Determining Respiratory
Impairment in Connective
Tissue Disease–Associated
Interstitial Lung Disease
Deborah Assayag, MDCM, FRCPCa,*,
Christopher J. Ryerson, MD, FRCPCb
INTRODUCTION
Connective tissue diseases (CTDs) include several systemic disorders that frequently
result in pulmonary involvement. CTDs can affect the lungs through diseases of the
chest wall, pleura, vasculature, airways, and parenchyma. A large percentage of patients with CTD develop interstitial lung disease (ILD), a group of typically progressive
and irreversible diseases that are characterized by inflammation or fibrosis of the lung
parenchyma.
A diagnosis of ILD in a patient with CTD is associated with significantly increased
morbidity and mortality. Dyspnea, the major symptom of ILD, is an important and
Disclosures: The authors of this manuscript have identified no professional or financial affiliations for themselves or their spouse/partner.
a Department of Medicine, McGill University, 3755 Cote-Ste-Catherine, G-200, Montreal,
Quebec H3T 1E2, Canada; b Department of Medicine, St. Paul’s Hospital, University of British
Columbia, Ward 8B, 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada
* Corresponding author.
E-mail address: Deborah.assayag@mail.mcgill.ca
KEYWORDS
Connective tissue disease Interstitial lung disease Respiratory impairment
Pulmonary function testing Diagnosis
KEY POINTS
ILD is a common complication of CTD that has unique management and a poor prognosis.
Patients with CTD without known pulmonary disease should undergo regular symptom
assessment and physical examination for findings suggestive of ILD or other respiratory
involvement.
A comprehensive evaluation for ILD in patients with high-risk features or suggestive findings should include symptom assessment, physical examination, pulmonary function tests,
and chest imaging (plain chest radiography or high-resolution computed tomography).
Clinical, physiologic, and radiologic findings should be integrated in a multidisciplinary
setting to guide diagnosis and management.
Rheum Dis Clin N Am - (2015) -–-
http://dx.doi.org/10.1016/j.rdc.2014.12.003 rheumatic.theclinics.com
0889-857X/15/$ – see front matter 2015 Elsevier Inc. All rights reserved.
independent predictor of physical function and well-being in patients with
CTD-associated ILD (CTD-ILD).1 ILD is the most common cause of death in patients
with systemic sclerosis (SSc)2 and the inflammatory myopathies.3 In patients with
Sjo ¨ gren syndrome, any respiratory involvement is associated with reduced quality
of life and a four-fold increased risk of death.4 Early recognition of ILD is therefore
important to help guide management and improve prognostication.
This article discusses the approach to the evaluation of respiratory impairment in
patients with CTD. We focus specifically on the initial evaluation of ILD in patients
with CTD, and summarize the evidence that guides the diagnostic work-up of suspected CTD-ILD.
PULMONARY INVOLVEMENT IN CONNECTIVE TISSUE DISEASE
Pulmonary symptoms in patients with CTD are nonspecific and can be secondary to
pulmonary or nonpulmonary causes. Nonpulmonary causes of dyspnea in patients
with CTD include anemia, chest wall disease, and cardiopericardial disease. Pulmonary
symptoms can also be related to treatment of the underlying CTD, including druginduced ILD and opportunistic infections or malignancy that have increased frequency
in patients who are chronically immunosuppressed. These nonpulmonary manifestations of CTD and complications of CTD therapy are important to identify because these
have unique therapies and often clear benefit from appropriate management.
Dyspnea and cough are also common symptoms of the pulmonary manifestations
of CTD, including serositis (eg, pleuritis and associated pleural effusions), vascular disease (eg, thromboembolic disease, pulmonary hypertension), airways disease (eg,
Table 1
Type of respiratory involvement and ILD patterns in CTD
Connective Tissue Disease
Respiratory Involvement
Frequent Non-ILD Diseases Frequent ILD Patterns
Rheumatoid arthritis Pleuritis/pleural effusion
Pulmonary nodules
Bronchiolitis
UIP, NSIP, OP, LIP, DAD
Systemic sclerosis Pulmonary hypertension
Ventilatory restriction from skin
sclerosis
Bronchiolitis
NSIP, UIP, OP
Sjo ¨ gren syndrome Bronchiolitis
Pulmonary amyloidosis
Pulmonary lymphoma
LIP, NSIP, OP, UIP
Inflammatory myopathies Respiratory muscle weakness
Pulmonary hypertension
NSIP, OP, UIP, DAD
Mixed connective tissue disease Pulmonary hypertension
Pleuritis/pleural effusion
Thromboembolic disease
NSIP, OP, UIP
Systemic lupus erythematosus Pleuritis/pleural effusion
Diffuse alveolar hemorrhage
Diaphragmatic dysfunction
(shrinking lung syndrome)
Pulmonary hypertension
Thromboembolic disease
NSIP, DAD, OP
Abbreviations: DAD, diffuse alveolar hemorrhage; LIP, lymphocytic interstitial pneumonia; NSIP,
nonspecific interstitial pneumonia; OP, organizing pneumonia; UIP, usual interstitial pneumonia.
