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Original Research: HIGH-RESOLUTION CT |

High-Resolution CT Scan Findings in Patients With Symptomatic Scleroderma-Related Interstitial Lung Disease* FREE TO VIEW

Jonathan G. Goldin, MB ChB, PhD; David A. Lynch, MD; Diane C. Strollo, MD; Robert D. Suh, MD; Dean E. Schraufnagel, MD, FCCP; Philip J. Clements, MD, MPH; Robert M. Elashoff, PhD; Daniel E. Furst, MD; Sarinnapha Vasunilashorn, BS; Michael F. McNitt-Gray, PhD; Mathew S. Brown, PhD; Michael D. Roth, MD, FCCP; Donald P. Tashkin, MD, FCCP; for the Scleroderma Lung Study Research Group
Author and Funding Information

Affiliations: *From the Departments of Radiological Sciences (Drs. Goldin, Suh, Vasunilashorn, McNitt-Gray, and Brown), Rheumatology (Drs. Clements and Furst), Biomathematics (Dr. Elashoff), and Pulmonary and Critical Care Medicine (Drs. Roth and Tashkin), University of California at Los Angeles, Los Angeles, CA; the Department of Radiology (Dr. Lynch), National Jewish Medical and Research Center, Denver, CO; the Department of Radiology (Dr. Strollo), University of Pittsburgh Medical Center, Pittsburgh, PA; and the Department of Pulmonary, Critical Care and Sleep Medicine (Dr. Schraufnagel), University of Illinois at Chicago, Chicago, IL.,  A list of SLS participants is given in the Appendix.

Correspondence to: Jonathan Goldin, MD, PhD, David Geffen School of Medicine at UCLA, Department of Radiology, 10833 Le Conte Ave, B2-165 CHS, Los Angeles, CA 90095-1721; e-mail: jgoldin@mednet.ucla.edu


Affiliations: *From the Departments of Radiological Sciences (Drs. Goldin, Suh, Vasunilashorn, McNitt-Gray, and Brown), Rheumatology (Drs. Clements and Furst), Biomathematics (Dr. Elashoff), and Pulmonary and Critical Care Medicine (Drs. Roth and Tashkin), University of California at Los Angeles, Los Angeles, CA; the Department of Radiology (Dr. Lynch), National Jewish Medical and Research Center, Denver, CO; the Department of Radiology (Dr. Strollo), University of Pittsburgh Medical Center, Pittsburgh, PA; and the Department of Pulmonary, Critical Care and Sleep Medicine (Dr. Schraufnagel), University of Illinois at Chicago, Chicago, IL.,  A list of SLS participants is given in the Appendix.


Chest. 2008;134(2):358-367. doi:10.1378/chest.07-2444
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Background: Lung disease has become the leading cause of mortality and morbidity in scleroderma (SSc) patients. The frequency, nature, and progression of interstitial lung disease seen on high-resolution CT (HRCT) scans in patients with diffuse SSc (dcSSc) compared with those with limited SSc (lcSSc) has not been well characterized.

Methods: Baseline HRCT scan images of 162 participants randomized into a National Institutes of Health-funded clinical trial were compared to clinical features, pulmonary function test measures, and BAL fluid cellularity. The extent and distribution of interstitial lung disease HRCT findings, including pure ground-glass opacity (pGGO), pulmonary fibrosis (PF), and honeycomb cysts (HCs), were recorded in the upper, middle, and lower lung zones on baseline and follow-up CT scan studies.

Results: HRCT scan findings included 92.9% PF, 49.4% pGGO, and 37.2% HCs. There was a significantly higher incidence of HCs in the three zones in lcSSc patients compared to dcSSc patients (p = 0.034, p = 0.048, and p = 0.0007, respectively). The extent of PF seen on HRCT scans was significantly negatively correlated with FVC (r = − 0.22), diffusing capacity of the lung for carbon monoxide (r = − 0.44), and total lung capacity (r = − 0.36). A positive correlation was found between pGGO and the increased number of acute inflammatory cells found in BAL fluid (r = 0.28). In the placebo group, disease progression was assessed as 30% in the upper and middle lung zones, and 45% in the lower lung zones. No difference in the progression rate was seen between lcSSc and dcSSc patients.

Conclusions: PF and GGO were the most common HRCT scan findings in symptomatic SSc patients. HCs were seen in more than one third of cases, being more common in lcSSc vs dcSSc. There was no relationship between progression and baseline PF extent or lcSSc vs dcSSc.

Trial registration: Clinicaltrials.gov Identifier: NCT00004563.

Figures in this Article

Scleroderma (SSc) is an uncommon systemic collagen vascular disease.13 Pulmonary involvement is a significant cause of morbidity and mortality in 74 to 95% of autopsy cases of SSc patients.1,4

Nonspecific interstitial pneumonia (NSIP) is the most common histopathologic diagnosis found in surgical lung biopsy specimens of symptomatic patients with SSc-related lung disease.57 NSIP typically manifests on CT scan as pulmonary fibrosis (PF) [ie, reticular intralobular interstitial thickening, traction bronchiectasis, and bronchiolectasis] and ground-glass opacity (GGO) [ie, increased lung attenuation in the absence of architectural distortion].,57 Pulmonary abnormalities have been reported in 60 to 90% of SSc patients assessed by high-resolution CT (HRCT) scanning.1,3,811 However, these imaging studies have been based on relatively small clinical cohorts, often after a less than optimal retrospective analysis of the clinical data.

This study aimed to evaluate the thoracic HRCT findings of a cohort with clinical and physiologic SSc-related lung disease evidence who were participating in a prospective clinical treatment trial.12 The HRCT scan findings obtained at entry into the Scleroderma Lung Study (SLS) and at 12 months after SLS entry were evaluated.

Patients

The SLS was a prospective, randomized, double-blinded, controlled clinical trial that evaluated the effectiveness of oral cyclophosphamide vs placebo therapy in the treatment of active, symptomatic pulmonary alveolitis inflammation secondary to systemic sclerosis.12 Institutional board approval was obtained at all 13 clinical centers; informed consent and Health Insurance Portability and Accountability Act compliance were obtained from all participants recruited over a period of 3 to 4 years.

