Etiology and Pathogenesis of Rheumatoid Arthritis-Interstitial Lung Disease

Abstract

Interstitial lung disease (ILD) is one of the most serious extra-articular complications of rheumatoid arthritis (RA), which increases the mortality of RA. Because the pathogenesis of RA-ILD remains poorly understood, appropriate therapeutic strategies and biomarkers have not yet been identified. Thus, the goal of this review was to summarize and analyze the reported data on the etiology and pathogenesis of RA-ILD. The incidence of RA-ILD increases with age, and is also generally higher in men than in women and in patients with specific genetic variations and ethnicity. Lifestyle factors associated with an increased risk of RA-ILD include smoking and exposure to pollutants. The presence of an anti-cyclic citrullinated peptide antibody, high RA disease activity, and rheumatoid factor positivity also increase the risk of RA-ILD. We also explored the roles of biological processes (e.g., fibroblast-myofibroblast transition, epithelial-mesenchymal transition, and immunological processes), signaling pathways (e.g., JAK/STAT and PI3K/Akt), and the histopathology of RA involved in RA-ILD pathogenesis based on published preclinical and clinical models of RA-ILD in animal and human studies.

Keywords: interstitial lung disease; pathogenesis; rheumatoid arthritis.

Figure 1

The most common three patterns in RA-ILD. The representative images of chest high-resolution CT with (a) UIP, (b) NSIP, and (c) OP patterns are shown. (a) Bilateral subpleural and basal reticular opacities (↑) with honeycomb (*) are typical of a UIP pattern. (b) Subpleural patchy parenchymal opacities (√) with underlying fibrosis and traction (↖) in both lungs. (c) Subpleural consolidations (↗).

Figure 2

Schematic diagram of the immunological pathway involved in the pathogenesis of RA-ILD. Activated macrophages, T cells, and neutrophils secrete several pro-inflammatory cytokines (narrow black arrows) to promote lung inflammation and fibrogenesis by up-regulating FMT (bold red arrow).

Figure 3

Schematic diagram of the PI3K/Akt pathways involved in RA-ILD pathogenesis. As illustrated, the phosphorylation of PI3K activates Akt through PIP2 to PIP3 conversion. PI3K/Akt/mTORC1 and ERK contributes to the up-regulations of target genes and proteins, which promote the inflammation by regulating macrophage, neutrophil, and pro-inflammatory cytokines.

Figure 4

Schematic diagram of risk factors that induce rheumatoid arthritis-interstitial lung disease (RA-ILD) and proposed pathogenesis. Although the exact pathophysiological mechanisms in which RA-ILD is developed remains unknown, several risk factors and plausible mechanisms have been proposed. Risk factors associated with RA-ILD include genetic variations, male sex, older age, race, smoking, exposure to pollutants, and anti-cyclic citrullinated peptide antibody (ACPA). Reported plausible pathophysiological mechanisms involve biological processes (e.g., fibroblast–myofibroblast transition [FMT], epithelial–mesenchymal transition [EMT], and immunological processes), signaling pathways (e.g., JAK/STAT and PI3K/Akt), and RA histopathology.