A long-term study of interstitial lung disease in systemic lupus erythematosus

A Long-Term

Study of Interstitial Lung Disease in Systemic Lupus Erythematosus

By Lisa Weinrib,

Om P. Sharma,

The clinical course of chronic diffuse interstitial lung disease (ILD) was studied in 14 patients with SLE. The mean duration of follow-up was 7.3 years. All patients had dyspnea on exertion, pleuritic chest pain, chronic cough, and basilar rales. Chest roentgenogram showed diffuse or basilar infiltrates, pleural disease, and elevation of both diaphragms. Systemic corticosteroids were given early in the course of the illness for lung involvement and multisystem disease. Diffusing capacity for carbon monoxide (DLCO) and inspiretory vital capacity (IVC) improved or remained unchanged in the majority of patients. Respiratory complaints improved in all patients; however, two patients died of pulmonary fibrosis and another died of bacterial pneumonia. Alveolar septal deposits of immunoglobulins and complement were found. This study showed that while variability existed among individual subjects, the clinical progression of ILD was slow and tended to improve or stabilize with time. 0 1990 by W.B. Saunders Company. INDEX WORDS: Pulmonary lupus erythematosus.

fibrosis;

systemic

T

HE RESPIRATORY system is frequently involved in patients with systemic lupus erythematosus (SLE). At one time or another along the course their illness, approximately one half of the patients develop respiratory symptoms. I-3These symptoms may be the presenting chief complaint, and in other SLE patients, lung disease constitutes the predominant clinical manifestation of the illness and becomes a signifFrom the Divisions of Rheumatology and Immunology and Pulmonary Medicine, University of Southern California, School of Medicine and the LAC+ USC Medical Center, Los Angeles, CA. Supported by a grantfrom the American Lupus Society. Lisa Weinrib, MD: Fellow in Rheumatology; Om P. Sharma, MD: Professor of Medicine, Chief Pulmonary Division; F.P. Quismorio, Jr, MD: Professor of Medicine and Pathology, Vice Chief. Division of Rheumatology and Immunology. Address reprint requests to F.P. Quismorio, Jr, MD, USC School of Medicine, HMR-71 I, 2011 Zonal Ave. Los Angeles, CA 90033. o 1990 by W.B. Saunders Company. 0049-0172/90/2001-0005%5.00/O 48

and Francisco

P. Quismorio,

Jr

icant parameter determining the overall prognosis. Respiratory involvement in SLE can manifest in a variety of clinical presentations. These include pleurisy with or without effusion, acute lupus pneumonitis, pulmonary hemorrhage, diffuse interstitial fibrosis, pulmonary function test abnormalities, pulmonary hypertension, diaphragmatic dysfunction, and airways obstruction.‘” Interstitial lung disease (ILD) is a well known clinical feature of patients with systemic connective tissue diseases, especially those with progressive systemic sclerosis (PSS) and rheumatoid arthritis (RA). Although the occurrence of ILD in SLE has been reported in earlier case reports,4 it was not until 1973 that its association with SLE became better recognized when Eisenberg et al’ described 18 cases from our institution. In a 1973 report of a patient with SLE with massive pulmonary fibrosis, Holder? could find only two similar cases in the medical literature. There is meager information currently available on the natural history of ILD in SLE. The purpose of our study is to report on a long-term clinical study of a group of SLE patients who developed symptomatic ILD. We describe the course of the illness, roentgenographic and radionuclide changes, serological abnormalities and histopathology of the lung. The response to corticosteroid therapy and serial pulmonary function test results are presented. MATERIALS AND METHODS The study group was composed of 14 SLE patients selected from the inpatient ward and clinic services of the Rheumatology Division at the Los Angeles County-University of Southern California (LAC + USC) Medical Center. All patients had respiratory symptoms associated with chronic parenchy ma1 lung infiltrates on chest radiographs and pulmonary function test abnormalities with a restrictive pattern. In addition, histopathological examination of lung tissue in four patients showed interstitial fibrosis. All patients were women with multisystem involvement, fulfilling an average of six criteria for the classification of SLE.’ Pulmonary function tests included inspiratory vital capacity (IVC), forced expiratory volume per second (FEV,), forced vital capacity (%FVC), and diffusing capacity for carbon monoxide (DLCO). All values were compared with predicted normal values matched for age and sex. The IVC,

Seminars in Arthritis and Rheumatism, Vol20.

NO 1

(August).