Every participant underwent an HRCT scan at baseline as part of the eligibility assessment.12The presence of any GGO irrespective of architectural distortion (the eligibility criterion definition for a GGO) and/or BAL fluid evidence for alveolitis (ie, ≥ 3% neutrophils and/or ≥ 2% eosinophils in BAL fluid) were eligibility requirements. The 162 patients who were randomized into the SLS fulfilled the American Rheumatism Association revised criteria for SSc (Table 1 ).13 SLS patients were considered to have limited SSc (lcSSc) if their skin thickening was confined to areas of extremities below the elbows and knees and above the clavicles. Patients were considered to have diffuse SSc (dcSSc) if their skin thickening involved proximal extremities and/or the torso.14 Randomized subjects completing 1 year of the study were required to undergo a follow-up HRCT scan.

HRCT Scanning

HRCT scans, baseline and follow-up, were obtained with one of four platforms (Somatom Plus 4; Siemens; Erlangen, Germany; TCT-900S; Toshiba Medical Systems; Tokyo, Japan; and HiSpeed Advantage or HiSpeed CTi; GE Medical Systems; Milwaukee, WI). The HRCT scanning protocol was standardized across sites. All sites used the same water phantom (GE Medical Systems) at baseline and yearly thereafter to assess scanner calibration and image characteristics.

The HRCT scan protocol required all sites to obtain scans using a beam potential of 140 kV and a beam current of 100 mA with 1-mm or 2-mm collimation at 10-mm intervals from the lung apices to the bases and to reconstruct images with a high-spatial-frequency algorithm. Patients underwent scanning during suspended end-inspiration in the prone position without IV contrast material. In 138 of 162 participants, images with the patient in the prone position were obtained from the apex to the base according to the image acquisition protocol. Deviation from the protocol occurred in 24 cases (supine position, 2 cases; excluded apex, 12 cases; routine clinical scans, 8 cases; arms at side, 1 case; and 5-mm collimation, 1 case). Baseline HRCT scans were considered to be acceptable for clinical scoring by the reading panel in 156 of 162 cases (96%). A total of 102 follow-up scans were available in digital format for assessment by the reading panel.

Interpretation of HRCT Scans

HRCT scans were initially assessed by the site radiologist for the presence or absence of significant comorbid pathology. At the radiology core, one of two thoracic radiologists with 6 and 10 years of experience (R.S. and J.G., respectively) interpreted HRCT scan images to determine patient eligibility. The readers knew that patients had SSc but were blinded to other clinical information and to BAL results. HRCT scan eligibility was determined by the presence or absence of any GGO irrespective of other pulmonary findings; in this article, this will subsequently be referred to as any GGO (Fig 1 ). HRCT scan images of randomized subjects were then read and scored by two other blinded, independent SLS thoracic radiologists with 15 and 20 years of experience (D.S. and D.L., respectively).15 A training disk with characteristic HRCT scan features of SSc-related lung disease was produced to assist with reading standardization and scoring. Following independent interpretations, discordant reports were jointly reviewed by the two readers and one University of California, Los Angeles (UCLA) core reader (J.G.), and a final consensus decision was reached. The same independent readers also read the follow-ups, with discordant reports read by the UCLA core reader, with the majority score being recorded as the final assessment.

For comprehensive reviews, each lung was divided into the following three zones: upper (lung apex to aortic arch); middle (aortic arch to inferior pulmonary veins); and lower (inferior pulmonary veins to lung bases). For baseline HRCT scans, the extent of the pulmonary abnormality in each of six zones was scored, using a scale from 0 to 4, as follows: 0, absent; 1, 1 to 25%; 2, 26 to 50%; 3, 51 to 75%; and 4, 76 to 100%. The following HRCT scan findings were recorded: pure GGO (pGGO) [ie, increased lung attenuation in the absence of reticular interstitial thickening or architectural distortion, thus differing from the definition of any GGO used as SLS entry criterion] (Fig 2 ); PF (ie, reticular intralobular interstitial thickening, traction bronchiectasis, and bronchiolectasis) [Fig 3 ]; honeycomb cysts (HCs) [ie, clustered air-filled lung cysts with contiguous walls] (Fig 4 ); and emphysema (ie, pulmonary lucencies without walls). For each HRCT scan pattern, the craniocaudal distribution of lung involvement was categorized as upper, middle, or lower zone predominant, or as diffuse or indeterminate; the transverse distribution was categorized as peripheral, central/peribronchovascular, diffuse, or indeterminate. For follow-ups, the change in the extent of pulmonary abnormality in each of the six zones was scored using an ordinal score (better, same, or worse). To readers who were presented with two paired HRCT scans, their order was randomized to ensure blinding regarding the true order in which the scans had been obtained.

Pulmonary Function Tests and BAL

Spirometry and measurements of total lung capacity (TLC) and single-breath diffusing capacity of the lung for carbon monoxide (Dlco) were performed according to American Thoracic Society guidelines.1617 The participants underwent a pulmonary function test (PFT) within 4 weeks of the HRCT scan. BAL was performed at each center with 240 mL of saline solution instilled into the right middle lobe in four aliquots according to a standard protocol. BAL fluid analyses were performed at the SLS BAL core. Alveolitis was defined by the study protocol as a BAL fluid cell count of polymorphonuclear leukocytes ≥ 3% and/or an eosinophil count ≥ 2%.1822 HRCT scanning was performed either shortly before BAL or, if BAL was performed first, at least 4 weeks after BAL.

Statistical Analysis

The interobserver agreement between two core radiologists was assessed by calculating the κ value for any GGO, pGGO, PF, and HC HRCT scan findings.23 Correlations among the Likert score for pGGO, HC, and PF extent, and clinical features (ie, age, gender, disease duration [lcSSc vs dcSSc], cigarette consumption-alveolitis seen in BAL fluid samples, and PFT results) were estimated with Pearson correlation coefficient (r value) and Spearman correlation, respectively.,23 In the placebo group, χ2 tests were assessed to compare the baseline scores of GGO, PF, and HCs between patients with dcSSc and those with lcSSc. Logistic regression was used to test the difference in PF progression (ie, worse vs not worse) from baseline between dcSSc and lcSSc patients by zones. The statistical analyses were performed using a statistical software package (SAS software, version 9.1; SAS Institute; Cary, NC).

