468

Connective Tissue Disease-Associated Interstitial

Lung Diseases: Unresolved Issues
Irene Jarana Aparicio, MD1

Joyce S. Lee, MD, MAS2

1 Department of Respiratory Medicine, Gregorio Maraon Hospital,

Madrid, Spain
2 Division of Pulmonary Sciences and Critical Care Medicine,
Department of Medicine, University of Colorado Denver,
Aurora, Colorado

Address for correspondence Joyce S. Lee, MD, MAS, Division of

Pulmonary Sciences and Critical Care Medicine, Department of
Medicine, University of Colorado Denver, 12700 E. 19th Avenue C-272,
Aurora, CO 80045 (e-mail: joyce.lee@ucdenver.edu).

Abstract

Keywords

connective tissue
disease
interstitial lung
disease
autoimmunity
interstitial pneumonia

Interstitial lung disease (ILD) complicating connective tissue disorders, such as scleroderma and rheumatoid arthritis, is associated with signicant morbidity and mortality.
Progress has been made in our understanding of these collective diseases; however,
there are still many unanswered questions. In this review, we describe the current views
on epidemiology, clinical presentation, treatment, and prognosis in patients with
connective tissue disease (CTD)-associated ILD. We also highlight several areas that
remain unresolved and in need of further investigation, including interstitial pneumonia
with autoimmune features, histopathologic phenotype, and pharmacologic management. A multidisciplinary and multidimensional approach to diagnosis, management,
and investigation of CTD-associated ILD patients is essential to advance our understanding of the epidemiology and pathobiology of this challenging group of diseases.

The term connective tissue disease (CTD) encompasses

multiple entities, whose common characteristic is the immune-mediated injury of collagen, which can affect many
organs, including the lungs. Interstitial lung disease (ILD) is a
common manifestation of these systemic autoimmune disorders and confers a signicant impact on morbidity and
mortality, making their diagnosis, classication, and treatment a priority.
Although signicant progress has been made in the understanding of CTD-related ILD (CTD-ILD), there are still many
unanswered questions in this eld. This review describes the
current views on epidemiology, clinical presentation, treatment, and prognosis in patients with CTD-ILD and highlights
several areas that remain unresolved and in need of further
investigation.

Epidemiology
The prevalence of CTD-ILD varies in the literature. Depending
on the study design and population studied, the prevalence of

Issue Theme Orphan Lung Diseases;

Guest Editors: Jay H. Ryu, MD, and Luca
Richeldi, MD

ILD can be anywhere from 1 to 80% (Table 1). The prevalence

estimate also depends on the criteria used to diagnose the
ILD. When using radiologic criteria for diagnosis, the prevalence is much higher, but likely captures patients who may
otherwise be asymptomatic.1
Risk factors for the development of CTD-ILD depend on the
underlying CTD (Table 1). For example, in rheumatoid
arthritis, ILD has been associated with more severe rheumatoid arthritis, male gender, older age, and smoking history.2
Serologies may also identify patients at higher risk for the
development of rheumatoid arthritis-associated ILD. In a case
series of 356 patients with rheumatoid arthritis, high titers of
rheumatoid factor (
100 IU/mL)3 and specic subtypes of
anticyclic citrullinated peptide antibodies4 were associated
with an increased risk of ILD. In scleroderma, development of
ILD has been associated with African American ethnicity,
hypothyroidism, cardiac involvement, higher skin scores,
and creatine phosphokinase levels.5 ILD in scleroderma also
appears to be less common in those with the anticentromere
antibody.6

Copyright 2016 by Thieme Medical

Publishers, Inc., 333 Seventh Avenue,
New York, NY 10001, USA.
Tel: +1(212) 584-4662.

DOI http://dx.doi.org/
10.1055/s-0036-1580689.
ISSN 1069-3424.

Downloaded by: Chulalongkorn University. Copyrighted material.

Semin Respir Crit Care Med 2016;37:468476.

Connective Tissue Disease-Associated ILDs

Aparicio, Lee

469

Table 1 Interstitial lung disease in connective tissue diseaseprevalence and associated risk factors
Connective tissue disease

Prevalence

Associated risk factors

1.641%

Age, cigarette smoking, serologies (rheumatoid factor and anticyclic

citrullinated peptide), male gender, rheumatoid arthritis severity

Idiopathic inammatory myopathies113

580%

Ethnicity, serologies
(anti-amino-acyl-tRNA synthetases, anti-MDA-5 antibodies)

Scleroderma5,114

5565%

Ethnicity, diffuse disease, serologies (anti-topoisomerase antibody),

hypothyroidism, cardiac involvement, and creatine phosphokinase

Sjgren syndrome115

975%a

Inconsistent data

115%

Age, disease duration, serologies (anti-(U1) RNP antibodies)

5070%

Limited data

Rheumatoid arthritis

112

Systemic lupus erythematosus

116

Mixed connective tissue disease

For lung involvement, no numbers on interstitial lung disease alone.

Clinical Manifestations

Diagnostic Evaluation

In many patients, CTD-ILD is initially asymptomatic followed by the development of nonspecic symptoms. The
most common symptoms are exertional dyspnea and dry
cough. Often times, the symptom of dyspnea can be confused with generalized weakness and deconditioning, particularly due to the systemic nature of CTDs. As the lung
disease progresses, patients can develop pulmonary hypertension resulting in signs and symptoms of right heart
failure. Other respiratory signs and symptoms associated
with CTD-ILD include resting and exertional hypoxemia,
pleuritic chest pain, hemoptysis, expectoration of mucus,
and wheezing.
Although the presence of an underlying CTD is often well
dened in many patients presenting with ILD, the lungs
may be the rst and/or primary manifestation of an underlying CTD.7,8 If the underlying CTD is not known at the time
of presentation, specic attention to symptoms suggestive
of an underlying CTD is important.9 The medical history
should include questions regarding joint pain and swelling,
muscle weakness, and morning stiffness. Other signs and
symptoms include fever, mechanics hands, skin thickening, Raynaud phenomenon, rash or telangiectasias, gastroesophageal reux and regurgitation, and dryness of the
mucosal surfaces.
In some cases, the clinical features suggestive of an
underlying autoimmune process may not meet established
criteria for a dened CTD. This population of patients has
gained increasing recognition and several researchers have
proposed differing criteria to dene these patients.7,8,10,11
Although each of these criteria differ in regard to clinical
symptoms, serologies, and pathology, they generally identify a similar group of patients.12 Given the lack of consensus in this area, the European Respiratory Society and
American Thoracic Society Task Force came together to
build a diagnostic platform on which to better understand
this condition.13 They proposed the term interstitial pneumonia with autoimmune features or IPAF. The proposed
denition is not meant for clinical use at this time and
future research should be done to better understand this
condition.

