Chest

Chest

Volume 145, Issue 3, March 2014, Pages 454-463
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Commentary: Ahead of the Curve
A Roadmap to Promote Clinical and Translational Research in Rheumatoid Arthritis-Associated Interstitial Lung Disease

https://doi.org/10.1378/chest.13-2408Get rights and content

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.

Section snippets

Current State of Knowledge

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

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, 7 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, 19, 20, 21, 22 Smoking

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

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

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

Selected Areas for Investigation

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, 70, 71, 72

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

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-D82, 83, 84, 85 appear to be common

Conclusions

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

Acknowledgments

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

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    • Cited by (0)

    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.

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