Connective Tissue Disease-associated Interstitial Lung Disease: A review.
ABSTRACT Interstitial lung disease (ILD) is commonly encountered in patients with connective tissue diseases (CTD). Besides the lung parenchyma, the airways, pulmonary vasculature and structures of the chest wall may all be involved, depending on the type of CTD. As a result of this so-called multi-compartment involvement, airflow limitation, pulmonary hypertension, vasculitis and extrapulmonary restriction can occur alongside fibro-inflammatory parenchymal abnormalities in CTD. Rheumatoid arthritis (RA), systemic sclerosis (SSc), poly-/dermatomyositis (PM/DM), Sjögren's syndrome (SjS), systemic lupus erythematosus (SLE), and undifferentiated (UCTD) as well as mixed connective tissue disease (MCTD) can all be associated with the development of ILD. Non-specific interstitial pneumonia (NSIP) is the most commonly observed histopathological pattern in CTD-ILD, but other patterns including usual interstitial pneumonia (UIP), organizing pneumonia (OP), diffuse alveolar damage (DAD) and lymphocytic interstitial pneumonia (LIP) may occur. Although the majority of patients with CTD-ILD experience stable or slowly advancing ILD, a small yet significant group exhibits a more severe and progressive course. Randomized placebo-controlled trials evaluating the efficacy of immunomodulatory treatments have been conducted only in SSc-associated ILD. However, clinical experience suggests that a handful of immunosuppressive medications are potentially effective in a sizeable portion of patients with ILD caused by other CTDs. In this manuscript, we review the clinical characteristics and management of the most common CTD-ILDs.
- SourceAvailable from: Huan Zhang[Show abstract] [Hide abstract]
ABSTRACT: The variation of G>T in the MUC5B promoter (rs35705950) has been associated with idiopathic pulmonary fibrosis (IPF) and familial interstitial pneumonia (FIP) in Caucasians, but no information is available regarding this variant in the Chinese population. We recruited 405 patients with interstitial lung diseases (ILD), including 165 IPF patients and 2043 healthy controls, for genotyping the MUC5B gene in the Chinese population. One hundred three patients with pneumonia and 360 patients with autoimmune diseases (ADs) were recruited as disease controls. Our results indicated that the prevalence of the minor allele (T) of the polymorphism rs35705950 in healthy Chinese subjects was approximately 0.66%, which was lower than that described in the Caucasian population. The frequencies of the T allele were 3.33% and 2.22% in IPF and ILD patients, respectively, and these values were significantly higher than those of healthy controls (P = 0.001, OR = 4.332 for IPF, and P = 0.002, OR = 2.855 for ILD). A stratified analysis showed that this variant in MUC5B associated with the risk for ILD mainly in older male Chinese subjects. No difference was observed between patients with pneumonia, AD patients, and healthy controls.PLoS ONE 08/2014; 9(8):e104919. · 3.53 Impact Factor
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ABSTRACT: Interstitial lung disease (ILD) is a relevant extra-articular manifestation of rheumatoid arthritis (RA) that may occur either in early stages or as a complication of long-standing disease. RA related ILD (RA-ILD) significantly influences the quoad vitam prognosis of these patients. Several histopathological patterns of RA-ILD have been described: usual interstitial pneumonia (UIP) is the most frequent one, followed by nonspecific interstitial pneumonia (NSIP); other patterns are less commonly observed. Several factors have been associated with an increased risk of developing RA-ILD. The genetic background plays a fundamental but not sufficient role; smoking is an independent predictor of ILD, and a correlation with the presence of rheumatoid factor and anti-cyclic citrullinated peptide antibodies has also been reported. Moreover, both exnovo occurrence and progression of ILD have been related to drug therapies that are commonly prescribed in RA, such as methotrexate, leflunomide, anti-TNF alpha agents, and rituximab. A greater understanding of the disease process is necessary in order to improve the therapeutic approach to ILD and RA itself and to reduce the burden of this severe extra-articular manifestation.BioMed research international. 01/2013; 2013:759760.
