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(Chest. 2006;130:976-981.)
© 2006 American College of Chest Physicians

Unique Characteristics of Systemic Sclerosis Sine Scleroderma-Associated Interstitial Lung Disease*

Aryeh Fischer, MD; Richard T. Meehan, MD; Carol A. Feghali-Bostwick, PhD; Sterling G. West, MD and Kevin K. Brown, MD

* From the Division of Rheumatology (Drs. Fischer and Meehan) and Interstitial Lung Disease Program (Dr. Brown), Department of Medicine, National Jewish Medical and Research Center, Denver, CO; Division of Rheumatology (Dr. West), University of Colorado Health Sciences Center, Denver, CO; and Division of Pulmonary, Allergy, and Critical Care Medicine (Dr. Feghali-Bostwick), Department of Medicine, University of Pittsburgh, Pittsburgh, PA.

Correspondence to: Aryeh Fischer, MD, Assistant Professor of Medicine, Division of Rheumatology, National Jewish Medical and Research Center, 1400 Jackson St, Denver, CO 80206; e-mail: fischera{at}njc.org

Abstract

Study objectives: To describe the characteristics of systemic sclerosis sine scleroderma (ssSSc)-associated interstitial lung disease (ILD) presenting as idiopathic interstitial pneumonia (IIP).

Design: Retrospective review of six patients with ssSSc-associated ILD diagnosed after referral for evaluation of IIP.

Measurement and results: All patients were white, their mean age was 56 years (range, 37 to 86), and gender was evenly divided. Sclerodactyly, skin thickening, and digital edema were absent in all patients. All patients had scattered telangiectasia, and four patients had Raynaud phenomenon with abnormal nailfold capillaroscopy findings. All described gastroesophageal reflux, and three patients had esophageal dysmotility by esophagography. All had restrictive pulmonary physiology and a reduced diffusion capacity. High-resolution CT revealed nonspecific interstitial pneumonia (NSIP) or usual interstitial pneumonia (UIP) radiographic patterns. Of the three patients who underwent surgical lung biopsy, two patients had NSIP and one patient had UIP pathologic patterns. Five patients had asymptomatic pericardial effusions and elevated pulmonary artery pressures by echocardiography. All patients had nucleolar-staining anti-nuclear antibodies (ANAs), and one patient was anti-Scl-70 positive. All five anti-Scl-70–negative patients were anti-Th/To positive, and the anti-Scl-70–positive patient was anti-Th/To negative.

Conclusions: In the presentation of an IIP, the presence of a nucleolar-staining ANA, telangiectasia, Raynaud phenomenon with abnormal capillaroscopy findings, gastroesophageal reflux, or pericardial disease suggests underlying systemic sclerosis. These findings should aid clinicians in the evaluation and treatment of patients with otherwise undefined ILD.

Key Words: anti-Th/To antibodies • interstitial lung disease • systemic sclerosis sine scleroderma

Systemic sclerosis (SSc) is a connective tissue disease (CTD) characterized by skin thickening and varying degrees of internal organ involvement. Almost all patients with SSc have some pulmonary disease, with pulmonary hypertension (PH) and interstitial lung disease (ILD) being the two most common manifestations.1 The prevalence of ILD in patients with SSc varies from 25 to 90%, depending on the sensitivity of the evaluation, and is associated with increased mortality.23456 Based on the degree of cutaneous involvement, patients with SSc are classified as having either limited cutaneous SSc (lcSSc) or diffuse cutaneous (dcSSc). SSc sine scleroderma (ssSSc) is a rare form of SSc whereby patients acquire visceral disease in the absence of the characteristic cutaneous involvement (skin thickening).

The ILDs are a heterogeneous group of lung disorders classified together based on similar clinical, radiographic, and histopathologic findings.7 It is estimated that approximately 15% of patients with ILD have an underlying CTD,8 and ILD may be the first or sole recognized manifestation of a CTD. As the clinical features of the CTDs may be subtle, it is often difficult for clinicians to identify an underlying CTD in individuals who present with ILD. It can be especially challenging to accurately characterize patients with subtle manifestations of SSc, and in particular with ssSSc.