Serologic testing is often performed when an underlying CTD

is suspected. Similar to most diagnostic tests, serologies alone
are often neither sensitive nor specic for a particular CTD. In
a study looking at patients with idiopathic pulmonary brosis
(IPF), a common form of ILD that is not associated with an
underlying CTD,14 the frequency of detectable serologies was
no different compared with healthy controls.15 Therefore,
developing a close collaboration with a rheumatologist is
essential to understand the signicance of positive (and
negative) serologies in the setting of nonspecic signs and
symptoms in the hunt for an underlying CTD. Identifying an
accurate CTD is important, as this has consequences for
prognosis, treatment, and the development of other comorbid conditions. In those with an established CTD, further
serologic testing is often not indicated.
Pulmonary function tests should be performed on all
patients with CTD-ILD. This helps determine the degree of
pulmonary impairment and is also necessary to monitor
disease activity. The most common physiologic abnormality
on pulmonary function testing is restrictive physiology and a
decreased diffusion capacity.
High-resolution computed tomography (HRCT) scans are
an important test in patients with CTD-ILD and is considered
the gold standard radiographic exam in patients with ILD. The
radiologic patterns most commonly found in CTD-ILD are
very similar to those found in the idiopathic interstitial
pneumonias.16 The most frequent radiologic patterns include
nonspecic interstitial pneumonia (NSIP), usual interstitial
pneumonia (UIP), organizing pneumonia (OP), and lymphoid
interstitial pneumonia (LIP) (Fig. 1). Mixed or unclassiable
patterns can also be observed.
If there is concern that the underlying ILD is not related to
the underlying CTD (e.g., infection, drug toxicity, malignancy), a bronchoscopy with bronchoalveolar lavage and/or a
lung biopsy may be necessary. The histopathologic patterns in
CTD-ILD also mimic those found in the idiopathic interstitial
pneumonias.17 The most common pattern observed is cellular
and/or brotic NSIP for the majority of CTDs (Fig. 2). The
exception is among those with rheumatoid arthritis, where
the prevalence of the UIP pattern is higher.18
Seminars in Respiratory and Critical Care Medicine

Vol. 37

No. 3/2016

Downloaded by: Chulalongkorn University. Copyrighted material.

117

Connective Tissue Disease-Associated ILDs

Aparicio, Lee

Fig. 1 (A) Radiologic pattern of nonspecic interstitial pneumonia in a patient with scleroderma. There are ground glass opacities with
reticulation and subpleural sparing. (B) Radiologic pattern of usual interstitial pneumonia in a patient with rheumatoid arthritis. There is
subpleural and basilar predominant honeycombing. (C) Radiologic pattern of organizing pneumonia in a patient with idiopathic inammatory
myositis. There are areas of dense consolidation. A subsequent lung biopsy demonstrated nonspecic interstitial pneumonia and organizing
pneumonia. (D) Radiologic pattern of lymphocytic interstitial pneumonia in a patient with Sjgren disease. There are scattered thin-walled cysts in
both lungs. (Images courtesy of Brett Elicker, MD.)

In most circumstances, a lung biopsy is not performed in

the setting of a dened CTD. This is because the management
approach to CTD-ILD is independent of the underlying histopathologic pattern. In other words, unlike the idiopathic
interstitial pneumonias where the underlying histopathologic pattern guides therapy and prognosis, all phenotypes of
CTD-ILD are treated the same.
This is another unresolved area in patients with CTD-ILD.
Identication of the underlying histopathologic phenotype
was a paradigm shift for the eld of ILD, specically for those
with idiopathic interstitial pneumonias. With the recognition
that patients with UIP pattern had a different clinical phenotype and prognosis compared with other histopathologic
patterns (e.g., NSIP), we have become more rened in our
approach to ILD diagnosis and management.19,20 We have
also learned that common immunosuppressive medications
used in the treatment of many forms of ILD, a combination of
prednisone, azathioprine, and N-acetylcysteine, is harmful in
patients with IPF, a form of idiopathic UIP.21 What is not clear
at this time is if patients with CTD and a UIP pattern should be
treated the same as a patient with CTD and an NSIP pattern. If
the biology of UIP pattern is consistent across etiologies (e.g.,
idiopathic or secondary to an autoimmune condition or
exposure), we could be harming CTD patients with a UIP
pattern with our general immunosuppressive strategy.22
Seminars in Respiratory and Critical Care Medicine

Vol. 37

No. 3/2016

Future research should be done to determine if histopathologic phenotype is important in the diagnosis and management of CTD-ILD patients.

Treatment and Management

The rst step in the treatment of a patient with CTD-ILD is to
determine if treatment is indicated.23 Treatment should be
considered in all patients with severe or progressive disease.
Determining disease severity and activity can be difcult, but
a combination of clinical symptoms, pulmonary function
tests, and imaging can be used. It is also important to consider
contraindications to therapy, including comorbid conditions
and drug interactions.24
For many CTD-ILDs, identifying patients at risk for progressive disease is challenging due to a variable disease
course. In IPF, the GAP (gender, age, physiology) model has
been used to categorize the risk of death over a 3-year time
period.25 A similar model was developed in a broader population of ILD patients, including CTD-ILD. However, this has
not been validated and risk prediction within specic CTDs is
not well understood. Among patients with sclerodermaassociated ILD, factors such as percentage of predicted forced
vital capacity (FVC), extent of disease on HRCT scan, and age
have all been identied as risk factors for progressive

Downloaded by: Chulalongkorn University. Copyrighted material.