INTERSTITIAL LUNG DISEASE (G TINO, SECTION EDITOR)
Connective tissue disease-associated interstitial lung disease:
Markus Gutsche & Glenn D. Rosen & Jeffrey J. Swigris
Published online: 21 September 2012
# Springer Science+Business Media, LLC 2012
Abstract Interstitial lung disease (ILD) is commonly en-
countered in patients with connective tissue diseases (CTD).
Besides the lung parenchyma, the airways, pulmonary vascu-
lature and structures of the chest wall may all be involved,
depending on the type of CTD. As a result of this so-called
multi-compartment involvement, airflow limitation, pulmo-
nary hypertension, vasculitis and extrapulmonary restriction
can occur alongside fibro-inflammatory parenchymal abnor-
malities in CTD. Rheumatoid arthritis (RA), systemic sclero-
sis (SSc), polymyositis/dermatomyositis (PM/DM), Sjögren’s
syndrome (SjS), systemic lupus erythematosus (SLE), and
undifferentiated connective tissue disease (UCTD), as well
as mixed connective tissue disease (MCTD), can all be asso-
ciated with the development of ILD. Nonspecific interstitial
pneumonia (NSIP) is the most commonly observed histopath-
ological pattern in CTD-ILD, but other patterns, including
usual interstitial pneumonia (UIP), organizing pneumonia
(OP), diffuse alveolar damage (DAD) and lymphocytic inter-
stitial pneumonia (LIP), may occur. Although the majority of
ILD, a small yet significant group exhibits a more severe and
progressive course. Randomized placebo-controlled trials
been conducted only in SSc-associated ILD. However, clini-
cal experience suggests that a handful of immunosuppressive
medications are potentially effective in a sizeable portion of
patients with ILD caused by other CTDs. In this manuscript,
we review the clinical characteristics and management of the
most common CTD-ILDs.
Lung involvement is common in connective tissue diseases
(CTDs) and can lead to significant morbidity and shortened
survival. Depending on the underlying CTD, various thoracic
compartments can be involved simultaneously; although, for
this review, we will focus on the parenchymal changes of
CTD-associated interstitial lung disease (CTD-ILD). Most
CTD-ILD presents with a dry cough, gradually progressive
dyspnea and a restrictive ventilatory defect on pulmonary
function tests (PFTs). Many patients diagnosed with CTD-
ILD have a classifiable CTD at the time ILD is recognized;
however, in up to 25 % of cases, a constellation of clinical and
serological findings suggest, but are not entirely diagnostic of,
a classifiable CTD. Patients in such a scenario have been
labeled with “undifferentiated” CTD (UCTD), lung-dominant
CTD and autoimmune-featured ILD by various investigators
[1••, 2]. Lung disease can also predate extrapulmonary CTD
manifestations by several years, thus making the distinction
between CTD-ILD and an idiopathic interstitial pneumonia
(IIP) difficult . Below, we provide a general description of
the physiological, histological and radiological findings and
management features of CTD-ILD and proceed to highlight
of each individual CTD.
M. Gutsche:G. D. Rosen
Interstitial Lung Disease Program, Division of Pulmonary
and Critical Care Medicine, Stanford University,
Stanford, CA, USA
J. J. Swigris (*)
Autoimmune Lung Center and Interstitial Lung Disease Program,
National Jewish Health,
1400 Jackson Street,
Denver, CO 80206, USA
Curr Respir Care Rep (2012) 1:224–232
Clinical features of CTD-ILD
Pulmonary function testing (PFT) The classic PFT pattern
observed in CTD-ILD is a restrictive ventilatory defect and
reduced diffusion capacity (DLco). However, when other
thoracic compartments such as airways, vasculature or chest
wall are involved (as may occur in CTD), clinicians should
be aware that a different constellation of PFT-abnormalities
can arise. For example, a disproportionate reduction in
DLco may signify ILD with coexistent emphysema or pul-
monary hypertension [4••], or a significant reduction in lung
volumes with relatively preserved DLco should raise suspi-
cion for extrapulmonary restriction (e.g., chest wall skin
thickening, respiratory muscle weakness or kyphoscoliosis).