1990:

PP

48-58

49

INTERSTITIAL LUNG DISEASE IN SLE

FEV,, and %FVC were measured on a Stead-Wells (W. Collins, Inc, Boston, MA) spirometer. The single breath carbon monoxide capacity was used as an index of diffusion. The value was based upon the average of three determinations that did not differ from the mean by more than 10%. On follow-up examination, changes in IVC and DLCO were expressed as difference in percent of the predicted value. A change of greater or less than 15% of the initial value was considered to be significant. An IVC greater than 79% of the predicted value was considered normal. We graded the impairment in IVC as follows: minimal impairment, 60% to 79%; moderate, 50% to 59%; severe, less than 50% of the predicted value. The normal value for FEV,/FVC was 75% or greater of the predicted value. A value of 60% to 74% of the predicted was considered to be mild impairment; a value of 40% to 59% was considered to be moderate impairment; a value of less than 40% was judged to be severe impairment. The DLCO was considered abnormal when the measured value was less than 80% of the predicted value. We graded the impairment as follows: minimal, 65% to 79%; moderate, 50% to 64%; severe, 50% or less.’ Antibodies to dsDNA were tested by the Crithidia luciliae immunofluorescent test.* Antibodies to Sm antigen, nuclear ribonucleoprotein (RNP), SSA/Ro and SSB/La were measured by a double diffusion in agarose gel as well as by a passive hemagglutination method.9 Reference sera for the specific types of antinuclear antibodies (ANA) were obtained from the ANA Reference Laboratory of the Communicable Disease Center, Atlanta, GA. Rheumatoid factor was measured by a latex fixation test. The presence of immune deposits in lung tissue was examined by direct immunofluorescent test using monospecific antiserum to human immunoglobulin classes, Clq, C3, C4, fibrinogen, and albumin, using methods described in detail in a previous report from our laboratory.’

Table

1:

Clinical

Features

of 14 SLE Patients

With

RESULTS

Clinical Features The age of the patients ranged from 30 to 64 years with a mean age of 49.8 years and a median of 50 years. Three patients smoked cigarettes and eleven never smoked tobacco. The duration of the SLE ranged from 3 to 30 years with a mean of 12.6 years, and median of 12 years. The mean duration of follow-up of the pulmonary disease was 1.3 years with a median of 6 years and a range of 1 to 15 years. All patients had multisystem disease (Table 1). In addition to the lung disease, the most common clinical manifestations were polyarthritis (14 patients), skin lesions (13 pts), hematologic abnormalities (6 pts), nephritis (7 pts), Raynaud’s phenomenon (5 pts), vasculitis (4 pts), and cardiac disease (4 pts). All patients complained of dyspnea on exertion, pleuritic chest pain, and a chronic cough. The cough was generally mild, nonproductive, and in some patients, the cough worsened with exertion. None of the patients had hemoptysis, digital clubbing, or cyanosis. The respiratory symptoms developed insidiously, over a period of several weeks to several months. An underlying infectious process such as tuberculosis, fungal infection, and other infections were excluded by sputum cultures, skin tests, and appropriate serological tests. Interstitial

Lung Disease

Duration

Pulmonary

Aga &

Smoking

Duration

Follow-up

Organ

Sex

History

of SLE (y)

(Y)

Involvement

1 2

55 F 63 F

_

18 13

12 8

3

49 F

+

12

4

64 F

-

Patient

W,J,C.R

Complaints

at

Last Follow-Up Improved

S,P,J,CNS,R

Improved

5

W.J.H

Worsened

29

8

S,P.J.R

Much Improved

(died)

5

42 F

_

3

3

S,P,J,R,V,RD

Unchanged

6

51 F

+

6

5

SS’,J

Worsened

7

60 F

_

18

12

S,P,J,C,RD

Worsened

8

34 F

_

3

3

S.P.J.R.H,M

Much Improved

9

30 F

-

7

2

S,P,J,Hc,RD

Much improved

10

50 F

_

15

15

S,P,J,R,CNS,V

Improved

11

66 F

_

14

6

S,P,J,R,RD,V

Improved

12

40 F

-

8

7

S,P,J,R,RD,V

Improved

13

42 F

+

30

15

S,P,J,R,RD,H

Improved

14

52 F

-

1

P,J,M,CNS,H

Worsened

Abbreviations:

S, skin; P. pulmonary; J,

M, myositis; V, vasculitis: R, renal

1

joints; H.

