, although this
was not statistically significant. In the DP group, only
3 of 17 patients had a deterioration in the DLco/LV,
compared with 8 of 10 in the control group (P < 0.05).
The DLco deteriorated in 3 of 17 DP-treated patients,
versus 5 of 10 patients in the control group ( P < 0.05).
One patient in the DP group (patient 9) died suddenly,
with no obvious cause. Control patient 18 died of
rhythm disturbances; an autopsy revealed multiple
lung emboli and signs of pericarditis. Patient 21 in the
control group died as a result of advanced respiratory failure. Control patient 14bis died because of
respiratory failure with cor pulmonale and cardiac
decompensation.
Figure 1 shows a cusum plot of the cumulative
changes in DLco and DLco/LV, with the data for each
subject represented as a function of time. The values
for all patients are joined by a line, and the endpoint of
each line indicates the cumulative change in the respective lung function parameter for the whole group
DE CLERCK ET AL
over the total number of patient years of followup.
Thus, the slope of the line joining the origin and the
endpoint is the weighted mean slope of the individual
segments, where the weighting factor is time. According to the Welch test, using regression coefficients
corrected for time interval, significant differences between the D-penicillamine group and the control
groups are seen for DLco (P < 0.005) and for
DLco/LV ( P < 0.02). In Figure 2, the same C U S U ~plot
is shown for TLC and for FEVJVC. There was no
significant difference between the 2 groups in either of
these parameters.
DISCUSSION
Interstitial and/or vascular lung disease is one
of the major visceral manifestations of scleroderma
and is often a contributing cause of death in patients
with this disease (4). In the scleroderma lung, the
interstitiurn becomes edematous, excessive collagen is
laid down, the alveolar walls are destroyed by fibrosis,
and the capillaries are obliterated by dense collagen
(24). This leads to ventilation-perfusion imbalances
and impaired diffusion capacity (25).
D-penicillamine has several effects on collagen
metabolism. It blocks aldehyde groups involved in the
intra- and intermolecular cross-linking of mature
collagen, causing an increase in the amount of soluble
collagen and an acceleration of collagen turnover (26).
It also inhibits the synthesis and maturation of
collagen (27). Furthermore, this drug may have immunosuppressive effects (28-30) and could interact
with oxygen radicals (3 1) released by inflammatory
cells involved in interstitial lung damage (32).
Treatment with DP at various dosage levels and
durations of therapy has been used in interstitial lung
disease, with variable results (7,8,33-37). In a pilot
study, Goodman et a1 (9) demonstrated increased
survival rates in DP-treated patients with lung fibrosis
who did not respond to corticosteroid therapy, especially in those patients who had associated connective
tissue diseases. Broll et a1 (11) reported favorable
effects on lung function findings and on chest radiographic findings in 5 scleroderma patients treated with
DP. In a previous study, we described 8 scleroderma
patients who had stabilization or improvement of the
lung diffusing capacity with DP treatment, in contrast
with 5 of 7 patients who had corticosteroid treatment
or no treatment and whose diffusing capacity deteriorated (12).
Some case reports have described a beneficial
effect of D-penicillamine on pulmonary manifestations
of scleroderma (10,38), while others have reported a
deterioration or no effect (13,39,40). Long-term followup of a large number of patients is needed to
evaluate the effect of any therapy on pulmonary fibrosis, however, since some types of fibrosis can
evolve more slowly than inflammation and since the
evolution of pulmonary fibrosis varies (14). In the
present study, the mean followup of the scleroderma
patients treated with D-penicillamine was 4.7 years,
with a range of 0.75-11 years.
Another difficulty in the evaluation of the effect
of treatment is the lack of objective parameters (15). It
is well known that clinical features and chest
radiologic findings are insensitive parameters of lung
fibrosis (3,41). DLco, in contrast, is a sensitive parameter of fibrosis (16). Another valuable tool in the
evaluation of pulmonary fibrotic activity in scleroderma could be bronchoalveolar lavage (4244). But
sequential bronchoalveolar lavage is more invasive
than lung function tests, and is therefore less suitable
for followup studies. Furthermore, the inflammatory
cell composition in bronchoalveolar lavage samples
does not necessarily reflect the inflammatory status in
the interstitium (14).
In this study, we demonstrated improvement or
stabilization of DLco and DLcoiLV values in the
D-penicillamine group, in contrast with a deterioration
of values in the control group. Cusum plots showed
significant differences between the 2 groups for DLco
( P < 0.005) and for DLco/LV ( P < 0.02). Cusum plots
are useful in that they give the cumulative, summed
changes for all patients together over time, and they
take into account not only the direction of the changes
(i.e., improvement, stabilization, or deterioration), but
also the number of changes. Results of statistical
analysis that took into account only the direction of
the changes, however, were consistent with the cusum
plot findings, i.e., there was >lo% deterioration in the
DLco in 3 of 17 DP-treated patients versus 5 of 10
control patients (P < 0.01, Fisher’s exact probability
test) and there was >lo% deterioration in the D L c o L V
in 3 of 17 DP-treated patients versus 8 of 10 control
patients ( P < 0.003, Fisher’s exact probability test).
Our control group was comparable with the DP
group in duration of illness and of followup. The
control group had a lower percentage of smokers. One
could argue that the presence of more MCTD patients
in the control group (3 of 10, versus 1 of 17 in the DP
group) could have had a negative effect on the outcome in this group. However, there is debate over the
nature of interstitial pulmonary disease in MCTD.
Taormina et a1 (45) reported that patients with sclero-
DP IN SCLERODERMA LUNG DISEASE
derma and overlap syndromes had milder fibrosis, as
judged radiologically. Furthermore, the existence of
MCTD as a separate disease entity is controversial
(46), and in our MCTD patients, the scleroderma
features predominated.
Internal organ involvement, especially congestive heart failure and pulmonary hypertension, were
equally distributed in both patient groups; thus, the
effect of DP was not skewed due to these conditions.
Three of the DP-treated patients, all of whom
had micronodular patterns seen on chest radiographs,
were former miners. However, the anthracosilicosis
process was stable, as was demonstrated by the absence of radiologic deterioration. Thus, their changes
in DLco were probably due to the scleroderma process.
Diaphragmatic dysfunction causing a restrictive
lung function pattern has been described in other
connective tissue diseases, especially systemic lupus
erythematosus (47), but is not a classic abnormality in
scleroderma (48). In the present study, we found only
1 patient with clear radiologic signs of diaphragmatic
paralysis, confirmed by measurements of transdiaphragmatic pressure.
We did not find a clear association between lung
function changes and any specific clinical or radiologic
pattern. It is known that chest radiographs are insensitive for the evaluation of fibrosis (41) and that there
is no correlation between the results of pulmonary
function tests and radiographic abnormalities (49,50).
In summary, although this study was mainly
retrospective, and a double-blind, long-term, prospective study would be more valuable, we conclude that
D-penicillamine treatment improves or stabilizes the
interstitial pulmonary process in a majority of scleroderma patients, in contrast with steroid therapy or no
treatment.
ACKNOWLEDGMENTS
We wish to thank Dr. J. Clement and J. Nijs for the
statistical analysis and J. Cartois and N. Nuyts for secretarial assistance.
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