Histopathological patterns Except for rheumatoid arthritis
(RA), in which usual interstitial pneumonia (UIP)-pattern
pathology is more common, the nonspecific interstitial
pneumonia (NSIP) pattern of lung injury is most common
across all CTD-ILD [5, 6•] Compared with cases in which
UIP-pattern injury is idiopathic (i.e., idiopathic pulmonary
fibrosis [IPF]), CTD-associated UIP (CTD-UIP) has fewer
fibroblastic foci, smaller honeycomb cysts, a greater number
of germinal centers and more inflammation . Although
results are conflicting, some studies suggest patients with
CTD-UIP have a better prognosis than IPF-patients. Also a
matter of debate, some studies suggest no difference in
prognosis between CTD-UIP and CTD-NSIP, contrasting
with what is known about the difference in prognosis be-
tween idiopathic NSIP and IPF [6•, 8, 9] Less commonly
encountered injury patterns of CTD-ILD include organizing
pneumonia (OP)—although OP not uncommonly occurs as
a secondary feature in patients with CTD—diffuse alveolar
damage (DAD), lymphocytic interstitial pneumonia (LIP)
and desquamative interstitial pneumonia (DIP).
Because of conflicting study results, many clinicians are
uncertain about the utility of surgical lung biopsy (SLBx) in
their patients with CTD-ILD. On the one hand, many clini-
cians believe that, among patients with CTD-ILD, UIP-
pattern histology confers a worse prognosis than NSIP-
pattern histology. Those in this camp would have their
CTD-ILD patients undergo SLBx, because the results could
better define disease trajectory. On the other hand, clinicians
not using SLBx in their patients with CTD-ILD are either
unconvinced that the histological pattern trumps pulmonary
physiology in determining prognosis, or more likely, do not
expect the results to change management: they plan to treat
(or perhaps already are treating) with immunosuppressive
medications, and the SLBx pattern would not affect their
choice of therapeutic agent or anticipated duration of thera-
py. When an etiology for the ILD other than CTD (e.g.
hypersensitivity pneumonitis) is seriously considered, or
when imaging features suggest malignancy or infection
(e.g. progressive nodules, cavitation, consolidation, pleural
thickening or effusion), there is greater consensus about the
utility of SLBx in this patient population.
High-resolutioncomputer tomography (HRCT) findings Most
parenchymal abnormalities in CTD-ILD are easily appreci-
ated with HRCT and commonly described using terminolo-
gy applied to IIPs (Figs. 1 and 2). While each CTD
demonstrates a predilection for a certain pattern of paren-
chymal involvement, significant overlap exists (Table 1)
[10••, 11]. Overall, a radiographic NSIP-pattern is found most
commonly in CTD-ILDs, and is characterized by intralobular
and interlobular reticular opacities in a predominantly sub-
pleural and basilar distribution. Ground-glass opacities are
usually considered to represent a higher degree of cellularity
and suggest the disease is potentially more responsive to
treatment, although in some cases this is not true. Subpleural
sparing—an opacity-free, thin rim of parenchyma directly
adjacent to the pleura in the posterior zones of the lung
bases—hints at an underlying NSIP-pattern of lung injury
and argues against the UIP-pattern. Reticulation, traction
bronchiectasis and honeycombing reflect fibrotic changes
and more advanced ILD. Abnormalities in other thoracic
structures (e.g., esophageal or pulmonary artery dilatation)—
hinting at the presence of multi-compartment involvement—
should raise suspicion for the presence of a CTD [12••, 13••].