2 Assayag & Ryerson
follicular or obliterative bronchiolitis), and ILD (Table 1). Each CTD is associated with
multiple pulmonary manifestations; however, different CTD subtypes predispose to
specific patterns of pulmonary involvement. ILD is most common in patients with rheumatoid arthritis (RA), SSc, the inflammatory myopathies, Sjo ¨ gren syndrome, and
mixed CTD, but occurs at a lower frequency in systemic lupus erythematosus. Similarly, each CTD predisposes to specific ILD subtypes. Nonspecific interstitial pneumonia is the most common pattern in most CTD-ILDs, but other patterns are
frequently observed, including usual interstitial pneumonia (UIP), organizing pneumonia, diffuse alveolar damage, and lymphocytic interstitial pneumonia.
EVALUATION FOR INTERSTITIAL LUNG DISEASE IN CONNECTIVE TISSUE DISEASE
The extent of evaluation for ILD in patients with CTD should be based on the pretest
likelihood of ILD. In patients with CTD with a high probability of ILD, a comprehensive
initial evaluation should include clinical, physiologic, and radiologic evaluations. This
can often distinguish between ILD and non-ILD pulmonary involvement (Table 2). Patients with a low probability of ILD should still undergo regular screening including
symptom assessment and physical examination, but may not require detailed physiologic or radiologic studies.
Symptom Assessment and Physical Examination
Patients with CTD should routinely be questioned regarding the presence of dyspnea,
because it is typically the first and predominant symptom of ILD. Dyspnea is a significant predictor of physical function, fatigue, psychological well-being, and global functioning in CTD-ILD, even after adjusting for the severity of lung involvement.1 Dyspnea
can be quantified using detailed questionnaires5; however, these questionnaires are
typically time consuming and none are validated in CTD-ILD. In a clinical setting,
Table 2
Common findings of respiratory involvement in CTD
ILD
Non-ILD Respiratory Disease
Airways Disease Pleural Disease
Pulmonary
Hypertension
Symptoms and
physical
examination
Dyspnea
Crackles
Dyspnea
Wheezing
Dyspnea
Pain
Decreased breath
sounds
Dyspnea
Loud P2
Right heart
insufficiency
Chest imaging Decreased lung
volumes
Reticulation
Traction
bronchiectasis
Ground glass
opacities
Honeycombing
Air trapping
Hyperinflation
Airway wall
thickening
Centrilobular
nodularity
Normal
parenchyma
Effusion
Pleural thickening
Atelectasis
Enlarged
pulmonary
arteries
Dilated right
ventricle
Mosaic perfusion
Centrilobular
ground glass
nodules
PFT Restrictive pattern
Low DLco
Obstructive or
mixed pattern
Normal or low
DLco
Restrictive pattern
Normal DLco
Low DLco
Normal flow rates
and lung
volumes
Abbreviations: DLco, diffusion capacity of the lung for carbon monoxide; PFT, pulmonary function
test.
Respiratory Impairment in Connective Tissue Disease 3
dyspnea and associated functional limitation can be quickly assessed and quantified
using the Modified Medical Research Council scale (ranging from 0 to 4, where 0 is
breathless on strenuous exercise, and 4 is too breathless to leave the house).6 The
Modified Medical Research Council scale, initially developed and validated in patients
with chronic obstructive pulmonary disease, is associated with activity limitation, anxiety, and depression in ILD.7,8 The Modified Medical Research Council scale is not
validated in CTD-ILD, but is likely an appropriate screening tool that can be used as
a baseline measurement to identify worsening dyspnea and function over time. Other
symptoms commonly reported in patients with CTD-ILD include cough, sputum production, and fatigue.9 Patients that develop these nonspecific symptoms without a
clear cause should undergo a detailed evaluation for CTD-ILD.