The initial evaluation of patients with ILD often includes serologic testing for underlying CTD by checking for the presence of an anti-nuclear antibody (ANA) or rheumatoid factor (RF).7 A positive ANA is found in most patients with a CTD, ranging from a prevalence of approximately 30% in rheumatoid arthritis to approximately 95% in patients with systemic lupus erythematosus (SLE) and SSc.8 However, the presence of an ANA or RF is not specific for CTDs, as these tests may be present in the general population and have been associated with various lung diseases including idiopathic pulmonary fibrosis.

Anti-nucleolar antibodies (AnoAs) may be more specific for SSc than other ANA patterns.9 In contrast to ANAs, specific AnoAs have not been reported in healthy control subjects91011 or in healthy relatives of SSc patients.912 The most widely recognized of the AnoA system include anti-PM-Scl, anti-U3-RNP, and anti-Th/To.913 Based on a study14 from the University of Pittsburgh database of SSc patients, anti-Th/To positivity has been associated with an increased risk of pulmonary fibrosis, PH, and reduced survival. The other AnoA associated with severe ILD and PH is anti-U3-RNP, which is associated with severe dcSSc in African Americans.913

In this study, we describe the clinical features of six patients with ssSSc who had been referred to our center for evaluation of idiopathic interstitial pneumonia (IIP). We describe clinical features of these patients that may help clinicians distinguish ssSSc-associated ILD from idiopathic ILD.

Materials and Methods

From August 2004 to February 2005, 235 patients were referred to the Interstitial Lung Disease Program at National Jewish Medical and Research Center in Denver, CO, for further evaluation of ILD. All of the patients underwent standardized evaluation including history and physical examination, thoracic high-resolution CT (HRCT) imaging, pulmonary physiology testing, and detailed rheumatologic serologic testing. After obtaining institutional review board approval, we retrospectively reviewed the clinical data of six patients referred for evaluation of an IIP who received a diagnosis of ssSSc.

All patients were formally evaluated by a board-certified rheumatologist (A.F.). The diagnosis of ssSSc required a clinical diagnosis of SSc with no skin thickening on physical examination and at least three or more of the following manifestations typical of SSc: Raynaud phenomenon with abnormal nailfold capillaroscopy findings, scattered telangiectasia, distal esophageal dysmotility by esophagography, ILD with a nonspecific interstitial pneumonia (NSIP) or usual interstitial pneumonia (UIP) by HRCT or surgical lung biopsy, echocardiographic evidence of PH (defined as estimated pulmonary artery pressure > 35 mm Hg), cardiac involvement (asymptomatic pericardial effusion), or nucleolar-staining ANA.

Five of the six patients underwent wide field, nailfold capillaroscopy, and three patients underwent esophagography. Three patients had undergone surgical lung biopsy prior to evaluation at National Jewish Medical and Research Center.

Analysis of SSc-associated autoantibodies was performed at the University of Pittsburgh in all six patients using immunoprecipitation assays as previously described.151617 Briefly, Igs in sera were allowed to adhere to protein A agarose beads (Invitrogen Life Technologies; Carlsbad, CA). For the detection of autoantibodies against small nuclear ribonucleoproteins, small cytoplasmic ribonucleoproteins, and Th/To, antigens were prepared from nonradiolabeled cells. Autoantigens were immunoprecipitated and separated by electrophoresis on denaturing acrylamide gels and detected by silver staining. Sera from healthy individuals were used as negative controls, and all autoantibodies were identified by comparison with standard sera.

Results

All patients were white, mean age was 56 years (range, 37 to 86 years), and gender was evenly divided among the group (Table 1 ). The mean duration of dyspnea prior to referral was 11 months (range, 1 to 24 months), and mean duration of ILD diagnosis was 7 months (range, 1 to 16 months). All of the patients had restrictive pulmonary physiology and a reduced diffusion capacity. The diffusing capacity failed to normalize when corrected for alveolar volume. All patients had HRCT patterns suggestive of NSIP (Fig 1 ) or UIP (Fig 2 ). Of the three patients who had undergone surgical lung biopsy, two patients had NSIP and one patient had UIP pathologic patterns.


