s-0036-1580689

7/26/2019 s-0036-1580689

1/9

Connective Tissue Disease-Associated InterstitialLung Diseases: Unresolved Issues

Irene Jarana Aparicio, MD1 Joyce S. Lee, MD, MAS2

1 Department of Respiratory Medicine, Gregorio Maraon Hospital,

Madrid, Spain2 Division of Pulmonary Sciences and Critical Care Medicine,

Department of Medicine, University of Colorado Denver,

Aurora, Colorado

Semin Respir Crit Care Med 2016;37:468476.

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:[email protected]).

The term

connective tissue disease

(CTD) encompassesmultiple entities, whose common characteristic is the im-

mune-mediated injury of collagen, which can affect many

organs, including the lungs. Interstitial lung disease (ILD) is a

common manifestation of these systemic autoimmune dis-

orders and confers a signicant impact on morbidity and

mortality, making their diagnosis, classication, and treat-

ment a priority.

Although signicant progress has been made in the un-

derstanding of CTD-relatedILD (CTD-ILD), there arestill many

unanswered questions in this eld. This review describes the

current views on epidemiology, clinical presentation, treat-

ment, and prognosis in patients with CTD-ILD and highlights

several areas that remain unresolved and in need of furtherinvestigation.

Epidemiology

The prevalence of CTD-ILD varies in the literature. Depending

on the study designand populationstudied, the prevalence of

ILDcanbe anywherefrom1 to80% (

Table 1). The prevalenceestimate also depends on the criteria used to diagnose the

ILD. When using radiologic criteria for diagnosis, the preva-

lence 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 rheuma-

toid 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 associatedwith 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

Keywords

connective tissue

disease

interstitial lung

disease

autoimmunity

interstitial pneumonia

Abstract Interstitial lung disease (ILD) complicating connective tissue disorders, such as sclero-derma 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 withconnective 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 manage-

ment. A multidisciplinary and multidimensional approach to diagnosis, management,

and investigation of CTD-associated ILD patients is essential to advance our under-

standing of the epidemiology and pathobiology of this challenging group of diseases.

Issue Theme Orphan Lung Diseases;

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

Richeldi, MD

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.

468
mailto:[email protected]://dx.doi.org/10.1055/s-0036-1580689http://dx.doi.org/10.1055/s-0036-1580689http://dx.doi.org/10.1055/s-0036-1580689http://dx.doi.org/10.1055/s-0036-1580689mailto:[email protected]

7/26/2019 s-0036-1580689

2/9

Clinical Manifestations

In many patients, CTD-ILD is initially asymptomatic fol-

lowed by the development of nonspecic symptoms. The

most common symptoms are exertional dyspnea and drycough. Often times, the symptom of dyspnea can be con-

fused with generalized weakness and deconditioning, par-

ticularly due to the systemic nature of CTDs. As the lung

disease progresses, patients can develop pulmonar y hyper-

tension 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 oftenwell

dened in many patients presenting with ILD, the lungs

may be the

rst and/or primary manifestation of an under-lying 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 thicken-

ing, Raynaud phenomenon, rash or telangiectasias, gastro-

esophageal 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 haveproposed 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 iden-

tify a similar group of patients.12 Given the lack of consen-

sus 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 Theyproposed the terminterstitial pneu-

monia 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.

Diagnostic Evaluation

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. Ina study looking at patients with idiopathic pulmonarybrosis

(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 comor-

bid 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 interstitialpneumonia (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, malignan-

cy), a bronchoscopy with bronchoalveolar lavage and/or a

lung biopsymay be necessary. Thehistopathologic patterns in

CTD-ILD also mimic those found in the idiopathic interstitial

pneumonias.17 The most commonpattern 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

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

Conn ective t issu e d is ease Prevalence Asso ciated r isk factors

Rheumatoid arthritis112 1.641% Age, cigarette smoking, serologies (rheumatoid factor and anticycliccitrullinated peptide), male gender, rheumatoid arthritis severity

Idiopathic inammatory myopathies113 580% Ethnicity, serologies(anti-amino-acyl-tRNA synthetases, anti-MDA-5 antibodies)

Scleroderma5,114 55

65% Ethnicity, diffuse disease, serologies (anti-topoisomerase antibody),hypothyroidism, cardiac involvement, and creatine phosphokinase