All patients with CTD should undergo a thorough physical examination for features
of ILD at baseline and this should be repeated at regular follow-up visits. The most
common examination feature of ILD is crackles on auscultation. Auscultatory crackles
can precede the development of clinically apparent symptoms10 and should prompt
further investigations when identified.11 Tachypnea, hypoxemia, and reduced chest
wall expansion can be observed, but are more typical of advanced ILD. Digital clubbing can occur in CTD-ILD, but is less common than in idiopathic pulmonary fibrosis
(IPF).12,13
Pulmonary Function Tests
Pulmonary function tests (PFTs) are used to screen patients with CTD for ILD, to support a new diagnosis in patients with suspected CTD-ILD, or to monitor disease activity and progression in patients with an established CTD-ILD diagnosis. PFTs should be
performed in all patients with unexplained symptoms or physical examination findings
that are consistent with ILD. However, PFTs can be normal in early ILD, and thus the
presence of normal physiology does not rule out mild ILD in patients with a high pretest
probability. A normal PFT can also indicate the presence of ILD if previous measurements showed supranormal values, illustrating the importance of comparison with
previous tests.
Reduced diffusion capacity of the lung for carbon monoxide (DLco) is often the first
physiologic manifestation of ILD,14 but this is not specific for ILD and pulmonary
vascular disease can present with similar findings. More advanced ILD is characterized by a restrictive pattern with proportionately reduced flow rates (forced vital capacity [FVC] and forced expiratory volume in 1 second), reduced lung volumes (total
lung capacity), and reduced DLco.14,15 Once a diagnosis of ILD is established,
repeated testing at regular intervals should be performed to quantify the severity of
the impairment, assess for disease progression, and monitor response to treatment.
A 5% to 10% decline in the FVC is considered clinically important in IPF16 and this
is likely a reasonable threshold to indicate worsening ILD in patients with CTD-ILD.
Functional Assessment
Functional assessment is most often performed in patients with ILD by measuring the
six-minute-walk distance (6MWD) or less commonly using a cardiopulmonary exercise test. The 6MWD is a standardized tool that provides a simple measure of functional capacity and may add prognostic information beyond standard PFTs.17 The
6MWD correlates with ILD severity (PFT measurements) and quality of life in
SSc,18,19 and both the baseline and change in 6MWD are independent predictors of
mortality in IPF.20 The major limitation of the 6MWD in CTD-ILD is the lack of organ
specificity, because abnormalities can also be caused by cardiac disease, pulmonary
hypertension, and musculoskeletal disease.18 In addition, patients with significant
4 Assayag & Ryerson
peripheral vascular involvement (eg, Raynaud phenomenon) often require pulse oximetry via a forehead or earlobe saturation probe and this equipment can be unreliable
and is not universally available. Despite its limitations in identifying ILD in patients with
CTD, the 6MWD can be used to monitor disease progression and provide prognostic
information in patients with established CTD-ILD.
Cardiopulmonary exercise testing provides a global assessment of the systems
involved in exercise and is typically performed in the evaluation of undiagnosed dyspnea. Cardiopulmonary exercise testing can be useful in CTD-ILD to determine if the
dyspnea is primarily caused by ILD (ie, ventilatory limitation to exercise with associated
hypoxemia),21 pulmonary vascular disease, cardiac disease, or some other etiology.22,23
Chest Imaging
Plain chest radiography lacks sensitivity and specificity for ILD in a screening setting24
but may still be useful in the initial evaluation of pulmonary symptoms in CTD because
it can identify ILD and other CTD-associated pulmonary manifestations (eg, pleural effusions or pneumonia). High-resolution computed tomography (HRCT) can be used to
reliably diagnose or exclude ILD; however, it is costly and associated with nontrivial
radiation exposure that increases the risk of malignancy.25 HRCT is thus not routinely
used as a serial screening test in asymptomatic patients with CTD. HRCT of the chest
is essential in patients with suspected ILD, and is more sensitive than plain radiography in diagnosing ILD.24 HRCT can also guide management by suggesting the
ILD subtype and providing prognostic information. A radiologic pattern of UIP (subpleural, lower lung–predominant reticulation, traction bronchiectasis, and honeycombing with an absence of ground glass or nodularity) is highly specific for
histopathologic UIP in patients with RA,26 and is associated with a poor prognosis.27
The extent of fibrosis on HRCT also suggests a poor prognosis in multiple CTD-ILD
subtypes,28–30 and can provide further evidence of stability or worsening in patients
with unclear evidence of progression.