470

Aparicio, Lee

Fig. 2 (A) Histopathologic pattern of brotic nonspecic interstitial pneumonia in a patient with scleroderma. There is relatively diffuse alveolar
septal thickening by brosis. (B) Usual interstitial pneumonia pattern brosis in a patient with rheumatoid arthritis. There is advanced subpleural
brosis with microscopic honeycombing and broblast foci. Other regions showed less brotic alveolar tissue. (C) Histopathologic pattern of
organizing pneumonia in a patient with dermatomyositis. Rounded plugs of granulation tissue are present within airspaces. (D) Histopathologic
pattern of lymphoid interstitial pneumonia in a patient with Sjgren syndrome. There are prominent lymphoid aggregates around bronchioles and
marked alveolar septal thickening by chronic lymphoplasmacytic inammation. (Images courtesy of Kirk Jones, MD.)

disease.2628 Unfortunately, many of the studies were limited

by lack of multivariate modeling, sample size, and lack of
validation. The development of practical risk prediction
models in patients with CTD-ILD may help identify those
who are at high risk for mortality, which could guide treatment, counseling, and clinical trial design.
Once a decision has been made to treat a patient with CTDILD, the general pharmacologic treatment approach is with
systemic immunosuppression. There are very few randomized controlled trials in patients with CTD-ILD and is another
area in which there are many unresolved issues. Until more
trials are performed, many of the treatment regimens used
are experience based rather than evidence based. In the
next section, we review the most common pharmacologic
treatment options for patients with CTD-ILD.

Corticosteroids
Corticosteroids are considered rst-line therapy in CTD-ILD29
despite the lack of controlled trials of corticosteroids in these
patients.3032 Corticosteroids are often used in combination
with other drugs called steroid sparing agents (e.g., azathioprine, mycophenolate mofetil). When utilized in combination, the corticosteroid dose can often be reduced, which
decreases the cumulative toxicity and adverse side effects

associated with long-term use of corticosteroids.33 Starting

dose is generally around 0.5 mg/kg (ideal body weight) of
prednisone (or equivalent), generally not exceeding 40 mg
daily.23 After a treatment response is achieved and the
steroid-sparing agent dose is escalated, the corticosteroids
can be tapered to a lower maintenance dose. In some cases,
the corticosteroids may be completely discontinued. The side
effects of long-term corticosteroid use are well recognized
and include weight gain, glucose intolerance, emotional
lability, and opportunistic infection.34

Cyclophosphamide
Cyclophosphamide is a potent immunosuppressive medication. The use of cyclophosphamide has been studied in several
prospective and retrospective studies in CTD-ILD demonstrating stabilization or improvement in lung function.3541
The largest of these was the Scleroderma Lung Study (SLS),
which was a clinical trial that randomized 158 subjects to oral
cyclophosphamide or placebo.42 After 12 months of treatment, subjects randomized to oral cyclophosphamide had a
more favorable change in FVC compared with placebo
(p< 0.03). This effect was not sustained, and the cyclophosphamide group and the placebo group had similar FVC
measures by 24 months. There is signicant toxicity
Seminars in Respiratory and Critical Care Medicine

Vol. 37

No. 3/2016

471

Downloaded by: Chulalongkorn University. Copyrighted material.

Connective Tissue Disease-Associated ILDs

Connective Tissue Disease-Associated ILDs

Aparicio, Lee

associated with cyclophosphamide, including bone marrow

suppression, infection, risk of malignancy, and bladder toxicity.43 This limits the routine use of cyclophosphamide in CTDILD and is often reserved for those with more severe manifestations of their disease.44

Azathioprine
Azathioprine is a commonly used and effective steroid-sparing agent for many CTDs.4548 The use of azathioprine for the
treatment of CTD-ILD is common; however, the data supporting its use are primarily limited to small retrospective series.40,4952 A retrospective review of 13 patients with
polymyositis- or dermatomyositis-associated ILD demonstrated a reduction in dyspnea, PFT stabilization, and a
reduction in corticosteroid dose after 12 months of treatment
with azathioprine.40 In another retrospective review of 11
patients with scleroderma-associated ILD, 8 subjects had at
least 12 months of treatment and had stable-to-improved
pulmonary function.52 The other three subjects discontinued
treatment due to side effects. A common starting dose is 0.5
mg/kg/day, increasing by 25 mg every 2 weeks up to 2 to 3
mg/kg/day, not exceeding a total dose of 200 mg/day.23 The
most common side effects are gastrointestinal intolerance,
bone marrow suppression, and infection.53,54

Mycophenolate Mofetil
Mycophenolate mofetil is an inhibitor of lymphocyte proliferation and is increasingly being used as a steroid-sparing
agent in CTD-ILD.44 The data supporting the use of mycophenolate mofetil are limited to small retrospective series.5558 The largest series included 125 patients with
CTD-ILD, including patients with scleroderma, myositis,
and rheumatoid arthritis.58 They reported that treatment
with mycophenolate mofetil was well tolerated and associated with effective reduction in corticosteroid dosing during
the follow-up period. They also reported stable-to-improved
pulmonary function in this retrospective cohort. A typical
starting dose is 500 mg twice daily, increasing by 500 mg
every 2 weeks up to 2,000 to 3,000 mg daily. The most
common side effects are similar to those of azathioprine
with gastrointestinal intolerance, bone marrow suppression,
and infection.59

Calcineurin Inhibitors
Calcineurin inhibitors (e.g., cyclosporine A and tacrolimus)
inhibit interleukin (IL-2)-mediated CD4 T cell activation.60
They are commonly used in the immunosuppression regimen
following solid organ transplantation.59 Among the CTD-ILDs,
the most experience is with the myositis-related ILDs
(e.g., polymyositis, dermatomyositis, antisynthetase syndrome).6166 A recent retrospective study of 49 untreated
patients with polymyositis- or dermatomyositis-associated
ILD were analyzed.65 Approximately half of the patients
(n 25) were treated with tacrolimus plus conventional
therapy, while the other half were treated with conventional
therapy, dened as prednisolone plus an additional agent
(intravenous cyclophosphamide or cyclosporine). They
reported that those in the tacrolimus group had longer
Seminars in Respiratory and Critical Care Medicine

Vol. 37

No. 3/2016

event-free survival and longer disease-free survival compared with the conventional therapy group. The most common side effects of calcineurin inhibitors include
hypertension and renal impairment.67 Both cyclosporine A
and tacrolimus require serum monitoring. Suggested trough
levels for cyclosporine A are between 100 and 200 ng/mL68
and between 5 and 20 ng/mL for tacrolimus.61,63