Patient Characteristics

Of the 267 subjects screened for eligibility, 162 were SLS randomized, including 114 female subjects and 46 male subjects. The mean (± SD) age was 51 ± 12.3 years; 40% of subjects (65 of 162 subjects) had lcSSc, and 60% of subjects (97 of 162 subjects) had dcSSc (Table 2 ). A total of 79 subjects were randomized to the placebo control group. Of the 105 screened-eligible subjects who failed randomization (for a variety of reasons), 68 underwent HRCT scanning and 53 underwent BAL. Figure 5 summarizes the cases meeting the criteria for any GGO seen on HRCT scans or alveolitis found in BAL fluid.

Dyspnea, which was a criterion for eligibility, was present in 100% of subjects, cough was present in 67.9% of subjects (108 of 159 subjects), and sputum production was present in 46.1% of subjects (72 of 156 subjects); 79% of subjects (125 of 159 subjects) had more than two symptoms. The mean interval of disease from the earliest onset of non-Raynaud syndrome symptoms to the time of randomization was 3.10 ± 2.1 years. Subjects were lifetime never-smokers except for 24 former smokers; the mean duration of smoking was 23.1 ± 16 years. Interestingly, sputum production was noted in a higher proportion in SLS participants than is generally observed in patients with SSc-interstitial lung disease. The productive cough noted in 46.1% of subjects may have been related to aspiration secondary to gastroesophageal reflux disease, the accumulation of mucus, and/or its impaired clearance in airways involved by traction bronchiectasis caused by PF.

HRCT Findings

Table 3 summarizes the frequency of all baseline HRCT scans for 156 subjects with clinically acceptable CT scans. Whereas any GGO was noted in 141 participants (91.2%), only 77 participants (49.7%) met the criterion for pGGO in the absence of architectural distortion. PF was identified in 145 participants (92.9%), and HCs were identified in 58 participants (37.2%). There were insignificant differences between lcSSc and dcSSc related to GGO frequency. The baseline PF score (total) was significantly higher (worse) in lcSSc patients (p = 0.046).

The interobserver agreement for the presence or absence of pGGO (κ = 0.72) and PF (κ = 0.61) was good, whereas the interobserver agreement for HCs was only fair (κ = 0.39). Agreement between any GGO eligibility and comprehensive reading for the presence or absence of pGGO was poor (κ = 0.14), as expected.

Regarding the regional distribution of abnormalities, HRCT scan findings of PF, pGGO, and HCs were most common in the lower lung zones without right or left predominance. Lower lung zones were equally affected by pGGO (right lung, 44.8% [69 of 154 subjects]; left lung, 45.5% [70 of 154 subjects]), PF (right lung, 91.0% [142 of 156 subjects]; left lung, 92.9% [145 of 156 subjects]), and HCs (right lung, 29.5% [46 of 156 subjects]; left lung, 29.5% [46 of 156 subjects]).

Regarding interval progression in the placebo group, HRCT scan parenchymal abnormalities reflected in the PF score demonstrated an interval of about 30% worsening in the upper lung zone (13 of 44 subjects) and middle lung zone (15 of 49 subjects), and 45% worsening in the lower lung zones (22 of 49 patients) [Table 4 ]. However, disease progression odds determined from the baseline PF score were statistically insignificant in six zones, regardless of their baseline score; the degree of worsening in PF disease between lcSSc vs dcSSc subjects was also insignificant.

Correlation of HRCT Findings With Clinical Characteristics and PFT Results

Neither PF pattern nor the extent observed on HRCT scans correlated with gender, age, or disease duration. There was, however, significantly more evidence for HCs in lcSSc patients compared to dcSSc patients in the right middle, left upper, and left middle zones (p = 0.034, p = 0.048, and p = 0.0007, respectively). The odds ratios of finding HCs (score > 1) in lcSSc patients were three, five, and six times higher in the right middle, left upper, and left middle lung zones, respectively (Table 5 ). Conversely, a history of smoking was negatively associated with PF HRCT scan findings (r = − 0.76; p = 0.03). No correlation was found between the pGGO or HC pattern or extent and age, gender, disease duration, or smoking history (Table 6 ). pGGO was not well correlated with FVC, Dlco, or FEV1/FVC ratio. PF was significantly negatively correlated with FVC, Dlco, and TLC, but was positively correlated with FEV1/FVC ratio (Table 7 ).

Assessment of BAL and CT Findings

The mean interval between HRCT scanning and BAL was 17 days. Of 162 patients, 148 patients (91.4%) underwent BAL and HRCT scanning, whereas 14 patients (8.6%) only underwent HRCT scanning; in 4 patients (2.5%), the BAL fluid was unanalyzable. BAL fluid was positive for active alveolitis in 70.1% of randomized participants (102 of 144 randomized participants) with analyzable samples. Of 102 participants with positive BAL results, 57 (55.9%) had pGGO, whereas 45 (44.1%) did not. Overall, there was agreement between CT scan findings and BAL in 59.7% of participants (86 of 144 participants), with discordance in 40.3% of participants (58 of 144 participants). A significantly moderate correlation was observed between BAL findings and both pGGO and HCs (r = 0.28, p < 0.01; and r = 0.16, p < 0.05, respectively). An insignificant correlation was observed between abnormal BAL findings and PF (r = 0.10; p = 0.21). There were insignificant differences between lcSSc and dcSSc patients related to BAL findings.14

This study confirms that thoracic HRCT scanning plays a central role in the detection and characterization of lung involvement in SSc patients.1,3,810,2425 The reported hallmark features5,2629 of SSc-related lung involvement are similar to those of idiopathic NSIP. This association has also been reported56,30 in radiology-pathology correlations in surgical biopsy specimens. Several studies11,3135 have summarized the results of SSc CT findings (Table 7).

In the SLS, PF and GGO were the most common HRCT scan abnormalities found, which is consistent with the NSIP pattern. However, HCs occurred in 37.2% of patients, which is similar to the finding in the study by Remy-Jardin et al10 (35.8%; 19 of 53 patients), but is higher than that in the study by Akira et al36(11%; 1 of 9 patients). Since HCs are usually markers for usual interstitial pneumonia (UIP),37these findings suggest that patients with SSc-related interstitial lung disease may have a mixture (or overlap) of UIP and NSIP patterns. This is consistent with the findings of Desai et al38 and other autopsy studies6,3940 in which typical histopathologic findings, in contrast to surgical biopsy specimens, included marked interstitial PF and HCs.