Serological studies Serum auto-antibodies will be explored
in the sections covering each of the CTDs below [13••].
General strategies in the management of CTD-ILD Not
every patient with CTD-ILD requires treatment; thus, it is
important to distinguish trivial disease (with low likelihood
for progression) from clinically significant ILD. HRCT and
PFTs are most helpful in objectively determining disease
severityand its courseovertime,but strongconsensus regard-
ing which patients to treat, when and for how long has not
been achieved for CTD-ILD. In our experience, patients with
disease extent <10 % on HRCT and/or forced vital capacity
Fig. 1 Slice from a HRCT scan from a 65-year-old man with rheuma-
toid arthritis. Note the honeycombing characteristic of a radiographic
Curr Respir Care Rep (2012) 1:224–232225
(FVC)>75 % and/or DLco>65 %, in the absence of respira-
tory symptoms, can be carefully monitored every 3–6 months
for evidence of progression. Since immunomodulatory med-
ications are associated with significant adverse effects, we
reserve treatment for those cases with severe, extensive or
progressive disease. Various regimens have been used to treat
CTD-ILD, but the only large-scale, randomized trials have
been conducted to examine the effectiveness of cyclophos-
phamide (or cyclophosphamide followed by azathioprine) in
patients with SSc-ILD [14, 15]. Data for other immunomod-
ulatory drugs (including azathioprine, mycophenolate mofetil
and tacrolimus) stem from case reports and observational case
series [16-18]. We typically evaluate the response to therapy
every three months. A favorable response may be defined as
improvement in symptoms and functional capacity, or disease
extent on HRCT or pulmonary physiology; however, in this
challenging spectrum of diseases, halting progression and
maintaining stability should also be considered a success. As
mentioned above, there are a number of questions that remain
ripe for investigation.
ILD in specific CTDs
Rheumatoid arthritis (RA) RA is the most common CTD
and is characterized by an erosive inflammatory polyarthr-
opathy with symmetrical arthritis and a range of pulmonary
manifestations. While RA occurs more commonly in
females (female to male ratio 3:1), RA-ILD is more frequent
in males. The prevalence of RA-ILD varies from 5–58 %,
depending on the case definition for ILD [19-21]. Smoking
is a risk factor for RA-ILD, and emerging data suggest that
cigarette smoke exerts its effects by promoting the citrulli-
nation of various proteins in the lung. In fact, theories have
arisen that seropositive RA “starts” in the lung [22, 23].
Severe ILD may occur when joint disease is mild or well
controlled with therapy—there appears to be no reliable
correlation between the extent or severity of the joint disease
and the development or progression of ILD in patients
RA-ILD manifests most commonly in the UIP-pattern,
and less commonly with NSIP-pattern injury. However,
clinicians caring for patients with RA must keep in mind
that medications used to treat extrapulmonary disease (e.g.,
methotrexate) can cause ILD and predispose to opportunis-
tic infections. Thus, a detailed drug history is crucial in all
patients with CTD-ILD. A temporal relationship between
drug initiation and symptom onset and then improvement
after withdrawal can point toward drug-induced lung dis-
ease. However, delayed reactions or continued progression
despite stopping the medication can occur, making the dif-
ferentiation between drug-induced ILD and worsening RA-
ILD challenging. In this situation, diagnostic BAL can help
to exclude infectious etiologies, while BAL-lymphocytosis
and/or eosinophilia with or without peripheral blood eosin-
ophilia can further support the diagnosis of drug-induced
ILD. Some of the most commonly prescribed medications
implicated in pulmonary toxicity include methotrexate,
leflunomide, gold salts, sulfasalazine, and anti-tumor necro-
sis factor (anti-TNF) antibodies [24-28] Ahelpfulonlinetool
listing all medications associated with pulmonary toxicity in
further detail can be found at pneumotox.com [29••]. We
toxicity in RA patients with pre-existing lung disease.