Rituximab
Rituximab is a monoclonal antibody against CD-20 B-cells,
which leads to B-cell depletion for up to 6 months. Rituximab
is a common treatment for many connective tissue disorders
(e.g., systemic vasculitis and rheumatoid arthritis),69 but is
less well studied in those with CTD-ILD. A retrospective
review of 50 patients with severe and progressive ILD, despite
conventional immunosuppression, had a median improvement in FVC and stability in the diffusing capacity for carbon
monoxide.70 In this cohort, 33 patients had CTD-ILD, 2
developed serious infections requiring hospitalization, and
10 died from progressive lung disease. There are also some
case series describing the use of rituximab in ILD associated
with antisynthetase syndrome,7174 scleroderma,75,76 and
rheumatoid arthritis.77 Rituximab is now being studied in a
randomized, double-blind, controlled trial compared with
intravenous cyclophosphamide in patients with CTD-ILD
(clinicaltrials.gov). The primary outcome of this study is
absolute change in FVC over 48 weeks. The most common
side effect of rituximab is opportunistic infection.7174

Emerging Treatment Options

Intravenous immunoglobulin (IVIG) contains pooled, polyvalent, IgG antibodies extracted from plasma.78 The mechanism of action of IVIG is not completely understood, but
likely has immunomodulatory as well as anti-inammatory
effects in patients with autoimmune or inammatory conditions.78 IVIG is often used as rescue therapy among
subjects with CTD, in particular those with inammatory
muscle disease and certain subsets of systemic lupus
erythematosus patients.7984 There are some emerging
data on the use of IVIG among those with CTD-ILD,85,86
but very little data are known about the efcacy of IVIG in
the treatment of this disease.
Novel antibrotic medications (e.g., nintedanib and pirfenidone) have been recently approved by the FDA for the
treatment of IPF, one of the most common forms of ILD. It is
unknown at this time if these medications have a role in the
treatment of CTD-ILD. In patients with scleroderma-associated ILD, the safety and tolerability of pirfenidone was tested in
the LOTUSS (Safety and Tolerability of Pirfenidone in Patients
with Systemic Sclerosis-Associated Interstitial Lung Disease)
study.87 In this open-label study, pirfenidone was found to be
safe and generally well tolerated, with adverse events that
were expected and consistent with those seen in the IPF trials.
Further studies will need to be performed to determine if
either of these medications is efcacious in CTD-ILD.
Lung transplantation for CTD-ILD can be considered in
those patients with severe or progressive disease despite
medical therapy. However, this remains a controversial area

Downloaded by: Chulalongkorn University. Copyrighted material.

472

Connective Tissue Disease-Associated ILDs

Additional Management Strategies

The care of patients with CTD-ILD should involve a comprehensive and multidisciplinary approach. Although there are
limited data to support this approach, these interventions are
generally low risk and may improve quality of life, exercise
tolerance, and reduce symptoms. General measures include
smoking cessation and infection prophylaxis. Infection prophylaxis includes the administration of appropriate vaccines
(e.g., yearly inuenza vaccine and the pneumococcal vaccine)
as well as Pneumocystis jiroveci pneumonia (PjP) prophylaxis.93 Prophylaxis for PjP is recommended when combination
immunosuppressive therapy is used or when corticosteroid
doses exceed 20 mg daily for a sustained period of time.94
Pulmonary rehabilitation is a structured exercise and
education program that increases exercise tolerance improves muscle deconditioning, and improves quality of life
in patients with chronic respiratory disorders, including CTDILD.95,96 Although these programs have been designed primarily for patients with chronic obstructive pulmonary disease, they are being increasingly used by patients with ILD.97
Efforts are ongoing to help tailor pulmonary rehabilitation
programs to patients with ILD.
Supplemental oxygen therapy should also be prescribed in
CTD-ILD patients with low resting oxygen saturations and
those who desaturate at night or with ambulation. There are
no studies demonstrating a survival benet of oxygen therapy; however, it can positively impact quality of life and
exercise tolerance in patients with ILD.98
Finally, a careful investigation for comorbid conditions
should be done in patients with CTD-ILD, as these can
impact morbidity and mortality.99101 Depending on the
underlying CTD-ILD, the comorbidities could include cardiovascular disease,102,103 lung cancer,104,105 thromboembolic disease, 106 gastroesophageal reux disease,99,100 and
pulmonary hypertension.107

now the leading cause of death in this group of patients.108 In

rheumatoid arthritis, patients with ILD had a median survival
after ILD diagnosis of 2.6 years, which is a threefold higher risk
for death compared with their rheumatoid arthritis counterparts without ILD.109 In addition, mortality rates due to
rheumatoid arthritis-associated ILD appear to be increasing
over time despite the overall decline in mortality in patients
with rheumatoid arthritis.110 Interestingly, in patients with
idiopathic inammatory myopathies (e.g., polymyositis,
dermatomyositis), the presence of ILD was not associated
with worse prognosis in a retrospective review of 62 patients,
approximately half of whom had ILD.111

Conclusion
Signicant progress has been made in our understanding of
CTD-ILD. Several of the areas requiring further investigation
were highlighted in this review, including the unclear signicance of patients who have features suggestive of an underlying CTD (i.e., IPAF patients), the unknown role of
distinguishing histopathologic phenotypes among patients
with CTD-ILD, and the lack of controlled clinical trials to
inform pharmacologic management of patients with CTDILD. Moving forward, a multidisciplinary and multidimensional approach to diagnosis, management, and investigation
of CTD-ILD patients will be essential for us to better understand the epidemiology and pathobiology of this challenging
group of diseases.

Funding
None.

Acknowledgments
We thank Brett Elicker, MD, for the radiology images and
Kirk Jones, MD, for the pathology images.