An important SLS finding was that the extent of PF seen on baseline HRCT scans was predictive of the progression rate in the absence of active immunosuppressive therapy as well as the response to cyclophosphamide therapy, which was greatest in those with the most extensive PF seen on baseline HRCT scans.12 Although confirmatory studies are required, these findings suggest that baseline HRCT scan findings may have some predictive value regarding the disease course and its response to therapy. However, the role of HRCT scanning in monitoring disease progression remains to be determined.

Early reports that correlated pulmonary CT scan features with abnormal SSc BAL results suggested that GGO was associated with “alveolitis,” and GGO was thought to indicate potentially reversible disease.8,10 Whereas the presence of GGO is an important radiologic feature of SSc and NSIP, the overall composite HRCT scan findings are more important than this single feature. In the SLS, the weak correlation between pGGO and abnormal BAL casts further doubt on the relationship between GGO and active alveolitis, and raises the question of the role of BAL in SLS patient assessment.41

In keeping with other studies,4243 approximately 40% of SLS patients had lcSSc. Although it is generally assumed that SSc-related lung disease is more common and severe in dcSSc patients, it was not the case in the SLS. While lcSSc and dcSSc patients were indistinguishable regarding their baseline pulmonary functions, lcSSc patients presented with more extensive PF, possibly reflecting a delay in diagnosing their lung disease, thus providing more opportunity for disease progression prior to study entry. The rate of progression of SSc-interstitial lung disease was similar in lcSSc and dcSSc patients after adjustment for baseline differences in the degree of PF. Given that baseline FVC and PF scores were the most important independent predictors of the decline in pulmonary function over time in SLS patients, all patients should be carefully evaluated for parenchymal involvement irrespective of disease extent.14

Our observation that the extent of PF was negatively correlated with FVC and Dlco suggests that the extent of PF is a valid reflection of restrictive physiologic impairment amount and gas transfer abnormality (Table 7).42 Our significantly positive but only weak correlation between pGGO HRCT findings and BAL fluid evidence of interstitial inflammation questions the general assumption that pGGO reflect active lung inflammation.

The SLS has several limitations. Due to cost and potential morbidity and mortality, lung biopsies were not performed. Thus, it is unclear whether HRCT scan findings accurately reflect active lung inflammation or underlying NSIP or UIP histopathology. Additionally, biopsy and BAL sample only a small area, which typically has heterogeneous disease involvement. Whereas BAL was performed only in the right middle lobe, CT scans evaluated the entire lung volume, diminishing the validity of correlating CT scan and BAL results.44

In conclusion, PF and pGGO were the most common CT scan findings in patients with symptomatic SSc-related lung disease. The overall interreader agreement of CT scan interpretation was good. The composite CT scan pattern was largely consistent with the presumed histopathologic NSIP diagnosis, although over one third of subjects exhibited HCs, which are more typical of UIP. Symptomatic lcSSc patients have more parenchymal abnormalities than those with dcSSc, and their progression rates, accounting for the baseline PF scores, are the same. HRCT scanning is an important technique for the detection and characterization of lung involvement in SSc patients, in predicting treatment outcome, and assessing disease progression.

SLS Participants
SLS Research Group: UCLA (National Heart, Lung, and Blood Institute [NHLBI] grants UO1 HL 60587 and UO1 HL 60606)

Philip J. Clements, MD, MPH; Donald P. Tashkin, MD; Robert Elashoff, PhD; Jonathan Goldin, MD, PhD; Michael Roth, MD; Daniel Furst, MD; Ken Bulpitt, MD; Dinesh Khanna, MD; Wen-Ling Joanie Chung, MPH; Sherrie Viasco, RN; Mildred Sterz, RN, MPH; Lovlette Woolcock, LVN; Xiaohong Yan, MS; Judy Ho, BS; Sarinnapha Vasunilashorn, BS; and Irene da Costa, MS.

University of Medicine and Dentistry of New Jersey, New Brunswick, NJ (NHLBI grant UO1 HL 60550)

James R. Seibold, MD (currently at: University of Michigan Scleroderma Program, Ann Arbor, MI); David J. Riley, MD; Judith K. Amorosa, MD; Vivien M. Hsu, MD; Deborah A. McCloskey, BSN; and Julianne E. Wilson, RN.

University of Illinois Chicago, Chicago, IL (NHLBI grant UO1 HL 60895)

John Varga, MD; Dean Schraugnagel, MD; Andrew Wilbur, MD; David Lapota, MD; Shiva Arami, MD; and Patricia Cole-Saffold, MS.

Boston University, Boston, MA (NHLBI grant UO1 HL 60682)

Robert Simms, MD; Arthur Theodore, MD; Peter Clarke, MD; Joseph Korn, MD; Kimberley Tobin, BS; and Melynn Nuite, BSN.

Medical University of South Carolina, Charleston, SC (NHLBI grant UO1 HL 60750)

Richard Silver, MD; Marcie Bolster, MD; Charlie Strange, MD; Steve Schabel, MD; Edwin Smith, MD; June Arnold, BS; Katie Caldwell, MS; and Michael Bonner, BS.

Johns Hopkins School of Medicine, Baltimore, MD (NHLBI grant UO1 HL 60597)

Robert Wise, MD; Fred Wigley, MD; Barbara White, MD; Laura Hummers, MD; Mark Bohlman, MD; Albert Polito, MD; Gwen Leatherman, MSN; Edrick Forbes, RN; and Marie Daniel, BS.

Georgetown University, Washington, DC (NHLBI grant UO1 HL 60794)

Virginia Steen, MD; Charles Read, MD; Cirrelda Cooper, MD; Sean Wheaton, MD; Anise Carey, BS; and Adriana Ortiz, BS.

University of Texas Houston, Houston, TX (NHLBI grant UO1 HL 60839)

Maureen Mayes, MD, MPH; Ed Parsley, DO; Sandra Oldham, MD; Tan Filemon, MD; Samantha Jordan, RN; and Marilyn Perry, BS.

University of California San Francisco, San Francisco, CA (NHLBI grant UO1 HL 60587)

Kari Connolly, MD; Jeffrey Golden, MD; Paul Wolters, MD; Richard Webb, MD; John Davis, MD; Christine Antolos, BS; and Carla Maynetto, BS.

