Pathogenesis of Extraarticular Manifestations in Rheumatoid Arthritis-A Comprehensive Review

Abstract

Rheumatoid arthritis (RA) is among the most prevalent and debilitating autoimmune inflammatory chronic diseases. Although it is primarily characterized by destructive peripheral arthritis, it is a systemic disease, and RA-related extraarticular manifestations (EAMs) can affect almost every organ, exhibit a multitude of clinical presentations, and can even be asymptomatic. Importantly, EAMs largely contribute to the quality of life and mortality of RA patients, particularly substantially increased risk of cardiovascular disease (CVD) which is the leading cause of death in RA patients. In spite of known risk factors related to EAM development, a more in-depth understanding of its pathophysiology is lacking. Improved knowledge of EAMs and their comparison to the pathogenesis of arthritis in RA could lead to a better understanding of RA inflammation overall and its initial phases. Taking into account that RA is a disorder that has many faces and that each person experiences it and responds to treatments differently, gaining a better understanding of the connections between the joint and extra-joint manifestations could help to create new treatments and improve the overall approach to the patient.

Keywords: inflammation mediators; pathogenesis; rheumatoid arthritis.

Figure 1

Depiction of discussed pathophysiological mechanisms in RA leading to atherosclerosis. MC/Mφ = monocyte/macrophage. Created with BioRender.com.

Figure 2

Illustration showing the described pathophysiological mechanisms leading to the development of interstitial lung disease. EMT = epithelial-to-mesenchymal transition, ECI = epithelial cell injury, DCs = dendritic cells, CP = citrullinated proteins, F = fibroblast, CP = citrullinated proteins, * IgA ACPAs. Created with BioRender.com.

Figure 3

Illustration showing proposed common mechanisms of local inflammation in RA-related membrane involvement including similarities in the development of synovitis, pleural and pericardial effusion, and meningitis. NEUT—neutrophils, LYM—lymphocytes, RF—rheumatoid factor, and C3a and C5a—complement components, * synoviocytes/pleural and pericardial mesothelial/leptomeningeal cells, ** replacement of mesothelial cells with macrophage derived cells. Created with BioRender.com.