0
Commentary: Ahead of the Curve |

A Roadmap to Promote Clinical and Translational Research in Rheumatoid Arthritis-Associated Interstitial Lung DiseaseRheumatoid Arthritis and Interstitial Lung Disease FREE TO VIEW

Tracy J. Doyle, MD, MPH; Joyce S. Lee, MD; Paul F. Dellaripa, MD; James A. Lederer, PhD; Eric L. Matteson, MD, MPH; Aryeh Fischer, MD; Dana P. Ascherman, MD; Marilyn K. Glassberg, MD, FCCP; Jay H. Ryu, MD, FCCP; Sonye K. Danoff, MD, PhD, FCCP; Kevin K. Brown, MD, FCCP; Harold R. Collard, MD, FCCP; Ivan O. Rosas, MD, FCCP
Author and Funding Information

From the Division of Pulmonary and Critical Care Medicine (Drs Doyle and Rosas), the Division of Rheumatology, Immunology, and Allergy (Dr Dellaripa), and the Department of Surgery (Immunology) (Dr Lederer), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; the Division of Pulmonary and Critical Care Medicine (Drs Lee and Collard), University of California San Francisco School of Medicine, San Francisco, CA; the Division of Rheumatology (Dr Matteson), and the Division of Pulmonary and Critical Care Medicine (Dr Ryu), Mayo Clinic College of Medicine, Rochester, MN; the Division of Rheumatology (Dr Fischer), National Jewish Health and University of Colorado, Denver, CO; the Division of Rheumatology (Dr Ascherman), and the Division of Pulmonary Medicine (Dr Glassberg), University of Miami Miller School of Medicine, Miami, FL; the Division of Pulmonary and Critical Care Medicine (Dr Danoff), Johns Hopkins University School of Medicine, Baltimore, MD; the Autoimmune Lung Center and Interstitial Lung Disease Program (Dr Brown), National Jewish Health, Denver, CO; and the Lovelace Respiratory Research Institute (Dr Rosas), Albuquerque, NM.

Correspondence to: Ivan O. Rosas, MD, FCCP, Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women’s Hospital, 75 Francis St, Thorn 826, Boston, MA 02115; e-mail: irosas@rics.bwh.harvard.edu


Drs Doyle and Lee contributed equally to this article.

Funding/Support: Dr Doyle is supported by the Harvard Catalyst MeRIT Program. Dr Lee is supported by the National Center for Advancing Translational Science, National Institutes of Health [Grant UCSF-CTI KL2TR000143]. Dr Ascherman is supported by the Department of Veterans Affairs. Dr Danoff is supported by the American College of Rheumatology Within Our Reach Grant. Dr Rosas is supported by the National Institutes of Health [Grant K23 HL087030].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(3):454-463. doi:10.1378/chest.13-2408
Text Size: A A A
Published online

Rheumatoid arthritis (RA) is a systemic inflammatory disorder affecting approximately 1.3 million adults in the United States. Approximately 10% of these individuals with RA have clinically evident interstitial lung disease (RA-ILD), and an additional one-third demonstrate subclinical ILD on chest CT scan. The risk of death for individuals with RA-ILD is three times higher than for patients with RA without ILD, with a median survival after ILD diagnosis of only 2.6 years. Despite the high prevalence and mortality of RA-ILD, little is known about its molecular features and its natural history. At present, we lack a standard validated approach to the definition, diagnosis, risk stratification, and management of RA-ILD. In this perspective, we discuss the importance of clinical and translational research and how ongoing research efforts can address important gaps in our knowledge over the next few years. Furthermore, recommendations are made to design multicenter collaborative studies that will expedite the development of clinical trials designed to decrease the significant morbidity and mortality associated with RA-ILD.

Figures in this Article

Rheumatoid arthritis (RA) is a destructive, systemic, inflammatory disorder1 that currently affects approximately 1.3 million adults in the United States.2 Compared with the general population, median survival in patients with RA is decreased by 10 to 11 years,3 with a major portion of disease burden and excess mortality being due to the extraarticular manifestations present in 40% of individuals with RA.4 Interstitial lung disease (ILD) is the most common clinical manifestation of lung involvement in RA,1,57 with clinically evident disease occurring in about 10% of the RA population. An additional 30% of individuals demonstrate evidence of subclinical disease8 on high-resolution CT (HRCT) scans.1,911 The presence of clinically evident RA-associated ILD (RA-ILD) has a poor prognosis,12 accounting for 7% of all RA-associated deaths1 and contributing to 13% of the excess mortality of patients with RA.6 This translates to a risk of death for individuals with RA-ILD that is three times higher than for patients with RA without ILD and a median survival after RA-ILD diagnosis of only 2.6 years.6 Studies have demonstrated that even though overall mortality rates for RA are declining, death from RA-ILD has increased significantly,1 further emphasizing the physical, psychosocial, and economic burden of RA-ILD.

This perspective briefly reviews the current state of knowledge of RA-ILD and proposes a roadmap for future translational research addressing important existing knowledge gaps (Table 1). We highlight three areas as examples of areas that would benefit from additional research: (1) the diagnosis and evaluation of subclinical RA-ILD, (2) the significance of radiologic and histopathologic subtypes of RA-ILD, and (3) the development of biomarkers. Collaborative cohort development focused on translational research would facilitate diagnosis, improve risk prediction, and allow testing of targeted treatments, ultimately leading to a decrease in the significant morbidity and mortality associated with RA-ILD.

Table Graphic Jump Location
Table 1 —Future Areas for Investigation in RA-ILD

6MWD = 6-min walk distance; CTD = connective tissue disease; DMARD = disease-modifying antirheumatic drug; HRCT = high-resolution CT; ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis; NSIP = nonspecific interstitial pneumonia; O2 sat = oxygen saturation; PFT = pulmonary function test; RA = rheumatoid arthritis; RA-ILD = rheumatoid arthritis-associated interstitial lung disease; UIP = usual interstitial pneumonia.

Although recognized as an important and prevalent complication of RA, there is no consensus in the literature as to the definition of RA-ILD. Borrowing from the American Thoracic Society/European Respiratory Society statements on the idiopathic interstitial pneumonias (IIPs)13 and idiopathic pulmonary fibrosis (IPF),14 an individual diagnosed with RA-ILD should have an underlying diagnosis of RA as well as evidence of chronic, diffuse interstitial pneumonia on HRCT scan, lung biopsy, or both without other identifiable etiology. This definition helps to distinguish RA-ILD from other forms of parenchymal lung involvement in RA, such as inflammatory (rheumatoid) nodules, respiratory infections, and treatment-related ILD.

Risk Factors

Although RA itself is a risk factor for the development of fibrotic lung disease, only a subset of patients with RA will develop ILD. Certain factors associated with a higher incidence of RA-ILD include advanced age, male sex, increased severity of joint disease,6 high-titer rheumatoid factor (RF),15 elevated levels of anticitrullinated protein antibodies (ACPAs),16 and smoking (shown to be a risk factor for both RA-ILD17,18 and fibrotic lung diseases in general).14,1922 Smoking promotes protein citrullination in the lungs, which may lead to generation of ACPA, and promotes lung abnormalities,23 especially in individuals with the HLA-DRB1 “shared epitope.”24 These findings suggest that anticyclic citrullinated peptide (CCP) antibodies25 and HLA-DR serotype are risk factors for the development of RA-ILD.26 The notion that RA may at times “start” in the lungs is suggested by the description of a cohort of patients with anti-CCP positivity and lung disease in the absence of existing RA or other connective tissue disease, some of whom developed articular disease within a short period of follow-up.27 Other potential risk factors associated with the development of RA-ILD include gastroesophageal reflux disease,28,29 genetic factors such as MUC5B,30,31 surfactant protein (SP) abnormalities,32 or TERT33,34 mutations and telomere length.35

Diagnosis

ILD usually arises within the context of well-established RA but can also be the presenting manifestation of RA; as such, in patients presenting with an IIP, the presence of an occult connective tissue disease (CTD), and RA in particular, should be considered.14 When ILD is identified in established RA, it is important to distinguish between primary or direct, disease-related, ILD and secondary or indirect complications presenting as diffuse lung disease. Primary RA-ILD has well-described histopathologic subtypes that are shared with the IIPs,13,14 in particular, usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (Fig 1).36,37 Other histopathologic patterns include organizing pneumonia38 and diffuse alveolar damage.39 Indirect complications include treatment-related diffuse lung disease that occurs as an adverse effect of therapy with disease-modifying antirheumatic drugs (DMARDs), infectious complications, and lymphoproliferative disease.40 The ability to distinguish between primary RA-ILD and secondary or indirect complications can be challenging and is primarily based on clinical judgment using the entirety of the clinical context, including features of disease presentation, temporal association of specific therapy with disease development, and response to stopping the suspected therapeutic agent.41

