Pulmonary Involvement in Systemic Sclerosis

Pulmonary Involvement in Systemic Sclerosis· Association with Anti-SCI 70 Antibody and Digital Pitting M. N. Manoussakis, M.D.;t s. H. Constantopoulos, M.D., F:C.C.~;+

A E. Gharavi, M.Sc., M.D.;§ and H. M. Moutsopoulos, M.D.II

The association of clinical and serologic features of 34 patients with systemic sclerosis was examined. Anti-Sci 70 antibody was found to identify patients with abnormal pulmonary function, particularly impaired diffusion (p<0.OO5), as well as patients with digital pitting scars (p<0.025). In addition, the presence of digital pitting scars correlated with

impaired diffusion (p<0.OO5), suggesting that interstitial pulmonary disease in systemic sclerosis may, like digital pitting, be secondary to vascular pathology. Anticentromere antibody-positive patients were less likely to have abnormalities of pulmonary function (p
sclerosis (or scleroderma) is a chronic autoSystemic immune disease characterized by fibrotic and de-

MATERIALS AND METHODS

Patients

*From the Department of Medicine,· Medical School, University of Ioannina, Ioannina, Greece. tResearch Fellow *Assistant Professor of Medicine, §Visiting Scientist. Dr. Gharavi was on leave from the Lupus Research Laboratory, St. Thomas Hospital, the Rayne Institute, London. IIProfessorand Head of Medicine, Manuscript received January 13; revision accepted February 19. Reprint requests: Dr. Constantopoulos, Department of Medicine, University ofloannina Medical School, loannina, Greece

Thirty-four consecutive nonsmoking Greek patients, fulfilling the American Rheumatism Association's criteria for systemic sclerosis (scleroderma)' were studied. Patients having only the clinical diagnosis of systemic sclerosis were not included in the study because this could have led to a less homogeneous population. The patients were 29 women and five men, aged between 15 and 78 years (mean ± SD, 49.8 ± 16.0 years) with the duration of the disease ranging from 2 to 28 years (mean ± SD, 9.4 ± 8.9 years). Twenty-six were classified as having diffuse systemic sclerosis with cutaneous involvement extending in the proximal portion of the extremities (proximal to the digits)," the fingers, the face, or the trunk (23 women and three men; mean age, 47.1 ± 7.2 years; mean duration of disease, 7.2 ± 5.5 years). The CREST syndrome (calcinosis; Raynauds phenomenon; esophageal dysmotility; sclerodactyly; telangiectasias) was diagnosed in eight patients (six women and two men; mean age, 58.6 ± 13.6 years; mean duration of disease, 14.3 ± 9.1 years), Clinical evaluation included a complete history and physical examination, pulmonary function tests," electrocardiogram and echocardiogram, esophageal manometric studies," urinalysis, and levels of serum creatinine and creatine phosphokinase. Visceral involvement was defined as follows: for pulmonary involvement, the forced vital capacity (FVC), forced expiratory volume in one second (FEV J, the FEV/FVC ratio, flow-volume curves with recording of the expiratory flow-volume curve and maximal flow at 75 percent, 50 percent, and 25 percent of vital capacity (MEF25, MEFso, and MEF-rJ, total lung capacity (TLC), and carbon monoxide diffusing capacity (Dsb) using the Single-breath technique were measured as previously described." Values of FVC and TLC less than 80 percent of predicted, of FEV/FVC less than 70 percent, of MEFl1J5less than 60 percent of predicted, and of Dsb less than 75 percent of predicted were considered abnormal, indicating restrictive, obstructive ventilatory defect, disease of the small airways, and isolated diffusion abnormality, respectively.9,l1 For esophageal involvement, lower (distal) hypoperistalsis or aperistalsis was demonstrated by manometry. For renal involvement, a serum creatinine level of 1.2 mgfdl or more or active sediment or proteinuria ofO.5 gfday or more was definitive. For cardiac involvement, electrocardiographic or echocardiographic abnormalities were criteria. For myositis, muscular weakness, elevated serum creatine

generative lesions in the skin, vasculature, and several internal organs. 1,2 The impairment of vital organs such as the kidney, heart, lung, and gastrointestinal tract contributes significantly in the morbidity and mortality of the disease:':' however, systemic sclerosis shows variability in its progression and severity of organ involvement.!" therefore its outcome is often unpredictable. Immune system abnormalities have been suggested to playa central role in the pathogenesis of the disease, since several aberrant serologic and cellular immune responses have been reported to occur. 1,2 The serologic study of these patients often reveals the presence of autoantibodies like anti-ScI 70 or anticentromere which are mainly detected in the diffuse form and the CREST variant of scleroderma, respectively.Y Recently, the presence of anti-Sol 70 antibody has been reported to correlate with the presence of pulmonary involvement in patients with systemic sclerosis.P In this study, we examined the association of several serologic parameters with clinical manifestations, including abnormalities of pulmonary function, in patients with systemic sclerosis. Our data suggest that both anti-Sol 70 antibody and digital pitting are associated with impaired pulmonary diffusing capacity in these patients.