Sjgren syndrome115 975%a Inconsistent data

Systemic lupus erythematosus116 115% Age, disease duration, serologies (anti-(U1) RNP antibodies)

Mixed connective tissue disease117 5070% Limited da ta

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

Seminars in Respiratory and Critical Care Medicine Vol. 37 No. 3/2016

Connective Tissue Disease-Associated ILDs Aparicio, Lee 469

7/26/2019 s-0036-1580689

3/9

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 histo-

pathologic pattern. In other words, unlike the idiopathic

interstitial pneumonias where the underlying histopatholog-

ic 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 pheno-

type and prognosis compared with other histopathologicpatterns (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, andN-acetylcysteine, is harmful in

patients with IPF, a form of idiopathic UIP.21 What is not clear

at this time is if patients with CTDand 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

Future research should be done to determine if histopatho-

logic phenotype is important in the diagnosis and manage-

ment of C TD-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 severityand activitycan 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 conditionsand drug interactions.24

For many CTD-ILDs, identifying patients at risk for pro-

gressive 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 popu-

lation 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 scleroderma-

associated ILD, factors such as percentage of predicted forced

vital capacity (FVC), extent of disease on HRCT scan, and age

have all been identi

ed as risk factors for progressive

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) Radiologicpatternof lymphocyticinterstitialpneumonia in a patient withSjgren disease. There arescattered thin-walledcysts in

both lungs. (Images courtesy of Brett Elicker, MD.)


Connective Tissue Disease-Associated ILDs Aparicio, Lee470

7/26/2019 s-0036-1580689

4/9

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 treat-

ment, counseling, and clinical trial design.

Oncea decision has been made totreat a patientwithCTD-

ILD, the general pharmacologic treatment approach is with

systemic immunosuppression. There are very few random-

ized 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 usedare experience basedrather than evidence based.In the

next section, we review the most common pharmacologic

treatment options for patients with CTD-ILD.

Corticosteroids

Corticosteroids are consideredrst-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 sparingagents (e.g., azathi-

oprine, mycophenolate mofetil). When utilized in combina-

tion, 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

CyclophosphamideCyclophosphamide is a potent immunosuppressive medica-

tion. The useof cyclophosphamide hasbeen studied in several

prospective and retrospective studies in CTD-ILD demon-

strating stabilization or improvement in lung function.3541

The largest of these was the Scleroderma Lung Study (SLS),

which was a clinical trial that randomized 158subjects to oral

cyclophosphamide or placebo.42 After 12 months of treat-

ment, subjects randomized to oral cyclophosphamide had a

more favorable change in FVC compared with placebo

(p

7/26/2019 s-0036-1580689

5/9

associated with cyclophosphamide, including bone marrow

suppression, infection, risk of malignancy, and bladder toxic-

ity.43 This limits the routine use of cyclophosphamide in CTD-

ILD and is often reserved for those with more severe mani-

festations of their disease.44

Azathioprine

Azathioprine is a commonly used and effective steroid-spar-ing agent for many CTDs.4548 The use of azathioprine for the

treatment of CTD-ILD is common; however, the data support-

ing its use are primarily limited to small retrospective se-

ries.40,4952 A retrospective review of 13 patients with

polymyositis- or dermatomyositis-associated ILD demon-

strated a reduction in dyspnea, PFT stabilization, and a

reduction in corticosteroiddose 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 3mg/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 prolif-

eration and is increasingly being used as a steroid-sparing

agent in CTD-ILD.44 The data supporting the use of myco-

phenolate mofetil are limited to small retrospective se-

ries.5558 The largest series included 125 patients with

CTD-ILD, including patients with scleroderma, myositis,

and rheumatoid arthritis.

58

They reported that treatmentwith mycophenolate mofetil was well tolerated and associat-

ed 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 CD4T cell activation.60

They are commonly usedin the immunosuppression regimen

following solid organtransplantation.59 Among the CTD-ILDs,

the most experience is with the myositis-related ILDs

(e.g., polymyositis, dermatomyositis, antisynthetase syn-

drome).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

event-free survival and longer disease-free survival com-

pared with the conventional therapy group. The most com-

mon 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

reviewof 50 patients with severe and progressive ILD,despite

conventional immunosuppression, had a median improve-

ment 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 associatedwith 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, poly-

valent, IgG antibodies extracted from plasma.78 The mech-

anism of action of IVIG is not completely understood, butlikelyhas immunomodulatory as well as anti-inammatory

effects in patients with autoimmune or inammatory con-

ditions.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 pirfe-

nidone) 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 thetreatment of CTD-ILD. In patients with scleroderma-associat-

ed 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 andconsistent with those seen in the IPFtrials.