University of Alabama, Birmingham, AL (NHLBI grant UO1 HL 60748)

Barri Fessler, MD; Mitchell Olman, MD; Colleen Sanders, MD; Louis Heck, MD; and Tina Parkhill, BS.

University of Connecticut Health Center, Farmington, CT (NHLBI grant UO1 HL 60587)

Naomi Rothfield, MD; Mark Metersky, MD; Richard Cobb, MD; Macha Aberles, MD; Fran Ingenito, RN; and Elena Breen, MLT.

Wayne State University, Detroit, MI (NHLBI grant UO1 HL 60839)

Maureen Mayes, MD; Kamal Mubarak, MD; Jose L. Granda, MD; Joseph Silva, MD; Zora Injic, RN, MS; and Ronika Alexander, RN.

Virginia Mason Research Center, Seattle, WA (NHLBI grant UO1 HL 60823)

Daniel Furst, MD; Steven Springmeyer, MD; Steven Kirkland, MD; Jerry Molitor, MD; Richard Hinke, MD; and Amanda Mondt, RN.

Data Safety and Monitoring Board Members

Taylor Thompson, MD (Harvard Medical School, Boston, MA); Sharon Rounds, MD (Veterans Affairs Medical Center, Brown University, Providence, RI); Michael Weinstein, MD (Cedars Sinai/UCLA, Los Angeles, CA); and Bruce Thompson, PhD (Clinical Trials Surveys, Baltimore, MD).

Mortality and Morbidity Review Committee Members

Harold Paulus, MD (UCLA); Steven Levy, MD (UCLA); and Donald Martin, MD (Johns Hopkins University).

Abbreviations: dcSSc = diffuse scleroderma; Dlco = diffusing capacity of the lung for carbon monoxide; GGO = ground-glass opacity; HC = honeycomb cyst; HRCT = high-resolution CT; lcSSc = limited scleroderma; NSIP = nonspecific interstitial pneumonia; PF = pulmonary fibrosis; PFT = pulmonary function tests; pGGO = pure ground-glass opacity; NHLBI = National Heart, Lung, and Blood Institute; SLS = Scleroderma Lung Study; SSc = scleroderma; TLC = total lung capacity; UCLA = University of California, Los Angeles; UIP = usual interstitial pneumonia

This study was funded by National Institutes of Health (grant UO1 HL 60748) and research grants U01 HL60587-01A1 and R01 HL072424, from the National Heart, Lung, and Blood Institute, Bethesda, MD.

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.

Table Graphic Jump Location
Table 1. The American College of Rheumatology Criteria for the Classification of Scleroderma*
* 

Require one major criterion or two minor criteria.

Figure Jump LinkFigure 1. Any GGO. Prone axial HRCT scan from an SLS subject to illustrate GGOs adjacent to and overlying a region of PF (encircled region). This finding, determined by the eligibility criteria for enrollment in the SLS, is considered to be any GGO.Grahic Jump Location
Figure Jump LinkFigure 2. pGGO. Top, A: prone axial HRCT images (lung window) of a SLS subject show multiple regions of GGO without architectural distortion or reticular interstitial markings. Bottom, B: based on the comprehensive reading criteria, a region of pGGO is highlighted (encircled region).Grahic Jump Location
Figure Jump LinkFigure 3. Prone axial HRCT scan (lung window) demonstrates PF with architectural distortion (white arrow) in a patient randomized into the SLS.Grahic Jump Location
Figure Jump LinkFigure 4. HCs. Prone axial HRCT scan images (top, A, and bottom, B) demonstrate clustered, air-filled cysts that share contiguous walls (top, A: white arrow).Grahic Jump Location
Table Graphic Jump Location
Table 2. Demographic Characteristics of Patients Enrolled in the SLS
* 

Values are given as the mean (SD).

Figure Jump LinkFigure 5. Number of screened, randomized, and nonrandomized patients with and without HRCT scan and/or BAL fluid evidence of alveolitis.Grahic Jump Location
Table Graphic Jump Location
Table 3. Frequency of HRCT Scan Findings*
* 

Total No. of participants randomized, 162.

 

Number of participants who had a consensus reading performed, 156.

Table Graphic Jump Location
Table 4. Baseline and 12-Month Follow-up of PF Score by Zone*
* 

All p values are > 0.05. Baseline score: 0, absent; 1, 1 to 25%; 2, 26 to 50%; 3, 51 to 75%; and 4, 76 to 100%. Worse = worse at 12-month follow-up; Not worse = not worse at 12-month follow-up.

 

n = 44.

 

n = 49.

Table Graphic Jump Location
Table 5. HC Score at Baseline*
* 

n = 78; one patient had indeterminate disease.

 

p < 0.05.

Table Graphic Jump Location
Table 6. Relationship Between Patient Parameters and Findings on HRCT Scans*
* 

Limited disease was observed to be significantly associated with both PF and HCs (p = 0.046). A smoking history was observed to be negatively associated with findings of PF on HRCT scans (p = 0.03). No other clinical features (age, gender, or disease duration) were found to be significantly associated.

 

Includes only pGGO found on consensus reads (n = 156).

Table Graphic Jump Location
Table 7. Correlation of Extent of CT Findings, PFT Results, and BAL Findings*
* 

The extent of PF seen on HRCT scans appears to be negatively correlated with FVC, Dlco, and TLC measures, and may thus be a reflection of the degree of restrictive interstitial pulmonary disease. BAL fluid evidence for alveolitis was positively associated with CT scan evidence of pGGOs and showed a weak association with HCs that was of borderline statistical significance.