References
1 Doyle TJ, Hunninghake GM, Rosas IO. Subclinical interstitial lung

Prognosis
ILD is one of the most serious complications observed among
patients with CTD and is associated with signicant morbidity and mortality. Among patients with scleroderma, ILD is

473

disease: why you should care. Am J Respir Crit Care Med 2012;
185(11):11471153
Kelly CA, Saravanan V, Nisar M, et al; British Rheumatoid
Interstitial Lung (BRILL) Network. Rheumatoid arthritis-related interstitial lung disease: associations, prognostic factors
and physiological and radiological characteristicsa large
multicentre UK study. Rheumatology (Oxford) 2014;53(9):
16761682
Mori S, Koga Y, Sugimoto M. Different risk factors between
interstitial lung disease and airway disease in rheumatoid arthritis. Respir Med 2012;106(11):15911599
Harlow L, Rosas IO, Gochuico BR, et al. Identication of citrullinated hsp90 isoforms as novel autoantigens in rheumatoid
arthritis-associated interstitial lung disease. Arthritis Rheum
2013;65(4):869879
McNearney TA, Reveille JD, Fischbach M, et al. Pulmonary
involvement in systemic sclerosis: associations with genetic,
serologic, sociodemographic, and behavioral factors. Arthritis
Rheum 2007;57(2):318326
Seminars in Respiratory and Critical Care Medicine

Vol. 37

No. 3/2016

Downloaded by: Chulalongkorn University. Copyrighted material.

due to specic challenges related to transplantation in CTDILD. In particular, the presence of comorbid conditions and
extrapulmonary manifestations of their underlying CTD (e.g.,
gastroesophageal reux disease, pulmonary hypertension,
cardiovascular disease, musculoskeletal disease) may adversely affect survival and graft function following transplantation.88,89 Prognosis is also difcult to predict in this
population due to heterogeneity in the disease course and
poor understanding of the natural history of many CTD-ILDs.
Some encouraging data suggest that survival after transplantation is similar among patients with and without an underlying CTD, specically in patients with sclerodermaassociated ILD.90,91 In addition, improvements in respiratory-related quality of life have been observed among rheumatoid arthritis-associated ILD patients who have undergone
lung transplantation.92

Aparicio, Lee

Connective Tissue Disease-Associated ILDs

Aparicio, Lee

6 Kane GC, Varga J, Conant EF, Spirn PW, Jimenez S, Fish JE. Lung

26 Winstone TA, Assayag D, Wilcox PG, et al. Predictors of mortality

involvement in systemic sclerosis (scleroderma): relation to

classication based on extent of skin involvement or autoantibody status. Respir Med 1996;90(4):223230
Fischer A, West SG, Swigris JJ, Brown KK, du Bois RM. Connective
tissue disease-associated interstitial lung disease: a call for
clarication. Chest 2010;138(2):251256
Kinder BW, Collard HR, Koth L, et al. Idiopathic nonspecic
interstitial pneumonia: lung manifestation of undifferentiated
connective tissue disease? Am J Respir Crit Care Med 2007;
176(7):691697
Vij R, Strek ME. Diagnosis and treatment of connective tissue
disease-associated interstitial lung disease. Chest 2013;143(3):
814824
Vij R, Noth I, Strek ME. Autoimmune-featured interstitial lung
disease: a distinct entity. Chest 2011;140(5):12921299
Corte TJ, Copley SJ, Desai SR, et al. Signicance of connective
tissue disease features in idiopathic interstitial pneumonia. Eur
Respir J 2012;39(3):661668
Assayag D, Kim EJ, Elicker BM, et al. Survival in interstitial
pneumonia with features of autoimmune disease: A comparison
of proposed criteria. Respir Med 2015;109(10):13261331
Fischer A, Antoniou KM, Brown KK, et al; ERS/ATS Task Force on
Undifferentiated Forms of CTD-ILD. An ofcial European Respiratory Society/American Thoracic Society research statement:
interstitial pneumonia with autoimmune features. Eur Respir J
2015;46(4):976987
Raghu G, Collard HR, Egan JJ, et al; ATS/ERS/JRS/ALAT Committee
on Idiopathic Pulmonary Fibrosis. An ofcial ATS/ERS/JRS/ALAT
statement: idiopathic pulmonary brosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med
2011;183(6):788824
Lee JS, Kim EJ, Lynch KL, et al. Prevalence and clinical signicance
of circulating autoantibodies in idiopathic pulmonary brosis.
Respir Med 2013;107(2):249255
Capobianco J, Grimberg A, Thompson BM, Antunes VB, Jasinowodolinski D, Meirelles GS. Thoracic manifestations of collagen
vascular diseases. Radiographics 2012;32(1):3350
Urisman A, Jones KD. Pulmonary pathology in connective tissue
disease. Semin Respir Crit Care Med 2014;35(2):201212
Kim EJ, Collard HR, King TE Jr. Rheumatoid arthritis-associated
interstitial lung disease: the relevance of histopathologic and
radiographic pattern. Chest 2009;136(5):13971405
Travis WD, Costabel U, Hansell DM, et al; ATS/ERS Committee on
Idiopathic Interstitial Pneumonias. An ofcial American Thoracic
Society/European Respiratory Society statement: Update of the
international multidisciplinary classication of the idiopathic
interstitial pneumonias. Am J Respir Crit Care Med 2013;
188(6):733748
Bjoraker JA, Ryu JH, Edwin MK, et al. Prognostic signicance of
histopathologic subsets in idiopathic pulmonary brosis. Am J
Respir Crit Care Med 1998;157(1):199203
Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ; Idiopathic
Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N-acetylcysteine for pulmonary brosis. N Engl J
Med 2012;366(21):19681977
Assayag D, Lee JS, King TE Jr. Rheumatoid arthritis associated
interstitial lung disease: a review. Medicina (B Aires) 2014;74(2):
158165
King TE Jr, Kim EJ, Kinder BW. Connective tissue disease. In: King
TE Jr SM ed. Interstitial Lung Disease. Shelton, CT: Peoples
Medical Publishing House; 2011:713
Fischer A, Chartrand S. Assessment and management of connective tissue disease-associated interstitial lung disease. Sarcoidosis Vasc Diffuse Lung Dis 2015;32(1):221
Ley B, Ryerson CJ, Vittinghoff E, et al. A multidimensional index
and staging system for idiopathic pulmonary brosis. Ann Intern
Med 2012;156(10):684691

