Imaging of Pulmonary
Involvement in Rheumatic
Disease
Arjun Nair, MD, MRCP, FRCRa, Simon L.F. Walsh, MD, MRCP, FFRRCSIb,
Sujal R. Desai, MD, FRCP, FRCRc,*
INTRODUCTION
The rheumatic diseases are a heterogeneous group of inflammatory disorders characterized principally by joint disease, but also, not infrequently, multiorgan dysfunction.
Lung disease is common in connective tissue diseases (CTDs) and is an important
Disclosure Statement: All authors have nothing to disclose.
a Department of Radiology, Guy’s and St Thomas’ NHS Foundation Trust, Great Maze Pond,
London SE1 9RT, UK; b Department of Radiology, King’s College Hospital, Denmark Hill, London SE5 9RS, UK; c Department of Radiology, King’s College Hospital, Denmark Hill, London
SE5 9RS, UK
* Corresponding author. Department of Radiology, King’s College Hospital, Denmark Hill,
London SE5 9RS, UK.
E-mail address: sujal.desai@nhs.net
KEYWORDS
Computed tomography Imaging Connective tissue diseases
Interstitial lung diseases
KEY POINTS
There is a high degree of overlap between the pulmonary manifestations of the various
connective tissue diseases (CTDs), particularly with respect to interstitial lung disease
(ILD) patterns.
Nonspecific interstitial pneumonia (NSIP) is the most common ILD pattern in all CTDs
apart from rheumatoid arthritis, where usual interstitial pneumonia (UIP) is the most
frequent pattern.
Distinguishing between acute exacerbation, infection, drug toxicity, or pulmonary hemorrhage as the cause for acute deterioration in CTD-associated lung disease is impossible
on high-resolution computed tomography (HRCT) appearances alone, but requires the
integration of clinical and serologic data with the evolution of appearances on plain
radiograph.
A role for HRCT in staging disease and aiding prognostication has recently been shown,
with traction bronchiectasis and extent of honeycombing both associated with increased
mortality in CTD-ILD.
Rheum Dis Clin N Am 41 (2015) 167–196
http://dx.doi.org/10.1016/j.rdc.2014.12.001 rheumatic.theclinics.com
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cause of both morbidity and mortality. The CTDs (sometimes termed collagen
vascular diseases) include rheumatoid arthritis (RA), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), polymyositis/dermatomyositis (PM/DM), primary
Sjo ¨ gren syndrome (SS), mixed connective tissue disease (MCTD), and undifferentiated connective tissue disease (UCTD). Radiologic assessment has a definite role in
the management of CTD-associated pulmonary disease. In this regard, plain chest
radiography and high-resolution computed tomography (HRCT) are the principal tests.
The indications for imaging will vary, but a typical scenario for the radiologist is to
establish whether lung disease is present and, if so, to characterize its nature and
extent. In cases in which a histospecific radiologic diagnosis of lung disease cannot
be provided, HRCT may be the best guide to the optimal site for surgical biopsy.
More recently, there has been interest in the utility of HRCT to assess longitudinal
behavior and prognosis.
In the present article, a general discussion of radiologic features is followed by a
description of the appearances in individual CTDs. We then consider the pulmonary
complications of CTDs on imaging, the use of imaging in prognostication, and the
role of multidisciplinary evaluation. Given the acknowledged limitations of plain chest
radiography in characterizing patterns of diffuse lung disease in general1,2 and in CTDassociated lung disorders,3–5 the article focuses primarily on HRCT appearances. Pulmonary involvement also occurs in other rheumatic disorders, such as vasculitides
and inflammatory disorders, including spondyloarthropathy, Behc ¸ et disease, and relapsing polychondritis, but the thoracic radiologic manifestations of these conditions
are distinct from the CTDs listed previously and are outside the scope of this article.
GENERAL RADIOLOGIC AND PATHOLOGIC CONSIDERATIONS
The CTDs can affect the pulmonary and extrapulmonary components of the thorax to
varying degrees. The main manifestations in the pulmonary interstitium, airspaces, airways, pulmonary vasculature, pleura, pericardium, heart, mediastinum, and thoracic
musculature are given in Table 1. Among the thoracic manifestations of the CTDs,
the interstitial diseases are perhaps the most intriguing and widely studied. In this regard, an important consideration is that almost all the patterns of idiopathic interstitial
pneumonias (IIPs) (but, importantly, not their prevalences), are mirrored in CTD-related
interstitial lung disease (ILD). The radiologic and histopathologic features of the IIPs
have been well documented (Table 2).6–8 Indeed, it may be argued that the true utility
Table 1
Thoracic manifestations of the connective tissue disorders
Compartment Manifestation
Airways Bronchial wall thickening, bronchiectasis, obliterative bronchiolitis
Lung parenchyma Interstitial lung disease: interstitial pneumonias (see Table 2)
Airspace disease: diffuse alveolar damage, pulmonary hemorrhage
Necrobiotic nodules, infection, malignancy
Pulmonary vasculature Acute/chronic pulmonary thromboembolism, pulmonary
hypertension
Pleura/pericardium Pleural/pericardial thickening, nodularity or effusion,
pneumothorax
Mediastinum Esophageal dilatation/dysfunction, enlarged mediastinal lymph
nodes
Thoracic musculature Muscle dysfunction leading to ventilatory impairment
168 Nair et al
Table 2
High-resolution computed tomography (HRCT) and histopathological characteristics of the interstitial pneumonias encountered in connective tissue diseases
Pattern HRCT Features Histopathologic Features Remarks
Usual interstitial
pneumonia (UIP)
Subpleural basal predominant
reticulation
Honeycombing traction
bronchiectasis
GGO usually inconspicuous
Marked fibrosis, architectural distortion
Subpleural/paraseptal predominant
honeycombing
Patchy involvement
Fibroblastic foci
Only mild interstitial inflammatory infiltrate
Criteria for definite, possible, and inconsistent
with UIP (on both HRCT and pathology) and
probable UIP (on pathology only) have been
defined
Nonspecific
interstitial
pneumonia (NSIP)
Bilateral GGO
Some basal and subpleural
predominance
Fine reticulation/irregular linear
opacities
Traction bronchiectasis/
bronchiolectasis
Honeycombing sparse/absent
Varying amounts of interstitial inflammation
and fibrosis
Uniform appearance
Honeycombing may become more prominent
with progression
Katzenstein grades of pure cellular (grade I),
mixed cellular and fibrotic (grade II), and
fibrotic (grade III) recognized
histopathologically
Organizing
pneumonia (OP)
Patchy, multifocal consolidation
Subpleural or peribronchial
distribution
May be associated with GGO,
perilobular pattern
Centrilobular nodules or
masses
Intraluminal plugs of inflammatory debris:
buds of granulation tissue and Masson bodies
(whorls of fibroblasts and myofibroblasts in a
connective matrix)
Predominantly within the alveolar ducts and
surrounding alveoli
Mild interstitial inflammation
May coexist with an NSIP pattern
Lymphocytic
interstitial
pneumonia (LIP)
Ill-defined GGO and centrilobular nodules
Peribronchial/interlobular
septal thickening
Thin-walled perivascular cysts
Lymph node enlargement
Diffuse interstitial infiltration: mostly T-lymphocytes, plasma cells, and macrophages
Predominantly alveolar septal distribution
Frequent bronchial mucosa-associated
lymphoid tissue hyperplasia
Can be regarded as interstitial-predominant
variant of diffuse pulmonary lymphoid
hyperplasia
Follicular bronchiolitis is another form of
predominantly peribronchial/
peribronchiolar lymphocytic infiltrate seen
in rheumatoid arthritis
Abbreviation: GGO, ground-glass opacity.
Adapted from Refs.6–8
Pulmonary Involvement in Rheumatic Disease 169
of HRCT is not in predicting the underlying CTD (because this invariably requires the
integration of clinical, serologic, and radiologic data), but in identifying the likely
pattern of interstitial pneumonia, which not only has prognostic implications but
also may influence the decision to biopsy. In this regard, it is important to stress
that overlapping HRCT appearances (particularly for usual interstitial pneumonia
[UIP] and nonspecific interstitial pneumonia [NSIP]9–11) are not uncommon; predominant ground-glass opacification is the important feature of NSIP,9,12 whereas the cardinal findings in UIP are subpleural, basal reticulation with honeycombing.7,13,14 In the
absence of honeycombing, attempting to make a radiologic diagnosis of “possible”
UIP rather than NSIP relies on the observation of less extensive ground-glass attenuation compared with coarse reticulation with a subpleural, basal predominance, and
the absence of the other features inconsistent with UIP.7 However, the use of such
an interpretation algorithm can still result in misdiagnosis of biopsy-proven NSIP as
UIP on HRCT, and vice-versa.11,15 It is also worth stating that inter-reader agreement
for honeycombing is, at best, fair to moderate16–18 and that differentiating honeycombing from peripheral traction bronchiolectasis, on transaxial interspaced HRCT
images, is not straightforward.16,19
In addition to what has already been stated previously, some general comments
about the imaging of CTD-related ILD also can be made. First, with the notable
exception of RA (in which a UIP pattern is most prevalent20,21), NSIP is the dominant
pattern of CTD-related ILD.22,23 Second, the presence of either mixed HRCT patterns (eg, features of lung fibrosis together with consolidation) or the coexistence
of an ILD with, say, signs of pleural or airways disease, should alert the radiologist
to the possibility of an underlying CTD, particularly when extrapulmonary abnormalities are present.24 Third, the notion that ground-glass opacification on HRCT denotes potentially reversible or treatable disease25,26 is no longer considered true
for the idiopathic interstitial pneumonias27–29 or the CTD-related ILDs.30,31
Ground-glass opacification may indicate fine fibrosis,32 particularly when there is
traction bronchiectasis/bronchiolectasis. The obvious message is that the mere
presence of ground-glass attenuation should not be used as justification for potentially toxic therapy.
IMAGING OF INDIVIDUAL CONNECTIVE TISSUE DISEASES
Rheumatoid Arthritis
The pulmonary and pleural manifestations of RA have continued to receive attention
ever since the early report from 1948 by Ellman and Ball.33 The true prevalence of
RA-associated thoracic disease is difficult to predict, chiefly because of differences
in the populations studied and discordance between HRCT findings and symptoms.