Due to the absence of randomized controlled trials, the
treatment of RA-ILD remains entirely empirical. High-dose
corticosteroids are often used in patients with potentially re-
versible patternssuchasOP or those withflares of RA-ILD.In
addition, cyclophosphamide, azathioprine, cyclosporine or
mycophenolate have been used as steroid sparing agents or
in steroid-refractory cases [17, 18, 30-32]. In our experience,
biologic agents control the joint disease very well, but have
minimal effect on ILD. Lung transplantation is offered by
certain centers to RA-ILD patients with limited joint disease
and relatively preserved functional status.
Fig. 2 Coronal view slice from a HRCT scan from a 58-year-old
woman with dermatomyositis. Notice the ground-glass opacities and
traction bronchiolectasis characteristic of mixed cellular and fibrotic
Table 1 Radiological pattern in CTD-ILD [10, 11]
NSIPUIP OPPHDAD LIPHemorrhage Airways
PM/DM ++++ +
The number of ‘+’ signs indicates the frequency of observed injury
pattern, i.e., ++++ 0 very common or clinically prominent manifestation,
+ 0 less common, empty cells 0 rare or not described in this disease;
RA0rheumatoid arthritis; SSc0systemic sclerosis; PM/DM0polymyosi-
tis/dermatomyositis; SjS0Sjögren’s syndrome; MCTD0mixed-connec-
tive tissue disease; SLE0systemic lupus erythematosus
226Curr Respir Care Rep (2012) 1:224–232
Systemic sclerosis Systemic sclerosis is the CTD with the
largest percentage of patients afflicted with ILD (40–80 %,
depending on method of ascertainment). Along with pulmo-
nary hypertension (PH), ILD is a major cause of death in this
disease [33•, 34]. The frequency of ILD depends on ethnicity,
autoantibody pattern, and less so on the extent of skin disease.
Most patients with SSc have high titers of antinuclear anti-
bodies (ANA)—most often in a nucleolar pattern. Three anti-
bodies with the highest specificity for SSc include
antibodies against anti-RNA polymerase III (Pol3), anti-
centromere antibodies (ACA) and antibodies against
topoisomerase (anti-Scl70). Anti-Scl70 antibodies are
strongly associated with ILD . Although ACA are
protective from significant ILD, patients with ACA carry a
high risk for the development of PH later in the course of the
disease [35•]. The Pol3 antibody is seen with diffuse skin
disease and renal crisis, but is rarely associated with signifi-
cant lung fibrosis [35•].
The majority of patients with SSc-ILD have NSIP-pattern
injury . Less commonly, a UIP-pattern is observed, and
other histophatological patterns (e.g., OP or DAD) are very
rare. As with other CTD-ILD patients, a subset with SSc-ILD
is believed not to require treatment. Some experts adhere to
using a staging system to help determine which SSc-
ILD patients to treat with immunomodulatory therapy:
Goh and colleagues observed that patients with lung
involvement greater than 20 % on HRCT and a FVC<
70 % of predicted were most likely to progress without
therapy . Such patients with more severe disease are
often treated aggressively.
Two randomized placebo controlled trials, the Scleroder-
ma Lung Study (SLS) and the Fibrosing Alveolitis Sclero-
derma Trial (FAST), evaluated cyclophosphamide (given
orally at 2 mg/kg for one year in SLS, and intravenously
at a dose of 600 mg/m2 monthly for six months, followed by
oral azathioprine for the following six months in FAST) for
SSc-ILD [14, 15]. Results from both studies demonstrated a
slower decline in FVC in the cyclophosphamide group
compared with placebo. Intravenous administration of cy-
clophosphamide was associated with a lower rate of gonadal
failure, severe infections and bone marrow toxicity com-
pared to oral medication, presumably due to higher cumu-
lative dose achieved with daily oral medication . Six
months after discontinuation of immunosuppression, the
improvements in FVC waned to baseline, suggesting pro-
longed immunomodulatory therapy may be required to
maintain stability of lung function .