(died)

(died)

hematologic; C, cardiac; CNS, central nervous system; RD. Raynaud’s phenomenon;

50

WEINRIB.

Pathology

Transbronchial lung biopsy was performed in three patients. Two of these patients later died from ILD and postmortem tissues were available for review. Autopsy material was also available in a fourth patient. The pathological changes were similar in the four cases, although the severity varied among patients. There was interstitial lymphocytic infiltrates along with peribronchial lymphoid hyperplasia. Interstitial fibrosis was present in all cases. There was mild muscular hypertrophy of the pulmonary blood vessels in two patients. Hyperplasia of type II pneumocytes along the alveoli was also observed. There was no histological evidence of vasculitis in any of the lung specimens examined. Direct immunofluorescent test showed granular deposits of immunoglobulin G (IgG), IgM, Clq, and C3 localized in alveolar septae. Immunoglobulin deposits within the nuclei of cells were also seen. Immune deposits in walls of blood vessels were not detected. Laboratory Findings

These values (Table 2) were taken when the patients had active pulmonary symptoms. All patients had positive fluorescent antinuclear antibody (FANA) test and antibodies to deoxyribonucleoprotein. Ten patients had antibodies to dsDNA (7 1%). Four patients had antibodies to RNP (29%), and one of these patients also had anti-Sm (7%) antibodies. Four patients had antiTable

2:

Patient

Laboratory

Findings

in SLE Patients

Anti-

Anti-

Anti-

Anti-

DNA

DNP

Sm

RNP

With Anti-

SSAlRo

SHARMA,

AND QUISMORIO

SSA/Ro (4/l 3, 31%), and one was positive for anti-SSB/La (l/13, 8%) antibodies. The prevalence of the specific types of ANA is the similar to that seen in a general SLE population, except for a lower frequency of anti-Sm antibody. The significance of this is not clear. Rheumatoid factor was present in 2 of 12 patients (16.7%) tested. Serum cryoglobulins were detected in 12 of 13 patients (92%). The concentration ranged from 5 to 60 mg/dl (normal, 0 to 3 mg/dl), with a mean value of 15.8 mg/dl. The serum hemolytic complement (C’H50) was reduced in 11 of the 14 patients. Radiographic

Findings

At the onset of the pulmonary symptoms, the chest radiographs showed diffuse infiltrates in eight patients and bilateral basal infiltrates in six patients (Table 3). Plate-like atelectasis was seen in six patients and linear atelectasis in one patient. Pleural effusion and/or pleural thickening was observed in nine patients. Both diaphragms were elevated in eight patients. The cardiac silhouette was slightly enlarged in six patients. At follow-up (mean duration, 7.3 y), the radiographs showed diffuse infiltrates in one patient and bilateral basal infiltrates in six patients. Both diaphragms were elevated in nine patients. Pleural thickening or reaction was observed in six patients and plate-like atelectasis in one patient. Interstitial AntiSW/La

Lung Disease Rheumatoid

Cryo-

Factor

globulin*

Serum Complement

1

-

+

-

-

-

-

-

14

2

+

+

-

-

+

-

11.5

160

3

+

+

-

-

+ -

5

320

4

+

+

-

-

+

+

-

-

nd -

nd

5 6

+

+

-

+

-

-

7

-

+

-

-

a

+

+

+

-

9

+

+

-

+

+ -

10

+

+

-

-

-

11

f

+

-

-

+

12

-

+

-

+

7

960

-

23.5

320

-

nd

80

20480

2

80

-

nd

60

320

-

nd -

-

13

+

+

-

-

+ -

14

-

+

-

-

-

320 -

160

8.5 6.5

80 320

25 -

-

8.5

160 960

a

80

12

960

*Normal Values: Cryoglobulins = i 3 mg/dl; Serum hemolytic complement = 480 to 1280 units; nd = no data available