With respect to RA-related ILD, Gabbay and colleagues3 reported that, in a population of 36 patients with joint manifestations of recent (2 years) onset, one-third had
HRCT manifestations of ILD, but there was clinically significant disease in only
14%. However, when clinically significant ILD was defined as RA-associated ILD
that contributes to death, Olson and colleagues34 found that the prevalence of
such ILD was closer to 7% in women and just less than 10% in men. The lifetime
risk of developing ILD in patients with RA has been estimated at 7.7%.35 In another
study of patients with RA having one or more of symptomatic ILD, abnormal pulmonary function tests, or chest radiographs, Biederer and colleagues36 found some
form of HRCT abnormality in 92% of patients. As such, the prevalence of HRCT abnormalities is undeniably greater than the proportion with clinically relevant pulmonary disease.
170 Nair et al
Airway disease
In patients with RA, airway abnormalities are common. Bronchiectasis, with or without
bronchial wall thickening, may be seen in up to 30% of patients (Fig. 1).36–41 Peripheral
branching nodular opacities (the tree-in-bud pattern) and heterogeneity in lung density
(the so-called mosaic attenuation pattern), both indicating involvement of small airways, also are relatively frequently seen on HRCT.20,40,42–45 In one study of 50 patients
with no evidence of RA-associated ILD, Perez and colleagues,40 identified bronchiectasis in 30%, with a third of such cases associated with bronchial wall thickening. It is
also noteworthy that, with time, the extent of bronchiectasis and severity of bronchial
thickening generally worsens with long-standing RA.46 The tree-in-bud pattern on
HRCT indicates intraluminal/peribronchial small airway exudate and is reported in
approximately 10% to 20% of patients with RA (Fig. 2).20,43,44 Tree-in-bud opacities
with centrilobular nodules also are seen in the rare entity of follicular bronchiolitis,
which is characterized histologically by peribronchial lymphoid hyperplasia.47–49 Indirect evidence of small airways disease, reflected on HRCT by mosaic attenuation, is
present in 44% to 52% of cases (Fig. 3).40,42 Although patients with this HRCT pattern
may be asymptomatic, a subset with the functional entity of obliterative bronchiolitis in
RA, as first reported by Geddes and colleagues,50 experience rapidly progressive dyspnea and airflow obstruction.42
Interstitial lung disease
It is now accepted that a pattern of UIP is more common than NSIP in patients with RA,
despite earlier reports of equal51 or higher22 prevalence of NSIP. Although Tanaka and
colleagues20 reported that HRCT findings accurately reflect histopathologic features,
in most cases the concordance between histopathologic and HRCT diagnosis can
vary. Indeed, Lee and colleagues52 demonstrated a histopathologic UIP pattern in
Fig. 1. A 69-year-old man with a long-standing history of RA. HRCT demonstrates minimal
bronchial wall thickening and cylindrical bronchiectasis, together with some nonspecific
pleural thickening (arrow).
Pulmonary Involvement in Rheumatic Disease 171
10 (56%) of 18 patients with RA, 9 of whom demonstrated HRCT-concordant UIP with
subpleural reticulation and honeycombing (Fig. 4A). By way of contrast, a more recent
study,52 which used the stricter HRCT definition of “definite UIP,”7 resulted in only 19
(45%) of 42 histopathologically proven cases of UIP being radiologically classified as
UIP.53 Broadening the UIP definition to include cases of possible UIP (see Fig. 4B)
improved the HRCT sensitivity for a UIP diagnosis to 81%, but at the expense of a
diminished specificity and poorer agreement between radiologists. The variation in
radiologic-pathologic concordance is undoubtedly due to differences in the proportions of patients with honeycombing, but this variation cannot easily be explained
Fig. 2. A 41-year-old woman with a short history of RA and recent increasing cough. Transverse HRCT slice demonstrates quite marked centrilobular nodularity in the middle lobe and
lingula, suspicious for an exudative small airways infection or follicular bronchiolitis. Mild
cylindrical bronchiectasis and bronchial wall thickening are also noted.
Fig. 3. An 88-year-old man with long-standing RA. Cylindrical bronchiectasis is accompanied
by mild mosaic attenuation on inspiration (A), accentuated on expiratory imaging (B), due
to air-trapping.
172 Nair et al
by the duration of disease, as honeycombing may be present in equal proportions in
both early and long-standing RA.46
There is an important possible link between smoking and pulmonary fibrosis in patients with RA. It would appear that tobacco smoke predisposes to RA-associated
ILD,54,55 particularly UIP over NSIP,31,52 although the prognostic implications of smoking in RA-associated ILD are yet to be determined.56,57 Intriguingly, a recent study
demonstrated that emphysema, in both smokers with RA-associated ILD and
smokers with idiopathic pulmonary fibrosis (IPF), was significantly more prevalent
than in controls who smoked but who did not have chronic obstructive pulmonary disease (48% and 35% respectively, vs 15%), despite a lower pack-year smoking history.58 This may be indirect evidence that shared mechanisms exist between
smoking-related lung damage and RA-associated fibrosis.
In general, lung abnormalities in RA are either exclusively or predominantly present
in the lower zones.36,38,40,43,45 It is also worth noting that, that although ILD and airway
abnormalities may coexist, one or the other usually predominates. In this regard, one
hypothesis is that variability in human leukcocyte antigen subtypes may predispose to
bronchiectasis, rather than ILD, in RA.39,41,59
Non–interstitial lung disease/airway manifestations of rheumatoid arthritis
Among the other recognized complications of RA in the chest, necrobiotic nodules
(which have historically been considered a classic feature of RA-associated pulmonary involvement60) are surprisingly rare; the frequency and HRCT characteristics of
necrobiotic nodules are difficult to ascertain because of a paucity of pathologic correlation. Pleural disease (usually pleural thickening rather than effusions), is common in
RA, being present in up to 30% of patients on HRCT36,38 and 50% in one autopsy series.61 Enlarged mediastinal lymph nodes in RA also have been reported.36
Systemic Sclerosis
Interstitial lung disease
ILD is prevalent in patients with SSc. Indeed, a higher prevalence of ILD on HRCT
(reportedly between 36% and 91%4,62–64), is seen in SSc compared with the other
CTDs. Pulmonary involvement contributes to mortality and ranks third in frequency
behind cutaneous and peripheral vessel involvement in patients with SSc.63 Although
Fig. 4. HRCT for ILD in 2 patients with RA. (A) In a 73-year-old man with increasing breathlessness, a transverse HRCT slice demonstrates the definite UIP pattern of subpleural basal
predominant honeycombing and traction bronchiectasis (arrow). (B) In a 74-year-old
woman with recurrent cough, the HRCT demonstrates only minor subpleural reticulation
and no definite traction bronchiectasis, but no features inconsistent with UIP. Honeycombing at the extreme base (block arrow) was thought to be present by one radiologist but not
another at multidisciplinary discussion; a radiologic pattern of possible but not definite UIP
was assigned.
Pulmonary Involvement in Rheumatic Disease 173
the extent of ILD on HRCT may vary between cases, limited disease is more common:
in one large study of more than 200 patients, the median extent of abnormal lung was
only 13% (range 5 1%–84%),65 reflecting, in part perhaps, the tendency for pulmonologists to “screen” patients for ILD.
It is now accepted that NSIP is more common than UIP as a pattern of ILD in
SSc.23,66 Other patterns of interstitial involvement, such as organizing pneumonia
(OP),67,68 are rare. In patients with SSc-associated NSIP, basal predominant subpleural ground-glass opacification with superimposed fine reticulation is the typical HRCT
finding (Figs. 5 and 6).30,69,70 Honeycombing may be present in up to 40% of
cases17,62,71 and, interestingly, appears to be more common in limited SSc.17 Honeycombing tends to be limited in extent and characterized by a microcystic pattern. In
one cohort of 52 patients with SSc with a median duration of 6.8 years of extrapulmonary disease, Remy-Jardin and colleagues62 showed that 32 patients had abnormalities on HRCT: ground-glass opacification and a nonseptal linear pattern were present
in 26 (50%) and 6 (12%) cases, respectively. When honeycombing was present, it was
localized in most (12 of 19 cases, 63%). The extent of honeycombing can increase on
serial HRCT and has been shown to correlate with a decline in the diffusion capacity
for carbon monoxide (DLco).62,72 From this, it is tempting to postulate that honeycombing is more prevalent in patients with disease of longer duration. However, no
such relationship was observed in the study by Remy-Jardin and colleagues.62 In
addition, the observation on follow-up CT that ground-glass attenuation not only fails
to resolve with treatment,71,73 but is replaced by honeycombing,62,71 supports the
notion that ground-glass opacities may represent fine fibrosis rather than a predominantly cellular inflammatory infiltrate.26
A preponderance of ground-glass opacity, fibrosis of limited coarseness, and the
relative absence of honeycombing should allow the differentiation of SScassociated NSIP from patients with IPF. However, it must be remembered that
the coarseness of fibrosis and extent of ground-glass opacity (relative to reticulation) may be similar in patients with idiopathic and SSc-associated NSIP, making
discrimination between the latter 2 entities impossible on parenchymal appearances
alone.65 In practice, radiologists suspecting an HRCT pattern of NSIP may look for
the other ancillary signs of diffuse SSc, such as esophageal dilatation or soft tissue
calcinosis.
Fig. 5. A 55-year-old woman with a new diagnosis of SSc, exertional breathlessness, and
DLco. Transverse HRCT slice demonstrates patchy, quite extensive pure ground-glass opacity
with no admixed reticulation or traction bronchiectasis.
174 Nair et al
Non–interstitial lung disease manifestations of systemic sclerosis
Mediastinal lymph node enlargement, esophageal dilatation, and pleural abnormalities
are the other CT abnormalities in patients with SSc. Nodal enlargement per se is seen
in many diffuse lung diseases and has been correlated with the CT extent of ILD in
SSc.74–76 Esophageal dilatation is present in 62% to 82% of patients,75,77,78 but
whether or not esophageal dysmotility predisposes to, or correlates with, ILD is unclear.79–81 Pleural abnormalities, manifest as subpleural micronodules or pleural thickening, are reported in as many as 81% of cases at autopsy,82 but the frequency in
HRCT studies is more variable.62,72 Finally, for the sake of completeness, mention
also is made of the complication of pulmonary hypertension in SSc, which is a key
contributor to mortality, and is discussed in greater detail later in this article.
Systemic lupus erythematosus
Lung disease in SLE is perhaps more prevalent than might first be appreciated; in one
study, more than half of patients developed some feature of pleuroparenchymal
involvement at some point during the course of disease.83 Autopsy series suggest
that pleural and pericardial abnormalities predominate84,85; however, the reported
prevalence, based on radiologic investigations, has varied. For instance, Sant and colleagues5 and Fenlon and colleagues86 reported pericardial thickening and pleural
involvement (ie, pleural tags, thickening, and effusions) in only 15% and 17% of
HRCTs, respectively. By way of stark contrast, Ooi and colleagues87 reported pleural
disease in as many as 80%.