Bronchoscopy and Surgical Lung Biopsy
Bronchoalveolar lavage has no clear role in establishing the diagnosis of CTD-ILD,31
although it can be helpful to exclude infection, diffuse alveolar hemorrhage, and other
causes of ILD in patients with an unclear diagnosis. Transbronchial biopsy has low
sensitivity and specificity for diagnosing CTD-ILD and should be discouraged outside
of specific situations (eg, patients with suspected sarcoidosis).
Surgical lung biopsy permits a more detailed evaluation of the lung histopathology
and is able to identify specific CTD-ILD subtypes. Surgical lung biopsy is particularly
useful in cases where the diagnosis of CTD is not yet established, or if a competing
diagnosis is possible. Some histopathologic features make the diagnosis of CTDILD more likely, including the presence of lymphoid aggregates, interstitial fibrosis
with overlapping patterns, bronchiolocentricity, lack of well-formed granulomas, and
the presence of rheumatoid nodules.32 Lung biopsies with any of these findings should
prompt a detailed assessment for an occult CTD. Surgical lung biopsy is generally not
performed in patients with established CTD given the significant risk of complications
and the current lack of evidence that the histopathologic pattern should influence
management of CTD-ILD.
INTEGRATING DATA TO GUIDE THERAPY: MULTIDISCIPLINARY EVALUATION
The data described previously should be synthesized to guide management. Central
to this process is a multidisciplinary team that includes a rheumatologist, respirologist,
Respiratory Impairment in Connective Tissue Disease 5
thoracic radiologist, and lung pathologist. This team is critical to determining the relative benefits and risks of therapy, based on the burden of disease, risk of progression,
expected response to therapy, and likelihood of adverse effects.
FOLLOW-UP EVALUATION
There is no evidence to guide how often patients with CTD should be screened for ILD
or how often patients with CTD with existing ILD should be monitored for disease progression. Patients with CTD without known ILD should have at least annual clinical
assessment for development of ILD, usually consisting of symptom assessment and
physical examination, with supplemental information provided by physiologic, functional, and radiologic evaluation in cases with suggestive findings or high-risk features.
Patients with CTD with existing ILD are typically evaluated every 6 months, with more
or less frequent evaluation depending on the overall prognosis and risk of ILD
progression.
Older age, male sex, and severity of lung function impairment are consistently associated with increased mortality in RA-ILD and SSc-ILD,33,34 and these variables are
included in a clinical prediction model that accurately predicts mortality in patients
with CTD-ILD.35 Longitudinal data (eg, decline in FVC, worsening HRCT fibrosis)
can provide additional prognostic information. As described previously, these data
can be synthesized in a multidisciplinary setting to identify patients with progressive
disease who may require frequent follow-up and more aggressive therapy.
DISCUSSION
The optimal method for determining respiratory impairment in patients with CTD is unknownbecauseofanabsenceofhigh-quality datainthis population.Recommendations
for the evaluation and management of CTD-ILD are thus primarily based on expert
opinion that is derived from clinical experience or extrapolation from evidence in other
ILDs. We propose the algorithm presented in Fig. 1 to guide the evaluation of possible
ILD in patients with CTD; however, there remain several unanswered questions.
Can We Reliably Predict Which Patients with connective Tissue Disease Will Develop
Interstitial Lung Disease?
It is difficult to predict which patients with CTD will develop ILD and which of these will
progress to clinically significant disease that requires therapy. Some asymptomatic
patients have abnormal pulmonary function and early ILD,36 suggesting that there
may be a role for ILD screening in asymptomatic individuals. This could be performed
using spirometry or DLco measurements. However, these are generally limited and
costly resources that are not ideal for regular screening in a large population. Other
strategies are therefore necessary to further narrow the population that requires targeted screening.
Several risk factors for ILD have been identified in patients with CTD; however, the
clinical utility of these is unknown. Demographic predictors of ILD in patients with CTD
include older age and male sex. The presence of certain autoantibodies is also associated with increased risk of ILD (eg, anticyclic citrullinated peptides in RA and Scl-70
in SSc).37,38 Additional biomarkers that are associated with the presence or severity of
CTD-ILD include Krebs von den lungen-6,33,39 CC chemokine ligand 18,40 and surfactant protein D.41 Despite these associations, there is currently no evidence that patients with high-risk clinical features should undergo more rigorous serial screening
for ILD. Additional studies are therefore needed to validate predictors of ILD onset
and to determine the role for these predictors in clinical practice.