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



7/26/2019 s-0036-1580689

6/9

due to specic challenges related to transplantation in CTD-

ILD. 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 ad-

versely affect survival and graft function following transplan-

tation.88,89 Prognosis is also difcult to predict in this

population due to heterogeneity in the disease course andpoor understanding of the natural history of many CTD-ILDs.

Some encouraging data suggest that survival after transplan-

tation is similar among patients with and without an under-

lying CTD, specically in patients with scleroderma-

associated ILD.90,91 In addition, improvements in respirato-

ry-related quality of life have been observed among rheuma-

toid arthritis-associated ILD patients who have undergone

lung transplantation.92

Additional Management Strategies

The care of patients with CTD-ILD should involve a compre-

hensive and multidisciplinary approach. Although there are

limited data to support this approach, these interventions aregenerally low risk and may improve quality of life, exercise

tolerance, and reduce symptoms. General measures include

smoking cessation and infection prophylaxis. Infection pro-

phylaxis includes the administration of appropriate vaccines

(e.g., yearly inuenza vaccine and the pneumococcal vaccine)

as well as Pneumocystis jirovecipneumonia (PjP) prophylax-

is.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 im-

proves muscle deconditioning, and improves quality of lifein patients with chronic respiratory disorders,including CTD-

ILD.95,96 Although these programs have been designed pri-

marily for patients with chronic obstructive pulmonary dis-

ease, 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 thera-

py; however, it can positively impact quality of life and

exercise tolerance in patients with ILD.98

Finally, a careful investigation for comorbid conditionsshould 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 car-

diovascular disease,102,103 lung cancer,104,105 thromboem-

bolic disease,106 gastroesophageal reux disease,99,100 and

pulmonary hypertension.107

Prognosis

ILD is one of the most serious complications observed among

patients with CTD and is associated with signicant morbidi-

ty and mortality. Among patients with scleroderma, ILD is

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

rheumatoid arthritis, patients with ILD had a median survival

after ILD diagnosisof 2.6years, which is a threefoldhigher risk

for death compared with their rheumatoid arthritis counter-

parts 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 withidiopathic inammatory myopathies (e.g., polymyositis,

dermatomyositis), the presence of ILD was not associated

with worse prognosis in a retrospective reviewof 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 signi-

cance of patients who have features suggestive of an under-

lying CTD (i.e., IPAF patients), the unknown role of

distinguishing histopathologic phenotypes among patientswith CTD-ILD, and the lack of controlled clinical trials to

inform pharmacologic management of patients with CTD-

ILD. Moving forward, a multidisciplinary and multidimen-

sional approach to diagnosis, management, and investigation

of CTD-ILD patients will be essential for us to better under-

stand 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.

References1 Doyle TJ, Hunninghake GM, Rosas IO. Subclinical interstitial lung

disease: why you should care. Am J Respir Crit Care Med 2012;

185(11):11471153

2 Kelly CA, Saravanan V, Nisar M, et al; British Rheumatoid

Interstitial Lung (BRILL) Network. Rheumatoid arthritis-relat-

ed interstitial lung disease: associations, prognostic factorsand physiological and radiological characteristicsa large

multicentre UK study. Rheumatology (Oxford) 2014;53(9):

16761682

3 Mori S, Koga Y, Sugimoto M. Different risk factors between

interstitial lung disease and airway disease in rheumatoidarthri-

tis. Respir Med 2012;106(11):15911599

4 Harlow L, Rosas IO, Gochuico BR, et al. Identication of citrulli-

nated hsp90 isoforms as novel autoantigens in rheumatoid

arthritis-associated interstitial lung disease. Arthritis Rheum

2013;65(4):869879

5 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



7/26/2019 s-0036-1580689

7/9

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

involvement in systemic sclerosis (scleroderma): relation to

classication based on extent of skin involvement or autoanti-

body status. Respir Med 1996;90(4):223230

7 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

8 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

9 Vij R, Strek ME. Diagnosis and treatment of connective tissue

disease-associated interstitial lung disease. Chest 2013;143(3):