Interstitial lung disease
Interstitial lung involvement (characterized by thickened interlobular septa, and parenchymal and subpleural bands) has been seen in 33% to 38% of patients with SLE, but,
when present, is usually mild in extent and severity86 and asymptomatic.5 Against this,
the preponderance of honeycombing and architectural distortion in just over half of
patients with an HRCT-derived ILD diagnosis studied by Ooi and colleagues87 is a
salutary reminder of the influence of selection bias and small samples in many CTDILD studies. Indeed, it is believed that symptomatic ILD occurs in the minority (ie,
<10%) of patients.88,89 A possible caveat is that a higher prevalence of interstitial abnormalities has been noted in patients with the antiphospholipid syndrome, in which
irregular subpleural linear opacities, ground-glass opacity, reticulation, and
Fig. 6. A 62-year-old woman with known SSc and increasing breathlessness over 18 months.
Transverse HRCT just below the aortic arch (A) and at the bases (B) demonstrate groundglass opacity with some admixed reticulation in the upper lobes, becoming more predominant in the lower lobes where there has been quite marked volume loss (note the retracted
position of the left oblique fissure) and traction bronchiectasis (arrow in B). Traction bronchiectasis is a poor prognostic sign.
Pulmonary Involvement in Rheumatic Disease 175
interlobular septal thickening are seen.90 The more serious and potentially lifethreatening complications of lupus pneumonitis and pulmonary hemorrhage are also
recognized in SLE and are discussed in the section on pulmonary complications of
CTD-associated disease.
An intriguing entity seen in patients with SLE that bears mentioning is “shrinking lung
syndrome,” characterized by unexplained and often progressive dyspnea, physiologic
small-volume lungs, and diaphragmatic elevation but with clear lungs on plain radiograph (Fig. 7).89–91 This clinico-radiologic constellation has been observed in approximately 10% of patients with SLE.91–93 On HRCT there is bibasal atelectasis coupled
with an elevated diaphragm. The pathogenesis of shrinking lungs remains unclear, but
the role of primary diaphragmatic and/or respiratory muscle weakness (caused by a
postulated subclinical myopathy94,95) is not supported by electrophysiologic data.96,97
Polymyositis/dermatomyositis
In patients with PM/DM, lung disease can be problematic, and this is particularly true
in the context of serum antibodies to aminoacyl-tRNA-synthetases (the so-called
Fig. 7. A 38-year-old woman with SLE and increasing breathlessness. Chest radiograph demonstrates a raised left hemidiaphragm (A), whereas transverse HRCT on lung windows at the
lung bases demonstrates the associated atelectasis at both bases in addition to the raised
left hemidiaphragm (B), with some pericardial thickening as a sequelae of previous pericarditis also noted on mediastinal windows (C). The appearances were suspicious for the
“shrinking lung” syndrome.
176 Nair et al
“antisynthetase” antibodies).98,99 Of the antisynthetase syndromes, antibodies to
histidyl-transfer RNA (more conveniently called anti-Jo1) are the most prevalent,
and their importance is that ILD reportedly occurs in more than 50% of patients
with anti-Jo1 positivity.100–102
The typical patterns of lung disease in PM/DM are NSIP and OP. Understandably, in
most patients with ILD associated with PM/DM, the imaging features will reflect these
patterns. Ground-glass opacification (present in 63%–92%) and consolidation (seen in
26%–55%) are frequently present, often with a peribronchovascular and lower lobe
predilection (Fig. 8).103–105 The consolidation and ground-glass opacification is often
admixed with traction bronchiectasis and reticulation, corresponding to a histologic
pattern of OP on a background of fibrotic NSIP.101,106,107 Indeed, the presence of predominantly basal reticulation and ground-glass opacification, traction bronchiectasis,
volume loss, and scattered bronchocentric foci of consolidation may be the radiologic
clue to the diagnosis of an antisynthetase syndrome.108 Foci of the perilobular pattern,
a recognized manifestation of OP,109 also may be seen.
There has been recent interest in the influence of different antibody profiles in DM
and HRCT patterns. For instance, in clinically amyopathic dermatomyositis (CADM),
the anti-CADM-140 antibody (recently renamed the anti-melanoma differentiationassociated gene 5 [anti-MDA5] antibody) is believed to be a factor in the development
of ILD. Accordingly, in one small study, 12 of 25 patients with DM who were anti–
CADM-140 positive, had significantly more lower-zone consolidation/ground-glass
opacity and an absence of intralobular opacities than those who were negative for
anti–CADM-140 (Fig. 9).110 Hoshino and colleagues111 also found a strikingly higher
frequency of ILD in anti-MDA5–positive subjects as compared with those without
anti-MDA5 antibodies (95% vs 32%, respectively) and there was a trend toward
rapidly progressive lung disease. An interesting, but as yet unexplained, observation
is the increased frequency of pneumomediastinum in patients with DM with a
CADM phenotype,112 especially in patients who are anti-MDA5 positive (see Fig. 9).111
Sjo ¨ gren syndrome
The prevalence of HRCT abnormalities in patients with SS with pulmonary symptoms
has been estimated at 11%,113 even though, somewhat counterintuitively, more than
two-thirds of asymptomatic patients may demonstrate such abnormalities.114 In SS,
patients are more liable to develop impairment of upper respiratory tract immune defenses, glandular dysfunction, and bronchiolar inflammation, which probably explains
why signs of airway involvement (ie, bronchial wall thickening, dilatation, and a mosaic
attenuation pattern) are commonly seen.115,116 The presence of airways disease
Fig. 8. A 31-year-old woman with a new diagnosis of polymyositis and anti-Jo1 antibody
positivity. Transverse HRCT slices show patches of peripheral consolidation in the upper lobes
(A) and more bronchocentric consolidation in the lower lobes (B), typical of the OP pattern
seen in these patients.
Pulmonary Involvement in Rheumatic Disease 177
makes it difficult to gauge exactly how much of the parenchymal injury seen in SS is a
consequence of airways-based inflammation, rather than a direct “hit” on the lung parenchyma. This notwithstanding, the ILD in SS is most commonly of an NSIP pattern,
characterized by lower-zone ground-glass opacification and interlobular septal
thickening.117,118
A pattern of lymphoid interstitial pneumonia (LIP) has been considered the commoner SS-associated ILD,119,120 but it is possible that such statements were based
on the subjective histologic interpretation of a homogeneous lymphocytic infiltrate
as LIP rather than a cellular NSIP.121 In some patients with LIP related to SS, HRCT
may show patchy ground-glass opacities together with thin-walled parenchymal
cysts, sometimes measuring up to 6 cm in diameter, as well as peribronchovascular,
centrilobular, and subpleural nodules (Fig. 10).114,117,118 The association among SS,
LIP, and other lymphoproliferative disease is also worth remembering.122 Indeed,
the spectrum of lymphoproliferative disorder in SS varies and ranges from benign,
as exemplified by the entity of follicular bronchiolitis (manifesting as a predominant
Fig. 9. A 50-year-old woman with a recent diagnosis of clinically amyopathic dermatomyositis and anti-MDA5 antibody positivity. (A) Transverse conventional (non–high-resolution)
CT (2-mm slice thickness) demonstrates a bandlike opacity of consolidation in the apical
segment of the right lower lobe, typical of OP. Note the pneumomediastinum (arrow),
well-described in such patients. (B) Follow-up HRCT slice 3 months later shows persistence
of consolidation in the right lower lobe, with the perilobular pattern of OP (block arrow)
noted. The pneumomediastinum has resolved.
Fig. 10. A 67-year-old woman with known Sjo ¨ gren syndrome and biopsy-proven LIP. Transverse HRCT slices show multiple foci of bronchocentric ground-glass opacity (A), as well as
multiple thin-walled parenchymal cysts (block arrow in B). Traction bronchiectasis is present
(arrowhead in B), concerning for an adverse prognosis. Note the surgical suture material
postbiopsy in the posterior right upper lobe (arrow in A).
178 Nair et al
tree-in-bud pattern on HRCT),116 to overt malignant lymphoma (usually of nonHodgkin type). Lymphoma in patients with SS will present as nodules larger than
10 mm in diameter, foci of consolidation, mediastinal lymph node enlargement,119,123
and pleural effusions.123 A rare but striking presentation of LIP in SS occurs when
there is associated pulmonary amyloid deposition; on HRCT there are multiple
bizarrely shaped nodules (which may appear calcified) often adjacent to cysts, with
no particular zonal predilection.124–126
Mixed connective tissue disease
There is continuing debate about whether MCTD represents a distinct entity or a
simply an “overlap syndrome” with features of, most commonly, SSc, SLE, and PM/
DM.127–129 There is support for the latter hypothesis in that the thoracic manifestations
of MCTD generally represent an overlap of features found in the other CTDs listed previously. Lung disease, based on review of HRCT, is reported in more than 50% of
patients with MCTD.130,131 The most common abnormalities are reticulation and
ground-glass opacification, which tend to be basal predominant and typically of
limited extent (Fig. 11).130–132 In one study, there was a reticular pattern at HRCT in
just more than one-third of patients; in most cases, reticulation was admixed with
fine intralobular lines or cysts measuring smaller than 4 mm in diameter.130
The reported prevalence of certain abnormalities in MCTD may differ from its
“component” CTDs. In a rare direct comparison, Saito and colleagues133 observed
a lower frequency of ground-glass opacity in patients with MCTD compared with patients with SSc, SLE, and PM/DM, but found that interlobular septal thickening was
present in all patients with MCTD, with an unexpectedly high proportion of honeycombing. A striking preponderance (98%) of subpleural nodularity also was noted in
another study,132 the reasons for which are unclear. Interestingly, although the clinical
features of PM/DM may be present in patients with MCTD, the mixed NSIP-OP pattern
described in PM/DM has, to the best of our knowledge, not been reported in MCTD.
Other radiologic findings of MCTD-related thoracic disease include pleural thickening/
effusions, esophageal dysmotility, centrilobular nodularity, and airway involvement,
but are rare.
Pulmonary Complications in Connective Tissue–Associated Disease
As discussed previously, the lung complications of CTDs are reasonably common. For
practical purposes, these can be broadly thought of as acute and nonacute sequelae
(Table 3). The imaging implications of these complications are reviewed in the
following sections.
