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Original Research: Diffuse Lung Disease |

Predictors of Mortality and Progression in Scleroderma-Associated Interstitial Lung DiseaseScleroderma-Associated Interstitial Lung Disease: A Systematic Review FREE TO VIEW

Tiffany A. Winstone, MD; Deborah Assayag, MD; Pearce G. Wilcox, MD; James V. Dunne, MD; Cameron J. Hague, MD; Jonathon Leipsic, MD; Harold R. Collard, MD, FCCP; Christopher J. Ryerson, MD
Author and Funding Information

From the Department of Medicine (Drs Winstone, Wilcox, Dunne, and Ryerson) and the Department of Radiology (Drs Hague and Leipsic), University of British Columbia, Vancouver, BC, Canada; and the Department of Medicine (Drs Assayag and Collard), University of California San Francisco, San Francisco, CA.

CORRESPONDENCE TO: Christopher J. Ryerson, MD, Department of Medicine, University of British Columbia-St. Paul’s Hospital, 1081 Burrard St, Ward 8B, Vancouver, BC, V6Z 1Y6, Canada; e-mail: chris.ryerson@hli.ubc.ca


FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(2):422-436. doi:10.1378/chest.13-2626
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BACKGROUND:  Interstitial lung disease (ILD) is the leading cause of morbidity and mortality in patients with systemic sclerosis (SSc); however, prognostication of SSc-associated ILD (SSc-ILD) remains challenging. We conducted a systematic review to identify variables that predict mortality and ILD progression in SSc-ILD.

METHODS:  Three databases were searched to identify all studies relating to predictors of mortality or ILD progression in SSc-ILD. Studies were eligible if they were published in English and included ≥ 10 adults with SSc-ILD. Two authors independently reviewed and extracted data from acceptable studies.

RESULTS:  The initial search identified 3,145 unique citations. Twenty-seven studies, including six abstracts, met the inclusion criteria. A total of 1,616 patients with SSc-ILD were included. Patient-specific, ILD-specific, and SSc-specific variables predicted mortality and progression; however, most predictors were identified in only one study. Most studies did not fully account for potential confounders, and none of the studies included a validation cohort. Older age, lower FVC, and lower diffusing capacity of carbon monoxide predicted mortality in more than one study. Male sex, extent of disease on high-resolution CT (HRCT) scan, presence of honeycombing, elevated KL-6 values, and increased alveolar epithelial permeability were identified as predictors of both mortality and ILD progression on unadjusted analysis. The extent of disease on HRCT scan was the only variable that independently predicted both mortality and ILD progression.

CONCLUSIONS:  Mortality and ILD progression were predicted by several patient-specific, ILD-specific, and SSc-specific factors. Additional prospective studies are required to validate these preliminary findings and to identify combinations of variables that accurately predict the prognosis of SSc-ILD.

Figures in this Article

Pulmonary involvement is a prominent feature in systemic sclerosis (SSc) and occurs more frequently in SSc than in any other connective tissue disease.1 The two most frequent types of lung involvement are interstitial lung disease (ILD) and pulmonary arterial hypertension.2 The reported prevalence of ILD in patients with SSc ranges from 25% to 90%, depending on the subtype of SSc and the criteria used to define ILD.3

ILD is the leading cause of mortality in patients with SSc4; however, there is substantial variability in the disease course, and prognostication of SSc-associated ILD (SSc-ILD) is challenging. We conducted a systematic review to identify variables that predict mortality and ILD progression in patients with SSc-ILD. Our objectives were to identify variables or composite scores that could be used to help guide management of SSc-ILD and to identify priorities for future research in the prognostication of these patients.

Data Sources and Search

We performed a systematic search of the literature using the MEDLINE, Embase, and Evidence-Based Medicine Reviews databases. The search was designed to capture all studies related to predictors of mortality and ILD progression in SSc-ILD. Two authors (T. A. W. and C. J. R.) reviewed citations independently using predefined criteria. Searches covered the period from the onset of the database to April 2013. Bibliographies from selected articles and major reviews were screened for additional relevant publications that were not identified by the database search. Details of the search strategy are available in e-Table 1.

