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Interstitial Lung Abnormalities in Rheumatoid Arthritis Are Common and ImportantInterstitial Abnormalities in Rheumatoid Arthritis FREE TO VIEW

Aryeh Fischer, MD; Gregory P. Cosgrove, MD, FCCP
Author and Funding Information

From the Department of Medicine, National Jewish Health.

CORRESPONDENCE TO: Gregory P. Cosgrove, MD, FCCP, 1400 Jackson St, A551, Interstitial Lung Disease Program, National Jewish Health, Denver, CO 80206; e-mail: CosgroveG@NJHealth.org


FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST the following conflicts of interest: Dr Cosgrove has provided expert testimony regarding rheumatoid arthritis associated interstitial lung disease. Dr Fischer serves as a consultant for Actelion Pharmaceuticals Ltd, Gilead Sciences Inc, and InterMune Inc.

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


Chest. 2014;146(1):8-10. doi:10.1378/chest.14-0030
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Rheumatoid arthritis (RA) is the most common of the connective tissue diseases, affecting approximately 1% of the adult population.1,2 RA is a result of a complex interplay of autoimmune phenomena that ultimately results in a symmetric, inflammatory, and destructive arthropathy, and the majority of patients with the disease have evidence of circulating autoantibodies to rheumatoid factor (RF) or anticyclic citrullinated peptide antibodies (ACPAs).1,2

The past 15 to 20 years have been witness to remarkable progress with respect to the understanding of the immunologic dysfunction and pathobiology intrinsic to RA.1,3 Despite advances regarding the articular aspects of RA, several paradoxic, perplexing, and troubling realities exist. Long-term functional morbidity remains high, and patients with RA remain at higher risk of mortality compared with the general population; indeed, the median survival in RA is decreased by 10 to 11 years.4,5 A major portion of the RA-associated disease burden appears to be due to its extraarticular manifestations—cardiovascular and lung disease in particular.4-6 Pulmonary complications are common in RA and are directly responsible for 10% to 20% of all RA-associated mortality.4-7 Despite the knowledge that the lungs are frequently involved in patients with RA, RA-associated lung disease remains poorly understood, underappreciated, underrecognized, of uncertain pathogenesis, and without proven treatment.

RA affects all of the anatomic compartments of the lungs (eg, airways, parenchyma, vasculature, and pleura), and interstitial lung disease (ILD) is both the most common and potentially most devastating form of RA-associated lung disease.6 The most frequent, thoracic, high-resolution CT (HRCT) scan and pathologically identified pattern of parenchymal lung injury in RA appears to be usual interstitial pneumonia6 and may have as grave a prognosis as that of idiopathic pulmonary fibrosis.8

The prevalence of RA-associated ILD (RA-ILD) varies depending on the criteria used to establish the diagnosis. Retrospective series have demonstrated a “clinically significant” prevalence of 7%, yet autopsy series have reported a prevalence of 35%.6,9,10 The advent of improved technology with thoracic HRCT imaging, in particular, has provided insights into the prevalence of ILD in RA, with various RA cohorts reporting prevalences as high as 19% to 67%.6,11,12

The widespread use of HRCT scans in clinical and research settings has increased the detection of interstitial lung abnormalities (ILAs) in asymptomatic individuals. The term subclinical ILD generally refers to undiagnosed individuals who have ILAs defined by HRCT scans, which are consistent with, but subtler than, those observed in patients with established clinical ILD.13 There is a growing awareness that some forms of ILD transition from asymptomatic or subclinical stages before an eventual clinical diagnosis.13 In two prior studies of subclinical ILD in RA, 34% to 57% of patients had radiologic evidence of disease progression within 1.5 to 2 years.13

The study by Doyle et al14 in this issue of CHEST (see page 41) is an important contribution to this evolving story and extends the findings of prior studies of ILA in other at-risk cohorts to a subset of patients with RA. In this study, 84 subjects with RA enrolled in the Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Study (BRASS) registry, a single-center, prospective, observational cohort of 1,145 subjects with RA, had thoracic HRCT scans performed for clinical indications unrelated to concurrent respiratory disease or known history of ILD. In total, 46 (55%) had evidence of ILA, of whom 12 (14%) had what was considered to be radiologically severe ILA.

There are several important findings identified by Doyle et al.14 Per earlier reports,11-13 HRCT scan evidence of ILD is common in patients with RA and, in many instances, the interstitial abnormalities may be considered to be subclinical, given limited symptoms but demonstrable physiologic abnormalities. The presence of radiographically identified interstitial changes (ie, ILAs), and especially radiologically severe ILA, appears to be associated with specific clinical characteristics: These patients with RA tend to be older, are typically men, are more likely to be former smokers, have more respiratory symptoms and impaired pulmonary physiology, have more severe “articular” RA (eg, more synovitis and more musculoskeletal impairment), and are more likely to be RF or ACPA positive. Another important finding in this study is that treatment with either traditional disease-modifying antirheumatologic drugs or biologic therapies was not associated with an increased risk of ILA. The investigators appropriately highlight important limitations of their study, including biases with respect to cohort selection, the retrospective nature of the study, questions about whether these individuals were truly “subclinical,” and lack of standardization in timing of pulmonary physiology testing and respective imaging.