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Remy-Jardin, M, Remy, J, Wallaert, B, et al Pulmonary involvement in progressive systemic sclerosis: sequential evaluation with CT, pulmonary function tests, and bronchoalveolar lavage.Radiology1993;188,499-506. [PubMed]
 
Fujita, J, Yoshinouchi, T, Ohtsuki, Y, et al Non-specific interstitial pneumonia as pulmonary involvement of systemic sclerosis.Ann Rheum Dis2001;60,281-283. [PubMed]
 
Tashkin, DP, Elashoff, RM, Clements, PJ, et al The Scleroderma Lung Study: oral cyclophosphamide versus placebo for the treatment of scleroderma-related interstitial lung disease.N Engl J Med2006;354,2655-2666. [PubMed]
 
American Rheumatism Association.. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee.Arthritis Rheum1980;23,581-590. [PubMed]
 
Clements, PJ, Medsger, TA Cutaneous involvement. Clements, PJ Furst, DE eds.Systemic sclerosis2004,129-150 Lippincott Williams & Wilkins. Philadelphia, PA:
 
Kazerooni, EA, Martinez, FJ, Flint, A, et al Thin-section CT obtained at 10-mm increments versus limited three-level thin-section CT for idiopathic pulmonary fibrosis: correlation with pathologic scoring.AJR Am J Roentgenol1997;169,977-983. [PubMed]
 
American Thoracic Society.. Standardization of spirometry, 1994 update.Am J Respir Crit Care Med1995;152,1107-1136. [PubMed]
 
American Thoracic Society.. Single-breath carbon monoxide diffusing capacity (transfer factor): recommendations for a standard technique; 1995 update.Am J Respir Crit Care Med1995;152,2185-2198. [PubMed]
 
White, B, Moore, WC, Wigley, FM, et al Cyclophosphamide is associated with pulmonary function and survival benefit in patients with scleroderma and alveolitis.Ann Intern Med2000;132,947-954. [PubMed]
 
Silver, RM, Warrick, JH, Kinsella, MB, et al Cyclophosphamide and low-dose prednisone therapy in patients with systemic sclerosis (scleroderma) with interstitial lung disease.J Rheumatol1993;20,838-844. [PubMed]
 
Behr, J, Vogelmeier, C, Beinert, T, et al Bronchoalveolar lavage for evaluation and management of scleroderma disease of the lung.Am J Respir Crit Care Med1996;154,400-406. [PubMed]
 
Ettensohn, DB, Jankowski, MJ, Duncan, PG, et al Bronchoalveolar lavage in the normal volunteer subject: I. Technical aspects and intersubject variability.Chest1988;94,275-280. [PubMed]
 
Ettensohn, DB, Jankowski, MJ, Redondo, AA, et al Bronchoalveolar lavage in the normal volunteer subject: 2. Safety and results of repeated BAL, and use in the assessment of intrasubject variability.Chest1988;94,281-285. [PubMed]
 
Altman, DG. Practical statistics for medical research. 1991; Chapman and Hall. London, UK:.
 
Remy-Jardin, M, Giraud, F, Remy, J, et al Importance of ground-glass attenuation in chronic diffuse infiltrative lung disease: pathologic-CT correlation.Radiology1993;189,693-698. [PubMed]
 
Pignone, A, Matucci-Cerinic, M, Lombardi, A, et al High resolution computed tomography in systemic sclerosis: real diagnostic utilities in the assessment of pulmonary involvement and comparison with other modalities of lung investigation.Clin Rheumatol1992;11,465-472. [PubMed]
 
Muller, NL, Colby, TV Idiopathic interstitial pneumonias: high-resolution CT and histologic findings.Radiographics1997;17,1016-1022. [PubMed]
 
Latsi, PI, Wells, AU Evaluation and management of alveolitis and interstitial lung disease in scleroderma.Curr Opin Rheumatol2003;15,748-755. [PubMed]
 
Lynch, DA Nonspecific interstitial pneumonia: evolving concepts.Radiology2001;221,583-584. [PubMed]
 
American Thoracic Society, European Respiratory Society.. American Thoracic Society/European Respiratory Society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias.Am J Respir Crit Care Med2002;165,277-304. [PubMed]
 
Wells, AU, Hansell, DM, Corrin, B, et al High resolution computed tomography as a predictor of lung histology in systemic sclerosis.Thorax1992;47,738-742. [PubMed]
 
Ooi, GC, Mok, MY, Tsang, KW, et al Interstitial lung disease in systemic sclerosis.Acta Radiol2003;44,258-264. [PubMed]
 
Saito, Y, Terada, M, Takada, T, et al Pulmonary involvement in mixed connective tissue disease: comparison with other collagen vascular diseases using high resolution CT.J Comput Assist Tomogr2002;26,349-357. [PubMed]
 
Kim, EA, Johkoh, T, Lee, KS, et al Interstitial pneumonia in progressive systemic sclerosis: serial high-resolution CT findings with functional correlation.J Comput Assist Tomogr2001;25,757-763. [PubMed]
 
Andonopoulos, AP, Yarmenitis, S, Georgiou, P, et al Bronchiectasis in systemic sclerosis: a study using high resolution computed tomography.Clin Exp Rheumatol2001;19,187-190. [PubMed]
 
Shahin, AA, Sabri, YY, Mostafa, HA, et al Pulmonary function tests, high-resolution computerized tomography, α1-antitrypsin measurement, and early detection of pulmonary involvement in patients with systemic sclerosis.Rheumatol Int2001;20,95-100. [PubMed]
 
Akira, M, Inoue, G, Yamamoto, S, et al Non-specific interstitial pneumonia: findings on sequential CT scans of nine patients.Thorax2000;55,854-859. [PubMed]
 
Hunninghake, GW, Lynch, DA, Galvin, JR, et al Radiologic findings are strongly associated with a pathologic diagnosis of usual interstitial pneumonia.Chest2003;124,1215-1223. [PubMed]
 
Desai, SR, Veeraraghavan, S, Hansell, DM, et al CT features of lung disease in patients with systemic sclerosis: comparison with idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia.Radiology2004;232,560-567. [PubMed]
 
Colby, TV, Carrington, CB Interstitial lung disease. Thurlbeck, WM Churg, AM eds.Pathology of the lung1995,589-737 Thieme Medical Publishers. New York, NY:
 
Piper, WN, Helwig, EB Progressive systemic sclerosis; visceral manifestations in generalized scleroderma.AMA Arch Derm1955;72,535-546. [PubMed]
 
Strange, C, Bolster, MB, Roth, MD, et al Bronchoalveolar lavage and response to cyclophosphamide in scleroderma interstitial lung disease.Am J Respir Crit Care Med2008;177,91-98. [PubMed]
 
Steen, VD, Conte, C, Owens, GR, et al Severe restrictive lung disease in systemic sclerosis.Arthritis Rheum1994;37,1283-1289. [PubMed]
 