Study Selection

Two authors (T. A. W. and C. J. R.) independently evaluated each study for eligibility, sequentially reviewing the title, abstract, and full publication. Studies were eligible if they were published in English and evaluated potential predictors of survival and/or ILD progression in ≥ 10 adults with SSc-ILD. ILD progression was defined by worsening FVC or radiologic findings of fibrosis. Studies focusing on treatment effects were excluded based on our objective of identifying variables that could help guide the management of SSc-ILD. There was no restriction on study design, study quality, or duration of follow-up. Published conference abstracts were included if sufficient information was provided to satisfy the inclusion criteria. Differences were resolved by iteration and consensus.

Data Extraction and Quality Assessment

Data were extracted from selected studies using predefined data-abstraction forms that included information on study design, subject characteristics, and study results as they pertained to the prespecified end points. Study quality was assessed using the Critical Appraisal Skills Program (http://www.casp-uk.net). Quality assessment was based on the method of population sampling, the definitions of SSc and ILD, how the outcome was ascertained, and whether confounders were appropriately identified and accounted for in the statistical analysis.

Data Synthesis and Analysis

We report hazard ratios and/or ORs for predictors of mortality and ILD progression in SSc-ILD. Results were grouped according to predefined categories including patient-specific variables (eg, age and sex), ILD-specific variables (eg, measures of ILD severity or activity), and SSc-specific variables (eg, serum autoantibodies and extrapulmonary features of SSc). We qualitatively summarized findings if similar variables were evaluated in multiple studies; however, a formal meta-analysis of results was not possible because of the heterogeneity of the included studies and the inconsistent methods for reporting study results.

Search Results and Study Characteristics

The initial search identified 3,145 unique citations, and 167 were reviewed in full text. Twenty-seven descriptive studies met the eligibility criteria,531 including six abstracts (Fig 1, Table 1).7,9,21,24,30,31 A total of 1,616 patients with SSc-ILD were included (range, 18-215 patients per study). The duration of follow-up was reported in 21 studies and ranged from 1 to 14 years. There was one prospective cohort study22 and one retrospective case-control study.6 All other full-text publications were either retrospective studies or post hoc analyses of prospectively recruited cohorts, including three post hoc analyses17,23,26 of the Scleroderma Lung Study.32

Figure Jump LinkFigure 1  Study selection. EBM = evidence-based medicine; SSc = systemic sclerosis; SSc-ILD = systemic sclerosis-associated interstitial lung disease.Grahic Jump Location
Table Graphic Jump Location
TABLE 1  ] Study Characteristics

ACR = American College of Rheumatology; CXR = chest radiograph; Dlco = diffusing capacity of the lung for carbon monoxide; dSSc = diffuse systemic sclerosis; DTPA = diethylene thiamine pentacetate clearance; ESLD = end-stage lung disease; HRCT = high-resolution CT; ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis; N/R = not reported; NSIP = nonspecific interstitial pneumonia; PAH = pulmonary arterial hypertension; PFT = pulmonary function test; PH = pulmonary hypertension; RNP = ribonucleoprotein; Sao2 = arterial oxygen saturation; SLS = Scleroderma Lung Study; Spo2 = oxygen saturation; SSc = systemic sclerosis; SSc-ILD = systemic sclerosis-associated interstitial lung disease; UIP = usual interstitial pneumonia.

a 

Mean.

b 

Published in abstract form only.

c 

Median.

d 

SLS post hoc analysis.

e 

Range.

Study quality is summarized in e-Table 2. American College of Rheumatology diagnostic criteria for SSc were used in 17 studies. Eight studies did not specify how the diagnosis of SSc was made.7,9,15,16,21,25,30,31 Variable criteria were used for the diagnosis of ILD, including the findings of chest high-resolution CT (HRCT) scans,10,11,1416,19,21,22,28 chest radiograph,31 lung biopsy,8,13 pulmonary function testing,25 or a combination of these variables.5,6,12,17,18,20,23,24,26,27 Four studies did not specify the criteria used for ILD diagnosis.7,9,29,30

Subject Characteristics

Subject characteristics are summarized in e-Table 3. Mean age ranged from 46 to 55.6 years, 23% of the subjects were men, and 33% had ever smoked in the 15 studies reporting smoking status. The duration of SSc ranged from 1.2 years to 10.5 years in reported studies. ILD severity was variable among studies, as indicated by the wide range of physiologic and radiologic abnormalities.