Fig. 11. A 52-year-old woman with MCTD with overlapping clinical features of SSc and RA.
Transverse CT slice at the lung apices (A) demonstrates mild subpleural reticulation, in addition to the prominent dilated esophagus and marked soft tissue calcinosis surrounding the
sternoclavicular and glenohumeral joints, while marked traction bronchiectasis and groundglass opacity is seen at the bases (B), compatible with a fibrotic NSIP.
Pulmonary Involvement in Rheumatic Disease 179
Acute complications
When an abrupt clinical deterioration occurs in a patient with known CTD-associated
lung disease, the clinician and radiologist must consider a number of possibilities.
These will include the diagnosis of acute exacerbation of ILD, iatrogenic lung disease,
opportunistic infection, and pulmonary hemorrhage.
Acute exacerbations, per se, are uncommon but statistically meaningful comparisons have been difficult because of the small study populations reported to date.
Indeed, acute exacerbations are seen as the first presentation of an ILD in only a minority of cases. That said, patients with RA (Fig. 12) and primary SS seem to be at
Table 3
Complications and their relative frequencies in different connective tissue diseases
Complication
Connective Tissue Disease
RA SSc SLE PM/DM SS MCTD
Acute
Acute exacerbation 111 1 11 1 111 1
Infection 111 1 11 1 1 11
Pulmonary hemorrhage 1 1 111a 1 1 1
Chronic
Pulmonary hypertension 1 111 11 1 1 111
Malignancy 11 1 11 111b 11 1
The number of 1 signs denotes the relative prevalence of the complication.
Abbreviations: MCTD, mixed connective tissue disease; PM/DM, polymyositis/dermatomyositis;
RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SS, Sjo ¨ gren syndrome; SSc, systemic
sclerosis.
a Particularly associated with the antiphospholipid syndrome.
b PM/DM may represent a paraneoplastic manifestation of an underlying occult malignancy.
Fig. 12. Acute exacerbation of ILD in a 74-year-old woman with RA (same patient as in
Fig. 4B) who had become significantly breathless after elective carotid endarterectomy.
(A) Contrast-enhanced transverse CT slice at the level of the main PA shows diffuse
ground-glass opacity with some fine reticulation, suggesting an alveolar infiltrate from
DAD, but it is uncertain whether this is being exaggerated by the combined effect of iodinated contrast and a predominantly expiratory CT (note the narrow caliber of the right and
left main bronchi proximally), or indeed if an element of alveolar edema is present. (B)
Transverse unenhanced HRCT at the same level only 10 days later demonstrates that the
pattern of predominant ground-glass opacity has evolved into predominantly coarse reticulation and patchy consolidation, concerning for the organizing phase of a DAD in the
context of an acute exacerbation.
180 Nair et al
highest risk of acute exacerbation.134–136 Acute deterioration also is recognized in SLE
(“lupus pneumonitis”) with earlier studies suggesting a prevalence of 2% to
9%,83,137–139 although one series (consisting solely of patients with SLE) reported
this as the presenting manifestation in as many as 50%.140 The outlook for patients
with RA with acute exacerbation is generally poorer with increasing age,134,141 and
in those with a known preexisting ILD.135 There are conflicting reports on whether
the survival of patients with RA with such exacerbations is worse in the presence of
a UIP pattern.48,141 Regardless of the underlying CTD, the histologic hallmark of acute
exacerbations is diffuse alveolar damage (DAD). As an aside, the term acute interstitial
pneumonia (AIP) has occasionally been used to denote any interstitial pneumonia of
acute onset, including acute exacerbations of IIP, and is characterized histologically
by DAD as well. However, AIP should be strictly reserved for acute rapidly progressive
dyspnea due to interstitial disease without an identified cause.8
Drug toxicity in patients with CTD typically arises from treatment with methotrexate
and leflunomide: the quoted toxicity rates are 0.3% to 11.0%142,143 and 1.0%,144,145
respectively. Interestingly, a recent prospective study found that when HRCT data
were integrated with the application of stringent criteria for a diagnosis of
methotrexate-induced drug toxicity (ie, radiologic improvement after drug cessation
and a clinical course consistent with a hypersensitivity reaction), the prevalence of
methotrexate toxicity was only 1%.146 At this point, it is important to note that the
histologic patterns of pulmonary injury are not specific to any particular drug. Indeed,
in cases in which biopsy has been undertaken, the pathologist may expect to
encounter a spectrum of histopathologic patterns, including DAD, OP, hypersensitivity pneumonitis, and pulmonary hemorrhage, as well as pulmonary edema caused by
cardiac toxicity.
Diffuse alveolar hemorrhage (DAH) can complicate the clinical and radiologic picture, especially in SLE.147,148 Radiographically, DAH manifests as airspace and/or
interstitial infiltrates that may be diffuse, basal, or perihilar in distribution, and is often
bilateral.148,149 Pleural effusions are not infrequent, being reported in 27% of episodes
in one study.150 On HRCT, patchy centrilobular nodules (representing conglomerations of hemosiderin-laden macrophages within alveoli) with no zonal predilection
and ground-glass opacities are seen (Fig. 13)151; a “crazy-paving” pattern (a
Fig. 13. A 46-year-old woman with known SLE and antiphospholipid syndrome, presenting
with 12 hours of hemoptysis. Contrast-enhanced CT demonstrates patchy ground-glass
opacity likely representing pulmonary hemorrhage. However, such an appearance can be
indistinguishable from DAD, atypical infection, or a lymphoproliferative disorder, and interpretation relies on clinical context and evolution on serial imaging.
Pulmonary Involvement in Rheumatic Disease 181
combination of ground-glass opacification and interlobular septal thickening) has
rarely been reported.152
Opportunistic infections may be problematic in patients with CTDs and contribute to
both morbidity and mortality.153 Of note, there is a predisposition to mycobacterial infections with the increased use of tumor necrosis factor inhibitors.154–156 Patients with
CTD also may develop Pneumocystis jiroveci pneumonia (PCP), primarily as a consequence of long-term immunosuppressive therapy.157
Distinguishing between the acute pulmonary complications described previously on
imaging tests can be challenging. For instance, the presence of a histologic pattern of
DAD (whether associated with acute exacerbation, caused by drug toxicity, or even as
a systemic inflammatory response to infection), will only ever manifest with diffuse
bilateral airspace opacification, with variably extensive ground-glass opacification,
admixed reticulation (with or without traction bronchiectasis) and foci of consolidation.43,134,135,158 These features are similar to acute DAD occurring in other clinical
contexts.159–162 In the absence of any consolidation, the pattern of DAD on HRCT
may be impossible to distinguish from pulmonary hemorrhage, opportunistic PCP
and pulmonary edema. The presence of pleural fluid might push the radiologist to
consider coexistent cardiac dysfunction, but, because pleural effusions are also a
feature of acute decline (particularly in SLE), the differential diagnosis of acute exacerbation would still need to be entertained. The presence of centrilobular or subpleural
micronodules might suggest an element of subacute hypersensitivity pneumonitis,163,164 but these also are a feature of pulmonary hypertension in some patients
(as discussed in the next section).
Nonacute complications
Pulmonary hypertension (PH) is perhaps the most serious of the nonacute complications of CTDs and is most problematic in patients with SSc and MCTD.165 PH has an
estimated prevalence in SSc, MCTD, and SLE of 10% to 16%,166–168 10% to 45%,169
and 4%,170 respectively. Interestingly, although the overall prevalence of PH is higher
in the presence of ILD, the severity of PH may be disproportionately greater than expected for the often limited ILD extent encountered in SSc171; this probably reflects
the contribution of vasculopathy in the microcirculation to raised pulmonary vascular
resistance, a phenomenon that is not immediately obvious on conventional HRCT.
On HRCT, PH is suspected when there is an increase in the transverse diameter of
the main pulmonary artery (PA), as seen at the level of its bifurcation: a diameter
greater than 2.9 cm172 or, alternatively, an increase in the ratio of diameters of the
main PA to ascending aorta (AA) higher than 1 (Fig. 14)173 has been considered predictive of raised PA pressure. However, the absolute measurement of PA is probably
an unreliable marker of PH in the presence of pulmonary fibrosis (from any cause),
whereas the usefulness of the PA/AA ratio appears to be preserved.174 Against this,
it is should be noted that the value of the PA/AA ratio has not been studied in CTDILD populations exclusively. An occasional feature of PH is centrilobular nodules, corresponding histopathologically to cholesterol granulomas.175 Pleural effusions may
occur in just fewer than 40%,176 but the mechanism for its occurrence in PH is not
clear.
A final mention should be made of the increased risk of malignancy in all
CTDs.177–182 The risk of lymphoma (particularly primary pulmonary lymphomas) is
higher in RA, SS, and SLE.181,183 In patients with PM/DM, the CTD may be a paraneoplastic manifestation of an underlying malignancy.184 An underlying malignancy
should thus always be considered in the differential diagnosis of nonresolving airspace
opacity or enlarged/enlarging thoracic lymph nodes.
182 Nair et al
THE ROLE OF HIGH-RESOLUTION COMPUTED TOMOGRAPHY IN DIAGNOSTIC
EVALUATION, MONITORING, AND PROGNOSTICATION
In CTD-related ILD, HRCT may have a role in monitoring patients with established lung
disease, identifying complications, evaluating treatment response, and predicting
outcome.
In monitoring CTD-ILD, serial HRCT may show progression in the extent of fibrosis.
However, trends in pulmonary function tests (PFTs) and clinical behavior are probably
as informative when there has been deterioration in HRCT appearances. For instance,
Moore and colleagues185 recently showed that in a cohort of patients with SSc followed for a mean of 3.5 years, patients who demonstrated a substantial deterioration
in their HRCT ILD abnormalities had a correspondingly detectable decline of at least
30% in forced vital capacity (FVC), DLco, or DLco corrected for alveolar volume.
For this reason, routine serial HRCT for disease monitoring may not be necessary.
However, HRCT may play an important role in complementing functional assessment
when physiologic decline is not easily attributable solely to ILD, for instance, in the
setting of SSc-related pulmonary vasculopathy in SSc, or progressive bronchiolitis
obliterans in RA.