814824

10 Vij R, Noth I, Strek ME. Autoimmune-featured interstitial lung

disease: a distinct entity. Chest 2011;140(5):12921299

11 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

12 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

13 Fischer A, Antoniou KM, Brown KK, et al; ERS/ATS Task Force on

Undifferentiated Forms of CTD-ILD

. An ofcial European Respi-ratory Society/American Thoracic Society research statement:

interstitial pneumonia with autoimmune features. Eur Respir J

2015;46(4):976987

14 Raghu G, Collard HR, Egan JJ, et al; ATS/ERS/JRS/ALAT Committee

on Idiopathic Pulmonary Fibrosis. An ofcial ATS/ERS/JRS/ALAT

statement:idiopathicpulmonarybrosis:evidence-based guide-

lines for diagnosis and management. Am J Respir Crit Care Med

2011;183(6):788824

15 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

16 Capobianco J, Grimberg A, Thompson BM, Antunes VB, Jasino-

wodolinski D, Meirelles GS. Thoracic manifestations of collagen

vascular diseases. Radiographics 2012;32(1):3350

17 Urisman A, Jones KD. Pulmonary pathology in connective tissuedisease. Semin Respir Crit Care Med 2014;35(2):201212

18 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

19 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

20 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

21 Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ; Idiopathic

Pulmonary Fibrosis Clinical Research Network. Prednisone, aza-thioprine, and N-acetylcysteine for pulmonary brosis. N Engl J

Med 2012;366(21):19681977

22 Assayag D, Lee JS, King TE Jr. Rheumatoid arthritis associated

interstitial lung disease: a review. Medicina (B Aires) 2014;74(2):

158165

23 KingTE Jr, Kim EJ, KinderBW. Connective tissue disease. In: King

TE Jr SM ed. Interstitial Lung Disease. Shelton, CT: Peoples

Medical Publishing House; 2011:713

24 Fischer A, Chartrand S. Assessment and management of connec-

tive tissue disease-associated interstitial lung disease. Sarcoido-

sis Vasc Diffuse Lung Dis 2015;32(1):221

25 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

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

and progression in scleroderma-associated interstitial lung dis-

ease: a systematic review. Chest 2014;146(2):422436

27 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

28 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

29 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 Socie-

ty. 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

30 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

31 Patterson CD, Harville WE, Pierce JA. Rheumatoid lung disease.

Ann Intern Med 1965;62:685

69732 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

33 Flaherty KR, Toews GB, Lynch JP III, et al. Steroids in idiopathic

pulmonary brosis: a prospective assessment of adverse reac-

tions, response to therapy, and survival. Am J Med 2001;110(4):

278282

34 Curtis JR, Westfall AO, Allison J, et al. Population-based assess-

ment of adverse events associated with long-term glucocorticoid

use. Arthritis Rheum 2006;55(3):420426

35 YamasakiY, Yamada H, YamasakiM, et al. Intravenous cyclophos-

phamide therapy for progressive interstitial pneumonia in pa-

tients with polymyositis/dermatomyositis. Rheumatology

(Oxford) 2007;46(1):12413036 White B, Moore WC, Wigley FM, Xiao HQ, Wise R A. Cyclophos-

phamide is associated with pulmonary function and survival

benet in patients with scleroderma and alveolitis. Ann Intern

Med 2000;132(12):947954

37 Steen VD, Lanz JK Jr, Conte C, Owens GR, Medsger TA Jr. Therapy

for severe interstitial lung disease in systemic sclerosis. A retro-

spective study. Arthritis Rheum 1994;37(9):12901296

38 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

39 Schnabel A, Reuter M, Gross WL. Intravenous pulse cyclophos-

phamide in the treatment of interstitial lung disease due to

collagen vascular diseases. Arthritis Rheum 1998;41(7):