Figure Jump LinkFigure 1. High-resolution CT (HRCT) and pathologic images of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) with usual interstitial pneumonia (UIP) and non-UIP pattern. A, B, UIP pattern in rheumatoid arthritis (RA). A, This HRCT image demonstrates the reticular opacities, traction bronchiectasis, and basilar/peripheral honeycombing diagnostic of UIP.14 B, This biopsy specimen of the UIP pattern in RA shows patchy fibrosis with marked fibrosis and microscopic honeycombing in the subpleural region and fibroblast foci at the interface between fibrotic and less-involved lung tissue (hematoxylin and eosin [H&E], magnification ×40). C, D, Non-UIP pattern in RA. C, This image demonstrates some of the HRCT scan changes that would suggest a non-UIP pattern: micronodules, air trapping, nonhoneycomb cysts, extensive ground-glass opacities, consolidation, a peribronchovascular-predominant distribution, or coexistent pleural abnormalities.14 D, This biopsy of the nonspecific interstitial pneumonia pattern in RA shows diffuse but variable alveolar septal thickening by dense fibrosis and chronic inflammation (H&E, magnification ×40).Grahic Jump Location
Natural History

Subclinical RA-ILD can be defined as specific radiologic, physiologic, and in some cases histopathologic abnormalities in the lungs of patients with RA who are either asymptomatic or have symptoms and physiologic abnormalities that are as yet unrecognized as being due to RA-ILD (Fig 2).42 Subclinical RA-ILD is most commonly identified on HRCT imaging of the chest by the presence of specific abnormal imaging features termed interstitial lung abnormalities, which are defined as nondependent ground-glass or reticular abnormalities, diffuse centrilobular nodularity, nonemphysematous cysts, honeycombing, or traction bronchiectasis affecting > 5% of any lobar region.8,43 In one study, 33% of patients with RA without dyspnea or cough had interstitial lung abnormalities on chest CT scan, and radiologic progression was observed in more than one-half over the next 1 to 2 years,17 suggesting that progression of asymptomatic radiologic changes could lead to the development of clinically evident RA-ILD. As it is unclear at this time how earlier detection of RA-ILD impacts disease course or alters treatment decisions, such as timing of immunosuppression and choice of agent, the role of routine chest imaging screening of asymptomatic patients with RA for subclinical RA-ILD is unclear.

Figure Jump LinkFigure 2. HRCT images of subclinical RA-ILD and RA-ILD. A, B, Interstitial lung abnormalities or subclinical RA-ILD. C, D, RA-ILD. See Figure 1 legend for expansion of abbreviations.Grahic Jump Location

A variety of clinical measures have been used to define disease severity and progression and to predict early mortality in clinically evident RA-ILD, most of which have been drawn from the IPF and lung transplant literature and not specifically validated in RA-ILD. These include the extent of honeycombing on HRCT imaging, decrease in diffusing capacity of lung for carbon monoxide (Dlco), longitudinal decline in FVC or Dlco, new onset of desaturation during exercise, presence of pulmonary hypertension, and level of dyspnea.14,23,44,45 In clinically evident RA-ILD, there are emerging data to suggest that prognosis may also be related to the underlying histopathologic phenotype, with RA-ILD with UIP pattern having increased mortality compared with non-UIP.36,4651 For example, patients with RA-ILD with UIP pattern have a lower median survival compared with patients with non-UIP pattern, and the HRCT scan pattern of UIP was independently associated with worse survival.47 Other investigators have reported episodes of acute exacerbation in patients with RA-ILD with UIP pattern, but not in those without the UIP pattern.5255 Although many of these studies are limited by small sample size, they collectively suggest that the natural history of RA-ILD with UIP pattern parallels that of IPF, with poor survival rates.

Currently, there are two staging systems for RA-ILD proposed in the literature, but their use is limited by lack of prospective validation. The first is based on the Goh et al56 staging system for ILD in systemic sclerosis, in which HRCT image-characterized ILD is classified as limited (involving < 20% of the lung parenchyma), borderline (20%-25% lung involvement), or advanced (> 25% lung involvement). The application of this staging system to RA-ILD demonstrated a better prognosis with limited disease.57 The second system suggests dividing individuals with RA-ILD into three broad categories: (1) asymptomatic, incidentally discovered ILD (subclinical disease); (2) limited ILD (< 20%) on HRCT scan with gradually increasing symptoms of dyspnea and slow decline in pulmonary function tests (PFTs); and (3) extensive ILD on HRCT scan with rapidly progressive course and rapidly declining PFTs.23

Treatment

The optimal treatment of RA-ILD is unclear, as there are no clinical trials, and it is unknown if any treatment is effective in RA-ILD. However, the decision to treat should balance patient-specific factors (age and comorbidities), disease-specific factors (degree of pulmonary impairment, evidence of progression), and the likelihood of response to the chosen therapy. It is important to note that many of these patients will already be on treatment for their synovitis, and in these individuals a diagnosis of RA-ILD may prompt a change in medication, although data to suggest that any agent preferentially targets the joints or lungs are lacking. Treatment initiated specifically for RA-ILD is empirical and, typically, includes corticosteroids, immunomodulating/steroid-sparing agents, or both.58 Adjuvant RA-ILD therapies can include smoking cessation, pulmonary rehabilitation, supplemental oxygen, and administration of pneumococcal as well as annual influenza vaccines.58 At the same time, both evaluation and treatment should account for comorbidities that can include gastroesophageal reflux disease59 and pulmonary hypertension.60 Lung transplantation is also an option in the appropriate clinical setting.44,61 Most of the DMARDs used to treat articular manifestations of RA (including methotrexate, leflunomide, and biologic agents) have been implicated in the development of pneumonitis at low, but variable, rates.17,6269 If this type of presumed drug-related toxicity occurs, it has been suggested that therapy should be interrupted and, after excluding infection, corticosteroid treatment initiated.41

Three ongoing areas of investigation in RA-ILD are discussed here to illustrate the need for collaborative translationally focused cohort studies in this disease. There are other areas of study (eg, extrapulmonary/serological manifestations, risk prediction, treatment) that are equally compelling and also deserve attention from the research community.

Subclinical RA-ILD

Approximately one-third of patients with RA will have HRCT imaging evidence of specific pulmonary abnormalities in the absence of respiratory symptoms indicative of subclinical disease, and a substantial minority will develop clinically evident RA-ILD over time (Fig 2).17 The significance of subclinical ILD lies not only in its risk of progression but also in its frequent association with physiologic and functional abnormalities that may not be clinically recognized.8,17,42,7072 Consequently, it is possible that some patients with evidence of subclinical RA-ILD may in fact have occult respiratory symptoms, physiologic impairments, and a reduced exercise capacity. Given the widespread use of HRCT imaging in clinical and research settings, we anticipate that an increasing number of pulmonologists and rheumatologists will evaluate and manage subjects with incidentally discovered subclinical RA-ILD on imaging. As such, clinical and translational research needs to focus on a better understanding of the clinical significance of these findings as well as risk factors for its progression to clinically evident disease, as timely completion of this research will enable us to develop a validated approach to the diagnosis, staging, and management of progressive subclinical disease.

Radiographic/Histopathologic Subtyping

Patients with RA-ILD with UIP pattern on lung biopsy or HRCT scan appear to have a distinct clinical, and perhaps biologic, phenotype compared with patients with RA-ILD without UIP pattern (Fig 1).36,38 It remains unclear to what degree RA-ILD with UIP pattern overlaps biologically with IPF. A multicenter randomized controlled trial of patients with IPF conducted by IPFNet found increased rates of death and hospitalization in the intervention group that received a combination of antiinflammatory medications (prednisone, azathioprine, and N-acetylcysteine).73 Given the potential pathophysiological overlap of RA-ILD with UIP pattern and IPF, we may need to reconsider the common approach to treatment of RA-ILD with prednisone and other immunomodulatory drugs, although available retrospective data suggest the potential benefit of this approach.74 Conversely, once successful IPF therapies are discovered, these could be tested in the subset of RA-ILD with UIP pattern. Beyond these treatment considerations, in future IPF studies, screening with autoimmune markers could help to elucidate the similarities and differences between RA-ILD and IPF. The similarities between these two entities also suggest that RA-ILD with UIP pattern may need to be approached similarly in terms of prognosis and timing of referral for lung transplantation.

In general, these considerations highlight the importance of current efforts to assemble large, multicenter cohorts of patients with RA-ILD with standardized characterization of histopathologic subtype (as well as associated HRCT imaging, functional abnormalities, and biomarker profiles) so that further prognostic comparisons can be made with the IIPs. Specifically, ongoing collection of serial clinical and biologic data in cohorts with well-characterized RA-ILD will facilitate exploration of biologic mechanisms that have been previously identified in IPF (eg, telomere biology,75 genetics,76,77 endoplasmic reticulum stress,78 and epithelial-mesenchymal transition79).