Predictors of Mortality in SSc-ILD

Fourteen studies evaluated predictors of mortality, including a total of 1,198 patients with SSc-ILD (e-Table 4). Several patient-specific, ILD-specific, and SSc-specific factors predicted mortality in SSc-ILD on unadjusted analysis (Fig 2, Table 2). Age, FVC, diffusing capacity of the lung for carbon monoxide (Dlco), HRCT scan fibrosis severity, BAL neutrophilia, and pulmonary hypertension (echocardiography [n = 1] and undefined criteria [n = 1]) were evaluated in multiple studies and were significant predictors in the majority of studies that evaluated these variables. One of five studies examining sex showed a statistically significant association with unadjusted mortality.15 Change in Dlco over 3 years was a significant predictor of mortality in the single study that evaluated this variable; however, change in FVC over time was not.8 The presence of anticentromere antibodies predicted unadjusted mortality in only one study.21 Compared with limited SSc, diffuse SSc did not predict mortality in the four studies that evaluated this possibility.5,8,11,21

Table Graphic Jump Location
TABLE 2  ] Statistically Significant Predictors of Mortality in SSc-ILD on Unadjusted Analysis

LVEF = left ventricular ejection fraction; Spo2max = Spo2 at maximal exercise. See Table 1 legend for expansion of other abbreviations.

a 

Published in abstract form only.

b 

Hazard ratio > 1.0 indicates improved survival with higher FVC to Dlco ratio.

Seven studies included multivariate models for the prediction of mortality in SSc-ILD (Fig 2, Table 3). The factors adjusted for in each study varied substantially, and details of the multivariate model were not provided in some studies. None of the studies provided a description of model discrimination or calibration. Baseline Dlco was identified as an independent predictor of mortality in four of seven multivariate models.8,14,15,19 An additional study found that change in Dlco after 3 years also predicted mortality after adjustment for baseline pulmonary function and BAL eosinophil levels.8 HRCT scan fibrosis severity and pulmonary hypertension were also identified as independent predictors of mortality in more than one study.14,15 Several additional variables, including increased age, lower oxygen saturation, presence of anti-U11/12 ribonucleoprotein, BAL neutrophil count > 4%, BAL eosinophil count > 2%, and presence of a pericardial effusion, were independent predictors of mortality in only one study.

Figure Jump LinkFigure 2  Statistically significant predictors of mortality in SSc-ILD. Variables listed in bold were associated with mortality on both bivariate and multivariate analysis. *Statistically significant predictors of mortality that were identified in multiple studies. DLCO = diffusing capacity of the lung for carbon monoxide; dSSc = diffuse SSc; DTPA = diethylene thiamine pentacetate clearance; ILD = interstitial lung disease; LVEF = left ventricular ejection fraction; PAH = pulmonary arterial hypertension; PH = pulmonary hypertension; SpO2 = oxygen saturation. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Predictors of ILD Progression in SSc-ILD

Twenty studies, which included a total of 1,524 patients with SSc-ILD, evaluated predictors of ILD progression. Several patient-specific, ILD-specific, and SSc-specific factors were identified as predictors of ILD progression on unadjusted analysis (e-Table 5). HRCT scan fibrosis severity and a shorter duration of SSc were the only significant predictors of ILD progression in more than one study.17,2225

Four studies conducted multivariate analyses that evaluated potential independent predictors of ILD progression16,23,24,26; however significant predictors of progression were identified in only two of these studies (Table 3).16,24 HRCT scan fibrosis severity predicted change in FVC in one study with adjustment for the presence of pulmonary hypertension.24 Abnormal alveolar epithelial permeability (determined by abnormal or fast pulmonary clearance of diethylene thiamine pentacetate) predicted time to FVC decline in the single study that evaluated this variable, including with adjustment for disease severity by HRCT scan or physiologic measures.16

We conducted a rigorous systematic review of the literature to identify variables that predict mortality or ILD progression in patients with SSc-ILD. Several patient-specific, ILD-specific, and SSc-specific variables predicted mortality and ILD progression in SSc-ILD; however, included studies were of variable methodologic quality, and the predictors identified in this review should be considered within the context of these limited data. A minority of studies performed a multivariate analysis, and these studies did not identify a variable or combination of variables that accurately predicted prognosis of SSc-ILD. The paucity of data highlights the challenge of accurately identifying prognostic factors in SSc-ILD and provides justification for additional research.