Earlier evidence suggests that the pattern of fibrosis on HRCT is unlikely to predict
response to treatment.186 However, Roth and colleagues187 recently showed that patients with SSc who demonstrate a reticular pattern, occupying at least half of any of
the 3 lung zones (upper, mid, and lower) as determined on HRCT, are more likely to
respond to treatment. Conversely, HRCT also may have a role when trying to assess
which patients may potentially suffer drug-related pulmonary toxicity. In one series,
57% of asymptomatic patients with RA and ILD abnormalities seen on HRCT demonstrated a tendency toward progressive ILD abnormalities, and this tendency was
significantly related to higher frequencies of methotrexate treatment.54
Several outcome studies, specifically in the setting of CTD-related fibrotic lung disease, have involved analysis of multiple variables, including HRCT pattern scores,
PFTs, and clinical data. The morphologic severity of fibrosis, assessed by HRCT,
and physiologic severity, assessed by lung function (in particular DLco), have
been shown to independently predict survival, raising the possibility that more
powerful prognostic discrimination may be expected from an integration of
Fig. 14. A 59-year-old woman with SLE and known antiphospholipid syndrome and PH
confirmed on right heart catheterization. Transverse contrast-enhanced CT slice at the level
of the main PA demonstrates an enlarged main PA (3.1 cm), but also markedly enlarged and
tortuous segmental PAs, suspicious for PH.
Pulmonary Involvement in Rheumatic Disease 183
both.18,21 Management decisions in ILD tend to be based on outcomes that are
dichotomous. For example, is the patient likely to respond to treatment or not?
Therefore, “staging” patients by separating them into 2 prognostic categories
(such as good prognosis/poor prognosis or limited disease/extensive disease) to
answer these dichotomous decisions is desirable. This dichotomous approach has
been applied to SSc-related ILD, using a simple staging system for rapid stratification of clinical risk (Fig. 15).188 By separating patients into 1 of 2 prognostically
distinct categories, patients who may benefit from treatment may be more readily
separated from those who are likely to progress regardless of treatment. First, an
evaluation of global interstitial disease extent on HRCT with respect to a threshold
of 20% is made. Patients whose global interstitial disease extent is considered
indeterminate (ie, close to the 20% threshold) are then evaluated based on their
percent-predicted FVC for which a threshold of 70% is used. In this way, patients
are categorized into 2 groups, namely “limited” or “extensive” disease, which are
strikingly prognostically distinct. The strengths of this system are twofold: first, by
combining HRCT and pulmonary function, a stronger prognostic discrimination is obtained than that provided by either of the 2 variables in isolation. Second, the staging
model allows for instances in which the HRCT data are marginal (ie, global disease
extent very close to 20%) by providing recourse to a threshold for FVC. This is an
important advantage, as it means that all patients may be categorized regardless
of the clinician’s experience in evaluating HRCT.
The overlap of clinical and ILD phenotypes in CTD-ILD may pose a particular problem, as it somewhat prevents the generalization of prognostic HRCT data from one
type of CTD to CTDs at large. To circumvent this limitation, Walsh and colleagues18
studied the prognostic discrimination provided by HRCT, as well as PFT data, in an
“all-comers” cohort of patients with CTD-ILD. On multivariate analysis, they demonstrated that traction bronchiectasis (either measured semiquantitatively or using a binary “absence or presence” score) and extent of honeycombing (both prognostic
indicators in IIPs),189 as well as DLco, were independently associated with increased
mortality. Furthermore, in a subset of patients with surgical biopsy data, it was shown
Fig. 15. A simple staging system for SSc that uses extent of disease on HRCT and PFTs to separate patients into 2 prognostically distinct groups. (From 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;177:1249; with permission.)
184 Nair et al
that a radiologic-pathologic concordance with respect to diagnosis influenced survival. Patients with a radiologic diagnosis of fibrotic NSIP but histopathologic evidence
of UIP had a more favorable outcome when compared with patients whose radiologic
and histopathologic appearances suggested UIP. The latter finding makes a possible
case for surgical biopsy to provide additional prognostic information in the setting of a
non-UIP pattern on HRCT, but such decisions would always need to be made on a
case-by-case basis.
The prognostic studies by Goh and colleagues188 and Walsh and colleagues18 are
perhaps even more pertinent because they provide simple reproducible systems for
prognostication, with good interobserver agreement, that are easily replicated.185
However, prospective studies on prognostication are still lacking to validate these
methods.
HIGH-RESOLUTION COMPUTED TOMOGRAPHY IN THE MULTIDISCIPLINARY WORKUP
OF INTERSTITIAL LUNG DISEASE WITH NO PREVIOUS CONNECTIVE TISSUE DISEASE
DIAGNOSIS
It has been estimated that 15% of patients presenting with IIP may have an underlying
CTD,190 and that 21% of apparently idiopathic NSIP and 13% of patients with IPF
could be classifiable as an undifferentiated CTD.191 Several descriptions of patients
with autoantibodies suggestive of, but not diagnostic for, an underlying CTD have
been published in recent years,93,108,192,193 highlighting the importance of multidisciplinary evaluation of these patients. The concept of a “lung-dominant” CTD as proposed by Fischer and colleagues194 and interstitial pneumonia with autoimmune
features to denote ILD where there is a suspicion of a connective tissue disorder,
have been suggested. In the authors’ experience, patients referred for ILD workup
are best evaluated by a multidisciplinary team that includes rheumatological expertise
(Fig. 16). It is worth highlighting the importance of not mislabeling patients as having
Fig. 16. A 55-year-old woman with recent-onset breathlessness, who had been given a diagnosis of IPF. When assessed in a joint rheumatology–diffuse lung disease clinic, she described
experiencing some muscle weakness and joint pains over the preceding 4 months, and
serology was positive for anti-Jo1 antibody. Although she did not satisfy all diagnostic
criteria for polymyositis, the HRCT findings of subpleural ground-glass opacity, peripheral
consolidation, and a perilobular pattern are consistent with the mixed NSIP-OP pattern
seen in antisynthetase syndrome. The patient was therefore considered to have a lungdominant connective tissue disease, and her symptoms successfully ameliorated with
immunosuppression.
Pulmonary Involvement in Rheumatic Disease 185
idiopathic ILD (and therefore limiting therapeutic options) when an undeclared CTD
may be present.
SUMMARY
The imaging features of the pulmonary manifestations of rheumatological disease and
their pathologic and functional correlations have been progressively characterized
over the past 3 decades. The interpretation of these images requires a methodical
approach incorporating pattern recognition, appraisal of the extents of various
component interstitial and airspace abnormalities, and awareness of prognostic signs,
as well as an understanding of the pulmonary complications that occur in these disease entities. As the multidisciplinary approach to diagnosing and treating these diseases evolves, the role of imaging in both research and clinical interpretation of these
diverse and challenging conditions will doubtless only continue to grow.
REFERENCES
1. Epler GR, McLoud TC, Gaensler EA, et al. Normal chest roentgenograms in
chronic diffuse infiltrative lung disease. N Engl J Med 1978;298:934–9.
2. 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.
3. Gabbay E, Tarala R, Will R, et al. Interstitial lung disease in recent onset rheumatoid arthritis. Am J Respir Crit Care Med 1997;156:528–35.
4. Schurawitzki H, Stiglbauer R, Graninger W, et al. Interstitial lung disease in progressive systemic sclerosis: high-resolution CT versus radiography. Radiology
1990;176:755–9.
5. Sant SM, Doran M, Fenelon HM, et al. Pleuropulmonary abnormalities in patients
with systemic lupus erythematosus: assessment with high resolution computed
tomography, chest radiography and pulmonary function tests. Clin Exp Rheumatol 1997;15:507–13.
6. American Thoracic Society, European Respiratory Society. American Thoracic
Society/European Respiratory Society International Multidisciplinary Consensus
Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the
American Thoracic Society (ATS), and the European Respiratory Society (ERS)
was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 2002;165:277–304.
7. 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.
8. Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/
European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit
Care Med 2013;188:733–48.
9. Hartman TE, Swensen SJ, Hansell DM, et al. Nonspecific interstitial pneumonia:
variable appearance at high-resolution chest CT. Radiology 2000;217:701–5.
10. Sverzellati N, Wells AU, Tomassetti S, et al. Biopsy-proved idiopathic pulmonary
fibrosis: spectrum of nondiagnostic thin-section CT diagnoses. Radiology 2010;
254:957–64.
11. Sumikawa H, Johkoh T, Fujimoto K, et al. Pathologically proved nonspecific
interstitial pneumonia: CT pattern analysis as compared with usual interstitial
pneumonia CT pattern. Radiology 2014;272:549–56.
186 Nair et al
12. Johkoh T, Muller NL, Cartier Y, et al. Idiopathic interstitial pneumonias: diagnostic accuracy of thin-section CT in 129 patients. Radiology 1999;211:
555–60.
13. Lynch DA, Godwin JD, Safrin S, et al. High-resolution computed tomography in
idiopathic pulmonary fibrosis: diagnosis and prognosis. Am J Respir Crit Care
Med 2005;172:488–93.
14. Elliot TL, Lynch DA, Newell JD, et al. High-resolution computed tomography features of nonspecific interstitial pneumonia and usual interstitial pneumonia.
J Comput Assist Tomogr 2005;29:339–45.
15. MacDonald SL, Rubens MB, Hansell DM, et al. Non-specific interstitial pneumonia and usual interstitial pneumonia: comparative appearances at and diagnostic accuracy of thin-section CT. Radiology 2001;221:600–5.
16. Watadani T, Sakai F, Johkoh T, et al. Interobserver variability in the CT assessment of honeycombing in the lungs. Radiology 2013;266:936–44.
17. Goldin JG, Lynch DA, Strollo DC, et al. High-resolution CT scan findings in patients with symptomatic scleroderma-related interstitial lung disease. Chest
2008;134:358–67.
18. 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.
19. Johkoh T, Sakai F, Noma S, et al. Honeycombing on CT; its definition, pathologic
correlation, and future direction of its diagnosis. Eur J Radiol 2014;83:27–31.
20. Tanaka N, Kim JS, Newell JD, et al. Rheumatoid arthritis-related lung diseases:
CT findings. Radiology 2004;232:81–91.
21. 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.
22. Tansey D, Wells AU, Colby TV, et al. Variations in histological patterns of interstitial pneumonia between connective tissue disorders and their relationship to
prognosis. Histopathology 2004;44:585–96.
23. 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 Med 2002;165:1581–6.
24. Hwang JH, Misumi S, Sahin H, et al. Computed tomographic features of idiopathic fibrosing interstitial pneumonia: comparison with pulmonary fibrosis
related to collagen vascular disease. J Comput Assist Tomogr 2009;33:410–5.
25. Muller NL, Staples CA, Miller RR, et al. Disease activity in idiopathic pulmonary
fibrosis: CT and pathologic correlation. Radiology 1987;165:731–4.