Biomarker Discovery

A limited number of RA-ILD biomarkers have been formally examined. These include RF, Krebs von den Lungen-6 (KL-6), and ACPA (including anti-CCP [HSP90] antibodies) (Fig 3A).24,26,80 While high-titer RF is associated with the presence of RA-ILD and a decreased Dlco,15 KL-6 levels have been shown to correlate with severity of CT scan findings.81 Based on research in other connective tissue disease-related ILD and subclinical ILD, KL-6, SP-A, and SP-D8285 appear to be common biomarkers of ILD that may prove useful in the assessment of disease activity and prognosis in RA-ILD (Fig 3B).8588 Other potential biomarkers of RA-ILD include CC-chemokine ligand-18,89,90 CXC chemokine ligand (CXCL)-9, CXCL10, C-reactive protein,91 IL-6,92,93 YKL-40,94 CCN2 (connective tissue growth factor),95 IL-8, intracellular adhesion molecule-1, vascular cell adhesion molecule-1,92 and various matrix metalloproteinases (MMPs).92,96,97 Furthermore, it has been demonstrated that levels of certain alveolar proteins, including platelet-derived growth factor (PDGF)-AB, PDGF-BB, transforming growth factor-β2, and interferon-γ, differed significantly based on the degree of RA-ILD, making this compartment another potential target.17 This assertion has been further substantiated by the alveolar profiling of cytokines in BAL fluid of individuals with systemic sclerosis, in which IL-8 and monocyte chemoattractant protein-1 were associated with lung fibrosis and prognosis.98,99

Figure Jump LinkFigure 3. Potential biomarkers of RA-ILD. A, Biomarkers drawn from RA-ILD literature. B, Select biomarkers drawn from CTD-ILD, IPF, and subclinical ILD literature. *Based on alveolar profiling of cytokines in BAL fluid. ACPA = anticitrullinated protein antibody; CCL = CC-chemokine ligand; CRP = C-reactive protein; CTD = connective tissue disease; CXCL = CXC chemokine ligand; ICAM = intracellular adhesion molecule; ILD = interstitial lung disease; INFγ = interferon-γ; IPF = idiopathic pulmonary fibrosis; KL-6 = Krebs von den Lungen-6; MCP = monocyte chemoattractant protein; MMP = matrix metalloproteinase; PDGF = platelet-derived growth factor; RF = rheumatoid factor; SP = surfactant protein; TGF = transforming growth factor; VCAM = vascular cell adhesion molecule. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location

We believe that short-term research goals need to focus not only on identification of additional biomarkers in RA-ILD but also on defining the role of these biomarkers in the evaluation of disease mechanisms, diagnosis, prognosis, and/or therapeutic response. In IPF, for example, more recent biomarker studies suggest that a panel of peripheral blood molecular markers, such as MMP7,92 SP-A, and SP-D,100 can complement and enhance the assessment and prognostication of patients when added to established clinical parameters.101 By extension, parallel clinical predictive models incorporating biomarkers may allow us to identify individuals at high risk for developing progressive RA-ILD, thereby facilitating earlier diagnosis as well as monitoring of disease progression and response to therapy. Biomarkers may also play an important role in distinguishing between primary RA-ILD and secondary or indirect causes of diffuse lung disease,102 in measuring the therapeutic response to treatment,103 and in providing surrogate end points for clinical trials.

RA-ILD is an increasingly recognized and highly morbid condition that is still poorly understood. We have summarized the current state of knowledge in RA-ILD and have provided examples of areas of focus for current and future translational research. Over the next few years, we hope that collaborative research efforts will help to address the current gaps in knowledge regarding diagnosis and management in RA-ILD, potentially leading to improvements in the lives of patients with this debilitating condition. Progress will be catalyzed by the development of large, multicenter longitudinal cohorts of well-characterized patients with matching biologic samples.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Fischer is an investigator and steering committee member of the Comparison of Therapeutic Regimens for Scleroderma Interstitial Lung Disease (The Scleroderma Lung Study II) study, sponsored by Philip Clements, and an investigator on the Safety and Tolerability of Pirfenidone in Patients with Systemic Sclerosis-Related Interstitial Lung Disease study sponsored by InterMune. Dr Rosas has received consulting fees from Biogen Idec, Synovex Corp, and Sanofi. Drs Doyle, Lee, Dellaripa, Lederer, Matteson, Ascherman, Glassberg, Ryu, Danoff, Brown, and Collard have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript.

Other contributions: We thank Brett Elicker, MD, for providing the CT images included in Figure 1 and Kirk Jones, MD, for providing the pathologic images and captions for Figure 1. This work was performed at Brigham and Women’s Hospital. The authors (Dr Ascherman) take full responsibility for the contents of this paper, which do not represent the views of the Department of Veterans Affairs or the United States Government.

ACPA

anticitrullinated protein antibody

CCP

cyclic citrullinated peptide

CTD

connective tissue disease

CXCL

CXC chemokine ligand

Dlco

diffusing capacity of lung for carbon monoxide

DMARD

disease-modifying antirheumatic drug

HRCT

high resolution CT

IIP

idiopathic interstitial pneumonia

ILD

interstitial lung disease

IPF

idiopathic pulmonary fibrosis

KL-6

Krebs von den Lungen-6

MMP

matrix metalloproteinase

PDGF

platelet-derived growth factor

PFT

pulmonary function test

RA

rheumatoid arthritis

RA-ILD

rheumatoid arthritis-associated interstitial lung disease

RF

rheumatoid factor

SP

surfactant protein

UIP

usual interstitial pneumonia

Olson AL, Swigris JJ, Sprunger DB, et al. Rheumatoid arthritis-interstitial lung disease-associated mortality. Am J Respir Crit Care Med. 2011;183(3):372-378. [CrossRef] [PubMed]
 
Helmick CG, Felson DT, Lawrence RC, et al; National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58(1):15-25. [CrossRef] [PubMed]
 
Minaur NJ, Jacoby RK, Cosh JA, Taylor G, Rasker JJ. Outcome after 40 years with rheumatoid arthritis: a prospective study of function, disease activity, and mortality. J Rheumatol Suppl. 2004;69:3-8. [PubMed]
 
Turesson C, O’Fallon WM, Crowson CS, Gabriel SE, Matteson EL. Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann Rheum Dis. 2003;62(8):722-727. [CrossRef] [PubMed]
 
Brown KK. Rheumatoid lung disease. Proc Am Thorac Soc. 2007;4(5):443-448. [CrossRef] [PubMed]
 
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):1583-1591. [CrossRef] [PubMed]
 
Crestani B. The respiratory system in connective tissue disorders. Allergy. 2005;60(6):715-734. [CrossRef] [PubMed]
 
Washko GR, Hunninghake GM, Fernandez IE, et al; COPDGene Investigators. Lung volumes and emphysema in smokers with interstitial lung abnormalities. N Engl J Med. 2011;364(10):897-906. [CrossRef] [PubMed]
 
Dawson JK, Fewins HE, Desmond J, Lynch MP, Graham DR. Fibrosing alveolitis in patients with rheumatoid arthritis as assessed by high resolution computed tomography, chest radiography, and pulmonary function tests. Thorax. 2001;56(8):622-627. [CrossRef] [PubMed]
 
Cervantes-Perez P, Toro-Perez AH, Rodriguez-Jurado P. Pulmonary involvement in rheumatoid arthritis. JAMA. 1980;243(17):1715-1719. [CrossRef] [PubMed]
 
Gabbay E, Tarala R, Will R, et al. Interstitial lung disease in recent onset rheumatoid arthritis. Am J Respir Crit Care Med. 1997;156(2 pt 1):528-535. [CrossRef] [PubMed]
 
Koduri G, Norton S, Young A, et al; ERAS (Early Rheumatoid Arthritis Study). Interstitial lung disease has a poor prognosis in rheumatoid arthritis: results from an inception cohort. Rheumatology (Oxford). 2010;49(8):1483-1489. [CrossRef] [PubMed]
 
American Thoracic Society, European Respiratory Society, American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med. 2002;165(2):277-304. [CrossRef] [PubMed]
 
Raghu G, Collard HR, Egan JJ, et al; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824. [CrossRef] [PubMed]
 
Luukkainen R, Saltyshev M, Pakkasela R, Nordqvist E, Huhtala H, Hakala M. Relationship of rheumatoid factor to lung diffusion capacity in smoking and non-smoking patients with rheumatoid arthritis. Scand J Rheumatol. 1995;24(2):119-120. [CrossRef] [PubMed]
 
Giles JT, Danoff SK, Sokolove J, et al. Association of fine specificity and repertoire expansion of anticitrullinated peptide antibodies with rheumatoid arthritis associated interstitial lung disease [published online ahead of print May 28, 2013]. Ann Rheum Dis. doi:10.1136/annrheumdis-2012-203160.
 