FVC is the only pulmonary function measurement that has been used as a primary outcome in randomized controlled trials in SSc-ILD.32 Although baseline FVC was an unadjusted predictor of mortality in multiple studies,8,15,21,25 it was not identified as an independent predictor in any of the multivariate analyses. Change in FVC was also not predictive of mortality8; however, this was evaluated in only a single study that was likely underpowered to test this hypothesis. The inconsistent association of FVC and change in FVC with mortality in previous studies suggests that further research is required to validate FVC as an outcome measure in SSc-ILD. The paucity of data limits speculation about the prognostic ability of FVC; however, these findings suggest that factors unrelated to ILD severity are important in determining prognosis in SSc-ILD. Conversely, Dlco was identified in multiple studies as a significant predictor of mortality in both unadjusted and adjusted analyses. The apparently stronger association of Dlco with mortality is likely related to Dlco being a marker for the severity of both ILD and pulmonary hypertension, two major contributors to mortality in SSc.4

The ability of Dlco to capture the severity of both fibrosis and pulmonary hypertension may also account for the lack of independent association between FVC and mortality in SSc-ILD, because FVC represents only one of these contributors to mortality. In addition, confounders may weaken the association of FVC with ILD severity in SSc (eg, extrathoracic restriction from extensive skin disease and respiratory muscle weakness). These findings differ from those of previous studies in idiopathic pulmonary fibrosis (IPF) in which FVC is a more reliable predictor of mortality,3335 likely related to the less frequent association of IPF with pulmonary arterial hypertension. Additional studies are required to confirm the prognostic ability of the FVC to Dlco ratio, a measure that may provide a more accurate estimate of pulmonary arterial hypertension.

Radiologic variables were significant predictors of prognosis in several studies17,22,24; however, the extent of disease on HRCT scan was the only predictor of mortality on adjusted analysis.15 The radiologic and histopathologic features of the usual interstitial pneumonia pattern had borderline prognostic ability in SSc-ILD8,11,13,15; however, only two of these studies reported histopathologic features, and these limited data prohibit definitive conclusions.8,13 These findings differ from those of IPF and other fibrotic ILDs, in which the radiologic and histopathologic features of usual interstitial pneumonia are strong predictors of poor outcome.3638 Although ground-glass opacification is generally considered a more inflammatory and potentially more treatable and reversible process than denser areas of fibrosis, the proportion of ground-glass opacification was not an independent predictor of progression on multivariate analysis in the single study that evaluated this variable.15 Additional research is required to determine the relative prognostic importance of ILD pattern (eg, usual interstitial pneumonia vs nonspecific interstitial pneumonia) and severity (ie, radiologic fibrosis score) in SSc-ILD.

A shorter duration of SSc predicted physiologic worsening in two studies; however, disease duration was not an independent predictor of progression on multivariate analysis.4,23 The apparent rapid progression of SSc-ILD early in disease may be accounted for by survivorship bias. Specifically, patients with rapid progression likely experience frequent early mortality and are not included in the group of patients who survived to have longer-term follow-up. An unadjusted comparison of patients with different disease durations will, therefore, falsely suggest that patients progress more rapidly early during the course of their disease. More rigorous evaluation of this potential association is required, focusing on the within-patient rate of progression in early vs late disease.

Previous studies have not identified a variable or combination of variables that can accurately predict the prognosis of SSc-ILD. Only one study reported some performance characteristics of a prognostic variable, showing that a Dlco < 30% had a sensitivity of 55% and specificity of 83% for death during a variable follow-up period.20 Other studies have not reported model performance, and no studies have been specifically designed to derive a clinical prediction model to estimate prognosis in SSc-ILD. Additional studies are, therefore, required to derive and validate clinical prediction models for SSc-ILD and to test other models that have been developed in similar entities such as IPF.3335 An accurate clinical prediction model could have a significant impact on patient care in SSc-ILD by identifying high-risk individuals who may benefit from closer surveillance, more aggressive therapy with potentially toxic medications, or earlier referral for lung transplant.

The main limitation of this systematic review is that the included studies were of variable methodologic quality. Most predictors were identified in only one study and few studies included rigorous multivariate analyses that attempted to adjust for potential confounders. In addition, there was potential for publication bias; however, this possibility is mitigated by our extensive search of multiple databases, including conference abstracts, as well as our primary interest in positive findings, which are more likely to be published. Finally, the heterogeneity of the included studies prevented pooling of study results, and it is, thus, more challenging to synthesize data from these sources. For example, the variable methods for assessing radiologic ILD severity may account for some of the inconsistencies across studies. Despite these limitations, the data summarized in this review provide a framework for future research in this field and suggest several areas for further investigation. In particular, few studies have evaluated SSc-specific variables (eg, autoantibodies and extrapulmonary manifestations) and these topics require further study.