White, B, Moore, WC, Wigley, FM, et al Cyclophosphamide is associated with pulmonary function and survival benefit in patients with scleroderma and alveolitis.Ann Intern Med2000;132,947-954. [PubMed]
 
Clements, PJ, Goldin, JG, Kleerup, EC, et al Regional differences in bronchoalveolar lavage and thoracic high-resolution computed tomography results in dyspneic patients with systemic sclerosis.Arthritis Rheum2004;50,1909-1917. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Any GGO. Prone axial HRCT scan from an SLS subject to illustrate GGOs adjacent to and overlying a region of PF (encircled region). This finding, determined by the eligibility criteria for enrollment in the SLS, is considered to be any GGO.Grahic Jump Location
Figure Jump LinkFigure 2. pGGO. Top, A: prone axial HRCT images (lung window) of a SLS subject show multiple regions of GGO without architectural distortion or reticular interstitial markings. Bottom, B: based on the comprehensive reading criteria, a region of pGGO is highlighted (encircled region).Grahic Jump Location
Figure Jump LinkFigure 3. Prone axial HRCT scan (lung window) demonstrates PF with architectural distortion (white arrow) in a patient randomized into the SLS.Grahic Jump Location
Figure Jump LinkFigure 4. HCs. Prone axial HRCT scan images (top, A, and bottom, B) demonstrate clustered, air-filled cysts that share contiguous walls (top, A: white arrow).Grahic Jump Location
Figure Jump LinkFigure 5. Number of screened, randomized, and nonrandomized patients with and without HRCT scan and/or BAL fluid evidence of alveolitis.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. The American College of Rheumatology Criteria for the Classification of Scleroderma*
* 

Require one major criterion or two minor criteria.

Table Graphic Jump Location
Table 2. Demographic Characteristics of Patients Enrolled in the SLS
* 

Values are given as the mean (SD).

Table Graphic Jump Location
Table 3. Frequency of HRCT Scan Findings*
* 

Total No. of participants randomized, 162.

 

Number of participants who had a consensus reading performed, 156.

Table Graphic Jump Location
Table 4. Baseline and 12-Month Follow-up of PF Score by Zone*
* 

All p values are > 0.05. Baseline score: 0, absent; 1, 1 to 25%; 2, 26 to 50%; 3, 51 to 75%; and 4, 76 to 100%. Worse = worse at 12-month follow-up; Not worse = not worse at 12-month follow-up.

 

n = 44.

 

n = 49.

Table Graphic Jump Location
Table 5. HC Score at Baseline*
* 

n = 78; one patient had indeterminate disease.

 

p < 0.05.

Table Graphic Jump Location
Table 6. Relationship Between Patient Parameters and Findings on HRCT Scans*
* 

Limited disease was observed to be significantly associated with both PF and HCs (p = 0.046). A smoking history was observed to be negatively associated with findings of PF on HRCT scans (p = 0.03). No other clinical features (age, gender, or disease duration) were found to be significantly associated.

 

Includes only pGGO found on consensus reads (n = 156).

Table Graphic Jump Location
Table 7. Correlation of Extent of CT Findings, PFT Results, and BAL Findings*
* 

The extent of PF seen on HRCT scans appears to be negatively correlated with FVC, Dlco, and TLC measures, and may thus be a reflection of the degree of restrictive interstitial pulmonary disease. BAL fluid evidence for alveolitis was positively associated with CT scan evidence of pGGOs and showed a weak association with HCs that was of borderline statistical significance.

References

Arroliga, AC, Podell, DN, Matthay, RA (1992) Pulmonary manifestations of scleroderma.J Thorac Imaging7,30-45. [PubMed] [CrossRef]
 
Geppert, T Clinical features, pathogenic mechanisms, and new developments in the treatment of systemic sclerosis.Am J Med Sci1990;299,193-209. [PubMed]
 
Schurawitzki, H, Stiglbauer, R, Graninger, W, et al Interstitial lung disease in progressive systemic sclerosis: high-resolution CT versus radiography.Radiology1990;176,755-759. [PubMed]
 
Geirsson, AJ, Wollheim, FA, Akesson, A Disease severity of 100 patients with systemic sclerosis over a period of 14 years: using a modified Medsger scale.Ann Rheum Dis2001;60,1117-1122. [PubMed]
 
Bouros, D, Wells, AU, Nicholson, AG, et al Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome.Am J Respir Crit Care Med2002;165,1581-1586. [PubMed]
 
Kim, DS, Yoo, B, Lee, JS, et al The major histopathologic pattern of pulmonary fibrosis in scleroderma is nonspecific interstitial pneumonia.Sarcoidosis Vasc Diffuse Lung Dis2002;19,121-127. [PubMed]
 
Minai, OA, Dweik, RA, Arroliga, AC Manifestations of scleroderma pulmonary disease.Clin Chest Med1998;19,713-731viii–ix. [PubMed]
 
Warrick, JH, Bhalla, M, Schabel, SI, et al High resolution computed tomography in early scleroderma lung disease.J Rheumatol1991;18,1520-1528. [PubMed]
 
Seely, JM, Jones, LT, Wallace, C, et al Systemic sclerosis: using high-resolution CT to detect lung disease in children.AJR Am J Roentgenol1998;170,691-697. [PubMed]
 
Remy-Jardin, M, Remy, J, Wallaert, B, et al Pulmonary involvement in progressive systemic sclerosis: sequential evaluation with CT, pulmonary function tests, and bronchoalveolar lavage.Radiology1993;188,499-506. [PubMed]
 
Fujita, J, Yoshinouchi, T, Ohtsuki, Y, et al Non-specific interstitial pneumonia as pulmonary involvement of systemic sclerosis.Ann Rheum Dis2001;60,281-283. [PubMed]
 
Tashkin, DP, Elashoff, RM, Clements, PJ, et al The Scleroderma Lung Study: oral cyclophosphamide versus placebo for the treatment of scleroderma-related interstitial lung disease.N Engl J Med2006;354,2655-2666. [PubMed]
 
American Rheumatism Association.. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee.Arthritis Rheum1980;23,581-590. [PubMed]
 
Clements, PJ, Medsger, TA Cutaneous involvement. Clements, PJ Furst, DE eds.Systemic sclerosis2004,129-150 Lippincott Williams & Wilkins. Philadelphia, PA:
 