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  		Table 1. Clinical Features of ssSSc-Associated ILD*

 

Figure 1
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  		Figure 1. Thoracic HRCT image with NSIP pattern (patient 6).

 

Figure 2
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  		Figure 2. Thoracic HRCT image with UIP pattern (patient 5).

 
None of the patients had sclerodactyly, skin thickening, digital pitting scars, or digital edema characteristic of scleroderma. Telangiectasia was present in all patients involving the oral mucosa, face, and anterior chest wall. Four patients also had palmar telangiectasia. Raynaud phenomenon with associated abnormal nailfold capillaroscopy findings in patterns consistent with SSc (Fig 3 ) was identified in four patients. Of these, Raynaud phenomenon preceded the onset of dyspnea by a mean of 26 months (range, 2 to 60 months). All patients had preexisting symptomatic gastroesophageal reflux disease of at least 2 years in duration. Of the three patients who underwent esophagography, all had esophageal dysmotility.


Figure 3
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  		Figure 3. Nailfold capillaroscopy demonstrating capillary dropout, dilatation, and tortuosity (patient 3) [digital photograph, original x 40].

 
Five of six patients had asymptomatic pericardial effusions detected by HRCT or echocardiography. All five patients had elevated pulmonary artery pressures of at least 45 mm Hg as estimated by echocardiography.

All six patients had nucleolar-staining ANAs and were anti-centromere antibody (ACA) negative. One patients was anti-Scl-70 positive. All five anti-Scl-70–negative patients were anti-Th/To positive, and the lone anti-Scl-70–positive patient was anti-Th/To negative. No other SSc-specific autoantibodies were detected.

Discussion

In this study, we describe the clinical features of six patients with ssSSc-associated ILD diagnosed after presentation as an IIP. The diagnosis of ssSSc was based on finding the characteristic visceral and serologic manifestations of SSc in the absence of the cutaneous abnormalities characteristic of SSc (skin thickening).

We have identified several clinical features in patients with ssSSc-associated ILD that may help clinicians in the evaluation of patients with an idiopathic ILD. When a patient with ILD presents with scattered telangiectasia, Raynaud phenomenon, symptomatic esophageal reflux, or pericardial effusion, further investigation for underlying SSc should occur. ANA testing, nailfold capillaroscopy, and esophagography should all be considered and could add additional support for the diagnosis. Given the higher specificity of the nucleolar-staining ANA for SSc, these findings highlight the usefulness of evaluating the ANA pattern in patients with ILD. And in light of the recently reported results of the Scleroderma Lung Study18 advocating the use of cyclophosphamide in patients with SSc-associated ILD, the differentiation of SSc-associated ILD from an otherwise idiopathic ILD has potential therapeutic implications.

Homma et al19 prospectively followed up 68 patients with an IIP over a period of 1 to 11 years. Thirteen patients (19%) subsequently acquired systemic manifestations of a CTD. They reported that the presence of an ANA or RF was not significantly different in the group of patients who acquired CTD. They did not look for specific AnoAs. The authors19 concluded that patients clinically and/or histologically defined as having IIP could not be distinguished from CTD-associated ILD before the systemic manifestations of the CTD appear.

Similar to our study, Lomeo et al20 reported the clinical features of six patients with ssSSc-associated ILD evaluated over a 9-year period. They concluded that ANA positivity, esophagography, and nailfold capillaroscopy might facilitate the diagnosis of ssSSc. They indicated the pattern of the ANA positivity in their cohort as being speckled or nucleolar.20 They did not check for specific AnoAs, and they did not comment on the presence of pericardial disease in their cohort of patients.

Asymptomatic pericardial disease is a common manifestation of SSc. Echocardiographic evaluations in patients with SSc reported a prevalence of asymptomatic pericardial effusions in 13 to 55%.2122232425 In patients with SSc, the presence of a pericardial effusion has been associated with the presence of PH.25 Our group has found that the presence of a pericardial effusion in patients with SSc-associated ILD is closely associated with echocardiographically defined PH.26 Others272829 have shown pericardial effusions to be commonly associated with primary PH and other forms of secondary PH. We found that all five patients with pericardial effusions had echocardiographically defined PH. The presence of PH was out of proportion to what would be expected from ILD alone (particularly in patients 2 and 5) and likely reflects the vasculopathy and PH strongly associated with SSc. These findings suggest that the presence of an asymptomatic pericardial effusion may not only be a useful marker in the evaluation of ILD but should also prompt more thorough evaluation for underlying PH.