Whether there is a causal relationship between ILD and
esophageal dysmotility/gastroesophageal reflux disease
(GERD)/microaspiration is unclear, but we believe aggres-
sive treatment of these abnormalities in patients with SSc-
ILD (and any other ILD patient with them) is warranted. Co-
management with gastroenterology can be helpful.
Polymyositis and dermatomyositis Both polymyositis (PM)
and dermatomyositis (DM) share the diagnostic criteria of
symmetrical proximal muscle weakness, raised serum mus-
cle enzymes, and muscle biopsy and electromyography
results consistent with myositis. In addition, DM requires
the presence of certain skin manifestations (e.g., heliotrope
rash and Gottron’s sign) to fulfill diagnostic criteria [40,
41•]. In amyopathic DM, classical skin findings of DM are
present without muscle involvement . Overall, pulmo-
nary disease is present in one-third to two-thirds of patients
and is a significant cause of mortality in PM/DM [43•].
In patients with clinically significant disease, two main
types of clinical presentations have been observed. The first
is characterized by subacute onset of dyspnea and wide-
spread basilar predominant ground-glass opacities and con-
solidation against a background of reticulation with traction
bronchiectasis on CT [44•]. Many patients presenting this
way progress significantly over a few weeks to months and
are refractory to therapy. Histopathologically, a DAD pat-
tern atop both OP and NSIP has been described in this
setting [45, 46]. The other form of presentation is more
common and involves an insidious onset and slowly pro-
gressive dyspnea. A combined pattern of NSIP and OP are
observed on HRCT and in histopathological specimens
[47-49]. Other patients with PM/DM can present with a
UIP-pattern of lung injury.
As with most CTDs, lung involvement in PM/DM may
occur before, after or at the same time of the development of
extrapulmonary manifestations [50, 51]. Risk factors for the
development of PM/DM-ILD include a higher age (>45),
joint involvement [51, 52], and in particular, the presence of
aminoacyl-tRNA synthetase (i.e., anti-synthetase or AS)
antibodies. The most commonly identified AS antibody is
directed against anti-histidyl-tRNA synthetase (anti-Jo1)
and is present in 25–40 % of all patients with PM/DM
[53•, 54, 55] and in 30–75 % of those cases with ILD [49,
52, 56-58]. Other less commonly found antibodies include
anti-PL-7, -PL-12, -OJ, -EJ, -KS and -Zo [51, 55, 59]. The
combination of arthritis, myositis, anti-synthetase antibodies
and ILD constitutes the anti-synthetase syndrome. Ray-
naud’s phenomenon, “mechanic’s hands” (dry, rough, fis-
sured skin of the hands, particularly on the thenar side of the
index finger and the finger tips) and fever, while not part of
the diagnostic criteria of anti-synthetase syndrome, are other
findings frequently encountered . It is not entirely clear
whether AS antibodies are pathogenic or merely disease
markers. In addition, it is unknown whether the different
AS antibodies portend different clinical phenotypes.
As with most other CTDs, no definitive recommenda-
tions for the treatment of PM/DM-associated ILD exist due
to the lack of randomized clinical trials. High-dose oral
prednisone is often used as first-line therapy in PM/DM-
associated ILD. In the US, azathioprine and mycophenolate
Curr Respir Care Rep (2012) 1:224–232 227
are the most frequently used immunomodulatory agents for
PM/DM-ILD; however, there are case reports and case
series suggesting a role for the calcineurin antagonists [60,
61]. In severe, rapidly progressive disease, intravenous cy-
clophosphamide in conjunction with high-dose methylpred-
nisone has been used [62, 63]. Rituximab has been tried in
patients who failed to respond to conventional immunosup-
pressive regimens or who presented with rapidly progres-
sive DAD [64, 65]. In addition to treating refractory
myositis, intravenous immunoglobulins have been used
with some success to treat rapidly progressive ILD . In
PM/DM, the risk of malignancy is increased and screening
for occult neoplasm should be considered, particularly in
patient without AS antibodies.