Kazerooni, EA, Martinez, FJ, Flint, A, et al Thin-section CT obtained at 10-mm increments versus limited three-level thin-section CT for idiopathic pulmonary fibrosis: correlation with pathologic scoring.AJR Am J Roentgenol1997;169,977-983. [PubMed]
 
American Thoracic Society.. Standardization of spirometry, 1994 update.Am J Respir Crit Care Med1995;152,1107-1136. [PubMed]
 
American Thoracic Society.. Single-breath carbon monoxide diffusing capacity (transfer factor): recommendations for a standard technique; 1995 update.Am J Respir Crit Care Med1995;152,2185-2198. [PubMed]
 
White, B, Moore, WC, Wigley, FM, et al Cyclophosphamide is associated with pulmonary function and survival benefit in patients with scleroderma and alveolitis.Ann Intern Med2000;132,947-954. [PubMed]
 
Silver, RM, Warrick, JH, Kinsella, MB, et al Cyclophosphamide and low-dose prednisone therapy in patients with systemic sclerosis (scleroderma) with interstitial lung disease.J Rheumatol1993;20,838-844. [PubMed]
 
Behr, J, Vogelmeier, C, Beinert, T, et al Bronchoalveolar lavage for evaluation and management of scleroderma disease of the lung.Am J Respir Crit Care Med1996;154,400-406. [PubMed]
 
Ettensohn, DB, Jankowski, MJ, Duncan, PG, et al Bronchoalveolar lavage in the normal volunteer subject: I. Technical aspects and intersubject variability.Chest1988;94,275-280. [PubMed]
 
Ettensohn, DB, Jankowski, MJ, Redondo, AA, et al Bronchoalveolar lavage in the normal volunteer subject: 2. Safety and results of repeated BAL, and use in the assessment of intrasubject variability.Chest1988;94,281-285. [PubMed]
 
Altman, DG. Practical statistics for medical research. 1991; Chapman and Hall. London, UK:.
 
Remy-Jardin, M, Giraud, F, Remy, J, et al Importance of ground-glass attenuation in chronic diffuse infiltrative lung disease: pathologic-CT correlation.Radiology1993;189,693-698. [PubMed]
 
Pignone, A, Matucci-Cerinic, M, Lombardi, A, et al High resolution computed tomography in systemic sclerosis: real diagnostic utilities in the assessment of pulmonary involvement and comparison with other modalities of lung investigation.Clin Rheumatol1992;11,465-472. [PubMed]
 
Muller, NL, Colby, TV Idiopathic interstitial pneumonias: high-resolution CT and histologic findings.Radiographics1997;17,1016-1022. [PubMed]
 
Latsi, PI, Wells, AU Evaluation and management of alveolitis and interstitial lung disease in scleroderma.Curr Opin Rheumatol2003;15,748-755. [PubMed]
 
Lynch, DA Nonspecific interstitial pneumonia: evolving concepts.Radiology2001;221,583-584. [PubMed]
 
American Thoracic Society, European Respiratory Society.. American Thoracic Society/European Respiratory Society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias.Am J Respir Crit Care Med2002;165,277-304. [PubMed]
 
Wells, AU, Hansell, DM, Corrin, B, et al High resolution computed tomography as a predictor of lung histology in systemic sclerosis.Thorax1992;47,738-742. [PubMed]
 
Ooi, GC, Mok, MY, Tsang, KW, et al Interstitial lung disease in systemic sclerosis.Acta Radiol2003;44,258-264. [PubMed]
 
Saito, Y, Terada, M, Takada, T, et al Pulmonary involvement in mixed connective tissue disease: comparison with other collagen vascular diseases using high resolution CT.J Comput Assist Tomogr2002;26,349-357. [PubMed]
 
Kim, EA, Johkoh, T, Lee, KS, et al Interstitial pneumonia in progressive systemic sclerosis: serial high-resolution CT findings with functional correlation.J Comput Assist Tomogr2001;25,757-763. [PubMed]
 
Andonopoulos, AP, Yarmenitis, S, Georgiou, P, et al Bronchiectasis in systemic sclerosis: a study using high resolution computed tomography.Clin Exp Rheumatol2001;19,187-190. [PubMed]
 
Shahin, AA, Sabri, YY, Mostafa, HA, et al Pulmonary function tests, high-resolution computerized tomography, α1-antitrypsin measurement, and early detection of pulmonary involvement in patients with systemic sclerosis.Rheumatol Int2001;20,95-100. [PubMed]
 
Akira, M, Inoue, G, Yamamoto, S, et al Non-specific interstitial pneumonia: findings on sequential CT scans of nine patients.Thorax2000;55,854-859. [PubMed]
 
Hunninghake, GW, Lynch, DA, Galvin, JR, et al Radiologic findings are strongly associated with a pathologic diagnosis of usual interstitial pneumonia.Chest2003;124,1215-1223. [PubMed]
 
Desai, SR, Veeraraghavan, S, Hansell, DM, et al CT features of lung disease in patients with systemic sclerosis: comparison with idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia.Radiology2004;232,560-567. [PubMed]
 
Colby, TV, Carrington, CB Interstitial lung disease. Thurlbeck, WM Churg, AM eds.Pathology of the lung1995,589-737 Thieme Medical Publishers. New York, NY:
 
Piper, WN, Helwig, EB Progressive systemic sclerosis; visceral manifestations in generalized scleroderma.AMA Arch Derm1955;72,535-546. [PubMed]
 
Strange, C, Bolster, MB, Roth, MD, et al Bronchoalveolar lavage and response to cyclophosphamide in scleroderma interstitial lung disease.Am J Respir Crit Care Med2008;177,91-98. [PubMed]
 
Steen, VD, Conte, C, Owens, GR, et al Severe restrictive lung disease in systemic sclerosis.Arthritis Rheum1994;37,1283-1289. [PubMed]
 
White, B, Moore, WC, Wigley, FM, et al Cyclophosphamide is associated with pulmonary function and survival benefit in patients with scleroderma and alveolitis.Ann Intern Med2000;132,947-954. [PubMed]
 
Clements, PJ, Goldin, JG, Kleerup, EC, et al Regional differences in bronchoalveolar lavage and thoracic high-resolution computed tomography results in dyspneic patients with systemic sclerosis.Arthritis Rheum2004;50,1909-1917. [PubMed]
 
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