51

INTERSTITIAL LUNG DISEASE IN SLE

Table

3: Chest

Patients

With

Roentgenogram Interstitial

Findings

in SLE

Lung Disease No. of Patients

Abnormalities Diffuse Infiltrates

8

Basal Infiltrates

6

Atelectasis

6

Pleural Effusion

2

Pleural Reaction

7

Elevated

8

Diaphragm

6

Cardiomegaly

Gallium-67 lung scans were performed in four patients (5,9, 12 and 14) at the time of the onset of the respiratory symptoms. The scans were taken as a measure of inflammatory activity in the lungs. There was diffuse bilateral increased uptake seen in all patients tested, most prominent at the lung bases. Repeat gallium-67 lung scans after corticosteroid therapy were not available for review. Pulmonary Function Tests At the onset of the pulmonary complaints, 10 of 12 patients tested had significant impairment of the DLCO, with mean value of 57% of the predicted value. The DLCO was severely impaired in four patients, moderately impaired in two patients, and minimally impaired in two patients (Table 4). Ten patients had a repeat DLCO determination at follow-up (mean duration, 7.3 years) and 5 Table

4:

Serial

Patient

Function

Tests

in 12 SLE Patients

With

ILD

DLCO

DLCO

%

WC

WC

%

FVC

FVC

%

Onset

Follow-up

Change

Onset

Follow-up

Change

Onset

Follow-up

Changs

f126

88

92

95

100

91

76

-16

113

120

28

38

+36

81

94

$16 +18

+5

1

50

113

2

83

86

3

nd

nd

nd

4

70

112

+60

85

100

t18

89

105

5

30

nd

nd

43

35

-19

95

91

-4

6

69

nd

nd

74

79

85

90

+5

+4

+6

+5 +6

7

60

94

+57

73

62

-15

100

99

-1

8

100

100

0

67

92

137

102

95

-7

9

39

39

0

47

50

+6

100

99

-1

10

40

78

+95

68

68

0

91

90

-1

11

52

40

-23

36

40

fll

108

104

-4

12

33

60

+82

61

56

-18

91

81

-11

85

+18

13 Mean

Pulmonary

patients showed abnormal values. Of the 10 patients, 6 subjects showed improvement in DLCO (> + 15%), 3 patients showed no change and 1 had a significant deterioration (> - 15%) in DLCO. Of the six patients whose values improved on follow-up, the DLCO changed from severe impairment to normal in two patients, from severe to moderate or minimal impairment in three patients, and from moderate impairment to normal value in one patient. At the onset of the pulmonary disease, the IVC was significantly reduced in 10 of 13 patients tested, with a mean value of 64% - 20% of the predicted value. Severe impairment of IVC was seen in 4 patients and minimal impairment in 6 patients. At follow-up determination, the IVC was still significantly reduced in 10 patients; however, 4 patients showed significant improvement from the initial values. The IVC remained unchanged in 6 patients and deteriorated in 3 patients (> - 15%). Among four patients with severe impairment of the IVC at the onset, the IVC remained severely impaired in all with one subject showing further deterioration. Among the six patients with minimally impaired IVC at the onset, the IVC became normal in two and remained minimally impaired in four subjects at follow-up. The IVC became minimally impaired in one patient whose value was normal at the onset of the illness. The %FVC was normal in all subjects at the

? SD

54 56.7

Abbreviation:

f

21

78.8

66

f22

+ 27.1

+42

nd, no data available.

72 64

* 20.1

67.2

+ 22.2

+5

80

nd 95.8

+ 9.3

96

& 10.6

nd +2

52

onset of the pulmonary complaints and remained normal at follow-up. Eflect of Drug Therapy

Three patients (4, 8, and 9) showed marked clinical improvement with resolution of pulmonary symptoms following treatment with high dose systemic corticosteroids (prednisone, 60 mg/d for at least 4 weeks). Two of the three patients were treated on two separate occasions for lung disease. One (Pt 4) showed improvement in IVC and DLCO while the other (Pt 9) did not show any improvement in IVC; however, the DLCO was normal at the onset of the illness and at follow-up. Six patients (1, 2, 10, 11, 12, and 13) showed good improvement in pulmonary symptomatology. All six patients received high dose of systemic corticosteroids for treatment of the pulmonary disease. The DLCO improved significantly in four, decreased in one patient, and remained unchanged in another. The IVC and %FVC remained unchanged in three patients. One patient showed a slight improvement in IVC, while two had decreased IVC after therapy. At followup, two patients (Pts 1 and 10) were in clinical remission, one patient (Pt 12) was improved. Patient 11 subsequently developed hematologic and neurologic complications, requiring high dose systemic corticosteroid and cytotoxic drug therapy. Patient 13 was on a tapering low dose of prednisone (10 mg/d) at follow-up. Pulmonary symptoms remained unchanged in one patient (Pt 5) at follow-up. High-dose corticosteroid therapy was given for multisystem disease and tapered gradually to low dose at follow-up. The IVC remained decreased. The persistent dyspnea in Pt 5 may be partly caused by the development of obesity during the follow-up period. Pulmonary symptoms worsened in four patients (3, 6, 7, and 14). Patient 3 received high-dose systemic corticosteroids. Despite some improvement in IVC, she developed progressive pulmonary symptoms and eventually died of ILD 5 years after the onset of the lung disease. Patient 6 showed no significant change in IVC and %FVC. She received high doses of systemic corticosteroids for multisystem disease including myocarditis, nephritis, and ILD. She responded satisfactorily and her illness remained stable for