26. Wells AU, Hansell DM, Rubens MB, et al. The predictive value of appearances
on thin-section computed tomography in fibrosing alveolitis. Am Rev Respir Dis
1993;148:1076–82.
27. Wells AU, Rubens MB, du Bois RM, et al. Serial CT in fibrosing alveolitis: prognostic significance of the initial pattern. AJR Am J Roentgenol 1993;161:
1159–65.
28. Silva CI, Muller NL, Hansell DM, et al. Nonspecific interstitial pneumonia and
idiopathic pulmonary fibrosis: changes in pattern and distribution of disease
over time. Radiology 2008;247:251–9.
29. Hartman TE, Primack SL, Kang EY, et al. Disease progression in usual interstitial
pneumonia compared with desquamative interstitial pneumonia. Assessment
with serial CT. Chest 1996;110:378–82.
30. Wells AU, Hansell DM, Corrin B, et al. High resolution computed tomography as
a predictor of lung histology in systemic sclerosis. Thorax 1992;47:738–42.
Pulmonary Involvement in Rheumatic Disease 187
31. Dawson JK, Fewins HE, Desmond J, et al. Fibrosing alveolitis in patients
with rheumatoid arthritis as assessed by high resolution computed tomography, chest radiography, and pulmonary function tests. Thorax 2001;56:
622–7.
32. Remy-Jardin M, Giraud F, Remy J, et al. Importance of ground-glass attenuation
in chronic diffuse infiltrative lung disease: pathologic-CT correlation. Radiology
1993;189:693–8.
33. Ellman P, Ball RE. Rheumatoid disease with joint and pulmonary manifestations.
Br Med J 1948;2:816–20.
34. Olson AL, Swigris JJ, Sprunger DB, et al. Rheumatoid arthritis-interstitial lung
disease-associated mortality. Am J Respir Crit Care Med 2011;183:372–8.
35. Bongartz T, Nannini C, Medina-Velasquez YF, et al. Incidence and mortality of
interstitial lung disease in rheumatoid arthritis: a population-based study.
Arthritis Rheum 2010;62:1583–91.
36. Biederer J, Schnabel A, Muhle C, et al. Correlation between HRCT findings, pulmonary function tests and bronchoalveolar lavage cytology in interstitial lung
disease associated with rheumatoid arthritis. Eur Radiol 2004;14:272–80.
37. Hassan WU, Keaney NP, Holland CD, et al. High resolution computed tomography of the lung in lifelong non-smoking patients with rheumatoid arthritis. Ann
Rheum Dis 1995;54:308–10.
38. Remy-Jardin M, Remy J, Cortet B, et al. Lung changes in rheumatoid arthritis:
CT findings. Radiology 1994;193:375–82.
39. Hillarby MC, McMahon MJ, Grennan DM, et al. HLA associations in subjects
with rheumatoid arthritis and bronchiectasis but not with other pulmonary complications of rheumatoid disease. Br J Rheumatol 1993;32:794–7.
40. Perez T, Remy-Jardin M, Cortet B. Airways involvement in rheumatoid arthritis:
clinical, functional, and HRCT findings. Am J Respir Crit Care Med 1998;157:
1658–65.
41. Cortet B, Perez T, Roux N, et al. Pulmonary function tests and high resolution
computed tomography of the lungs in patients with rheumatoid arthritis. Ann
Rheum Dis 1997;56:596–600.
42. Devouassoux G, Cottin V, Liote ´ H, et al. Characterisation of severe obliterative
bronchiolitis in rheumatoid arthritis. Eur Respir J 2009;33:1053–61.
43. Akira M, Sakatani M, Hara H. Thin-section CT findings in rheumatoid arthritisassociated lung disease: CT patterns and their courses. J Comput Assist Tomogr 1999;23:941–8.
44. Nakamura Y, Suda T, Kaida Y, et al. Rheumatoid lung disease: prognostic analysis of 54 biopsy-proven cases. Respir Med 2012;106:1164–9.
45. Wilsher M, Voight L, Milne D, et al. Prevalence of airway and parenchymal abnormalities in newly diagnosed rheumatoid arthritis. Respir Med 2012;106:
1441–6.
46. Mori S, Isamu C, Koga Y, et al. Comparison of pulmonary abnormalities on highresolution computed tomography in patients with early versus long-standing
rheumatoid arthritis. J Rheumatol 2008;35:1513–20.
47. Howling SJ, Hansell DM, Wells AU, et al. Follicular bronchiolitis: thin-section CT
and histologic findings. Radiology 1999;212:637–42.
48. 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.
49. Hayakawa H, Sato A, Imokawa S, et al. Bronchiolar disease in rheumatoid
arthritis. Am J Respir Crit Care Med 1996;154:1531–6.
188 Nair et al
50. Geddes DM, Corrin B, Brewerton DA, et al. Progressive airway obliteration in
adults and its association with rheumatoid disease. Q J Med 1977;184:427–44.
51. Yoshinouchi T, Ohtsuki Y, Fujita J, et al. Nonspecific interstitial pneumonia
pattern as pulmonary involvement of rheumatoid arthritis. Rheumatol Int 2005;
26:121–5.
52. Lee HK, Kim DS, Yoo B, et al. Histopathologic pattern and clinical features of rheumatoid arthritis-associated interstitial lung disease. Chest 2005;127:2019–27.
53. 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.
54. Gochuico BR, Avila NA, Chow CK, et al. Progressive preclinical interstitial lung
disease in rheumatoid arthritis. Arch Intern Med 2008;168:159–66.
55. Doyle TJ, Dellaripa PF, Batra K, et al. Functional impact of a spectrum of interstitial lung abnormalities in rheumatoid arthritis. Chest 2014;146:41–50.
56. Assayag D, Lubin M, Lee JS, et al. Predictors of mortality in rheumatoid arthritisrelated interstitial lung disease. Respirology 2014;19:493–500.
57. 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.
58. Antoniou KM, Walsh SL, Hansell DM, et al. Smoking-related emphysema is
associated with idiopathic pulmonary fibrosis and rheumatoid lung. Respirology
2013;18:1191–6.
59. Mori S, Koga Y, Sugimoto M. Different risk factors between interstitial lung disease and airway disease in rheumatoid arthritis. Respir Med 2012;106:1591–9.
60. Yousem SA, Colby TV, Carrington CB. Lung biopsy in rheumatoid arthritis. Am
Rev Respir Dis 1985;131:770–7.
61. Sahn SA. Immunologic diseases of the pleura. Clin Chest Med 1985;6:83–102.
62. 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. Radiology 1993;188:499–506.
63. Devenyi K, Czirjak L. High resolution computed tomography for the evaluation of
lung involvement in 101 patients with scleroderma. Clin Rheumatol 1995;14:
633–40.
64. Arroliga AC, Podell DN, Matthay RA. Pulmonary manifestations of scleroderma.
J Thorac Imaging 1992;7:30–45.
65. Desai SR, Veeraraghavan S, Hansell DM, et al. CT features of lung disease in
patients with systemic sclerosis: comparison with idiopathic pulmonary fibrosis
and non-specific interstitial pneumonia. Radiology 2004;232:560–7.
66. 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 Dis 2002;19:121–7.
67. Muir TE, Tazelaar HD, Colby TV, et al. Organizing diffuse alveolar damage associated with progressive systemic sclerosis. Mayo Clin Proc 1997;72:639–42.
68. Bridges AJ, Hsu KC, Dias-Arias AA, et al. Bronchiolitis obliterans organizing
pneumonia and scleroderma. J Rheumatol 1992;19:1136–40.
69. Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo
in scleroderma lung disease. N Engl J Med 2006;354:2655–66.
70. De Santis M, Bosello S, La Torre G, et al. Functional, radiological and biological
markers of alveolitis and infections of the lower respiratory tract in patients with
systemic sclerosis. Respir Res 2005;6:96.
Pulmonary Involvement in Rheumatic Disease 189
71. Launay D, Remy-Jardin M, Michon-Pasturel U, et al. High resolution computed
tomography in fibrosing alveolitis associated with systemic sclerosis.
J Rheumatol 2006;33:1789–801.
72. 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 Tomogr 2001;25:757–63.
73. Shah RM, Jimenez S, Wechsler R. Significance of ground-glass opacity on
HRCT in long-term follow-up of patients with systemic sclerosis. J Thorac Imaging 2007;22:120–4.
74. Warrick JH, Bhalla M, Schabel SI, et al. High resolution computed tomography
in early scleroderma lung disease. J Rheumatol 1991;18:1520–8.
75. Bhalla M, Silver RM, Shepard JA, et al. Chest CT in patients with scleroderma:
prevalence of asymptomatic esophageal dilatation and mediastinal lymphadenopathy. AJR Am J Roentgenol 1993;161:269–72.
76. Chan TY, Hansell DM, Rubens MB, et al. Cryptogenic fibrosing alveolitis and the
fibrosing alveolitis of systemic sclerosis: morphological differences on
computed tomographic scans. Thorax 1997;52:265–70.
77. Abu-Shakra M, Guillemin F, Lee P. Gastrointestinal manifestations of systemic
sclerosis. Semin Arthritis Rheum 1994;24:29–39.
78. Vonk MC, van Die CE, Snoeren MM, et al. Oesophageal dilatation on highresolution computed tomography scan of the lungs as a sign of scleroderma.
Ann Rheum Dis 2008;67:1317–21.
79. Christmann RB, Wells AU, Capelozzi VL, et al. Gastroesophageal reflux incites
interstitial lung disease in systemic sclerosis: clinical, radiologic, histopathologic, and treatment evidence. Semin Arthritis Rheum 2010;40:241–9.
80. Marie I, Dominique S, Levesque H, et al. Esophageal involvement and pulmonary manifestations in systemic sclerosis. Arthritis Rheum 2001;45:346–54.
81. Gilson M, Zerkak D, Wipff J, et al. Prognostic factors for lung function in systemic sclerosis: prospective study of 105 cases. Eur Respir J 2010;35:
112–7.
82. D’Angelo WA, Fries JF, Masi AT, et al. Pathologic observations in systemic sclerosis (scleroderma). A study of fifty-eight autopsy cases and fifty-eight matched
controls. Am J Med 1969;46:428–40.
83. Kim JS, Lee KS, Koh EM, et al. Thoracic involvement of systemic lupus erythematosus: clinical, pathologic, and radiologic findings. J Comput Assist Tomogr
2000;24:9–18.