CHEST / 92 /3/ SEPTEMBER. 1987

509

phosphokinase level, and positive histopathologic findings were definitive.

Serologic Studies Coded samples of serum collected at the time of clinical evaluation were studied blindly. Antibodies to nuclear antigens (ANA) were detected by the indirect immunoHuorescence technique using Hep2 epithelial cells as substrate (positive ANA titer~I:80). The centromere pattern was considered when discrete speckles were present in interphase nuclei, with the characteristic clustering in mitotic cells. Rheumatoid factor (RF) was detected by the latex and antibodies to Ro(SSA), fixation test (positive RF titer~I:40); La(SSB), and UlnRN~ and Sm cellular antigens were detected by double immunodiffusion and counterimmunoelectrophoresls" using extracts of human spleen and calf thymus. Antibodies to ScI 70 were detected by counterimmunoelectrophoresis using freshly prepared extracts from rabbit thymus powder" (Pel-Freez), an anti-ScI 70 reference serum was kindly supplied by Dr. G. R. V. Hughes (Lupus Research Laboratory, the Rayne Institute, St. Thomas Hospital, London). The presence of cryoglobulins in the serum of patients was assessed, as previously described. 13

Statistical Analysis

Data were analyzed using the x2 test with Yates' correction and Students t-test, where applicable. RESULTS

The serologic profile of the patients studied is shown in Table 1. Positive ANA tests were found in 97 percent (33) of the 34 patients. The majority of them (91 percent; 30/33) displayed ANA titers greater than 1:320. Several nuclear patterns were detected (fine speckled, speckled, discrete speckled, nucleolar, diffuse, and combinations of them, as previously described"), Half of the patients displayed anti-ScI 70 antibodies, while anticentromere antibodies were found in 15 percent (five) of the patients. No patient exhibited both anti-ScI 70 and anticentromere antibodies. Other precipitating antibodies found included six anti-UlnRNP (one of them together with anticentromere antibodies) and three more, heterogeneous to each other, undefined precipitins detected with calf thymus extracts. Antibodies to ScI 70 and to centromere were more frequent in patients with diffuse systemic sclerosis and CREST syndrome, respectively (Table 1). The presence of other antibodies under evaluation, including anti-UlnRNP and RF could not identify any subgroup of patients. Polyclonal cryoglobulins were recovered in low concentrations (3.9 to 13.3 mg/dl) in 26.5 percent

(nine) of the patients, and their presence could not be correlated with any clinical or serologic manifestation under study. The results of the tests of pulmonary function disclosed impaired diffusion in 17patients (50 percent). This was more frequent in patients with diffuse disease (58 percent [15/26] vs 25 percent [218] in CREST). Only one patient had a moderately reduced FEV/FVC ratio (69 percent of predicted), indicating mild obstructive disease, while reduced values for TLC were encountered in seven patients who had also reduced values for Dsb. Isolated reduction of MEF15 was found in seven patients. Ten additional patients had reduced MEF25' but this was associated with low values for Dsb. The clinical associations of anti-Scl 70 and anticentromere antibodies are presented in 'Iable 2. The presence of anti-Sol 70 antibody correlated with the presence of digital pitting scars (p<0.025), as well as with the presence of impaired diffusion (p<0. (05). Esophageal dysmotility was more frequent in anti-Sol 70-positive patients, but the difference was not statistically significant. In this series the small number of anticentromere-positive patients expressed proximal scleroderma less frequently, while the pulmonary function of these patients disclosed no abnormality, except for low MEF25 in three of them. Table 3 shows the mean values for pulmonary function in the various subgroups of patients (with and without anti-Sol 70; with and without anticentromere antibody). Patients with anti-ScI 70 antibody, compared to those patients without this antibody, exhibited significantly lower values ofTLC (p<0.05) and Dsb (p
Table I-Serologic Prqfile ofthe Patients Studied Percent Positive Group Diffuse scleroderma CREST Total

510

No. of Patients 26

8 34

ANA

RF

96 100 97

15 13 15

Antibody to Scl-70

Antibody to Centromere

Antibody to UlnRNP

Cryoglobulins

58

8 38 15

15 25 18

27 25 27

25

50

PulmonaryInvolvement in SystemicSClerosis (ManoussaJds 8f aJ)

Table 4-Mean Age and Duration ofDiaetUJe in the Subgroups ofPatientll Studied·

Table 2-Clinical AaocitJtiona ofAnti-Sci 70 and Anticentromere Antibodie. Percent Positive Anti-Sci 70

Data

Present (n= 17)

Proximal scleroderma Sclerodactyly Raynaud's phenomenon Telangiectasias Digital pitting Pulmonary involvement (impaired diffusion) Esophageal dysmotility Renal involvement Cardiac involvement Arthritis Myositis