Sjögren’s syndrome In 1933 Sj gren introduced the term
“keratoconjunctivitis sicca”, also referred to as “sicca com-
plex” to describe a syndrome characterized by dry eyes and
dry mouth . Sj gren’s syndrome (SjS) is a chronic in-
flammatory condition characterized by lymphocytic infiltra-
tion of exocrine glands (including salivary and lacrimal
glands), and other structures, including the lungs. It can
occur either in isolation, when it is referred to as primary
SjS, or as a secondary phenomenon in the setting of another
established CTD, in which case it is termed secondary SjS
[68•]. The primary form displays more severe exocrine
dysfunction, including renal tubular disorder, neurological
involvement and vascular disorders (Raynaud’s phenome-
non and vasculitis) . In the absence of a salivary gland
biopsy demonstrating focal lymphocytic sialoadenitis, the
presence of “keratoconjunctivitis sicca” and anti-nuclear anti-
bodies against ribonucleoproteins Ro/SSA and La/SSB is
required to fulfill diagnostic criteria in both primary and
secondary SjS . Polyclonal hypergammaglobulinemia,
elevated sedimentation rate and other autoimmune antibodies
(e.g., rheumatoid factor) can be found with varying frequency
in SjS and are nonspecific [70, 71]. Patients with SjS are at
increased risk for pulmonary and other lymphomas [72•, 73].
Although restriction and reduced DLco have been found
in 17–37.5 % of patients with SjS, clinically significant ILD
is rare, and in most cases SjS-ILD follows a mild and self-
limited course [74, 75]. Respiratory symptoms mostly relate
to dry mucous membranes predisposing patients with SjS to
hoarseness and dry cough (due to xerotrachea). Patients with
SjS are at increased risk of respiratory tract infections, due
to impaired immune function of the mucosal barrier lining
the airway epithelium. Exertional dyspnea is reported by
some patients [75, 76]. Pleuritis, PAH, middle lobe syn-
drome and shrinking lung syndrome have been described
in SjS rarely [77•, 78-80].
Authors of older series reported LIP as the most common
histopathological pattern in patients with SjS, but more
recent studies have revealed a higher frequency of NSIP-
pattern injury in this disease [81•, 82]. This finding is likely
based on the reclassification of many cases as cellular NSIP,
which in the past would have been interpreted as LIP .
Other less commonly observed patterns include OP and UIP.
In patients with SjS-ILD, HRCT and histopathological find-
ings correlate well with each other, so SLBx is usually not
recommended [82, 84, 85]. However, radiographic features
suggestive of lymphoma (see below) require thorough in-
vestigation [86•]. Ground-glass opacities and thin-walled
cysts in a peri-bronchovascular distribution can occur with
LIP. Centrilobular nodules are noted with LIP or lympho-
cytic bronchiolitis. Pulmonary lymphoma accounts for ap-
proximately 20 % of all SjS-associated lymphomas [73, 74].
Both LIP and pulmonary lymphoma have overlapping fea-
tures, including ground-glass opacification, small nodules
and hilar-mediastinal lymphadenopathy. Consolidation,
large nodules measuring more than 10 mm, as well as
pleural effusions, are more common in lymphoma, whereas
cysts are more frequently observed in LIP .
Unclassifiable connective tissue disease
A large minority of patients with ILD do not fulfill the
diagnostic criteria for any specific CTD, but display features
including positive serologies and systemic extrapulmonary
manifestations that are reminiscent of an underlying auto-
immune disease. Such patients have been labeled as having
an “autoimmune flavor” . Over the course of follow-up,
a number of these patients go on to develop clinical and
serological characteristics that fulfill diagnostic criteria for a
specific CTD [88•]. Ongoing investigations aim to deter-
mine how best to follow, treat and conduct research in this
interesting population. Such patients are different from those
with anti-U1 RNP antibodies and features of more than one
specific CTD who have mixed connective tissue disease
(MCTD)—a specific CTD [89•]. While a large number of
patients with MCTD have pulmonary involvement, most
have relatively mild disease, and many are asymptomatic
. Pleural effusions, ILD consistent with NSIP and some-
times UIP, and PAH, either as a result of CTD-ILD or in
isolation, have all been described in MCTD [91•, 92].