WEINRIB, SHARMA, AND QUISMORIO

several years, but she experienced persistent mild dyspnea on exertion. Subsequently, she developed lupus cerebritis and died of an overwhelming Pseudomonas aeroginosa pneumonia. Patient 7 received moderate doses of prednisone (30 mg/d) for multisystem disease. The DLCO greatly improved; however, she continued to have pulmonary symptoms. Subsequently, she developed arteriosclerotic heart disease and congestive heart failure; it became difficult to assess clinically the contribution of ILD from cardiac involvement to her symptoms. Patient 14 was treated with high dose of prednisone (60 mg/d) for several weeks primarily for ILD and myositis. Because of poor cooperation on the part of the patient, reliable pulmonary function tests were not obtained. There was clinical improvement observed during the first few months of the steroid therapy. Subsequently, the pulmonary symptoms worsened, progressed, and the patient died from severe ILD, 15 months after the onset of the pulmonary complaints. DISCUSSION

The prevalence of clinically symptomatic ILD in SLE is not completely known; however, our own experience is similar to others in that the condition is relatively uncommon, probably seen in less than 3% of SLE patients.” In a prospective study of 150 SLE patients, Estes and Christian” listed 14 cases of lupus pneumonitis, and 9 of these patients developed radiographic evidence of pulmonary fibrosis. It is unclear from their report if the patients had chronic respiratory symptoms or not, and how severe the pulmonary function abnormalities were. As a group, the patients in our study tended to be older (mean age at onset of the disease, 37 years) than the general SLE population. The clinical features of our patients are similar to those reported by Eisenberg et al.’ The most common presenting manifestations were dyspnea on exertion, pleuritic chest pain, and a chronic cough that developed and progressed insidiously over a period of months. These features are different from that of lupus pneumonitis or pulmonary hemorrhage that generally manifest with an acute and febrile onset. On the other hand, ILD may simulate the clinical presentation of other lung involvement in SLE, such as pulmonary hypertension.‘,” All of our patients had

INTERSTITIAL LUNG DISEASE IN SLE

muitisystem involvement with significant renal disease in half of the patients. Antibodies to DNA were prevalent and the frequency of other antinuclear antibodies of defined specificity was not different from the general SLE population except for the lower prevalence of anti-Sm antibodies. These observations are somewhat different from those of Holgate et aLi3 who reported a lower prevalence of severe renal disease and anti-DNA antibodies among 30 SLE patients with respiratory involvement, including 4 patients with diffuse fibrosing alveolitis. Our clinical and serological data do not define the group of SLE patients with ILD as a separate subset of patients. Two types of initial presentation of ILD in SLE have been described. First, ILD may develop following a bout of acute lupus pneumonitis. Matthay et all4 reported the clinical course of 12 patients with acute lupus pneumonitis. The patients had fever, cough, tachypnea, pleuritic chest pain, basilar rales, arterial hypoxemia, and diffuse acinar infiltrates on chest radiographs. Three of the six patients who survived the acute episode developed residual interstitial infiltrates with abnormal pulmonary function tests, indicating that acute lupus pneumonitis can progress to chronic ILD. Similar cases have been reported by Estes and Christian. l2 The second type of presentation is that seen in our patients and similar to that described by Eisenberg et aL5 which followed a slow and a more insidious clinical course with dyspnea on exertion, chronic cough, and pleuritic chest pain. The clinical course of ILD in the majority of our patients was slowly progressive. Nine patients improved clinically, one remained unchanged, and four patients deteriorated. Of the nine patients who improved clinically, there was marked improvement in three and good to moderate improvement in six. The clinical course of ILD in SLE differs from idiopathic pulmonary fibrosis by tending to be less severe and less rapid. It follows a similar slow clinical course observed in patients with PSS and RA.11915Serial pulmonary function studies in PSS have shown that although there is also an individual variability, as we have observed in our SLE patients, in the majority of the patients, the lung disease followed a slowly progressive restrictive ventilatory defect.16-i8