6 Assayag & Ryerson
What Changes Should Prompt Escalation of Therapy in Connective Tissue Disease–
Interstitial Lung Disease?
ILD progression can be measured by symptoms, physiology, or radiology. However, it
is not clear what constitutes a minimum clinically important difference (MCID) for each
of these domains. There is no reliable threshold for a clinically meaningful change in
Fig. 1. Proposed algorithm for the evaluation of ILD in patients with CTD. a High-risk features can include demographic features (eg, increased age, male sex), CTD subtype (eg,
diffuse cutaneous SSc), autoantibody status (positive anti–Scl-70 antibody), and others.
CXR, plain chest radiography.
Respiratory Impairment in Connective Tissue Disease 7
subjectively reported dyspnea. The MCID has been reported in other populations for
several standardized dyspnea questionnaires. However, these questionnaires are not
typically used in a clinical setting, have not been validated in CTD-ILD, and their
MCIDs in CTD-ILD are unknown. Similarly, the MCID for physiologic change is uncertain, although there are data from other ILD populations that can likely be extrapolated
to CTD-ILD. In patients with IPF, an absolute decline of 5% to 10% in the FVC is
considered clinically significant.16 This magnitude of decline is likely also meaningful
in CTD-ILD. However, CTD-ILD often progresses less rapidly than IPF, and thus fewer
patients with CTD-ILD meet this relatively high threshold of change during a single
follow-up interval. It is unknown whether smaller changes in FVC are meaningful in
CTD-ILD, and particularly if serial small declines in FVC are significant. There are no
data on the MCID for radiologic findings and, similar to dyspnea, these changes are
typically reported in a subjective manner in clinical practice that prevents a quantitative comparison among serial studies.
Patients can have progression in any one or in all three of these domains, and it is
challenging to confidently identify progression in individuals with borderline or inconsistent findings. Patients with progression in at least two of these three domains are
generally considered to have had ILD progression, although there are some exceptions
to this rule (eg, respiratory muscle weakness can worsen both dyspnea and physiology
in the absence of ILD progression). Patients with borderline changes in all domains, and
patients with change in only one domain, have uncertain findings that may prompt
short-interval reassessment or further evaluation with functional assessment.
Should the Approach to Management Be the Same for All Connective Tissue Disease–
Interstitial Lung Disease Subtypes?
CTDs are associated with several underlying ILD subtypes, most often including
nonspecific interstitial pneumonia, UIP, and organizing pneumonia. The ILD subtype
provides important prognostic information, specifically with UIP having worse prognosis than non-UIP patterns in RA-ILD and some other CTD-ILD subtypes.27,42 However, it is unclear whether the approach to management should also differ among
these subtypes.
Most CTD-ILD subtypes are managed with systemic immunosuppressive medications, regardless of the underlying ILD pattern. Recent studies have shown lack of
benefit and significant harm from immunosuppressive medications in IPF (ie, idiopathic UIP),43 but it is unknown whether these therapies have similar deleterious effects in UIP associated with CTD. Future studies of treatment in CTD-ILD should
stratify patients according to their ILD pattern (ie, UIP vs non-UIP) to determine
whether treatment strategies should differ among ILD subtypes, and specifically
whether immunosuppressive therapies are beneficial in CTD-associated UIP. The
role of histopathologic evaluation in CTD-ILD would increase if therapeutic responses
were found to differ according to ILD subtype.
SUMMARY
ILD and other forms of respiratory involvement are common in CTDs. The evaluation
for lung disease in patients with CTD at high risk of ILD should be comprehensive and
include at least annual clinical, physiologic, and radiologic assessment. Patients with a
low pretest probability of ILD may require only intermittent screening with a symptom
assessment and physical examination. The data gathered during the evaluation for
CTD-ILD should be integrated using a multidisciplinary approach to determine the
most appropriate management for each patient. Additional studies are needed to
8 Assayag & Ryerson
clarify how and how often patients with CTD should be screened for ILD, whether there
are features that can reliably identify high-risk patients, what monitoring should be
performed in patients with established ILD, and how findings should be integrated
to guide management.
