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

Abstract

Interstitial lung disease (ILD) is a well-known complication ofrheumatoid arthritis (RA) which often results in significant morbidity and mortality. It is often diagnosed late in the disease process via descriptive criteria. Multiple subtypes ofRA-ILD exist as defined by chest CT and histopathology [1]. In the absence of formal natural history studies and definitive diagnostics, a conventional dogma has emerged that there are two major subtypes ofRA-ILD (nonspecific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP)). These subtypes are based on clinical experience and correlation studies [2–4]. However, recent animal model data are incongruous with established paradigms ofRA- 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 RA-ILD 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 RA-ILD 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 ofRA-ILD is critical for the development of effective interventions for RA-ILD.

TNF-Induced Interstitial Lung Disease in a Murine Arthritis Model: Accumulation of Activated Monocytes, Conventional Dendritic Cells, and CD21+/CD23− B Cell Follicles Is Prevented with Anti-TNF Therapy

“…This progressive pathologic condition involves a primary exacerbation, which initiates an inflammatory state predominated by cellular infiltration, leading to an NSIP pattern of pathologic conditions. This is followed by secondary environmental triggers, leading to fibrotic change in the peripheral pulmonary tissue, consistent with a UIP pattern (28,29). The idea of distinct stages of progressive disease fits well with the previously addressed epidemiologic studies looking at the specific subsets of RA-ILD.…”

Selective Sexual Dimorphisms in Musculoskeletal and Cardiopulmonary Pathologic Manifestations and Mortality Incidence in the Tumor Necrosis Factor–Transgenic Mouse Model of Rheumatoid Arthritis

“…Furthermore, patients with RA who are diagnosed as having ILD have poor survival expectancy, with some studies reporting a median survival time as low as 2.6 years after diagnosis, and growing evidence suggests an increased mortality incidence in female patients with RA . In a recent review from our group focusing on RA‐associated ILD, we discussed the lack of consensus regarding the relationship between sex and morbidity and mortality in patients with RA‐associated ILD . Whereas men with RA have historically been presumed to have an increased incidence of all‐cause mortality compared to women with RA, more recent data suggest that women may be at higher risk of death from RA, in particular those with RA‐associated ILD.…”

Rheumatoid arthritis-interstitial lung disease: manifestations and current concepts in pathogenesis and management

“…Understanding RA-ILD pathogenesis via animal models Acknowledging that there are currently no widely accepted animal models for RA-ILD, the most commonly employed methods used to generate animal models in RA-ILD include induction via immune stimulants or through genetic engineering via gene mutation or transgenic systems [88]. Though there are multiple models of RA designed to replicate joint pathology, there are currently only three main arthritic models which contain lung pathology: the SKG murine model; the adjuvant arthritis model; and the tumour necrosis factor (TNF)-transgenic model [89]. The pathogenesis of RA is thought to involve an interplay between various risk factors (including smoking history, male sex and older age) and genetic predisposition (such as the shared epitope HLA-DRB1).…”

“…RA-ILD animal models have led to improved understanding of pulmonary pathology secondary to systemic inflammation [89]. There are, however, limitations to RA-ILD animal models, as they cannot replicate clinical pathology and are limited in experimental research application.…”