1215122040 Mira-Avendano IC, Parambil JG, Yadav R, et al. A retrospective

review of clinical features and treatment outcomes in steroid-

resistant interstitial lung disease from polymyositis/dermatomy-

ositis. Respir Med 2013;107(6):890896

41 Akesson A, Scheja A, Lundin A, Wollheim FA. Improved pulmo-

nary function in systemic sclerosis after treatment with cyclo-

phosphamide. Arthritis Rheum 1994;37(5):729735

42 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

43 Brummaier T, Pohanka E, Studnicka-Benke A, Pieringer H. Using

cyclophosphamide in inammatory rheumatic diseases. Eur J

Intern Med 2013;24(7):590596



7/26/2019 s-0036-1580689

8/9

44 Chartrand S, FischerA. Management of connective tissuedisease-

associated interstitial lung disease. Rheum Dis Clin North Am

2015;41(2):279294

45 Yazici H, Pazarli H, Barnes CG, et al. A controlled trial of azathio-

prine in Behets syndrome. N Engl J Med 1990;322(5):281285

46 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

47 Nicholls A, Snaith ML,Maini RN, Scott JT. Proceedings: controlled

trial of azathioprine in rheumatoid vasculitis. Ann Rheum Dis

1973;32(6):589591

48 Felson DT, Anderson J. Evidence for the superiority of immuno-

suppressive drugsand prednisone over prednisone alonein lupus

nephritis. Results of a pooled analysis. N Engl J Med 1984;

311(24):15281533

49 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

50 Hoyles RK,Ellis RW,Wellsbury J, et al. A multicenter, prospective,

randomized, double-blind, placebo-controlled trial of cortico-

steroids and intravenous cyclophosphamide followed by oral

azathioprine for the treatment of pulmonary brosis in sclero-derma. Arthritis Rheum 2006;54(12):39623970

51 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

52 Brezn A, Ranque B, Valeyre D, et al. Therapeutic strategy

combining intravenous cyclophosphamide followed by oral aza-

thioprine to treat worsening interstitial lung disease associated

with systemic sclerosis: a retrospective multicenter open-label

study. J Rheumatol 2008;35(6):10641072

53 Huskisson EC. Azathioprine.Clin RheumDis 1984;10(2):325332

54 Singh G, Fries JF, Spitz P, Williams CA. Toxic effectsof azathioprine

in rheumatoid arthritis. A national post-marketing perspective.

Arthritis Rheum 1989;32(7):837843

55 Swigris JJ,Olson AL,Fischer A, et al. Mycophenolate mofetil is safe,

well tolerated, and preserves lung function in patients withconnective tissue disease-related interstitial lung disease. Chest

2006;130(1):3036

56 Liossis SN, Bounas A, Andonopoulos AP. Mycophenolate mofetil

as rst-line treatment improves clinically evident early sclero-

derma lung disease. Rheumatology (Oxford) 2006;45(8):

10051008

57 Gerbino AJ, Goss CH, Molitor JA. Effect of mycophenolate mofetil

on pulmonary function in scleroderma-associated interstitial

lung disease. Chest 2008;133(2):455460

58 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

59 Bhorade SM, Stern E. Immunosuppression for lung transplanta-

tion. Proc Am Thorac Soc 2009;6(1):4753

60 Tsokos GC. Immunomodulatory treatment in patients with rheu-matic diseases: mechanisms of action. Semin Arthritis Rheum

1987;17(1):2438

61 Wilkes MR, Sereika SM, Fertig N, Lucas MR, Oddis CV. Treatment

of antisynthetase-associated interstitial lung disease with tacro-

limus. Arthritis Rheum 2005;52(8):24392446

62 Takada K, Nagasaka K, Miyasaka N. Polymyositis/dermatomyosi-

tis andinterstitial lung disease: a new therapeutic approach with

T-cell-specic immunosuppressants. Autoimmunity 2005;38(5):

383392

63 Oddis CV, Sciurba FC, Elmagd KA, Starzl TE. Tacrolimus in

refractory polymyositis with interstitial lung disease. Lancet

1999;353(9166):17621763

64 Ochi S, Nanki T, Takada K, et al. Favorable outcomes with

tacrolimus in two patients with refractory interstitial lung

disease associated with polymyositis/dermatomyositis. Clin Exp

Rheumatol 2005;23(5):707710

65 Kurita T, Yasuda S, Oba K, et al. The efcacy of tacrolimus in

patients with interstitial lung diseases complicated with poly-

myositis or dermatomyositis. Rheumatology (Oxford) 2015;