Gochuico BR, Avila NA, Chow CK, et al. Progressive preclinical interstitial lung disease in rheumatoid arthritis. Arch Intern Med. 2008;168(2):159-166. [CrossRef] [PubMed]
 
Saag KG, Kolluri S, Koehnke RK, et al. Rheumatoid arthritis lung disease. Determinants of radiographic and physiologic abnormalities. Arthritis Rheum. 1996;39(10):1711-1719. [CrossRef] [PubMed]
 
Antoniou KM, Hansell DM, Rubens MB, et al. Idiopathic pulmonary fibrosis: outcome in relation to smoking status. Am J Respir Crit Care Med. 2008;177(2):190-194. [CrossRef] [PubMed]
 
Vassallo R, Ryu JH. Tobacco smoke-related diffuse lung diseases. Semin Respir Crit Care Med. 2008;29(6):643-650. [CrossRef] [PubMed]
 
Patel RR, Ryu JH, Vassallo R. Cigarette smoking and diffuse lung disease. Drugs. 2008;68(11):1511-1527. [CrossRef] [PubMed]
 
Baumgartner KB, Samet JM, Stidley CA, Colby TV, Waldron JA. Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1997;155(1):242-248. [CrossRef] [PubMed]
 
Malik S, Saravanan V, Kelly C. Interstitial lung disease in rheumatoid arthritis: an update on diagnosis and management. Int J Clin Rheumatol. 2012;7(3):297-308. [CrossRef]
 
Klareskog L, Stolt P, Lundberg K, et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006;54(1):38-46. [CrossRef] [PubMed]
 
Aubart F, Crestani B, Nicaise-Roland P, et al. High levels of anti-cyclic citrullinated peptide autoantibodies are associated with co-occurrence of pulmonary diseases with rheumatoid arthritis. J Rheumatol. 2011;38(6):979-982. [CrossRef] [PubMed]
 
Inui N, Enomoto N, Suda T, Kageyama Y, Watanabe H, Chida K. Anti-cyclic citrullinated peptide antibodies in lung diseases associated with rheumatoid arthritis. Clin Biochem. 2008;41(13):1074-1077. [CrossRef] [PubMed]
 
Fischer A, Solomon JJ, du Bois RM, et al. Lung disease with anti-CCP antibodies but not rheumatoid arthritis or connective tissue disease. Respir Med. 2012;106(7):1040-1047. [CrossRef] [PubMed]
 
Tobin RW, Pope CE II, Pellegrini CA, Emond MJ, Sillery J, Raghu G. Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1998;158(6):1804-1808. [CrossRef] [PubMed]
 
Raghu G, Freudenberger TD, Yang S, et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J. 2006;27(1):136-142. [CrossRef] [PubMed]
 
Seibold MA, Wise AL, Speer MC, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med. 2011;364(16):1503-1512. [CrossRef] [PubMed]
 
Hunninghake GM, Hatabu H, Okajima Y, et al. MUC5B promoter polymorphism and interstitial lung abnormalities. N Engl J Med. 2013;368(23):2192-2200. [CrossRef] [PubMed]
 
Pantelidis P, Veeraraghavan S, du Bois RM. Surfactant gene polymorphisms and interstitial lung diseases. Respir Res. 2002;3:14. [CrossRef] [PubMed]
 
Diaz de Leon A, Cronkhite JT, Yilmaz C, et al. Subclinical lung disease, macrocytosis, and premature graying in kindreds with telomerase (TERT) mutations. Chest. 2011;140(3):753-763. [CrossRef] [PubMed]
 
Mushiroda T, Wattanapokayakit S, Takahashi A, et al; Pirfenidone Clinical Study Group. A genome-wide association study identifies an association of a common variant in TERT with susceptibility to idiopathic pulmonary fibrosis. J Med Genet. 2008;45(10):654-656. [CrossRef] [PubMed]
 
Liu T, Ullenbruch M, Young Choi Y, et al. Telomerase and telomere length in pulmonary fibrosis. Am J Respir Cell Mol Biol. 2013;49(2):260-268. [CrossRef] [PubMed]
 
Kim EJ, Collard HR, King TE Jr. Rheumatoid arthritis-associated interstitial lung disease: the relevance of histopathologic and radiographic pattern. Chest. 2009;136(5):1397-1405. [CrossRef] [PubMed]
 
Tanaka N, Kim JS, Newell JD, et al. Rheumatoid arthritis-related lung diseases: CT findings. Radiology. 2004;232(1):81-91. [CrossRef] [PubMed]
 
Lee HK, Kim DS, Yoo B, et al. Histopathologic pattern and clinical features of rheumatoid arthritis-associated interstitial lung disease. Chest. 2005;127(6):2019-2027. [CrossRef] [PubMed]
 
Parambil JG, Myers JL, Ryu JH. Diffuse alveolar damage: uncommon manifestation of pulmonary involvement in patients with connective tissue diseases. Chest. 2006;130(2):553-558. [CrossRef] [PubMed]
 
Furst DE, Breedveld FC, Kalden JR, et al. Updated consensus statement on biological agents for the treatment of rheumatoid arthritis and other immune mediated inflammatory diseases (May 2003). Ann Rheum Dis. 2003;62(suppl 2):ii2-ii9. [CrossRef] [PubMed]
 
Picchianti Diamanti A, Germano V, Bizzi E, Laganà B, Migliore A. Interstitial lung disease in rheumatoid arthritis in the era of biologics. Pulm Med. 2011;2011:931342.
 
Doyle TJ, Hunninghake GM, Rosas IO. Subclinical interstitial lung disease: why you should care. Am J Respir Crit Care Med. 2012;185(11):1147-1153. [CrossRef] [PubMed]
 
Washko GR, Lynch DA, Matsuoka S, et al. Identification of early interstitial lung disease in smokers from the COPDGene Study. Acad Radiol. 2010;17(1):48-53. [CrossRef] [PubMed]
 
Orens JB, Estenne M, Arcasoy S, et al; Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. International guidelines for the selection of lung transplant candidates: 2006 update—a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2006;25(7):745-755. [CrossRef] [PubMed]
 
Vinik O, Marras T, Shapera S, Mittoo S. Rheumatoid arthritis interstitial lung disease. in Harjacek M, ed.Challenges in Rheumatology. InTech website. http://www.intechopen.com/books/challenges-in-rheumatology/rheumatoid-arthritis-interstitial-lung-disease. Published 2011. Accessed August 24, 2013.
 
Flaherty KR, Colby TV, Travis WD, et al. Fibroblastic foci in usual interstitial pneumonia: idiopathic versus collagen vascular disease. Am J Respir Crit Care Med. 2003;167(10):1410-1415. [CrossRef] [PubMed]
 
Kim EJ, Elicker BM, Maldonado F, et al. Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease. Eur Respir J. 2010;35(6):1322-1328. [CrossRef] [PubMed]
 
Park JH, Kim DS, Park IN, et al. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med. 2007;175(7):705-711. [CrossRef] [PubMed]
 
Hakala M, Pääkkö P, Huhti E, Tarkka M, Sutinen S. Open lung biopsy of patients with rheumatoid arthritis. Clin Rheumatol. 1990;9(4):452-460. [CrossRef] [PubMed]
 
Yousem SA, Colby TV, Carrington CB. Lung biopsy in rheumatoid arthritis. Am Rev Respir Dis. 1985;131(5):770-777. [PubMed]
 
Flaherty KR, Thwaite EL, Kazerooni EA, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax. 2003;58(2):143-148. [CrossRef] [PubMed]
 
Akira M, Sakatani M, Hara H. Thin-section CT findings in rheumatoid arthritis-associated lung disease: CT patterns and their courses. J Comput Assist Tomogr. 1999;23(6):941-948. [CrossRef] [PubMed]
 
Pratt DS, Schwartz MI, May JJ, Dreisin RB. Rapidly fatal pulmonary fibrosis: the accelerated variant of interstitial pneumonitis. Thorax. 1979;34(5):587-593. [CrossRef] [PubMed]
 
Park IN, Kim DS, Shim TS, et al. Acute exacerbation of interstitial pneumonia other than idiopathic pulmonary fibrosis. Chest. 2007;132(1):214-220. [CrossRef] [PubMed]
 
Dawson JK, Fewins HE, Desmond J, Lynch MP, Graham DR. Predictors of progression of HRCT diagnosed fibrosing alveolitis in patients with rheumatoid arthritis. Ann Rheum Dis. 2002;61(6):517-521. [CrossRef] [PubMed]
 
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):1248-1254. [CrossRef] [PubMed]
 
Sathi N, Urwin T, Desmond S, Dawson JK. Patients with limited rheumatoid arthritis-related interstitial lung disease have a better prognosis than those with extensive disease. Rheumatology (Oxford). 2011;50(3):620. [CrossRef] [PubMed]
 
O’Dwyer 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):597-603. [CrossRef] [PubMed]
 
Lee JS, Ryu JH, Elicker BM, et al. Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;184(12):1390-1394. [CrossRef] [PubMed]
 
Vassallo R, Thomas CF. Advances in the treatment of rheumatic interstitial lung disease. Curr Opin Rheumatol. 2004;16(3):186-191. [CrossRef] [PubMed]
 