and progression in scleroderma-associated interstitial lung disease: a systematic review. Chest 2014;146(2):422436
Ryerson CJ, OConnor D, Dunne JV, et al. Predicting mortality in
systemic sclerosis-associated interstitial lung disease using risk
prediction models derived from idiopathic pulmonary brosis.
Chest 2015;148(5):12681275
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(11):12481254
Bradley B, Branley HM, Egan JJ, et al; British Thoracic Society
Interstitial Lung Disease Guideline Group, British Thoracic
Society Standards of Care Committee; Thoracic Society of
Australia; New Zealand Thoracic Society; Irish Thoracic Society. Interstitial lung disease guideline: the British Thoracic
Society in collaboration with the Thoracic Society of Australia
and New Zealand and the Irish Thoracic Society. Thorax 2008;
63(Suppl 5):v1v58
Sullivan WD, Hurst DJ, Harmon CE, et al. A prospective evaluation
emphasizing pulmonary involvement in patients with mixed
connective tissue disease. Medicine (Baltimore) 1984;63(2):
92107
Patterson CD, Harville WE, Pierce JA. Rheumatoid lung disease.
Ann Intern Med 1965;62:685697
Holgate ST, Glass DN, Haslam P, Maini RN, Turner-Warwick M.
Respiratory involvement in systemic lupus erythematosus. A
clinical and immunological study. Clin Exp Immunol 1976;
24(3):385395
Flaherty KR, Toews GB, Lynch JP III, et al. Steroids in idiopathic
pulmonary brosis: a prospective assessment of adverse reactions, response to therapy, and survival. Am J Med 2001;110(4):
278282
Curtis JR, Westfall AO, Allison J, et al. Population-based assessment of adverse events associated with long-term glucocorticoid
use. Arthritis Rheum 2006;55(3):420426
Yamasaki Y, Yamada H, Yamasaki M, et al. Intravenous cyclophosphamide therapy for progressive interstitial pneumonia in patients with polymyositis/dermatomyositis. Rheumatology
(Oxford) 2007;46(1):124130
White B, Moore WC, Wigley FM, Xiao HQ, Wise RA. Cyclophosphamide is associated with pulmonary function and survival
benet in patients with scleroderma and alveolitis. Ann Intern
Med 2000;132(12):947954
Steen VD, Lanz JK Jr, Conte C, Owens GR, Medsger TA Jr. Therapy
for severe interstitial lung disease in systemic sclerosis. A retrospective study. Arthritis Rheum 1994;37(9):12901296
Silver RM, Warrick JH, Kinsella MB, Staudt LS, Baumann MH,
Strange C. Cyclophosphamide and low-dose prednisone therapy
in patients with systemic sclerosis (scleroderma) with interstitial
lung disease. J Rheumatol 1993;20(5):838844
Schnabel A, Reuter M, Gross WL. Intravenous pulse cyclophosphamide in the treatment of interstitial lung disease due to
collagen vascular diseases. Arthritis Rheum 1998;41(7):
12151220
Mira-Avendano IC, Parambil JG, Yadav R, et al. A retrospective
review of clinical features and treatment outcomes in steroidresistant interstitial lung disease from polymyositis/dermatomyositis. Respir Med 2013;107(6):890896
Akesson A, Scheja A, Lundin A, Wollheim FA. Improved pulmonary function in systemic sclerosis after treatment with cyclophosphamide. Arthritis Rheum 1994;37(5):729735
Tashkin DP, Elashoff R, Clements PJ, et al; Scleroderma Lung
Study Research Group. Cyclophosphamide versus placebo in
scleroderma lung disease. N Engl J Med 2006;354(25):
26552666
Brummaier T, Pohanka E, Studnicka-Benke A, Pieringer H. Using
cyclophosphamide in inammatory rheumatic diseases. Eur J
Intern Med 2013;24(7):590596

10
11

12

13

14

15

16

17
18

19

20

21

22

23

24

25

Seminars in Respiratory and Critical Care Medicine

Vol. 37

No. 3/2016

27

28

29

30

31
32

33

34

35

36

37

38

39

40

41

42

43

Downloaded by: Chulalongkorn University. Copyrighted material.

474

44 Chartrand S, Fischer A. Management of connective tissue disease-

45
46

47

48

49

50

51

52

53
54

55

56

57

58

59
60

61

62

63

64

associated interstitial lung disease. Rheum Dis Clin North Am

2015;41(2):279294
Yazici H, Pazarli H, Barnes CG, et al. A controlled trial of azathioprine in Behets syndrome. N Engl J Med 1990;322(5):281285
Willkens RF, Urowitz MB, Stablein DM, et al. Comparison of
azathioprine, methotrexate, and the combination of both in the
treatment of rheumatoid arthritis. A controlled clinical trial.
Arthritis Rheum 1992;35(8):849856
Nicholls A, Snaith ML, Maini RN, Scott JT. Proceedings: controlled
trial of azathioprine in rheumatoid vasculitis. Ann Rheum Dis
1973;32(6):589591
Felson DT, Anderson J. Evidence for the superiority of immunosuppressive drugs and prednisone over prednisone alone in lupus
nephritis. Results of a pooled analysis. N Engl J Med 1984;
311(24):15281533
Nadashkevich O, Davis P, Fritzler M, Kovalenko W. A randomized
unblinded trial of cyclophosphamide versus azathioprine in the
treatment of systemic sclerosis. Clin Rheumatol 2006;25(2):
205212
Hoyles RK, Ellis RW, Wellsbury J, et al. A multicenter, prospective,
randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral
azathioprine for the treatment of pulmonary brosis in scleroderma. Arthritis Rheum 2006;54(12):39623970
Dheda K, Lalloo UG, Cassim B, Mody GM. Experience with
azathioprine in systemic sclerosis associated with interstitial
lung disease. Clin Rheumatol 2004;23(4):306309
Brezn A, Ranque B, Valeyre D, et al. Therapeutic strategy
combining intravenous cyclophosphamide followed by oral azathioprine to treat worsening interstitial lung disease associated
with systemic sclerosis: a retrospective multicenter open-label
study. J Rheumatol 2008;35(6):10641072
Huskisson EC. Azathioprine. Clin Rheum Dis 1984;10(2):325332
Singh G, Fries JF, Spitz P, Williams CA. Toxic effects of azathioprine
in rheumatoid arthritis. A national post-marketing perspective.
Arthritis Rheum 1989;32(7):837843
Swigris JJ, Olson AL, Fischer A, et al. Mycophenolate mofetil is safe,
well tolerated, and preserves lung function in patients with
connective tissue disease-related interstitial lung disease. Chest
2006;130(1):3036
Liossis SN, Bounas A, Andonopoulos AP. Mycophenolate mofetil
as rst-line treatment improves clinically evident early scleroderma lung disease. Rheumatology (Oxford) 2006;45(8):
10051008
Gerbino AJ, Goss CH, Molitor JA. Effect of mycophenolate mofetil
on pulmonary function in scleroderma-associated interstitial
lung disease. Chest 2008;133(2):455460
Fischer A, Brown KK, Du Bois RM, et al. Mycophenolate mofetil
improves lung function in connective tissue disease-associated
interstitial lung disease. J Rheumatol 2013;40(5):640646
Bhorade SM, Stern E. Immunosuppression for lung transplantation. Proc Am Thorac Soc 2009;6(1):4753
Tsokos GC. Immunomodulatory treatment in patients with rheumatic diseases: mechanisms of action. Semin Arthritis Rheum
1987;17(1):2438
Wilkes MR, Sereika SM, Fertig N, Lucas MR, Oddis CV. Treatment
of antisynthetase-associated interstitial lung disease with tacrolimus. Arthritis Rheum 2005;52(8):24392446
Takada K, Nagasaka K, Miyasaka N. Polymyositis/dermatomyositis and interstitial lung disease: a new therapeutic approach with
T-cell-specic immunosuppressants. Autoimmunity 2005;38(5):
383392
Oddis CV, Sciurba FC, Elmagd KA, Starzl TE. Tacrolimus in
refractory polymyositis with interstitial lung disease. Lancet
1999;353(9166):17621763
Ochi S, Nanki T, Takada K, et al. Favorable outcomes with
tacrolimus in two patients with refractory interstitial lung

