J Rheum Dis.  2022 Apr;29(2):61-70. 10.4078/jrd.2022.29.2.61.

Recent Advances in Basic and Clinical Aspects of Rheumatoid Arthritis-associated Interstitial Lung Diseases

• Lee H
• Lee SI
• Kim HO

• KMID: 2527544
• DOI: http://doi.org/10.4078/jrd.2022.29.2.61

Abstract

Rheumatoid arthritis (RA) is a common autoimmune disease that mainly affects the joints and systemic organs, such as the skin, eyes, heart, gastrointestinal tract, and lungs. In particular, among various pulmonary involvements, interstitial lung disease (ILD) is closely related to the selection of anti-rheumatic drugs and the long-term prognosis of patients with RA. Although the exact pathogenesis of RA-ILD is not well defined, several mechanistic pathways, similar to those of idiopathic pulmonary fibrosis, have been elucidated recently. Conversely, RA-related autoantibodies, including anti-cyclic citrullinated peptide antibody, are detectable in circulation and in the lungs, even in the absence of articular symptoms. RA-ILD can also predate years before the occurrence of joint symptoms. This evidence supports the fact that local dysregulated mucosal immunity in the lung causes systemic autoimmunity, resulting in clinically evident polyarthritis of RA. Because the early diagnosis of RA-ILD is important, imaging tests, such as computed tomography and pulmonary function tests, are being used for early diagnosis, but there is no clear guideline for the early diagnosis of RA-ILD and selection of optimal disease-modifying anti-rheumatic drugs for the treatment of patients with RA with ILD. In addition, the efficacy of nintedanib, a new anti-fibrotic agent, for RA-ILD treatment, has been investigated recently. This review collectively discusses the basic and clinical aspects, such as pathogenesis, animal models, diagnosis, and treatment, of RA-ILD.

Keyword

Rheumatoid arthritis; Interstitial lung disease; Idiopathic pulmonary fibrosis; Anti-citrullinated protein antibodies; Nintedanib

Figure

• 

  Fig. 1 Pathogenesis of rheumatoid arthritis (RA)-interstitial lung disease (ILD). The first step in RA pathogenesis in ILD is damage to the airways and alveolar epithelial cells. Risk factors of airway and alveolar epithelial cell damage include genetic susceptibility, smoking, periodontitis, infection and dysbiosis, and gastroesophageal reflux disease (GERD). Persistent and repeated damage to epithelial cells leads to the activation of immune cells, such as neutrophils, dendritic cells (DCs), and macrophages. Neutrophils produce matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and neutrophil elastase (NE). Macrophages secrete transforming growth factor (TGF)-β and platelet-derived growth factor (PDGF), thereby promoting fibrosis. DCs induce immune responses in B and T cells. B cells are associated with the production of anti-citrullinated protein antibodies (ACPAs), which induce the secretion of cytokines such as IL-6, IL-8, and tumor necrosis factor (TNF) for inducing epithelial cell damage. ACPAs also induce the formation of neutrophil extracellular traps (NETs). T cells activate myofibroblasts through interleukin (IL)-17 and IL-13. In addition, chemokines such as CCL2 and CXCL12 are involved in lung fibrosis. Collectively, these effects lead to the excessive deposition of extracellular matrix (ECM) components, such as hyaluronan, fibronectin, and interstitial collagens.

• 

  Fig. 2 Changes in pathological lung features on different days in collagen-induced arthritis (CIA). The lung fibrosis score increased till day 29 after CIA induction, but decreased spontaneously from day 36 after CIA induction. Masson’s trichrome staining (magnification, ×200).

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