Reinterpreting Evidence of Rheumatoid Arthritis-Associated Interstitial Lung Disease to Understand Etiology

Abstract

Interstitial Lung Disease (ILD) is a well-known complication of rheumatoid arthritis (RA) which often results in significant morbidity and mortality. It is often diagnosed late in the disease process via descriptive criteria. Multiple subtypes of RA-ILD exist as defined by chest CT and histopathology. In the absence of formal natural history studies and definitive diagnostics, a conventional dogma has emerged that there are two major subtypes of RA-ILD (nonspecific interstitial pneumonia (NSIP) and Usual Interstitial Pneumonia (UIP)). These subtypes are based on clinical experience and correlation studies. However, recent animal model data are incongruous with established paradigms of RA-ILD and beg reassessment of the clinical evidence in order to better understand etiology, pathogenesis, prognosis, and response to therapy. To this end, here we: 1) review the literature on epidemiology, radiology, histopathology and clinical outcomes of the various RAILD subtypes, existing animal models, and current theories on RA-ILD pathogenesis; 2) highlight the major gaps in our knowledge; and 3) propose future research to test an emerging theory of RAILD that posits initial rheumatic lung inflammation in the form of NSIP-like pathology transforms mesenchymal cells to derive chimeric disease, and subsequently develops into frank UIP-like fibrosis in some RA patients. Elucidation of the pathogenesis of RA-ILD is critical for the development of effective interventions for RA-ILD.

Keywords: Computed Tomography (CT); Histology; Nonspecific Interstitial Pneumonia (NSIP); Rheumatoid Arthritis-Associated Interstitial Lung Disease (RA-ILD); Usual Interstitial Pneumonia (UIP); animal models; fibrosis; inflammation..

Figure 1:

Representative high-resolution CT images of rheumatoid arthritis (RA) associated interstitial lung disease. A: Nonspecific usual interstitial pneumonia (NSIP) with ground glass opacities (red arrow in A). This patient was diagnosed with RA three years prior to the CT image. B: Usual interstitial pneumonia (UIP), characterized by reticular opacities (green long arrow) and honeycombing (green short arrow). This patient was diagnosed with RA 10 years prior to the CT image.

Figure 2:. Theory of progressive ILD development.

Systemic inflammation leads to the production of inflammatory cytokines, such as TNF-α and INF-γ. These factors circulate and act on the lung, where they induce the upregulation of several adhesion factors, such as P and E selectin, and ICAM-1. These ultimately lead to the recruitment and extravasation of circulating monocytes/macrophages, while the cytokines continue to activate tissue-resident inflammatory cells such as alveolar macrophages. With the activation of the local environment, the tissue is primed for exacerbation by an external antigen, such as cigarette smoke. Once there is antigen presentation, a secondary immune response is activated, leading to the recruitment and activation of T and B cells, thereby resulting in ACPA production. Antigen-presentation and activation of the macrophage and DC populations can also induce the expression of TGF-β, which activates local fibroblasts and leads to collagen deposition, resulting in fibrosis.