In summary, we found that several patient-specific, ILD-specific, and SSc-specific features predict worse prognosis in SSc-ILD. Dlco was the most consistent predictor of mortality and may help identify patients with a poor prognosis; however, more rigorous studies are needed to confirm and expand on these preliminary findings. A clearer understanding of how to determine prognosis with variables such as Dlco is required prior to incorporation of these findings into clinical practice. Additional research is specifically required to derive and validate clinical prediction tools in SSc-ILD and to test models developed in other ILD subtypes. Such studies would likely require a coordinated multicenter effort given the relative rarity of SSc-ILD and the need for a large and distinct cohort for appropriate validation. Although such a study would present many challenges, there is a significant unmet clinical need for an accurate clinical prediction model in SSc-ILD, and validation of such a model should be a priority for future studies.

Table Graphic Jump Location
TABLE 3  ] Significant Predictors of Mortality and Progression in SSc-ILD on Multivariate Analysis

CPI = composite physiologic index. See Table 1 and 2 legends for expansion of other abbreviations.

a 

Published in abstract form only.

Author contributions: C. J. R. takes responsibility as the guarantor of the manuscript, including the data and analysis. T. A. W. and C. J. R. contributed to the design of the study, primary analysis and interpretation of the data, production of the initial draft of the manuscript, and approval of the final version and D. A., P. G. W., J. V. D., C. J. H., J. L., and H. R. C. contributed to the analysis and interpretation of the data, drafting of the manuscript, and approval of the final version.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Collard is a consultant for Intermune. Drs Winstone, Assayag, Wilcox, Dunne, Hague, Leipsic, and Ryerson have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Additional information: The e-Tables can be found in the Supplemental Materials section of the online article.

Dlco

diffusing capacity of the lung for carbon monoxide

HRCT

high-resolution CT

ILD

interstitial lung disease

IPF

idiopathic pulmonary fibrosis

SSc

systemic sclerosis

SSc-ILD

systemic sclerosis-associated interstitial lung disease

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Figures

Figure Jump LinkFigure 1  Study selection. EBM = evidence-based medicine; SSc = systemic sclerosis; SSc-ILD = systemic sclerosis-associated interstitial lung disease.Grahic Jump Location
Figure Jump LinkFigure 2  Statistically significant predictors of mortality in SSc-ILD. Variables listed in bold were associated with mortality on both bivariate and multivariate analysis. *Statistically significant predictors of mortality that were identified in multiple studies. DLCO = diffusing capacity of the lung for carbon monoxide; dSSc = diffuse SSc; DTPA = diethylene thiamine pentacetate clearance; ILD = interstitial lung disease; LVEF = left ventricular ejection fraction; PAH = pulmonary arterial hypertension; PH = pulmonary hypertension; SpO2 = oxygen saturation. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1  ] Study Characteristics

ACR = American College of Rheumatology; CXR = chest radiograph; Dlco = diffusing capacity of the lung for carbon monoxide; dSSc = diffuse systemic sclerosis; DTPA = diethylene thiamine pentacetate clearance; ESLD = end-stage lung disease; HRCT = high-resolution CT; ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis; N/R = not reported; NSIP = nonspecific interstitial pneumonia; PAH = pulmonary arterial hypertension; PFT = pulmonary function test; PH = pulmonary hypertension; RNP = ribonucleoprotein; Sao2 = arterial oxygen saturation; SLS = Scleroderma Lung Study; Spo2 = oxygen saturation; SSc = systemic sclerosis; SSc-ILD = systemic sclerosis-associated interstitial lung disease; UIP = usual interstitial pneumonia.

a 

Mean.

b 

Published in abstract form only.

c 

Median.

d 

SLS post hoc analysis.

e 

Range.

Table Graphic Jump Location
TABLE 2  ] Statistically Significant Predictors of Mortality in SSc-ILD on Unadjusted Analysis

LVEF = left ventricular ejection fraction; Spo2max = Spo2 at maximal exercise. See Table 1 legend for expansion of other abbreviations.

a 

Published in abstract form only.

b 

Hazard ratio > 1.0 indicates improved survival with higher FVC to Dlco ratio.

Table Graphic Jump Location
TABLE 3  ] Significant Predictors of Mortality and Progression in SSc-ILD on Multivariate Analysis

CPI = composite physiologic index. See Table 1 and 2 legends for expansion of other abbreviations.

a 

Published in abstract form only.

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