Taken together, the emerging picture of RA-ILD is becoming slightly clearer and includes the following concepts: (1) ILAs are identified on HRCT scans frequently in patients with RA; (2) the presence of ILA may preclude its clinical relevance; (3) the presence of ILAs on HRCT scans is associated with a risk of progressive lung injury and requires subjective and objective assessments to determine whether symptomatic ILD develops; (4) specific RA clinical phenotypes appear to be at higher risk for ILA, and these include male sex, smoking history, and RF or ACPA positivity.

Despite these advances, there are far too many unanswered questions regarding RA-ILD. We have yet to understand why some patients with RA do not develop ILD, some have mild ILD, and yet others progress to chronic, progressive forms of ILD. We have yet to identify reliable determinants of progression of RA-ILD. Perhaps most pressing, despite the tremendous advances in how to manage the articular components of RA, is a better understanding of how to treat patients with RA-ILD, as we have limited, evidence-based information to guide the management of RA-ILD.

Buttressed by the current work by Doyle et al,14 it is our hope that, similar to the incredible progress witnessed over the past 15 to 20 years pertinent to understanding the intrinsic pathobiology and immunology of the articular aspects of RA, the next several years will herald the formation of well-designed, prospective studies to more definitively answer a number of fundamental gaps in our knowledge of the pulmonary manifestations of RA.

References

McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205-2219. [CrossRef] [PubMed]
 
Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet. 2010;376(9746):1094-1108. [CrossRef] [PubMed]
 
O’Dell JR. Therapeutic strategies for rheumatoid arthritis. N Engl J Med. 2004;350(25):2591-2602. [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]
 
Sihvonen S, Korpela M, Laippala P, Mustonen J, Pasternack A. Death rates and causes of death in patients with rheumatoid arthritis: a population-based study. Scand J Rheumatol. 2004;33(4):221-227. [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]
 
Solomon JJ, Ryu JH, Tazelaar HD, et al. Fibrosing interstitial pneumonia predicts survival in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Respir Med. 2013;107(8):1247-1252. [CrossRef] [PubMed]
 
Suzuki A, Ohosone Y, Obana M, et al. Cause of death in 81 autopsied patients with rheumatoid arthritis. J Rheumatol. 1994;21(1):33-36. [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]
 
Bilgici A, Ulusoy H, Kuru O, Celenk C, Unsal M, Danaci M. Pulmonary involvement in rheumatoid arthritis. Rheumatol Int. 2005;25(6):429-435. [CrossRef] [PubMed]
 
Zrour SH, Touzi M, Bejia I, et al. Correlations between high-resolution computed tomography of the chest and clinical function in patients with rheumatoid arthritis. Prospective study in 75 patients. Joint Bone Spine. 2005;72(1):41-47. [CrossRef] [PubMed]
 
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]
 
Doyle TJ, Dellaripa PF, Batra K, et al. Functional impact of a spectrum of interstitial lung abnormalities in rheumatoid arthritis. Chest. 2014;146(1):41-50.
 

Figures

Tables

References

McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205-2219. [CrossRef] [PubMed]
 
Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet. 2010;376(9746):1094-1108. [CrossRef] [PubMed]
 
O’Dell JR. Therapeutic strategies for rheumatoid arthritis. N Engl J Med. 2004;350(25):2591-2602. [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]
 
Sihvonen S, Korpela M, Laippala P, Mustonen J, Pasternack A. Death rates and causes of death in patients with rheumatoid arthritis: a population-based study. Scand J Rheumatol. 2004;33(4):221-227. [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]
 
Solomon JJ, Ryu JH, Tazelaar HD, et al. Fibrosing interstitial pneumonia predicts survival in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Respir Med. 2013;107(8):1247-1252. [CrossRef] [PubMed]
 
Suzuki A, Ohosone Y, Obana M, et al. Cause of death in 81 autopsied patients with rheumatoid arthritis. J Rheumatol. 1994;21(1):33-36. [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]
 
Bilgici A, Ulusoy H, Kuru O, Celenk C, Unsal M, Danaci M. Pulmonary involvement in rheumatoid arthritis. Rheumatol Int. 2005;25(6):429-435. [CrossRef] [PubMed]
 
Zrour SH, Touzi M, Bejia I, et al. Correlations between high-resolution computed tomography of the chest and clinical function in patients with rheumatoid arthritis. Prospective study in 75 patients. Joint Bone Spine. 2005;72(1):41-47. [CrossRef] [PubMed]
 
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]
 
Doyle TJ, Dellaripa PF, Batra K, et al. Functional impact of a spectrum of interstitial lung abnormalities in rheumatoid arthritis. Chest. 2014;146(1):41-50.
 
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