Chest
Commentary: Ahead of the CurveA Roadmap to Promote Clinical and Translational Research in Rheumatoid Arthritis-Associated Interstitial Lung Disease
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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2020, ChestCitation Excerpt :This is an important area of study, given that there are no current recommendations from rheumatologic societies regarding the necessity for or method of screening for ILA in individuals with RA. In addition, improved identification of high risk individuals with clinical and biomolecular risk factors for RA-ILD can further inform such recommendations and be used to design effective screening algorithms.30 Previous studies suggest that individuals with RA with ILA are at an increased risk of experiencing clinically significant disease with its associated morbidity and death, which is a premise that is supported by recent data that demonstrated that ILA in smokers is associated with an increase in all-cause mortality rates.4,6
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].
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