54(1):3944

66 Cavagna L, Caporali R, Abd-Al L, Dore R, Meloni F, Montecucco C.

Cyclosporine in anti-Jo1-positive patients with corticosteroid-

refractory interstitial lung disease. J Rheumatol 2013;40(4):

484492

67 Azzi JR, Sayegh MH, Mallat SG. Calcineurin inhibitors: 40 years

later, cant live without ... J Immunol 2013;191(12):57855791

68 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

69 McDonald V, Leandro M. Rituximab in non-haematological dis-

orders of adults and its mode of action. Br J Haematol 2009;

146(3):233246

70 Keir GJ, Maher TM, Ming D, et al. Rituximab in severe, treatment-

refractory interstitial lung disease. Respirology 2014;19(3):

353359

71 Unger L, Kampf S, Lthke K, Aringer M. Rituximab therapy in

patients with refractory dermatomyositis or polymyositis: dif-ferential effects in a real-life population. Rheumatology (Oxford)

2014;53(9):16301638

72 Sem M, MolbergO, Lund MB, Gran JT. Rituximab treatment of the

anti-synthetase syndrome: a retrospective case series. Rheuma-

tology (Oxford) 2009;48(8):968971

73 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

74 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

75 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):S17S2276 Daoussis D, Liossis SN, Tsamandas AC, et al. Experience with

rituximab in scleroderma: results from a 1-year, proof-of-princi-

ple study. Rheumatology (Oxford) 2010;49(2):271280

77 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-asso-

ciated interstitial pneumonia. Open J Rheumatol Autoimmune

Dis 2012;2:5358

78 Gelfand EW. Intravenous immune globulin in autoimmune and

inammatory diseases. N Engl J Med 2012;367(21):20152025

79 Perricone R, De Carolis C, Kregler B, et al. Intravenous immuno-

globulin therapy in pregnant patients affected with systemic

lupuser ythematosus and recurrent spontaneousabortion. Rheu-

matology (Oxford) 2008;47(5):646651

80 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 dermatomy-

ositis resistant to corticosteroids: a randomized double-blind

placebo-controlled trial. Mod Rheumatol 2012;22(3):382393

81 Dalakas MC, Illa I, Dambrosia JM, et al. A controlled trial of high-

dose intravenous immune globulin infusions as treatment for

dermatomyositis. N Engl J Med 1993;329(27):19932000

82 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

83 Boletis JN, Ioannidis JP, Boki KA, Moutsopoulos HM. Intravenous

immunoglobulin compared with cyclophosphamide for prolifer-

ative lupus nephritis. Lancet 1999;354(9178):569570



7/26/2019 s-0036-1580689

9/9

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

nephritis. Controlled trial of prednisone and cytotoxic drugs. N

Engl J Med 1986;314(10):614619

85 Suzuki Y, Hayakawa H, Miwa S, et al. Intravenous immuno-

globulin therapy for refractory interstitial lung disease associ-

ated with polymyositis/dermatomyositis. Lung 2009;187(3):

201206

86 Bakewell CJ, Raghu G. Polymyositis associated with severe inter-

stitial lung disease: remission after three doses of IV immuno-

globulin. Chest 2011;139(2):441443

87 Khanna D, Albera C, Fischer A, et al. Safety and tolerability of

pirfenidone in patients with systemic sclerosis-associated inter-

stitial lung disease- the LOTUSSstudy. Am J Respir Crit Care Med

2015;191:A1175

88 Fisichella PM, Jalilvand A. The role of impaired esophageal and

gastric motility in end-stage lung diseases and after lung trans-

plantation. J Surg Res 2014;186(1):201206

89 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

90 Sottile PD, Iturbe D, Katsumoto TR, et al. Outcomes in systemic

sclerosis-related lung disease after lung transplantation. Trans-

plantation 2013;95(7):975

98091 Bernstein EJ, Peterson ER, Sell JL, et al. Survival of adults with

systemic sclerosis following lung transplantation: a nation-

wide cohort study. Arthritis Rheum (Munch) 2015;67(5):