REFERENCES
1. Swigris JJ, Yorke J, Sprunger DB, et al. Assessing dyspnea and its impact on patients with connective tissue disease-related interstitial lung disease. Respir Med
2010;104:1350–5.
2. Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-
2002. Ann Rheum Dis 2007;66:940–4.
3. Cottin V, Thivolet-Bejui F, Reynaud-Gaubert M, et al. Interstitial lung disease in
amyopathic dermatomyositis, dermatomyositis and polymyositis. Eur Respir J
2003;22:245–50.
4. Palm O, Garen T, Berge Enger T, et al. Clinical pulmonary involvement in primary
Sjogren’s syndrome: prevalence, quality of life and mortality: a retrospective
study based on registry data. Rheumatology (Oxford) 2013;52:173–9.
5. Parshall MB, Schwartzstein RM, Adams L, et al. An official American Thoracic Society statement: update on the mechanisms, assessment, and management of
dyspnea. Am J Respir Crit Care Med 2012;185:435–52.
6. Papiris SA, Daniil ZD, Malagari K, et al. The Medical Research Council dyspnea
scale in the estimation of disease severity in idiopathic pulmonary fibrosis. Respir
Med 2005;99:755–61.
7. Kozu R, Jenkins S, Senjyu H. Evaluation of activity limitation in patients with idiopathic pulmonary fibrosis grouped according to medical research council dyspnea grade. Arch Phys Med Rehabil 2014;95:950–5.
8. Holland AE, Fiore JF Jr, Bell EC, et al. Dyspnoea and comorbidity contribute to
anxiety and depression in interstitial lung disease. Respirology 2014;9:1215–21.
9. Pan L, Liu Y, Sun R, et al.Comparison of characteristics of connective tissue diseaseassociated interstitial lung diseases, undifferentiated connective tissue diseaseassociated interstitial lung diseases, and idiopathic pulmonary fibrosis in Chinese
Han population: a retrospective study. Clin Dev Immunol 2013;2013:121578.
10. Gochuico Br, Avila NA, Chow CK, et al. Progressive preclinical interstitial lung disease in rheumatoid arthritis. Arch Intern Med 2008;168:159–66.
11. Cordier JF, Cottin V. Neglected evidence in idiopathic pulmonary fibrosis: from
history to earlier diagnosis. Eur Respir J 2013;42:916–23.
12. Rajasekaran A, Shovlin D, Saravanan V, et al. Interstitial lung disease in patients
with rheumatoid arthritis: comparison with cryptogenic fibrosing alveolitis over 5
years. J Rheumatol 2006;33:1250–3.
13. Ishioka S, Nakamura K, Maeda A, et al. Clinical evaluation of idiopathic interstitial
pneumonia and interstitial pneumonia associated with collagen vascular disease
using logistic regression analysis. Intern Med 2000;39:213–9.
14. Nogueira CR, Na ´polis LM, Bagatin E, et al. Lung diffusing capacity relates better
to short-term progression on HRCT abnormalities than spirometry in mild asbestosis. Am J Ind Med 2011;54:185–93.
15. Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function
tests. Eur Respir J 2005;26:948–68.
16. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement:
idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183:788–824.
Respiratory Impairment in Connective Tissue Disease 9
17. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit
Care Med 2002;166:111–7.
18. Deuschle K, Weinert K, Becker MO, et al. Six-minute walk distance as a marker
for disability and complaints in patients with systemic sclerosis. Clin Exp Rheumatol 2011;29:S53–9.
19. Schoindre Y, Meune C, Dinh-Xuan AT, et al. Lack of specificity of the 6-minute
walk test as an outcome measure for patients with systemic sclerosis.
J Rheumatol 2009;36:1481–5.
20. du Bois RM, Albera C, Bradford WZ, et al. 6-Minute walk distance is an independent predictor of mortality in patients with idiopathic pulmonary fibrosis. Eur Respir J 2014;43:1421–9.
21. Ross RM. ATS/ACCP statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med 2003;167:211–77.
22. Dumitrescu D, Oudiz RJ, Karpouzas G, et al. Developing pulmonary vasculopathy in systemic sclerosis, detected with non-invasive cardiopulmonary exercise
testing. PLoS One 2010;5:e14293.
23. Armstrong HF, Thirapatarapong W, Dussault NE, et al. Distinguishing pulmonary
hypertension in interstitial lung disease by ventilation and perfusion defects
measured by cardiopulmonary exercise testing. Respiration 2013;86:407–13.