65

66

67
68

69

70

71

72

73

74

75

76

77

78
79

80

81

82

83

Aparicio, Lee

disease associated with polymyositis/dermatomyositis. Clin Exp

Rheumatol 2005;23(5):707710
Kurita T, Yasuda S, Oba K, et al. The efcacy of tacrolimus in
patients with interstitial lung diseases complicated with polymyositis or dermatomyositis. Rheumatology (Oxford) 2015;
54(1):3944
Cavagna L, Caporali R, Abd-Al L, Dore R, Meloni F, Montecucco C.
Cyclosporine in anti-Jo1-positive patients with corticosteroidrefractory interstitial lung disease. J Rheumatol 2013;40(4):
484492
Azzi JR, Sayegh MH, Mallat SG. Calcineurin inhibitors: 40 years
later, cant live without ... J Immunol 2013;191(12):57855791
Nagasaka K, Harigai M, Tateishi M, et al. Efcacy of combination
treatment with cyclosporin A and corticosteroids for acute
interstitial pneumonitis associated with dermatomyositis. Mod
Rheumatol 2003;13(3):231238
McDonald V, Leandro M. Rituximab in non-haematological disorders of adults and its mode of action. Br J Haematol 2009;
146(3):233246
Keir GJ, Maher TM, Ming D, et al. Rituximab in severe, treatmentrefractory interstitial lung disease. Respirology 2014;19(3):
353359
Unger L, Kampf S, Lthke K, Aringer M. Rituximab therapy in
patients with refractory dermatomyositis or polymyositis: differential effects in a real-life population. Rheumatology (Oxford)
2014;53(9):16301638
Sem M, Molberg O, Lund MB, Gran JT. Rituximab treatment of the
anti-synthetase syndrome: a retrospective case series. Rheumatology (Oxford) 2009;48(8):968971
Marie I, Dominique S, Janvresse A, Levesque H, Menard JF.
Rituximab therapy for refractory interstitial lung disease related
to antisynthetase syndrome. Respir Med 2012;106(4):581587
Andersson H, Sem M, Lund MB, et al. Long-term experience with
rituximab in anti-synthetase syndrome-related interstitial lung
disease. Rheumatology (Oxford) 2015;54(8):14201428
Daoussis D, Liossis SN, Tsamandas AC, et al. Effect of long-term
treatment with rituximab on pulmonary function and skin
brosis in patients with diffuse systemic sclerosis. Clin Exp
Rheumatol 2012;30(2, Suppl 71):S17S22
Daoussis D, Liossis SN, Tsamandas AC, et al. Experience with
rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology (Oxford) 2010;49(2):271280
Matteson EL, Bongartz T, Ryu JH, Crowson CS, Hartman T,
Dellaripa PF. Open-label, pilot study of the safety and clinical
effects of rituximab in patients with rheumatoid arthritis-associated interstitial pneumonia. Open J Rheumatol Autoimmune
Dis 2012;2:5358
Gelfand EW. Intravenous immune globulin in autoimmune and
inammatory diseases. N Engl J Med 2012;367(21):20152025
Perricone R, De Carolis C, Kregler B, et al. Intravenous immunoglobulin therapy in pregnant patients affected with systemic
lupus erythematosus and recurrent spontaneous abortion. Rheumatology (Oxford) 2008;47(5):646651
Miyasaka N, Hara M, Koike T, Saito E, Yamada M, Tanaka Y;
GB-0998 Study Group. Effects of intravenous immunoglobulin
therapy in Japanese patients with polymyositis and dermatomyositis resistant to corticosteroids: a randomized double-blind
placebo-controlled trial. Mod Rheumatol 2012;22(3):382393
Dalakas MC, Illa I, Dambrosia JM, et al. A controlled trial of highdose intravenous immune globulin infusions as treatment for
dermatomyositis. N Engl J Med 1993;329(27):19932000
Cherin P, Pelletier S, Teixeira A, et al. Results and long-term
followup of intravenous immunoglobulin infusions in chronic,
refractory polymyositis: an open study with thirty-ve adult
patients. Arthritis Rheum 2002;46(2):467474
Boletis JN, Ioannidis JP, Boki KA, Moutsopoulos HM. Intravenous
immunoglobulin compared with cyclophosphamide for proliferative lupus nephritis. Lancet 1999;354(9178):569570
Seminars in Respiratory and Critical Care Medicine

Vol. 37

No. 3/2016

475

Downloaded by: Chulalongkorn University. Copyrighted material.