Maurer JR, Frost AE, Estenne M, Higenbottam T, Glanville AR. International guidelines for the selection of lung transplant candidates. The International Society for Heart and Lung Transplantation, the American Thoracic Society, the American Society of Transplant Physicians, the European Respiratory Society. Transplantation. 1998;66(7):951-956. [CrossRef] [PubMed]
 
Ito S, Sumida T. Interstitial lung disease associated with leflunomide. Intern Med. 2004;43(12):1103-1104. [CrossRef] [PubMed]
 
Tomioka R, King TE Jr. Gold-induced pulmonary disease: clinical features, outcome, and differentiation from rheumatoid lung disease. Am J Respir Crit Care Med. 1997;155(3):1011-1020. [CrossRef] [PubMed]
 
Stein HB, Patterson AC, Offer RC, Atkins CJ, Teufel A, Robinson HS. Adverse effects of D-penicillamine in rheumatoid arthritis. Ann Intern Med. 1980;92(1):24-29. [CrossRef] [PubMed]
 
Barrera P, Laan RF, van Riel PL, Dekhuijzen PN, Boerbooms AM, van de Putte LB. Methotrexate-related pulmonary complications in rheumatoid arthritis. Ann Rheum Dis. 1994;53(7):434-439. [CrossRef] [PubMed]
 
Alarcón GS, Kremer JM, Macaluso M, et al; Methotrexate-Lung Study Group. Risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis. A multicenter, case-control study. Ann Intern Med. 1997;127(5):356-364. [CrossRef] [PubMed]
 
Ramos-Casals M, Perez-Alvarez R, Perez-de-Lis M, Xaubet A, Bosch X; BIOGEAS Study Group. Pulmonary disorders induced by monoclonal antibodies in patients with rheumatologic autoimmune diseases. Am J Med. 2011;124(5):386-394. [CrossRef] [PubMed]
 
Camus P, Fanton A, Bonniaud P, Camus C, Foucher P. Interstitial lung disease induced by drugs and radiation. Respiration. 2004;71(4):301-326. [CrossRef] [PubMed]
 
Dixon WG, Hyrich KL, Watson KD, Lunt M, Symmons DP; BSRBR Control Centre Consortium; British Society for Rheumatology Biologics Register. Influence of anti-TNF therapy on mortality in patients with rheumatoid arthritis-associated interstitial lung disease: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis. 2010;69(6):1086-1091. [CrossRef] [PubMed]
 
Doyle TJ, Washko GR, Fernandez IE, et al; COPDGene Investigators. Interstitial lung abnormalities and reduced exercise capacity. Am J Respir Crit Care Med. 2012;185(7):756-762. [CrossRef] [PubMed]
 
Lederer DJ, Enright PL, Kawut SM, et al. Cigarette smoking is associated with subclinical parenchymal lung disease: the Multi-Ethnic Study of Atherosclerosis (MESA)-lung study. Am J Respir Crit Care Med. 2009;180(5):407-414. [CrossRef] [PubMed]
 
Rosas IO, Ren P, Avila NA, et al. Early interstitial lung disease in familial pulmonary fibrosis. Am J Respir Crit Care Med. 2007;176(7):698-705. [CrossRef] [PubMed]
 
Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ; Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366(21):1968-1977. [CrossRef] [PubMed]
 
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):640-646. [CrossRef] [PubMed]
 
Diaz de Leon A, Cronkhite JT, Katzenstein AL, et al. Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations. PLoS ONE. 2010;5(5):e10680. [CrossRef] [PubMed]
 
Fingerlin TE, Murphy E, Zhang W, et al. Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis. Nat Genet. 2013;45(6):613-620. [CrossRef] [PubMed]
 
Peljto AL, Zhang Y, Fingerlin TE, et al. Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis. JAMA. 2013;309(21):2232-2239. [CrossRef] [PubMed]
 
Tanjore H, Blackwell TS, Lawson WE. Emerging evidence for endoplasmic reticulum stress in the pathogenesis of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2012;302(8):L721-L729. [CrossRef] [PubMed]
 
Jayachandran A, Königshoff M, Yu H, et al. SNAI transcription factors mediate epithelial-mesenchymal transition in lung fibrosis. Thorax. 2009;64(12):1053-1061. [CrossRef] [PubMed]
 
Harlow L, Rosas IO, Gochuico BR, et al. Identification of citrullinated hsp90 isoforms as novel autoantigens in rheumatoid arthritis-associated interstitial lung disease. Arthritis Rheum. 2013;65(4):869-879. [CrossRef] [PubMed]
 
Kinoshita F, Hamano H, Harada H, et al. Role of KL-6 in evaluating the disease severity of rheumatoid lung disease: comparison with HRCT. Respir Med. 2004;98(11):1131-1137. [CrossRef] [PubMed]
 
Yanaba K, Hasegawa M, Takehara K, Sato S. Comparative study of serum surfactant protein-D and KL-6 concentrations in patients with systemic sclerosis as markers for monitoring the activity of pulmonary fibrosis. J Rheumatol. 2004;31(6):1112-1120. [PubMed]
 
Greene KE, King TEJ Jr, Kuroki Y, et al. Serum surfactant proteins-A and -D as biomarkers in idiopathic pulmonary fibrosis. Eur Respir J. 2002;19(3):439-446. [CrossRef] [PubMed]
 
Kohno N, Kyoizumi S, Awaya Y, Fukuhara H, Yamakido M, Akiyama M. New serum indicator of interstitial pneumonitis activity. Sialylated carbohydrate antigen KL-6. Chest. 1989;96(1):68-73. [CrossRef] [PubMed]
 
Sato S, Nagaoka T, Hasegawa M, Nishijima C, Takehara K. Elevated serum KL-6 levels in patients with systemic sclerosis: association with the severity of pulmonary fibrosis. Dermatology. 2000;200(3):196-201. [CrossRef] [PubMed]
 
Saketkoo LA, Ascherman DP, Cottin V, Christopher-Stine L, Danoff SK, Oddis CV. Interstitial Lung Disease in Idiopathic Inflammatory Myopathy. Curr Rheumatol Rep. 2010;6(2):108-119. [CrossRef]
 
Kashiwabara K. Characteristics and disease activity of early interstitial lung disease in subjects with true parenchymal abnormalities in the posterior subpleural aspect of the lung. Chest. 2006;129(2):402-406. [CrossRef] [PubMed]
 
Tsushima K, Sone S, Yoshikawa S, Yokoyama T, Suzuki T, Kubo K. The radiological patterns of interstitial change at an early phase: over a 4-year follow-up. Respir Med. 2010;104(11):1712-1721. [CrossRef] [PubMed]
 
Prasse A, Pechkovsky DV, Toews GB, et al. CCL18 as an indicator of pulmonary fibrotic activity in idiopathic interstitial pneumonias and systemic sclerosis. Arthritis Rheum. 2007;56(5):1685-1693. [CrossRef] [PubMed]
 
Kodera M, Hasegawa M, Komura K, Yanaba K, Takehara K, Sato S. Serum pulmonary and activation-regulated chemokine/CCL18 levels in patients with systemic sclerosis: a sensitive indicator of active pulmonary fibrosis. Arthritis Rheum. 2005;52(9):2889-2896. [CrossRef] [PubMed]
 
Richards TJ, Eggebeen A, Gibson K, et al. Characterization and peripheral blood biomarker assessment of anti-Jo-1 antibody-positive interstitial lung disease. Arthritis Rheum. 2009;60(7):2183-2192. [CrossRef] [PubMed]
 
Richards TJ, Kaminski N, Baribaud F, et al. Peripheral blood proteins predict mortality in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2012;185(1):67-76. [CrossRef] [PubMed]
 
Collard HR, Calfee CS, Wolters PJ, et al. Plasma biomarker profiles in acute exacerbation of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2010;299(1):L3-L7. [CrossRef] [PubMed]
 
Furuhashi K, Suda T, Nakamura Y, et al. Increased expression of YKL-40, a chitinase-like protein, in serum and lung of patients with idiopathic pulmonary fibrosis. Respir Med. 2010;104(8):1204-1210. [CrossRef] [PubMed]
 
Kono M, Nakamura Y, Suda T, et al. Plasma CCN2 (connective tissue growth factor; CTGF) is a potential biomarker in idiopathic pulmonary fibrosis (IPF). Clin Chim Acta. 2011;412(23-24):2211-2215. [CrossRef] [PubMed]
 
Pardo A, Selman M. Matrix metalloproteases in aberrant fibrotic tissue remodeling. Proc Am Thorac Soc. 2006;3(4):383-388. [CrossRef] [PubMed]
 
Rosas IO, Richards TJ, Konishi K, et al. MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis. PLoS Med. 2008;5(4):e93. [CrossRef] [PubMed]
 