84. Wiedemann HP, Matthay RA. Pulmonary manifestations of systemic lupus erythematosus. J Thorac Imaging 1992;7:1–18.
85. Orens JB, Martinez FJ, Lynch JP III. Pleuropulmonary manifestations of systemic
lupus erythematosus. Rheum Dis Clin North Am 1994;20:159–93.
86. Fenlon HM, Doran M, Sant SM, et al. High-resolution chest CT in systemic lupus
erythematosus. AJR Am J Roentgenol 1996;166:301–7.
87. Ooi GC, Ngan H, Peh WC, et al. Systemic lupus erythematosus patients with
respiratory symptoms: the value of HRCT. Clin Radiol 1997;52:775–81.
88. Weinrib L, Sharma OP, Quismorio FP. A long-term study of interstitial lung disease in systemic lupus erythematosus. Semin Arthritis Rheum 1990;20:48–56.
89. Jacobsen S, Petersen J, Ullman S, et al. A multicentre study of 513 Danish patients with systemic lupus erythematosus. I. Disease manifestations and analyses of clinical subsets. Clin Rheumatol 1998;17:468–77.
90. Oki H, Aoki T, Saito K, et al. Thin-section chest CT findings in systemic lupus erythematosus with antiphospholipid syndrome: a comparison with systemic
190 Nair et al
lupus erythematosus without antiphospholipid syndrome. Eur J Radiol 2012;81:
1335–9.
91. Hoffbrand BI, Beck ER. “Unexplained” dyspnoea and shrinking lungs in systemic lupus erythematosus. Br Med J 1965;1:1273–7.
92. Thompson PJ, Dhillon DP, Ledingham J, et al. Shrinking lungs, diaphragmatic
dysfunction, and systemic lupus erythematosus. Am Rev Respir Dis 1985;132:
926–8.
93. Allen D, Fischer A, Bshouty Z, et al. Evaluating systemic lupus erythematosus
patients for lung involvement. Lupus 2012;21:1316–25.
94. Gibson CJ, Edmonds JP, Hughes GR. Diaphragm function and lung involvement
in systemic lupus erythematosus. Am J Med 1977;63:926–32.
95. Martens J, Demedts M, Vanmeenen MT, et al. Respiratory muscle dysfunction in
systemic lupus erythematosus. Chest 1983;84:170–5.
96. Laroche CM, Mulvey DA, Hawkins PN, et al. Diaphragm strength in the shrinking
lung syndrome of systemic lupus erythematosus. Q J Med 1989;71:429–39.
97. Hawkins P, Davison AG, Dasgupta B, et al. Diaphragm strength in acute systemic lupus erythematosus in a patient with paradoxical abdominal motion
and reduced lung volumes. Thorax 2001;56:329–30.
98. Betteridge Z, Gunawardena H, North J, et al. Anti-synthetase syndrome: a new
autoantibody to phenylalanyl transfer RNA synthetase (anti-Zo) associated with
polymyositis and interstitial pneumonia. Rheumatology (Oxford) 2007;46:1005–8.
99. Gunawardena H, Betteridge ZE, McHugh NJ. Myositis-specific autoantibodies:
their clinical and pathogenic significance in disease expression. Rheumatology
(Oxford) 2009;48:607–12.
100. Schmidt WA, Wetzel W, Friedlander R, et al. Clinical and serological aspects of
patients with anti-Jo-1 antibodies—an evolving spectrum of disease manifestations. Clin Rheumatol 2000;19:371–7.
101. Mileti LM, Strek ME, Niewold TB, et al. Clinical characteristics of patients with antiJo-1 antibodies: a single center experience. J Clin Rheumatol 2009;15:254–5.
102. Vancsa A, Csipo I, Nemeth J, et al. Characteristics of interstitial lung disease in
SS-A positive/Jo-1 positive inflammatory myopathy patients. Rheumatol Int
2009;29:989–94.
103. Bonnefoy O, Ferretti G, Calaque O, et al. Serial chest CT findings in interstitial
lung disease associated with polymyositis-dermatomyositis. Eur J Radiol
2004;49:235–44.
104. Fathi M, Vikgren J, Boijsen M, et al. Interstitial lung disease in polymyositis and
dermatomyositis: longitudinal evaluation by pulmonary function and radiology.
Arthritis Rheum 2008;59:677–85.
105. Ikezoe J, Johkoh T, Kohno N, et al. High-resolution CT findings of lung disease in
patients with polymyositis and dermatomyositis. J Thorac Imaging 1996;11:
250–9.
106. Richards TJ, Eggebeen A, Gibson K, et al. Characterization and peripheral
blood biomarker assessment of anti-Jo-1 antibody-positive interstitial lung disease. Arthritis Rheum 2009;60:2183–92.
107. Ingegnoli F, Lubatti C, Ingegnoli A, et al. Interstitial lung disease outcomes by
high-resolution computed tomography (HRCT) in anti-Jo1 antibody-positive
polymyositis patients: a single centre study and review of the literature. Autoimmun Rev 2012;11:335–40.
108. Fischer A, Swigris JJ, du Bois RM, et al. Anti-synthetase syndrome in ANA and
anti-Jo-1 negative patients presenting with idiopathic interstitial pneumonia. Respir Med 2009;103:1719–24.
Pulmonary Involvement in Rheumatic Disease 191
109. Ujita M, Renzoni EA, Veeraraghavan S, et al. Organizing pneumonia: perilobular
pattern at thin-section CT. Radiology 2004;232:757–61.
110. Tanizawa K, Handa T, Nakashima R, et al. HRCT features of interstitial lung disease in dermatomyositis with anti-CADM-140 antibody. Respir Med 2011;105:
1380–7.
111. Hoshino K, Muro Y, Sugiura K, et al. Anti-MDA5 and anti-TIF1-gamma antibodies
have clinical significance for patients with dermatomyositis. Rheumatology
(Oxford) 2010;49:1726–33.
112. Le Goff B, Cherin P, Cantagrel A, et al. Pneumomediastinum in interstitial lung
disease associated with dermatomyositis and polymyositis. Arthritis Rheum
2009;61:108–18.
113. Ramos-Casals M, Solans R, Rosas J, et al. Primary Sjogren syndrome in Spain:
clinical and immunologic expression in 1010 patients. Medicine (Baltimore)
2008;87:210–9.
114. Uffmann M, Kiener HP, Bankier AA, et al. Lung manifestation in asymptomatic
patients with primary Sjogren syndrome: assessment with high resolution CT
and pulmonary function tests. J Thorac Imaging 2001;16:282–9.
115. Koyama M, Johkoh T, Honda O, et al. Pulmonary involvement in primary Sjogren’s syndrome: spectrum of pulmonary abnormalities and computed tomography findings in 60 patients. J Thorac Imaging 2001;16:290–6.
116. FranquetT,Gimenez A, MonillJM, et al.PrimarySjogren’s syndromeand associated
lung disease: CT findings in 50 patients. AJR Am J Roentgenol 1997;169:655–8.
117. Lohrmann C, Uhl M, Warnatz K, et al. High-resolution CT imaging of the lung for
patients with primary Sjogren’s syndrome. Eur J Radiol 2004;52:137–43.
118. Parambil JG, Myers JL, Lindell RM, et al. Interstitial lung disease in primary
Sjogren syndrome. Chest 2006;130:1489–95.
119. Ito I, Nagai S, Kitaichi M, et al. Pulmonary manifestations of primary Sjogren’s
syndrome: a clinical, radiologic, and pathologic study. Am J Respir Crit Care
Med 2005;171:632–8.
120. Yamadori I, Fujita J, Bandoh S, et al. Nonspecific interstitial pneumonia as pulmonary involvement of primary Sjogren’s syndrome. Rheumatol Int 2002;22:89–92.
121. Nicholson AG. Classification of idiopathic interstitial pneumonias: making sense
of the alphabet soup. Histopathology 2002;41:381–91.
122. Kokosi M, Riemer EC, Highland KB. Pulmonary involvement in Sjogren syndrome. Clin Chest Med 2010;31:489–500.
123. Honda O, Johkoh T, Ichikado K, et al. Differential diagnosis of lymphocytic interstitial pneumonia and malignant lymphoma on high-resolution CT. Am J Roentgenol 1999;173:71–4.
124. Jeong YJ, Lee KS, Chung MP, et al. Amyloidosis and lymphoproliferative disease in Sjogren syndrome: thin-section computed tomography findings and histopathologic comparisons. J Comput Assist Tomogr 2004;28:776–81.
125. Desai SR, Nicholson AG, Stewart S, et al. Benign pulmonary lymphocytic infiltration and amyloidosis: computed tomographic and pathologic features in three
cases. J Thorac Imaging 1997;12:215–20.
126. Baqir M, Kluka EM, Aubry MC, et al. Amyloid-associated cystic lung disease in
primary Sjogren’s syndrome. Respir Med 2013;107:616–21.
127. Swanton J, Isenberg D. Mixed connective tissue disease: still crazy after all
these years. Rheum Dis Clin North Am 2005;31:421–36, v.
128. Lazaro MA, Maldonado Cocco JA, Catoggio LJ, et al. Clinical and serologic
characteristics of patients with overlap syndrome: is mixed connective tissue
disease a distinct clinical entity? Medicine (Baltimore) 1989;68:58–65.
192 Nair et al
129. Aringer M, Steiner G, Smolen JS. Does mixed connective tissue disease exist?
Yes. Rheum Dis Clin North Am 2005;31:411–20, v.
130. Gunnarsson R, Aalokken TM, Molberg O, et al. Prevalence and severity of interstitial lung disease in mixed connective tissue disease: a nationwide, crosssectional study. Ann Rheum Dis 2012;71:1966–72.
131. Bodolay E, Szekanecz Z, De ´ve ´nyi K, et al. Evaluation of interstitial lung disease
in mixed connective tissue disease (MCTD). Rheumatology 2005;44:656–61.
132. Kozuka T, Johkoh T, Honda O, et al. Pulmonary involvement in mixed connective
tissue disease: high-resolution CT findings in 41 patients. J Thorac Imaging
2001;16:94–8.
133. 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 Tomogr 2002;26:349–57.
134. Suda T, Kaida Y, Nakamura Y, et al. Acute exacerbation of interstitial pneumonia
associated with collagen vascular diseases. Respir Med 2009;103:846–53.
135. Parambil JG, Myers JL, Ryu JH. Diffuse alveolar damage: uncommon manifestation of pulmonary involvement in patients with connective tissue diseases.
Chest 2006;130:553–8.
136. Tachikawa R, Tomii K, Ueda H, et al. Clinical features and outcome of acute
exacerbation of interstitial pneumonia: collagen vascular diseases-related
versus idiopathic. Respiration 2012;83:20–7.