Although Th/To testing is not commercially available, our findings suggest that anti-Th/To positivity may be a useful marker for underlying ssSSc-associated ILD. While the characterization of the Th/To antigen has been well documented,3031323334 the clinical significance of the anti-Th/To antibody is less clear. Studying subjects in the University of Pittsburgh SSc database has generated almost all of the clinical associations of anti-Th/To antibodies.143536 Okano and Medsger35 were the first to study the clinical, laboratory, and prognostic associations of anti-Th/To antibodies. Among 371 sera from SSc and SSc-overlap patients (152 of whom had nucleolar-staining ANA), 15 patients (4%) were found to be positive for anti-Th/To (14 sera were from lcSSc patients and 1 was from a patient with dcSSc). Among 224 controls (consisting of SLE, polymyositis/dermatomyositis, SLE-myositis overlap, undifferentiated connective tissue disease, and primary Raynaud phenomenon), anti-Th/To was detected in only three serum samples (all having primary Raynaud phenomenon of < 2 years in duration). They reported that the anti-Th/To subgroup had significantly greater frequencies of digital edema, small bowel involvement, and hypothyroidism, and a significantly lower frequency of arthralgias or arthritis. In addition, anti-Th/To–positive patients had a cumulative survival rate that was lower than that for patients who were anti-Th/To negative.35

More recently, Mitri et al14 compared 87 anti-Th/To–positive patients to 306 ACA-positive patients with lcSSc. They reported that patients who were anti-Th/To positive had more subtle skin changes, less severe vascular disease, less sicca findings, and less esophageal disease. Intrinsic PH was found to be present in 28% of anti-Th/To–positive patients compared with 19% of ACA-positive patients. Anti-Th/To–positive patients were also more likely to have radiographic evidence of ILD (48% vs 13% of the ACA group) and SSc renal crisis. Mitri et al14 also reported reduced survival in the Th/To group compared with that in the ACA group.

To our knowledge, the only other study that has looked at Th/To antibodies in patients with ssSSc was by Poormoghim et al.36 In their study,36 1 of 16 patients with ssSSc was anti-Th/To positive, compared to 15 of 136 patients with lcSSc. They also reported a high incidence of Raynaud phenomenon, telangiectasia, and esophageal disease. In comparison with patients with lcSSc, their ssSSc cohort had a significantly larger percentage of patients with dyspnea (65% vs 37%), although no differences in spirometry or gas exchange were found, with 35% of their ssSSc patients having a reduced FVC while 77% had a reduced diffusion capacity.36

In conclusion, when a patient presents with an idiopathic ILD, the presence of a nucleolar-staining ANA, scattered telangiectasia, Raynaud phenomenon with abnormal capillaroscopy findings, gastroesophageal reflux or dysmotility, or pericardial disease suggests underlying SSc. We believe prospective studies are needed to define the role of Th/To testing in patients with nucleolar-staining ANA and ILD, as this antibody may be overrepresented among patients with ssSSc-associated ILD.

Footnotes

Abbreviations: ACA = anti-centromere antibody; ANA = anti-nuclear antibody; AnoA = anti-nucleolar antibody; CTD = connective tissue disease; dcSSc = diffuse cutaneous systemic sclerosis; IIP = idiopathic interstitial pneumonia; ILD = interstitial lung disease; lcSSc = limited cutaneous systemic sclerosis; NSIP = nonspecific interstitial pneumonia; PH = pulmonary hypertension; RF = rheumatoid factor; SLE = systemic lupus erythematosus; SSc = systemic sclerosis; ssSSc = systemic sclerosis sine scleroderma; UIP = usual interstitial pneumonia

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Received for publication December 22, 2005. Accepted for publication March 20, 2006.

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