53

All patients in this study received high to moderate dose of systemic corticosteroids for at least 4 weeks. It is not possible, however, to draw definite conclusions as to the efficacy of the drug therapy in a relatively small and uncontrolled series. The limited information available on the response of SLE patients with chronic ILD to drug therapy suggests that it is unfavorable.” Systemic corticosteroids remain the mainstay of therapy of acute lupus pneumonitis. Some of the patients respond favorably and some require additional form of therapy such as cytotoxic agents and plasmapheresis.‘4*‘5~19The efficacy of corticosteroids and/or cytotoxic drug therapy in acute lupus pneumonitis has not been validated by controlled studies. In our study, two of three tobacco smoking patients died. Whether smoking was a significant contributory factor is unclear because of the small number of patients studied. In addition, none of the patients showed significant obstructive abnormalities regardless of smoking status. The DLCO was the most sensitive indicator of pulmonary function abnormality in our patients. It was the only laboratory parameter that showed overall significant change in those patients who showed clinical improvement. The pathophysiological basis for the reduced DLCO may be due to a reduction in the pulmonary capillary membrane from the destruction of alveolar septae.” The %FVC was within normal range and reflected a proportional decrease in FEVJFVC typical of a restrictive lung disease-in contrast to an obstructive lung disease. The IVC was low, as characteristically seen in restrictive lung disease. None of our patients showed significant changes in FEV,/FVC and IVC with time. The histopathology of the lung in our patients is similar to that described by other investigators.5,6 In addition to the thickening of the alveolar walls and interstitial fibrosis, a spectrum of abnormalities is seen. These changes include interstitial lymphocytic infiltrates; hyperplasia of type II pneumocytes; and, in the more advanced cases, extensive fibrosis of the alveolar wall with honeycomb changes5 Electron microscopic study of the lung in a SLE patient with interstitial fibrosis showed tubular structures in the endothelial cells.20 Granular deposits of immunoglobulins and complement components on the alveolar septae

WEINRIB, SHARMA, AND CllJlSMORlO

have been described in the lung of SLE patients with acute pneumonitis, pulmonary hemorrhage, pulmonary hypertension, and ILD.5,‘0,21,22That these deposits represent immune complexes is supported by the following observations:10*2’ (A) the deposits have been eluted from the lung tissue by acid buffers, as well as by digestion with deoxyribonuclease; (B) antinuclear antibodies, including anti-DNA antibodies, have been found in the lung eluates; (C) the putative antigen, DNA, has been demonstrated in alveolar septae.24 It is believed that immune complexes play a role in the pathogenesis of ILD not only in SLE but also in idiopathic pulmonary fibrosis, as well as in other connective tissue diseases such as RA and PSS.” The hypothesis is based on the induction of interstitial lung disease in experimental animals given repeated injections of foreign serum protein. 23 In humans, immune complexes have been detected in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis and systemic sclerosis. 24,25Moreover, Dreisin et a125reported a positive correlation between serum immune complexes and the deposits of immunoglobulin and complement in the lungs of patients with idiopathic pulmonary fibrosis. Recent investigations have shown that inspiratory muscle dysfunction contributes to the lung volume restriction and dyspnea in SLE.26,27Gibson et a126 found that diaphragmatic function was grossly abnormal in “shrinking lung syndrome,” a term coined by Hoffbrand and Beck’* to refer to a group of SLE patients who presented with unexplained dyspnea, reduced vital capacity, and elevated and sluggish diaphragms. It is suggested that the respiratory muscle weakness may be a part of a generalized muscle disease in SLE, although it does not always appear to correlate with clinical signs of proximal skeletal muscle weakness, overall disease activity, or immunologic abnormalities.27 Diffuse fibrosis of the diaphragm without evidence of acute inflammatory infiltrate was described in a SLE patient with shrinking lung syndrome. 29 Long-term follow-up showed that many patients with this syndrome demonstrated stable nonprogressive restrictive ventilatory defect over a period of several years.26*27Although we did not measure diaphragmatic function in