Schmidt K, Martinez-Gamboa L, Meier S, et al. Bronchoalveolar lavage fluid cytokines and chemokines as markers and predictors for the outcome of interstitial lung disease in systemic sclerosis patients. Arthritis Res Ther. 2009;11(4):R111. [CrossRef] [PubMed]
 
Meloni F, Caporali R, Marone Bianco A, et al. BAL cytokine profile in different interstitial lung diseases: a focus on systemic sclerosis. Sarcoidosis Vasc Diffuse Lung Dis. 2004;21(2):111-118. [PubMed]
 
Kinder BW, Brown KK, McCormack FX, et al. Serum surfactant protein-A is a strong predictor of early mortality in idiopathic pulmonary fibrosis. Chest. 2009;135(6):1557-1563. [CrossRef] [PubMed]
 
Doyle TJ, Pinto-Plata V, Morse D, Celli BR, Rosas IO. The expanding role of biomarkers in the assessment of smoking-related parenchymal lung diseases. Chest. 2012;142(4):1027-1034. [CrossRef] [PubMed]
 
Oka S, Furukawa H, Shimada K, et al. Serum biomarker analysis of collagen disease patients with acute-onset diffuse interstitial lung disease. BMC Immunol. 2013;14:9. [CrossRef] [PubMed]
 
Ascherman DP. Interstitial lung disease in rheumatoid arthritis. Curr Rheumatol Rep. 2010;12(5):363-369. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. High-resolution CT (HRCT) and pathologic images of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) with usual interstitial pneumonia (UIP) and non-UIP pattern. A, B, UIP pattern in rheumatoid arthritis (RA). A, This HRCT image demonstrates the reticular opacities, traction bronchiectasis, and basilar/peripheral honeycombing diagnostic of UIP.14 B, This biopsy specimen of the UIP pattern in RA shows patchy fibrosis with marked fibrosis and microscopic honeycombing in the subpleural region and fibroblast foci at the interface between fibrotic and less-involved lung tissue (hematoxylin and eosin [H&E], magnification ×40). C, D, Non-UIP pattern in RA. C, This image demonstrates some of the HRCT scan changes that would suggest a non-UIP pattern: micronodules, air trapping, nonhoneycomb cysts, extensive ground-glass opacities, consolidation, a peribronchovascular-predominant distribution, or coexistent pleural abnormalities.14 D, This biopsy of the nonspecific interstitial pneumonia pattern in RA shows diffuse but variable alveolar septal thickening by dense fibrosis and chronic inflammation (H&E, magnification ×40).Grahic Jump Location
Figure Jump LinkFigure 2. HRCT images of subclinical RA-ILD and RA-ILD. A, B, Interstitial lung abnormalities or subclinical RA-ILD. C, D, RA-ILD. See Figure 1 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 3. Potential biomarkers of RA-ILD. A, Biomarkers drawn from RA-ILD literature. B, Select biomarkers drawn from CTD-ILD, IPF, and subclinical ILD literature. *Based on alveolar profiling of cytokines in BAL fluid. ACPA = anticitrullinated protein antibody; CCL = CC-chemokine ligand; CRP = C-reactive protein; CTD = connective tissue disease; CXCL = CXC chemokine ligand; ICAM = intracellular adhesion molecule; ILD = interstitial lung disease; INFγ = interferon-γ; IPF = idiopathic pulmonary fibrosis; KL-6 = Krebs von den Lungen-6; MCP = monocyte chemoattractant protein; MMP = matrix metalloproteinase; PDGF = platelet-derived growth factor; RF = rheumatoid factor; SP = surfactant protein; TGF = transforming growth factor; VCAM = vascular cell adhesion molecule. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Future Areas for Investigation in RA-ILD

6MWD = 6-min walk distance; CTD = connective tissue disease; DMARD = disease-modifying antirheumatic drug; HRCT = high-resolution CT; ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis; NSIP = nonspecific interstitial pneumonia; O2 sat = oxygen saturation; PFT = pulmonary function test; RA = rheumatoid arthritis; RA-ILD = rheumatoid arthritis-associated interstitial lung disease; UIP = usual interstitial pneumonia.

References

Olson AL, Swigris JJ, Sprunger DB, et al. Rheumatoid arthritis-interstitial lung disease-associated mortality. Am J Respir Crit Care Med. 2011;183(3):372-378. [CrossRef] [PubMed]
 
Helmick CG, Felson DT, Lawrence RC, et al; National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58(1):15-25. [CrossRef] [PubMed]
 
Minaur NJ, Jacoby RK, Cosh JA, Taylor G, Rasker JJ. Outcome after 40 years with rheumatoid arthritis: a prospective study of function, disease activity, and mortality. J Rheumatol Suppl. 2004;69:3-8. [PubMed]
 
Turesson C, O’Fallon WM, Crowson CS, Gabriel SE, Matteson EL. Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann Rheum Dis. 2003;62(8):722-727. [CrossRef] [PubMed]
 
Brown KK. Rheumatoid lung disease. Proc Am Thorac Soc. 2007;4(5):443-448. [CrossRef] [PubMed]
 
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):1583-1591. [CrossRef] [PubMed]
 
Crestani B. The respiratory system in connective tissue disorders. Allergy. 2005;60(6):715-734. [CrossRef] [PubMed]
 
Washko GR, Hunninghake GM, Fernandez IE, et al; COPDGene Investigators. Lung volumes and emphysema in smokers with interstitial lung abnormalities. N Engl J Med. 2011;364(10):897-906. [CrossRef] [PubMed]
 
Dawson JK, Fewins HE, Desmond J, Lynch MP, Graham DR. Fibrosing alveolitis in patients with rheumatoid arthritis as assessed by high resolution computed tomography, chest radiography, and pulmonary function tests. Thorax. 2001;56(8):622-627. [CrossRef] [PubMed]
 
Cervantes-Perez P, Toro-Perez AH, Rodriguez-Jurado P. Pulmonary involvement in rheumatoid arthritis. JAMA. 1980;243(17):1715-1719. [CrossRef] [PubMed]
 
Gabbay E, Tarala R, Will R, et al. Interstitial lung disease in recent onset rheumatoid arthritis. Am J Respir Crit Care Med. 1997;156(2 pt 1):528-535. [CrossRef] [PubMed]
 
Koduri G, Norton S, Young A, et al; ERAS (Early Rheumatoid Arthritis Study). Interstitial lung disease has a poor prognosis in rheumatoid arthritis: results from an inception cohort. Rheumatology (Oxford). 2010;49(8):1483-1489. [CrossRef] [PubMed]
 
American Thoracic Society, European Respiratory Society, American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med. 2002;165(2):277-304. [CrossRef] [PubMed]
 
Raghu G, Collard HR, Egan JJ, et al; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824. [CrossRef] [PubMed]
 
Luukkainen R, Saltyshev M, Pakkasela R, Nordqvist E, Huhtala H, Hakala M. Relationship of rheumatoid factor to lung diffusion capacity in smoking and non-smoking patients with rheumatoid arthritis. Scand J Rheumatol. 1995;24(2):119-120. [CrossRef] [PubMed]
 
Giles JT, Danoff SK, Sokolove J, et al. Association of fine specificity and repertoire expansion of anticitrullinated peptide antibodies with rheumatoid arthritis associated interstitial lung disease [published online ahead of print May 28, 2013]. Ann Rheum Dis. doi:10.1136/annrheumdis-2012-203160.
 
Gochuico BR, Avila NA, Chow CK, et al. Progressive preclinical interstitial lung disease in rheumatoid arthritis. Arch Intern Med. 2008;168(2):159-166. [CrossRef] [PubMed]
 
Saag KG, Kolluri S, Koehnke RK, et al. Rheumatoid arthritis lung disease. Determinants of radiographic and physiologic abnormalities. Arthritis Rheum. 1996;39(10):1711-1719. [CrossRef] [PubMed]
 
Antoniou KM, Hansell DM, Rubens MB, et al. Idiopathic pulmonary fibrosis: outcome in relation to smoking status. Am J Respir Crit Care Med. 2008;177(2):190-194. [CrossRef] [PubMed]
 
Vassallo R, Ryu JH. Tobacco smoke-related diffuse lung diseases. Semin Respir Crit Care Med. 2008;29(6):643-650. [CrossRef] [PubMed]
 
Patel RR, Ryu JH, Vassallo R. Cigarette smoking and diffuse lung disease. Drugs. 2008;68(11):1511-1527. [CrossRef] [PubMed]
 
Baumgartner KB, Samet JM, Stidley CA, Colby TV, Waldron JA. Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1997;155(1):242-248. [CrossRef] [PubMed]
 
Malik S, Saravanan V, Kelly C. Interstitial lung disease in rheumatoid arthritis: an update on diagnosis and management. Int J Clin Rheumatol. 2012;7(3):297-308. [CrossRef]
 
Klareskog L, Stolt P, Lundberg K, et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006;54(1):38-46. [CrossRef] [PubMed]
 
