A roadmap to promote clinical and translational research in rheumatoid arthritis-associated interstitial lung disease

Abstract

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.

Figure 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. 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. 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).

Figure 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.

Figure 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.