our patients, it is possible that diaphragmatic muscle dysfunction was an important contributing factor to the pathogenesis of the lung disease, because the chest radiographs showed persistently elevated diaphragms in many of our patients. In contrast to the infrequent occurrence of clinically symptomatic ILD in SLE, pulmonary function test abnormalities are very prevalent, even in those patients without respiratory complaints and with normal chest roentgenoIn a prospective study of ambulatory grams. 30331 SLE patients, Silberstein et a132 found pulmonary dysfunction in 88% of patients with impairment of diffusing capacity and reduction in lung volumes as the most common abnormalities. Neither the severity nor the type of pulmonary functional abnormality correlated with measurement of disease activity including anti-DNA antibodies and serum complement level. In the absence of clinical symptoms, abnormalities of pulmonary function usually do not require drug therapy. However, whether these abnormalities improve when the patient receives systemic corticosteroids or cytotoxic agents for other organ involvement, such as lupus nephritis, is not known. Longitudinal studies correlating serial pulmonary function tests with bronchoalveolar lavage fluid changes or lung histology should be undertaken. SUMMARY

A long-term study of the clinical course of symptomatic diffuse interstitial lung disease in 14 SLE patients is presented. All patients had dyspnea on exertion, pleuritic chest pain, chronic cough, and basilar rales from the lung disease. Multisystem disease involvement and serological abnormalities-including anti-DNA antibodies, hypocomplementemia, and cryoglobulinemiawere present in all patients. Chest roentgenogram showed diffuse or basilar infiltrates, evidence of pleural disease, and elevation of both diaphragms. All patients received systemic corticosteroids early in the course of their illness for lung involvement and/or multisystem disease. The DLCO and IVC improved or remained unchanged in the majority of patients. The %FVC was normal at presentation and remained so.

INTERSTITIAL

55

LUNG DISEASE IN SLE

Although the pulmonary complaints improved in most patients with treatment, three deaths occurred, two from pulmonary fibrosis and one from bacterial pneumonia complicating lupus cerebritis. Deposits of immunoglobulin and complement were found in alveolar septae, suggesting a possible role of immune complexes in the pathogenesis of the pulmonary fibrosis. Our study shows that while variability existed among the individual subjects, the progression of ILD in the majority of the SLE patients ap-

peared to be slow and tended to improve or stabilize with time. The efficacy of systemic corticosteroid therapy for symptomatic ILD in SLE remains to be established in controlled studies. ACKNOWLEDGMENT The authors gratefully acknowledge the expert assistance of Dr Michael Koss in reviewing the lung biopsies and the help of MS Juie Lai, Mrs Maria Hutchinson, Mrs Cecile Tejada, and Mrs Carolyn Nelson.

REFERENCES 1. Quismorio FP Jr: Clinical and pathologic features of lung involvement in systemic lupus erythematosus. Semin Resp Med 9:297-304,198s 2. Segal AM, Calabrese LH, Ahmad M, et al: The pulmonary manifestations of systemic lupus erythematosus. Semin Arthritis Rheum 14:202-224, 1985 3. Hunninghake GW, Fauci AS: Pulmonary inlvement the collagen vascular disease. 119:471-503, 1979 4. Sperryn PN: Systemic lupus erythematosus brosing alveolitis. Proc Sot Med 64:58-59, 1971

in

with fi-

5. Eisenberg H, Dubois EL, Sherwin RP, et al: Diffuse interstitial lung disease in systemic lupus erythematosus. Ann Intern Med 79:37-45,1973 6. Holden M: Massive pulmonary fibrosis due to systemic lupus erythematosus. NY State J Med 73:462-465, 1973 7. Tan EM, Cohen AS, Fries JF, et al: The 1982 revised criteria for the classification of SLE. Arthritis Rheum 25: 1271-1275,1982 8. Beaulieu AD, Quismorio FP Jr, Kitridou RC, et al: Complement fixing antibodies to ds-DNA in SLE: A study using the immunofluorescent Crithidia luciliae method. J Rheumatol6:389-396, 1979

of twelve cases of acute lupus pneumonitis. 405,1974

Medicine

54:397-

15. King TE Jr, Dunn TL: Connective tissue disease, in Schwarz MI, King TE Jr (eds): Interstitial Lung Disease. Toronto, Ontario, Decker, 1988, pp 139-200 16. Colp CR, Riker J, Williams MH Jr: Serial changes in scleroderma and idiopathic interstitial lung disease. Arch Intern Med 132:506-515, 1973 17. Bag LR, Hughes DTD: Serial tests in progressive systemic sclerosis. 1979

pulmonary function Thorax 34:224-228,

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