137. Mochizuki T, Aotsuka S, Satoh T. Clinical and laboratory features of lupus patients with complicating pulmonary disease. Respir Med 1999;93:95–101.
138. Grigor R, Edmonds J, Lewkonia R, et al. Systemic lupus erythematosus. A prospective analysis. Ann Rheum Dis 1978;37:121–8.
139. Estes D, Christian CL. The natural history of systemic lupus erythematosus by
prospective analysis. Medicine (Baltimore) 1971;50:85–95.
140. Matthay RA, Schwarz MI, Petty TL, et al. Pulmonary manifestations of systemic
lupus erythematosus: review of twelve cases of acute lupus pneumonitis. Medicine (Baltimore) 1975;54:397–409.
141. Hozumi H, Nakamura Y, Johkoh T, et al. Acute exacerbation in rheumatoid
arthritis-associated interstitial lung disease: a retrospective case control study.
BMJ Open 2013;3:e003132.
142. Rossi SE, Erasmus JJ, McAdams HP, et al. Pulmonary drug toxicity: radiologic
and pathologic manifestations. Radiographics 2000;20:1245–59.
143. Cannon GW. Methotrexate pulmonary toxicity. Rheum Dis Clin North Am 1997;
23:917–37.
144. Sakai F, Noma S, Kurihara Y, et al. Leflunamide-related lung injury in patients
with rheumatoid arthritis: imaging features. Mod Rheumatol 2005;15:173–9.
145. Savage RL, Highton J, Boyd IW, et al. Pneumonitis associated with leflunomide:
a profile of New Zealand and Australian reports. Intern Med J 2006;36:162–9.
146. Sathi N, Chikura B, Kaushik VV, et al. How common is methotrexate pneumonitis? A large prospective study investigates. Clin Rheumatol 2012;31:79–83.
147. Carette S, Macher AM, Nussbaum A, et al. Severe, acute pulmonary disease in
patients with systemic lupus erythematosus: ten years of experience at the National Institutes of Health. Semin Arthritis Rheum 1984;14:52–9.
148. Zamora MR, Warner ML, Tuder R, et al. Diffuse alveolar hemorrhage and systemic lupus erythematosus: clinical presentation, histology, survival, and
outcome. Medicine 1997;76:192–202.
149. Schwab EP, Schumacher HR Jr, Freundlich B, et al. Pulmonary alveolar hemorrhage in systemic lupus erythematosus. Semin Arthritis Rheum 1993;23:8–15.
Pulmonary Involvement in Rheumatic Disease 193
150. Santos-Ocampo AS, Mandell BF, Fessler BJ. Alveolar hemorrhage in systemic
lupus erythematosus: presentation and management. Chest 2000;118:1083–90.
151. Cheah FK, Sheppard MN, Hansell DM. Computed tomography of diffuse pulmonary haemorrhage with pathological correlation. Clin Radiol 1993;48:89–93.
152. Murayama S, Murakami J, Yabuuchi H, et al. “Crazy paving appearance” on high
resolution CT in various diseases. J Comput Assist Tomogr 1999;23:749–52.
153. Tyndall AJ, Bannert B, Vonk M, et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis 2010;69:1809–15.
154. Wallis RS, Broder MS, Wong JY, et al. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis 2004;38:1261–5.
155. Thavarajah K, Wu P, Rhew EJ, et al. Pulmonary complications of tumor necrosis
factor-targeted therapy. Respir Med 2009;103:661–9.
156. Hagiwara K, Sato T, Takagi-Kobayashi S, et al. Acute exacerbation of preexisting interstitial lung disease after administration of etanercept for rheumatoid
arthritis. J Rheumatol 2007;34:1151–4.
157. Pareja JG, Garland R, Koziel H. Use of adjunctive corticosteroids in severe adult
non-HIV Pneumocystis carinii pneumonia. Chest 1998;113:1215–24.
158. Park IN, Kim DS, Shim TS, et al. Acute exacerbation of interstitial pneumonia
other than idiopathic pulmonary fibrosis. Chest 2007;132:214–20.
159. Desai SR, Wells AU, Suntharalingam G, et al. Acute respiratory distress syndrome caused by pulmonary and extrapulmonary injury: a comparative CT
study. Radiology 2001;218:689–93.
160. Owens CM, Evans TW, Keogh BF, et al. Computed tomography in established
adult respiratory distress syndrome. Correlation with lung injury score. Chest
1994;106:1815–21.
161. Goodman LR, Fumagalli R, Tagliabue P, et al. Adult respiratory distress syndrome due to pulmonary and extrapulmonary causes: CT, clinical, and functional correlations. Radiology 1999;213:545–52.
162. Chung JH, Kradin RL, Greene RE, et al. CT predictors of mortality in pathology
confirmed ARDS. Eur Radiol 2011;21:730–7.
163. Silver SF, Muller NL, Miller RR, et al. Hypersensitivity pneumonitis: evaluation
with CT. Radiology 1989;173:441–5.
164. Lacasse Y, Selman M, Costabel U, et al. Clinical diagnosis of hypersensitivity
pneumonitis. Am J Respir Crit Care Med 2003;168:952–8.
165. Hoeper MM. Pulmonary hypertension in collagen vascular disease. Eur Respir J
2002;19:571–6.
166. McLaughlin V, Humbert M, Coghlan G, et al. Pulmonary arterial hypertension:
the most devastating vascular complication of systemic sclerosis. Rheumatology 2009;48:iii25–31.
167. Wells AU, Steen V, Valentini G. Pulmonary complications: one of the most challenging complications of systemic sclerosis. Rheumatology 2009;48:iii40–4.
168. Solomon JJ, Olson AL, Fischer A, et al. Scleroderma lung disease. Eur Respir
Rev 2013;22:6–19.
169. Prakash UB. Respiratory complications in mixed connective tissue disease. Clin
Chest Med 1998;19:733–46, ix.
170. Prabu A, Patel K, Yee CS, et al. Prevalence and risk factors for pulmonary arterial hypertension in patients with lupus. Rheumatology 2009;48:1506–11.
171. Kawut SM, Taichman DB, Archer-Chicko CL, et al. Haemodynamics and survival
in patients with pulmonary artery hypertension related to systemic sclerosis.
Chest 2003;123:344–50.
194 Nair et al
172. Kuriyama K, Gamsu G, Stern RG, et al. CT-determined pulmonary artery
diameters in predicting pulmonary hypertension. Invest Radiol 1984;19:
16–22.
173. Ng CS, Wells AU, Padley SP. A CT sign of chronic pulmonary arterial hypertension: the ratio of main pulmonary artery to aortic diameter. J Thorac Imaging
1999;14:270–8.
174. Devaraj A, Wells AU, Meister MG, et al. The effect of diffuse pulmonary fibrosis
on the reliability of CT signs of pulmonary hypertension. Radiology 2008;249:
1042–9.
175. Nolan RL, McAdams HP, Sporn TA, et al. Pulmonary cholesterol granulomas in
patients with pulmonary artery hypertension: chest radiographic and CT findings. AJR Am J Roentgenol 1999;172:1317–9.
176. Luo YF, Robbins IM, Karatas M, et al. Frequency of pleural effusions in patients
with pulmonary arterial hypertension associated with connective tissue diseases. Chest 2011;140:42–7.
177. Hill C, Nguyen A, Roder D, et al. Risk of cancer in patients with scleroderma: a
population based cohort study. Ann Rheum Dis 2003;62:728–31.
178. Huang YL, Chen YJ, Lin MW, et al. Malignancies associated with dermatomyositis and polymyositis in Taiwan: a nationwide population-based study. Br J Dermatol 2009;161:854–60.
179. Bernatsky S, Boivin JF, Joseph L, et al. An international cohort study of cancer in
systemic lupus erythematosus. Arthritis Rheum 2005;52:1481–90.
180. Rosenthal AK, McLaughlin JK, Gridley G, et al. Incidence of cancer among patients with systemic sclerosis. Cancer 1995;76:910–4.
181. Bin J, Bernatsky S, Gordon C, et al. Lung cancer in systemic lupus erythematosus. Lung Cancer 2007;56:303–6.
182. Hesselstrand R, Scheja A, A ˚ kesson A. Mortality and causes of death in a Swedish series of systemic sclerosis patients. Ann Rheum Dis 1998;57:682–6.
183. Kassan SS, Thomas TL, Moutsopoulos HM, et al. Increased risk of lymphoma in
sicca syndrome. Ann Intern Med 1978;89:888–92.
184. Buchbinder R, Hill CL. Malignancy in patients with inflammatory myopathy. Curr
Rheumatol Rep 2002;4:415–26.
185. Moore OA, Goh N, Corte T, et al. Extent of disease on high-resolution computed
tomography lung is a predictor of decline and mortality in systemic sclerosisrelated interstitial lung disease. Rheumatology 2013;52:155–60.
186. Dawson JK, Fewins HE, Desmond J, et al. Predictors of progression of HRCT
diagnosed fibrosing alveolitis in patients with rheumatoid arthritis. Ann Rheum
Dis 2002;61:517–21.
187. Roth MD, Tseng CH, Clements PJ, et al. Predicting treatment outcomes and
responder subsets in scleroderma-related interstitial lung disease. Arthritis
Rheum 2011;63:2797–808.
188. 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.
189. Edey AJ, Devaraj AA, Barker RP, et al. Fibrotic idiopathic interstitial pneumonias:
HRCT findings that predict mortality. Eur Radiol 2011;21:1586–93.
190. Strange C, Highland KB. Interstitial lung disease in the patient who has connective tissue disease. Clin Chest Med 2004;25:549–59, vii.
191. Mosca M, Neri R, Bombardieri S. Undifferentiated connective tissue diseases
(UCTD): a review of the literature and a proposal for preliminary classification
criteria. Clin Exp Rheumatol 1999;17:615–20.
Pulmonary Involvement in Rheumatic Disease 195
192. Homma Y, Ohtsuka Y, Tanimura K, et al. Can interstitial pneumonia as the sole
presentation of collagen vascular diseases be differentiated from idiopathic
interstitial pneumonia? Respiration 1995;62:248–51.
193. Tzelepis GE, Toya SP, Moutsopoulos HM. Occult connective tissue diseases
mimicking idiopathic interstitial pneumonias. Eur Respir J 2008;31:11–20.
194. Fischer A, West SG, Swigris JJ, et al. Connective tissue disease-associated
interstitial lung disease: a call for clarification. Chest 2010;138:251–6.
196 Nair et al