24. Mathieson JR, Mayo JR, Staples CA, et al. Chronic diffuse infiltrative lung disease: comparison of diagnostic accuracy of CT and chest radiography. Radiology 1989;171:111–6.
25. van der Bruggen-Bogaarts BA, Broerse JJ, Lammers JW, et al. Radiation exposure in standard and high-resolution chest CT scans. Chest 1995;107:113–5.
26. Assayag D, Elicker BM, Urbania TH, et al. Rheumatoid arthritis-associated interstitial lung disease: radiologic identification of usual interstitial pneumonia
pattern. Radiology 2014;270:583–8.
27. Kim EJ, Elicker BM, Maldonado F, et al. Usual interstitial pneumonia in rheumatoid
arthritis-associated interstitial lung disease. Eur Respir J 2010;35:1322–8.
28. Kocheril SV, Appleton BE, Somers EC, et al. Comparison of disease progression
and mortality of connective tissue disease-related interstitial lung disease and
idiopathic interstitial pneumonia. Arthritis Care Res 2005;53:549–57.
29. Walsh SL, Sverzellati N, Devaraj A, et al. Connective tissue disease related
fibrotic lung disease: high resolution computed tomographic and pulmonary
function indices as prognostic determinants. Thorax 2014;69:216–22.
30. Goh NS, Desai SR, Veeraraghavan S, et al. Interstitial lung disease in systemic
sclerosis: a simple staging system. Am J Respir Crit Care Med 2008;177:
1248–54.
31. Kowal-Bielecka O, Kowal K, Chyczewska E. Utility of bronchoalveolar lavage in
evaluation of patients with connective tissue diseases. Clin Chest Med 2010;31:
423–31.
32. Urisman A, Jones KD. Pulmonary pathology in connective tissue disease. Semin
Respir Crit Care Med 2014;35:201–12.
33. Winstone TA, Assayag D, Wilcox PG, et al. Predictors of mortality and progression
in scleroderma-associated interstitial lung disease: a systematic review. Chest
2014;146:422–36.
34. Assayag D, Lubin M, Lee JS, et al. Predictors of mortality in rheumatoid arthritisrelated interstitial lung disease. Respirology 2014;19:493–500.
35. Ryerson CJ, Vittinghoff E, Ley B, et al. Predicting survival across chronic interstitial lung disease: the ILD-gap model. Chest 2014;145:723–8.
10 Assayag & Ryerson
36. Chen J, Shi Y, Wang X, et al. Asymptomatic preclinical rheumatoid arthritisassociated interstitial lung disease. Clin Dev Immunol 2013;2013:406927.
37. Kelly CA, Saravanan V, Nisar M, et al. Rheumatoid arthritis-related interstitial lung
disease: associations, prognostic factors and physiological and radiological
characteristics. A large multicentre UK study. Rheumatology (Oxford) 2014;53:
1676–82.
38. Cepeda EJ, Reveille JD. Autoantibodies in systemic sclerosis and fibrosing syndromes: clinical indications and relevance. Curr Opin Rheumatol 2004;16:
723–32.
39. Arai S, Kurasawa K, Maezawa R, et al. Marked increase in serum KL-6 and surfactant protein D levels during the first 4 weeks after treatment predicts poor
prognosis in patients with active interstitial pneumonia associated with polymyositis/dermatomyositis. Mod Rheumatol 2013;23:872–83.
40. Tiev KP, Hua-Huy T, Kettaneh A, et al. Serum CC chemokine ligand-18 predicts
lung disease worsening in systemic sclerosis. Eur Respir J 2011;38:1355–60.
41. Elhaj M, Charles J, Pedroza C, et al. Can serum surfactant protein D or CCchemokine ligand 18 predict outcome of interstitial lung disease in patients
with early systemic sclerosis? J Rheumatol 2013;40:1114–20.
42. Tsuchiya Y, Takayanagi N, Sugiura H, et al. Lung diseases directly associated
with rheumatoid arthritis and their relationship to outcome. Eur Respir J 2011;
37:1411–7.
43. Idiopathic Pulmonary Fibrosis Clinical Research Network, Raghu G, Anstrom KJ,
et al. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis.
N Engl J Med 2012;366:1968–77.
Respiratory Impairment in Connective Tissue Disease 11