Connective Tissue Disease-Associated ILDs

Connective Tissue Disease-Associated ILDs

Aparicio, Lee

84 Austin HA III, Klippel JH, Balow JE, et al. Therapy of lupus

99 Miura Y, Fukuda K, Maeda T, Kurosaka M. Gastroesophageal

nephritis. Controlled trial of prednisone and cytotoxic drugs. N

Engl J Med 1986;314(10):614619
Suzuki Y, Hayakawa H, Miwa S, et al. Intravenous immunoglobulin therapy for refractory interstitial lung disease associated with polymyositis/dermatomyositis. Lung 2009;187(3):
201206
Bakewell CJ, Raghu G. Polymyositis associated with severe interstitial lung disease: remission after three doses of IV immunoglobulin. Chest 2011;139(2):441443
Khanna D, Albera C, Fischer A, et al. Safety and tolerability of
pirfenidone in patients with systemic sclerosis-associated interstitial lung disease- the LOTUSSstudy. Am J Respir Crit Care Med
2015;191:A1175
Fisichella PM, Jalilvand A. The role of impaired esophageal and
gastric motility in end-stage lung diseases and after lung transplantation. J Surg Res 2014;186(1):201206
Diamond JM, Lee JC, Kawut SM, et al; Lung Transplant Outcomes
Group. Clinical risk factors for primary graft dysfunction after
lung transplantation. Am J Respir Crit Care Med 2013;187(5):
527534
Sottile PD, Iturbe D, Katsumoto TR, et al. Outcomes in systemic
sclerosis-related lung disease after lung transplantation. Transplantation 2013;95(7):975980
Bernstein EJ, Peterson ER, Sell JL, et al. Survival of adults with
systemic sclerosis following lung transplantation: a nationwide cohort study. Arthritis Rheum (Munch) 2015;67(5):
13141322
Yazdani A, Singer LG, Strand V, Gelber AC, Williams L, Mittoo S.
Survival and quality of life in rheumatoid arthritis-associated
interstitial lung disease after lung transplantation. J Heart Lung
Transplant 2014;33(5):514520
van Assen S, Elkayam O, Agmon-Levin N, et al. Vaccination in
adult patients with auto-immune inammatory rheumatic diseases: a systematic literature review for the European League
Against Rheumatism evidence-based recommendations for vaccination in adult patients with auto-immune inammatory
rheumatic diseases. Autoimmun Rev 2011;10(6):341352
Vananuvat P, Suwannalai P, Sungkanuparph S, Limsuwan T,
Ngamjanyaporn P, Janwityanujit S. Primary prophylaxis for Pneumocystis jirovecii pneumonia in patients with connective tissue
diseases. Semin Arthritis Rheum 2011;41(3):497502
Nici L, Donner C, Wouters E, et al; ATS/ERS Pulmonary Rehabilitation Writing Committee. American Thoracic Society/European
Respiratory Society statement on pulmonary rehabilitation. Am J
Respir Crit Care Med 2006;173(12):13901413
Ryerson CJ, Cayou C, Topp F, et al. Pulmonary rehabilitation
improves long-term outcomes in interstitial lung disease: a
prospective cohort study. Respir Med 2014;108(1):203210
Holland AE, Dowman LM, Hill CJ. Principles of rehabilitation and
reactivation: interstitial lung disease, sarcoidosis and rheumatoid disease with respiratory involvement. Respiration 2015;
89(2):8999
Visca D, Montgomery A, de Lauretis A, et al. Ambulatory oxygen
in interstitial lung disease. Eur Respir J 2011;38(4):987990

reux disease in patients with rheumatoid arthritis. Mod Rheumatol 2014;24(2):291295

Bodukam V, Hays RD, Maranian P, et al. Association of gastrointestinal involvement and depressive symptoms in patients with
systemic sclerosis. Rheumatology (Oxford) 2011;50(2):330334
Ahmed S, Palevsky HI. Pulmonary arterial hypertension related to
connective tissue disease: a review. Rheum Dis Clin North Am
2014;40(1):103124
Ponnuswamy A, Manikandan R, Sabetpour A, Keeping IM, Finnerty JP. Association between ischaemic heart disease and interstitial lung disease: a case-control study. Respir Med 2009;
103(4):503507
Villa-Forte A, Mandell BF. [Cardiovascular disorders and rheumatic disease]. Rev Esp Cardiol 2011;64(9):809817
Khurana R, Wolf R, Berney S, Caldito G, Hayat S, Berney SM. Risk of
development of lung cancer is increased in patients with rheumatoid arthritis: a large case control study in US veterans. J
Rheumatol 2008;35(9):17041708
Adzi TN, Pesut DP, Nagorni-Obradovi LM, Stojsi JM, Vasiljevi
MD, Bouros D. Clinical features of lung cancer in patients with
connective tissue diseases: a 10-year hospital based study. Respir
Med 2008;102(4):620624
Petri M. Update on anti-phospholipid antibodies in SLE: the
Hopkins lupus cohort. Lupus 2010;19(4):419423
Goldberg A. Pulmonary arterial hypertension in connective tissue
diseases. Cardiol Rev 2010;18(2):8588
Steen VD, Medsger TA. Changes in causes of death in systemic
sclerosis, 1972-2002. Ann Rheum Dis 2007;66(7):940944
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(6):15831591
Olson AL, Swigris JJ, Sprunger DB, et al. Rheumatoid arthritisinterstitial lung disease-associated mortality. Am J Respir Crit
Care Med 2011;183(3):372378
Ikeda S, Arita M, Misaki K, et al. Incidence and impact of
interstitial lung disease and malignancy in patients with polymyositis, dermatomyositis, and clinically amyopathic dermatomyositis: a retrospective cohort study. Springerplus 2015;4:240
ODwyer DN, Armstrong ME, Cooke G, Dodd JD, Veale DJ, Donnelly
SC. Rheumatoid arthritis (RA) associated interstitial lung disease
(ILD). Eur J Intern Med 2013;24(7):597603
Kiely PD, Chua F. Interstitial lung disease in inammatory myopathies: clinical phenotypes and prognosis. Curr Rheumatol Rep
2013;15(9):359
Wells AU. Interstitial lung disease in systemic sclerosis. Presse
Med 2014;43(10, Pt 2):e329e343
Kreider M, Highland K. Pulmonary involvement in Sjgren syndrome. Semin Respir Crit Care Med 2014;35(2):255264
Mittoo S, Fell CD. Pulmonary manifestations of systemic lupus
erythematosus. Semin Respir Crit Care Med 2014;35(2):249254
Gunnarsson R, Aalkken TM, Molberg , et al. Prevalence and
severity of interstitial lung disease in mixed connective tissue
disease: a nationwide, cross-sectional study. Ann Rheum Dis
2012;71(12):19661972

85

86

87

88

89

90

91

92

93

94

95

96

97

98

Seminars in Respiratory and Critical Care Medicine

Vol. 37

No. 3/2016

100

101

102

103
104

105

106
107
108
109

110

111

112

113

114
115
116
117

Downloaded by: Chulalongkorn University. Copyrighted material.

476