Aubart F, Crestani B, Nicaise-Roland P, et al. High levels of anti-cyclic citrullinated peptide autoantibodies are associated with co-occurrence of pulmonary diseases with rheumatoid arthritis. J Rheumatol. 2011;38(6):979-982. [CrossRef] [PubMed]
 
Inui N, Enomoto N, Suda T, Kageyama Y, Watanabe H, Chida K. Anti-cyclic citrullinated peptide antibodies in lung diseases associated with rheumatoid arthritis. Clin Biochem. 2008;41(13):1074-1077. [CrossRef] [PubMed]
 
Fischer A, Solomon JJ, du Bois RM, et al. Lung disease with anti-CCP antibodies but not rheumatoid arthritis or connective tissue disease. Respir Med. 2012;106(7):1040-1047. [CrossRef] [PubMed]
 
Tobin RW, Pope CE II, Pellegrini CA, Emond MJ, Sillery J, Raghu G. Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1998;158(6):1804-1808. [CrossRef] [PubMed]
 
Raghu G, Freudenberger TD, Yang S, et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J. 2006;27(1):136-142. [CrossRef] [PubMed]
 
Seibold MA, Wise AL, Speer MC, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med. 2011;364(16):1503-1512. [CrossRef] [PubMed]
 
Hunninghake GM, Hatabu H, Okajima Y, et al. MUC5B promoter polymorphism and interstitial lung abnormalities. N Engl J Med. 2013;368(23):2192-2200. [CrossRef] [PubMed]
 
Pantelidis P, Veeraraghavan S, du Bois RM. Surfactant gene polymorphisms and interstitial lung diseases. Respir Res. 2002;3:14. [CrossRef] [PubMed]
 
Diaz de Leon A, Cronkhite JT, Yilmaz C, et al. Subclinical lung disease, macrocytosis, and premature graying in kindreds with telomerase (TERT) mutations. Chest. 2011;140(3):753-763. [CrossRef] [PubMed]
 
Mushiroda T, Wattanapokayakit S, Takahashi A, et al; Pirfenidone Clinical Study Group. A genome-wide association study identifies an association of a common variant in TERT with susceptibility to idiopathic pulmonary fibrosis. J Med Genet. 2008;45(10):654-656. [CrossRef] [PubMed]
 
Liu T, Ullenbruch M, Young Choi Y, et al. Telomerase and telomere length in pulmonary fibrosis. Am J Respir Cell Mol Biol. 2013;49(2):260-268. [CrossRef] [PubMed]
 
Kim EJ, Collard HR, King TE Jr. Rheumatoid arthritis-associated interstitial lung disease: the relevance of histopathologic and radiographic pattern. Chest. 2009;136(5):1397-1405. [CrossRef] [PubMed]
 
Tanaka N, Kim JS, Newell JD, et al. Rheumatoid arthritis-related lung diseases: CT findings. Radiology. 2004;232(1):81-91. [CrossRef] [PubMed]
 
Lee HK, Kim DS, Yoo B, et al. Histopathologic pattern and clinical features of rheumatoid arthritis-associated interstitial lung disease. Chest. 2005;127(6):2019-2027. [CrossRef] [PubMed]
 
Parambil JG, Myers JL, Ryu JH. Diffuse alveolar damage: uncommon manifestation of pulmonary involvement in patients with connective tissue diseases. Chest. 2006;130(2):553-558. [CrossRef] [PubMed]
 
Furst DE, Breedveld FC, Kalden JR, et al. Updated consensus statement on biological agents for the treatment of rheumatoid arthritis and other immune mediated inflammatory diseases (May 2003). Ann Rheum Dis. 2003;62(suppl 2):ii2-ii9. [CrossRef] [PubMed]
 
Picchianti Diamanti A, Germano V, Bizzi E, Laganà B, Migliore A. Interstitial lung disease in rheumatoid arthritis in the era of biologics. Pulm Med. 2011;2011:931342.
 
Doyle TJ, Hunninghake GM, Rosas IO. Subclinical interstitial lung disease: why you should care. Am J Respir Crit Care Med. 2012;185(11):1147-1153. [CrossRef] [PubMed]
 
Washko GR, Lynch DA, Matsuoka S, et al. Identification of early interstitial lung disease in smokers from the COPDGene Study. Acad Radiol. 2010;17(1):48-53. [CrossRef] [PubMed]
 
Orens JB, Estenne M, Arcasoy S, et al; Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. International guidelines for the selection of lung transplant candidates: 2006 update—a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2006;25(7):745-755. [CrossRef] [PubMed]
 
Vinik O, Marras T, Shapera S, Mittoo S. Rheumatoid arthritis interstitial lung disease. in Harjacek M, ed.Challenges in Rheumatology. InTech website. http://www.intechopen.com/books/challenges-in-rheumatology/rheumatoid-arthritis-interstitial-lung-disease. Published 2011. Accessed August 24, 2013.
 
Flaherty KR, Colby TV, Travis WD, et al. Fibroblastic foci in usual interstitial pneumonia: idiopathic versus collagen vascular disease. Am J Respir Crit Care Med. 2003;167(10):1410-1415. [CrossRef] [PubMed]
 
Kim EJ, Elicker BM, Maldonado F, et al. Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease. Eur Respir J. 2010;35(6):1322-1328. [CrossRef] [PubMed]
 
Park JH, Kim DS, Park IN, et al. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med. 2007;175(7):705-711. [CrossRef] [PubMed]
 
Hakala M, Pääkkö P, Huhti E, Tarkka M, Sutinen S. Open lung biopsy of patients with rheumatoid arthritis. Clin Rheumatol. 1990;9(4):452-460. [CrossRef] [PubMed]
 
Yousem SA, Colby TV, Carrington CB. Lung biopsy in rheumatoid arthritis. Am Rev Respir Dis. 1985;131(5):770-777. [PubMed]
 
Flaherty KR, Thwaite EL, Kazerooni EA, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax. 2003;58(2):143-148. [CrossRef] [PubMed]
 
Akira M, Sakatani M, Hara H. Thin-section CT findings in rheumatoid arthritis-associated lung disease: CT patterns and their courses. J Comput Assist Tomogr. 1999;23(6):941-948. [CrossRef] [PubMed]
 
Pratt DS, Schwartz MI, May JJ, Dreisin RB. Rapidly fatal pulmonary fibrosis: the accelerated variant of interstitial pneumonitis. Thorax. 1979;34(5):587-593. [CrossRef] [PubMed]
 
Park IN, Kim DS, Shim TS, et al. Acute exacerbation of interstitial pneumonia other than idiopathic pulmonary fibrosis. Chest. 2007;132(1):214-220. [CrossRef] [PubMed]
 
Dawson JK, Fewins HE, Desmond J, Lynch MP, Graham DR. Predictors of progression of HRCT diagnosed fibrosing alveolitis in patients with rheumatoid arthritis. Ann Rheum Dis. 2002;61(6):517-521. [CrossRef] [PubMed]
 
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):1248-1254. [CrossRef] [PubMed]
 
Sathi N, Urwin T, Desmond S, Dawson JK. Patients with limited rheumatoid arthritis-related interstitial lung disease have a better prognosis than those with extensive disease. Rheumatology (Oxford). 2011;50(3):620. [CrossRef] [PubMed]
 
O’Dwyer 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):597-603. [CrossRef] [PubMed]
 
Lee JS, Ryu JH, Elicker BM, et al. Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;184(12):1390-1394. [CrossRef] [PubMed]
 
Vassallo R, Thomas CF. Advances in the treatment of rheumatic interstitial lung disease. Curr Opin Rheumatol. 2004;16(3):186-191. [CrossRef] [PubMed]
 
Maurer JR, Frost AE, Estenne M, Higenbottam T, Glanville AR. International guidelines for the selection of lung transplant candidates. The International Society for Heart and Lung Transplantation, the American Thoracic Society, the American Society of Transplant Physicians, the European Respiratory Society. Transplantation. 1998;66(7):951-956. [CrossRef] [PubMed]
 
Ito S, Sumida T. Interstitial lung disease associated with leflunomide. Intern Med. 2004;43(12):1103-1104. [CrossRef] [PubMed]
 
Tomioka R, King TE Jr. Gold-induced pulmonary disease: clinical features, outcome, and differentiation from rheumatoid lung disease. Am J Respir Crit Care Med. 1997;155(3):1011-1020. [CrossRef] [PubMed]
 
Stein HB, Patterson AC, Offer RC, Atkins CJ, Teufel A, Robinson HS. Adverse effects of D-penicillamine in rheumatoid arthritis. Ann Intern Med. 1980;92(1):24-29. [CrossRef] [PubMed]
 
Barrera P, Laan RF, van Riel PL, Dekhuijzen PN, Boerbooms AM, van de Putte LB. Methotrexate-related pulmonary complications in rheumatoid arthritis. Ann Rheum Dis. 1994;53(7):434-439. [CrossRef] [PubMed]
 