82

100 100

Anticentromere

Absent (n= 17)

53 94 94

Present (n=5)

Absent (n=29)

20

76 97 97 79 62

100 100 100

Group of Patients

n

Mean Age, yr

Mean Duration of Disease, yr

With impaired diffusion Without impaired diffusion With anti-ScI 70 Without anti-ScI 70

17 17 17 17

49.3±17.2 5O.4± 15.2 49.6± 15.1 5O.1±17.3

7.5±6.9 10.1 ±7.1 7.7±5.8 10.0±8.1

*Table data are means ± SD.

pulmonary disease." These reasons directed us to use pulmonary function tests as the sole indicators of pulmonary involvement in this study. No attempt was 59 o 77 24t made to evaluate the clinical or radiographic findings 100 88 53 66 in these patients. On the other hand, the use of more o 7 o 11 17 11 22 20 specific but invasive procedures, such as lung biopsy 47 20 55 53 (open or transbronchial) was not considered justified. 21 18 22 20 The prevalence of anti-ScI 70 antibody in patients *p
82

35*

40

Anti-ScI 70

Anticentromere

Data

Present (n= 17)

Absent (n= 17)

Present (n=5)

Absent (n =29)

FVC, percent of predicted FEV/FVC% TLC, percent of predicted Dsb, percent of predicted MEFIS' percent of predicted

9O.3±12.2 84.6± 14.3 64.8±21.5 58.2±27.8

BO.9±16.3

87.6± 14.6 81.4±6.8+ 95.6± 16.211 83.8± 17.91 63.8 ± 26.4

106.0±8.0

BO.8± 13.7t 87.1± 11.51 86.7± 14.71 68.3± 18.5t 59.3±26.2

BO.4±2.6

106.3± 12.7 101.8±18.7 59.0± 14.1

*Table data are means ± SD.

tp<0.05.

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511

Table 5-Association of Digital Pitting Scar. with Abnormalitie. of Pulmonary Function Digital Pitting Data TLC, percent of predicted* Dsb, percent of predicted* Pulmonary involvement, percent§

Present (n=20)

Absent (n=14)

85.3± 17.9 65.1±19.9

95.8± 10.3t 87.2± 18.3*

75.0

14.3*

*Mean±SD.

tp
§Impaired diffusion.

patients with systemic sclerosis (sensitivity of 76.5 percent; specificity of 76.5 percent; predictive value, 76.5 percent; and relative risk, 10.6). Prospective studies will be required to ascertain whether its presence in patients with systemic sclerosis predicts those prone to develop diffuse interstitial pulmonary disease. In addition, it remains to be determined whether anti-ScI 70 antibody is directly involved in the pathogenesis or is only an indirect marker of pulmonary involvement in systemic sclerosis. The exact pathogenesis of the interstitial pulmonary disease in systemic sclerosis remains unknown. Although recurrent aspiration due to esophageal dysmotility has been implicated," most studies suggest that the major disorder is vascular in nature.P'" A variable degree of thickening is often displayed in the small pulmonary vessels (arterioles) of patients with systemic sclerosis.P:" Such vascular lesions could be responsible for the pulmonary interstitial disease, since similar lesions have been incriminated for the pathologic changes found in other organs in scleroderma.P Such an example is the formation of the digital pitting scars observed in patients with systemic sclerosis. Digital pitting (depressed areas at the tips of the digits) is considered as the result of digital ischemic necrosis and ulcerations which eventully lead to the loss of digital pad tissue. 4 In the light of these considerations, one can suggest that the association observed in our series between the presence of digital pitting scars and abnormality of diffusion (sensitivity, 88.2 percent; specificity, 70.6 percent; predictive value, 75.0 percent; and relative risk, 18.0) is not accidental, but rather indicative of a common pathogenesis, apparently vascular, This is strengthened by the fact that the main functional abnormality in our study was reduced Dsb, often unaccompanied by reduced FVC or TLC. This has been considered typical for diffusion abnormality secondary to the destruction of pulmonary capillaries." It might be argued that these associations are the result of the severity of the disease; however, the lack of association between pulmonary dysfunction and other clinical 512

manifestations make this possibility less likely. In this study the limited number of anticentromerepositive patients were found to have normal pulmonary function. A reduced incidence of pulmonary restrictive disease and radiographic evidence of interstitial fibrosis among patients with anticentromere antibody has been reported previously.P':" Thus, the anticentromere antibody could be useful in a way opposite to the anti-ScI 70 antibody, namely, as a negative predictor of pulmonary involvement. ACKNOWLEDGMENTS: We thank Dr. E. B. Tsianos, Assistant Professor of Medicine, for the esophageal manometric studies and Ms. E. E. Papanikolaou for excellent secretarial assistance. REFERENCES

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