13141322

92 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

93 van Assen S, Elkayam O, Agmon-Levin N, et al. Vaccination in

adult patients with auto-immune inammatory rheumatic dis-

eases: a systematic literature review for the European League

Against Rheumatism evidence-based recommendations for vac-

cination in adult patients with auto-immune inammatory

rheumatic diseases. Autoimmun Rev 2011;10(6):341352

94 Vananuvat P, Suwannalai P, Sungkanuparph S, Limsuwan T,Ngamjanyaporn P, Janwityanujit S. Primary prophylaxisfor Pneu-

mocystis jirovecii pneumonia in patients with connective tissue

diseases. Semin Arthritis Rheum 2011;41(3):497502

95 Nici L, Donner C, Wouters E, et al; ATS/ERS Pulmonary Rehabili-

tation Writing Committee. American Thoracic Society/European

Respiratory Society statement on pulmonary rehabilitation. Am J

Respir Crit Care Med 2006;173(12):13901413

96 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

97 Holland AE, Dowman LM, Hill CJ. Principles of rehabilitation and

reactivation: interstitial lung disease, sarcoidosis and rheuma-

toid disease with respiratory involvement. Respiration 2015;

89(2):8999

98 Visca D, Montgomery A, de Lauretis A, et al. Ambulatory oxygenin interstitial lung disease. Eur Respir J 2011;38(4):987990

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

reux disease in patients with rheumatoid arthritis. Mod Rheu-

matol 2014;24(2):291295

100 Bodukam V, Hays RD, Maranian P, et al. Association of gastroin-

testinal involvement and depressive symptoms in patients with

systemic sclerosis. Rheumatology (Oxford) 2011;50(2):330334

101 AhmedS, Palevsky HI. Pulmonary arterialhypertensionrelated to

connective tissue disease: a review. Rheum Dis Clin North Am

2014;40(1):103124

102 Ponnuswamy A, Manikandan R, Sabetpour A, Keeping IM, Finn-

erty JP. Association between ischaemic heart disease and inter-

stitial lung disease: a case-control study. Respir Med 2009;

103(4):503507

103 Villa-Forte A, Mandell BF. [Cardiovascular disorders and rheu-

matic disease]. Rev Esp Cardiol 2011;64(9):809817

104 Khurana R, Wolf R, Berney S, Caldito G,Hayat S, Berney SM.Riskof

development of lung cancer is increased in patients with rheu-

matoid arthritis: a large case control study in US veterans. J

Rheumatol 2008;35(9):17041708

105 AdziTN, Pesut DP, Nagorni-ObradoviLM, StojsiJM, 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

106 Petri M. Update on anti-phospholipid antibodies in SLE: theHopkins lupus cohort. Lupus 2010;19(4):419423

107 Goldberg A. Pulmonary arterialhypertension in connectivetissue

diseases. Cardiol Rev 2010;18(2):8588

108 Steen VD, Medsger TA. Changes in causes of death in systemic

sclerosis, 1972-2002. Ann Rheum Dis 2007;66(7):940944

109 Bongartz T, Nannini C, Medina-Velasquez YF, et al. Incidence and

mortality of interstitial lung disease in rheumatoid arthritis: a

population-based study. ArthritisRheum 2010;62(6):15831591

110 Olson AL, Swigris JJ, Sprunger DB, et al. Rheumatoid arthritis-

interstitial lung disease-associated mortality. Am J Respir Crit

Care Med 2011;183(3):372378

111 Ikeda S, Arita M, Misaki K, et al. Incidence and impact of

interstitial lung disease and malignancy in patients with poly-

myositis, dermatomyositis, and clinically amyopathic dermato-

myositis: a retrospective cohort study. Springerplus 2015;4:240112 ODwyer DN,ArmstrongME,CookeG, Dodd JD,Veale DJ,Donnelly

SC. Rheumatoid arthritis (RA) associated interstitial lung disease

(ILD). Eur J Intern Med 2013;24(7):597603

113 Kiely PD, Chua F. Interstitial lung disease in inammatory myop-

athies: clinical phenotypes and prognosis. Curr Rheumatol Rep

2013;15(9):359

114 Wells AU. Interstitial lung disease in systemic sclerosis. Presse

Med 2014;43(10, Pt 2):e329e343

115 Kreider M, Highland K. Pulmonary involvement in Sjgren syn-

drome. Semin Respir Crit Care Med 2014;35(2):255264

116 Mittoo S, Fell CD. Pulmonary manifestations of systemic lupus

erythematosus. Semin Respir Crit Care Med 2014;35(2):249254

117 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 Dis2012;71(12):19661972



Documents

s-0036-1580689