Alarcón GS, Kremer JM, Macaluso M, et al; Methotrexate-Lung Study Group. Risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis. A multicenter, case-control study. Ann Intern Med. 1997;127(5):356-364. [CrossRef] [PubMed]
 
Ramos-Casals M, Perez-Alvarez R, Perez-de-Lis M, Xaubet A, Bosch X; BIOGEAS Study Group. Pulmonary disorders induced by monoclonal antibodies in patients with rheumatologic autoimmune diseases. Am J Med. 2011;124(5):386-394. [CrossRef] [PubMed]
 
Camus P, Fanton A, Bonniaud P, Camus C, Foucher P. Interstitial lung disease induced by drugs and radiation. Respiration. 2004;71(4):301-326. [CrossRef] [PubMed]
 
Dixon WG, Hyrich KL, Watson KD, Lunt M, Symmons DP; BSRBR Control Centre Consortium; British Society for Rheumatology Biologics Register. Influence of anti-TNF therapy on mortality in patients with rheumatoid arthritis-associated interstitial lung disease: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis. 2010;69(6):1086-1091. [CrossRef] [PubMed]
 
Doyle TJ, Washko GR, Fernandez IE, et al; COPDGene Investigators. Interstitial lung abnormalities and reduced exercise capacity. Am J Respir Crit Care Med. 2012;185(7):756-762. [CrossRef] [PubMed]
 
Lederer DJ, Enright PL, Kawut SM, et al. Cigarette smoking is associated with subclinical parenchymal lung disease: the Multi-Ethnic Study of Atherosclerosis (MESA)-lung study. Am J Respir Crit Care Med. 2009;180(5):407-414. [CrossRef] [PubMed]
 
Rosas IO, Ren P, Avila NA, et al. Early interstitial lung disease in familial pulmonary fibrosis. Am J Respir Crit Care Med. 2007;176(7):698-705. [CrossRef] [PubMed]
 
Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ; Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366(21):1968-1977. [CrossRef] [PubMed]
 
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):640-646. [CrossRef] [PubMed]
 
Diaz de Leon A, Cronkhite JT, Katzenstein AL, et al. Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations. PLoS ONE. 2010;5(5):e10680. [CrossRef] [PubMed]
 
Fingerlin TE, Murphy E, Zhang W, et al. Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis. Nat Genet. 2013;45(6):613-620. [CrossRef] [PubMed]
 
Peljto AL, Zhang Y, Fingerlin TE, et al. Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis. JAMA. 2013;309(21):2232-2239. [CrossRef] [PubMed]
 
Tanjore H, Blackwell TS, Lawson WE. Emerging evidence for endoplasmic reticulum stress in the pathogenesis of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2012;302(8):L721-L729. [CrossRef] [PubMed]
 
Jayachandran A, Königshoff M, Yu H, et al. SNAI transcription factors mediate epithelial-mesenchymal transition in lung fibrosis. Thorax. 2009;64(12):1053-1061. [CrossRef] [PubMed]
 
Harlow L, Rosas IO, Gochuico BR, et al. Identification of citrullinated hsp90 isoforms as novel autoantigens in rheumatoid arthritis-associated interstitial lung disease. Arthritis Rheum. 2013;65(4):869-879. [CrossRef] [PubMed]
 
Kinoshita F, Hamano H, Harada H, et al. Role of KL-6 in evaluating the disease severity of rheumatoid lung disease: comparison with HRCT. Respir Med. 2004;98(11):1131-1137. [CrossRef] [PubMed]
 
Yanaba K, Hasegawa M, Takehara K, Sato S. Comparative study of serum surfactant protein-D and KL-6 concentrations in patients with systemic sclerosis as markers for monitoring the activity of pulmonary fibrosis. J Rheumatol. 2004;31(6):1112-1120. [PubMed]
 
Greene KE, King TEJ Jr, Kuroki Y, et al. Serum surfactant proteins-A and -D as biomarkers in idiopathic pulmonary fibrosis. Eur Respir J. 2002;19(3):439-446. [CrossRef] [PubMed]
 
Kohno N, Kyoizumi S, Awaya Y, Fukuhara H, Yamakido M, Akiyama M. New serum indicator of interstitial pneumonitis activity. Sialylated carbohydrate antigen KL-6. Chest. 1989;96(1):68-73. [CrossRef] [PubMed]
 
Sato S, Nagaoka T, Hasegawa M, Nishijima C, Takehara K. Elevated serum KL-6 levels in patients with systemic sclerosis: association with the severity of pulmonary fibrosis. Dermatology. 2000;200(3):196-201. [CrossRef] [PubMed]
 
Saketkoo LA, Ascherman DP, Cottin V, Christopher-Stine L, Danoff SK, Oddis CV. Interstitial Lung Disease in Idiopathic Inflammatory Myopathy. Curr Rheumatol Rep. 2010;6(2):108-119. [CrossRef]
 
Kashiwabara K. Characteristics and disease activity of early interstitial lung disease in subjects with true parenchymal abnormalities in the posterior subpleural aspect of the lung. Chest. 2006;129(2):402-406. [CrossRef] [PubMed]
 
Tsushima K, Sone S, Yoshikawa S, Yokoyama T, Suzuki T, Kubo K. The radiological patterns of interstitial change at an early phase: over a 4-year follow-up. Respir Med. 2010;104(11):1712-1721. [CrossRef] [PubMed]
 
Prasse A, Pechkovsky DV, Toews GB, et al. CCL18 as an indicator of pulmonary fibrotic activity in idiopathic interstitial pneumonias and systemic sclerosis. Arthritis Rheum. 2007;56(5):1685-1693. [CrossRef] [PubMed]
 
Kodera M, Hasegawa M, Komura K, Yanaba K, Takehara K, Sato S. Serum pulmonary and activation-regulated chemokine/CCL18 levels in patients with systemic sclerosis: a sensitive indicator of active pulmonary fibrosis. Arthritis Rheum. 2005;52(9):2889-2896. [CrossRef] [PubMed]
 
Richards TJ, Eggebeen A, Gibson K, et al. Characterization and peripheral blood biomarker assessment of anti-Jo-1 antibody-positive interstitial lung disease. Arthritis Rheum. 2009;60(7):2183-2192. [CrossRef] [PubMed]
 
Richards TJ, Kaminski N, Baribaud F, et al. Peripheral blood proteins predict mortality in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2012;185(1):67-76. [CrossRef] [PubMed]
 
Collard HR, Calfee CS, Wolters PJ, et al. Plasma biomarker profiles in acute exacerbation of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2010;299(1):L3-L7. [CrossRef] [PubMed]
 
Furuhashi K, Suda T, Nakamura Y, et al. Increased expression of YKL-40, a chitinase-like protein, in serum and lung of patients with idiopathic pulmonary fibrosis. Respir Med. 2010;104(8):1204-1210. [CrossRef] [PubMed]
 
Kono M, Nakamura Y, Suda T, et al. Plasma CCN2 (connective tissue growth factor; CTGF) is a potential biomarker in idiopathic pulmonary fibrosis (IPF). Clin Chim Acta. 2011;412(23-24):2211-2215. [CrossRef] [PubMed]
 
Pardo A, Selman M. Matrix metalloproteases in aberrant fibrotic tissue remodeling. Proc Am Thorac Soc. 2006;3(4):383-388. [CrossRef] [PubMed]
 
Rosas IO, Richards TJ, Konishi K, et al. MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis. PLoS Med. 2008;5(4):e93. [CrossRef] [PubMed]
 
Schmidt K, Martinez-Gamboa L, Meier S, et al. Bronchoalveolar lavage fluid cytokines and chemokines as markers and predictors for the outcome of interstitial lung disease in systemic sclerosis patients. Arthritis Res Ther. 2009;11(4):R111. [CrossRef] [PubMed]
 
Meloni F, Caporali R, Marone Bianco A, et al. BAL cytokine profile in different interstitial lung diseases: a focus on systemic sclerosis. Sarcoidosis Vasc Diffuse Lung Dis. 2004;21(2):111-118. [PubMed]
 
Kinder BW, Brown KK, McCormack FX, et al. Serum surfactant protein-A is a strong predictor of early mortality in idiopathic pulmonary fibrosis. Chest. 2009;135(6):1557-1563. [CrossRef] [PubMed]
 
Doyle TJ, Pinto-Plata V, Morse D, Celli BR, Rosas IO. The expanding role of biomarkers in the assessment of smoking-related parenchymal lung diseases. Chest. 2012;142(4):1027-1034. [CrossRef] [PubMed]
 
Oka S, Furukawa H, Shimada K, et al. Serum biomarker analysis of collagen disease patients with acute-onset diffuse interstitial lung disease. BMC Immunol. 2013;14:9. [CrossRef] [PubMed]
 
Ascherman DP. Interstitial lung disease in rheumatoid arthritis. Curr Rheumatol Rep. 2010;12(5):363-369. [CrossRef] [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543