Systemic lupus erythematosus SLE is a multisystem disor-
der afflicting joints, skin, kidneys, central nervous system,
and serosal surfaces of internal organs including heart and
lungs. The disease is more prevalent in women of reproduc-
tive age and African Americans . Almost all patients are
anti-nuclear antibody (ANA) positive [94, 95]. Four or more
criteria are required to establish the diagnosis [96•]. Inter-
estingly, these criteria do not include any pulmonary mani-
festations, except for pleuritis. Although respiratory
symptoms associated with SLE are often absent, abnormal
228Curr Respir Care Rep (2012) 1:224–232
PFT and HRCT findings are common, and the prognosis is
significantly worse in patients experiencing pulmonary
complications [97, 98•, 99, 100].
While trivial lung disease is present in one third of
patients, clinically significant disease afflicts only 3–8 %
of the lupus population [101, 102]. In some cases, acute
lupus pneumonitis (ALP) with a DAD-pattern heralds the
development of ILD . Similar to most other CTD-
ILDs, NSIP is the most commonly observed histopatholog-
ical pattern, but LIP, OP and UIP have all been described
[98•, 104-106]. Diffuse alveolar hemorrhage (DAH) and
ALP are characterized by acute onset of dyspnea with fever,
cough and in the case of DAH, sometimes hemoptysis. A
sudden decrease in hemoglobin is highly suggestive of
DAH [99, 104, 107, 108]. Approximately one-half of
patients with DAH require mechanical ventilation. An in-
creasingly bloody return on BAL is diagnostic and sup-
ported by high counts of red blood cells and hemosiderin-
laden macrophages on the differential cell count. A neutro-
philic capillaritis and alveoli filled with red blood cells are
seen on histopathology of lung tissue from patients with
DAH . In ALP, the histopathological picture resembles
DAD, but without hemorrhage or capillaritis . Both
ALP and DAH present with diffuse, bilateral ground-glass
opacities on HRCT. In this setting pulmonary edema, drug
reactions as well as infection all need to be excluded.
Due to the high incidence of infections in SLE, broad-
spectrum antibiotic therapy should be started empirically with-
out delay, while infectious etiologies are excluded and before
aggressive immunosuppression is initiated. DAH and ALP
carry a mortality rate of 50 % [104, 109]. In patients requiring
mechanical ventilation, a lung protective strategy with low
tidal volumes should be used. We recommend high-dose in-
travenous methylprednisone (1 g daily for 72 hours), followed
mide. In refractory cases of DAH or ALP, plasmapheresis and
intravenous immunoglobulins have been described [99, 104].
Success with rituximab has also been reported .
CTD-ILD comprises a heterogeneous group of disorders
marked by varying degrees of fibrosis and/or inflammation
within the lung parenchyma. ILD is a potentially morbid and
life-threatening complication of any CTD, but it is most
commonly seen in patients with RA, SSc or PM/DM. A
large group of patients have features suggestive of CTD, but
cannot be classified according to currently available sys-
tems. How best to treat them—or other patients with CTD-
ILD—is based largely on experience and observational
studies. Future research is required to advance understand-
ing of the pathogenesis of CTD-ILD and to help determine
which patients require therapy, what drugs to use and how
long to use them.
Development Award from the NIH (K23 HL092227).
Dr. Swigris is supported in part by a Career
No potential conflicts of interest relevant to this article
Papers of particular interest, published recently, have been
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